Herbal Formulation Improves Memory Components

SELECT RESEARCH PAPERS ON EVIDENCE BASED DRUGS IN AYURVEDA J
DEPARTMENT OF INDIAN SYSTEMS OF MEDICINE AND HOMOEOPATHY MINISTRY OF HEALTH AND FAMILY WELFARE GOVERNMENT OF INDIA
FOREWORD
Ayurveda is one the ancient systems of medicine, originated in lndia thousands of years back and having successfully practiced over many centuries. The unique feature of Ayurvada is it's emphasis on promotion of positive health and prevention of possible diseases apart from the curative aspects. This system has been founded and evolved on solid fundamental principles based on hypothetical approach. Many Saints and Rishis, by their extra perception and super natural power, have contributed for Ayurveda. They have documented their findings through constant expetimentations by trial and was practiced as such over centuries and error methods. Hence A y u ~ e d a stood the test of time. Since Ayurveda is becoming very popular in many foreign countries, it has become the need of hour to prove A y u ~ e d a treatment as safe and effective confirmed by scientific trials, clinical and experimental. In India, such trials are being conducted in many Govt. Institutions like Central Council for Research in Ayuweda and Siddha, Banaras Hindu University, Oujarat A y u ~ e d a University, National Institute of Ayu~eda,Indian Council of Medical Research, 1\11 lndia lnstitute of llledical Sciences, Defence lnstitute of Physiology and Allied apart from many private Sciences and Post Graduate Colleges of A y u ~ e d a organizations and drug industries. I am very glad to place this compendium of 29 such research studies conducted on five areas i.e. neuroactive drugs, immunomodulators and adaptogens, antiarthritic drugs, hypolipidimic agents, Kshar S u t r a a specialized Ayurvedic surgical procedure for the management of piles and fistulain-ano and finally some general research articles. These research papers quickly and randomly collected by the Department of ISM 8 H , represents a sample of voluminous research work carried out in lndia with international parameters as per the W O guidelines. H I hope this compendium will be of much use for the reference to the scientists, scholars and researchers as well.
Date :0152001 Place: New Delhi
(Dr. G. Veluchamy) Director, Central Council for Research in A y u ~ e d a and Siddha
INDEX
SL.NO.
TITLE OF THE STUDY
PAGE NOS.
I
1.
NEUROACTIVE DRUGS
I
I
A Double Blind Clinical Trial to Objectively Evaluate the Efficacy of a Herbal Preparation on Memory
2.
3.
4.
5.
I
Neuropsychopharmacological Effects of the Ayurvedic Nootropic Bacupa monniera L ~ M . (Brahmi)
12 19
I
I
I
. I
Role of an Ayuwedic Drug Brahmi (Bacopa rnonnieri ) in the Management of Senile Dementia Role of an Ayuwedic Drug Brahmi (Bacopa rnonnieri) in the Management of Senile Dementia The Effect of Mandookparni (Centella asiacita) on the General Mental Ability of Mentally Retarded Children
25
31
I
6.
I
Short Communication - Antistressor Effect of Wiihania somnfera A Double Blind Study of the Effect of Mandookapami on the General Mental Ability of Normal Children
45
I
7.
I
48
IMMUNOMODULATORS AND ADAPTOGENS

8.
I
Adaptogens in High Mountains

I
54
9.
Membrane Integrity Changes at High Terrestrial Altitudes (with Geriforle - Himalaya)
61
I
10.
1I Endurance Enhancement in Adverse Environment

A Clinical Study on the Role of Amalaki Rasayan in the Management of Subadusti with special reference to Asthenozoospermia Effect. of a Composite Indian Herbal Preparation on on&! Effectiveness in Low-intensity-conflict Operations Enhanced Thennogenesis in Rats by a Composite Indian Herbal Preparation -I and its Mechanism of Action
67
7b
11.
1
-
12. 14.
78
92
ANTI-ARTHRITIC DRUGS
15.
I
A Pvliminary Controlled Clinical Trial of Indigenous Conipound Drugs in Cases of Rheumatoid arthritis
I
99
108
I
16.
I
Eff~cacy of Rhumayog and Rhumayog with Gold in Rheumatoid arthritis - A Double Blind Study Study of Ayurvedic Drugs in Rheumatoid arthritis Compared to Auranofin Open Study to Evaluate the Efficacy of Sallaki as an Addon Therapj along with NSAID in the Management of Patients with Osteoarthritis Double Blind Randomized Controlled Trial of Sallaki (600 mg) vs. Diclofenac (50 mg) in the Treatment of Rheumatoid arthritis
17. 18.
120 135
19.
160
HYPOLlPlDAEMlC AGENTS
20.
Guggulipid : a Promising Hypolipiadaemic Agent from Gum Guggul (Commiphora wighlii)
189
I
!I.
Commiphora wightii Engl. (Gum Guggul)
KSHARASUTRA
22.
Multi-centric Randomized Controlled Clinical Trial of Kshaarsootra (Ayurvedic Medicated Thread) . in the Manigement of Fistula-in-Ano
229
I
2%
Treatment of Fistula-in-Ano by a Medicated ThreadKshara Sutra Treatment, Review and Follow-up of 182
238
GENERAL
24.
Pharmacology of Medicinal Plants and Natural Products Pharmacology of Medicinal Plants and other Natural Products Pharmacology of Medicinal Plants
25 1 289
31 7
25.
26.
27.
28.
I
Vijaysar, Pterocarpus marsupium in the Treatment of Madhumeha (Diabetes mellitus I - A Clinical Trial Flexible .Dose Open Trial of Vijayasar in cases of newlydiagnosed Non-Insulin-Dependent Diabetes mellitus
I
356
363
29.
Managing Morphine-Induced Constipation : A Controlled Comparison of an Ayun'edic Formulation and Senna
369
~UROACTIVE: DRUGS
AIM : The aim of the study was to evaluate the efficacy of a polyherbal formulation on the essential components of memory METHODS : A double blind, randomized, placebo controlled parallel group study was undertaken in normal human volunteers to evaluate the efficacy of this formulation. The individual ingredients of each are known for their effects of cognition. The treatment was administered for a period of 35 days. Various parameters which were used to evaluate memory were Sensory Perception (SP), Centrd Integration (CI) and Sensorimotor Co-ordination (SC). Tests used for SP were D2 cancellation test for SC were Choice Reaction Test (CRT) and V i s b l Reaction Test (VRT) and for CI were Immediate and Delayed Verbal Recall (IVR & DVR), Figure Recognition (FR), Digit Span (DS) and Critical Flicker Fusion Frequency (CFFF). The computerized tests were developed in the ~ e ~ a r t r n e n t Pharmacology. Grant of every Medical College, Sir J. J. Hospital, Mumbai. Volunteers first under'went tra~nfng two or three days to get acclimatized to the above test battery. The tra~ningwas provided in the period of two weeks prior to study. They were evaluated on a weekly interval till the end of 5 weeks. This study showed interesting results in terms of objective evaluation and cognit~on
RESULTS : Detailed results will be discussed CONCLUSION : The preparation had a stimulant effect on detection percepbon and recognition of stimuli which made the volunteers more alert and Improved thelr concentration. It had beneficial effects on many essential aspects of memory
SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS
o To evaluate the efficacy of the preparation containing five herbal ingredients in

improving ones memory To study the effect of the combined formulation in a setting where its effect on the essential components of memory as mentioned below were studied.
+
+ +
Sensory perception Central integration and processing Overall sensorimotor coordination
TRIAL DESIGN: Double bllnd, random~zed, placebo controlled parallel group study TRIAL SUBJECTS: Medical students' 18-22 years of age NUMBER OF SUBJECTS: 10 in each group INCLUSION CRITERIA Medical students of age 18 years and above of either sex EXCLUSION CRITERIA Subjects who are smokers alcohol~cs are on any other drugs or Subjects wlth end stage renal d~sease hepat~c or disease Sublects with underlying d~sorders l~kely affect the lnterpretatlon of the trial results to lmmunocompromlsed or pat~ents wlth dlabetes meliltus METHODOLOGY Subjects recruited in the trial underwent trainlng 2 weeks prlor to the study day, for every 2-3 days for acclimatizing to the test-battery. The training was continued tlll the Individual scores for each test reached a plateau and showed no further increase. The cr~teria which were used before randomizing the volunteers to receive either of the two treatments were that their individual Score should be, 70% for Immediate Verbal
and 7 60 %for Figure Recognition. Recognition. > 60 %for Delayed Verbal Recognit~on Volunteers having a score less than the above values in any singie test were not included in the study. The volunteers underwent the same tests every week i.e. Day 0, Day 7, Day 14, Day 21, Day 28 and Day 35 respectively.
MEMORY The followng tests were employed to evaluate memory IMMEDIATE VERBAL RECOGNITION (IVR): The volunteers were subjected to a series of meaningful words on the computer screen at a speed of one word every three seconds, immediately after which 24 similar looking or sounding words were displayed which included 12 previously shown words. The volunteer was then asked to press
YES/NO key to indicate whether the word was shown before or not and the score was
given based on the number of correct answers with a maximum score of 24. DELAYED VERBAL RECOGNITION (DVR): The volunteers were subjected to a serles of meaningful words on the computer screen at a speed of one word every three seconds, 20 minutes after which 24 similar looking or sounding words were d~splayed which included 12 previously shown words. The volunteer was then asked to press
YESlNO key to indicate whether the word was shown before or not and the score was
given. based on the number of correct answers with a maximum score of 24. FIGURE RECOGNITION (FR): The volunteers were shown 12 geornetr~calf~gureson after the computer screen at a speed of one figure every three seconds lmmed~ately whlch 24 figures were d~splayedwhich Included 12 previously shown flgures The volunteer was then asked to press YESlNO key to indrcate whether the f~gurewas shown before or not and the score was given based on the number of correct responses w ~ t h maxlmum score of 24 a DIGIT SPAN (DS): The volunteer was asked to listen to a series of 10 digits played on an audiocassette recorder and immediately recall the digits in the same sequence. Five such series were given totally with 50 total digits. The number of correct digits wa$ considered to be the total score,
5
ATTENTION TASKS VISUAL REACTION TEST (VRT): A digit was displayed .on the computer screen, following which a serles of digits were displayed rapidly and the volunteer was asked to press YES every time the displayed digit appeared on the screen. The test was carried out till the marked digit appeared 10 times on the screen. The mean time taken was displayed on the computer screen and considered as visual reaction time. Visual reaction test is carried out taking into consideration the number of correct entries and the time taken in seconds to complete the correct entries. CHOICE REACTION TEST (CRT): Red, yellow and green coloured circles were displayed on the computer screen. Numbers 1,2,3 were displayed below the circle respectively. Thereafter, the three coloured circles will be displayed in a randomized fashion. Totally 25 such circles were displayed. The volunteers were asked to press the respective numbered key for the respective circlelcolour. Mean of the reaction time was displayed on the computer screen as CRT. Choice reaction test is carried out taking into consideration the number of correct entries and the time taken.in seconds to complete the correct entries. CRITICAL FLICKER FUSION (CFF): The volunteers were subjected to a particular light source of fixed luminosity flickering at a spec~ficfrequency. The frequency of the flickering was increased and the investigator was asked to note the frequency at which the volunteer could no longer perceive the flickering and found the source of light to be stationary. This was noted as increasing reading. Similarly the frequency was slowly again. reduced starting at a higher value till the light source appeared to be fl~cker~ng This was taken as the decreasing readings.
D2 CANCELLATION: The volunteers were given a chartlsheet containing ds and ps
with one or two commas or apostrophes attached to the particular alphabet in a random in order. Helshe was asked to cancel the number of d2s in a specific l~ne 10 seconds. After 10 seconds helshe were asked to cancel the ds in the next line. 14 such lines were completed and the number of d" and d, cancelled would determine the total score
of that volunteer.
SELECT RESEARCH PAPEHS ON EVIDENCE BASED AYURVEDIC DRUGS
EFFECT OF LEARNING ON THE TEST BATTERIES

45
U
Y)
25
z
10 0
Sessmn
1
Session Sesvon Servon Session

1 2 3 t1VR-m-DVR+FR+DS
4
Sessmn Sesslon 3 2
Sesslon 4
t V R T CE
+D2
-+CFF
1 ~ 2 ~ )Z E P z / E L R l
The preliminary experiments were performed with 2 objectives: 1. To get the volunteer accustomed to the various test batteries involved
2. To get the maximal reading as the plateau reading following which the volunteer
cannot improve further
SENSORY PERCEPTION
D2 CANCELLATION
TEST GRP
~ ~
PLACEBO GRP
~-
~~
~-
p~~ ~
PLACEBO GRP UTEST GRP

fls: NONSIGNIFICANT DIFFERENCE FROM PLACEBO
: SIGNIFICANT DIFFERENCE FROM THE DAY 0 SCORE AT PC 0.001.
CENTRAL INTEGRATION
CRITICAL FLICKER FUSION
The test results did not show any statistically significant ~mprovement CFF at the end in of the study in both placebo and the treatment group.
IMMEDIATE VERBAL RECOGNITION (IVR)
DELAYED VERBAL RECOGNITION (DVR)
FIGURE RECOGNITION (FR)
PLACEBO GRP
DIGIT SPAN (DS)
TEST GRP
PLACEBO GRP
ns : NON-SlGNlFlCANT DIFFERENCE FROM PLACEBO
* **
***
a
: SIGNIFICANT DIFFERENCE FROM THE DAY o SCORE AT PC 0.001. : SIGNIFICANT DIFFERENCE FROM THE DAY 0 SCORE AT PC 0.005. : SIGNIFICANT DIFFERENCE FROM THE DAY 0 SCORE AT PC 0.01.
: SIGNIFICANT DIFFERENCE FROM THE DAY 0 SCORE AT PC 0.03
SENSORIMOTOR CO-ORDINATION
VISUAL REACTION TEST
The ratio of v~sual reaction correct entries 1 time, referred to as Visual Reaction Ratio was calculated to determine the exact time required by the volunteer to complete the maximum number of correct entries.
VISUAL REACTION RATIO
'
w
150
0 100
50 0
TEST GRP PLACEBO GRP
2 I
IlS
: NONSIGNIFICANT DIFFERENCE FROM PLACEBO

: SIGNIFICANT DIFFERENCE FROM THE DAY 0 SCORE AT PC 0.004. A T Dc n n17 .SIGNIFICANT DlFFERFNCF cD".n Tuc n r V n
** ***
CHOICE REACTION TEST The ratio of choice reaction correct entries I Choice reaction time, referred to as Choice Reaction Ratio was calculated to determine the exact time required by the volunteer to complete the maximum number of correct entries. CHOICE REACTION RATIO
ns
: NONSIGNIFICANT DIFFERENCE FROM PLACEBO : SIGNIFICANT DIFFERENCE FROM THE DAY 0 SCORE AT PC 0.037
ANALYSIS OF DATA All the above results have been analyzed by using the following statistical tests:
1. Within treatment group paired T Test

2. Between treatmenl group: T test
Results displayed are only of DAY 0 and DAY 35 although the test were carried out in the interim perlod I e DAY 7, DAY 14, DAY 21 AND DAY 28. The tests were repeated in the interim period to ensure that the volunteers would not forget the tests once acclini=tized to it.
10
It was found that this comb~ned preparation has some interesting findings: The preparation has a stimulant effect on detection, perception and recognition of a stimulus. This made the volunteers more alert and their concentration improved, not only for a short span but also enabled them to maintain their concentration for a longer period of time as shown by the D2 cancellation test. The tests used for detecting the effect of the preparation onthe central integration and processing aspect showed some conflicting results. Although the preparation showed improvement in short term memory and learning (IVR, DVR, FR) the better used parameters of this test for effect on central integration i.e
CFF showed no effect.
For the sensorimotor coordination, which is the basis of most skilled behavior especially, recalled information, we have used CRT and VRT. We studied not only the reaction time but also the number of correct entries as we felt both the components were essential for indicating memory, attention, concentrationand reaction. It was found that when a ratio of correct entries to time was calculated the ratio was found to be statistically high thereby indicating its effect on memory, attention and reaction.
From the above discussion we can claim that the combined preparation has a stimulant profile and a beneficial effect on all aspects of memory. A lot of work yet remains to be done to elucidate the mechanism of action of the preparation and further studies are yet warranted to further our results. However as of now we claim that the effects seen from the combined preparation are helpful in acquisition and retention of memory and affect all the aspects of memory.
-
lndian Journal of Pharmacology 1997; 29: S359-5365
NEUROPSYCHOPHARMACOLOGICAL EFFECTS OF THE AYURVEDIC

NOOTROPIC BACOPA MONNIERA LINN. (BRAHMI)
H.K. SINGH. B.N. DHAWAN
Central Drug Research Institute. SUMMARY
Lucknow
- 226
00(.
India.
Bacopa monmNeraLinn. (Brahmi) has been used since times immemorial as nerve tonic fW improvement of memory. The authentication of the traditional claims ol brahmi was initiated by investigating the effect of an alcoholic extract of this plant on acquisition. conroliation and relentinn of Wee newly acquired behaviourd responses in albino rats, viz.. a foot-shock motivated brightness discrimination response. active conditioned avoidance response and Sidman conlinvous avoidance response. The facililatory effect of Ihe brahrni extract (40 mghg. p.0. x 3d) was manifest in all.!h8 three learning responses as it augmented both the cognitive function and mental retention capacity. The chemical constituent responsible for the tacilitatory eflect of b r a w l on learning schedules was identified as a rnixture of hvo saponins designated as bacosides A and B. The bacosides significantly improved the acquisition. consolidation and retenlion in the shock~molivated brightness discrimination avoidance responseand produced a dose.dcpendenl lacrlilationof discretion response. acldvc cond~t~oncd between an averslve (LICI) and oalalable ftu~d fsucrosc) In the condilioncd taste aversion ICTAI resomse. Bacosides also altenualed the' retrograde amnesia produced by immobilisation induc'ed sires;. ECS and scopdamine. They also enhanced protcin kinase octivily and produced an increase in protcin in hippocampus. Bacosides \.rere also lound to be sale in requlalory pharmacolo~ical and toxicological studies and wcce well tolerated by normal healthy male human votunleers in single dose (20-300-mg) and multiple doscs f1OO and 200 ma\ administcred lor 4 ceceks in double blind olacebo controlled an3 non-crossover
KEY WORDS Nsolropic
Oacopa monniera
bacos~des
Brahrni
Biological evaluation of plants based on their use in the trad~tional systems of medicine is a sound and cost effective strategy to develop new drugs from Since time immemorial, Ayurveda, the science of life, has provided a rationale basis for treatment of various ailments. Based on the medicinal properties of selected plants as described in the Ayurvedic texts, our Institute has in recent yeats developed several drugs for refractory diseases lor which' no effective remedy is available in the modern system of medicine. These include hypolipidaemic, hepatoprotective, macrofilaricidal agents etc. The hypolipidemic agent is being marketed. Another promising lead thus obtained is the confirmation of the traditional claim of Bacopa monniera (Linn.) Pennel (Syn: Herpestis monniera (Linn.) HBLK) (Hindi: Brahmi, Jal Neem) (Family : Scrophulariaceae), which has been in use since times immemorial as nerve tonic for improvement of memory. Although, it has been frequently mentioned in the religious, social and medical treatises of lndia since the time of Alhar - Ved (C 800 B.C.), the
first clear reference to its CNS effect is to be round in Carak Samhifa written in the tst century A.D.. where Brahmi is prescribed as a cure for menlal disorder (retardation) leading to insanity (10:62). The etiology of the mental disorder according to Carak is a combination of anxiety, weak intellect and lack of concentration. Another authentic Ayurvedic treatise, i.e.. Susrutu Samhita describes brahmi as efficacious in loss of intellect and memory. Bacopa monniera is a perennialcreeping plant found throughout lndia in wet, damp and marshy areas. An infusion of the plant has also been used in Indian folklore as a nerve tonic3./Th8 plant has been investigated in several Indianlaboratories forits n e u y pharmaacological effects. Malhotra and Das reporled a sedative effect of glycosides named by them as hersaponins. Aithal and Sirsis found that the alcoholic extract, and to a lesser extent the aqueous eXtraCt,of the whole plant exhibited tranquilising effects on albino rats and dogs. ~rakash and Sirsi6, on the other hand, have found that !he alcoholic extract of the plant and chlorprornazlne improved the performance of rats in motor learning.
Correspondcncc: B.N. Dhaw
12
It was found that this combined preparation has some interesting findings: The preparation has a stimulant effect on detection, perception and recognition of a stimulus. This made the volunteers more alert and their concentration improved, not only for a short span but also enabled them to maintain their concentration for a longer period of time as shown by the D2 cancellation test. The tests used for detecting the effect of the preparation on'the central integration and processing aspect showed some conflicting results. Although the preparation showed improvement in short term memory and learning (IVR, DVR, FR) the better used parameters of this test for effect on central integration i.e. CFF showed no effect. For the sensorimotor coordination, whlch the bass of most skilled behav~or
IS
espec~ally, recalled lnformat~on, have used GRT and VRT We studled not only the we react~on t~me but also the number of correct entr~esas we felt both the components were essential for ~nd~catlng memory, attentlon, concentration and react~on It was found that when a ratlo of correct entrles to tlme was calculated the ratlo was found to be statlstlcally h ~ g h thereby lnd~catlng~ t s effect on memory, attentlon and reactlon
From the above discussion we can claim that the comblned preparation has a stimulant profile and a beneficial effect on all aspects of memory. A lot of work yet remains to be done to elucidate the mechanism of action of the preparation and further studies are yet warranted to further our results. However as of now we claim that the effects seen from the combined preparation are helpful in acquisition and retention of memory and affect all the aspects of memory.
11
NEURWSYCilOPHARMACOLOGY
O F
BACOPA MONNERA
5360
fisure I Eneclol Dacorider (20 mg*g, po. x 36) on immob~!~ml~on . induced amnEria.
Barnrides pre~reament m )leads toan improved rclentipn as compared to !he canlrols (Dl. (
Anmeria induced by immabilirason
(m)is anenualedby bacoride. f a ) .
,' 0 . 0 1 compared to 1) .. p.O.01 far compued lo ~ far

3
~
p.O.01 la$ compared lo 3)

4)
00 p.O.01 ( a s compared 10 31
Sinha7 has repofled that a single dose 01 the glyaside hersaponin is bePer than pentobarbitone in facilitating acquisition and retention of brightness discrimination reaction: It is d~llicult,however, l o Merprel these results fn the context of the available known traditional claims. Therelore the evaluation of the traditional claims ol brahm was in,eat;d by invest!galng its ellect M the acqu sltlon. consol~dal!on and relenlnon ol href newly acqulred behavioral responses .n alolno rah
lraining (Ts) and relearning (Rs), were used lo.calculate percent saving which was the dillcrence bctween the two, expressed as per cent of the former: Percent Savings = Ts-Rs x IOOTTs. The results obtained from the relearning lest were also analysed on the basis ol increase in posit~ve responses during relearning (&R), i.e the dillerence between RR (positive responses during relearning) and TR (posilive responses during training). A response was considered to be positive wher. the rat ran immediately into the lighled alley in the last run prior to, and the first run alter, the change in the direction of alley illumination. In the active conditioned avoidance response, which was the second learning schedule, the rats had to jump on a wooden pole l o avoid a loot-shock. A tone 01 50 Hz was used as a conditioned stimulus (presented for 1 sec.) which was also given in com5 bination wilh the unconditioned stimulus (loot shock 01 I mA) for lurlher 1 s. The trial ended either aller 5 the animal responded by jumping on the pole or afier 30 sec. whichever even1 occurred first.
-.
The lirst learning schedule was a l w t shock mobaled brightness discriminafion reaction in a semit i c Y-maze. Rals were trained.10 run into the illuminated alley 01 the chamber to avoid an loot-shock (I mA) given in the dark alley. h direction of alley illumination was changed after n Wery 3 triak to avoid position discrimination. The M n g consisted of 40 trials. Retention was tested 24 h aner training using a relearning procedure similar to the training procedure. Number of negative WS,i.e. Ihe number 01 shocks received during
13
S3G1
H.K. SINGH /\NO B.N. OHAWAN
Figure 2. Ellecl ol bacos~der (20 rngkg, p.0. x 36) on ECS induced amnesia.
earnsides preVeamenl(
H )ieids to an im;:oved
O( )
retenlion as cnmpared lo the controls (
0)
The ECS induced amnesia (
is anenua:cd b bacosides ( y
B).
(as (as (as (as compared compared compared compared to to to to
3)
70 SAVINGS
1)
4)
3)
ihe third learning schedule was the continuous -ivoidance response as evolved by Sidmang. It is 1 relatively easy task for rats, and well trained ani:nals respond repeatedly by lever pressing at a starate to avoid shocks. The training comprised daily session of I h (Monday Friday), with lever ?ressingselected as the avoidance response. The ?nsemble,for the present investigations, was proirammed so that each leverpress delayed theshock 3r 25 sec. Thus a minimum intewal of 25 sec. vas assured between avoidance behavior and shock and another interval of 1 see. between shock5 ;hock i.e. when no avoidance behaviour occurred. JO other contingencies between avoidance behav3ur and extetoceptive stimulation were involved.
3 days prior to commencement of experiments. A support dose of 40 mgkg p.0. every allernate day was given in all experimentsexceptin the brightness discrimination reaction.
The effect of the extract on the acquisition, consolidation and retentionolthe newly acquired ness behaviour was judged by changes in re-learning and
The facilitalo~effecl the brahmiextract was man(ol lest in the training (acquisition) itself. Brahmi sip nificanlly facilitated all the temporo-spatial panmeters of the acquisition, i.e. time per response, number of positive trials and number of positive responses as compared to control. Similarly in the re-learning test, the retention parame1ers;i.e: in. crease in posilive responses and percent savings , of the brahrni treated animals were significantly higher than the controls. The brahrnitreated animals also showed signilicanlly improved retention as evp dented in the delayed extinction, In the conditioned avoidance response. 1heexperimental group also learned \he avoidance reacton
-he air dried Plant material was powdered and a :Ot alcoholic extract (90% ethanol) ws prepared. . a ;he procedure extracted 2.6% material on fresh ?\ant basis (20% on dry plant basis). The alcohol was evaporated under reduced pressure and the 2xtract was suspended in water using 10% gum :cacla. The experimental groups received the exmet in a dose of 40 mgkg orally, once daily for
14
NEUROPSYCHOPHARI.lACOLOGY OF
BACOPA MONNIERA
5362
figure 3. Ellecl of bacorides (20 mgkg, pa. x 36) o scopolamine induced amnesia. n
m)leads to an improved retention as cumparod to the controls ( T e chdinolylic scopolamine caused amnesia ( 5 ), and bacosides abolished il (m). h
Eacoridcs prolreaimenl (
a/. SAVlNGS
80r
..
a. p*O.Ol (as compared to 1) . 1~;31 pc0.01 (as compared to 4)

0 v v p.0.01
l a s compared to 3)
00
o.o.01 ( a s compared to 3)
more quickly than the controls. The experimental animals evidenced conditioned response after 6 days, whersas the control animals took more than 1 davs. 0 Likewise, in the Sidman's avoidance response, the brahmi treated rats showed a successive increase in the number of lever-pressing responses which was statistica!ly significant from the controls. The ,increase was accompanied by a progressive decrease in the number of shocks received, which W s agaln significantly lower than the controls. a
tified compounds included two saponins designated as bacosides A and 0. Since these saponins were the major chemical components ol the plant, we have investiaated the mnemonic effect of the mixture of these two-saponins. used as aqueous suspension in several learning schedules13 The learning schedules used were shock motivaled brightness discrimination reaction and active conditioned avoidance response, as described above and conditioned taste aversion (CTA) response. The mixture of these two saponins in a dose of only 1 mgkg p.0. given for three days produced fa0 on the training pedormance in the cilitatory Shock motivated brightness discrimination reaction, rats required significantly less The bacosides time to perform the trial both during training and relearning. This facilitatory effect was manifest also in the significant increase in number of positive trials both during training and relearning. The percent savings was also significantly higher for the bacosides treated group. Similarly. in the a+ve con-
The results of the investigation using these three

learning schedules clearly indicate that the .effect of brahmi extract is manifest both in facilitating the cognitive function and augmenting the mental retention capacity. Having conlirmed the traditional'claim, the next logical step was to identify the chemical constituents tor this activity. Several chemical comPWnds had already been i ~ o l a t e d ' ~ - ' ~the idenand
--
15
S363
H.K. SINGH AND B.N. OHAWAN
dttioned response, bacosisdes treated animals in 0 a dose of 1 mg/kg po., given every alternate days, required significantly less time l o jump on the wooden pole as compared to controls after 7 days. In the CTA response, male rats were kept in individual cages containing openings for two 30 ml Richter tubes with 0.5 ml gradations. Each was allowed to drink tap water for I h only every morning. After a few exposures, all rats started drinking immedialely afler presenlalion. The rals had adlibitum access to food pellets. These rats were lesled in exposing the gustatory discrimination a p p a r a l ~ s ' ~ , them simullaneoulsy to two drink spouts, one delivering sucrose, the other containing an aversive lluid Lithium Chloride (LiCI). The CTA test 1 based s . . on the capability of rats to avoid a novel lood or liquid, the mgestion of vrhich leads to undesirable side effects (moderate gastrointestinal disorder). A trained rat rapidly finds the sucrose containing spout and starts drinking therefrom. After the stabilisaiion of licking, sucrose is suddenly replaced by the aversive LiCl fluid by exchangicg the position of the spouts. An important prerequisite of stationary retrieval condition is that prolonged testing dces n3t cause CTA extinction. HI;^ motivation of the animals to avoid the aversive concenlratlons eilc~ting moderate gastrointestinal dlsorder after the ingestion of a few ml of isotonic solution of LiCl (0.15 M) can servo as a combined CS (sal:y taste) and US (symptom of poisoning).
tistically significant increased intake of sucrose sG lution. The results of these investigations confirm that ba. cosides A and B are the actual constituents which have lacilitatory effects on bothmemory and learning in a wide variety. of responses. The effect ol ba. cosides is manifest both in negative reinforcement (shock -motivated brightness discrimination reaction and conditioned avoidance responses) as well as positive reinforcement (condilioned lasfe aversion), This is significant as lhe bacosides facilitated the responses which are susceptible to the effects punishment as well as reward. The bacosides are thus markedly effectivein increasing the probabilities in a variety of responses.
A feature ol memory formation across the animal kingdom is its progression from short-lived labile form lo a long lasling slabte form. But memory formation is not a direct flow of neuronal activity from short lerm to long term storage. Congruent lines of evidence have pointed instead to an intricate. multiphasic palhway of consolidation. Essentially memory exisls in two forms, viz. short-term and long-term. Both these forms starl simullaneousl)~ and a deficit in retention curve is obtained at a poinl where these hvolorms overlap. The hypothesis was tested in the foot shock motivated brightness descrimination reaction in the Y-maze and it ivas found that the retention curve instead of being Vshaped was W-shaped, i.e. there were deficits ocThe rats were randomized into 5 qroups ( G r o u ~ c u r r i n ~ two points. viz. at 1.5 h and 4.0 h training at - . -relea;ning inlerval. Therefore, it was presumed that I-V) of 9 rats each. Each group was treated with graded doses (2.5 - 7.5 mg!kg) ol bacosides and at least, in this experimental model, there are pep were immedialely presenied wilh a novel 10% su- haps three forms of memory, i.e., short-term (few crose solution for 2.5 min. Ninty minutes later group secondsto minutes)";,ld long-term (few hours to I-IV were intubaled with 0.15 LiCI (1 m11100g body days) and in between these exists an intermediate weight). A single exposure to LiCl was sufficient form of memory (few minutes to hours). The hvo to elicit the aversive response. The group V was deficits apparently occur at points where the lablie exposed only to the experimental environment and phase of one memory overlaps with labile phase not totheaversive fluid withanobject of investigating of the other memory The bacosides i n a dose, of 20, mglkg p.0. when given 30 min prior lo trainlng the elfectof bacosides on non LiClexposed animals. Two days later, each subgroup (excepl the control) in a shock motivated brightness descrimination rea received oral administration of bacosides in doses action abolished these deficits when relearning W s similar tothose prior to LiCl exposure. Thirty minutes done at various time intewals after training. A SUP* 0 after administration, subjects were presented with dose of 1 mg!kg p.0. given 30 min prior to the sucrose and LiCl solutions. The amount of each 24 h relearning test also produced a significant em hancement in the relearning index's. These results solution consumed by ihe individual rats during the suggest that the lacilitatory effect of bacosides are following 30 min was recorded. apparently due to their abili!y to consolidate the The bacosides produced a dose-dependent efretention at the earliest form, i.e. short-term memow fect wilh 5 and 7.5 m g k g doses resuliing in a sla- The facililatory effect of bacosides persists eve"
NEUROPSYCHOPHARl.!~\COLOGY OF
BACOPA MONNICRA
5364
hen the other two forms, i d , intermed~ateand long term memories occur.
During the penod of consolidztion, rnemory can be. disrupted through administration of a wide variety ofamnestic agents. Electroconvulsive shock (ECS), hypothermia and hypoxia are some of the non in"asive procedures which induce retrograde amnesia. While most of the arnnestic agents used induce retrograde amnesia, there are others which cause temporary amnesia. For instance, diethyldithiocarbamate, an inhibitor of synlhesis ol noradrenaline. disrupts intermediate rnemory when applied before trainingI6. Similarly, hypoxia disrupts intermediate memory specifically when administered immediately after trainingI6. Therefore, it appears that memory consolidation involves both serial and paratlet processing of information. In order to have comparable ii1formation, tt.e experimental protocols were kept uniform, and rctrograde amnesia was produced in rats by 2n im,mobilisation stress administered for 1 h, or by 8 aamin;stering ECS (0.5 mA. 5OHz. 0.5 sec.) Both Ihe treatrncnts viere admirlistered immfdiatsly after ihe completion c l tlainir.-,. The training scii~.duIc used v!as a b:ightfiess disci:mlna!ior~ reaction. 3.3cosides were used in a dose of 20 rngikg p o . x 3 d. The amnestlc treatments ied to a significant disrup!ion of consot~s'ationin control groups, as measured by % savicgs in the relearning test performed 24 h after tne cornpl-lion of training. The bacosides pretreatmen: signilicantfy attenuated !he amnestic elfects of these treatments as shown in Figures 1 snd 2. Pmnesia was also proddced with scopclamine, a Cholinergic receptor blocker. Unl~kethe amnesia caused by other pha:macological agents, the imPairme,~l induced by scopolamine is not total. Under our experimental conditions, i t was found that scopolamjne (0.63 mg!kg i.p.) when administered I before relearning produces amnesia and the retention is disrupted. This treatment caused 3 significant impairment of the retention in rats and the attenuating effect of bacosides is manifest when the experimental group is prelreated with a dose 0 20 rnglkg p o . for three consecutive days (Figure 1
31
chanois were also observed in h ~ ~ O t h a l a m u s anti cereb;al corlex. Furlher biochemical sludies have indicated lack of effect ol bacosides on catecholamine, serotonin, acetylcholine or NMDA receptors. The bacosides were also found to be safe in regulatory pharmacological, and toxicdogical studies. After obtaining the approval of the Drug Controller (India), Phase I clinical trial in single and multiple doses were conducted in male human volunteers. The trial was double blino placebo controlled and noncrossover. The bacosides in single dose (20-300 mg) and multiple doses (100 and 200 mg) administered for 4 weeks were well tolerated and were devoid of any untoward rcaction or side effects.
REFERENCES
I. Ohaaan BN. Ceo:r,?lly ncrin3 agents from Indian p;,,rilr In. Y\o51m, 5)1 S;i~-l;,;ii~ R. COCIIIO. (26%) OCCl.htl~lily V, ad? a! tllc 6:mn tnd;a~USARcscn:ci~ tn Mcnlal HcaII!, and Nou;;sciencer. Rocki,illc ti:@. Nalion~llr5i;tule Menof IJI He3::h. 1993'197.202.
p>,l,,..t
*-, . , a
k.t
" , r;,. :>.: . ,* -~ Re$i:i,;h in h:Cn131 H i a l ! ~ ? d IJcilrost rnces. Rocki,,flc tilD National lr:l,iu:e of h!s-.lli HcaIl>. 1395105.9.
~ ~
ti.
-?.
, ..n
I-! - . r . : - :
,,5':"
,,. .... , ,,,.-,,: -,, .,, .; - ' c > ; . . :., <j.7.,<. :,. 3:--..?':".:: , 3 L - s . ,,,,
1.
'
3. Chowa RN. N3y2i SL. Cno;,ia IC. Glcssa.) al tnd:an r.42rii:inaI PIan:r Nsw Sc!I>i Councl! ot Sci~.n:#fic In. and
du'rtnai R~scaic5.l'lj6.32.
4.
IAilalI~otla Das PK. ?harmacolog.~cat CL. slvdiesaf Herpeslis nilnniera Linn. (arahmi]. Indian J Msd Res 1459:47:234305.
5 . A1th21 HN. Sirs; 1. Plia;macotogicirl mv6st~gat;oii tier. 4 . an pc5:is rnlnn.oia. icd J D1~arm~:y 1961:23:2.5. 6. Prakash JC. Sirsi M. Comparallve s1ud.f ol [he eltecls
0 :
Brahmi (Bacopamonniera) and chlorpromazineon rnolot learning in rats. J Sci lndusf Res 19G2:21:93-6.
7. Sinha MM. Some empirical behavioral data indicalive 01 concomitant bio-chemical reactions. Prmeedings of the 58th fndian Science Congress. 1971;2:1.20.
8.
Singh HK. Dhawan EN. EHect ol Bacopa monnicra Linn. (Brahmi) exlract in avoidance responses in rats. J ~ f h . no~harmacal 1982;5:?05-14.
",.
The bacosides enhanced the pro:?in kinase activity !"ippocampus. They a'so jnduced an increase '0~:lIein and serotonin and lowered the no'epinephrine level in the sams region. Similar
8. Sidman M. Avoidance condilioning wilth b r ~ eshock arld l no exteroceptive warning signat. Scicnce 1953,118:157-8.
10. Bas" N. Raslogl R?, Dhai ML. Che:ii~catexaminallon a: Sacopa molritera Wcllsl. Par: 111 - B2coside 5. Indian
J Cherrl 1~67:s a4-6.
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H.K. SlNGH AND B.N. OHAWAN
11. Chaltorice N. Rarlogi RP. Dhar ML. Chemical Cxaminalion 01 &,cop monniera Wcltrt. Pan-l lsdalion ol Chemical ~onsliluenls.Indoan J Chem 1963:1:212.5. 12. cha~erjen Raslogi RP. Dhar ML.Chemical examination N. 01 &copa monniera Wensl: Parl I! The conslifulion of Bacoride A. Indian J Chem 1965;3:24-9. 13. Singh HK. Rasl~gi RP, Srimal RC. Dhawan BN. Enecl 01 bacosides A and B on avoidance responses in rals. Phyiolherapy Res 1988:2:70-75.
14. Orozck G. Buressova 0.Buros 1. EleClrophysioiopiWI analysis or relrieval ol conditioned lasle aversion: phyuolopical lechniqver and data processing. PhysiologiCa , s hemsbviJ 1979:28:537-45.
15,
singh"~.ohawanBN. Dwgs anecting learning ory In: Tandon PN. filani V. Wadhwa S. ieds). L m r e S in Neurobidogy. New Deihi. Wiley Easlern. 1992:189.202,
16. Allwcis C. Qwled b y OeZazzo J. Tully T Disseclh memory lormatian: from behavioral pharmacology lo lecular genelics. Trends in Neurosciences-1995;18!212.7,
, ,
CALORIC RESTRICTION MAY EXTEND THE LIFE AND HEALTH

Two recent animal studies offer a possible explanation for how caloric restriction might possibly enhance h u m a n health and help extend lite as well.
One new study ( A m J Physiol, October. 1997. Vol. 36. No. 4) from the National lnslitute on Aging (NIA) and Dr. Roy Verdew at the Arizona Center on Aging shows that a 30 percent reduction in calories in a monkey's diet leads to elevation in good cholesterol (HDL2B) levels with a subsequent reduction in risk for cardiovascular
disease. A second study (J Clin Endocrin Metab. 1997,82.2093-2096) has shown that caloric restriction slows the age-related decrease in amounts 01 a naturally occurring steroid hormone. DHEA. Using natural DHEA levels a s a biomarker of aging may assist scientists in their search for a w a y to slow down the aging process. It is demonstrated for the first time that caloric restriction c a n lead to changes HDLs and other lipid profiles that may be associated with health benefits.
in
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Phamawpsychoecologia (1990). 3,47-52
Role of an Ayuwedic drug Brahmi (Bacopa monnieri) in the management of senile dementia
Aruna ~grawal', P. G.
B.S. Guptd, K.N. ~ldtrpd
'DepaNoent of Hasic l'rinciples, Faculty of Ayurveda, lnstitut'e of Medical Sciences, B.kI.U., Varanasi 'Department of Psychology, Banmas Hindu U~versily, Varanssi %ofessor Emeritus Institute of Medical Sciences. Banaras Hindu Ilpivmity, Varanasi
Ahstmo. The ellicacy of an Ayurvedic drug, Rrahmi (Racopa'rnonnieri). in the management ol
xnilc dementia was examined The drug was adminisled to diagnosed cascs of W e dementia and normal controls, bath within the 64-79 yrs age-range at tk.commencement of the study, in a five your follow-up. The results reveal: (I) Brahmi arrests rnembiy loss in normal as wl as el dementia cases: (2) Brahmi also leads to slowine 6f acewlcholine loss in dementia cases. The fuulbdlty of drug's use In dcmen(la qf N7helrna.i ty$ 1s Ascussed Key llbrdr Acetylcholmne. Hrahm~ (Hawpa rnonnlcn), Senlle dementla, Memop. I r p mull
The advances in neurobiology, neurophysiology, neurochemistry and neuropharmacopsychology during the last more than three decades have led to the discovery of established deficits in electrocortical activity, neurochemistry of the brain, cerebral circulation and metabolism, and cognitive hnctioning (capabilities associated particularly with learning and memory) as a consequence of aging. An important problem which has baffled the scientists all over the world is the. prohlem of senile and other forms of demmtia exhibiting symptoms of progrm;ve impairment in cognitive functions, especially learning and memory, &.". age. Bil'ren and Schaie (1977) and Eisdorfer and Friedel (1977) also state that cognitive and emotional alterations (deficits) constitute an inevitable manifestation of normal aging. However, the most dramatic alterations in memory and neurotransmiYers
hpve been found .in patients with cerebral infirction and with neuronal atrophies in h ? e dementia, Alzheimer's, Huntington's and Parkinson's disease (Meyer et al., 1976). The enormity of the ptoblem may be judged from. the,wry fact that the population of persons o w r 65 years of age is the most rapidly .gowing segment' and about 10-15 per cent of this populati6n are the likely victims of m e or the other form of dementia. Attempts have beeh made to bring this phenomenon. of cerebral aging under control or to mitigate its- worst effects by neuro-interventions using mainly the nootropic drugs such as hydergine, piracetam, vincamine, centrophenoxine, nafiidrofuryl (see for review: Gershon & Raskin, 1975; Elias, Eleilheriou & Elias, 1976; Eisdorfer & Friedel, 1977; Lipton, DiMascio & Killam, 1978; Corkin et al , 1982; Reisburg, 1983; Wurtman, Corkin & Growdon, 1984). but mod of these
f i s study is part of a larger p r o g r m e devoted to scientific and clinical investigations of indigenous drugs like Jatamanasi. Shankhapu~hpi, Ilrahmi, commonly know as Smnri Ra.~a,w~as, inregardto biogenic aniinn. and verhal. non-verbal and perceptual learning and memory.
SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDlC DRUGS
19
interventions are far from satisfactory because they suffer from serious side-effects. In Ayurvedic system of medicine many herbal preparations have been advocated for slowing down the aging process and thus prevent memory loss and dementia. Brahmi (Bacopa monnieriChatterji, Rastogi & Dhar, 1965; Rastogi & Dhar, 1967) is commonly used by the practitioners of Ayurvedic system of medicine for the improvement of memory. The preliminary results of a study, done on albino rats, have indicated that Brahmi not only facilitates discrimination learning but also mitigates stress induced by sleep deprivation. In another study (unpublished) also, this drug has led to an increase in the memory span of school going children. In still another invdgatmn (unpublished) Brahmi has provided promising results in the management of mild and moderate mental deficiency. In a series of other experiments Brahmi has also provided encouraging results in the prevention of epileptic seizures. The purpose of the present investigation was to study the effects of the organic extract of Brahmi on the acetylcholine levels, and immediate and delayed free recall of the diagnosed senile dementia cases and the normal controls in a five year follow-up. An incidental learning paradigm was used for the measurement of memory. Materials and Methods
Quite a few cases died during the five year tenure of this long$udinal study. Complete information wuld be obtained only for 20 dementia cases and 22 normal wnlrols.
Materials
1 . Aceqlcholine m e n m m e n t . Acetylcholine was measured by the method developed by McIntosh and Pmy (1950) and mdfied by Pandey, Singh and Udupa (1975). The details of the method are given in Pandey el 81.' (1 975). The acetylcholine activity was expressedin terms of mglml RBC.
2. M o n o 7 measurement. ' h e list used for the measurement of memory contained 34 words from Hindi language in six categories selected from the BaUig and Montapue (1969) norms (cities, 6; frruts. 6; animals, 6; flowem, 6, relatives, 5; wupations or professions, 5). The I e were selected in such a h manna that they could be equally potent as alternative sorts into conceptual or rhyming categories. The subjects could, therefore, classify the words either in terms of conceptual or acoustic relationships. l h e number of categories for awuslic categorization was also six All 34 words were pnnted in six h h n t a l lines on the upper part of the sorting page in such a way that Ule word5 to be categorized in a category were not closeted togetha.
Procedure
Twelve cases of senile dementia and 12 normal controls were given the organic exlract of Brahrm, in a powdered form concealcd in a capsule, and the remaining 8 dementia cases and 10 normal conhols were kept on placebo. The dose of the Rrahmi exhact was one gram Both Hrahmi and placebo were administered, twice a day, in identical capsules using a double-hlind procedure continuously for live years Only thosc p m n s who gave a nfiten consent were allowed to m c i p s t e in the study. In all six measurements were taken for each subject: one basal and others a h every one year. for live years. AU the cases were thoroughly mo~tored for their general health as well as behavioral changes throughout. For the acquisition task, subject was given the list conlaining 34 words printed in the upper patl of a shed in six horizontal lines. lust below the last line, category (conceptual or acoustic) names were printed in six columns (one in each wlumn). For the
.Subjecls
Twentv diagnosed w of senile dementia and 22 normal wnhols, both in the 64-79 yn age-range at U commencement of the study, served as subjects. C I I'ersons abusing one or the other kind of psychotropic drug (incluhg alcohol) or surering from depression or other psisten1 endocrine disorder were excluded.
Brahmi and ~ a n mof t senile dementia aoncevtual catemktion l & subikt WBP told to . the . sort &r& wx&q lo their'coxepk relatiamhip and mite them on the sotling ghed llOder appmpriate Table 1. Acetylcholine level (mghnlRBC)in n
mcoutal ultcporv names. For acoustic categkzation, k s"bject was told to sort wads accading to their acoustic relationships and mite them
&UP
Normal
Tetet ramn
Placcbo (N=lO) Mean SD Mean SD Mew SD Mew SD
Initial
0.64 0.12 0.68 0.22 0.32 0.13 0.32 0.12
d and demmtia cases following Brahmi treatment Acetvlcholine level A h After After After After Iw 2 ITS 3m 4m 5 ITS 0.62 0.13 0.66 0.17 0.31 0.13 0.31 0.14 0.61 0.14 0.67 0.19 0.31 0.11 0.31 0.13 0.61 012 0.67 0 20 0.24 0.10 0.32 0.14 0.60 0.12 0.66 018 0.22 0.09 0.31 0.11 0.60 0.13 0.67 019 0.18 0.05 0.30 0.09
Comparison Initial vs ARn 5 y s p > 0.05 p>0.05 p<O.OOI p>0.05
Brahmi
(N=12) Dementia Placebo (N=8)
Brahmi
(N=12)
Table 2. Free recall scures of normals unda various conditions
Task
Treahnent
Testing condition
Immediate Delayed Mean SD Mean SD Mean SD Mean SD Mean SD Mew SD Mean SD Mean SD
Initial
After l yr 14.84 3.27 10.34 2.63 15.34 3.91 10.68 2.79 14.59 2.34 10.91 1.79 14.30 2.69 11.56 2.79
A m 2 yrs 14.08 3.11 9.64 2.21 15.65 3.18 10.92 2.34 12.31 2.57 8.78 1.82 14.63 2.41 11.19 2.35
Free recall Afler After After 3 yrs 4 ~ T S 5 yrs 13.95 2.78 9.25 2.90 14.97 3.29 11.34 2.52 11.69 2.04 8.04 1.31 13.98 2.63 10.97 2.01 13.15 2.01 8.67 1.76 14.85 3.41 9.68 3.01 11.07 1.98 7.85 1.56 13.75 2.98 10.89 2.96 12.50 2.62 8.43 1.82 13.65 3.01 9.04 3.13 10.64 1.38 7.38 1.04 12.89 2.77 9.95 2.64
Comparison Initial vs Afler 5 VTS p<0.05

p c0.05
Conceptual
Placebo (N=10)
15.49 3.14 10.76 2.01 15.54 3.78 10.70 2.67 14.02 2.56 10.97 1.62 14.34 2.45 11.27 2.15
Bratuni
(N=IZ)
Inmediate
Delayed
p>O.OS
p > 0.05
Acoustic
Placebo @=lo)
Immediate Delayed
p<0.01 p<0.001 p>0.05 p>0.05
Brat
(N=12)
Immediate Delayed
SELECT RESEARCH PAPERS O N EVIDENCE BASED AYIJRVEDIC DRUGS
Table 3. Free recall scores oidrmentia cases under various conditions

Task Treatment Testing Initial
After ARer After After After
Comparison
Conceptual
Placebo (N=10)
Immediate lklayed
Mean SD Mean SD Mew SD Mean SD Mean SD Mean SD Mean SD Mean SD
Brahmi (N=I2)
Immediate Delayed
Acoustic
Placebo (N=8)
Inundate Delayed
Brahmi (N=I2)
Immediate Delayed
on the sorting page unda a p p n a t e acoustic category names. Following tbe sorting task, subjects under the immediate free recall condition were asked to recall words b r n the scrted List and write tbon in three mindes on a sheet of paper provided for this plrpose, as many as tbey could remember and in any orda that occurred to l h m . The subjects mx told to came for the w n d session ihe nnd day at ihe same hour hut no information was given to them as to what t b q would be required to do in tbe s m d session. On their arrival a similar type of free recall test was gival. Half tbe number of subjects in each of the Brahmi and placebo groups (for both dementia @ normal wntrol d a cases) w e e first tested on the conceptual task and one week lata on the acoustic task: the order was reversed for the remaining 50 per cent subjects in the two groups. This sequence was changed b m year to year. The measure of memory was the numba of words recalled
Results and Discussion

Means and standard deviations for the criterion scores, i.e., the level of
acetylcholine and free recall scores for the conceptual and acoustic tasks of the two groups are given in Tables 1-3. The t-test was applied to test the significance of differences between the initial (before treatment) and final (five years after the commencement of treatment) mean values of the respective groups; the obtained significance levels are reported in the last column of the corresponding tables. The ttest was also applied for other mean comparisons. The results of the study show quite unambiguously that Brahmi, an indigenous drug, not only arrests further memory loss but also slows the process of subsequent acetylcholine reduction in persons suffering from senile dementia. The study also shows that memory loss due to normal aging is arrested by the drug. Studies are underway in
22
h and management of senile dementia

Repofl o j P m p r in Research. New York:
which the effects of Brahmi are being examined on the recall and recognition measures of the aged persons after varying the level of complexity. The main focus of these studies is on attentional capacity and processing speed. Memory has been suggested to be intict particularly dependent upon cholinergic (Smith & Swash, 1978) or noradrenergic (Zometzer, 1978) function. Koella (1979) also states that both dopaminergic and adrenergic. transmission mechanisms seem to decline in activity andlor efficiency with age. It is quite established that these are the functions which get greatly disrupted in dementia. The present study showing arrest of further acetylcholine loss in persons suffering from dementia by Brahmi leads us to speculate that some components of this drug perhaps cross the blood-braiir barrier and regulate the cholinergic system by acting on some specific receptors in the brain. As memory impairment is the prominent feature of the Alzheimer's disease, it is speculated that the drug, Brahmi, might also be successfully used in the management of dementia of Alzheimer's type.
Raven Ress Eidorfer C, Friedel KO (Eds) (1977) (hgnihve and

Emotional Disturbance in rhe Elder@.
Chicago: Year Hook Medical Publishers Elias MF, Eleftheriou BE, Ellas PK (Eds) (1976) Expenmono1 Aging Reseomh: Pragrees.$in B i d o l y Bar Harbor. Maine: FAR (iershon S, Raskin A (Eds) (1975) Aging. ibl. 2:
(iore.~i.r und Trpommrt 4 P . ~ h o l o p r c Disorders in the i<lder!v. New York: Kavcn
Press Koclln W (1979) Ncunnphysiology of aged nln~tnals 13iophysical and hi~~hemlcal nervous system aspects of aging. In Honineister F, Muller C (Eds) Bmin Function in Old Age. BerlinMeideltergMew York: SpringerVerlag, pp. 394407 Lipton MA, DiMascio A, Killam KF (Eds) (1978)
Pq~chophormacolagv: A tienemhot1 o f Pmgress. New York: Raven Press
References
Batlig WF, Montague WE (1969) Category nanns for verbal items in 56 categories: A replication and extension of the C o ~ e c t i c u tcategory norms. Journal o Eqerinental Psychdogv. f 80 (3, @2), 1 4 5 Birren JE. Schaic KW (Eds) (1977) Handbook $the PsychologvofAging. Vol. 2. New York: Van Nosmnd Chalteqi N, M ~ RP, Dhar ML (1965) Chemical J examination of Bacopa monniaa wenst.: Part II- 7he constitution of Bacopa A. Indian Journal o Chemislty.3. 24-29 f Corkin S, Davis KI., Cmwdon JIi U d i n E, Wlutman RJ (Eds) (1982) Alzheimeri Iliseare: A
Mclntosh FC, Peny WLH (1950) Bioaswy of acetylcholine. Methods in A4edical Research. 3.78-81 Meyer JS, Welch KMA, 'Titus JI., Suzukt M, Kim HS, P r z FI,'Mathew NT, C d y e Jl., Hrstnik 1'. ee Miyakawa Y, Achar VS, I M w n I .(19%) U Neurotransmtlter failure in cerebral mfmtion and dementia. In Tary RI), Gershon S (Eds)Aging. Val. 3: Neurdiologv ofAging. New York: Raven Press Pandey HP. Singh RH, Udupa KN (1 975) An improved melhod for biological assay 01- n)lhrccytes acetylcholine. Indian Jovmol o f Exp'mencal Biology. 13, 327-33 1 Rastogi RP,Dhar MI. (1967) Chemical examination of Hacopa monniera wettd.:,l'arl Ill- I3acoside I%. Indian Jmmal o/('hemi.~tp. 84-XO 5, ; Reisburg U Ed) (1983) Ablteimrr:~ II8seare. NewYork : E Press m Smith CM, Swash M (1978) Possihlr h~cchemical hasis of memory disorder in Alzheimer's disease. A m a h o hieUr010gv. 3,471 -473 f Wurtman W , r n h Sli, Cnowdon M (I*) (1984) C Alzheimerf iJzsease: Advances in Basic Re.smrrh m ' Thempie,$.Cambridge: Center u for Brain Sciences and M t b l s eaoim Charitable Tnrst Zometzer SF (1978) Neurotransmilter.mndnlation and memory: A new neuropharmacological phrenology. In I.ipton MA. DiMascio A. Killam KF (Eds) Ps)vhophamu~cdogv: A
23
Generation o Progresc New York: Raven f
Ress, pp. 637449
G.P. Dutey Psychosomatic and Biofeedback LaWory DmuUnent of Basic Pnncioles Banaras Hindu University Vnranasi 221 INS, India
SELECT =SEARCH
PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS
24
Role of an Ayurvedic drug Uraliini (Uacol~a ii~onnicri) n tllc i lnanagelnent y,f senile deiilciltia
Aruna ~ ~ r a w a lUP.~ u b e y ' ,DS. ~ u ~ > r d , ~ d u ~ a ' ', KN. '~cpurmmtofl3asic Pfinciplcs. Faculty of Ayuned& Institulo of Mcdical Scicnccs. l3.H.U Varnnvi 2~cputment Prychqlpgy. Bmnrrr Hindu Univcrsiv. Vuanasi of '~~plcssor Eqcri~w. Iqrlilutc of M d i c d Scicnccs. Dmrru Hindu Univcrsily. Yunnnsi
AbstrncLnlc efficacy yf e.i Ayurvcdic drug. Bralmi (Uacopa monnicri), in h c rnmagmcnt of senile dcmcntia wn. exunincd. n l o drug w q adn;iLlercd lo dingnosd wsu sf nil^ Jcrnenlin and norrnnl conlmis, boor wiIlliIl h c 64-79 of yrs agc-range u Lhc corq,pacunenlofll~c study. in a fivc ycar follow-up.Thcrcsulu rovcal: (I) Braluni nncsls mcmury loss in normal as well 4, dcmenlia cascs: (2) Brahmi also leads to slowing oface~yls!~oliic in dcmcnrin cnscs. Thc loss fcnsibiiity of drug's us? in dcrncntia of AW~cimer'slypc is discussed. Kcy Words Acctylchqllnc, Br8hmi (Brcupr monniui). Scnile dententic. Memory. Freo rccnil.
10-15 per ccnt 01 Ulis pol~ulalion arc Iltc likcly The advanccs ill ncurobiology. ncuropltysiology..ncurochcmisvy qrld ncurophar~nacopsychology victitns of onc or d ~ odlcr Corm 01dcntcntin. c during Ulc l a 1 mon: 1Ilan Uucc dcwdcs havc lcd lo Allctnpu havc bccn lnndc lo bring Ulis phclloOlcdiscovcryofcswb!isllcd dcEciu in cl~=uocortiwl lncnon orccrcbral under conlrol or lo 1nitig;gc activity, ncurochcrni~yyof UIC brain, cerebral cir- its cflccu n c u r c l ~ i n ~ r v c n ~using nlninly by ons culalion and mclabofi?m. and fognilivc runcliorling tilc noouopic drugs sucll as ~lydcrgillc, piracclallt, (ca~abililicsassociald particularly wit11 lwmillg villcolllillc,ccll~rol,llcnoxil~c, n:ll~idroluryl(see [or and memory) as a consequcnu: of agillg. An inl~or. ,view: Gcrsllon & Raskin, 1975: E I ~ ~ wnlproblcn~ l ~ i clrai bdfled chc scicnlisu all ovcr w l~ Elias, 1976; Eisdorlcr & Fricdcl, 1977; Liplon, Uic world is Urn problc(~~ofsenilc ocher lormg 01 DiM3Kio & Killaln, 1978; Corkin ct and lYXZ: dcmcntia cxhihiiing w ~ p l o m ~progrcssivc im- Ilcisburg, 1983; W u r t ~ n a ~ ~ , 01 Corkill Sr Cirowtlo~~. pairmcnl in cognihvc Frictions, cspccially l w n ~ i r ~ g 1984). bul ntosl of lllcsc inlcrvc~~lio~ts far lrolll nrc and memory, with ngc. Uirrcn and Schaic (1977) and solislaclory bccausc tltcy sullcr lrom scrious sidc-clEisdorlcr and Fricdcl(!977) also s m c U t a ~ c o g ~ ~ i ~ i v c 1ccu. and crnolional al~cratiohs (dcliciis) consliluu: M ineviwb~emani~cs~~on~jnona4~aging.~owcvcr,~c , In AyLrvcdic syslclll 01~llcdicillc tllilll)~l l c l h l llavc h n b d v o c a t c d lor S l 0 ~ i l l g down lnosr d r a m a t i c altccalions in nlclnory a n d prcpw~ticns lllc aging proccss and Ulus prcvcltl ~ncniory loss and ncuromsmilcrs llavc been round in p a l i c l l ~ Uraltlni (Bacopa ~nonrticri Cltollcrji, ccrebnl inlvclion and with n z u r p ~ ~ auol~llicsin d c ~ t s r ~ t i a . al senile dc~ncnlia,Alzlj~imcr's, huntinglon's and Rastogi & Dllar. 1965; Raslogi & Dllu. 1967) is l Parkinson's d i s u s c (Mcycr ci:~I.. 1976). n t c enor- corn~nonlyuscd by Ur prnclilioncrs 01 Ayurvcdic lu::l~citt~provc~~~c~ttol~~~c~nury. mily of UIC pmblcm-qi~ybc jl~dgcdlmln UIC vcry $yslcot o f ~ ~ ~ c d i c i n c fact Ulat t l ~ c populatioq of pcrsrt~~s 65 ywrs of Thc prclilninary rcsults 01 n sltidy. donc on albino ovcr no1 ogc is thc'most rapidly growing scglncnl w ~ d aboul rau. ltavc indiwtcd ilraL Brfill~ni ollly lilciliUt~3
f
Tltir study is pul of. lnrgur progranutle Jcrutd lo seicnlilic and clinical invcsti~n~iustr in~Jifc81ot1s of Jnlns likc Jaunanui. SIIJRWIP~UIII~I~. c~nm~only UrJmai. known ~ S m r i lRPIO~O-. ~ I U E ~ U biog~llic I I I L I W .alld YC~OJI, i ~ I O ~ non-vcrbd nnl paccped levninp awl memory.
25
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~~
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(1950) and n~c,difidby I'nndcy. Sitigli and Uduw (1975). discriminadon Icaining but a<<? i l l i l g i ~ ~ c s strcss in1'11~d~lails l l ~ c or IIIC~IO~ arc given i n 1';udcy cl nl. (1975). d u c d by dl;privalioll, illailodIcr l'l~e;~cc~ylcl~oli~~cnc~ivity worcrlrrcsscd i n l c r n ~ s o l ~ ~ ~ d n ~ l publisllcd) also. Y,is *rug lo all in KIIC. Illc lncrnory spa11o r s c l ~ wgoing cllildrcn. 111still l 2. hlmaory hfcasue,rtertr.l'ltc l i s l uscd lor lllolacnranOlllCr iltvcs1ig;llioli (unpublisllcd) Uri1111ni laas urentcnt 01 nlsvnoty contdncd 34 words l r u n ~ lliidi Improvided l~rolt~isi~&! rcsulc; i n lllc 11rd1vagc111cr11r o c"lcbarier sclcsled m,,, ox C il,l md 6uag in m i l d and modcralu nlcnwi dcficicllc~.In a scri- of M~~~~~~~ (1969) norms (cilicr, rruils. 6; m,. r 6: 6: ",~. ollicr expcri~ncnlgB r e l ~ ~ IUS n i also provided Cllrlowcrs, 6; rela1ivcr.5; occupnlionr orprolcssions. S).Tllc couraging r c s u l h in dlc p r C v ~ l l t i 0 no f cpik.plic words wcrc rclcclcd in such a manncr l1.1 llley could bc equally w l c l l l ns nllcrnalive sorliinlo conccplu~d rllynlor SC~LUCS: . .. ing calcgoricr. T l ~ c u b j m could. tl~crclorc, l ~ s s i l y ~ u c lllc The puvose of dlc prescnl invesligalioll was words c i d l u in ICor conltptunl kir%courdc relalionsLudy lhC yr *Ic c en'rac' ucBrallrni c[fecLS Organi rl~ips.Tl~cnurnbcro1 catcgoricr lor ocousliccnlcgorizalion [lie acetylcholine lpvcls. and ilnlncdialc and d e l a y 4 wcrc irnc ,i l d in ~ sh ~ also ,ix. I ~ A 34 CrccrecalloCtl~cdingnoscdscnilcdcnicnliacascsand lines on UIC ul,pcr yrl01tltc rar~ing pngc in sucll n way lllc normal ConUulS in a five v u r rollow-un. A n I I Lllc words 10 bc calc~orizcdn n C ~ I C C O ~ Ywcro I W ~ IP I i " closc~ed logclllcr. incidental l e a m i n i paradigm was used Tor ilic lncaurcrncnt o l r n c m q y . Proccd~trc M a l c r i a l s ittttl M c l l l u d s 'l'\vclvc cues 01 seltilu dcmcnlio nnd I 2 t ~ u r ~ a a l canuolr wcrc givcn ll,c orgnnic crlmcu o f Urnluni, i n a Subj,jecl$ powderd form concedd in a cnpsuls m d l l ~ rcrnnining e Twcn~y dingl~oscd cases 01 scniic demenlia and 22 8 dcrncn~ia corer arid 10 norn~nl co~xuolrwerc kcyl on n o m d cunuol*. L*ldl in dac 64-'l'J.~rs ngc-rv.0 dlc ~IXC)~. dorc 01 utc iirdtfit~i s u " ~ ~u ono gmstt. c wl conuncncc~Cnl ihc slu*~.sewed as subjccu. I'crsoW of Uollt Umluni a,d ploccbo were ndn~i~tirlerd, twicc n day. abuiing olleor Ole ygrcr k i ~ ~ i o f p s y c I ~ o U o y i c(includdr~g in idcnlical winga doublc.blind procdurc con. ins dcoliol)orsu[lu!ing lrolndc~r-ionorolllerpusistcnt I ~ ~ U O W for five ycms. only dl sc persons who gave I~ o cndocrinc disardciwcrc cacludd. Quilc a lcw c a w d i d wriucn consent were o l l o w d lo participate i n Ihc nudy. during IIIC livc ycirr ~cnurcor t i i s longitudinal sludy. In dl sir rncnrurcmcnu wcrc lakcn lor cncl~ subjccl: Complclc inlonnslion could bc oblaiscd only lor 20 ond basal and atl~crs aller cvcry onc ycar lnr five )cars. 1\11 dcmcnlin C~LTCSitnd 22 llornlal COIIIIUIS. ~ l c-cs wcrc ll~oraughlyn~unilorcdlur lllcir gcncml ~ c Ileallll as wcll ar brhnviaral cliulgcs ihruug~:oul blarcrirrls
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(ccncopludor ocounic)nmu wc(8:prinlcd insix colutanns :aria i n each culunm). Far lllc cu~nccl~aol caegociwlion - . luk. llw subject w u lold lo sorl i ~ r dnaardin&p hcif l K X I (1979) also SWLCS I I ~ L ~OIII d ~ ~ ~ a l l l and ~ r g i ~ ~ ~ i ~ w n q l u a l rclalionrlip m d w! rc cl~cmon lltc rorling ndrcncrgic um~s~nission ~ c c l ~ a nsccm l o l l c c k ~ c ~~ isms rllccl undcr aouomiaw cnnccn~ud cawrow n w . For i n nclivily nn~llorclficicncy wit11 ngc. I t is ~ l u i l c scousiccalcgoriuliun. lluo rubjout v o s gold lo to81 wouJs cswblisl~ul Ulat tllcsc arc I I l u ~ ~ c l i o wllicll gc! IC ~ls according lo lltfir OSOYIL~C rcI~L/ol~dllpt wtilo lltcnt on .Dd llic rarling pagc undcr npproprmm ocnwlic calcgo~y prcally J i s r u ~ ~ l ci d dc111cntia. Tllc Ilrcscut sldy n nnmes. Following llm sorting tr(~k. ~ u b j c s uundu llno illowing ur&t o l lurtllcr ncclylcl~olinc loss ill ixr-. inunuliclo Iroo rccall sondilion wncr ask.cd u rocall words , sons s u l l u i i ~ lrr o r l ~ JCIIICIII~by U r n l l ~ llcuds us l o ~l lrom lllc sorlfd lilm d wrile ~~IFIII in llum I LUC on n ~I I S s@cculalc I I t p solnc coa~ppncnu f l l ~ i clrugpcrll:lps o s sheer of papa providcd lor IIw p1drpl.z as n l a ~ ~ ylltcy u uors i!~irblood-bnin banicr and rcguloa lllc cl~olincould rcmcmba ~d in m y ordyy lllal occuncd la tllcm. crgic syslctn by acting 011 solnc slxcilic rcccplors i~! Tl~c subjccu werc lold lo come 1 1 e rccand rcssian lltc 0h lllc brain. ncxlday 1 lllcsamcl~our 1 bulno i!llorn~aLion givfn lo was 'lllun as lo w l ~ o ~ l l would bc rul!dird 10 do i n ihcscmnd ~cy is As tnclnory inlpair~l~cnt [he pmlnincnt fcascssion. On lllcir arrival, a similtt lypo of lrcc rccnll lerl lurc o l lllc Alzllci~ncr's tliswsc, ili s spcculalcd tllqt w u givcn. Half lllc number of bubicru in w c l ~ lltc of II drug. U~IIIII~. m i g l ~Also bc succ&slully uscd i n IC l Uralm~i l~laccln md groups (for Lw~h domcaia and itor~nal I l ~ ic ~ a n ~ g c ~ ~l dcn~cnlia l Alzl~cilacr'sljqrc. t o ~cnl o conuol CJJEI) E,= ~UIL IEILC~ 011 LUI EO~ICE~IU~I W IU~ and onc WECL Ialcr on (I acousdc msb; l l w order w u ~ C Y C ~ I C ~ IE Hclcre~~ccs lor llic rcdnaining 50 per ccnl sul;!.xu in lltc two groly~s. Uallig \\'F, hloslzgt~cW E (1969) Calcgory n o ~ ~ s s fur .Tlhis sequcncc w= cl,mgcdfron~ ypruv~ycu.n:cmeasurc verbal ilsn~si n 56 cnlcgorier: A rcl,liclnion nnd olnlcmory w LCnumb- of w"i.1~ rfcnllcd. u extcilsian01 ~ l t Conncclisu~ c c~~tcgorj. nor~ns. Jootrt~al o/rxpcrbu,nral Psycltology. (10 (3. 11at12). 1.45 Rcsulls 2 n d D~SCUSS~UII B Mcans apd swndard dcvidons lor lllccrilcriol~ Uincn J Sclmic K\V (&Is) (1977) llmslbmk o/ lhc Prychology o/ ,lgittg. Vol. 2. Ncw Yurk: Van scorcs, LC.. UIC lcvcl of acc!y!cl~olinc alld Ulc frcc Nosumd r c w l l scorcs lor tllc conccplujj and acoustic u k s of CI~allcrjiN. Kas~ogiKP. Ul~:u hlL (1965) C l ~ c ~ n i u ~ l tllc two groups arc givcn in 'lablcs 1-3. n l c t-kst cxxnin~lion llocopn ntonrlicrr welsl.: I ' n r l I 01 I was applied to &st thc s i g n i l i w ~ ~ c c dillcrcnccs of n l c cons~i~u~ionllac01>a A. Ittdia!~Jourt~ulO/ 01 bclwcin rho initial (bcforc uyficnt) nnd final (live Clmnisrry. .. I 24-29 ycars d l c r thc commcnccmcllt of ucauncnt) m a n Corkin S. Davis K L Growdon 1 1 Urdh E. Wurunan KJ 1. values o f lhc rcspccdve groqlls; l l ~ c obwincd sig(Eds) (1982) ,Ilrheir,lcr'r Dircnrc: A Rcporl of nificancc lcvcls arc r c p n c d i n tllc lastcolu~nn I I 01 I C Progrcsr b t Rerenrch. Ncw York: Kmen I'rcrr corrcspnding wblcs. Thc I k; was also applicd for - ; Eidurfcr C. Fricdcl KO (E&) (1977) Cng,~irivc o , ~ d EmriortdDisr~ubonc~rl8e Elderly. Cldcago: Y C J ~ in other mcan comparisons. Wmk Mcdical Publirl~crr Thc rcsulls of lhc study sllow quilc unalnEli- hlF. Elel~l~eriou Elinr I'K (Edr) (1976) f_rIIE. biguously that Bnhmi, an indigenous d p g , not only perirncm'ol Agltag Rcrcwcb:Pro~rcrri t 8 Oiology. Ilur m c s l s lurlhcr mcmory loss b u l also slows lllc 1Ixlar. hlaine: EAK process of subscqucnt acclyl$holinc reduction i n Curlson S. Raskin A (Ws) (1975) Agir,p. Vol. 2 Ccncrir ; pcrsons sullcring from scniidrlc~~~cnlia. study Tlbc o ~ t d 'liroltnoa o P.cycliologic Dirordcrs i n rlae / also shows lhal mclnory loss duc lo llonnai aging is Eldcrly. New Yurk: Ilnven I'resr arrcslcd by ihc drug. Studies q c undcrwny i n wllicll Kocll~ \VP (1979) Ncur~~pl~yrialogy ngcd ~ n i ~ ~ ~ a l s : 01 dlc clfccu 01Brallmi arc k i n g cxail~incd UIC on Ilioldtyrical nrnl biucltemicnlncrvrn~r ryrlrlu inrlrclr r c w l l and rccogl~ilion rncasurcd 01Ulc agcd persons of ?zing. I n Ilallnteir~crF. hlullcr C (Cclr) nroi.t aller varying ihc lcvcl olcornplcxily.Tl~cmain locus I;uncrio,r in Old Agc. I l e r l i n / l l e i d e i l r ~ ~ Yurk: Slxingcr-Vevlng. 1 1 394.407 1. ' 01 lllcsc sludics i s OII auclllional capacily and proccssingspccd. Lipun hlA. Uihlascio A. Killant KI: (Cds) (1978)
..
..
-.
--
29
~~rnwnl/D~~hcylOupldUdupa
Psychopl~rmacology: A Gcrwafion of Progrus. Wurlman RJ. Corkin S l l . O r o w d o ~JII (Eds) (1984) ~ Ncw'York Hayn Prus Alrhcimcr'r Discarc: Advor~ccsin Dnsic Rrscanh andllcrapies. Csntbridp: Ccntw lor Urain Scicnm Mclnmsh FC. I'cny WLH (1950) Uiousay of acctyland M c ~ b o l i r n ~ CI~arihbb TIMI cholii. Mdhc+ in M e d u d Research 3.78-81 modulalion ~d Mcycr IS. Welclt KMA. Tilw J L Svrvki M. K HS. Zurncrrcr SF (1978) Ncumtrans~~tillcr i m mcmory: A ncw neuro~ll~~naacolugicd pluct~olu~y. P u c z FI. Mag~cw NT, G d y a J L Hrrtnik F . v Miyakawn Y . " ~ c h a r VS.' Dodson RP (1976) in Lipton MA. DiMvcio A. Killam KF (W) Ncumuansmi~~u failure in cezcbral infuslion uJ ~ s ~ c b ~ ~ h m a c A lGemtoion of Progrus. o o~~: NcGYork Rovcn P r c s s . ~ .6 3 7 a 9 dementia. JnTcuy RD. Gcrshon S (Eds)A h * . V d . 3 Ncwobidogy if gin^. New York: Hav-m-~ru. : Pandcy HP. S i g h RU. Udupa KN (1975) An improved 8a1ylmethod for biolvgiul assay of ay~luocy~ea cholinc. l n d i Jflwna! of&xpcrimuUdDidogy. 13. ~ 327-331 Rulogi RP. D h u ML (1967) Chcmicd cxvninvion o l G.P. Dubey Buopa nmnnieq w c l b ~ :P u t 111-B.cosi& D In. Psycholomatic d Uiolcedback Laborator). d i m JOWMIof ~ h u n k y5: 8 4 4 6 , Dcpamncnt ofB.ric Principles Reisburg B (Ed)(1983)AlzhrLnu's Disease. New York ~ a i u l l y Ayurvcda of Frcc P r u s lnstitulc 01 Mcdicd Scicnccr Smih CM: S w u h M (1978) Possible biochuniul b u i s llnnuns Hiidu Univcrsily of memoly disorder in Akhcimu's discA & VWMYI 221 005 of NcwoIogy, 3, 471473 India
30
THE EFFECT OF F~~.NDCUKAPARI~I (CENTELLA RSIACISA ON TKE CEflERA! FflE!iTAL AGHITY OF BJEIGTALLY RETARrfED GII19RSM
Airs. I<anchana Sr~nivasan** and hlr. T. I{oteswara Raodh+
( Late Dr. 11. V. R. Appo h a , *
(Dr. A. L a k s h ~ n i ~ x ~Unit for Itesenrch in Intlinn iledicine, thi Voluritary Health Services, Adyar, bI:~clras- 0000.'0 )
The results of a double blind trlnl of A1nndooliapr.-111:

Sanskrit ( Ccntella nsintica ) intlicatcd that there was significant increase ill a the general mental ability of
nientally retarded children after 3 rnontlis (difference from the controls P. 001) and after 6 inonths (.ililference from
the controls P
. D l ) oi tirug
ndrn~iiislrntion. In the
hclinvioural area, significant i.mprovement was found in tlie overall general a~ljustrnent(1' .05) ; u ~ d atte:~:ion & cunce~~trztlon (P. .05) after six months.
M a n d ~ o k a ~ a r(~Centelln nsiatica) is an hyiiri-cdic herb used extenli sively as Rasayana drug, This ~ I r u gllas been llie~~tioned for its Rasayana Property and inec-lhya effect in Ayurvedic c1assics.l
-2--___
project Olficcr .**I?ese;~rch Assistant ( I'sycliology ) "'Research Assistxi~t( Statistics ).
31
AYC
April, li The chemistry and pharmacology pf the Centella glycosides of :
Centella asiatica, Indian variety, have been studied by Bhattacharya (19: Basu and Rastogi (1967) and Ramaswamy et a t (1970). T h e effect Centella asiatica on the blood constituet~tsof normal healthy adults in age group of 45 to 50 years over a peroiod of 42 months has been repori by Appa liao et al (1967;. 1969) and its effect on growth, longevity
2;
tissue biochemistry on albino rats has been reported by Rajagopalan et (1970). Toxicity studies ( hfululterji, 1953; flitha1 & Sirsi, 1961) indicate th the alcoholic extract is non-toxic even in fairly high doses. Various dru have been tried with meutal'retardates to irnprove their intelligence. Amo. thern~wrreg1ut:lnlic acid (e. g. Zimrnennan et al, 1949, vitamins (e. g. 1 glridice, 1900) sti~nulantsand cnergisers like deanols metrazonal, arnpil, mines etc. (e. g Ua~nettand Latnpert, 1957; Ijlue et al, 1960) tmt~qnillizers(e. g. Tarjan et al, 1957) Indian lierbs ( e . g. 1 1 I i 1 10 Morris et al, 195.1) etc. The present stiicly deals with the effect of Ccntella asiatica on general mental ablllty of thirty menially retarded children.
Subjects :
Tllirty chiltlren ( 7 girls and 25 boys ) in the age range of 7 to years \rill] a11 average agc of 13 years, 3 inontlls and mostly of the socio-economic statits and free of epilepsy anrl other ~leurolgical deic frorn a local home for the mintally retarded, were selected for this t , The case histories of the children were obtained from t h e . records of ..... . institution and also froin parents residing locally. 'A protocol tor recor case histories was prepared and filled up before drugs administratioil.
SELECT RESEARCH PAPERS ON EVlDENCE BASED AYURVEDIC DRUGS
32
~ p r i l ,1976
AYU
T h e Binet ltatnat test (1964 revision) was selected for intelligence since the test has mainly 3 advantages over its counterparts namely: test is s t a n d ~ r d i s e dto It~clian population; I<atnat himself has used t!ie
est with mentally retardecl children and found it satisfactory (I<amat, 1967); :he' verbal items of the test were tliougut to be not too complicated for the sample in this study. The detailed tlescriptibn of the iest is givcu
in Kamat's book. (Kamat, 1967).
Procedure
T h e whole plants of cent ell:^ asiatica were tlrie,iT, puwderetl ant1 made into
0. 5
gm. tablets. Placebo tablets were tnadc of starch ntid \vcre
suitably coloured to rnalcli tile drug t;lblets. Thc teclinique, lopled led for the :ssue of drug was basetl on a coniplctcly ranilotniscd double blind method. .he.children were given
I tablet. (0. gtn.) a dny for six mot~tlis. 5
At the time of selection of sullahlc cl~ildrcn, the uriiie uf the children vas screetied for atiiii~oaciiluria.and other inborn errors uf tnetal~oliat~i. 1\To detectable inborn errors of inctabolisn~ were tlctcctctl atnotl:: the seleclctl :roup. A thorough clinical esaniin:ltion id all t l ~ ethirty cliiidrct~ was also done. Apart form tninor notritiotlal deficiences, no triajor illnesses were found. Bcfore administration, all the- children were given the BinetKamat test and their Intelligetice Quotients were recorded. A separate protocol for evaluating beliavioural ndjustmetit of the children was also prepared :inti filled u p during the actuol intelligetlce testing of the children. The protocol comprised co-operation, tnemory, attention and concentration, speech (coherence) and overall general adjusttnent with 3 rating (poor, good. very good) f o r each item. The last item i. e. overall general adjustment was rated on the. basis of 10 itetirs natnely, 1. Silly giggling and grimacing
33
AYU
April, 1'
2. S c a n t a n d ttivial conversation 3. Fixecl face? ancl blank stare 4. Stra?,
5. Overt tension or " Nerves on edge" 6 Repetit movements and bizarre mannerisms 7. Self muttering 8. Irrelevant : .
Postural movements incoherent responses 9. Apathy and indifference t o the test lO.~Restlsessi-, and fidgetiveness. between 3 & 6 I More 'than six less than sysmptoms indicated poor adjustme very good. T h e Binet-Kamat test 11.:
- good;
repeated after 3 months and
6 months of drug administration' along wi
the protocol for behavioural adjustment.

Results
T h e observed difference in I. Q. a t the initial examination betwc the Placebo ant1 Drug group was not statistically significant. ( T a b l e : T h e tlnta with regards to the bellavioural items of the Drug group a t
I
initkrl examination were compared with t l ~ a tof the l'lacebo group and fou t o Sc not statistically signliic;int. vT;l\J-ie 1V a). Ilcnce we could coi~c!; that both the samples were [row the same populntion. All the other conditions being the sanle, the increase in I ,
9. she,.
by the Placebo group, coultl be attributed t o thc repetition of test itc. and the resulting improved understanding and that by the Drug group thk repetition
of
the trst plus tlie effect of the drug.
0 1 statistical 1
annly
(Table I1 b) using L't'' test, it. was found that the increase sho~vnin I. by the drug group a t the end of 3 months and. G montl~swhen compared c.l that of the Placebo group was statistically significant a t P.001. and P. respectively. However, there weie no significant differences in the improvem in I.
9.
between 3 months and 6 months indicating that the drug I in the intellectual level of the mental retardates q
produced a n increase
3 months after which it had maintainetl the same 'improveme~i~. From

Figures of coefficient of variation .(Table 11 b), it can be inferred t l s ~ t
34
April, 1976
AYU
improvement shown by the drug group a t the end of 3 months and 6 months was more consistant when compared with that of Placebo. The statistical analysis of the data, relating to the behavioural
b. As can be seen, the chi-squares for attehtion & concentration and overall general adjustment between the initial and 6 months alone were statistically significant ( P 0.05 for both). The drug had thus improved the powers of concentration & attention and also the overall adjustment of the mental retardatates. This finding was further supported by the evidence given by the Matron of the Institution from which the children were drawn.
ratings is given in Table IV
The results of tlrc present study clearly de~nonstrzte the elfect of Centella asiatka in i n ~ r o ithe intelligence and gcnernl ntlaptive i~ehaviourof the mentally retarded children. From a psychiatrist's point
of view, ( Trethowon, 1963) proper trc;rtlnent of mental retardation relieves symptoms and reduces morbidity and allows the individual sufferer to operats the best way he can within the limits of his permanent disability. i<specially in the field of mental retardation, as Blacliman ( 1957 ) pointed aut "any drug which malies a 'just notieable dii'lerence' in a positive direction should be considered to be effective" since total cure is ruled out. The beneficial effects of Centela asiatica seen in the study would therefore :o a long way and should have very significant implications in the care and inanagcment of mentz.1 retardates. The absence of significant increase in I.
9. during
the 3-6 months
period, in the continuance of the drug indicates that peak action of the
35
AY U
-
April, 127
intellectual area was attained at about 3 months and that it had maintainer a t the en:l of 6 months \vh:iteve: effects it had brought forth. However, i was proposed to repeat the inteiligence test and the behavioural protocol a t tlle end of one ycar to confinn whether the drug retains its effects eve; after it is vrithdrawn.
In the beliaviouml 'area, 3 models of drug action can be discenled

( Wolicnsbcrger, 1966 ). First mciel concerns the use of drugs like tran-
cluillizers, to treat secoi,iiary co;;:iitions like anxiety wliich interfere with tla furtller devclopmci~tof ~iitelligen:~.Second model uses drugs lilie stin;uiaiAL
;unti cr!eigiscrs which ii~asirniseti:? subjscts utility of his currently
exist it^^
resources. Tliiril model cot~ccriisrile use of drugs like vitainiris and glutaniir acid, \:.hich iniproce bclinvio~rrnlprocesses lilie arousal, attention etc., tin' i ~ n i l ~ r i l~ l u b a lintcili~ciicc.The ~:rcseiit drug, Centella asiatica, would fail c iiitu tliis invdcl 2nd t l ~ efiiiclii~~ it had substantially imjirored attcntio!; ;:!at
S: cviiccntmtion and overall gcnc:;l
adjustment coulci be taken as a furtliei
sul>stnriti:~tionof this. Tlic
tlr~i;.,
ihus l~ro~nises bc dcfiiiitely an advlu~ce to
in the tl~erapyof ~ncntalretardation.
Acknowledgement
\17e are extremely grateful to our Project Officer, Dr. I< S. Sanjivi, Emeritus Professor, Maclras hIedical College for his valuable cornrnents and suggestions. W e acknowledge the co-operation and assistance given by the authorities and staff of
" B ~ l aI'L'lar " home for-the mentally retarded. W e
are tnankful to the Director, Central Couucil for Research in lndiafi M e d i c i ~ ~ e Homoeopathy for pem~ittingus to publish this paper. Sc
36
ril, 1976
AYW REFERENCES
Aithal, H. N., & Sirsi, M. Preliminary phartnecological studies on Centella Asitatica, Linn. (N. 0 Umbelliferae). Antiseptic, 1961. 58,
405 09.
Appa Rao, M. V. R., Usha, S. P., Rajagopalan S. S., & sarangan R. six ponths results of a double blind trial to study the effect of Mandookaparni and Punarnava on normal adults. Journal of Research in India Medicine, 1967, 2, 79-85.
Appa I<ao &I. V. R., Rajagopalan S. S., Srinivasam V. R., CE Sarangan Study ot blnt~c\ookaparniand Punarnava for their' liasayana effect on normal healthy adults. Nagarjun, 1969, 12, 33-41.
Earnett, C.I>., c Lnmpcrt, I;. Effects of metrazol on intellectual funcb tioning in duiectives. Psycllological Izeports, 1957, 3, 551-54. Basu, N., & Rastogi, R. P. Friterpenoid Phyto~hemistr~, 1967, 6, 1249. Saponins and Sapogenins.
Bhattacharya, S.C. Constitution of Centella asiatica L. (111) Examination of the Indian variety. Journal of the Indian Chemical Society 1956, 33, 893:
Blackman, L. S. Toward the concept of a "j8.1st noticeable difference" in 1. Q. remediation. American Journal of Mental deficiency, 1957, 62, 322-25.
37
AYU
April,
8 Blue, A. W., Lytton, G.J., & Miller, 0. .W. The effeet of methylnidate (Ritalin) on intellectually handicapped children. American chologist, 1960, 15, 393. (Abstract).
Del Guidice, A. Large doses of vitamin E as a factor iq the me]. improvement of subnormal children. The summary, 1960, 12, 21.
10 Hakin, S. A. E. Indian remedies for poor memory; letter to the e d t British Medical Journal, 1951, 2, 852.
11 Kamat, V. V. Measuring Intelligence of Indian children. (4th ed.) Oxford University Press, 1967
12 Morris, J. V., bloc Gillivary Ji. C., & Mathieson, Constance, M. experimental administration of Celastrus paiculata in mental dcficie practice. Amercian Journal of hlental Deficiency, 1954, 59, 235-44.
1 3 Mukerji U. Indian pharmaceutical codex, Vol. I Council of Scicnt and Industrial Research, New Delhi, 1953. 14 Nadkarni, A . I<. Indian Materia Medica, Vol. I. Popular Book Del Bombay, 1954. 15 Rajagopalan. S.S , Appa Rao M. V. R. & Sitaraman, R. Effect of M: ookaparni on growth and tissue composition of albino rats fed o low protein diet. Nagarjun, 1970, 13, 29-35.
SELECT RESEARCH PAPERS ON EVWENCE BASED AYURVEDIC DRUGS
3I
April, 1976
AE'U
d
16 Rarnaswamy, A. S., Periyasamy S. &I., & Mrs. Basu N., Piiamaco1ogic;~I

studies on Centella asiatica Linn ( Brahma Rlanduki ) ( N. 0. Umf>elliferae ). Journal of Research in !.idian 1LIdicine. 1970, 4, 160-75. 17. Tarjan,-G., Lowery V. E., \Vright S. CV. Use of chlorpromazine in
P ic
two hundred seventy eight mentally deficient patients. Journal of Diseased child, 1957, 94, 290-300.
!8 Trethowan, W. II. A psychiatrist looks a t mental sub-norm2li:y.
T h e Journal of Mental Snbriormalily, 1905, 11, 18-24. 9

Welfensberger, \Voll., hhlenolascino, Fr:lnk. Easic considcrrrt-ions in
C%
evaluating ability of dru:;s t o stiinulnte cogiiitive dcvclopnieiit in rctardates. American Jonrl?nl of hIe11ta1 Dcfccie:icy, 1968, 73, 414
-
?3.
0 Zirnmerman, F. T , Bi~r_.crneistcr, B , '5 Putnn~n, T. J. The effec!. of glutarnic acid upon the mcntal and physical growth of monyols. American Jourlial of Psychiatry, 1949, 105, 661-68
39
AYU
TABLE
April, i
-I
Statistical analysis of I. Q. a t tho Initial Fxamination
Group
Sample size
Mean levels of
Standard deviation 11.580
Levei o significa~
Intelligence
Quotient Experimental Control 15
12*
32.306
1.042t
P L"
37.716
15.415
*
t
One child expired and two chidren went home. The obs5rved difference in tlie Mean levels of I. Q was not statistically signiiicant a t 10% level.
Mean Lcvcls o f I. Q
-
Mean levels of I. Q. Group Experimental Control Sample size Initial 3 montlis
6. montl-
40
April, 1976
AYU
TABLE II B
;tatistical analysis of I. Q. showing mean difference and i t s standard Error.
Group
Inivital vs 3 months
3 months vs 6 months 0.303 + 0.353 ( 448.8 )
Initial
VS
6 months 7 381 + 0.947 ( 48.57 ) 0,Olt
Experimental
7.576 + 0.923 ( 47.05 )
P 0.001"
The ir~creasein 1.
9.shown
9. shown
by the experimental group when compared
with that of the control group was statistically significant at The increase in I.
P 0.01.
by the experimental group when comparkd
with that of the control group was statistically significant at P Figures in the parentheses represent coefficient of variation.
0.001.
41
AY U
TABLE Ill
April,
Raw Data with Regard t o Behavioural Ratings Experimental Gr
Initial
3 months
6 month. -
Poor good very Poor good very Poor good good good fi Co-operation Attention & Concentration Memory Speech (Coherence) Overall general adjustment
7
1 7 1 1
5
4
1
6
2
3
3 6
3
4
8 5
6
6 9
9
6
7
6
2 2
7
3
2 2
5
10
7
9
Control Group Initial 3 months 6 rnontlls Poor good very Poor good very Poor good \ good good g Co-operation Attention & Concentration Memory Speech (Coherence) Overall general adjustment
5
7
1 8
6
3
5
10
1
0 10
5
11
0
0 10
2
10
1
3
2
6 7
1
2
4
0
2
5
1 6
6
4
1
42
SELECT RESEARCH PAPERS ON EVWENCE BASED AYURVEDIC DRUGS
------
April, 1976
-.-- .--.-
TABLE I V A
AYU
Statistical analysis of behavioural data a t the intial examination between the experimental and control groups.
1 Co-operation
x2 = 0,073
N. S.
2 Attention and Concentr- t' a 1011
x2 = 2.85
N. S.
3 Menlory
xZ = 2.416
N. S.
4 S p e e c l ~(Coherence)
x2 = 4.072
N. S.
N S.
Overall general adjustment
xZ = 1.699
N. S.
Not statistically significant.

43
AYI:
April, 1976
TABLE IV B
Statistical analysis of d a t a pertainings to behavioural rating.
--
Parameter
Group
Comparison Initial vs
Initial vs 3 months Co-opcmtion Attention & T < s ~ c r i ~ n e ~ ~ t a l s2 = 0.58; N. S. Coi~trol

x L 0 00; N.
6 months
xZ = 3.36; N. x2 =
S.
S. i.045 N.S.
iiIeo>ory
Exj~eriine~rtal Control
s2 = 0.44;
x2 =
N. S. 1.33; N. S.
x2 = 0.88; N. S. x2 = 0.00; N. S. x2 = 0.00; N.
Sjxccl~ (Colicrcncc) Experiinc~ital Control Overall General

adjustment
x2 = 0.156; N.S.
sZ
= 2.28;
N. S.
xZ =
S. 2.28; N. -S.
Experimental
x2 = 3.363; N.S.
x2
r2 =6'510;P<O.O!,
Control
= 3.345; N S .
x Z = 1.840; N, S.
N. S.
Not statistically significant.
44
Journal of Ethnopharmacology 64 (1999) 91-93
Short communication
Antistressor effect of Withania sornnifera

R. Archana, A. Namasivayam
Department of Physiology. Dr ALM PC. Institute of &sic Medical Sciences, University of Madras. Taramani, Madras 600 1 13, India
Received 29 December 1997; received in r~visedform 18 May 1998; accepted 1 June 1998
Abstract
U'ithaniu sonlnijera is an Indian medicinal plant used widely in the treatment of many clinical conditions in India. Its antistressor properties have been investigated in this study using adult Wistar strain albino rats and cold water' swimming stress test. The results indicart: that the drug treated animals show better stress tolerance. O 1999 Elsevier S:ience Ireland Ltd. All rights reserved. A'ej.words: Uithania s o m n f e r a ; Antistressor: Cold swimming stress
I. Introduction Ayurveda, the traditional system of medicine practiced in India can be traced back to 6000 BC (Charak Samhita. 1949). Wirhania somnifera Dunal (Solanaceae), commonly called Ashwagandha, (Sanskrit) is an Ayurvedic medicinal plant which has been widely used as a home remedy for several ailments. The root is regarded as a tonic, aphrodisiac and is used in consumption, emaciation, debility, dyspepsia and rheumatism. A decoction of the root is used for colds and
Corresponding author.
chills. The plant is used in treating syphilis and a decoction of the root bark is administered in asthma (Nadkarni, 1954), It is used for all age groups, in both sexes and even during pregnancy without any side effects. Various withanolides have been isolated from W. somnifera. Withaferin A and 3-P-hydroxy-2,3dihydrowithanolide F show promising antibacterial, antiturnour, immunomodulating and anti-inflammatory properties (Budhiraja and Sudhir, 1987). Glycowithanolides withafurin-A and sitoindosides VII-X isolated from the roots of W. somnifera significantly reversed ibotenic acid induced cognitive defecits in Alzheimer's disease model (Bhattacharya et al., 1995). The aerial parts
0378-8741/99/$ - see front matter O 1999 Elsevier Science Ireland Ltd. All rights reserved. PI1 S0378-8741(98)00107-X
45
R ArchanaCA. Namasivayam /Journal of Ethnopharmatology 64 (1999) 91 -93 ,
of W. somnifera yielded 5-dehydroxywithanolideR and withasomniferin-A (Atta-ur-Rahman et al., 1991). The pharmacological action of the different extracts from various parts of the plant have been studied extensively. W. sornrtifera has shown antitumor activity (Devi et al., 1992), anti-inflammatory activity (Al Hindawi et al., 1989), immunomodulatory activity (Ziauddin et al., 1995) and analgesic activity (Twaij et at., 1989). Studies on its antistress activity have shown that in mice, which are subjected to swimming stress, an increase in the swimming time and reduction in gastric ulcers was noted (Grandhi et al., 1994). The antistress effect of W. somnifera was manifested by the inhibition of stress induced increase in dopaminegic receptor population in corpus striatum (Sakena et al., 1988). The present study was undertaken to evaluate the antistress activity of W. soinnifera on cold swimming stress.
constant to avoid changes due to circadian rhythm. Ether was used to anesthetize the animals to collect blood samples using the technique of Feldman and Conforti (1980), to avoid further stress and the blood samples were collected from the jugular vein in heparinised syringes for the estimation of plasma corticosterone (Mattingly, 1962). The phagocytic activity of polymorphonuclear leucocytes was estimated (Wilkinson, 1977) using heat killed Candida albicans and the phagocytic index and avidity index were calculated. The total' swimming time for the rats subjected to cold swimming stress was also noted. All the data were statistically analyzed using One way ANOVA followed by Tukey's Multiple comparison test keeping the level of significance at P < 0.OS.The data obtained from the total swimming time was analyzed using Student's t test.
2. Materials and methods

Adult Wistar strain albino rats of either sex (weighing 150-180 g) were used for the study. All the animals were maintained under standard laboratory conditions and fed with rat feed pellets and water ad libitum. The commercialiy available powdered root of W. sonlnifeiu was obtained from Indian Medical Practitioners Cooperative Society, Adyar, Madras, India and its aqueous suspension was used at 100 mg/kg dosage, (derived from recommended human dosage on body weight basis) in this study. The experimental animals were divided into four groups. Group 1 (n = 10) were control rats. Group 2 (n = 10) rats were given the drug orally by intragastric intubation for- 7 days and sacrificed on the 8th day. Group 3 (n = 6) animals were subjected to cold water swimming stress ( 10C) till exhaustion and were sacrificed immediately. Group 4 (n = 6) animals were pretreated daily with the drug orally for 7 days. On the 8th day, these animals were subjected to cold water swimming stress till exhaustion and sacrificed immediately. The sacrificial time (9- 11 am) was kept
3. Result
The results indicate a sisnificant increase in the plasma corticosterone level, phagocytic index and avidity index in rats subjected to cold swimming stress. In the rats pretreated with the drug. these parameters wcre near control values and an increase in the ~ o t a lswimming time was observed (Table 1 ).
4. Discussion and conclusion
It is known that cold swimming stress increases plasma corticosterone level (Paris et al., 1987). Cold swimming stress has also been shown to increase the phagocytic index and avidity index (Sheela Devi and Namasivayam, 1986). The present study indicates that the above stress indices have been brought back to normal in I+'. somnlferu treated rats. In addition, the increase in the total swimming time indicates, better stress tolerance in these rats. Similar increase in total swimming time in mice subjected to swimming stress has been reported by Grandhi et al. (1993) in U sonlrlifern treated animals. In addition these ' .
'
46
R. A r c h . A. Nomar;wy~t/Journal o E!hnophnr~colo~y (1999) 91-93 f 64

Table I stress Indices before and afvr W somnfira Parrmeterp Group l Control Plasma Corticorterone @#dl) P h a g q i c index Avidity index Total swimming time (min)
p~~ ~
Group 2 Drug alone 98.95 i 0 . 2 7 69 6 i 0 . 7 2.519i0.08
Group 3 Stm 107.20 i 0.38. 78 i 0.583.840 i 0.13' 5.30 0.24
Group 4 S I M and drug 99.77i0.14 68.83 i 1.2 2.395 i 0.09 8.9 i 0.5'
98.65 i 0.51 68.5 i 0.56 2.261 i 60.1
value are exp& as mean i SE.M *Significantly different at PcO.05.
authors have also shown decreased numbers of gastric ulcers in W. somnifera treated mice indicating their antistressor activity. However their results are not directly comparable with the results obtained in this study as neither the animals nor the type of stress used in both these studies are identical. Furthermore it may be pertinent to point out that though many withanolides have been isolated from W. somnifera it is not known which one of them has the antistressor activity. Hence funher work with the isolated withanolides are essential to clinch the active component in this plant. The above results indicate that W. somnifera is a potent antistressor agent in the crude form used in this study and further in-depth studies are required to elucidate its mechanism of action. References
Al Htndawi. M.K., A1 Deen. H.S., Nabi. M.H.A., Ismail, MA.. 1989. Anti inflammatory activity of some lraqi Plants using intact rats. Journal of Ethnophamacology 26, 163-168. Atta-ur-Rahmm, Samina-Abbar, Dur-c-Shahwar. Jamal. S.A.. Choudhary. M.I. and Abbar. S. (1991) New withanol i d s from Withania rpp. Joumal of Natural Products 56, 1 -W . mI 6 Bhattacharya, S.K, Kumar, A,, Gholal, S., 1995. Eflectr of @Ycomthanolids fmm Wirhoni. romn$c~a an animal model af Alzheimer's d i m and perturbed central cholinm a r k m of cognition in rats. Phyiothmapy Revarch 9. 110-113. &dhirph R.D., Sudhir, S., 1987. Review of biological activiV of withmolida. Journal of Scientific and Industrial . R a u ~ h 488-491. 46.
Charak Samhita (1949) Translator: Shree Gulabkunverba Ayurvcdic Society. Jamnagar, India. ~.~ Devi. P.U., Sharada. A.C., Solomon, F.E.and, Kamath, MS.. 1992. In-vivo growth inhibitory effect of Withmi. romnfem on n transplantable m o u e tumor, Sarcoma 180. Indian Journal of Experimental Biology M. 169-172. Feldman. S.. Conforti. N., 1980. Participation of d o ~ l hippocampus in the glucocorticoid feedback effect o n . adrenocortical activity. Neuroendocrinology M. 52-55. Grandhi, A,, Mujurndar, A.M., Patwardhan, E., 1994. A comparative pharmacological investigation of Ashwagandha and Ginreng. Journal of Ethnophamacology M, 131-135. Mattingly, D., 1962. A simple Ruorimctric method for the study of free Il-hydrory conicooteroids in human plasma. Journal of Clinical Pathology 15, 374-379. Nadkarni. A.K. (1954) Indian Materia Medica. 3rd Ed.. Vol. 1. Popular Book Depot. Bombay, p. 1292-1294. Pan4 J.M. Lorens, S.A.. Van de Kar, L.D.. Urban, J.H.. Richardson Morton, K.D.. Bethea, C.L. 1987. A companson of acute strerr paradigms: hormonal rerponwr and hypothalamic wrolonin. Physiology and BEhaviour 39. 33-43. Sakena. A . Singh. SF., Dixit. K.S., Singh, N., Seth. P.. Guota. G.P. (1988). Eflect of Wirhoni. romnifrro and Panax ginwng on dopamincrgic r a r p t o n in rat brain dunng strcrr. Proceedings of the 36th Annual Congrnr on Medicinal Plant Rcwarch. Frciburg, Thicmc. Stuttgart. New York. p. 28. Sheela Devi. R., Namarivayam, A,, 1986. Candida phagocytosir in acute stress. radian Journal of Medical Microbiology 4. 271 2 7 7 . Twaij, H.A.A., Elirha, E.E., Khalid, R.M., 1989. Analgcrlc rludicn on same Iraqi medicinal plants, lnlernational Journal of Crude Research 27. 109-1 12. Wilkinron, P.C. (1977) P h a g q o s i s of killed Candida albicans In: Thompson, R A . (ed.) Tshniquer in Clinical Immunology. Blackwcll Publicationr, Oxford, p.212. Ziauddin, M., Phansalkar. Neeta, Patki, Ralhsd, Diwanay, Sham, Patwardhan, Bhurhan. 1995. Studia on the Immunomodulatory cffmr of Ashwagandha. Journal of Ethnophamacology 50. 69-76.
47
lour. Ind. Med. Yoga & Howoeo. 13 c . / 1 9 7 8 Res.
A DOUBLE BLIND STUDY OF THE EFFECT OF MANDOOI<APARXI ON THE GENERAL MENTAL ABILITY OF NORMAL CHILDREN K.KUPPURAJAN1, KANCHANA SRINIVASAN' ANIj K. JANAKIC'
(Dr. A . Lalishmipalhi Unit for Research in Indian Medicine, Voluntary Health Services bledicai Centre, Adyar, Madras-20) [ Received for Publication on April 26, 1977 ] quotient scores ranging between 90 and 110 Introduction were either below 90 1. Q. ~ ~ ~ ( ~ d ~ t name-~entel[a k i. e. those cascs who ~ ~~ ~ ~i ~ ~ l ~ ~ ~ ~ i points Or above 110 were rejected since they ,ia,ica) is a slender trailing and rooting herb commonlygrowing in marshy placer all over come under .*backward" and *'above average" ,India.The drug finds a variety of uses in the categories respectively. Strictly cases belonging to "average" category only, were taken for the as a hdigenoua systems of for variousskin diseases, an alterative, tonic, tdd. Of the 65 cases rejected, 49 were below diuretic, n stimulant of memory and intellige. go 1- Q. Points, 5 cases were above 110, one rice etc. (xadkami, 1954). since the drug has child was not conversant with either Enzlish bcec specially nlentioned for its intelligence 0' Tamil. 3 cases were very non-c~o~erati\~e, promoting'property in the ancient texts, (cia and for the remaining 11 cases the time lapse between the assessment and administration of raka Samhita), a study was conducted by Rao et a1 (1973) on the mentally retarded the drug exceeded one month. Many studies children of a local home for ;he menta!ly (Thurstone & Ackerson. 1929; B?yelej, 19jj) retarded and the results :ndjcated a positive have established the fact that a E, rmal child mmiftsts an apparently consistant increase in effect on the intel]jgencr al;d bcbaviour of retarded children. -rhe intellectual and social maturity over short .itudy Was undertaken to see whether thir drug intervals of time and the rate of progress is considerably- more rapid during 'the develop mentally normal children. mental years. Hence a period of 1 month was Metllods andMaterials tentatively fixed as the criterion period, before SELECTION OF CHILDREIS which the children should have been assessed TO ensure homogenity of population, a for intelligence and if found fit, should have =Carby Destitutes3 Home was selected for this been started on the drug. However, these 11 Totally' 126 children were screened for cases, who were initially rejected for ths above .acir.intelligence quotients of whom only 57 said reason were again tested after a lapse of 'h:bjldren were found Et with their intelligence time of whom. 10 children were included with
,;!.keaearch Officer '2cXcaiarch Assistant (Prycholagy) "REc6~l.r~h Assistant [stat.)
48
Effect o Mandookaparni on the General mental ability f fresh I. Q. scores. The remaining one child was found to be "above average" on 2nd examination and hence could not be included in the trial. The age range of the children selen cted was between 6 t o 12 y . with a n average age of 9.1 yrs. Care was taken to eliminate epilepsy and other neurological defects like hemiplegia, monoplegia etc. and defects like stammering, even for the initial screening. TEST USED The Binet-Kamat test (1964 revision) which is an adaptation of Stanford Binet test by V. V. Kamat, was selected for intelligence tcsting. The test has 3 advantages over its covnter-part?., namely, it is standardised to an Indian population, it has both verbal and non-verbal items a n d the verbal items of the test were thought to be not too complicated for the sample in this study. The detailed description of the test is given in Kamat's book (Kamat, 1967). PROCEDURE A thorough clinical examination of the 57 children was done and apart from nutritiona! deficiences, no major illnesses were found. Before drug administration, all the children vere given the Binet Karnat Test and their intelligence quotients were recorded along with height in cms. and weight in kgs. The whole plant of Mandookaparni (Samoolam) was shade dried, powdered and tabletted into 0.5 gm. tablets. The children were given one tablet (0.5 gm.) a day for 1 ygar. Placebo tablets (0.5 gm,) were'made of starch and suitably coloured to match the drug tablets. The technique adopted for the issue of the drug was based on a completely randomised double blind method. The Binet-Kamat Test was repeated after 6 months and 1 year of drug administration along with recordings of height and weight. Results Of the 57 children, 14 dropped out of the trial due to various reasons like transfer to another orphanage and irregular intake of medicines so that only 43 (26 boys & 17 girls) children came up for the final analysis. Before proceeding to find the efficacy01 the drug. the homogenit), of the 2 groups was tested with the help of s't" test and the obse. rved difference between the mean levels o f the two groups a t the initial examination was found to be statistically not significant. ( t = 2.021 P>O 5) (Table I). The mean differences in the height, weight and I. Q. scores between experimental and control groups at 6 months and 12 month were tested by means of *'t" test and the observed differences between the mean values were found to be statistically not significant (t = 2.021 P > 0.05; (Table 2 a, b, c). Discussion
A great deal of effort has been expended in search of pharmacological agents that will improve the intelligence and cognitive fun* tioning of normals and mental retardates, Glutamic acid, (Zimmerman et a/. 1947; ~ s t i l and Ross, 19601, Thiamine (vit. BI) (Harrell 1946) a n d Amphetamines \Loutiit, 1964.653 have not been conclusively proved to bc effective in normals but generally accepted tc be effective in improving the intelligence of mental retardates. Mandookaparni had a19 shown a beneficial effect in retardates (App3 R a o et al. 1973) while this study had shown nb effect in normals. The plausible reason ~ b ! certain drugs act in mental retzrdates 3flE not in normals is outlined in ~olfensbergefl article (1968), The primary objective of a stud! designed t o assess a drug's ability to accelarat' development should bc to explore whether tb
49
TABLE I
Sample Mean
Group
size
I. Q.
100.00* 96.72
Variance 25.48 50.1 1
Standard error 5.9
P >0.05
~ ~ ~ e r i r n e n t a l2+ Control 19
0.56
*Values are corrected to two decimal points.
Croup Experimental Control
TABLE 2 A
6 ~on;hs Sample
1 2 Months
No.
24 19
Mean
Variance
Mean
Variance
>0.5
1.41 1.68
12.71 10.87
0.22 *N.S.
0.50 2.56
20.70 11.89
1.26
*N.S.
TABLE 2 B
6 Months Group Sample N. O
21
19
12 Months Variance
t
Mean
Mean
Variance
bpcrimental Control
3.54
2.38
33.45 2.47
1.37
4.96 3.68
32.82
6.40
0.89 >0.05
*N.S.
*N.S.
TABLE 2 C
6 Months 1 2 Months Variance
t
Group
Sample No.
Mean
I
I
Mean
Variance
--4
*N.S.
- Not significant.
.
50
Eflect a/ Mandookoparni on ;he General nt~nral ability

drug has got any developmental effect. For example, in a 7 year old severely retarded boy, exhibiting behavioural defects in speech, language etc,, a developthe area men, enhancing drug is likely to work gradu. ally, additively directionally and selectively. If the underlying processes do not show any change, then no change is likely to be there on the global level. In otherwords, the observed signs of subnormal mental functioning like defective concentration, inability to plan and lack of prevision, repetition of observed error;, failure to compreheild the simplest, failure to manipulate items of knowledge previously acqui~ed, perseveration in speech and action etc. are not present in normal children and hence the drug which had improved the behavioural processes, thereby bringing about an increase in the intellectual status, in mental retardates could not beneficially act in normal children in whom, these defects are not presect.
suqrnary
The double blind stGdY of Mandookaparni on the height, weight and intelligence of men. tally normal children showed no effect. The probable reason for not finding an merit is outlined.
ACKNOWLEDG,.,MENT
We are extremely grateful to our Project Officer, Dr. M. V. Chari, and ~ e ~ u Project t y Officer, Mr. S. S. Rajagopalan for their valuable comments and suggestions. U'P acknowledge the co-operation and assistance given by the authorities and staff of "Seva Samajam* Pallipattu. We owe a debt of gratitude to the staff of this Unit for the help rendered by them. We are thankful to the Director, Central Council for Research in Indian hledicine & Hoinoeopathy for financing and permitting us to publish this paper.
REFERENCES 1. Appa Rao, M V. R., Kancliana Srinivasan a n d Koteswara Rao. (197 3) T h e effect of MandooLapami ( ~ ~ , , ~ ~ l I o asinticn) on the general mental abi. lity (hledhya) of mentally retarded children, Journal of Research 10 Indian Medicine, Vol. 8, KO. 4, pp. 9-16.
:
2. Astin, A. W. a n d R o a , S. (1960)
Glutamic acid and human intelli~cncc Psychological Bulletin, Vol. 57,

429-34.
3. Baylcy, N. (1 955)
: :
O n the growth of intelligence, America0 Psycholcgist, Vol. 1n, p , S I 1. Chil;itsastanam, Chapter Rasayana, 30,31 Mental response to addcd thiamin'l Journal ?02-4$. of Nutrition, Vol, 3l'
4. Charakasamhita
5 . Harrell, R. F. ( 1 9 4 6 )
SELECT RESEARCE PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS

51
6 . Kamat, V. V. (1967)
7 , Louttit, R. T . (1965)
:
:
Measuring intelligence of Indian children, Oxford University Press. Chemical facilitation of intelligence among the mentally retarded, American Journal of Mental Dificiency, Vol. 69, 495-50 1. Indian Materia Medica, Vol. I, Popular Book 'Depot, Bombay. The mental growth curve for the Binet tests, Journal of educational Prychologl, 20, 569-83. Basic considerations in evaluating ability of drugs to stimulate cognitive dcvelopment in retardates, American Journal of Mental Deficiency, Vol. 73, 414-23. A group study of the effect of glutam c acid upon mental functioning in children and adclesccnts, Psychosomatic medicine, 9, 175-83.
8. Nadkarni, A. K. (1954)
: :
g. Thurstone, L. L. and Ackerson, L. (1929)
10. Wolfensberger, W. and Menolascino, F,(1968)
11. Zimmerman, F. T., Burgemeister, B. B. and Putnam, T. J. (1917)
sl;rf~
aih
8 ww TT ,q?wii m a r ; qsmq (Double blind study) % ~
fi
ma
www mi pn $T I a8 T Y 5'iB k @ sha 8 I
SIWW T@
ha* ihr
r n ~
P P G ?Ten*$,'il?liwi
ahm n X ii T*
52
IMMUNOMODULATORS AND ADAPTOGENS
UNDUAh! JOURNAL OF N U n L PRODUCTS A RM
Special Number
ADAPTOGENS IN HIGH MOUNTAINS DR. K.K. Srivastava Defence Institute of Physiology &Allied Sciences, Timarpur, Lucknow Road, Delhi - ; I 0 054. Stress.thepsycho-physiological response to a change in the environment,internalorexternal.inan organismandindividualhasacquired a dirty name, though it is an integral part of life. From the birth of an infant to the end of life, stresses continuously hammer at the harmony and homeostasis of life. The processes which keep harmony and homeostasis maintained inspite of the hammering are theones which constitute development and adaptation in the living being. This is essential, otherwise manwill be without challenges and would lead a lifewithout adaptation and therefore wither away without achiev~ng something which was hitherto beyond the capacity and 'capability' of man. Thus, stress hasbeen responsible for achieving the impossible and performancebeyond the 'capability' of man and extending its horizon step by step with time. However,too muchstresswould lead to exhaustion, manifesting itself in the form of stress induced diseases and maladjustments. The management of unusual psycho-physiological stress, therefore, has acquired enormous significance in day to day life. Such a manageme~t does not endeavour to eliminate strsss but raise the threshold beyond which stress would start injuring and disturbing the life and living processes. The technology n f such management essentially includes, psycho-physiological training and conditioning of the mind and body. The techniques include increasing load of stress such as exercise. sports training.endurance running and mountaineering, etc. A certain amount of general resistance develops as a result of cross adaptation, viz. a larger degree of heat iolerance is observed among marathon runners and cold exposure may lead to betterhypoxictolerance.Emotional and mental stress is the essence of competitive life. Its management is possible through powerful meditation and concentrationpractices such as those followed in different forms of Yoga. Mantras and Tantras. A goldmine of information exist on such methodologies in ancient and medieval oriental medical systems. Another area of interest in several oriental medical systems including Ayurveda, is that of using food supplements, dietaryelements. herbs and minerals for increasing physical endurance and mental per-
formance. These have been de- chamber and cooled to Sic (cold). scribed as 'Adaptogens' (Rasayana The physiological vital function moniand Vajikaran of Ayurveda). tored tomeasure endurance was, the maintenance of body temperature. Adaptogens are biologically This vital function represented the active substances which improve thermogenic efficiency and capacity physical endurance for doing work in cold, hypoxic and restraint(C-H-R) even in adverse circumstances and environmentand indicatedthe proper in difficult environmental conditions. functioning of central nervous sysThey increase tolerance to change in tem, cardiovascular efficiency and environmental conditions and resis- integrity of metabolic system of skeltance to noxious stimuli such as ex- etalkuicles. The rectal temperature posure to cold, heat, pain and infec- oftheratstartsfalling in the restrained tious organisms. Such health food state un'der cold and hypoxia. The supplements have been claimed to rate and time to attain a rectal temarrest ageing processes and age in- perature of 23% was determined. duced deterioration in physical and The rat at this stage was taken out of mental performance. However, ex- cold-hypoxia chamber and was alperimental evidence ofthe efficacyof lowed to recover at 32O i lo the C in such biologically active substances restrained state. Again the rate and as vitalizers and rejuvenators was time to recover the rectal temperalacking. For this, one needed an ex- ture to 37O C was determined. The perimental model which could repre- nature and shape of the curve during sent generalstresssituation,as stress fall of rectal temperature to 23O C and has many facets some common and recovery to 37O C along with the time other specific to one type of stress, were important indices, which are and at least one physiological, vital related to endurance running, swimfunction which could deteriorate non ming time in cold water (23%) and specifically under stress and could be the nature of the themagenic promaintained as a result of treatment cesses. This experimental model is with adaptogens. capable of evaluating quantitatively the endurance promoting property of We developed an experimen- an adaptogen. tal model for general stress. The experimental animal was white rat. Using this model, we have Stress consisted of restraining it in evaluatedseveralherbalpreparations overnight fasting state in a restrainer and some composite herbal prepara(creating emotional anxiety stress) tions which contain minerals and vitaand exposing it to 428 mm Hg atmo- mins and single plant extracts. Some spheric pressure in a decompression of them posses poweful adaptogenic
55
property which keeps on increasing on repeated intake over several days and weeks(cumulative action), whereas others, though acclaimed, d o not increase adaptogenic action on repeated intake. In some cases delay in fall of rectal temperature increased but recovery time remained unaffected. Whereas, in some the time to cool down to 23O C was unaffected but the recovery time to 37O C was shortened suggesting that the thermogenesis in cold-hypoxia was through different processlprocesses as compared with that occurring at 3Z3C in a restrained rat. Some of this data is presented in Tables 1-3. As a result of these investigations, the experimental model is now recognized t s a standard model for evaluation of adaptogens.
ments (adaptogens) has never been attempted This generated interest in exploring the possibility whether the adaptogens could be of any use in ameliorating the problems at high altitudes.
The experiments were started with rats exposed to a simulated altitude of 25.000 ft. for six hours a day1 six days a week. It was shown that a Composite Indian Herbal Preparation (CIHP) administrationstimulated oxygen delivery system to the tissues which in turn possibly maintained the muscular permeability integrity, adversely affected in rats exposed to similar altitude but without CIHP administration. The acclimatization to hypoxia of extreme altitudewasfacilitated by the administration of CHIP during the exposure. The stage now The environment of high ter- was set to carry out human trials. restrial altitudes pose hypoxia, cold and isolation (anxiety) problems in A comprehensive humanstudy combination with some others like was undertaken on two hundred solincreased solar and cosmic radia- diers, who had spent one year at tions. The stay ana workin high moun- moderate high altitude (3000 - 4500 tains beyond 5000 m is invariably m). The subjects were divided in two accompanied with the deterioration groups, one group stayed at extreme in physical and mental working effi- altitude (4800-6000 m) for 3 months, ctency and capability of man. Studies while the other stayed for 6 months. with restrained-cold-hypoxia model The efficacy of the Panax ginseng suggested that adaptogens might be and CHIP, given to men during their of help in combating and arresting the induction and stay at extreme high high altitude induced deterioration in altitude was evaluated in double blind mental and physical performance. fashion during their stay in extreme The possibiliity of improving the per- high altitude and after their arrival in formance of man at high altitude by plains (230 m.) The 'build up' dose means such as health food supple- was two, tablets twice a day (CHIP
SELECT ESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS
56
Table 1 Effect of Single dose of various adptogenic substances on the fall of rectal temperature (T,) to 23OC and recovery to 37% of rats in cold-hypoxia-restraint (C-H-R) model. Time in minutes Drug dose (mean S.E.M.) (mode of administration To attain T, 23OC To attain T, 37OC per oral) Control Exptl Control Exptl
Panax ginseng Root extract (12)
50 mg/Kg
67.9 7.2
74.7 i 5.7 102 1.' i 9.5 91.5 i 3.0 8.' 33 k2.6
124.5 105.3' i 5.6 k6.9 164.5 129.5' k 14.5 k7.2
Ginkgo biloba 50 mgIKg Leaves extract (14) Whania sornnifera Root extract (15)
75.2 5.2
.I00 mg/Kg
83.9 k 3.3
76.7 3.5
* 5.7 * 3.5
*
141.1 124.1'
Composite Indian 15 mglKg Herbal Preparation I (CIHP 1 (6) ) aqueous extract

I
171.3 167.5 i2.6 5.8
The number in parenthesis ihdicates size of treatment group Significantly different from controls at Pe0.05
Table 2
Effect of five doses of various adptogenic substances on the fall of rectal temperature (T,) to 23OC and recovery to 37OC of rats in cold-hypoxia-restraint (C-H-R)model.
Drug dose (mode of administration TOattain T,23OC per oral) Control Exptl
Time in minutes (mean S.E.M.)
To attain T, 37OC Control Exptl

-
Panax ginseng Root extract (6) Ginkgo biloba Leaves extract (7) Wifhania somnifera Root extract (15)
50 rng/Kg
67.9 k7.2
193.8 k27.8 118.8' . k 9.4 101.4 k3.2 98.2' k 5.6
124.5 k 5.6 164.5 k 14.5 141.1 k5.7

7 1, 4 9 f 2.6
8."
101.2 12.7
50 mg/Kg
75.2 5.0
116.9' f 9.4 122.1' i5.1

.rn
100 rnglKg
83.9 i3.3
7E 7 . . ,
Corn~osite Indian 15 mnfKg Herbal Preparation I (CIHP 1 (6) ) aqueous extract
t-vw.w
mr
k 3.5
f 4.2
The number in parenthesis indicates size of treatment group Significantly different from controls at Pc0.05
58
Table 3 Effect of long term intake of various adptogenic substances, on the fall of to rectal temperature (5) 23OC and recovery to 37OC of rats in cold-hypoxia -testraint (C-H-R) model. Tme in minutes Drug dose (mean S.E.M.) (mode of adrn~nlstrationTo attain T, 2 O 3 C To attain T, 37OC , per oral) Control Exptl Control Exptl
Composite Indian Herbal Preparation (CIHP 1 (12) ) aqueous extract
50 mglKg 6 weeks
65.4 1 0 0 4.' 4.0 i 5.0
165.0 1 7 9 0.' k2.8 8.3
7.5mg/Kg ClHP I aqueous extract (12) 12 weeks

1 mg/Kg ClHP II aqueous extract (6) , 6 weeks
Rasa s~ndur ~n2% gelatin (6) Rasa s~ndur In 2% gelatln (6)
70.0 1 5 0 3.' k4.8 i 3.0
159.2 116.7' 7.0 5.2
* *
87.3 149.8' 6.5 10.3
165.5 i11 2 124.6 i 14.5 124.6 k14.0
8.' 65 i6.7 154.8 i 22.6 141.2 k15.8
40 mg1Kg 6 weeks 40 mglKg 12 weeks
107.0 87.0 32.1 i 10.9
107.0 99.0 k32.1 i31.4
The number in parenthesis indicates size of treatment group Significantly different from controls at Pe0.05
59
550 mgltab; Panex ginseng 250 mgl tab) for one week followed with a maintenance dose of one tablet twice a day for the entire period of stay in extreme altitude.
1. Developmentof a standard model for the evaluation of comprehensive antistress and endurance promotingproperties of an adaptogen accepted by the pharmaceutical industry.
In the extreme altitude (48002. The psycho-physiological 6000 m) environment, thedeteioration in psycho-physiologicalperformance performance, physical performance was arrested. The recovery in physi- and sensitive indices of oxygen availcal performance on return to plains ability to the tissues were improved improved and the sensitive indices of by the intake of adaptogens upto a oxygen availability to the tissues in- period of three months stay in high cluding heart was shown to be im- mountains (4800-6000 m).As the proved in men given adaptogens dur- adaptogens intake provided protecing three months of prolonged stay in tion from high altotude stress therethe high mountains. However, during fore, they should be given as health six months of stay, the physical and food supplements. mental preformance could not be re3. The above studies on comstored to normal level even by the administration of adaptogens. Thus, posite herbal preparations of Indian the studies on the management of origin, viz. Rasayana and Vajikaran extreme high altitude stress by the of Ayurveda established them as administrationof adaptogens brought preparations of real value. aboutthefollowingvaluablecontr~butions;
ACKNOWLEDGEMENT The valuable contribution of a group of scientists who worked in the projects on adaptogens is greatfully acknowledged. They are Vimla Asnani. S.K. Bhardwaj, Fakir Chand, H.M.Divekar. R.K.Gautam, S.K. Grover, A.K.Gupta. Ratan Kumar. M.L. Pahwa. M.R. Panwar, Radhey Shyam, Omveer Singh and T.N.Upadhyay.
(R@t
6pm PRUtlb Val. XXLI
NO. Z
Jm-Mm. 1 m .
I .112-117) T
MEMBRANE INTEGRITY CHANGES AT HIGH TERRESTRIAL ALTITUDES*

K. K. ~RIVASTAVA, S. K. GROVER and UMA RAMACHANDRAN, Dcfcnce Institute of Physiology and Allied Sciences. New Dclhi 110010.
*Prcscnted at Intcmational Confercncc on Biomcmbranu in H d t h add Disease, November 1 - 4. 1988. Industrial Toxicology Research Ccnm. (Council of Scientific and Industrial Rcscarch), Lucknow, India.
Abstract
Creatine : ATP Phosphotransferase (CPK) remains generally tightly bound within the cellular membranes in the neuroskeletal system. However, it leaks out irito the circulation and its activity increases in the blood in neuroskeletal disorders as well as under such stress conditions which result in tissue hypoxia. This indicates aliention in cellul;~rmembnne integrity and pcxmeability. Exposure to high terrestrial altitude in man (4,000 m) and simulated altitude (6000 m) in white rats resulted in several fold increase in serum CPK activity. With 'acclimatization, the SCPK activity decreased to almost normal level. Administration of a composite herbal preparatio~i(CHP)* * was observed to decrease the hypoxia-induced increase in SCPK activity. This could be linked to the improvement in the oxygen delivery system of CHPadministered rats.
Introduction High terrestrial altitudes pose a scrious multiple envimnrnental strcss situation. Low partial prcssurc of available oxygen consequent to low barometric prcssurcs and cold constitute major'strcss producing elements. Hypoxia is a rnapr rcstraining element on physical activity. If the latter
*.Guibone (Himalaya)
is continued without taking proper care of the individuals, specially in unacclimatized condition during the initial phase of high altitude exposure, disastrous consequcnces in the form of High Altitude Pulmonary Ocdema rnay follow. Changes in cellular membrane integrity and pexmeabili~y have been implicated specially in lung alveoli, in high altitude pulmonary oedema. Maintenance of cell membrane
61
permeability and its structural integrity is an energy requiring process' and, thcrcfom, likely to be affected under conditions of low oxygen availability. Such changes are difficult to measun in man. However-, variation in blood enzyme levels, which otheqvh a n generally contained within tight cellular permeability bamers, are likely to indicate the changcs in membrane permeability of the tissues in the abscncc of pathophysiological disordeis. Keeping this in view, the blood levels of Creatine : ATP Phosphotransfcrase (SCPK), Aspartate and Alanine Aminotransferascs werc measured in man at sea level and during stay of two years at an altitude of 4,000 metres. Taking SCPK activity as an indicator of the neummuscular membrane intcgrity, its leakage in circulation was measured in rats exposcd to a simulated altitude of 6,000 metres with and without feeding a Composite Indian Herbal Preparation (CHP). This pmpa&n was earlier found to enhance thennoregulatory endurance in rats under multiple stress of tcstraint, cold and hypoxia.
ported to a high altitude arca and rc-examined at intervals of 2, 8, 40, 60 and 96 weekstof stay at Mgh altitudes. After the last examination at high altitude, they were bmught back to Delhi and reexamined during the first and fourth weeks of their arrival. For simulated altitude experiments. Wistar rats of 150-200 g body wt were exposed 6 hr daily for seven days to an altitude of 6,000 metres (32OC, 345 mm am. pressure) in a decompression chamber. CHP was administered orally at a dosage of 150 mg1100g body wt once daily 30 min prior to exposure. On the 7th day aRer 6 hr of. exposure, the rats were sacrificed by decapitation and their blood collected for SCPK and diphosphoglycerate estimation. The SCPK'activity was determined in the scrum by the colorimetric method of Hughes2. Aminotransferases were estimated by the method of Reitman and Frankel3 at 31C and subsequently convened to international units. 2. 3 diphosphoglycerate (2,3 DPG) was estimated in whole blood by the enzymatic method utilising Sigma kits. Results The SCPK activity in man at sea 1 level (Dclhi), high altitude and on return from altitude has been presented in Table 1 as the percentage frequency distribution and the mean levels of activities with standard enor of the mean. In the beginning all subjects had SCPK activity upto 40 m IU with a mean value of 15.3f0.90. Within 8 weeks of their arrival at high altitude the activity increased to a mean value of
62
Materials and Method

A group of 12 normal, healthy men. residents of plains of coastal south India, who had never been exposed to high altitude anas WCFC sclecled for exposum lo high terrestrial altitudes of 4,000 mctrcs in the Ladakh %@on. Their agcs and body weights varied bctwccn 18-30 ycars and 47.2 ; 62.1 kg rcspcctively. Thcir diet was composed of 4830 caljday. They were first examined at the base lab (Delhi 200 m) for SCPK, A ~ p h r t ~ tand Alaninc Amie notransfemsc activities and thcn trans-
TARLE 1
APT :Creatine phosphotransferarc mivity of serrun in men d w h g 96 wee& qfstay a an t aIIifudeof 4000 metres and at sea h i (200 metres)
Range of activity
Pcrccnt distribution Sea
m IU
- levcl
100 0 0 0 0 0 8 0 71.5 28.5 0
0
altitude (weeks)
Ser level mum 1 (

80 0 70.0 30.0 0
0 %
Initial
1-40 41 80 81 120
40 0 0
10.0 30.0
40.0
60
0 66.6 33.4
I21 160 161 - 200 201 - 217
0 90.9 9.1 0' 0 0
0
0
0
20.0
1 80.0 20.0 0 0 0 0
4 87.4 12.6 0 0 0 0
Statistically significant as compared wid1 sca lcvcl (inidal) values (P<O.O5)
Serum aspartate a d alanine arninotranrferases in man during prolonged stay a high altifurl t and at sea level (values expressed in I are Mean S&) U
Sea - level (Initial)
Su level renun (weeks)
'Significantly different f o initial sea level values at P ~ 0 . 0 5 rm
63
TARLE 3
Serum CPK levels in whire rats exposed to a simulared alrirudr o dOOO m and given CUP f
Control
CHP
Altitude
Altitude + CHP
m 1Uldl : mean f SE
+
+0
Saum CPK
3.6 43
33.65
6.9 84
4.1 42
Significantly different From Control at P~0.001

0 Significantly different from altitude exposed at P< 0 0 1 .0 Significantly different from CHP . supplemented at P<0.05
TARLE 4
Changes in oxygen
- delivery .cyslcm of
while rats exposed ro a simula~edahilude of 6000 m (345 mm 11s) and given CIIP
Conbol
CH P
Altitude
Altitude
+ CHP
*
2 3 DPG . umlml 19 f 0.052 . 17 f 0 0 .3 . 4 24 f 00 .2 .5
+. 28 f 0 0 .7 . 3
Significantly diffcrcnt from Contml at P<O.O5 Significantly different from Contml + CHP - supplemented at P<0.001 Significantly different from altitude exposed at P<0.001
64
67.3k6.21, most of the valucs bcing in the range of 41 to 80 m IU. During the 40th week. 90% of the values shifted towards higher levels with a mean value more than eleven fold higher as compared with the initial sca - Icvel valucs. During .the 60th week the mean SCPK values decreased to a levcl quivalcnt to that obscrvcd during the 8th wcck. Subscqucntly thc valucs of SCPK morc or Icss rcmaincd at this Icvci. On return to sea - lcvcl, thc SCPK dccreased funhcr. Howcvcr, thcsc wcrc still significantly highcr as compared to thc initial valucs.
neous estimation of 2, 3 DPG in whole blood (Table 4) indicated a significantly large increase in CHP-administered and altitudeexposed rats as compared with altitude separately, although the administration of the drug alone for seven days resulted in slightly decreased values for haemoglobin and PVC. Discussion The increase in blood CPK activity buring physical exercise4' aid cold exposud has been ascribed to relative tissue hypaxia as a result of increasep oxygen demand. Hcncc in exercise-adapted individuals7 and in marathon ~nners'the increase in Mood CPK was not observed to that extent as was seen among sedentary men. Similariy, the serum CPK levels did not rise in acclimatized mountaineers9. In muscular and ncural disorders serum CPK levels increase as a result of damage to the cellular membrancsI0. As a corollary t such observao eu tions the increase in s r m CPK under conditions such as environmental stress, has been ascribed to alteration in cellular permeability which is an energy-requiring pmCcss. Under high altitude hypoxia, the encrgy-requiring processes are known to bc deranged and improve with acclimatization. at tissue and cellular levelsI1. The major acclimatizational change in relation to high terrestrial altitude relates to oxygen capture. transport and delivery systems. O r observations on increase in blood u CPK levels and more or less maintained levcls of aminotransferases, suggest that undcr conditions of high terrestrial altitude hypoxia, the membrane permeability of the skeletal and neural systems undergoes al-
Thc V ~ ~ U Cof Serum aminotransfcrasc's S arc prcscnted in Table 2. Thc lowlandcrs had aspartatc and alanine aminotransfcrasc activities of 8.70f0.94 and 5.84f0.53 IU, rcspcctivcly. At thc cnd of 2 wccks' stay at an altitudc of 4,000 mctrcs thc activity of aspanatc aminotri~nsfcrasc was incmascd to a valuc of 18.23f1.71. During suhscquent obscrvalions. thc mean activity of this cnzymc dccrcascd to thc initial sca levcl value and remained morc or less unaffcctcd at altitudc and on rctum to the plains. Alaninc aminotnnsfcnsc, on thc othcr hand, did not show any consistent pattcm of changc at altitudc. Thc activity of this cnzymc dccrcxcd during thc 40th wcck and incrcascd during thc 96th wcck significantly.
In rats the administration of CHP did not affect thc SCPK levcls (Tnblc -3). However, as cxpcctcd, its activity was almost 2 fold higher on cxposure to simulated nltitudc. On exposure to simulatcd altitudc CHP-administercd rats did nt;i show such a large increase in SCPK activity. Simulta-
65
terations in comparison with the hepatic and renal systems. With improvement in tissue oxygenation accompanicd with ac~limatization~~, tissue membrane pcrthe meability also gets rcstomd but it takes nearly 10-12 months of stay at high temstrial altitude. The expcrimcnts on exposure of rats to simulated altitude confirm this. 'The CHP administration was earlier round to increase the therrnoregulatory cndurancc of rats in a cold hypoxic cnvironmnt. It has been found lo partially prcvcnt CPK leakage into circulation with improvement in oxygen delivery system. 1.e. oxyhacmoglobin dissociation with incrcasc in 2,3 DPG levels of red blood cclls. Thesc rcsults suggest that CHP might bc uscrul in acclimatization to high altitude hypxia.
REFERENCES'
1. Pardce; A.R.. Membrane transport proteins. Science (1968) : 162. 532. 2. ~ t k h c s B. I>.. A mctlitd lor the cstinitttion of . serum crcatinc kinrsc nnd nldolrsc activity in norma1 and patholngicnl sera. Clin. Chem. (1962) : 7. 597.
3. Reitmm, S. ant1 Frnnkel, S.. Am. I . Clin.
Parhol. (1957) : 28. 56.
4. Laeg:erin8. D. 1. and Critz J.B., Effect of hyp x i a and muscular activity on plum. enzyme levels in dogs. Am. I. Physiol. (1971) : 220. 100.
5. N u t d . F. Q. and Jones, B., Creatine kinme and glutamic oxdoacetic tramaminam .ctiviry in rmun; kinetics of change with exmire and effect of physical conditioning. J. Lob. C h Med. (1968) : 71. 847.
6. Petajan 3. H., Vogwill. M. T. ad M m y . M. R.. Plasma neatine phosphokinase c h r n g u induced by frcezing injury and adaptation lo cold J. Appl.
Physiol. (1969) : 27. 528.
7. Nuurl,. F. Q., Tissue and serum acatine vtivity in hypohFoid ,au. Endoc,iml . ( l w 8 ) : 42, 4g5.
.,
8. ~ d s c L. I.. Bousser. J. E. and Cooper. K. H.. . S c ~ m enzymes after n~arathonm i n g * 3. APP~. Physiol.. (1970) : 29, 355.
9. Albrccht. E. and Albrecht H.. Metabolism and hnematology at high altitude an& the effect of drugs on acclimatiznion. Fed. Proc. (1969) : 28. 1118.
10. Rodansky. M. and Bodansky, 0.. In: Biochemistry of Diseases (1957) :The MacMillrn CO, New York, p 693.
I I . Srivastava. K. K. and Om Rdcash. Animal metabolism and nutritional rquirements under physiological stress - Effect of high altitude. Def Science 1. (1966) : 16, 125.
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66
Fmt International Seminar on Force Multipiicr Technologies for Naval and Land Warfare Vigyan Bhavm, New D&i, India, Ostober 13-15, 1999
ENDURANCE ENHANCEMENT I ADVERSE N ENVIRONMENT

KK Srivastava, Ratan Kumar and SK Grover
Abstract Success in battlefield depends on superior tactics, high-tech odvMced equipments and high performing troops who can under any condition, optimaIly h e thc equipmenr to achieve the objectives set for them. Thus, the methodr and sechnology for increasing humnn endurance assumes great significance both in active a d passive combat situations. The most widely utilised method of increasing physical endurance effort, mlerance and nsistance to a wide variety of stressors is exposure to gradually hcreding Ioad of such a stressor: However; all stressors elicit certain reactions in the living system which are non-specific and l e d to the development or loss of general resistance, &pendent upon whether the living system is adapting or failing to adapt. This lerrdr io develov'ment of Cross adaptation. The Indian traditional medicines, specially, Ayurveda. has been using food suppfements, dietary elements, herbs and minerals (Rasuyanas and Vojikaran)for increasing phvsical endurance and mental pelformance. nese subsmces have been described in modem medicine as Adaptogens,'A Composite Indian Herbal Pnparation-I (CIHP-I)was tested for its adaptogenic activity using a passive Cold-Hypoxia-Restraint(C-H-R)animal model and found to have a strong curnularive endurance promoting activity. CIHP-I intake also alleviated the combat stress induced deteriorations in physical and mental performance of Bonier Security Fotre personnel engaged in anti-insurgency opemtiom. Another Composite Indian Herbal Prcpararion-II (CIHP-11)a&o tested and found to possess anti-stress and endurance promoting activiry. The drug intake consewid glucose utilisarion, potentiated oxygen delivery system and impnrved cell membrane permeability. It incrtased glucose turnover and adipose fat mobilisation and its myocardid oxhkion. In -a double blind placebo controlled trial, CIHP-II intake for 3 months in anny personnel, at 4800-6000 m helped in accelerating the acclimatization process and ~csroring n o d jirnctions in the high altitudes. Several dietaryfactors like amino &id,choline, camitbe ad anti-oxidants have also been tested as potential mental Md physical performance enhancers. We may see in the near ficture the emergence of food supplements whkh endow man enonnous physical strength and mental balancefor rational decision-making M C oing and adverse Br conditions.
--
Defence Institute of Physioiogy and Allied Sciences. Delhi, India
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The optimum performance of a task in any work setting requires the confluence of physical and mental processes. The reduced endurance of man both physical and mental during a long and strenuous task results primarily due to decreased availability of energy to the system. However, a large number of factors defining conditions of environment such as heat, cold, altitude and combat also result in d t c d performance as they incmse the demand on M y resources including energy. Such processes and interacting factors ate potential targets for performance enhancement. The experimental studies have been focused on measurement of physical performance at level ranging from the isolated muscle cell to the whole organism, though the techniques for accurate quantitative measurements of physical and mental "performance" are still not available. The physical and cognitive performance measurements need to be well integrated. We are still unable to measure fatigue which has both cognitive and physio-biochemical dimensions. Then are rive distinct areas in which soldier's performance is to be evaluated and enhanced to the optimum limits under all conditions; operational and otherwise. These five capabilities are: (1) mobility, (2) lethality, (3) survivability, (4) sustainment and ( 5 ) command and control. The mobility would mean soldiers capacity to move at a faster pace aided by mechanical transport system, his body flexibility to change his posture and his mental llexibility to adapt to changing situations including the psycho-social mileau. The lethality would mean using soldier's arms and ammunitions to pick out his targets out of background 'noise* with accuracy and'cettainty, the target could be enemy or a signal. The survivability is related to endurance of the vital life processess in extreme climatic and trying circumstances and sustainment generally means continuation of a repeatitive, monotonous work for longer periods without deterioration in totai output. The command and control attributes are related to leadership and decision making in adverse. conflicting and difficult circumstances with insufficient or without information. The performance of a person, is to be evaluated in both stressed as well as non-stressed conditions. Stress could be .a simple one such as low environmental temperature or a complex one such as in Combat and Psycho-Social stress. Success in battlefield depends on superior tactics, high-tech advanced equipments and high performing troops who can under any condition, optimally use the equipment 10 achieve the objectives set for them. Thus, the methods and technology for increasing human endurance assumes great significance both in active and passive combat situations. The available techniques [ I ] for increasing endurance performance are:
PHYSlCAL TRAINING FOR ENDURANCE WORK

rhe most widely utilised method of increasing physical endurance effort, tolerance and resistance to a wide variety of stressors is exposure to gradually increasing load of such a stressor. The organism over a prolonged period varying from few hours to several months depending upon the nature of stressors, acquires a better capacity to overcome the insults and develops tolerance or resistance to face an increasing load of strenuous work.
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CROSS AIIAPTATION
The elements which produce disturbance in the internal or external environment of a living system produce two kinds of reactions because of their alien nature. The first reaction is a specific response to combat the effect of that stressor, such as heat production during cold and increased heat dissipation through sweating in man during heat exposure. However. all stressors dicit certain reactions in the living system which are non-specific and lead to development or loss of general resistance, dependant upon whether the living system is adapting or failing to adapt. This leads to development of cross adaptation.
YOGIC AND MEDITATION PRACTICES

Yoga comprises a rich treasure of physical and mentai techniques which can be effectively used to creitte physicai and mental well being. It is an ancient Indian science and way of life. It has been claimed that yogic practices can lead to remarkable resistance and tolerance to cold and hypoxic conditions 12-41. However. most of the times such remarkable achievements have been demonstrated by a [ew individuals who have attained a particular status in the art of yogic development. Yogic practices are claimed to increase the pulmonary vital capacity, strengthen the heart muscle and improve mental tranquillity. Three months yogic training resulted in decreased lipid profile, cardiovascular risk factor and blood pressure in human subjects especially in those with elevated leveis of these panmeters [ 5 ] . Pranayamas have been shown to modify oxygen Gnsumption and heart rate [6,7] and increased hand grip strength [8]. In another study, yogic pnctices in decreasing the exercise induced increased in heart rate and pulmonary ventilation was found to be associated with better maintained blood glucose level (91. Yoga training also improved visual perception in human subjects as observed by ability to detect intermittent light of fixed luminance at varying frequencies [lo].
CHEMICAL INTERVENTION BY ADAPTOGENS

chemical interventions for increasing endurance performance are largely concerned with increasing energy supply and influencing biosynthesis of proteins and nucleic acids. Genenlly. natural products of herbal nature called 'Adaptogens' have been found to possess such activity without leading to addiction. Such substances have wide range of therapeutic activity having minimal alterations of body functions, manifest activity only under conditions of challenge to the system and their actions are non-specific. There are several substances known to have 'adaptogenic' properties, used in countries other than India vir. Panax ginseng, Eleu~herococcvs re$i&ss etc. [l I]. The endurance f ~ running and doing hard work and working in adverse environmental conditions appear r to be significantly increased in experimental animals and men taking Panux ginseng (Pg). It has been reported to be used for increasing physical work eficiency and capacity of mountaineers, miners, submariners, soldiers and factory workers [12]. In a study conducted on Indian sportsmen taking a mixture of Pg with vitamins and minerals, anaerobic threshold was found to be shifted towards higher side (75% V02 rnax as compared with 47.5% in
69
controls) [13]. Using the same preparation. Kevital (Trade-name), it was again confirmed in animals that a dose of 11mg/kg body weight helped in increasing resistance to Cold (5C)-Hypoxia(428 mmHg) and Restraint (C-H-R) induced hypothermia (Trec 23C) and faster recovery (Trec 37'C) from hypothennia 1141. High terrestrial altitudes pose a serious multiple environmental situation which challenges army personnel's adaptability and capacity to endure physically as well as mentally. The efficacy of Pg intake at a dose of 500mglday for 3 and 6 months was tested on army personnel who stayed and worked at 4800-6000m. Panax ginseng was found to restrict high altitude induced deteriorations in the.subjects, better maintained cell membrane permeability and increased oxygen delivery to tissues by enhancing 2'3-Diphosphoglyceric acid levels. It also helped the subjects in their faster recovery and better physical performance on de-induction to plains from high altitudes [15]. The mechanism of endurance promoting effect of ginseng was partly explained by the investigation of Avakian et. al. 11 6). In their study methanolic extract of Pg at a dose of 2 mgllOO g body weight prevented exercise induced lactate accumulation in the blood of rats, an indirect evidence for increased oxidation of non-esterified fatty acids, thus sparing carbohydrate reserves. Adaptogenic effect of Eleurherococcus senricosus in increasing endurance has also been studied extensively. In a single blind cross over study [17], methanolic extract of E. senticosus was found to increase work capacity of human subjects, approximately by 23% and it was attributed to the increased maximum oxygen uptake. It is recommended to be taken in competitive sports for a minimum of ten days and maximum of one month before the event. Extract of E. senricosus improved the mental and physical power of Soviet athletes, cosmonauts and workers [I 81. The lndian traditional medicines. specially, Ayurveda has been using food supplements. dietary elements, herbs and minerals for increasing physical endurance and mental performance. These substances, Rasayanas and Vajikaran have been described to possess properties of Adaptogens [19]. number of Indian herbs such as Withanin somrtifero, Asparagus racemosus and Ocimum sanctum have .been reported to possess anti-stress and endurance promoting activity [20-221. A Composite Indian Herbal Preparation-I (CIHP-I) was tested for its adaptogenic activity using a passive Cold-Hypoxia-Restraint (C-H-R) animal model [23] and found to have a strong cumulative endurance promoting activity. CIHP-I intake also alleviated the combat stress induced deterioration's in physical and mental performance of Border Security Force personnel engaged in anti-insurgency operations
1241.
Another Composite lndian Herbal Preparation-11 (CIHP-11) was also tested and found to possess anti-stress and endurance promoting activity [25-261. ~ h mechanism of action of d CIHP-I1 was also investigated and found that drug intake conserved glucose utilisation, potentiated oxygen delivery system and improved cell membrane permeability [27]. Further, it was observed that CIHP-I1 intake helped in generating energy by increased glucose turnover and increased adipose fat mobilisation and its myocardial oxidation. It had a carbohydrate sparing effect during stressful situations[28]. In a double blind placebo controlled trial, CIHP-11 intake for 3 months in army personnel, who stayed and worked at 4800-6000 m
70
helped in acceIerating the accIimatisation process and restoring the normal functions in high altitudes. When subjects were de-inducted to plains, the drug helped in their faster recovery and increased physical performance. In view of the above findings the intake of CEP-II as a nutritional supplement was recommended to be introduced for army personnel serving at extreme altitude [26]. Another Composite Indian Herbal Preparation III (CIHP--EII)intake, containing herbs reputed to possess beneficial effect on mental perfonnance, was found to increase conditioned avoidance learning of rats viz. avoidance of electrical shock [29].
SUPPLEMENTATION OF FOOD COMPONENTS OR 'NEUTRACEUTICALS'

Additional quantities of macro- and micro-nutrients are required to cater for the caloric needs of working man in alien hostile environments 130) and maintain his endurance capability. In other words the physical performance of man in strenuous condi!ions is dependent on the availability of appropriate balanced diets pl-321. The nutrition and performance research has been focused on following general areas:
Dietary macronutrients: Fat and carbohydrates-are important oxidative fuels to meet the energy requirements of man during Situations of increased energy demands. However. carbohydrate reserves are small and fat reserves relatively abundant. Therefore, fat plays an important role of energy production in stressful situations lasting for long durations. Stressors viz. hypoxia and cold (33, 341 produce neuro-humorai changes which result into increased adipose tissue lipolysis to provide more circulatory free fatty acids as energy fuel at the time of energy deficit. Caffeine: Caffeine has been shown to be effective at maintaining alertness and to function as a potent reinforcer [35]. It functions as a weak stimulant that, in iow doses tends to delay sleep and reduce the deterioration's in performance. At higher dose it reverses the sleep deprivati~ninduced deterioration in cogditive performance, mood and alertness. Caffeine is safe at levels required to achieve the desired effects and its effects are reversible overtime. Caffeine at a dose of 20-250 mg has been shown to elevate mood and these effects can last upto 3 hours [36]. Caffeine dose of 100 mg postpones the onset of sleep [37] and a dose of 300 mg significantly improves daytime alertness [38]. Caffeine can be an ideal stimulant for use during military operations when performance declines secondary to sleep deprivation and sleep fragmentation. Continued research on the mechanism for the evident effects of caffeine on cognitive performance, mood and alertness and how these may be enhanced in combination with other dietary measures is warranted. Neural monoamines (Tyrosine): When an organism is exposed to smnuons conditions, the
neuronal firing rate increases and synthesis of dopamine and norepineykiine also increases [39]. Acute stress (immobilisation)increased both rate of synthesis and turnover of serotonin (S-HT) in brain [40]. The precursor for serotonin is tryptophan while for dopamine and norepinephrine is tyrosine. Stress elevates the brain level of tryptophan, an effect that has not been observed for tyrosine [41]. Under stressful conditions concentration of tyrosine
71
is limited by its supply which can be enhanced by a large dietary supplement to improve the performance. Tyrosine m a y have wide application as a performance enhancing f w d supplement for military personnel, serving at extreme high altitudes, t o ameliorate deteriorations caused b y strenuous conditions and t o enhance performance. However. longterm studies are needed t o confirm these findings, dose dependent functions for its beneficial effects, risks and benefits of acute versus chronic administration and safety o f such large doses o f tyrosine. In addition an appropr'w form for providing tyrosine supplementation is to be looked into. Cltoline: Choline deficiency i n diet decreases the conduction and velocity o f nerve transmission and produced fatigue. The usual intake o f free choline or choline containing esters through diet in humans is 700-1000 mglday. A choline intake o f 500 mglday resulted i n choline deficiency and reduced muscle performance. Supplementation o f dietary cholilie (2.8 g) during a 20 mile (32 km) run was found to prevent the drop i n plasma choli~ie concentration usually seen and improved run time [42]. Choline si~pplementation was also found to enhance memory and reaction time in animills and enhanced memory lime ill humans [43. 44). C(~rttiritre: The effect of carnitine (2.0 g) supplementation has been studied ill human subjects. performing maximal exercise tests on bicycle ergometer. Maximal exercise induced increases i n plasma lactate and pyruvate levels were lower after carniline odminislri~tio~i 1451. Carriitine supplementation prior to exercise increased work output it1 some. but 1101 i n all studies [46, 471. At~ri-oxidnrtts: There is evidence to suggest that the increase in energy metabo\ism b y aerobic, performance enhances intracellular concentration o f oxygen free radicals. Free radicals Stimulate rate of autocatalytic lipid peroxidation including damage in the muscular stmcture [48]. Generation o f free radicals occur i n various stressful conditions viz. intermittent exposure to hypoxia [49], cold (501 and immobilisation (511. Free radicals induced damage i n muscular structures resulted i n muscle fatigue with lowered performance o f an individual [51j. Various anti-oxidant vitamins and minerals which ure dietary components viz. Vitamins A, E, C and selenium are important antioxidants. During the strenuous task. requirements o f antioxidant vitamins increased [53-54). Vitamin C suppl'ementation was found to exert protective effect against eccentric exercise induced muscle damage [55]. In an another study on humans [56] six weeks intake o f vitamin mixture (592 m g alpha-tocopherol: 1000 m g ascorbic acid and 30 m g o f (-carotene) with daily 30 min. exercise at 60% VO? max. served to lower markers of lipid peroxidation but did not prevent exercise induced increase i n oxidative stress. Substantial evidence indicates that intakes greater than the recommended dietdry allowances (RDA) o f certain vitamins and minerals reduce the risk of certain diseases but, the margin of safety between the usual dietary intakes and the intake that would produce adverse effects varies greatly among the different nutrients [57] which should be worked out.
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CONCLUSION
Enhancing mental and physical performance under various environments is of vital importance for the development of human civilisation. Muscle power, mental alertness and neuromuscular coordination with capacity to think in a ntional manner under all conditions are of major consequence in a combat situation. The effective technique of gradual increase in exposure to stresscr and keeping mental alertness for a rational decision making by yoga and meditation have been used since the dawn of civilisation to enhance endunnce. However. the natural products including various food components, named now neutnceuticals. have also been known to influence mental and physical performance, behaviour and attitudes of man. Several of such preparations derived from traditional systems of medicine. Indian and Chinese. have been experimentally proven to be endurance enhancers in hostile and adverse climates. Several dierary factors like amino acids, choline, camitine and antioxidants have also been tested as potential mental and physical performance enhancers. We may see in the near future the emergence of food supplements which endow man enormous physical strength and mental balance for rational decision-making under trying and adverse conditions.
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22. 23. 133-139. Bhargava KP and Singh N. "Anti Stress activity o f Ocimum sanctum linn". Ind.3. Med. Res. 198 1. 73. 433-451. 23. Ramachandran U. Divekar fiM. Grover SK and Srivastava KK "New experimental model for the evaluation of adaplogenic produc~s"J. Ethnopharmacol. 1990. 29. 275-281. . 24. Srivastava KK and Co-workers, "Studies oii combat stress: Physidogical. Biochemical and psychological correlates" Report No. 11/96. DIPAS, Delhi. 1996. 25. Sinph N.. Nalh R, hlisra N. a d Kohli RP. "An erpairnenral cvaluatian of anti-stress effect of Gcrilortc (An Ayurvedic dmg)",Quart. I. CrCdc. Drug. Res. 1978. 16. 125-136. 26. Srivastava KK and Co-workers. tManagement of environmental stress with Composite lndian Herbal Preparationi 1995. Defence Institute of Physiology and Allied Sciences. Delhi. 27. Grover SK. Divekar I i M . Raran Kumar, Pahwa ML. Bhardwaj SK, Gupta AK and Srivastasa KK. "Experimental evaluation of a Composite lndian Herbal Preparation II (CIHP-Ill as an adaptopen and its mechanism of aclion" In!. J. Pharmacology. 1995. 33. 148-k54. 28. Kumar R, and Co-workers. "Mechanism of increased toferance to stress after Composite Indian . Herbal Preparation (ClHP) administration" Report no. 14/96. DIPAS. f996. 23. Bhardwaj SK and Srivastava KK. "Effect of Composke lndian llerbal Preparation ClHP I\\ on avoidance learning during endurance performance of rats" Ind. 1. Expt. Biol. 1995. 33. 9 0 - 5 R 4 . 30. Askew EW. "Environmenfal and physical slress and nutrient requirement" Am. I. Clin. Nutr. 1995. 61tSupptl, 631s-6375. 31. Srivastava KK. "Convenience foods : Nutritional requirements and environmental stress" Probe. 1991. 31. 141-150. 32. Miller SA. "Perspective on the inter-relations between nutrition and the environment" Am. J. Clin. N F 1995. 6i(Suppl.). 678s-68 IS. U. I 33. Chattopadhyay DP, "Adipose tissue metabolism during hypobaria" Del. Sci. J. 1974, 24. 155-162. 34. Blilkrishna and Bhatia B, "Biophysical and physiological basis of human cold acclimarization" Dcf. Sci. 1. 1968. 18. 29-98. 35. Griffiths RR and Woodson PP. "Reinforcing effects of calfeine in humans" 1. Pharmacol. Exp. Ther. 1988. 246. 21-29. 36. Liberman HR. Wurtlnan RJ. Emde GG and Coviella ILG. "The effects of caffeine and aspirin on mood pcrfonnaoce" 1. Clin. Phatmac~l. 1987, 7, 3L5-320. 37. Dew PB, "Calleinc" Ann. Rev. Nurr. 1982, 2, 323-341. 38. Lumley M,Roehrs T. Asker D. Zorick F and Roth T. "Ethanol and caffeine effects on da!. tlmc sleepiness/alenness" Sleep 1987, 10, 306-3 12.
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39.
40.
41.
4 . 43.
3j.
45.
46.
47.
Stanford C. Fillnez 34,and Ryan E. 'The effect of repeated mild s m s on cerebro-conical adrenoreceptors and nor-adrenaline synthesis in the rat" Neurosci. Lett. 1984. 45. 163-167. Bliss EL. Xilion J and Zwan Ziger 1. "Metabolism of norepinephrine. serotonin and dopamine in rat brain with stress". J. Pharmacol. Exp. Ther. 1968; 1634. 122-134. Cunon G. Joseph MH and Knott PI. "Effect of immobilisation and food deprivation on rat brain tryptophan metabolism". J. Neurochem. 1972. 19. 1967-1974. Sandage BW. Sabounjian RN. White R and Wunman RI "Choljnc cirratc may enhance atheletic performance" Physiologist. 1992. 35. 236a. Bmus RT. Dean RL. Goas JA and Lippa AS. "Age related changes in passive avoidance retention: modulat~onwith dietary choline" Science. 1980, 209. 301-303. Meck WH. Smrth RA and Williams CL. "Organisational changes in choiinergic activity and enhanced visuospatial memory as a funct~on choline 3dministered prenatally or postnatally or both" Behav. of Neurosc~.1989. 103, 1234-1241. Silprandi N. Dilisha F, Pieralisi G. Ripari P, Maccari F. Menabo R. Giam Bendino MA and Vecchiet L. "Metabolic changes induced by maximal exercise in human subjects following L-Carnitrne adrn~n~str~tron" Biochem. Biophys, Acta. 1990, 1034. 17-20. Oyono ES. Freund H. 01tC. Ganner M. Heitz A. Marbach J. Maccari F. Frey A. Bigot H. and Bach AC. "Prolonged submax~malexercise and L-Carnitine in humans". Eur. J. Appl. Physiol. 1988. 58. 53-61. Vccch~ctL. Dilisha F, Pieralisi G. Ripari P. Menabo R. Giamberardino MA and Silprandi N. "Influence of L - C ~ r n ~ u ~dm~nlstration maximal physical exercise". Eur. J. Appl. Physiol. 1990:62, 486ne on
490.
48
Bcnz~G. "Aerob~cperfc . lncc and oxygen free radicals". I. Spons. Med. Physical Fitness. 1993. 33. 205-222. R a d d Z. Lee K. Chai W. Sunoo S. Kizaki T. Ohishi S. Suzuki K. Tanaguchi N. Ohno H and Asano K. "Oxtdstlve strcss induced by intcrrnrttcnt exposurc at a simulated altitude of 4000 m decrc:: cs m~~ochondnal superoxide disrnutase content of soleus muscles of tats". Eur. J. Appl. Physiol. 1994. 69. 392-395. Bhaum~c Srivastava K K and Sclvarnurthy W. 'Tnc role of free radicals in cold injuries" Int. J. G. Biomcteorol. 1995, 38. 171- 175. Hisao K. Ikuko N, Sadao S. Seiki H and Yoshihori I. "Mechanism of oxidative strcss in skclctzl muscle atrophied by imrnobilisation". Am. J. Physiol. 1993. 165. E 839-E 844. Barclay JK and Hansel M. "Free radicals may contribute to oxidative skeletal muscle fatigue". Can. J. Phys~ol. Pharmacol. 1991, 69. 279-284. Brandt RB. Doyle BA, Chan W, Poland JL and Seibel HR. 'The effect of running stress on plasma vltamln A lcvels In the rat". Food and Chemical Technology. 1997. 35, 459-463. (Quoted in Nutr. Abstr. and Rev. Series G 1997. 67. 7594) Z Tverdokhlib VP, Shmakova EN, Blazheevich NV, Meerson F and Spirichev BP. "Influence of emot~onalpain stress on content of vitamrns-antioxidant in the blood. serum of rats". Vopr. Pitan. 1987. O(6). 52-54. (~uotedin Biolog~calAbstr. 1988. 86 (3). 31924. Jakeman P and Maxwell S. "Effect of antioxidant vitamin supplementation on muscle function after eccentnc exercrses", Eur. J. Physiol. 1993, 67. 426-430. Mitchell M K. Lori AN and John OH, "Effect of anti-oxidant vitamin mixture on lipid peroxidation at rest and post exercises", I. Appl. Phys~ol.1993. 74. 965-969. John NH. "Vitamins and minerals: Efficacy and safey", Am. J. Clin. Nutr. 1997. 66. 427-130.
SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUM
75
A Clinical study on the role of Arnaiaki Rasayana in the

management of Sukradus'ii with special reference to Astfienozoospermia
* Soni Haresh N.
** Prof. Gurdip Singh

asthenozoospermia. Keeping this in view Amalaki was selected in the form of Amalaki Rasayana. Because Amalaki is tridosaghna, Rasayana, Vrsya, Raktapittahara and Yonidosahara. Drugs which are Raktapittaghna and Yonidosahara are also benefical in Sukradusti (Ca.Ci. 301 147). Along with this Amalaki Rasayana is advised in treatment of Kaphaja Sukradusti (Ca.Ci. 301150).Amalaki Rasayana was prepared in University phan-nacy by triturating Amalaki Curna seven times with Amalaki decocticjn. Because this process provides potent vrsya effect to Arnalaki Rasayana (SU. Ci. 26/24).
Infertility is the clinical condition which obstructs t h l progeney, It is observed in past 50'-years that sperm quality is getting of poor vatu and sperm density is also declining (osser, 89). Poor semer, quality specially low sperm rnotility is also getting higher condition. Therefore, asthenozoospermia was selected as a problem for the present study. In this condition sperm motility is below of its normal value i. e. <50/0. Therefore, the conceptual part of this study deals with the concept of Sulira, Sirkradusti, asthenozoospermia and critical eveluation of asthenozoospermia. During critical evaluation it was decided that according to Ayurveda asthenozoospermia is of tvcles :
In the present study 14 patients were registered for clinical evaluation, ( i ) asthenozoospermia related to From them one patient left out the Vatakaphaja Sukradusti. treatment, Selected patients were (ii) asthenozoospermia related to administered 3 gm. Amalaki Rasayan Upasarga. 3 times a day with Madhu, Ghrta and Treatment of the disease should I<sira for 30 days. Patients were be in accordance to involvement of followed up for further 15 days with Dosas. In asthenozoospermia all the suitable placebo. Results obtained on three Dosas are having their own role. the basis of observation of 14 patients Therefore, the drug which is and effect of therapy on 13 patients Tridosaghna, Rasayana and Vrsya gave the conclusion as presented should be employed in treatment of below :
* M. D. (Ayu.) Scholar. ** Dean & Head, Deptt. of Kayachikitsa, I F G. T. & R. A., Guj.Ayu. Uni. Jamnagar
76
[ AYU 1 Total 14 patients were studied in this thesis, out of which 35.71 % were from age group of 21-25 years, 92.86% were Hindus, 57.14% were educated upto the level of secondary education, 35.71% were labourers, 71.43% were from lower middle class, 85.71 % were from urban area. 2 14.29% had mumps and 7.14% had testicular swelling during their childhood, 7.14% patients gave the family history of diabetes mellitus. 3 Maximum patients (64.29%) had Mandagni, Madhyama Kostha (57.14%),Vatakaphaja Prakrti (57.14), Rajasika Prakrti (42.85%), Madhyam Satrnya (42.85%), Tvaka and Mamsa Sara (28.57%), Madhyama Sattva (50%), Avara Samhanana (42.86%) and Avara Dehabala (42.88%). 4 Evaluation'of Nidanas showed the presence of Viruddhasana (50%), Tobacco addiction (50%), alcohol addiction (42.85%), hot water bathing (71.43%), prolonged use of tight .undergarment (64.28%), disturbed sleep (50%), exposure to antibiotics (42.86%) and analgesics .(35.71%) Akalayonigamana (50%), Rajasvalagamana (14.29%), Maithune Nigraha (14.29%), Atimaithuna (7.14%), Sastravibhrama (7.14%), Ativyayama (21.43%), Vyadhikarsana (21.43%), Narinamarasajnta (14.29%), Agantu Hetus (14.29%), Ativyavaya (7.14%), Cinta (7.14%), and Bhaya (7.14%) in 14 patients of asthenozoospermia.
5 Some of the clinical findings were tender epididymis (2'1.43%), enlarged prostate (14.29%). 6 N o incidence o f Varicocele, agglutination and Headless sperm was found. 7 Laksanas elicited were Vandhyatva (78.57%) Daurb 7lya (28.57%), Garbhapata (28.57%), Kindu after Maithuna (28.57%), Premature ejaculation (50%), loss of penile rigidity (35.71%), Lack of erection (21.43%) and lack of sextual enjoyment (21.43%). 8 Effect of Amalaki Rasayana : 13 patients of as~knozoospermia were treated by Arnalaki Rasayana for 30 days in the dose of 3 gms. 3 times per a day with Ghrta, Madhu and Milk, Amalaki Rasayana provided significant effect on RLP motility and in decreasing immotility. Other semen parameters were got improved except head abnormality but these effects on semen parameters were statistically insignificant. Sexual health parameters wer6 also increased and improved, amogst them pe,nis rigidity, ejaculation and orgasm were statistically significantly improved. Total effect of therapy on asthenozoospermia showed that 38.4 0% patients of asthenozoospermia got improved. 30.77% were markedly improved and 30.77% patients remained unchanged.
77
Mil Mrd 1999 Nov:l64(11):814-9
Effects of a composite Indian llerbal preparation or1 combat efl eetiveness in low-intensityconflict operations.
Gupinnthan Phl. Grover
SK. Guptr AK,
E.rivrstrur KK
Defense l~utitrne Physiology and Allied S~:iences,Timarpur. Dclhi. India of [~cdliae record in process) The cl(ic;l~y of a compostte I d i n n herbal prcprration (CIHP) in sustaining tile mental perform:~nce ofsoldiets engaged in prolonged low-inten~ilyconflict operations has been evsluoted. For this purpose. a colionbf 56 soldiers acted as volunt:cn in combat situations. Aner recording their initial responses 10 psychologicnl tests such as Lhe d l tes~. rrsil-makingtest. the,serial addition tes~. short-term memory test. and the Institute for the the Personalityand Ability Testing Anxiety ScrL:. they were nndonily given either CIHP or placeto illa double-blind fashion for 8 days while they performed their urud combnr dulics. Tile l i m I 3 days of nssignmcnts included physically exhawtirq mnd life-threateningevents. On day 8. they were witltdrawn from combat duties and the yaycIt~)logicnl tests were readnvinis:cred immediately. Afier 7 .lays of mt. the tests werc repeated once again. Tl ~ results indicnte comparatively bctte:-perf ~rmonce c immedintely after the missic,n by the CltIP gloup. CIHP was effective at s'usraining \he menot abilities of soldiers in a low-in~onsity-cor~Rict ntviroclcncnt, PMID: 10578595. Ul: 30045557
78
Effects of a Composite Indian Herbal Preparation on Combat Effectiveness in Low-Intensity-ConflictOperations

Guarantor: Kaushal I(. Srivastnva. I'hl) Contributors: P.M. Gopinalhan. MA: Strrjntler K. Grover. I'hD: Ajay K. Glrpta. B 5 : Katlshal K. Srivastava. I'hD The efflcacy of a composite Indian herbal preparation [CIHP)in sustaining the mental performance of soldiets engaged in prolonged low-lntenslty-confllct operations has been evaluated. For this purpose, a cohort of 56 soldiers acted a s volunteers in combat situations. After recording their initial responses to psychological tests such a s the d2 test. the trail-maklng test. the serial addition test. the short-term memory test, and the IPAJAxiety Scale, they were randomly given either CMP or placebo in a double-blind fashion for 8 days while they performed their usual combat duties. The final 3 days of assignments included physically exhaustlng and life-threatening duties and events. On day 8, they were withdrawn from con~bat .the psychological tests were readministered immediately. Altrr 7 days of rest. the tests wrrc rcpralcd onrr again Thr results indicate cornparatively k t t e r pcrfurt~~ar~cc immediately after the mission by the ClHP group. ClHP was effective at sustaining the mental abilities of soldiers in a low-intensityconflict environment sure ol ron~hat~Nertivencssshould lwus both objrctive and su~)cctivc lncasurcs and must include intuitive assessment of the unit colnmanders at the highest level possible. Several lormulaLions of natural products derived from plants arc reported to ltave antl-stress and physical- and mental-endurancc-promotlrtg properties.!' Various composite Indian herbal prrparations have been reported to have such properties. Recently. Grover et al.I2 reported that a composite Indian herbal prcparatlon (CIIII'] had adaptwnir cllerts on exposurc to extrcn~c high aliitudc. nulTcring the stressor e k t olcombal. sperifirally tllc fn~strc~tit~g, prolot~gcd;~nti-t~~iIit;it~cy operation. by c ~ ~ l ~ a n c i t ~ g illc iccline ol physical wcll-bcing is thc stratrgy attctr~pted hcrc IIV i ~ d ~ ~ ~ i ~ ~ i s t v t ' i n g ('liil',
Materials and Methods

171c study was canied out on 56 hcalthv male volunteers draltcd lrorn the paramilitary force engaged In combat assign ments altej obtatning their Informed consent. I h e combat duties of these soldiers include ambushing the bulwark of the militants located In deep jungles and capturing the militants. Illis task is very dangerous and anxiety provoking. It involves stren~rous trckking through unlaniliar jungles Illled Wth rnllitants with thelr deadly rontrapUons of explosives laid on appro;~cllpaths and snipers in the soaring trees surrounding their hiding places. I'eriodically, heavily populated buildings are to be checkcd for ihc militantsoccupying them, and this exercise gocs on lor rnanv hours and oltcn results in heavy msunllirs. Thcsr arc rrr~ly icw ol thc rouline tasks of thc partirlpati~iy! u soldiers. who were continuously engaged in these mission actlvlties for at le'ast 10 months without any rest or respite tmmedlately preccding the study. They were free from any clinical disorders and were not on any medications. The age, weight, and height of these subjects ranged fro11123 to 40 years. 5 1 to 69 kg. and 154 to 174 rm. rcspecttvely. Before the initial observations, the subjects were wiltldrawn from their active combat duties and rested for 7 days. During this period, they were glven detailed accounts ol the various te$s and the exact procedures to be followed during the psvchologlral testing. After the initial ohsetvation of physical vartables. the subjects were randomly divtdcd into two age-matched groups of 28. One group was given CltlP and the other group was given placebo in a double-blind fashion. The composition of CiHP is given in Table I. The plant extracts used in ClllP have been widely used in AytIweda. the Indlatl traditional system ol medicine. Wihania sornniJem extract has been shown to possess anti-anxiety and anu-stress elTects and is highly regarded a s an adaptogen. Asprmgus racernosus is a strong adaptogen that is known to Increase physical endurance. Mucuna pnvienus seed contains L-dopa and tryptamine and acts as a relaxant and a neuronic tonic. Aqyreia speciosa is known to improve general debility and digestion. firererib 11tMllilav Medicine. Vol. 164. November 1999
Introduction
he stress experienced by combatant arises from two diexternal. rauscd by verse milieu: Tvibration: and first. the thc ainternal, rauscdnoise. heat. cold. second. by pllvsiologlral or latigue. lack of sleep. food. ap8 drink. a d psycl~ologlcalfear. anxiety. and apprehension of the consrqucrlcrs ol the enrountcr. I.c.. k i n g killcd, maimed, or rapt~lrcd. inability to ovcrAn come elfectively or cope with ernotionc~lstress ~villrcsult in disnrglni7.rd ;md irrational Ixliavior that will r c d ~ ~ the rlTecrc tivrncss nl the it~dlvidual rombatant. Tlic problctn ol maintainlng ~nissionprrhnllat~ccundcr slrrss Ilas hcen ctrnsistcntly idcntilicd a s a priority area for military studies.' Tlie topic of battlefield stress was the focus ol militruy research as early as 1917.2 The prohlem ol combat stress-induced degradation of rombat emciency is doruntented luridly in the desrription of the Normandy can~paign during World War I1 by Sicgal et al." They reported that 'the soldlcr was slow witted: slow to romprchcnd ordrrs. dircrtbris and tccl~niqucs.Memory dclccts beeanlc so cxtrcnlc that he could rtot be taurlted upon to relay a verbal order." Ille concern with countering strcss derrements In milllury performanre is shared by many rountrics. as it~dlcatcdby studies cnrricd out by A~tlcrican.'" IJritish.'Isracli." and Soviet" researchers. In summarizing this thrcat. a repon from U.S. Army School ol Advanred Military Studies concluded. 'Combat stress will be one of the most significant causes of loss of man-
power.-"'
In a conflict. the only sure measure of combat eKectivcncss is the performance of the unit in actual combat. A realistic mea-~ -
1998.Ihc m i d nlanuscrlpt was nccrplrd lor publlm!io~~ Marc111999. 111 llrpnlll A ('olwrl~l!l :< bv i\ssorl;lllollor Mllllilw Surfimllsnr 1's.. I?KM.
k l h l 1 I 054. Indla. 0
D~lcllsr lnslllutr of Physlolopy and Allled Srlenrrs. Lucknow Road. Tinlarpur.
Tills elanuscrlp(was r~rlvcd rwiw In Mav lor
79
Composfte Indian Herbal Reparation and Combat ElTecUveness

TA~UI
courwrnon OF couposnt INDIAN HERBALmuwARAnoN
I'orl ol
mmposlllon.
the pndl from the paper. Thls Is a Umed test of 60 seconds. Only comet connectforts made are taken note of, and the mean number o l uurect sequences fined per second C taken as \he sC0m.I' Arllltmrllr ICJWny&rial ArlrlMlnn TrsO Thls test determines the emclency of mental addltlon of randonlly calledout stngledlgit numbers. Slxty randomsingle-digit numbers are grouped Into 10 sets of six numbers each, and these numbers from each set arc read to the sublect at a llxed m t e d rate of one number every second. The subject is instructed to add the six consecuUw numbers read out and wtte down the sum agahst the numbers serlally on the sheets marked 'I to 10.'The pemntage o f m t answers Is reported as Ule arlthmeUc emclency score." Shai-Tenn M e m o n ~ Test Thls test Involves a 15-wordlist that is read to the subjects at a n l e of one word every 2 seronds from a 60-wordIlsl. Thls Ilst Is also kept upside down i n front of the silbjerts. and Immediately alter hearing all oflhe 15 stlrnuti words. the s~~bjertsitre asked to turn the list over and start marking as many of the called-out words as they can recall. The percenlage of c m c t recognltlons is the score.'5 Mop-PlottingTest n Thls Is a military task and has importance i a mllltary operational context. The tesl conslsts of a blank grid of 200 I-cm squares with hvo digits east and north. The task glven Is to mark the sector correspondingto a six-figure grM reference and label Ule sector with tile letters called out al the end ofgtid reference. A typical instruclion would be '46 37 81 PM.' Duringthe tesl. 10 surh grid references are called out at 10-semd Intervals,thus allocvlng the subjects 10 scronds to plol the referenceand lab1 I t wttll the lxilr of Icttcrs glvctr at the end of lhc six dlgils. The ]PAT Anxiety Scale is prlmarlly deslgned to measure freefloallng manifest anxlety level. whether I1 Is sltuaUonally determined or relati\*elyindependent of the immediate slt~ation.'~ Anxlety as measured by the ]PAT W e t y Scale Is hlghly and consistenlly associated with all forms of dlsoiier (neuroses. psychoses, character disorders. and physleal dlsablliUesI. I t is what comes clwe to belng the common element In all [oms of disorder. and lack of anxiety as reflected by a low score on the scale is reflective of sound mental health status. StaUsUcal Analysis Data arc presented as the nlean and SD. .Analyses ol the significance between dillerent groups arc based on two-way analysts of variance and Student's 1 tesl. p values 5 0.05 are consldercd slgnillcant.
D l m m r m ~ U M
An3mspfflmn.-
Rhlmmcs
Asphall exlrael
m m u M
-m
aAqueo~rs c t d all tngrrdlmts In the given pmpa~on dtkd b a urp vacuo and mlxcd.
berosa Is knownto Improve female reproductive functions and is an adaptogen. Dioscwea buIbrJemis known to Improve HbMo. volce. and conrplexlon In both males and females. Asphalt 1 a s conlplex mlxtrlre of mlnenls and organic che~nlwls and Is a well-knownAyl~rvedic multifunctional adaptogenmlxture. Piper lorqltm has bcen shown lo eohancc thc blologlcal emcacy of drugs In general and Is an adjuvant for many Ayurvedlc preparations. The placebo capsules contained lactose only. The ClHP and placebo capsules were Identical in appearance. and the dosage was one capsule twlce a day. After 7 days of rest In the laboratory premises, the Inlual readingswere taken. Thls lnltial phase Is phase 1of the study. lmmedhtely after completing the lnltlal readings, the subjects wcre sent back to their unit for operational assignments in groupsol I 0 each Iw8days.. U r last 3daysoltheir task Includeda very high degree of physlcal endurance and hlgh levels of mxlcty-pmoklngasslgnmelils (mlsslonl. On the morntng of the 9th day. the subjecls wcre wiUldrawn Iflots the mlsslon and hro~lght hark lo Ihc ncld 1;thoralory. All 1~01s rcpe;~tcd. wen. 'llits is lcnl~cvl pll;lw I toCtlic sttlcty. A lllirtl 1 ob&~ationwas made agatn alter 7 days or resl and rerupcraUon. which IS phase Illof the study.
PsychologicalTesta ConcenlmlbnAssessmen1 fd2 TesO Ihe test Is Intended to measureconcentratlon and conslsts or 15 Ilnes. each wlth 51 6s that have the lorn: d. .d. d. d'. 6. d. 6, or .&. The task glven to the subject Is to cross out the d's d', that have the form d'. d., and .' The Ume llmlt to complete the d. test Is 300 seconds. The d2 test conslsts of three subscales: speed. accuracy. and lack of concentratlon. Speed is measured by thc number of slgns sranned prr xcond, ocrrrrary Is measured hy t l x rluntber old's crossed mrrectly. and lack or conrentrallnn Is measured by mistakes, both omlsslons and commissions.
Speed and Allention ma-Making TesO This test involves two functions: motor speed and attention. The test sheet contans 52 scattered symbols, of whlch half are consecutive numbers and half are consecutive letters ol the d2 Test 'llie scan sped, whlch Is the number or characters scanncd e English alphabet. The subJst Is requiredlo t ~ s a trall Ihrnugh Ih~w synihols In r o m l scqucntli~l order but i~llcrnatlng hc- per sccond. for lhc plncrhogroup In phase Iwas 1.404, and alier tweert number and letter as fast as Ile or she can without lil'ttng the mission It was 2.292. Illis Increase was found lo be slatis-
MIUtafy Mcdleiru, Vd. 164, Novernlxr I!i!A
Composllb lndlan Herbal Fl'cparaUon and Combat EIkcUMnesr

TABLE II
EFFECT OF COMI'OSrreINDIAN HERWL IW'ARATION ON CONCWRUnON ASSESSMEW ($27 M
CBP
ValM
0.552 10.zsn
mean (n = 251 ullh S in parrnlhm. D
0.4s
10.1361
0 . ~ 2 '(0.2484
Glgnllleantiy dlRercnl lmm phase I value % g N b n U y dllkrcnt Imm phase I1 value.

TABU
A N A L ~ I S VARIANCE FO'ORHZr (SCAN SIQEED) OF m ICORRECT X A N I
J.
AND^
TEST
% m dva-mll a
d2 lea Iscan sped
4
5
sum or Sqllarcs 49 177

36 452 62472
Ms
FTables W and M. 7hc w m m d m belmnDhase I and ~ h a s Ill c lhshman~ crlgnlGtfha~.=~L-nt'mtedat lhe md of phase 1 wwnot s~stalned. nt thc end of phase Ill 1 and them was a slgnllkmt Ip < 0.02) dekrkwaUon compared wlth the phase I p c n h m e . In the drug group. the lmprowment In 1 prlwmance notcd at the end of phase II was highly s l g n l h t
(p<O0001).andthercLapseshoMlattheendofphapeIIIwas
24
shofi.~llx compiulaon bchvccn phase I and phase II did not show any statiatkally a&nUkant change ~ndther the dnrg gmup or the placebo group fRiblc8 Rr and V). H m , at the end d lcharacterlxcondll & t m n cdtlmn mcans 5 0 523 0 105 1341 phase Ill there was a hlghly signllicant deterloration In the wween mw IIWN 24 2 723 0 1 14 2 538 placebo group Ip < 0.0(n) as well as In the drug group Ip < Restdual 120 5363 0447 0 001) compared wlth thelr phase I mponse. Thls signillcant ~ o l a ~ 149 8610 detedoraUon was obscmd only at the end of phase Ill. and thc phase I' and phase 'I1 'Iso showed a 'lgtlnlly highly slplllcant (p < 0 0 0 1 ) rraMcs II and Ill) The 'Omparlson ame also obsewed in drug p u p . the a"Incant d d m t h In both IPOUPS at the end 11 1 spondlng readlngs bdng 1 708 and 2 536, thls change was also YP~Plo* statistically hlghly slgnlkant (p < 0 0001) At the end of phase Both the placebo gmup (p < 0.02) and the drug group (p < Ill. the placebo group (2 7041 as well as dmg group f3 072) Improvement In the mapplotting shaved a further lncmse In scan speed, whlch was hlghly 0 003) showed a ~lgnllkant signilkant (p < 0 00 1 for the placebo group and slgnlllcant Ip < tesl at the end of phase Ill compared wlth the phase I response 1 I 0 01) for the drug group Behveen-group cornpatsans dld not WaMes V and Vln. 7%lhen was no slgnillcant change at the end of phase II In dther the placebo group or the drug group The yield any significant change 1 The correct wan per second did not show any slgnlllcant Improvement shown at the end 01 phase I 1 was very hlghly 1 changc between phase I and phase II for either the placebo signillcant (p < 0.0001) r o m p a d wlth the phase I values group or the drug group However, the comparison between phase 11 and phase Ill for the placebo gmup shaved a highly IPAT,4~uidySulc slgnlllcant (p < 0 001) Increase In c o m t aean, from 0.54 to was lnol s thl p( change the of dey In 0 652. The drug gmup showed only a significant b < 0.01) &herthe dmggmupor the placcbogmup a Ill Increase. from 0 456 to 0 592 l r a k VI and VII) TRU-Wlng T a t In the placcbo group, there was no slgnlllcant dlffbeDiacwsion hnen the MI-making test score In ph& I and phase 1: how1 The present study assaua, menW performance during hvo ever. at the end d phase Ill thls group showal a hlghly slgnlllcant improvement (p < 0.0011 Vables W and Vl. The drug gmup important faeets of combat stress. Flrst. it measures the status e a showed hlghly slgndcant improvement (p< 0.0051 at the end of ofm@Uve ~unctlonal f f ~ e s durlng and Immedlatdy afphase 11. Thls lmprovnnent was sustained through phase Ill at t e r a h l g h - r l s k ~ ~ I n a p low-lntensltym n -tbn. nw Mit mP m , eW ota cmnplte a hlgher kvel ofslgnlllcann @ < 0.00021. lndlan hwbal pqarathm. Sedd MdltlonTest The d2 testis a test d focused attenion. wlth sped, a m The placebo gmup showed statlstlcally slgnlllcant @ < 0 . W ) rev,and lack dattmtlan as Its components. 'lhe hlghly slgnlflmpmvement only at the end ofphase.11compared with phase I lcant Inmeas2 1 scan spml in both gmups denotes the the
Wual
letam~erl~ll 1*tumnmlumn means Delwccli rmv nttanr
120
9835 1 512 0521
la921 2 916
not statatlstidly s Um @k t
compared with phase 1 1
~ o l a ~ dz 11 ~comcc scan
149
,,,
t E
M W M ~ d bVd. 164. Novanhr 1999 U l .
C o n ~ l ~ m iInctlun Il e l l w l I'relhm-allnn anct Conltwl &Ilec.llvc~neliu lc
EFFECT OF COMI'OSITE INDIAN HERBAL I'REI'ARATION ON TRAIL-MAKINGTEST. S E W AODmON TEST. AND SIIOlV.lERM MEMORYW Test
Phase l
0.442 10.1201 0.363 (0.1211 72.857 121.8391 66.788 195.3941 81.W K)l1.3111 85.239 8.&121
Phasr l l
0.532 10.2221 O . W (0.225) 85.714a(11.6041 78.036.119.81 1) 83.309 112.%l 82.451 110 5571
Phase Il l
O.Wd10.2001
0 . W K1.2491
78.038" 118.5741 73.714 lZ0.033l 72.380d'tIO 6891 72.858'" 113.9291
Tlall-msklq1-1 lcomcl seq~meclvcrmdl

Placebo ClHP
S e w addlUcn teslI9b m m c l l Placebo

ClHP mIII eO r-IS t I'Iarrho CIHI' menay I n 1 I%!m m c l molpllllonl
Vttlt~rs III~~II281 wlllb Sl) 11) ~ x ~ r t ~ t 1 l l 8 a ~ . It, "SI*lIllr.;s~lly ~llllrrco~l PII.~C IICB~~I I\.II~II.. ' ~ S I ~ t ~ l l l r nl~&~ rl tl~ l In,lni (lltaw 1 value. c l r y 1
TABLE V
ANALYSIS OF VARIANCE FORTRAIL.MAKING TEV. SERIAL ADDWON TEST. AND StIORT.TERM MEMORY TEST Sot~rrc olVarlallon
41
Stlnll dSql~ams
I
&IS
02617 0 0R:l8 0.M36
F
6.MX) I.'JP
Tralt-nlaklllg lrsl lrolrecl ~ t ~ r n r e / x c o ~ ~ d t t k ~ w u n - c d l l nlral\s ~n~~ 5 UI.IVW)I rowS K II I. 17 Reslcl~lat 135 Tolal 187 Scrlal ;uldltioa lest l'k correct1 Belwcen M~IIIIII o~entw 5 k l w r n ~ r~~ri~ns mw 27 1: I S Rcshlual 167 Tolal Shun-term nKlllOry lest (lit rorrcrl rcmgnnLMIl Htlmcn-col~~nlrl means 5 lJ~.Iw~r~~-rou. 1 1. 1 2 1c 1 1 27 135 I<ralrl88al 167 Tolitl
sn
2.21;-I 5 890
W7Y.W 221250 :17040.1:3 1,4847 50 4382.60 7554 70 I'llML4 Ill 2lAWlI X I 876 5 270 8 104.1
4 130 2 W4
8.4 1 2.68
TABLE YI
EFFECT OF COMlVSrrE INI>IANIIEHHAI. I'REI'ARKI'ION ON MAI' I'I.UlTIN(i 'TEST AN0 II'AT ANXIETY SCAlE.
~
----------p. .--..--.--.p .-p--p----.
Tlal
l'll;,~. I
S2.50 I%8441 46.42 133.%)7l 35.26 17.8431 36.11 (102821
l'l,.,~ 11
Milp-(,lulll~y!c % l FHt n l m e l l I I'Ladw UIIII' II'AT Alukly Scale lraw smrel I'laccbo Ctlll'
4 8 57 I28 767l
1
I'llasr Ill
A
($5101a" 125.MUl
rhange brnught abnul by the exceptlonal demand placed o n l the rogntttve resnurces by the r o m l ~ amisslon ;~sslgnmenl. The corrwt scan dld not reglsler a rorrespondi~lg slgt~lflranlInrrcase. showing that the specd-acrurary tradmlT prlnclple Is operative to some exlent wlthoul any delrlmcntal cllecl o n overall emciency. The suslalned Increase shown at the end of phase Illin I h c CIHP gmup as well as (he placebo grnup Indicates that the stresslul mivvlon events In mmbat stress orlents the mgnltlve
systml loward emrlent vlgllance. The stgnlllrunt Increase i n the correct scan may be a n addillonal a m m i i l l o n o l lhls h r t . I l ~ e cnn~pirralkelybetter values shown by the drug group may I : n attribulable to the known speclnc performance relurblshmenl actton o l C l l l P i n stressh~l ~ n d i t l o n s . ~ ' c The trail-making test involves two lunctbns: motor speed and nllenlbn.These two h ~ n c t b n s a r e rclevanl i n a mmbat envlrnnmenl, and any decrement In lhex Iimcttons will be dewmenla1 l o combat pedormance. The beneficial eliects oCClHP in combat
Mtltla~y Mcdkinr.
Vd. 164. Nnvc.mbcr I!JY!I
82
Composlle lndlan Herbal Rcparatlon and Combat Ellecllveness end of phase 11compared with phase Ii values. Thls task places 1 demands on the wwklng memory and mental models. In the combat environment there are many tasks competing for the allocation of these mgnlthn resouras, and thelr limlted availability may allst performance advascly. t h e significant Improvement shown at the end of phase Ill Indicates the llmlts imposed by the combat envimnalent nkntlng and thereby (adlltathg better p e r f o n n w . there was no staUsUcally slgnlncant change In the level of anxlely of these subjects during the study, as nlkcted by thelr responses to the IPATANdely Scale. Wese subjects were conthuously In the mmbat environment wUh f r q ~ ~ ehigh-rlsk mlsslon assignments, which mlght have nt enhanced thelr confidence of s u d u l l y aecompllshlng the m l m n tasks. According to Abraham,'" mmi ellective preventhre measures against psychological stress are group coheslon, arduous lralnlng, and d l s U c combat tralnlng. 'lhese subjects. by vlrtue of their 8 to 10 months of continuous exposure to combat, have fully met the requirements for prwenuve measures against psychdogical stress and thus were able to maintain the anxlety level wlthln normal llmlts. The comparaUvely better performanceIn the d2 test and the trail-maklng test by the CIHP group I a clear indlcatlon olthe emcacy ofClHP In s strengthening the crltlwl task elements of combat, 1.e.. attenUon and vlsuomotortracking, and thereby enhancing their combat elTectiwness.
Map Ilocllng r!!h m t l B e l m n mlurrtn
5
27
117196 454493 88497 0
23439 357 16833 2 56

655 5
meam
Mmn m m m Residual Total
135 135
s t r s s conditions are seen through the results ol this test. The placebo group did not show any statlsUcally slgnllkant change at the end of phase 11. slgnlfying that mmbat stress per se did not alter the visuomotor tracking emclency. n)e drug group reglstcred a hlghly signUlcant Improvement In tlie trall-maklng test at the end of phase II. 1.e.. immediately anei the compleUon of a dangerous mission aslgnment. Thls Improvement wlthout corresponding improvemenl In the placebo group points to the e k t of CIHP on cognitive performance amelloration during Ih-threatenfng mission episodes of combat stress. Attenlional focus and motor speed are t o critical cognitlve aspccts of comw bat perlormanre, and the better performance of the d ~ group g 1s tndicatlve of the emracy of CIHP in impmvlng combat ellecUveness. The serial addlllon test response also showed the e k t of Acknowledgment ClllP in reinforcing the cognitive component of combat pedornwncc. In fhls test, the p l m b o gmup also showed a sfgnilkint Improvement only at the end of phase II compand wlth their ~ u d y~u t e s~ u m lor ~ r i u n r u n u q . - r a & n . . and b p l n Lab. lnltlal m w n s e , and at the end of ~ h a s c there was a sII!IIIII- oratories lor e u o d v l m ~ l ~ ~ ' a n d b o M mr Uw spcUlratlons elven. Ill oha Stauatkal tml;~;&t i f data by ~:~lshnanl V.N. 'Sast~ys @a&fully &d 1 cant deteioratton. Thls nndlng sh& that the mlsslon &lgnment places a hcavy demand on attentional resources for ac- a r k t w w l ~ ~ ~ . compllshments. and any fallure to fulnll the demand may result In ineplit~~de. the dmg group. the impmvement el thr end of In References phase I1 was Illghly slgnlncant (p 0.00011 and the relapse at the end o l ~ h a s e iuas not slgniflcant. This again confirms that Ill I I,,I.~I .IE. anlnud U: I ' ~ . ~ U I W ud thr rmu~ury. V W ~ applUilttons and W trmds. h Ikyrkd IW.44: 4 ~ 5 1 . CIHP helps to cope wlth combat stress and sustain mental 1 vn*o WI: ~'q~huluyy r r b ~ l m ~ h c . in 10 war. ~syrhd e v 18: 8% 11s. ~ IY 25: performance In adverse environments. M. fiwdn w. Pd-n W. adovan Ma* me p;lttem ofsho,..lerm was ldentlcd In :I. S*wJa w m m l d slm In Anny O p c m l h .A. Sllhv WE. llrw FW. I*!. test Ml: M HN8n.h pmdwl81- 19. the drug group and the group. and the pllasell response 4, w ~~: * r r l o p n r n ~ d ~ ~ ~ U M s(J~~~~~ IW rrslnrn~ n c ~ r rrprt ISZ. ~mB C ~ ~ I ( C ~ rh CA. US h y . I=. did not reglster any slgnlncant change m either group. However. Rrwnlednl~uulnualmecUq at the end of phase Ill both groups showed a highly slgnlncant 5. D W c l J E : T ~ l a r I h c M t l e - m m t . dIhc---llon.Tmlo.hda. Iw. deterloratlon in immediate recall. After the mlsslon assignment, these subjects were resthg and recuperathg, and thelr reticular 6' ~ ~ ~ ~ ~ ~ n R W m " ; " T r s l ~ ~ * U ~ ~ ~ 7 T e c h n I . activating systems andlor thelr general state of arousal mlght 7 ih s 10 IU~ i i nrparrd I ~ h r W ~cduuc-d Km IT r u W w*. ~ rite T m h d a ~ Cmpmtlan Itngram have been at a low ebb because there was no demand. In such Inm4. mndWons. the ohmved changes mlght fall under the normal M WlW" h1k! X l lmporcantly, thae suqjecls had been 8. Frhdbd N. WW" C:" I a"d I& ha~d ssllulmm'lM m hr nvponsec:alegov. Inlmduud dvlnp lmlnlq lar d pl(orawrr m svMlul J llum In a hlghly m a i n g combat W m n m e n t Nth frequent danger71-8, dmWmnrvr -tar vndcr ~ htunr our m k b n assigninenla for the prcccdlng 8 to 10 months, and 9. so;&ycn ~ e~i y e h m ~ ~ l d ~ U S U ~ U Fpn - ~ ~ - ~. . U S ~ Y MD. bank fPtlgoemupled N t h the safe. f m W r m m e n t olT&q no It nandlmum w. challenge mlght have e a u d edb dctcrloratkm In thdr lmrnedlate r e d . 'lhe ImpllcPtlonr of UU8 llndlng arc that CIHP may lo' ~ & ~ ~ & ~ b - ~ w ~ ~ have spedllc &r on mgnlthn functlona, and In a relaxed, &KS. 6 - comavnd.ndbaenl swrcdkp. loss. N: NCW sutomrm d p b t unl d h ~ncrrvx mnstress-fm environment, cogniUve p e d o m n e may depend on I I. mulawn 11. the task demand, and tasks that place heavy demand on the 12, ~ S I C ~ D h a Y ~ ~ K R r r U W ~ R m n ~ ~ ST(Mv Y M, ~ ~ c eognlthn m u m s may be adversely aaected. ts.. IUC ~qmmnul * u ~ md n cmmwllc lndm w prrparallon 11 m ?he map-plotung 1 s t response was ldentlcal in boUl placebo sd.pgn .nd U merh.wm .s-. . I ~JI~hwnsO ~ I PI I IS+% XI: 14s-sr. and dmg groups. showing a slgnlficant Improvement only at the
c n '
Mllitary Medldne. Vd. 164. November 1999
Cornposile Indian Herbal Reparallon and Combs1EllaUvmesr
1WB. Nn IlvIN. Indlr. ~~lhn1Y.IWwPShmrrW:Rdrd~UmhhcYlrUeu ~ndu.~d~~~hmaUlpabrmrrr.~MlcnIlubh 1511: 8: 167. IS. ~V.Go&nwthmPI(:Mar.dy#caoclam O a h l p n u r r l r r l ~ m k h hnponynnvl hnllh and B*+nj.1-4 r l IhSmnnd Inlmwlkml
Mllilsly Mcdlcl~~e. 164. Nu\.c~rIx!r I!ll!l Vd.
84
l i ; r ~ : n a t t o ~Jourrl.ll o i I'l~;~rmaco~nosy i;~l I?''>. Vol. 33. So. 1.pp. I JY- 154
0925- 16 15/9513302-0I -1SC6.00 Q Suets Sc Zei~linger
EXPERIMENTAL EV.ALUATION COMPOSITE OF A INDIAN HERBAL I1 (CIHP 11) AS AN ADAPTOGEN PREPARATION AND ITS MECHANISMACTION OF
S.K. Grover, H.M. Divekar, Ratan Kumar. M.L. Pahwa, S.K. Bhardwaj. A.K. Gupta and K.K. Srivastava* Defence Institute of Physiology and Allied Sciences. Delhi 110054. India
ABSTRACT
CIHP 11. a11Ayiir~fedic conrbirrariotr of severalplanr Crgre. clicnrs artd rr~it~erals. resred for irs adaprogenic acrion. was CIHP I1 liod a srrorrg udaprogerric acrion in single. rrritlriplant 'Iairn possess such properties (Brekhman and D a r d ~ m o v .1969). pb.. orld prolorrged dose sclleditles. 11 had a curnrilarive A number of Indian herbs such as Wirlrat~iasotlro~icproqerrlc properr!. CIHP I1 rtlrake resttlred in a11 irn~ r r r ~ trrcrit~rerrnr~cc blood Q ~ ~ I C O S lC ~ ~ eor rhe e~td ~rd of e ls of nif;.ra D ~(Solanacene),A.~paragus racenloslls \\:ild, ~ . c.~i:c~lrsrr~ c swirnrrrrtrg exercises tvirlr lirrle difference in blood (Lilliaceae), Asparagus adsce,ldens R ~ (Lillia~ lorrrc nerd ns corrrptired tvrrh conrrol rats wirhour CIHP /I tnr,;ie. T / I I ~ u ~ g e s r e o n s h - a r i o t ~ glrrcose rr~rlisarion. ceae)' Ocimum cd of Cenrella Urban CIHP // I ! rrs foltr~dro porenriare rlrc o r x c n deliver?. s ~ - bclliferae) and Ph~(lanrhlls emblica L. Euphorbi3ceae, have been reported to possess antr-stress and rc.rvr ! rt~crrrisrrrg I \ tcd cell 2.3 Diphosplrogl~cerrc acrd (2.3DPGr l e ~ ~ con r.tposr1r.P ro hypobnric h ~ p o r i a11U~rproved endurance promoting properties (Bhargava and Singh. ls . cc.ilrrlor rt~etrrbrorre perr~rectbrlirv, rlre release of crearas 198 1: Chatterjee er 01.. 1592; Sen el al.. 1991: Shar1 1 1 ~ .~ / r o . ~ / t o k i ~ rr n s e r r circirlariort durirlg hvpobaric 11,vpo.rma et al., 1985; Singh et al., 1982; and Roy er a / . . t c r : S ' I S tcsrr~icrcdor1 CIHP 11 Ormkc. Hou.e~.er,se~,ernl 1991). A Composite Indian Herbal Preparation 11 rrssrte tt~crc~bolire ~ ~ c c r r r r a ~tvercs nor alrered during c~ ion (CIHP 11) contains these and other herbs. CIHP 11 rltt rt3srittgsmre. T11cCIHP I1 oppenred ro irtdrtcc a srare r~it;c~n-rl~rcrfic rrrcrcased resisrar~ce (SNIR) drtrtrrg stress. has been found safe and nontoxic on prolonged me
iological functions of the organism, and act only under conditions of challenge to the systcm. Several products and preparations derived from animal and
'urn-
(Kothari er al.. 1986). The approximate LDSOof the drug in albino mice was between 5-6 glkg hod! ISTRODUCTION weight when given p.o., and its effective dose was 100- 200 rnglkg body weight (Singh er al.. 197s). Bic~lo~ical stress. in response to physical. chemical. However. for humans the recommended dose for the i-~~!ogical emotional change. consists of a pat- first 7 days is 30 mglkglday followed with a mainteand tern drenctions that help to strengthen the organism nance dose of 15 mglkglday. The drug is used either rSsJ!e. '1938). It is possible to support the body's in liquid form or as tablets made from powder mix ati;lptxion by using chemical intenrention. and sub- and coated with lactose (The Himalaya Drug Co.. s t m e s ha\ ing such 3 property are called "adapto_~ens" India). CIHP I1 has been tested for its antistress ei1L2:arev. 1 9 8 ) . Such preparations increase non-spe- fect during swimming (Singh er al.. 1978) under ancitic reslstnllce. cause minimal disorder in the phys- oxia (Tomar er al., 1984). and under multiple stress. of cold and immobilization (Singh er al., 1978 ). The drug increased swimming time, tolerance to anosra and decreased the gastric ulceration in rats induced Cc:.::ords: .AJaptogen. hypoxin. restraint. exercise. therby cold and restraint. The present study evaluated rn;lr:pulatron. the adaptosenic effect of CIHP I1 using stvimminp .Ac&eno \\.horn J I I correspondence sho;ld he addressed. as well as a passive, multiple stress, resrraint-cold-
85
CIHP I1 EVALUATION
h!poxia IR-C-H) animal model (Ramachandran et (11.. 1990). and the mechanism of action.
Table I. Composition o i CIHP I1 Powder (Concentmri@n in w/w%). Chayavanprash Concentrate t Euphorbiaceae) Black pepper Cardarnon Cinnamon tamala Clove Ginger Long pepper Mesiiaferrea L. (Guttiierae) Nutmeg Sandal Wood Tenninalia chebula Retz. (Combretace3e) Abltrilon indicrrtn (L.) Sweet (Xlaivaceaei Asparagus adscendens Roxb. (Liliacc~e) Bombax tnalabaricutn DC. (Xlal\ aceact gum Etttbelia rrbcs Burm:f. (&lyrsinacex) Hygrophilia spir~osa T.Anders. (.-\cmthacc;le) rUrtclina prlrriens (L.) DC. (Leguminosac) Terrr~rrrnlia belerica Roxb. (Combreraceae) Tribiclirs rerresrris L. (Zygophyllncew) 1Virltania so~~tni/cra Dun. (Solanace3e) Abhrak bhasma Rasa sindur (Hg.S.)
Pltyllant/tris emblica L.
SI.\TERIXLS AND METHODS El?-riments icere carried out on randomly bred, hc-!thy. adult male albino rats of the Sprague DawIc! s:rain \veighin_r 1 7 0 2 30 g. The rats y e r c kept in S a room [hat W ~ maintained at 25 2 "C with sulficicnr ni~tuml light. The room remained dark from day 191>0hrs until morning The animals had free access to dr~nkingwater and food in pellet forrn (Lipton India Ltd.. Calcutta). All experiments were done on o\s:nlght fasted mts.
CIHP 11 P r e p a r a t i o n CIHP 11 in powder form (Geriforte) was supplied by Dr. R.hl. Caprain o l the Himalaya Drug Co. Bomba!. India. The composition is given in Table 1. It contained many plant extracts and mincrals prepared 'in 3 rcproducibie manner. CIHP I1 in powdcr form tvas ~ o a k c d water overnight. The suspension was in tiltcrcd rhrouzh rnuslin cloth and aclear brown colored aqu:ous-suspension was obtai.ned. One ml of aqueous q t r a c t was equivalent to 200 mg crude powder of' CIHP 11. The oral drug dose was water extract equivalent to I rnglg body weight of CIHP powdcr. CIHP 11 powder was extracted with 75% ethanol In Soxhlet apparatus for 6 hr. The, extract. after hitrariun, was concentrated in vacuo in a flash evaporator. The dricd resinous substance was diluted with \vatcr to the required concentration. One ml of diluted e.xtract was equivalent to 240 rng of CIHP powder. The intraperitoneal (ip) dose of the alcohol extract was equivalent to 48 mg1100 g body weight of CIHP Powder. Adaptogenic activity using cold water swimming and restraint-cold-hypoxia models In experiment one, the alcohol extract o f CIHP I1 was given to rats at a dose of 48 mgi100 g body weight either once or once a day for five consecutive d q s by intraperitoneal administration. Control rats \\ere given an equivalent volume of normal saline, i.p. CIHP I1 was administered to overnight fasted rats 30 min prior to forced swimming in cold water (23'C). The rats were made to swim until their rectal temperature (T,)reached 23OC. At that point, the rars \\,ere taken out, wiped dry and allowed to recov-
Shilajeet (purified) Abhrak bhasma Jasad bhnsrna Saffron Loh bhasrna Mandur bhasma Extracts
Wirhania sornnifera Dun. (Solanaceae) Asparagus racernosus Wild. (Liiiaceae) Cenrella asiarica Urban (Umbelliier3e) G1ycprrlli:a glabra L. (Legum1nos3e) Tertninalia chebula Rctz. (Combretaceae) Capparis spinosa L. (Capparidaceae) Cichorium intybus L. (Compositae) Adharoda vasica Nees (Acanthaceae) Argyreia spcciosa Boj. (Convolvul;lceae) Berberis arisrara DC. (Berberid~ccae) Cacsalpinia digyna Rottl. (Leguminosre) Eclipta alba (L.) Husk. (Compositae) Mrrcrma p r u r i c a (L.)DC. (Legurninosac) Mjristica fragrans Houtt. (Myristisaccac) Piper longum L. (Piperaceae) Solanum nigrttm L. (Solanaceae) Terminalia arjuna Wight & Am. (Cornbretaceae) Cantm copticrtm (L.).Benth. & Hook. ex C.B.
4.57
7 :
-.7 ;
I .67
1.14 1.14 6.S6

157
4.57
4.57 3.J; 3.16 3.16 2.3 2.3

2.3 2.3
2.3 23 . 2.3 2.; 1.46 1.46 1.14
Clarke (Umbelliferae)
Celasrrus panicularlcs Wild. (Celastraceae) 1.14 C~ircirma longa L. (Zingiberaceae) 1.11 Elerraria cardamomum (L.) Maton (Ziigiberaceae) I. I4 Syiygiurn aromaticum (L.) Merr. & Perry
(h4 y rtaceae)
Acllillea ttlille-. L. (Cornpositae) Cassia occidentalis L. (Lcguminosae) Tamari.~ gallica L. (Tamaricaceae)
Mace
1.14 0.73 0.73 0.73 2.3
86
S.K GROVER ET.4L
Estimation of some tissue metabolites and enzymes in rats exposed to hypoxia Rau were divided into two groups. One group was given an aqueous extract of CIHP I1 orally through gastric canula at a dose of 1 mglg body weight, once a day for 7 days 30 min prior to hypoxic exposure. The hypobaric hypoxia was at a simulated altitude of 6096 m at 32C in a decompression chamber, 6 hr daily for 7 days. The control group was given normal saline and further subdivided into two groups, Estimation of some tissue metabolites and enzymes ' one group was exposed to hypoxia 3 0 min after adduring the resting state ministration of normal saline orally. 6 hr daily for 7 R.irs uere divided into two groups. One group was days. The other control group was not exposcd to gr\en an aqueous extract of CIHP I1 intragastrically hypoxia. After the hypoxic exposure on the seventh at a dosc of 1 mglg hody weight for six wecks. In the day. the rats were sacrificed by decapitation. Blood control group, an equivalent volume of normal sa- was collected from the jugular vein. Tissues were line \vas given orally. After six weeks. the rats wcre removed. tvarhed in cold normal saline. blotted. fasted overnight and sacrificed by decapitation. Blood upeighed,and processed for further analysis. Blood it.35 collected from the jugular vein. Tissues were hematocri~value was determined using a microhcremoved. immersed in cold physiological norms1 matocrlt centrifuge (Carl Zeiss Instruments, W. Gers:~iinc. blotted. xveighed and processed for furthe? many). In whole blood, glucose (Nelson, 1944). he~ n a i y s ~Blood ~ l u c o s e s. wasestimated in whole blood moglobin (Dacie and Lewis, 1963) and 2.3-DPG ~Sclson.1944). Glursmate-pyruvateaminotransferase (Sigma Diagnostic Kit, Procedure NO 665. Sigma (GPTI (Re~tman and Frankel. 1957), carbamoyl-or- Chem. Co., St. Louis) were estimated. Serum proni~hine aminotransicrase (COT) (Brown and tein (Lotvry er a[.. 1951). creatine phosphokinase Gr~,olia. 1959), glutamate-oxaloacetate-aminotrans- (SCPK) [Hughes, 1962). tri_c!ycerides (kit obtained te:ase (GOT) (Reitman and Frankel, 1957). lysozyme from Ranbaxy Diagnostics, New Delhi) and muscle (Smolelis and H3rtsell. 1919), protein (Lowry et glycogen (hlontgomery. 1957) were determined. Liver '11.. 195 1 ). free fatt!. acids (Anstall and Trujillow, and adrenal gland weights were also determined. IYbj), and cholesrerol (Zlatkis et al.. 1953) were The results of CIHP I1 administered animals \\ere measured colorimetrically in serum. hluscle glyco- compared with saline treated c o n m l animals and data gcn (hlontgotner~.1957) was estimated in gastroc- were analysed statistically using the Student's r test.
er in a room maintained at 32 "C. The fall in the rectal lemperaturc to 23' C and its recovery to 37 O C at room temperature (32 ? 1 OC) was continually recorded with a YSI telethermometer initially every minute and later ar 5 min intervals. In experiment t\vo, the aqueous extract of CIHP Il at d o s e of 1 mg/g body weight was given ro rats orally once aday through gastric canula for six weeks. Control rats were given normal saline. After six Lveeks the rats were fasted overnight and subjected to the multiple stress of R-C-H. In this model, rats were exposed in 3 decompression chamber maintained at 5'C and lo\\*atmospheric pressure of 428 mm Hg pressure equivalent to an altitude of 4572 m. The wind flow in tcrdecompression chamber way 2 literslmin. The rats ~ ' c r e k c p t a restrainer and its colonic temperature in (TI\ \ u s mon~torcdcontinuously with a Isothermex Trmpzrature Recorder (Columbus Instruments. C S.X.\once a minute. The rectal probe was inserted 2 ~.m past the rcclum. When the rat attained a colonic temperature of 23'C. i t was taken our of the chamber and 3llowed to recover to normal colonic temperature of 5i'C at atmospheric pressure and at 32 -+ 1OC. However. the rat csntinued to be in the restrained state. of The trr~le T, fa11 to 13'C and its recovery to 37'C \\ere used as a mcasurc of endurance in advzrsc environmental condrtions.
nemius muscle and weight of adrenal glands \\,as recorded. Blood glucose a n d lactic aciil'levels after cold n-ater swimming a n d recovery frqm cold Rats were divided into two groups. One group was gisen an alcohol extract of CIHP 11, i.p.. at a dose of 48 mgl100 g body weight 30 min prior to swimming. The control group was given normal saline i.p. in a volume equivalent to drug. Rats were forced to s\\*im in cold water (23 OC) for 25 min and taken out, wiped dry and allowed to recover at 32 rt: 1 "C for 80 min. Blood was collected from the tail vein three times. i.e.. before swjmming, after 25 min of swimming 'and after 80 min of recovery. Blood glucosc (Nelson, 1944) and lactic acid (Barker and Summerson. 1911) levels were estimated colorimetrically.
CIHP I I EVXLCXTlOi':
T ~ h l c . El'l'cct or 1.p. 'idm~nratrationof CIHP I 1 (ethanol extract) on maintenance of rectal temperature while suimmlng 2 ln C P I ~\ \ x e r t 25'C) 2nd reco\.ery 3t room temperature 32 i 1C. Control (n= 10)
Single dose (n=9)
Five dose In=S)
Tl~nc raken to reco\er ilur1n.11rect~l rsmpsrature ( m ~ n )

i.1lue5are me2n
106 4 f 5.1
112.8
f 13.5
92.4 f 10.5
S i ~ n ~ r i c ~ nd~ffsrer~t controls: P<0.001 tl! trom r S.E.
RESULTS
Thc ctI;.ct o i C I H P I1 admtnistrcltion after single and t i \ ? JOSSS [he fa11 and recovery of rectal temperen Jturc (T;) of rats while swimming in cold water 1C) IS shonn ~ n , T a b l e Swtmnilng time to reach 2. .I Trot' 23C increased significantly after single and I I V C dobes o i C I W 11. ~ b w e v e r recovery time from , T, 23?C to 37'C was not affected by single o r five iloscs ol' CIHP 11. When the adaptogenic activity of CIHP I1 was tcstcd in rais after six weeks of CIHP I1 ~ntakc a dose o f I mglg body weight in the R-C-H Table 4. Effect of six weeks of CIHP I1 (aqueous extract) at modcl. the time For attainins Tr 13C was increased intake on some tissue metabolites, enzlmes and adrenal weight in rats. si~ntficcln~l) < 0.001) and recovery to 37 "C was IP 3150 significantly reduced ( P < 0.001) (Table but Control ClHP I I did not cause any significant change in the ~ u n c e n (n= I I) -~--Tn=i) 1 [ration of blood $ucose. free fatty acids andrhserved c:lrhohydrates in the form of muscle glycogen in restBlood glucose (mg%) 103.4 107.0 tng rats (Table 4). Serum protein, cholesterbl and 1.2 f 5.3 Serum free fatty acids ( W I L ) 937.1 819.0 f 55.9 69.9 I. I 0.9 Muscle glycogen (mglg tissue) f 0.2 50.3 'Table 3. Eliect of six weeks of orai administrationof CIHP 7.1 7.0 I1 (aqueous extract) on maintenance of rectal tem- Seruin protein (g%) f 1.4 0.4 perature under acute cold (5qC),restraint and hy205.7 200.0 ~oxic stress (4572 m) and recoverv at room tem- Serum cholesterol (mg%) perature (32 IC). Serum GOT (pnollmin/l) at 37C Control CIHP Serum GPT (pnollminll) (n=6) (n=6) at 37C Time raken to attain 23 "C 87.3 149.8 * Serum COT (m.i.u) rectal temperature (min) f 6.5 f 10.3 Serum lysozyme (pglml) Time taken to recover 160.5 86.5 * Adrenal weight (mg) normal rectal temperature (min) f 12.1 f 6.7
enzyme activities of aminotr~nsferascs(GOT. GPT. and COT) and lysozyme were comparable in'CIHP I1 administered rats with control rats (Table 4). .\l,o there was no change in weight of adrenal glands. Blood glucose and lactic acid concentra~ionof rats swimming for 25 min at 2C and after recovery 3 ' of SO min at 32'C are givcn in Table 5. In control rats, blood glucose decreascd after swimming ( 6 0 4 ) and recovered more than 50C; of the loss after SO
Sien~ficantlvdifferent from controls: P < 0.001 Values are mean f S.E
Values are mean f S.E.
88
S.K. GROVER ETAL
Table 5. Effect of ClHP I1 (ethanol extract) i.p. administration on blood glucose and lactic acid in rats swimmine ior 25 min at 23 'C and after 80 min of recovery at 32 f 1C. Blood glucose (mgQ) Control CIHP I1 ClHP I1 Single Five dose dose (n=6) (n=6) (n=6) Blood lactic ac~d (mgQ) Control CIHP I1 CIHP I I Single Five dose dose (n=6) (n=6) (n=6)
After 25 min of c\vlmmlng .Afrer S mln O of reco\.cry 53.9 f 0.9. 89.2 * 72.2 '
? 6.9
f 7.9
21.3 t 0.4
21.7
f 0.7
19.5 f 1.7
Stgn~licantlydifferent from control; P < 0.05 Values arc mean f S.E. T.,rle 6. Effect of CIHP I1 (aqueous exlract)'inrake on some hematological parameters. tissue metabolites, enzymes and in organ wci~hts rats exposed to hypobaric hypoxia equivalent to 6096 m. Control (n=12)
Pactcu :ell volu~ne
Hypoxia (n=i I)
Hypox~a CIHP I1 + (n=6)
(t)
H~cmoclobln
8C'i)
R'ed cell 2.3-DPG ~umol:ml) %)ood glucose

0 5) :
.+luscle glyco$en tmgfg ctssue) Serum lr~glycer~des 11ng5) Serum CPK cm.1.c. rng protein) L ~ \ e uetrht r
,c :
.Adrcnals weight
Imp)
Signiiiiantly differenr from controls at P c 0.05. Slynliic3ntly different from hypoxia group at P < 0.05 Valu;.z lrc. mean k S.E.
mln ot' the reco\.ery period. Lactic acid levels increased hy about 80% after swimming exercise'but after recovery period the values were comparable \\ ith initial values. In CIHP 11-treated rats, after 25 mln of s\\.imming. the decrease in blood glucose level5 \ v n j df the magnitude observed in the control
group. The blood glucose recovered 314th of initial loss after the recovery period. Lactic acid increased after swimming and was comparable with controls at the end of recovery in CIHP LI-treated rats (Table
5). Hypobaric hypoxiacaused significant increase in
ClHP I1 E\'ALUATION
p-:L;d cell ~ o l u m e (PCV). blood 2.3-DPG, serum CFK a11d I ~ \ eand adrenal uetghts in rats (Table 6). r ClHP I1 adtninistration (1 mg/g body \\.eight) prior I(> !I posic exposure further increased blood 2.3 DPG, J:.r:~sed SCPK levels and prevented the increase In '!\cr and adrenal weights observed in controls not g!::n CIHP I1 and exposed to hypoxia (Table 6). Ht.~ir:\.cr. h>poxia-induced increase in PCV and deL ...-.>cJ Acletal muscle glycogen was not modified r. . h! CIHP I1 inrakc prior to hypoxic exposure.
D!jCCSSION E\~luatlon i the endurance-promoting actibity of o ~ d ~ p r o < r :1ssgenerally done by either t'orcing a rat n or niousr: to clirnb i n endless rope (Fulder, 1980) or ~o:<sd,wirnrnins tn cold or warm warer until exh;uit~on t ) ~ . Jsath (Brekhman and Dard)nlov. 1969). \\r: i h \ c uscd the capacity of the rat to maintain its i<>rr: rctnpcrature (T,) while swimming in cold water I ~ Z ' C ) facing acute multiple strcss of restraintor cold-hypoxia (R-C-H) as an indicator of the resistJniz In LIII adverse environment. This proved to be a prs:lse 2nd specific indicator of the physical and nicn~:~I psrt'ormance capacity of the organism (Bergh. 1950 ~ n Colquhoun. 1970). CIHP 11 intake (alcohol d e.\lrJct cqutvalenl to 48 mg1100 g body weight) incrca,ed swinimtn: time in cold water until the T, of rxs reached 23'C. both in single and five consecutt\c doses. by about 5 0 8 , without affecting recovcr! ttme ro T, 37'C. Long term administration of s ClHP 11 ( ~ q u e o u extract equivalent to 100 mgllOO g body weight for six weeks) resulted in strong resistance to cold stress and also decreased recovery time oi rats in the R-C-H model. The delay in attaining T, 23'C was 72% and recovery was enhanced by 4670. Th~s suggested that water extract of CIHP I1 had a curnularive action and favorably affected endurance lo cold and recovery. The preparation did not affect the body weight gain of the animals in comparison to controls during 6 weeks of administration. In subsequent experiments we have used water extract of ClHP 11. The mechanism by which the CIHP I1 promoted the thermogenic process during acute cold stress and during recovery from hypothemia required investigation. Some tissue metabolites and enzyme levels ucre determined in rats treated with CIHP I1 for 6 nceks. The 6 week intake of CIHP I1 (100 m_e/100g
body wetght) did not affect the circulating components such as blood _ulucose and free fatty actds. or muscle glycogen concentration. Circulating proteln. cholesterol. aminotransferases (GOT. GPTand COT, and lysozyme levels were maintained. This suggts;ed that CIHP 11 intake did not result in any metabclicalteration in the bodydurin_e the resting stare. Hw\ever, this did not explain the mech'anism of increased thermal resistance. Swimming in cold water required heavy'expenjiture of energy for escrcise and maintenance of bod?tempenrure. In our experiments. a decrease in blood glucose level and an increase in lactic acid occuncd at the end of 1 5 min of swimming in cold \r.ar-r (23C). After 80 min of reco\.ery at 31'C. the blocJ glucose level partially recovered. In mts treated wirh CIHP 11. the blood glucose level was better maind tained ~ n recovered more rapidly than the conlrol rats. The lactic acid increase, was, ho\vever. cornprable to that seen in control rats. It appears that ClHP I1 intake stimulated fat utilisation for energy purposes and spared glucose utiiisation. Similar glucose sparing effects have been observed in the case of other adaptogens such as Parras:;iitseng (Avakian u a/.. 198J) and Elr~rtherococctrs senricostrs (Katsum~ el al., 1986). Polycythemia. an increase in RBC U D P C kt els and a decrease in carbohydrate res6rucull;un. 1981 and Martin, 1975) are well-know respomcs to hypobaric hypoxia. Polycythemia enhanced the oxygen carrying capacity.'while 1.3-DPG impro\ed (he delivery of oxygen to the tissues (Claude er ul.. 1968). Similar changes were observed by us in rats exposed to hypoxia (6096 m, 32'C). The CIHP I1 intake prior to hypoxic exposure potentiated the increase in hypoxia induced red cell 2, 3-DPG in rats. This would improve the availability of oxygen to tissues. CIHP I1 intake also arrested the hepatic and adrenal gland hypertrophy induced by hypoxic stress. The increase in circulating CPK is a sensitive indicator of structural integrity of the neural, cardiac and skeletal systems. The circulation of this enzyme was increased (about 200%) in rats exposed to hypoxia in comparison to unexposed rats. The intake of CIHP 11, prior to hypoxic exposure restricted the release of CPK to only 1 3 0 8 . It appears that CIHP I1 \\-as able to restore energy processes required for the maintenance of the cellular membrane pcrmsability. Thus, CIHP I1 was found to be 3 strong adaptogen with a cumulative action. The ylucosr. Ir\-el
S . K . GROVER ET.-IL.
during and after exhaustive swimming exercise was hettcr maintained in rats fed CIHP 11. Further, it strengthened the oxygen delivery system and maintained ceilular membrane permeability during hypo\ic exposure. CIHP I1 administration did not result in any metabolic alteration if taken long term in the resting state. However, more work is required to explain its mechanismof action.
REFERENCES
Allin. F. (198 1 ). Comp. Bioche~n. Plrysiol. 70: 427-434. Anstall. H.B.. and T ~ u J ~ ~ D.IM.v . ~ o \ (1965). Clin. Clrern. 11: 741-747. A\ d i m . E.V.. Supirnoto. R.B.. Tazuchi. S.. and Horvath. S.11. (1984). Plnnra Med. SO: 151-1 54. Barter and Sumrnerson.~ method "Determination of lactic actd" (1941) as descnbed in Hawk's Phy~iologtcal Chemistry S I V ed.. Tala McGraw Hill Publishing Co. Ltd.. 1976. pp. 1103-1105. Bc:yh. L. (1950). A\ta. Plrysiol. Scand. 109: 1-39, l Bti~rg3\.a.K.P.. and Singh N. (1981). lnd. I. Mrd. Res. 73: 443-45 I . Brelh~ian. and Dardymov. 1.V.(1969).Atm. Rev. Plror1.1. mnr<,!.9: 419-430. Brwn. .\.W. Grisolia. S. (1959). 1. Lub. Clitz. bled. and 54: h i 7 - 6 3 , Ch3lterjee. T.K.. Chakraborry, A.. and P~thak. (1992). Irl. lrrd I. E.rp. Biol. 50: SS9-89 I . C13udc. L.. John. T.. Eugcnta. E.. Clements. .4.F., Cesar. R.. Jose. R.. and Jose. F. (1968). I. Clin. lrwcsr. 47: . 2652-2656. Colquhnun. W.P. (1970). Ergonomics 13: 558-560. D~cic. J.Y.. and Lewis. S.M. (eds.) (1963). Prncrrcal Hen:nrolog~.3rd ed.. J & A Churchill Ltd.. London. pp. 14-33. Fuid-r. S. (1960). In: Tlrc Roo1 of Being. pp. 122-125. Hutchinson. London.
Hu_ehes.B.P. (1962). Clin. Cltrm. Acfu 7: 597-600. Katsumt. A,. Takahashi. T.. Miyashita. M.. Matsuzaka. A., Muramatsu, S., Kliboyama. M.. Kugo. H. and Imai. 1. (1986). Pkanta Mrd. 3: 175-177. Kothan. L.K.. Dass. C.M.S.. and Patni, M.K. (1986). Probe 25: 316-322. Lazarev. N.V. (1958). F a m c o l Toxic01 21: 81-86,Quored from Brekhman, 1.1 and Dardymov. I.V. (1969). Lowry. O.H., Rosebrough. N.J., Farr. A.L., and Randall. R.J. (1951). J. BioL Chem 193: 265-275. Manin. L.G. (1975). 1. Appl. Physiol. 39: 258-261. Montgomery. R. (1957). Arch Biochem Biophs. 67: 378-386. . Nelson. N. (1944). 1 Biol. Chem 153: 375-380. Ramachandran. U . Divekar, H.M..Grover. S.K.. and Sri\as. lava, K.K. (1990). J. Ethanophar1nacol29: 275-281. Reitman. S.. and Frankel. S. (1957). Am. I. Clin. Parhol. 2 : 56-63 . 8 Roy. A.K., Haimanti. D., Shanna, A.. and Talukdar. G. (199 1). Int. I. Phannacog. 29: 1 17- 126. Sclye. H. (1938). Am. J. Physiol. 123: 758-765. Sen. P.. Malti. P.C.. Puri,. S.. Ray. A.. Audulov. N.A.. and Valdman, A.V. (1992). I d . I. Erp. Biol. 30: 592-596. Shanna. S., Dehanukar. S., and Karandikar, S.M. (1985). lnd. Drugs 23: 133-1?9. Singh. N.. Narh. R., Mi=. N.. and Kohli. R.P. (1978). Quarterly J. Crude Drvg Res. 16(3): 125-136. Singh. N.. Nath. R., Lata, A., Singh, S.P.. Kohli. R.P.. and Bhargava, K.P. (1982). Inr. J. Crude. Drug. Rcs. 3(k 29-31. Smoletis. A.N.. and Hansell. S,E. (1949). J. Bucr. 5th 731-736. Tomar. V.S.. Singh.S.P.. Singh. N.. and Kohli. R.P. (1934). Probe 24: 25-27. . ZlatLis. A.. Wr. N.. and Boyle. A.J. (19531.1. Lub. Clin. bird. 41: 486-492.
Acccp~ed: October 7. 1993
91
THE JOURNAL OF ALTERNATlVE AND COMPLEMENTARY MZDlClNE Volume 5, Number 3, 1999, pp. 245-251 M~N Ann Uebert, Inc.
Enhanced Thermogenesis in Rats by a Composite Indian Herbal Preparation-I and its Mechanism of Action
RATAN KUMAR, M S . , Ph.D., S.K. GROVER, M.Sc., Ph.D., RADHEY SHYAM, B.S., A.I.C., H.M. DIVEKAR, B.Sc., A.K. GUMA, B.Sc., and K.K. SRIVASTAVA, M.S., Ph.D. M.D.P.A.
ABSTRACT Objective: A composite Indian herbal preparation-I (CIHFI) containing ingredients derived from 7 different plants and asphalt was tested for its adaptogenic activity and its mechdnism of action was investigated. Design: CIHP-I was tested using the cold-hypoxia-restraint (C-H-R) animal model in which the restrained rats were exposed to 5C at 428 mm Hg atmospheric pressure. Rectal temperature (T,) of the rats was continuously monitored during the exposure and the recovery pe, riods. The time for fall of T to 23C and its recovery to 37OC were used as indices of endurance and the adaptogenic activity. Carbohydrate and lipid parameters were investigated to find out the nature of fuel being used during thermogenesis. Resdts: After 12 weeks of administration of an oral dose of 7.5 mglkg-'lday-', CIHP-I was found to possess significant adaptogenic activity. CIHP-I helped impmve resistance to C-HR induced hypothermia (, 23C) in animals by increased mobilization of free fatty acids T , (FFA) from adipose tissue. Blood glucose and dluscle glycogen levels were maintained. CIHPI treatment restricted the release of creatine phosphokinase (CPK) into the circulation during C-H-R exposure. Conclusions: The results suggested that CIHP-I is a s m n g adaptogen. It improved cold resistance during C-H-R exposure and enhanced recovery from hypothermia. The energy-dependent cell membrane permeability was maintained. Stored lipids were mobilised and possibly used for thennogenesis in preference to carbohydrates.
INTRODUCTION erbal formulations have been in use for many years not only in Asian countries but globally for well being of human beings (Brekhman, 1980; Fulder, 1980; Nadkami, 1954; Srivastava, 1994). The Indian system of medicine, Ayurveda, has particularly used a number of herbal formulations for this purpose (Nadkarni, 1954). These herbal formulations,
which claim to enhance physical endurance, mental functions, and nonspecific resistance of the body have been termed adaptogens (Brekhman, 1980). An ancient Chinese herb Panax ginseng has been described as an adaptogen (Kumar et al., 19%; Srivastava, 1994). Some Indian herbs such as Withania somnifea, Asprngtcs rccemosus, Asparagus adscendens, Ocimtrm sanctum, and Pueraria tuberosn have been shown to enhance resistance to stress and phys-
Department of Biochemistry, Defence Institute of Physiology and Allied Sciences, T i u r , New Delhi, India.
92
KUMAR ET A L
ical and mental performance (Bhargava and Singh, 1981; Jani et al., 1981; Shanna et al., 1985; Singh et al., 1982). Several composite Indian herbal preparations (CIHP) are being developed and have been evaluated for their antistress and endurance-promoting properties (Kandeparker and Kulkarni, 1981; Kulkarni and Verma, 1992; Sohrab, 1951). A CIHP I1 containing 39 plants and 6 minerals has been observed to have antistress properties (Singh et al., 1978; Grover et al., 1995). The mechanism of action of this CIHP-I1 in ihcreasing tolerance to stress was also evaluated and shown to be due to its action in increasing glucose turnover rate and preferential utilization of fat (Kumar et al.. in press). Another composite Indian herbal preparation (CIHP-I) that contained only 7 hrrbal components LVitlmr~in soirrirjfirn, Aslinrn-,
p i s rnwiirosrs, P~rrrnricihrbcrosn, Mttstrtrn pr~tri(.its, Diossort,n brtlb!firn, A l ; q l r i n sprciosii, Pipcr lorrgtirir,
MATERIALS AND METHODS

The CIHP-I in water soluble sterile powder form was provided by Lupin Labs Ltd., India. The composition of the CIHP-I is given in Table 1. Several batches of the drug were produced by a reproducible process. The shelf life of the preparation was 1 year. Median lethal dose (LDH))amount of substance to kill one-half of the population of test animals, of CIHP-I for rats was more than 10 g/kg-' body weight in a 14-day observation trial after administering it in a single dose per day.
and asphalt has been e\.aluated for its antistress and adaptogenic activity and its effect on fat mt~bilizationfrom adFpose tissue in rats. Asphalt (Shilajeet) which is a palo brown to blackish brown resinous product of fresh and modifiod remnants of humus, admixed with plant and microbial mctabolitcs, occurs worldrvidc in steep rocks (at altitudes ranging from 1200-5000 m). .The chemistry of asphalt has been worked out (Ghosal et al., 1995). It is used in Indian medicine to stimulate pnvsical and mental performance (Nadkarni, 1954). The CIHP-I is being commercially produced by Lupin Labs Ltd. (India) as One-Be.
Experiments were carried out on randomly bred, healthy, adult rnalc albino rats of the Wistar strain weighing 100-150 g. The rats were maintained at 25'C 2 2C with natural light during the day and no light after 1900 hours until morning. The animals were reared on a laboratory chow (Gold Mohur rat diet from Lipton India I-td.), fed nd libihtrir, and had free access to water at all time. To evaluate the adaptogenic activity, CIHP-I powder was dis~ o l \ ~ e d water in concentration of 40 mg/mL in and suhscqut~ntlvaftcr dilution, the desired dose of CIHP-I was administered to rats orally in 0.5-mL volume with the help of a gastric cannula. Control rats were administered orally 0.5 mL water. In the experiment one, CIHP was ekluated for its adaptogenic activity after a single Jose administration (starting from 0 to 150 mg/kg-I body weight) using cold-hy-
Aspnrnnprts n~ci~rrrii.i~rr. Wild Wil11n111n sortrrr~firrr.Dunal Pclcrnrtn r~thrrosn.DC M~rc~r~rn ~~rtrriots. DC Diosmrc-ri Il~rlh~firn. Linn A r f v r ~ nb}?rciosn.Sweet Pipcr I U ~ I $ I I ~ I I . Linn
Rcmts
29.33
16.92 16.92
Roots Tubers hds Rhizomes Whole plant Fruit
8.46 8.46 8.46 4.32
Asphalt extract
7.23
'Aqucous extract of all the ingredients in the given proportion was vacuum dried and mixed.
93
THERMOGENESIS BY CIHP-I AND ITS MECHANISM
poxia-resttaint (C-H-R) animals model (Ramachandran et a]., 1990).The CIHP-I wasgiven at a dose of 7.5, 15.0, 75.0, and 150.0 mg/kg body weight orally as described earlier to overnight fasted rats 30 minutes prior to exposure in an animal decompression chamber maintained at 5 C and low atmospheric presO sure of 428 mm Hg equivalent to an altitude of 4572 m. The rat was kept in a restrainer and its rectal temperature was monitored by a 16 Channel Isothermex Temperature Recorder (Columbus Instruments, Columbus, OH) once a minute. The rectal probe was inserted 2 cm past the rectum. When the rat attained a rectal temperature of 23C it was taken out of the chamber and allowed to recover to normal rectal temperature (T,) of 37C at normal atmospheric pressure in a room maintained at 32'C z lCC.However, during the recovery period, thp rat continued to be in the restrained state. A. constant room temperature was maintained because the recovery time to T 37'C of rats de, pends on the room temperature. The cooling of thc rats to 23OC was taken as the termination point ot the cold-hypoxic exposure, as any furthcr fa11 in rectal temperature was found to result in high mortality. The time and pattern of thc , fall to 23OC and its recovery to 37C T were used as a measure of endurance (Ramachandran et al., 1990). After establishing optimum dose, l set of rats was given CIHP-l orally at a dose of 15 mg/kg-I body weight, once a day for 5 days. In another experiment another set of rats was given CIHP-Imlly at a dose of 7.5 mg/kg-' body weighf for 6 and 12 weeks, once each Jay prior to the C-H-R exposure. The last dose was administered 30 minutes before exposure.
blood, weighed, and processed for further analysis. Other organs, uiz. heart, lung, liver, kidney, adrenals, testes, and spleen were removed and their weights were recorded. Blood glucose in hepahizedblood was estimated using kits obtained f o J. Mitra k Sons,DeM, rm India (Glucose oxidase/peroxidase, Cat. NO. ME0 12000).Serum protein (Lowryet a]., 1951) and free fatty acids (FFA)were estimated by the method of Falholt et al. (1973). The serum creatine phosphokinase (SCPK) activity was_assayed by the method of Hughes (1%2).:Gastrocnemius skelebl muscle tissue was digested in 30% (w/v) KOH and 0.5% (w/v) NazSO, and glycogen was isolated by the method of Good et al. (1933) and dissolved in 5N HzSO4. After neutralization suitable aliquots of this solution were taken for estimation of free glucose equivalents of glycogen by the kits obtained from J. Mitra & So*. To determine the adipose tissue lipolysis, epididymal fat pads of an average weight of 250 mg were incubated in 5 mL Krebs Ringer bicarbonate buffer, pH 7.4 (Umbreit, 196.1) containing So/" fat free albumin in an atmosphere of 95% O2 and 5% COz at 37'C in a Dubnoff metabolic shaker (Exton et al., 1972). One milliliter aliquot of incubation medium was taken out at 1 hour of incubation and FFA were d c termined in the aliquot by the method of Falholt et a1.(1973). At the end of incubation, adipose tissue was removed, washed with normal saline and after delipidization, protein content was determined (Lowry et al., 1951). The results are expressid as microequivalent FFA released per milligram protein per hour at 3 . 7C
Stntistical ailnlysis The results from CIHP-I administered anitissue liyol!/sis nild mals were compared with water-heated control animals in all the experiments and the data Rats were given CIHP-I for 12 weeks (7.5 was analysed statisticallyusing Student's t test. mg/kg-l day), and exposed to the multiple Results were considered significant at the p < stress of cold hypoxia-restraint (SC, 428 mm 0.05 level. Hg pressure). When the T reached 23"C, an, imals were killed by decapitation and blood RESULTS was collected in heparinized hrbes. Blood samples were also collected for serum separation. CIHP-I administration, at B dose of 15 mgl Epididymal adipose tissue and-gastrocnemius skeletal muscle were removed, blotted free of kg-' day for up to 3 weeks kesulted in low
KUMAR ET AL.
TABLE E c O F CIHP-I ADMINlSTlUllON 2. m r (15MG/KG/DAY) THREE W R WEEKS AND
THREE WEEKS THE BODY OF; WEIGHT GAIN RATS OF M y wight (g) mcun 2 SEM
%/BSEQUE~TLY R C ~ E D C OVER FOR
Weeks
Initial
First week
Second week Third week C~OSJOV~~
Fwrth week Fifth week Sixth week
--
After third week, animals were crossed over. Composite Indian herbal preparation-! (CJHP-I) was given to controls and its intake in experimental animals was *ope. Significantly different as compared with vehicle led control rats.
body weight gain as compared with the control rats. The administration of CIHP-I was crossed over in the following 3 weeks. The low gain in body we~ghtwas observed in control rats given CIHFI (Table 2). When the CIHP-I dose was reduced to 7.5 mg/kg per day and given for 12 weeks, there was no significant change in the body weight gain as compared with the control rats. The weight of different organs of rats administered CIHP-I (7.5 mg/ kg-'/day) for 12 weeks were also not different when compared with control rats (data not given). The effect of single dose of CIHP-I at different dosage, rliz. 7.5, 15.0, 75.0, and 150.0 mg/ kg body weight, in relation to maintenance T model are and recovery of , in the C-H-R
given in Table 3. The duration of cooling time to 23C increased by 30% at a dose of 7 5 mg. It was not increased further with increasing dcsage kom 7.5 mg to 75.0 mg/kg. At a dose of 150.0 mg/kg the cooling time was observed to be further increased ( ! % o control values). 45 f Recovery t m o , to 3TC from 2 was ie f T 3C also observed to be decreased (approximately 40%) at a dose of 75.0 mg/kg and above. The effect of a single dose of CIHP-1 administration, 15 mg/kg-'/day, for 5 days on the , maintenance 01T during exposure, are given in Table 4. The time required for , to fall to T 23C was increased by 9% after administration of single dose of CIHFI. When the rats had been given five dose of CIHFI 1 dose per day, the time for , to fall 23C was significantly T increased by 29% and recovery time of'T,, 3T"C decreased by 18%. The thermoregulatory capacity of the rats during exposure, after oral administration of CIHP-I for 6 and 12 weeks at a single dose of 7.5 mg/kg, is shown in Table 5. After 6 weeks the duration of the cooling time was increased by 11550 (from 65 minute to 110 minute) as compared with control rats. The intake of CIHP-I decreased recovery time by 34.5"h and 26.7%after 6 and 12 weeks, respectively. CIHPI administration (7.5 ing/kg-'/day) for 12 weeks in rats, prior to C-H-R ( T , 23"C), resulted in a significant increase in blood glucose, muscle glycogen, adipose tissue lipol$is, and serum FFA levels in comparison to control rats (Table 6). CIHP-I treatment also restricted the release of CPK in circulation by 48?" (Table 6) during acute hypothemia (T,, 2') 3C.
TABLE EFFECT SINGLE OF CIHP-I 1 RATS ox MAIWEXA~CE 3. OF ~XBE s OF RECTAL TEMPERATURE OX EXPOSURI: (,, T,) to S0C, 428 hlhr HC ATMOSPHERIC PRESSL.RE RESTRAIPCD IS STATE
fTintc i ~ tniirtl
Dose
tngAcg-
'
To attain
n
T WC ,
(Mcnn
-
To nttaB~T, 3' 7C
SEMJ
-
Vehicle (controls) 75 . 15.0
5 5
5 5 5
75.0
150.0
65.40 2 2.23 83.80 t 2.02' 04.20 t 3.42' 85.80 2 3 6 ' .9 95.00 t 5.62.
157.80 2.47 163.60 2.75 lf0.00 = 6.72 103.00 2 6.86* 9 . 0 r 42' 34 .3
T~gnificantly different as compared with veh$k fed control rats. C W - I , c o m p i t e Indian herbal preparation-.
95
THERMOGESESIS BY CIHP-1 AISD ITS MECHANISIM
DISCUSSION
CIHP-I administration at a dose of 7.5 mg/kg body weight was found suitable for prolonged intake, and body weight was comparable with To attiti11 T 2jCC To attaal T,, 37'C control animals up to 12 weeks. The prepara, Dowrs~ 1 1 ( M L ~ = ISE.\,l) ~ I tion had no gross effect on the weight of the internal organs even after prolonged intake for Vehicle 6 76.70 = 3.51 171.50 = 2.65 12 weeks at a dose of 7.5 mg/kg. (control) Single 6 86.30 = 2 5 ' .9 167.30 = 5.84 The-single daily dose response of CIHP-I Five 6 98.20 = 55' .91W.00 = -1.208showed that the preparation was effective in increasing the resistance to cold-hypoxia at a 'Signlticantly different irom vehicle ied control rats. -5gnificimtly different irom single dow administered dose of 7.5 mg/kg, but was unable to increase rats. the recovery from C-H-Rstress at a CIHP-I CIHP-I. composite Indian h;rhal prepamtion-I,
fTi1il)te1 I I I ~ I I ~ 11
(T,,,) c>s E X ~ L R TO 5'C, 428 11s1HG E AT>~OSPHERIC PRESSURE RESTRAISED IS STATE
T !I{I
I q. EI ITLT or SI\ \XI> TWI ir LVI I h\ 01CIHP-I A I ~ I I \ I S T R , \ (7.5> \ I ~ I I \IG/K(;)\ R,\rs c)\ MAI~TI:X,\\~ I c (11. RI i r \ I Ti-\l~-ra.\rcccr ) 0 E\I*~-L re> 5'C. 42n \I\( He. . \ ~ \ I ~ ~ I . I ~ H IPHESSLIII RISTI<,\I\I.II\ I I tT..,. \ wc \ Sr
(
TIIIIC1 111111I 1 1
)I
T ettitr~~ 23C o T.,, T ~ I ~ ~ ~T,,.,I .:i-C o II I (MI.OII SEIM)
svl.cL.
I.?\vt~cL~.
\'~-l~~zlc. ~zimtroll CIH1'-I Trc~trd Vchlclc icontrol) Cllir-l Treat4
n
12
h
12
h5.W z 4.IX) 14o.00 r 5 . 0 . 7O.tN) r 4.M 135.(X) I 3.00'
Ih5.00 = 107.~0 159.20 r 1Ih.il1
= n.30~ 7.iN) = 5.2l)*
2.80
'%<~i~l~t..~ntly dllh~rent from vrhlclc t c d iontrcll r.its CII 11'-I, iompiisltc. lnd~an hcrbal prcparattc~n-I.
T.\III h. EII:I:C.T CIHP-I :IU\II\ISTII.\III~\ K IOI<) T ~ I I WEEKS BICWO I ill: (7.5 \ I C ; / ~ ; \.E os GI.LCOST, .MLWI.KI )C.~K;I:\, (; SI:RL\I FFA. SI~ L \ IPlrirrl.l\, Au11.tr;i TISSLE LIPOI.\SIS ASD SCPK A c r ~ v ~ n R ~ r s (IF Eurhl v ro Ct11v ,\XU H ~ I T ) \ ( i. '\C . 428 \ I \ I He. Ar\loLj1~111:~1(~ I PHFSSURE)ATT..\IXI\(; 23C 0% Tub. Bt.tori. C-If-R 1-.rjmsrrriP
II
(011
A k r C-H-R ~..rp$rrrc~ obtnr11111~q 23'C) T,,.
Co#ltn~l 65.30 =1.70 3.03 ~0.36 51 1.00 32.19 7.45 =U.15

0.U
E . ~ p e n ~ ~ ~ n ~ t n l Co11tr01 68.70 =5.20 +3.21 10.56 52.80' ~3.80 +2.81 ~0.32 18.18.00' 153.00 7.15 ~0.28 0.62' ~0.07
E.rjwrbr~c~~rtnl 105.00'=10.10
B I I M J gluccw Img "it) hluxle glycogen mg/g tissue Serum FFA (mq/L) Serum protein
(go:,) Adipow tlssue lipolysis (meq FFA released/mg proteinihr at 37C) Serum CPK (mlU)
5
3
. I
545.60
~53.57 7.69 =O.N 0.58 10.06
3.89 ~0.38 2565.60'177.69
=0.07 12
7.60 20.31 0.89'20.10

87.6)I0.Z
169.48 23.00
'Significantly different in comparison to unexposed rats of the respective group. -Sisnificantly different in comparison to vehicle ied and cold-hvpoxia-mtrain (C-H-R)exposed control rab, CIHP-I. composite Indian herbal preparation-I; FFA, free fatty acids; XPK, serum creatine phosphokim;,T , rectal temperahare.
96
KUMAR ET AL.
dose less than 75.0 mg/kg. However, when CIHP-I at a dose of 15.0 mg/kg was given for 5 days, it was able to increase the recovery time as well. This suggested that CIHP-I had a cumulati\re action. The thermoregulation capacity of the rats under extreme conditions increased significantly after 6 and 12 weeks of CIHP-I (7.5 mg/kg) intake in terms of delayed , T fall of T to 23C and faster recovery to , 37'C. The CIHP-I evaluated in the present study contained 7 herbal components and asphalt. Five herbal components i n d asphalt presbnt in CIHP-I were common to ClHP 11, an earlier investigated preparation which contained 39 plant components and 6 minerals (Grover et al., 109.5). Stress-induced neurohumoral changes play an important role in increasing adipose tissue lipol!.sis and providing more FFA (Chattopadhyay, 1974) through the circulation to energy Jc~ticicnttissues, wherr they undergo intramitochondrial oxidation to generate energy. We lia\.c observed that in rats administcreci C1HI'I (7.5 mg/kg) for 12 ~vccks and cxyosccl to C11-li (T,.,. 23"C), adipose tissuc lipolysis increased bv 43..5':ab wliile thc rise in serum FFA was only 3H.Wq9, comparison to control rats. in This suggested that some part of FFA mobil i ~ c dfrom adipose tissue is being utilized for cvtra energy generation under the influence of CIHP-I intakc that might be responsible for increased cold tolerance (T,.,23C) in the animals, observed earlier. The results also suggcsted that CIHP-I acted in s p r i n g carbohydrate reserves as evidenced from better maintained blmd glucose and muscle glycogen Ic\,els in rats treated with this preparation (7.5 nig!kg) for 12 weeks and exposed to C-H-R (Table 6). The increase in SCPK activity is a sensitive indicator of energy-dependent cellular permeability and injury to muscular, cardiac, and administration has neural cells. ~ d a ~ t o ~ e n been shown to restrict the release of CPK in circulation by aiding the oxygen delivery system (Srivastava, 1991). In the present studv, administration of ~ ~ ~ (7.5 mg/kg per. body p - 1 weight) for l2 weeks was observed '0 restrict the release of CPK into the ~ i r ~ u l a t iof l l ~ C-Hexposed rats. This suggested that CIHFl was
acting at a cellular level in maintaining the energy dependent process of membrane permeability. The results of the present study show that CIHP-I had strong adaptogenic activity as tested by C-H-R animal model. The preparation had a strong cumulative effect during long-term administration even at a low dose of 7.5 mg/kg-'/day and it helped with better resistance to the C-H-R-induced hypothermia (T,,, 23OC) of animals by more mobilisation of FFA from adipose tissue and better maintained carbohydrate reserves; The adaptogens offer an interesting alternative to managing cold and hypoxic stress of extreme terrestrial altitudes. ACKNOWLEDGMENT The authors thank Lupin Laboratories Ltd., India for providing the CIHP-I and sponsoring this work. REFERENCES
Uliarg.iva KI'. Singh, S . :\iitistrrss ~ctivit!. 01 ~~irttttott u?rrt.trr~tt I.ii~ti. Ind I %1'~1 Rc?. IYH1;73:443451. Urrkhman 11. \Ian aiid Bic~logic.ill!. Activr Suhstancrs. Oxiord: I'crgamt~nPr~?is. 1YA). Chattoyadh\ay Dl'. Adipow tissuc mrtabolism during li\pobaria. Dcf Sci J 19;4;24:155-161. Exton JH. Fricdmonn X, Ellcii H, \Vong .A. Park JB, Carbin JD. I'ark CR. Intrractic~n of glucocorticoids with glucagon and epinephrine in the ccmtrol of gluconrogenesis and glycogenolysisin the liver and oi lip~lysis in adipose tissue. J Biol Chem 197?;117:3519-3588. Falholt K, Lund B Falholt M . An easy colorimetric mi. ' cromethod ior routine determination oi free iatty acids in plasma. Clin Chim Acta IYi3;16:IOF111. Fulder S. The drug that builds Russians. New Scientist lY(W;b:37&3i9. Ghcwal S.Kawanishi K. Saiki K. The chemistry of shilaiit (dour. Ind J Chem 1993;SLB:4o-U. Ccmd CA. Kramer H. Somcxyi hl. The determination of glycc~en. BicJ Chem 1933:11K).U;~491. J Grover SK,Divelwr Hhl. Kumar R. l'ahwa ML. Bhardtvaj SK. Gupta AK. Srivastava KK.Experimental evaluation 1 of a Commite Indian Herbal Pre~oration1 (CIHl' 11) as an a d a ~ t q e and its mechanism of action. Int J Pharn macW"Y1995;33:1*13. Hakim SAE. lndian remedies for p r memory Br Med J 1951;2:851-853. A method for the estimation of serum creaHughtine kina, and &jolaw jctivit, In normal and pathological serum. Clin Chim Acta 1%2;7597-600
THERLMOGENESISBY CIHP-1 AND ITS IMECHANISIM

Jan1 YK. Patel \lR. Pawl RB. Ptrt*riirm ttrll~*rowl: An Singh .\I, Nath R. Lata A, Singh SP. Kohli RP. Bhargava overview. Ind D r y s 1981;19:93-95. KP. Witlm~rm sotitrr!~trn(Ashwagandha), a rejuvenating Kandcprkar CK. Kulkam~ RD. Antltatig~le etiec!s ot inherbal drug which enhances survival during stress (an di~enous r u ~ d 'Centorte' in rats. Ind Drugs 1981;18: adaptogen). Int J Crude Res 198220:29-35. 246-549. Singh N,Nath R, Yishra N, Kohli RP. An experimental Kulkarni SK. Verma .A. Evidence for nootropic eifect of evaluation of anti-stress effects of Geiiforte. Q J Crude BR- 16.4 (&lentat\. herbal psychotropic preparation in A . Drug Res 1978;16:15136. rnlzc. Ind I Ph!.stol Phdrrn~col1991;3629-34. Srivastava KK. Stay in High .Mountains and Pa)tfl.r ~ J I Kurn.lr R. Gro\.er SK. Divekar HM, Gupta AK. Radhey w11,y. Delhi, India: Publication Detence Institute of PhysSh\am. Sri\.astava KK. Enhanced thermol;cnrs~s rats in iolop and Allied Sciences, 1994. b \ I'ii~m.v:;r~t~stt~, rnult~vttarnina and minerals. Int I Bio- Srivastava KK, Grover SK, Ramachandran U. The memmctcc)rol IWh:.iY:IS;-iYl. brane integrity changes at high terrestrial altitudes. In: Kumar R. Shyam R. Divt*harHSI. Pahwa ML,Sri\.astava Kidwa~ AM. Upreti RK. Ray. Biomembranes in Health KK. Slechan~srnot ~ n c r e a ~ d tolerance to stress .liter and Disease. New Delhi, India: Today & Tomorrow iornposltc Intitan herbal preparation I1 (CIHPll) .ldPrinters & Publishers, 1991;501-505. mlnlhtratlon. Pharm.~icutlcalBiol (in prms). Lrnbreit WW, Burris RH, Stauffer IF. Manometric TechI.tn\.r\ O H , Ro~ctrrcxtxh Fxr .AL, Rand.ill RJ. Protein XI. nlques: Minneapolis. WN: Burgess Publishing Cornrncasurcmcntz wth Foiln-phenol rc.lgcnt. J Biol Chem pan!, 19M:132. I Y q I , lc13 2(>.3-25. Address reprint requests to: \.itih.lrn~ .\K, ell. Indl.in \l.itrrt.l XIc~li~3. edition. 3rd 130nib.l\. 11iti1.1: P~~pi11.ir Dcpot. 1954. Bt>oL K. K. Srirnstflzn M.Sc. Plr. D., M.D.P.A. I<,lni,~ch.indr.ln C. V I c.~.11 H.\ Cro\.cr SK. Sri\.,ista\..~ A I. Director (Projects) Kh. New cxycr~m~~it.il nu)Jel tor thc c\valu.lt~ontit Difcrice lr~stitlltc Plty~lsiolugy . ~ ~ l . ~ p t i ~proctuits. c I Eth.~noph.lrm,~ctil IY40;2Y: ~t~tl~ airti A l l i ~ ~Sri~vrccs ii -,7-2s I Llrckt~oi~ o d , Tiiimrprr R <I\.I~III.I Ileh.~~ii~h.~r 5. -;. h;.rr.ititiih.ir 5M. L:.fi~.ct> long tit ttSrm .l~tmln~slr.lt~c,n 'the , ro~thot :\hh!vd~dndh.i . trt D~7111i1 10 054 (Irrrlin) I\.\ 1tli.1n1.1 .~~nililtc.r.~t tih.~t.~v.lr~ .inti IA~p.lragusracct i i o ~ t 111~119 l~ittIlru+ IYSi;Z.?:i.7.3-:3Y. ~ r.i
of
3--
98
ANTI-ARTHRITIC DRUGS
A PRELIMINARY CONTROLLED CLINICAL TRIAL OF INDIGENOUS COMPOUND DRUGS IN CASES OF RHEUMATOID ARTHRITIS*
By :
R, H Singh .
S S ~ishra . .
K. M. Tripathi & N. S Bhat .
R e p r W from :
Rheumatism
Vol, 19
No. 2
99
tablet8 three times a day. The patients were followed up every fortnight and the results were recorded on the following parameters. (I) Qmptomatic relief and changes in feeling of well/ill being.
(2) The rate of shift of the grade of severity of major signs and symptoms of the disease rated with the help of a symptom rating scale (Table-I).
(3) Rate of functional recovery in terms of changes in the following indices :
(4 Walking time.
(b) Grip power in both hands and (c) The pressing power measured with the help of a sphygmomanometer. (4) Laboratory investigations in terms of changes in haemogram and E.S.R.
(5) Psychological assessment in terms of changes in tbe level of anxiety measured k i t h the help of Swamoolyankan prashnawali (anxiety scale, constructed by Dr. R. R. Tripathi of the Department of Psychology of 'B. H. U.)
RESULTS AND DISCUSSIONS The results, in cases which could be followed up for a period of three months a r e summarised in tables 2-6. The patients treated under this trial showed a moderate degree of improve&ent both at the level of symptoms and joint functions. The clinical manifestations like fatigue, malaise, fever, loss of appetite, canstipation, joint pain, stiffness, tenderness, swelling, soft tissue changes and deformities if any were found influenced by the treatment. The grades of these manifestations showed a minor reduction in 11 patients treated in group A. The 'e $ cases receiving trial treagment in group B showed notably better result-s I compared to other group (Table - 2). Similarly the assessment of the functional status showed only a slight functional improvement in case of group A while the functional recovery was found more in case of group B (Table-3). The haematological studies revealed significant reduction In E.S.R. while the haemoglobin percentage and other aspects of haemogram did not show any change.(Table-4).
In psychological assessment only 10 cases (4 in group A, 5 in group B) could be followed up for a conclusive duration of time. here is evidence of reduction in state and free floating anxiety after treatment. (Table-5).
Thus if can be conclued that the drug Rh-1B (Rhumayoga)may have a moderate degree of anti-arthritic effect insubacute cases of Rheumatoid arthritis.
101
Rh. 1A (AU)was tried in the dose of two tablets three times in a day in three patients of Rheumatoid arthritis with acute presentation for one montheach. These patients showed significant improvement (Table- 6) and tbe drug appears to be superior than the two other coded trial drugs, which did not show very good response in acute cases. Rh. 1A (AU) also.took a minimum of one weak to show respoose in acute cases. However, it appears useful and is worth trial in acute Rheumatism. Further extended trials are suggested.
Sbowing Rating Scale for Symptoms of Rbeumtfslll 1.
Joint pain
Absent Minor Moderate Severe Absent Minor Moderate Disabling Absent Minor Moderate Severe
Absent
0 1 2
3
-
2.
Stiffness
0 1 2 3 0 1 2 3
0, 2 2
3.
Swelling
4.
Tenderness
Minor Moderate Marked

5.
3
0 1 2 3 0 1 2 3
Functional Disability
Absent Minor Moderate Crippling Absent Minor & Localized Moderate Severe and Multiple
6.
Deformity
SELECT RESEARCH PAYkHS ON EVIDENCE BASED AYURVEDIC DRUGS
102
Sbowing the rate of symptomrtic recovery in terms of grades of some systemic and local manifestation in the twe comparative groups
Group Rh IA Observations Initial Group Rh IB Initial
15 days
I 2 month monfhs
15
days
I 2 month nronths
Fatigue Malaise Fever Loss of appetite Constipation Joint pain Stiffness Tenderness Swelling
1.90 1.90 1 9 1.80 .0 1 6 1.40 .3 1 7 1.50 .2 1 6 12 . 3 .1 ,2.45 2 1 .0 2 3 2.00 .6 2.10 1 7 .0 16 14 .3 .0
1.33 13 .3 1.10 1.00 1.W 16 .6 1.66

1.44
16 . 16 . 12 .5 07 .5 0.50 17 .5
2.52 22 .3 1.64 16 .6 17 .0 2.82 2.58 2.47 2.29 21 .1 2.27 2.17 1.00 0.83
19 .1 1.72 13 .6 12 .7 11 .8 2.36 2.18 21 .8 18 .1 16 .6 20 .0 16 .3 09 .1 0.77
2.0 19 . 06 . 04 . 06 . 16 . 14 . 12 . 14 . 10 . 12 . 10 . 10 . 08 .
15 . 15 . 04 . 0.00 05 . 10 . 10 . 10 . 10 . 0.75 0.75 0.75 10 . 10 .
1.60 1.60 1.20 10 .0 1.25 1.00 10 .0 0.75
1.11
Local temperature 1.55 1.40 Soit tissue Loss of function Deformities
11 1 . 12 .0
1.20
16 14 .3 .0 1 6 1.40 .3 1.00 1 0 .0
11 .0 0.77
Muscular wasting 0.63 0.70
Values are mean grade Scores.
103
Showing the pattern of functional recovery in the two compuati~e pomp&

--
Functional tests
Group Rh I A Initial Follow up

28.5 25.0
Group Rh 1B Initial Follow up

45.42 31.50
Walking time in second Grip power in mm Hg. Rt. hand Et. hand Pressing ponrerin m a Hg. Rt. hand
58.0 55.1
63.5
49.14 51.19
72.19 62.14
Et. hand
66.6
Showing the haematological changes following treatment in two groups

-
Investigations
Group Rh I A Initial Follow up
Group Rh 1B Initial Follow up

35.23 21.50
E. S. R. in am.
4 1.OO
32.00
104
Showipg the pattern of ebisgee is anxiety level io selected cases in the two group
Group Rh IA. Anxiety Initial Trait Free State flooring
73 64 66
a+++
S. No. Patient#
State
Follow up Trait Free floating
1.
Asha Rani Dasa Raj Nath
2.
3. 4 .
Abrar Ahmtd
Ram k h a w
Average
+++ 4++ 70 56 +++ ++ 35 60 + +f 42 63 + +++ 51.25 63 +++ -t++
58
+++
42
-t+
++ ++ 58
59
61
39
+ 49
+ ++
54.5
+ 36.5
31
++ +
34
47.3
58.5
++ ++
Group Rh 2B Anxiety Initial Trait Free Slate floating

49 40 42
S . No. Patients
State
Follow up Trait Free floating

67 46
1.
2.
Awadhesb Yadav Banarasi Pd. Singh Subhash Chandra
46
3.
4.
5.
+++ +++ + +C+ +++ + 103 80 76 91 64 80 +++ +++ +++ +++ +++ +++ Sahodara Singh 76 63 80 74 67 82 +++ +++ +++ +++ +++ +++ 44 32 47 Amar Deo Cbaubey 37 51 57 + + ++ + + Average
58.6 74 62 54.6 70.8 54.2
+++ +++ + 54 84
53
49
++ +++ +
82 45
105
Showing the pattern of shift of grades of symptom towards the betterment in some systemic, and locrl manifestations, and some fanction81 changes -by the Rh 1A (AU)h Acute Rheumatoid Arthritis cases.
Observations
Initial
Follow up
Systemic Features
Fatigue Malaise Fever Appetite Constipation Others
Local Manifestations
Joint p a i ~ Stiffness Tenderness Swelling Local temperature Soft tissue Loss of functions Deformities Musclar wasting
Functional Tests
Walking time Grip power
40 sec.
30 sec.
R 5
60 mm Hg.
Pressing Power
R L
H. g 30 m m Hg. 40 mm H . g
70 m m
65 mm Hg. 75 m m Hg.
35 mm
Hg. 45 m m H . g
106
SUMMARY
The modern treatment of Rhotubatoid Arthritb is lpostly pplliative, Certain indigenous drugs are suggested to W useful. Indigenous compound drugs, Rh-1 A, Rh-IB and Rh-1 (Au) ,were tried clinically. In tlks controlled clinical trial Rh-1B is found to have moderate degree of anti-arthritic effect in subacute cases of Rheumatoid Arthritis. Rh-l' (Au) is found to be d i in Acmte Rheumatism, Furqer extended trials are suggested.
107
Ref.
.......... GY..1.PPc2..4.C! ....
Reprint fim :
The Indian
Practitioner
Vol. XLVl No. 12
Cllnlcal Trlal
DECEMBER 1993
Pages:931-941
Efficacy of Rhumayog and Rhumayog with Gold in Rheumatoid Arthritis A Double.Blind Study
U.R.K. Rao Addttional Professor, Dept. of Medicine, NIMS, Hyderabad N.S. Bhatt Medical Director (Ayu), Zandu PharmaceuticalWorks Ltd., Bombay M.U.R Naidu Additional Professor T.R. Kumar Assstant Professor U.Shobha Senior Resident CPMR, NIMS. Hyderabad
K Venubabu Resident, General Medicine, NlMS.Hyderabad
Paper presented at "XVlllth (ILAR) International League Against Rheumat~sm, Congress of Rheumatology held at Barcelona, Span, July 1993.
101, Lawrence Apartments 11, Vidyanagan Marg, Kal~na, Santa Cruz (E), Bombay-400 098 (a 61 1 6170 or 613 0329
108
me Indian Practitioner
Clinical Trial
December 1993 Vol. XLVl No. 12
Efficacy of Rhumayog and Rhumayog with Gold in Rheumatoid Arthritis A Double Blind Study
U.R.K. Rao*, N.S. I3hattQ, M.U.R. Naidu*, T.R. Kumarw*, U.Shobha+,K. Venubabu" SUMMARY Thirty patients (women-22, Seropositive-21) with active rheumatoid arthritis were studied to evaluate the efficacy of Ayurvedic products Rhumayog (Rh)) (n=:5) and Rhumayog with Gold (Rh Au) (n= 15) for a period of 6 months. Both drugs showed antiinflammatory and disease modifying activity. Patients on Rh showed improvement in articular index (A/) (p=0.001). pain index (PI) (p=0.01), walking time (WT) (p-0.05), ESR (p=0.01), CRP (p=0.01) and in lmrnunoglobulins (IG) (p=0.001), WT (p=0.05), E S R (p=0.001), Rheumatoid Factor (p=0.001) and lg levels - IgG (p=0.001), lgA (p=0.05) and IgM (p=0.01). However, Rh Au was better in improving the grip strength (p=0.05) and morning stiffness (P=0.01). No side effects were encountered with the drugs during the study .period. Ayurvedic preparations Rhumayog and Rhumayog with Gold have positive role in the management pf Rheumatoid Arthritis due to their antiinflammatory and disease modfiing acivities.
KEY WORDS
Rheumatoid Arthritis, Rhumayog, DMARDS, Ayurvedic Drugs. INTRODUCTION RheumatoidArthritis (RA) is a chronic disease with uncertain aetiology affecting about 1 per cent of the population. Untreated deformities and/or ankylosis of joints will ensue with marked suffering. Drug therapy forms the mainstay of the treatment which has two fundamental objectives:
1. Short term suppression of inflamma-
achieved by nonsteroidal antiinflammatory drugs (NSAIDs) and

2. Long term suppression of inflammation which may lead to presewation of joint structure and function to lessen the likelihood of deformities which is achieved by disease modifying anti rheumatoid drugs (DMARDS)'. The currently used drugs in relieving the symptoms are not free from untoward side effects, the major being gastrointestinal. Gold salts which belong to the group of DMARDs are not without side effects but are used in therapy of established disease2.
tion in joints which lead to lesser pain and greater mobility, generally
Additional Professor, Dept. of Medicine, NIMS, Hyderabad, @ ~ e d i c aDirector (Ayec),Zandu Phamaceutical l Works LM., Bombay, *Additimal Professor, *Assistant Profesx)r,'Senior Resident, CPMR, NIMS, Hyderabad, *+Resident, General Medicine, NIMS, Hyderabad. Paperpresentedat ';YVlllth (ILAR) International League Against Rheumatism,Congress of Rheumatology held at Barcelona, Spain, July 1903".
--
The lndlan Prectltloner
Ayurvedic medicine widely practised in India has description of disease similar to RA and is claimed to offer treatment of the same through drug and non drug therapies31415 Gold preparation in a different form as Gold Bhasma a colloidal form of metalic gold- is used in Ayurvedic treatment for variety of disease including R A ~ . Two Ayurvedic pharmaceutical preparations Rhumayog (Rh) and Rhumayog with Gold (Rh Au) in two earlier preliminary studies were found to exhibit a moderate degree of antiarthriiic In an experimental study Rhumayog also was observed to potentiate the antiinflammatory activity of other NSAlDs when used concomitantly9. A double blind study involving Rhumayog (Rh) and Rhumayog with Gold (Rh Au) was undertaken to evaluate 'the antiinflammatory and the disease modifying effect in patients with active RA. MATERIAL AND METHODS Thirty three consecutive cases with R A attending rheumatology services of Nizam's lnstiitutp of Medical Sciences were enrolled into the study. The diagnosis of R A was based on the American Rheumatology Association (ARA) criteria1'. Each patient had thorough clinical, haematological, serological, immunologjcal and biochemical, radiological evaluation. The disease was graded according to the Steinbrocker's classification1'. Inclusion and Exclusion Criteria Male or female cases with R A seropositive or seronegative - with morning stiffness of more than 30 minutes
and E S R levels more than or equal to 30 mmllst hr. belong to the age group from 18-60 years were included for the study. Patients having active peptic ulcer disease or major systemic illness with renal or hepatic impairment and female patients planning for progeny or lactating mothers were excluded. Patients using steroids or disease modifying drugs such as chloroquine, auranofin, injectable gold, sulfasalazine and methotrexatewere also excluded. EvaluatlonCriteria The parameters for evaluation were as follows Clinical- Articular lndex (Al), Pain lndex (PI), Loop Size (LSr) right, Loop Size (LSI) left, Grip Strength (GS) mm Hg., Walking Time (WT) 15 mt in seconds and Morning Stiffness (MS) in minutes. Laboratory- Haemoglobin (Hb), Erythrocyte Sedimentation Rate (ESR), Rheumatoid Factor (RF) , C-Reactive Protein (CRP) and Immunoglobulins (IgG, IgA, bM). After basal evaluation the clinical evaluation was done every month, the haematological biochemical and urinalysis every two months whereas the immunological and radiological studies were done at the end of 6 month therapy. Routine parameters including liver and renal function tests were also done at regular interyals so as to notice any untoward effects. A case recordform specially designed for the study was followed.
-
110
The Indian Practitioner
The medicines coded as Rh-1 and Rh-2 were supplied in the identical capsules to the randomised patients in a daily dose of 4 capsules (500 mg each) three times a day in a weekly packing which was specially prepared for the study. No concomitant therapy such as aspirin, naproxen, diclofenac or ibuprofen were allowed. A provision for record of any other illness during the
period study and that Of any effect were in the case record form.
in group Rh-2 belonged to functional class II or Ill and anatomical stage II or Ill. In the Rh-1 group statistically significant improvement was observed in Al (P<0.001), PI (P<0.01) WT (P<0.05') with the treatment. There was significant fall of acute phase reactants namely ESR (P<0.01) and CRP (P<0.01). There was significant change in immunoglobulin levels (P<0.001), (Table24 In the Rh-2 group statistically significant improvement was observed in Al (P<0.001), PI (P<0.001), GS (P<0.005), WT (P<0.05) and MS (P<0.01). There was significant fall in ESR (P<0.001) and RF (P<0.01). The change in immunoglobulin levels though variable was also significant [ IgG (P<0.001), IgA (P<0.05), IgM (P<0.01) 1. (Table- 3). Figures 1 to 6 indicate the Comparative Percentage Variation in clinical parameter with both the drugs. Figs 7 and 8 provide the same in ESR and immunological parameters respectively.
RESULTS
The study was designed so as to get 15 cases in each of the two groups which either will complete the study or provide specific information for the drop out. However, totally 33 cases were enrolled of which 3 were dropped, 2 due to non compliance (non reporting) and 1 due to occurrence of pregnancy. At the end of the six month trial it was known after decoding that there were 15 patients' in each group of Rh-1 (Rhumayog) and Rh-2 (Rhumayog with Gold). The demographic data of the patients is given in Table-1 The analysis of results showed improvement and interestingly comparable results. All the patients except one case
The analysis of variance though did not show any statistically significant difference between the drugs.
Table 1 Demographic Data

Parameter
No. of Patients
(Rh-1) Rhumayog 15
12: 3
38.2 + 10.4 (range 22-52)
(Rh-2) Rhumayog with Gold 15 10: 5 38.13 + 09.34 (range 22-50)

25.60 + 33.13
9
Female : Male Age (years) (Mean + SD) Duration of Disease (Months-Mean+ SD) Seropositivity
36.73 t 26.40
12
DISCUSSION
Ayurvedic durgs are claimed to have beneficial effects in the treatment of Rheumatic disorders. Many of these drugs have Guggulu- gum exudate of a plant Commiphora Mukul, is the main irtgredient. Purified, steroidal fractions of Guggulu show a marked inhibition of platelet aggregation by ADP, Adrenalin and Serotonin, the effect being comparable to that of clofibrate14.
The steroidal component of fraction A of the petroleum ether extract has marked antiarthritic effect, comparable to that of hydrocortisone, anq more potent than ~henylbutazone'~. "
A steroidal moiety isolated from guggulu the main component of Rhumayog was found to be more potent than hydrocortisone in inhibiting the severity of the secondary lesions in the animal model of adjuvant atthritis12*". Guggulu is always prescribed together with Maharasnadi quath in the Ayurvedic practice. The quath possess a mild antiinflammatory activity (Sharangdhar Samhita Part 2, Chapter 2). The exact mechanism of their beneficial action is not yet fully known in terms of b i h e m i wl prameters16 Rasnadi Quath, another component of Rhurnayog, has Rasna (Pluchea lanceolate) as main ingredient. The antiinflammatory potential of some
The Indian RaotWoner
December 1993Vd. XLVl No. 12
13. 14.
IgA (mg/l) IgM (mg/l)
582.26 + 291.47 484.86 + 292.46 267.2 + 84.64 185.46 + 58.18
2.46 5.9
0.05 0.01
Ayu~edic formulations containing b j the Pluchea lanceolate extract was tested on experimental Arthritis and granuloma pouch. This showed marked antiinflammatory activii in both rn~dels'~. Although remission induced by gold therapy may be associated with better immuno regulation and suppression. of inflammatory activity, it is unclear whether this reflects direct ahion of gold on the disease itself or epiphenomena. Gold has been shown to alter the humoral immunity, complement systems, lymphocyte, monocyte and neutrophil activitiesf8.
Rhumayog is considered to be analgesic and antiinflammatory where as Rhumayog with gold has both antiinflammatory activity and disease. modifying property. Antiinflammatory activity is measured by the reduction of pain and swelling of joints, reduction of severity and duration of morning stiiness and improvement in grip strength and walking time. The disease modifying property is guazed by reduction of acute phase reactants as well. They include ESR and CRP". Progressively decreasing acute phase reactants with improvement in clinical parameters denote regression of rheumatoid disease activlty. This was 0bse~Bd both groups in
113
December 1993 VQI. XLVl No. 12
The lndlan Practitioner
RHUMAYOG I N RHEUMAT010 ARTHRITIS CLINICAL :ARTlCULAd INDEX
o \
-10
X CHANCE
- \<
--
--
I _ _ I -
---
--
__-_ -
._ -
-----50
-80 0
--
- - - ---
-0-
-- -- -- -- -- .
-%
- -3
4
-. - -- - --- -
MONTHS AFTER TREATMENT

Fig. 1
-a-RHUMAYOG-NOGOLD
_
..
+RHUMAYOG
-WITH GOLD
'RHUMAYOG IN RHEUMATOID ARTHRITIS CLINICAL :PAIN INDEX
.-..... ..
-..
-
---.I
I
--,
,
-30
.-
--A-
2-
6 0 ,-
4 0
----..
-..-I
..
--------I
-.--- I
--- - - -.------ --..- 2
-70
1.
'
..
MONTHS, AFTER TREATMENT

~ i g2 .
-P- RHUMAYW&O
GOLD
+RHUMAYOG
-WITH GOU)
114
RHUMAYOG IN RHEUMATOIDARTHRITIS
CUNICAL :MORNINQ STIFFNESS (MIN)
--_.-.- - Q-
...---
..
-60
---- 0
"
-.-I
I
-.-
-....
-.
I
-80
' . 2

Fig. 3
-0-RHUMAYOG-NO GOLD
+RHUMAYOG
-WITH GOLD
RHUMAYOG IN RHEUMATOIDARTHRITIS
CUHICAL :WALKING TIME (SEC)
..- .> -10 - --. +:

-20
v,---i3.. ..:.-.
..-.
5 CHANCE
-0
--
'\
-
,
-.
.
--
- ...
.-
- .-
--a
- - - . ..
-____.=-
-33
-40 -50
.. .
-. -
- -- - -
---- - --
--
- - - .
- . .3- -- -- 1
, - - .- . . --.-\.-.. . --- - , a*-.. ' $ '--*-- -,

3..
7
--
-80 *
-1

Fig. 4
-a-- RHUWYOGNO GOLD
+RHUMAYOG
-WITH GOLD
115
December 1993 VOI. XLVl NO. 12
RHUMAYOG IN RHEUMATOID ARTHRlnS CLINICAL : GRIP STRENGTH (LEFT)

X CHANGE
120 100 80
.
- -- -. - --- I
60 40
-
- .--20
0
I I
--
5'

Fig. 5A
-+RHUMAYOG-NO GOLD
+RHUMAYOG
-WITH GOLD
RHUMAYOG IN RHEUMATOID CLINICAL : GRIP STRENGTH (RIGHT)
ARTHRITIS
zoo
5 -. OHANCE
150-
.--
,
.
.
100
; & : L
/-a' _-
..----
(3
MONTHS -AFTER TREATMENT

Fig. 5 8
-a---RHUMAYOG-NO GOLD
ARHUMAYOG -WITH GOLD
116
RHUMAYOG IN RHEUMATOID ARTHRITIS CLINICAL :JOINT CIRCUMFERENCE (LEFT)

1 .
: CHANCE
-3 -4
'

Fig. 6A
-fl-RHUMAYOG-NOGOLD
A R H U M A Y O G -WITH GOLD
RHUMAYOG IN RHEUMATOID ARTHRIIS CLINICAL :JOINT CIRCUMFERENCE (RIGHT)

X CHANCE
I
U
,, ,
..- -r3
-,a.
.._.-2
-- -
.... _
---
----- -
--- - -
-3
------ ------I
------ -.- . ------ - - - --.

I
-4 -
-I
--
-5

Flg. 6 8
-0-
RHUMAYOENOGOLD
+RHUMAYOG
-WITH GOLD
117
RHUMAYOG IN RHEUMATOID ARTHRITIS CLINICAL :ESR (mm;lhour)
z CHANGE
-20 -
-30
-40
--
- . -
- -- - " . --
---
-50J

Fig. 7
-a-RHUMAYOG-NOGOLD-
+RHUMAYOG
-WITH GOLD
J
RHUMAYOG IN RHEUMATOID ARTHRITIS

IMMUNOLOGICAL PARAMETERS
% CHANGE AT THE END OF TREATMENT
CHANGE
0
-1 0
-2 0
-3 0
4 0
-50
ROSE W U R TEST
IgG (mg/L)
(nW/L)
IN (mi3 L)

Fig. 8
-0--RHUMAYOG-NO GOLD
-CRHUMAYOG -WITH GOLD
SELECT RESEARCH PAPERE '2N EVIDENCE BASED AYURVEDIC DRUGS
118
taking Rhumayog or Rhumayog with gold. Though the latter was better in irnproving morning stiffness and grip strength and reducing RF titres there was no statistically significant difference in both groups. Treatment complication .are well known with established DMARDs such as gold salts2' and NSAlDs such as aspirin, ibuprofen and indomethacin2'. In the present study both the drugs did not elicit any side effects.
~ i n g h Mishra SS, Tripathi KM , Bhatt-NS; RH, A preliminary controlled d i n i d trial of Indigenow Compound Drug in cases of Rheumatoid Arthritis, Rheumatism, 1984 : Vd. 19, NO.2 PP 1-8. Mahajani SS and Parikh KM; Some experimental observations on the antiinflammatory activity of Rhumayog An Ayurvedic herbomineral formulation (Abstract) workshop on selected medicinal plants used in traditional system of mediane, Bombay 1985.
Arnett F C et at. The American Rheumatism Association 1987 revis,ed ctiteria for the classifmtion of rheumatoid arthritis. Arthritis Rheum 1988 : 31 ; 315-24. Steinbrocker, Trager CH, Batterman RC. Therapeutic Criteria in rheumatoid arthritis. J Am Med Ass* 1949, 140: 659. Arora RB et al. Isolation of crystalline steroidal compound from Commiphora mukul and its antiinflammatory activity. Ind J Exp.Bid 1979,9: 403. Arora RB et al. Antiinflammatory studies on a crystalline steroid isolated from Commiphora mukul. Ind J Med Res 1972,60: 920. Master, L. et al: Planta Med. 1979 : 37: 367. Sharma J.N. and J.C. Jain: Ind. J. Pharmacol 1960 : 4: 267. Chopra RN Indigenous dru$s of India. N Dhure Sons Pvt. Ltd. Calcutta 1958:444. Karandikar G.K. et al: Ind. J. Med. Res. (1960) 48: 482. Gordon DA. Gold Compounds. In Text book of Rheumatology Kelley WN, Harris ED, Ruddy S, Sledge CB (Ed), W B Saunders Co. Philadelphia 1989,804-23. Bull BS, Westengard JC, Farr M, Bacon PA, Meyer PJ. Staurd J. Efficacy of tests used to monitor rheumatoid arthritis. Lancet 1989, 2: 965-67. Husain Z, Runge LA. Treatment complications of rheumatoid arthritis with gold, hydroxychloroquine, D-pt ~icillamine and levamisole. J. Rbeum 1090, 7:825. Paudus HE. steroidal antiinflammatory drugs. In the Text book of Rheumatology.1 Kelly WN. Harris ED, Ruddys, Sledge CB (Ed) W B Saunders Co.,Philadelphia 1989, 770-71.
CONCLUSION Both ayurvedic preparations Rhumayog and Rhurnayog with gold were found to be efficacious and safe in the management of RA. It requires further studies involving larger group for longer periods. REFERENCES
1. Harris ED. Management of Rheumatoid Arthritis. In Kelly WN Harris ED, Ruddy S, Sledge CB (Ed) Text book of Rheumatology WB Saunders Co,Philadelphia1989: 982-92.
2.
O'Duffy JD. Luhra HS. Current status of disie s a e modifying drugs in progressive rheumatoidarthritis. Drugs 1984: 27:373-377.
Yoga Ratnakar. Amavata Chikitsa Publi. Chowkhamba Sanskrit Series Office, P.O.Bix 8, Varanasi 1955, (PP. 486-92,) . k i n AK, Upadhyay VP, Chaudhary VP, Agarwal RK. A dinical trial of Ajmcdadi Churna and Yograj guggulu in Amavata (Rheumatoid Arthropathies): Nagarjun 1980 : 23 (6). Bhatt NS. Role of Ayurvedic Treatment in rheumatic disorders (Ab). East West Conference on Rheumatology Madras 1988. Rasa Tarangini. Chap. 15 V. 79, Plbli. MotilalBanarasidas, Nepali Khapada, P. Box. 75, Varanasi. Pullarao G: Rhumaycg with gold the drug of choice in the treatment of Osteoarthritis, X Annual Conference of Andhra Pradesh Chapter of Association of surgeons of India Kakinada 1985.
3.
4.
5.
6.
7.
on
119
Reprint f i o m
-.
The Indian
Practitioner
Vol. XLVll No. 6 Drug Action JUNE 1994 Pages: 489-502
Study of Ayurvedic Drugs in Rheumatoid Arthritis Compared to Auranofin

ChandrasekaranA.N. Professor and Head Porkodi R. Asst. Professor Radhamadhavan Addnl. Professor Parthiban M. Biochemist, Department of Rheumatology, Madras Medical College and Gevernment General Hospital, Madras-600 003 (India) Bhatt N.S. Medical Director (Ayu), Research Division, Zandu Pharmaceutical Works Ltd., Bombay400 025 (India)
101, Lawrence Apartments-ll,V~dyanagan Marg, Kalna, Santa Cruz (E), Bombay-400 098. 0 61 1 6170 or 613 0329
120
June 1994 Vol. XLVll No. 6
489
Drug Action
Study of Ayurvedic Drugs in Rheumatoid Arthritis Compared to Auranofin

Chandrasekaran A.N.*, Porkodi R.*, Radhamadhavanm Parthiban M * . , Bhatt N.s.@
SUMMARY In a randomised double blind clinical study two Ayurvedic drugs were compared for their DMARD potential with Auranofin in Rheumatoid Arthritis. 60 patients with definite RA were randomly allocated into Group A (Ayurvedic Drug), Group B (Rhumayog with Gold), and Group C (Auranofin) and studied for a period of 6 months. Clinical and laboratory parameters including Serum Gold levels were assessed periodically and analysed statistically by Wilcoxon's signed Rank Test and Friedman's Test for Trend. Female to male ratio was 18:2, 17:3 and 18:2 and the average age in years were 39.15,38.75 and 34.90 in respective groups. Group A drug showed a statistically significant improvement in Ritchie lndex (0.006) duration of morning stiffness (0.008) platelet aggregation (0.19) sero conversion (0.012). Group I3 drug showed statistically significant improvement in Ritchie lndex (0.001) and plstelet aggregation (0.000). Group C drug showed statistically significant improvement in Ritchie lndex (0.000), no. of joints involved (0.000) duration of morning stiffness (0.0 13), walking time (0.020) and platelet aggregation (0.000). It is concluded that there is a disease modifying effect in group A (Ayurvedic Drug) as in Auranofin. whereas DMARDS have marrow, renal KEY WORDS
Rheumatoid Arthritis, Rhumayog, DMARDS, Ayurvedic Drugs, ~ u r a n o i n . ~ and hepatic Ayurved, the ancient system of medicine, is practised in. Indian subcontinent for' many centuries and several drugs are used for the treatment of rheumatoid arthritis, a disease which is described as ~mavaata*. Not only anti inflammatory drugs are used but also gold preparations in the form of Gold Bhasma. have been widely used3. In the modein system of medicine gold is used in the form of gold salts. The goid used in Ayurvedic system is in a colloidal form.
INTRODUCTION Rheumatoid arthritis is a chronic inflammatory disorder due to inflammatory mediators generated by immunocompetent cells during the process of elimination of the hypothetical antigen from the system. While drugs are available to ameliorate the symptoms due to inflammation in the form of NSAIDS, the long term suppression is achieved by the DMARDS' . Most of the NSAIDS have gastrointestinal side effects
'
*Professor and Head, -Asst. Professor -Addnl. Professor, -Biochemist, Depattment of Rheumatology, Madras Medical College and Government General Hospital, Madras 600 003 (India) @~edical Director (Ayu), Research Division, Zandu Pharmaceutical Works Ltd., Bombay 400 025 (India)
121
June 1994 Vd. XLVll No. 6 and who consented to ,comply with the therapeutic schedule were included in the study. Patients with other connective tissue disease and with clinically manifest abnormal test function of heart, lungs, liver, kidney or those with endocrinological or neurological distrurbances or those having haematological or psychiatric disorders were excluded from this study. Patients having malignant tumours were also exluded. Evaluation Criteria The following criteria were followed: Clinical:
1. Ritchie Index
The two Ayurvedic drugs were found to be effective in preliminary clinical studies4". It was therefore decided to compare the efficacy of these two Ayurvedic drugs, one corisisting of Guggulu extracted in Triphala water and the other Rhumayog with Gold with Auranofin an existing DMARD in a randomised double blind study.
MATERIAL AND METHODS 68 patients fulfilling the ARA criteria for the diagnosis of RA were included in the study. The patients were randomly allocated into groups A,B, and C. It was decided to have minimum 20 completed cases in each group for better comparison. 8 patients dropped out and remaining 60 formed the comparative groups. The period of study was from December '89 to June '92. The drugs were administered in the form of capsules of 500 mg each in the dose of 4 capsules three times a day. The dose of comparable drugs being quite different administration required special packing as follows: Group A: Ayurvedic Drug (Guggulu extracted in Triphala water) Each Capsule contains 500 mg. of the above extract. Group 6: Morning dose - 3 caps. of Rhumayog with gdd corresponding to 1 mg of Gdd in each and 1 cap of plain Rhumayog. Noon and evening doses - plain Rhumayog. GroupC: Morning dose - 2 caps of Auranofin (3 mg each) and 2 caps of placcL,a. Noon and evening doseplacebo. Inclusion and Exclusion Criteria Patients above the age of 18 years suffering from active rheumatoid arthritis
2. Number of Joints involved 3. Circumference of the proximal interphalangeal joints 4. Duration of morning stiffness 5. Grip strength 6. 50 feet walking time 7. Functional class by Steinbrocker's classification Laboratory parameters Haematqlogical: Complete Haemogram, Platelet aggregation, B.T., and C.T., P.T. were studied. Biochemical Parameters: Hepatic and renal toxicity, Blood sugar, Cholesterol and Serum cortisol levels were studied. immunological Parameters: RA factor both by Rose Waaler and RF Latex Agglutination methods as well as important markers CRP, ANA IgA, IgM, IgG, C3 and C4. Serum Gold levels were specifically studied. Urine analysis- Complete urine analysis, creatinine clearance, protein excretion fbr 24 hours.
SELECT RESEARCH PAYERS ON EVIDENCE BASED AYURVEDIC DRUGS
122
491
Radiological Changes: X - rays of the involved joints were'taken. Time schemes for evaluation was as follows:
U@e Analysis, lmmunological Radiological
- Basal and every

two months
- Basal and at the

end of the study.
General followup and drug supply
- Every week
- Basal and
every month
Clinicel assessment - Basal and every fortnight Haernatological and biochemical
Patlent Consent Informed consent of the patient was obtained in writing before administering the trial drug. RESULTS
CLINICAL TRIAL ON R~UMAYOG I N
RHEUMATOIDARTHRITIS
Table 1 Parameter: a. Age

Group A Group B Group C
20-52 YW.
34.90 yrs.
Age Range
27.60 yrs.
39.15 yrs.
18-57 yrs.
38.75 yrs.
Mean Age
b. Sex
Female Male
18
2
17
18
2
123
Parameter: Total no of Joints
124
The Indian Practltloner
493
Friedman's test for trend
0.046*
Total
15
20
15
20
4
19
20
Improved Deterlorated
P. Value
2
2
NS
3
NS
0 Signj.'(P=O.OS)
June 1994 Vol. XLVil No. 6
June 1994 Vol XLVll No. 6
The lndlan Practitioner
41 &
Friedman'stest for trend
.225 ns
Group C
Mean 59.50
57.50 ..678ns
:63 ns I
62.30
66.00
Wilcoxon'ssigned rank test

Friedman's test for trend
.308ns
.485 ns
127
The Indian RactRloner
June 1994 Val. XLVll No. 6
128
The Indiah Practitioner
Table 15, Parameter: lgGU IU/ML

Drug Group
0
Months after treatment
Group A Mean Wllcoxon's s~gned rank test Frledrnan's test for trend . Group B ~ean Wtlcoxon's slgned rank test Fr~edrnan's for trend test Group C
284.95 283.60 .760 ns ,420ns 2813 5 ,794 ns 298.75
,478 ns
275.00
295.25 ,433 ns ,337 ns
281.45 .673 ns
306.95 ,205 ns
. Mean
Wilcoxon's slgned rank test
'
,277 40
259.90 .695 ns ,815 ns
248.60 ,463 ns
255.75 .519 ns
Fr~edrnan's test for frend
Wilcoxon's signed rank test Fr~edrnan's for trend test Group C Mean W~lcoxon's s~gned rank test Fr~edrnan's for trend test
' I
.091 ns
,167 ns
.968ns
,090 ns
257.00
289.60 0.571 ns
273.85 0.5?6 ns
2d.50 0.570 ns
0.829 ns

Table35 Parameter: C 3 Mglml.
Drug Group
0
Months after treatment

2 4
6
Group A
Mean Wilcoxon's sianed rank test
10086.40
1131.00 .480 ns
1116.40 .407 ns
1023.50 .705 ns
'
I Friedman's test for trend I I Group B

Mean Wilwxon's signed rank test Friedman's test for trend 1 1 58.75
I -
.605ns
I
1171.00 .825ns
I
1200.00 .747ns
I I
11 76.50
.409ns .721ns
I Group C
I Mean
[
-
1314.50
1113.00 .248ns
1068.00 .I70ns
'1
1148.50 .067 ns
Wiicoxon's signed rank Jest Friedman's test for trend
.749ns
Wilcoxon's signed rank test Friedman's test for trend
.844ns .693ns
.981ns
.602 ns
Qroup C
Mean Wilwxon's signed rank test Friedman's test for trend
431.55
392.05
.064*
392.30 .259 ns
443.40 .687 ns
.2% ns
130
Rheumatoid arthritis is -an inflam-
I
sqt-l&
bpu#shef+found to have antiinflammatory effects". The steroidal constituents of guggulu may be responsible for the antiinflammatory action. ey ac y In I I lng p a e e aggregatni bCt 9CM3R29t 6 xarrdi
k~rrsiarcsludprzGra4wd b @
was ~ ~ r n b ~ t l B ~ d d , n h f t&@q!& ~st%ta~dn%dP &its m q w g ~i!$iW%gk$&!Q o " b k c 9 h j ri;fit W ~ 'Mf6@1 '$Sif;n&~~~Fti6~Su~
&w
fertWi&W%R @fWri#B@ifiQQ%~i!
bsrl -mt nwode bsrl zjnsl:sq 3 .l:ss~tlne~z '
~y significant irRij?6HW~F R 9fid
"%hu#P~%)agiSlad~9flbwflIa IltYME81a
i W
Writ xebd~pr~wftmmt intnsnt$%~ nt

p q p W s r e J J~ b n # W ~ o ~ a f L s t ~ b a ~ @ ~ -mg@tb Wl~mplpvaC);m s l r w l u v r , & ~ E B l ~ ~ ~ - ~ r n s t i llr I s W i W Mprmmllbttf), bMml; C
June 1994Vol. XLVll No. 6
AYURVEDIC DRUG / AURANOFIN I N RHEUMATOID ARTHRITIS
ESR (mm/hr)
10
x
CVCE
-30
-40
. -- . . - - I
1
&..- L --- & * .
..".*= .'
1

AWRVEDIC DRUG
-!
BBWYOO-rn [ ) WU
'*.
AUP*WOm
Latex aggutination test. The fall in the

CRP levels also showed EL statisticdlly
significant trend by Friedman's test, The ESR had also shown a fall at the end of the trial though not statistically significant. Similarly IgM levels had shown a fall though not statistic811y significant. 2 patients had shown irnprovement in their functional class while 2 had deteriorated. Group 6 drug (Rhumayog with Gold) showed a statistically significant improvement in Ritchie Index and Friedman's test for trend wes also significant. 4 patients hed shown improvement in'their functional class white 3 had deteriorated. In the , I@ paraineteq , platelet aggregation8howqta signiflm irriprovement by Friedman's test: The fdl in ESR was not statistical@slgnifkant.
Similarly the fa! in the Rheumatoid Factor titres was also not significant though 5 patients had become sero negative by Rose Waabr t?t.and two patients had became seroi .negative by latex agd glutination t ~ t the end of ihe trial. Group -'C drbg (Auranofin) in the present also'showed a significant impmvment in . several clinical . parameters like Ritchie Indw, No. of joints Mvolved, duration of morning s t i i e s s and walking' time. The Friedman's test for twnd was also siggnificant faf all these parameters. Thefe was a remarkable improvement in the functional 7 patients had improvedwhile non had deteriorated.
elks.
In We paramatp.ESR had f how Lb a'fall. a8 shoyn by the Friedmq'a test for trend: Platelet' .aggcegruti& had
132
June 1994 Vd. XLVll No. 6
..
AYURVEDIC DRUG / AURANOFIN IN RHBUMATOID ARTHRITIS
ROSE WAALER TEST
-60 i' 0

i -
AWRVEDIC DRUG
RBUYAYOG-WITE GOLD
-".
AURANOPIN
shown a significant fall Sero conversion by Latex aggultination while 4 had become negative by Rose Waaler test. A unique feature in this study was the estimation of Serum gold levels. Patients who were on Group C drug namely Auranofin showed a significant level ranging from 10.63 to 2077.50 nonograms, while patients on Group B drug namely Rhumayog with Gold had lower levels ranging from 1.50 to 457.5 nonograms. Patients on group A, Ayurvedic drug shown negligible amount of Gold in few cases. The side effects with all the three drugs were mild and did not necessitate withdrawal. The 8 dropouts were due to non compliance of the patients and not due to side effects of the drugs.
This study confirmed our previous study that Auranofin has disease modifying efficacy. Among the two Ayurvedic Drugs Group A drugs has a definite disease modifying tendency as evidenced by a fall in the levels of ESR, CRP, Serum IgM levels and sero conversion by Rose Waaler test. Probably the amount of Ayurvedic Gold (3 mg) in Group B drug was not sufficient to have any disease modifying effect, Thus this study shows that Ayurvedic drug is comparable to Auranofin in its disease modifying property in rheumatoidarthritis.
REFERENCES
1.
0. Duffy JD, Luhra HS; Current Status of disease moditying drugs in progressive Rheumatoid arthritis. Drugs 1984,27: 373-77.
133
The Indian Practitioner :2-.n:$il!)zr, r:&?rd stfl

8 ;
June 1994 Vol. XLVll No. 6 a .OH !IVJX.IOV pee t snuL
AWRWDIC DRUG
4 -
REUU~OG-~ITH COW
- -
moa
HTW-~OYAW'JHH
c l *
AURANOFIN
wao s l a s a w ~
1%
2
Yog
Ratnakar, Aamavata chikista; Publ.
-- --
--
8.
Chandrasekaran AN. Ramakrishnan S, Rad-
r~QtracAmgmkeSabrtn-&rtBs orf~b&Mar&i&i
nbanedhnmro~C8antR6~aia~~~dz
E;WfiWer!) n;tonsruA f rf vbutz es;J si

ces Academy 1989, Vol. 2,No. l,21-25.
b~51f?!?f%3 as y,lnetnsj pni.4ibom szss

, : ~ j & ~ r y j m w t r ib ~ ~j '1 ~ ~ digenous compound yd Rheumatoid arthrlt~s; Rheu at~sm, o
& q , & s. ~ .~ g q
ma192
nFdP?H$%iYRldt.WisplMdslaplnb aibsv
6. rikob@wC#ale Arthritis; Pharma. I
&q&@~.~ ?'%%hid
011
19@&@&6bdOkm~9dl
11. Bhatt N S; Review of ~ y i r v e % c~#tnlcal Re-
zs 63 gt ni bioa
7.
Manthrope R, Horbov S, S lvest J, sod Vinterharg H; Auranofin Vs & w d ~ ' b % . l @V &% c ~ u i b ~niytiborn szse IT-CTE :TS ,&Bet a~uiCJ .eitiidfis biotsrnusdR
~ f l 00WiuJla?Bi&QMT3116Wri#w .r I ja~~~~dkre 2. da~1)8qtaWo1 j w 3 d non .eeuib srlt to ej39tf9 sbie ot sub
.-.".SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS 134 rE h 2 3 U R U 31a3VRU'llA a 3 Z A 8 33MRUIV3 MO 21I34AP H 3 R A 3 2 3 R T 3 3 J 3 2
-.-"- - .- -----
OPEN STUDY TO EVALUATE THE EFFICACY OF SALLAKI A S AN ADD-ON NSAM).CN ,THF M4W4CirF;rMFNT,OF! PATIRN,TSF1. LTH
* Author for correspondence Dr. A. Rajadhyaksha M.D. Assoc. Prof. in Medicine K.E.M. hospital, Parel, Mumbai - 400 0 12
--
SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVED~C-DRUGS
f33
ABSTRACT
In a double blind, randomized parallel grobp study, forty-seven patients with classic or definite rheumatoid arthritis were treated with SallakiO (600-mg t.i.d) or Diclofenac sodium (50-mg t.i.d). The duration of the treatment period was four weeks. An interval of five days was established as a washout period. Paracetamol tablets were used as rescue analgesics during the washout as well as the trial period. The following variables were tested: Duration of morning stiffness, grip strength, time to walk 50 feet, pain severity using VAS score, number of swollen and tender joints, degree of swelling and tenderness in the affected joints, digital joint circumference, paracetamol consumption, ESR and overall efficacy by the physician. A statistically significant improvement in VAS score, duration of morning stiffness, tenderness and swelling of the affected joints and a decrease in the number of swollen joints was observed. No statistically significant differences were found between SallakiB and Diclofenac sodium. ~ o t h drugs were well tolerated but a trend towards the fewer adverse reactions of SallakiQ was found.
Key words: Diclofenac sodium, Sallaki @, Rheumatoid arthritis
SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVRDIC DRUGS
136
INTRODUCTION
Osteoarthritis is one of the most common rheumatological conditions to affect humans. In India, thc prevalence of osteoarthritis in adult rural population was found to be 5.78% . It is a leading cause of chronic disability in the elderly population rendering them unable to perform their daily routine activities independently.
'
The disease represents failure of a diarthrodial (movable, synovial lined) joint and is characterized by degeneration of articular cartilage, hypertrophy of bone at the margins, and changes in the synovial membrane. The progress of the disease is variable and in some patients relentless, leading to end stage joint disease necessitating joint replacement. 'The most common presentation of osteoarthritis is insidious onset of pain, stiffness and disability in the involved joints. Pain in and around the involved 'joints is a cardinal symptom in OA that typically is aggravated by joint use and relieved by rest, but, as the disease progresses, it may become persistent. Stiffness of the involved joint on arising in the morning or after ,a period of inactivity may be prominent but usually lasts less than 20 minutes Functional impairment in OA however is highly variable and depends on associated muscle wasting and weakness and correlates with the radiological severity of the disease.. Treatment of OA is aimed at nlinimizing pain, optimizing fbnction and reducing disab~lity Amongst drugs, non-steroidal anti-inflammatory drugs (NSAIDs) are most often prescribed for relief of pain and control of inflammation. However their use is limited b i gastric and renal toxicity. Elderly patients are particularly prone to develop serious NSAlD related gastrointestinal complications like Perforation, Ulceration, Bleeding (PUB) and death Some NSAIDs particularly aspirin and indomethacin have been implicated in cartilage degeneration'and their .. use is best avoided in osteoarthritis The preferential cyclooxygenase 2 (COX-2) inhibitors like meloxicam that are chondroneutral, equally effective and with fewer side effects are thus widely employed in the management of osteoarthritis "4 However the magnitude of improvement with NSAlDs is generally modest - on an average there is 30% improvement in pain and 15% improvement in knction 5 . This could be due to the inhibition by NSAlDs of only one of the mediator of inflammatio; i.e. cyclooxygenase. Leukotrienes, f& which the 5-lipooxygenase (5-Lox) is the key enzyme,arx a h - i d v d in the initiation and the maintenance of inflammation. From t b e f i y ~Tleukotrienes type mediators, leukotriene Bq is a potent stimulator a-leukocyte responses like chemotaxis, cell adhesion, superoxide production, calciu~rlnslocation,and release of hydrolytic enzymes. They also stimulate pronounced_plasffia exudation in vivo - 9 Thus cgaedmitant administration of lipooxygenase inhibitors and cyclooxygenase inhibitors wmkflead to a better control of inflammatory conditions
137
The gum resin exudate of Bo,weIlru serrutu used In traditional Ayurvedic ~!;?F;tk'd(aJa%kfI treatment of inflammatory diseases is a potent inhibitor of 5-lipooxygenase but does not impair t h d - p ~a & { ~ # ~ ~ ~ ~ ~ f h ~ g g g sl' i & : ~ e f @Hbrrt~fich? ~2 & &f#tg~ jzor11 -XI r t o grir, 11 rill rrIfr~ostA. 1
r i j ,;I r: ~ j ~ ~ , j *{~ h;i!17 tj;j!>j: H I - ~ i 1 ! 1 1 j j a t>jt>~'3fbJ ~ I ~ I I ; ' ! ~ I ~ [?ti' : ~ * > P h a f ~ l u g i c ~ j ~ p o t s t i $ ~ t@I;&~irh g ~kw;i.ey4ediithfe &&I i i gI ~ rr tpda&&;arhi4n&W&toyt) J agent devoid of side effects like gastro-intestinal irritation, hemorrt$gt$bkp@i& &ilmaNdio? 1 1 electrolyte retention ' - I 2 A marked analgesic effect has also been reported for the drug I ;:ttol (bun11 !h1,rlr1/2.3ldr;~,,m) ltihc11lf71;i0 t; 'jrj ~ I I J ~ I I ~ ~~ 1 3 d * 3 i ( j 3 1~ Z I ; Y Z I ~sri'i ;f E%petiwnfal $ t b d i e s f m d d n h h llpmbd.?&&tFe3 &Wi; ~~ akhifl~ ~ w y t r b i ~ a k s y E ~ l rebM ai1mats t~bke3ld9treox&&di~ajMtIb1 ~ i & t ' E W ~ ~ i t & ~ 16mf&b&dis3@113 spondylitis without a n ~ : ~ 8 a ~ t l A ~-" th" ~fi ' L 3 3 3 1 1 szsserb tnrol ~gfildilns oJ gnrbrcrl , ~ C ~ I $ ~ I ~ J I t
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early cases having mild pain with no radiological standing disease w ~ t h moderate to severe radiological changes it showed a fair to poor response
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ovrv nr 11orj6bu-/;s xrnzslq bs3nuonorq sjs;lurntJz Acute inflammatory flares and low-grade persistent inflammation has been shown to be present z i n M M f t a & i t i 8 ) ~ ~ 9 ~ibds~-b!&Md %dbg$~&@fn~o~da%tl~BPrind~ijltt~&ihd8)me2t~i~ ir articular cartilage and worsening of the 63 0 ~ofsrtrmsIfni lo.rjno:, ~ a j j s d of bsvl blr~ow 70 s
It was conceived that if a lipooxygenase inhibitor i.e. SaIlaki and KZ~C16bti)ige"nae Zh'itjitbi i;6: NSAIDs were used simultaneously in the treatment of osteoarthritis a considerable jmnrouernenk in the pigns ,a@ symptqvs' of the ,disease wovld, probably be.achieved.
(-$~$~$NGI ~ j F ~ * h ~ ~ ~s~wlt$ "a~ a @t~at 1s 9 ~ dutej ; p ~ofi4Fidp,&*fl; G+3Niiiif1 P a m of the , $ i { a so f y free I side ~ ect3 would help in contaj&g,& ~ fi e
MATERIAL AND METHODS

Patients selecti Consecutive pat1 nts with primary osteoarthritis of the knee and/or hip (clinico-radiological 3! ARA criteria) attending the rheurnatology O.P.D. at K.E.M. Hospital were enrolled into the study. The patients were in the age group of 18-70 years. In addition all patients included in the study had: 1 history of taking any one NSAlD in adequate doses for at least past one month without satisfactory relief ii pain and/or stiffness in the knee and/or hip joints and/ or difficulty in walking and/or climbing The patients were excluded if they had undergone prior replacement surgery or were incapacitated or bedrhden, or eligible for surgical intervention, or had active peptic ulceration or prior gastrointestinal bleeding. Other exclusion criteria included cardiorespiratory insufficiency, significant disease of any other major organ system, allergy to aspirin or other NSAID, concurrent anticoagulant therapy, concurrent ayurvedic drug therapy, or recent systemic or intraarticular corticosteroid therapy. The protocol had been reviewed and ratified by the ethics committee at K.E.M. Hospital. All the patients gave written informed consent before enrollment into the trial.
Study deslgn The study was conducted as an open trial. After the patient satisfied the entry requirements, a complete medical history was taken and a general examination performed. The disease activity was measured by' grading the pain, tenderness, swelling, morning stiffness and hnctional impairment for the right knee, lee knee, right hip and leR hip o n a five point scale.
The patients ihen underwent a global assessment ooMioting of an administered questionnaire. The questionnaire included all the thirteen physic4 function criteria of the KGMC Index, which is a validakd-nmdified WOMAC Index to evaluate response in Indian Patients with osteo&tic bee. A scoring pattern different from the one used for arriving at the KGMC Index was adoptid owing to the failure in obtaining the original scoring pattea. 'Ilkus the KOMC Index w s renamed as Modified KGMC Index EorPhysical Function Criteria a The disease activity measurements were conducted during the screening visit, at the end of the second week, fourth and the sixth week i.e. the final assessment. The physical function questionnaire was admin~steredonly at the end of the fourth and sixth week. At the end of the study both the investigator and the patient assessed the overall efficacy and tolerability to the tre-ent. The patients were k d to consume Sallaki (400 mg) 1 t.i.d. along with their routinely prescribed NSAID. T y 'were asked not to change their therapy or consume any other analgesic
"8,
during the study period At the 'end of the fourth week the patients were asked to discontinue their NSAID medication and consume only Sallaki (400 mg) 1 t.i d. for a period of additional two weeks At every visit the return tablet count was made to ascertain the compliance to the medication. The patients were instructed to contact the investigator at any time if they developed an exacerbation of any of the symptoms. Additionally at every follow-up visit i.e. Week 2, Week 4 and Week 6 the patients were asked to participate in a questionnaire for adverse events. Evaluation procedures
Efficucy parameters
The disease activity was assessed at the screening visit, at Week 2, Week 4 and Week 6. The following symptoms were assessed. 1. Joint Pain: Pain in the right knee, left knee, right hip, and left hip was graded separately by the patient as 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe Averaging the pain score of the affected joints arrived at the joint pain score. The maximum attainable score is 3 while the minimum attainable score is 0 2. Joint Tenderness: Tenderness in the right knee, left knee, right hip, and left hip was graded separately by the investigator as 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. Averaging the tenderness score of the affected joints arrived at the joint tenderness score. The maximum attainable score is 3 while the minimum attainable score is 0 3. Joint Swelling: Swelling in the right knee, left knee, right hip, and left hip was graded separately by the investigator as 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. Averaging the swelling score of the affected joints amved at the joint swelling score. The maximum attainable score is 3 while the minimum attainable score is 0 4. Morning StiBess: Morning Stiffness in the right knee, left knee, right hip, and left hip was graded separately by the patient as 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. Averaging the Morning Stiffness score of the affected joints arrived at the Morning Stiffness score. The maximum attainable score is 3 while the minimum attainable score is 0 5 . Functional Impairment: Functional Impairment in the affected joints was graded separately by the patient as 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe. Averaging the Functional Impairment score of the afiected joints amved at the Functional Impairment score. The maximum attainable score is 3 while the minimum attainable score is 0 6. Modified KGMC lndex for Physical Fun~tion Criteria: The patients were asked to describe the difficulty in performing the below mentioned functions as 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe and 4 = Prohibitive. i. ii. iii. iv. Ascending stairs Descending stairs Rising from sitting Standing Walking on floor Going shopping Rising from bed
v.
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fl-khv-y ddm9t4c diititis' 'Bqh~W&'fdrdoiM Getting inlout from cycle/autorickshaw -+hCTh&l~ b ~ ~ ~ & ~ i b h ~ Daily prayers raki#'a- dbtf?
'
The ~ o d i f i e d ' ' k & h tihd& kdr~h'ysica~ Fdnction Ctiteria 'comprised the sum of the score for all the thirteen physical function criteria The maximum attainable Modified KGMC Index for Physical Function Criteria is 52 while the minimum attainable index is 0 lnve&gators hsessment of Overall Efficacy:
The 49veSt%?t9,1
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S f t parameters aey TheL*dq&sesemti&to thes-&io~ ift!im$ w ~ s ~ ~ m d c k k ~ ~ W k@&atH'JCheck %pd%y' z h ~ ~ list #,$he. Pnd ~ f l h e s e c a d ~ M h ! a r rs&lrdesk W1Q ~ ~ w B ~ P & ~ T o w #&@8fi~''' ri I~ I Heavy headlheadache ii :f&l&r&ctlrsisi~cmi iii Qiddihesst iv I @ mtruth @ v wd.us& vi. irg'~iktdg vii IJ ~ ~ s f i 'iSd$o?t ~ f n ~ viiP E iil h 9 n) i? a ix E igastric burnihg x ~&S*W&G The adverse reactions were graded as 0 = None, 1 = MiId,.2 = Moderate and 3 = Severe Investigatomassessment ~f overall tolerability The investigator graded the overall tolerability to the inve~tigati*~&,~q;&epsog* patient as:
1 = Good - no side effects 2 = Fair - mild to moderate side effects 3 = Poor - severe side effects requiring withdrawal from therapy.
S E L ~ RESEARCH P # ~ ~ ~ ) E B C B X S E T J ' ~ Y ~ # ~ D I ~ ~ C ; 1-42 T I :
the
'&W#WBf3"aMXctifify' 3S~ssment'vy,$i;bres ~!@oi&i'% & w & ~ ~ ~ @ s ? r ?nbll h h o hells t ste he significant difference within the group for change from fourth and sixth week. t#~~kidk&ir,Ws'Wi& t k ~ at'g~sigmcatdt! levdl W ~ ' O W t
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Demographics and patient k
FiRy patients were enrolled in the study amongst which forty-six patients c o m @ k % d W
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duration of the disease was 3 1 46
* 39 59 months
The nature of the complaint of the ehP&!XI
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Clinical efficacy Results
'The cllnlcal responses of the patients were determined and the r e s ~ ~ & ~ ( ~ \ s W & i n \ T W \ \ w
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'hb$lhne@lrg l h i ekiiiiiib pain of the affected joints at the ??-wee an 4 week e mean score for joint pain at the end of the second and fourth week were 0 96 i 0 4 and 0 66 & 0 28 resggs%&\,p :@n;lfi:antly less (p,< 0 05),tbw 2 6 5 0.42,th.e me@.bqeline si~orgf~r,iGndmm. R,
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h ~ a i 1 & - ~ ~dlt~%uft~Ck&aSc809e~aB '%W' e % cbf M at the end of the sixth week was 0.73 0.39 that was significantly(fe%w ??a9 0.42, the mean baseline score for joint pain (Figure 1)
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tenderness at the end of the second and fourth week were 0.69 0.3 and 0.46 0.31 respectively that were significantly less @ < 0.05) than 1.09 0.33, the mean baseline score for joint tenderness (Figure 2).
Comparison of pre (NSAIDs supplemented with M & and post treatment (Sallaki after I) withdrawal of NSAIDs) values When therapy with NSAlD was withdrawn and only Sallaki administered for a period of two weeks from the fourth week of study period, no significant difference in the joint tenderness score at the sixth as compared to the fourth week was observed. However the mean score for joint tenderness at the end of the sixth week was 0.46 h 0.35 that was significantly less (p < 0.05) than 1.09 0.33, the mean baseline score for joint pain (Figure 2).
Joint swelling Comparison of pre flSAIDs therapy) and p i treatment (NSAIDs supplemented with ,%llakr} s values Supplementing the existing NSAID therapy with Sallaki resulted in a significant reduction in the swelling of the affected joints at the 2-w&k and 4-week endpoint. The mean score for joint swelling at the end of the second and fourth week were 0.54 0.28 and 0.33 0.29 respectively that were significantly less (p < 0.05) than 0.82 0.27, the mean baseline score for jbint swelling (Figure 3)
Comparison of pre (IvSAIDs supplemented with S a l U ) and post treatment (Sallaki sfter withdrawal of NWDs) values When therapy with NSAID was withdrawn and only Sallaki administered for a period of two weeks fiom the fourth week of study period, no significant difference in the joint swelling score at the sixth as compared to the fourth week was observed. However the mean score for joint swelling at the end of the sixth week was 0.34 0.33 that was significantly less @ < 0.05) than 0.82 0.27, the mean baseline score for joint swelling (Figure 3).
Morning s t i f f n ~ s Comparison of pre (1VUIDs therapyl and post treatment (NLUIDssupplemented with SallakI) values Supplementing the existing NSAID therapy with Sallaki resulted in a yignificant reduction in mcrning' stiffness of the affected joints at the 2-week and 4-week endpoint. The mean score for morning stiffness at the end of the second and fourth week were 0.7 0.34 and 0.47 0.3 respectively that were significantly less @ < 0.05) than 1.05 0.46, the mean baseline score for morning stiffness pigure 4).
Comparison o pre (NSAIDssupplemented with Sallaki) and post treatment (Salk& after f withdrawal of NWDs) values When therapy with NSAlD w s withdrawn and only Sallaki administered for a period of ,two a weeks &om the fourth week of study period, no significant diffwence in the morning stiffness score at the sixth as compared to the fourth week was observed. However the mean ocore.for morning stiffness at the end of the sixth week wab 0.45 0.37 that was significantly less @ < 0.05) than 1.05 0.46, the mean baseline score for morning stiffness (Figure 4).
144
Functional Impairment Comparison of pre (IvSAIDs therapy) and post treatment (NSAIDS supplemented with Sallaki) values Supplementing the existing NSAID therapy with Sallaki resulted in a significant reduction in hnctional impairment of the affected joints at the 2-week and 4-week endpoint. The mean score for functional impairment at the end of the second and fourth week were 0.88 0.4 and 0.58 0.29 respectively that were significantly less (p < 0.05) than 1.14 0.4, the mean baseline score for fiinctional impairment (Figure 5).
Comparison of pre (hrWfLls supplemented with ,%llaRi) and post treatment fsbllak~ afier withdrawul of NLWIDs)values When therapy with NSAlD was withdrawn and only Sallaki administered for a period of two weeks from the fourth week, of study period, no significant difference in the functional impairment score at the sixth as compared to the fourth week was observed. However the mean score for hnctional impairment at the end of the sixth week was 0.64 h 0.43 that was significantly less (p 0.05) than 1.14 0.4, the mean baseline score for functional impairment (Figure 5). Modified KGMC Index for Physical Functjon Criteria omp par is on of pre (N,c;AILlstherapy) and post treatment (NUIDS supplemented wzth ,!!llub) values Supplementing the existing NSAlD therapy with Sallaki resulted in a significant reduction in the KGMC lndex for Physical Function Criteria at the 2-week and 4-week endpoint. The mean index at the end of the fourth week was 14.62 6.53 that was significantly less (p < 0.05) than 22.3 k 5.86, the mean baseline index (Figure 6).
Comparison of pre (N,SAIDs supplemented with Sallaki) and post treatment (.%llaki after withdrawal of NS4IUs) values When therapy with NSAlD was withdrawn and only Sallaki administered for a period of two weeks from the fourth week of study period, no significant difference in the KGMC lndex for Physical Function Criteria at the sixth as compared to the fourth week was observed. However the mean index at the end of the sixth week was 16 7.39 that was significantly less (p < 0.05) than 22.3 5.86, the mean baseline index (Figure 6).
Overall efficacy The investigator reported the following responses as the overall efficacy of the treatment. An excellent response to the treatment in four patients, a good response in twenty-one patients, a fair response in sixteen patients, a poor response in four patients while a very poor response in just one patient. (Table 4) Overall tolerability All the forty-six patients who completed the trial reported a very good tolerability to the treatment. One patient reported of vomiting and epigastric burning of mild severity on the fourth week of study period but it discontinued gnrdually until the sixth week without necessitating any change in the medication.
145
DISCUSSION
fnstfr'liaqml Isnoifx~ar?
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h e nsion ca v&?, d%n sd~%~3?&~fuX~~f$~B BRF~ J~&RRI%B~ ~klp$rp*itLt &m~wd~s4fan~nf&$9f@t B i,!to72J0JRt~ 9 ~ f !?R&P%c!~.H?$sPT~~!R f Pain-=. -- ."ih ...-.. ..-, -- '. y ptM& c tien" d xi n3m m P b n o l f 3 q lobs 6A0!#i bJii+d.%%t~ w~PMIR B$$@ (k dh@cl yP ~ w ? & evlden'Ee o synovia in ammation may e as marked as that in the synovium of a p+twJ&h rheumatoid arthritis Synovitis in OA may be due to phagocytosis of shards of cartilaie and%one from the abraded joint surface
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divided into non-drug therapy and pharmacological options The vigor of the therapeut~c terv i~ dic(gg~~~;$%~~e~Q,~?fiL~~~$~nQ~~~~&i?Ck\cjAv.~~~~q~,F~~&f3 reassuran e, instruction in joint p~otection,a * , ~ f i , ~ q < ~ l \ ~ y ~ y ~
J s bn3 ad1 ti3 xabni nssm b rl;~iiirr< 16 db ~ R C [ Q F T + d I Z6W ;k3w ~ J X I Z d t ' i ~ ' Y h 2 r i p ~ ) & 9 ~howev& is $liatrve, no p b~ t ~ ~~~~9~~~ ~ grg.fegs, m ~ ~ y the progression of, or reverse the pathologic c anges of OA in humans. Analgesics such as paracetamol and at times even a combination of paracetamol and codeine arf+&&gg~a
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ations w ~ I ~ ~ ~ ~ 3 1 ~~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ h . ~ re ~ 3 f ~ ? w ere a a swt 3 % ~ S ~ ? $f B49 e~intRfi&~fi~i~~9i~fide7t a esic sr f 4 1 M ~~z trot nt 9znocJh 1%f&$W (1PbdP B % ~ @ ' B ~ ~ E o N ~ @ M sni~3znoqr.n (P sldsT) fnsi3~ sno Concern with respect to the appropriateness of NSAID administration in OA because o their side effects, especially those related to the gastrointestinal tract is growing yfTbmmk.&@e
SI
IOBJ~~V
In a short-term study comparing an anti-inflammatory dose of ibuprofen (2.4 dday), an analgesic dose of ibuprofen (1.2 glday) and paracetamol (4 glday), no significant differences were found 20 between the treatments in terms of disability or pain on walking . In a study in which patients were repeatedly randomized to receive paracetamol or diclofenac, symptoms were adequately controlled by paracetamol alone in approximately 30 % of patients 21. Also in two recent 2-years comparative studies o f NSAIDs (naproxen and sustained release diclofenac) in the treatment of osteoarthritis of the knee, significant number of patients previous1 controlled on NSAIDs were x2-23 able to continue on paracetamol alone for the duration of the study Given that the symptomatic relief afforded by NSAIDs is no greater than that achieved by simple analgesics while the frequency and severitv of adverse effects are more with the former, NSAIDs are used only when analgesics and other hleasures have failed However NSAlDs when used, should be employed for short periods of tlme ( L 1 to 2 months) and attempts continually made to withdraw treatment and reintroduce or mcrease the dosage of analgesic drugs Thus it may be concluded despite their being an inflammatory component in the pathogenesis of the disease, the magnitude of improvement afforded by NSAIDs is generally modest-as reported on an average, about 305'0 reduction in pain and 15 % improvement in unction However the inflammation needs to be controlled as persistent inflammation ftllther results in cartilage degeneration and worsen~ng the disease of It may be suggested that the poor control of Inflammation is due to the inhibition of just one of the mediators of inflammation i e cyclooxygenase Simultaneous inhibition of lipooxygenase, the second major mediator of inflammation by the concomitant use of lipboxygenase inhibitors would probably result in a better control of inflammation. The present study was conducted with an attempt to prove the assumption Patients w ~ t h osteoarthritis were prescribed Sallaki (400 mg) t i d for a period of four weeks in addition to their routinely prescribed NSAID After a period of four weeks their therapy with NSAlD was withdrawn and only Sallaki administered for an additional two weeks perlod A significant improvement in all the variables assessed was observed at both the Zweek and 4 week end points The improvement in the signs and symptoms was sustained until the sixth week i e even aRer discontinuation of the NSAID therapy Supplementation of the existing NSAID therapy with Sallak~ resulted in a significant reduct~on in pain, tenderness, swelling, morning stiffness and fbnctional impairment of the affected joints the effect was observed both at the end of the second week and fourth week The modified KGMC index for physical function criteria also decreased at the end of the fourth week The KGMC index for physical function criteria is a powe&l instrument to study the health status of OA patients belonging to the Indian population It is a reliable and valid, multidimenaonal, quantitative tool to assess symptomatic benefits in Indian patients with OA knee Thus it cab be said that s~multaneous administration of Sallaki results in significant reduct~onIn pain and disability while improving the mobility
tFt,
A synergistic effect of lipooxygenase inhibitors and cyclooxygenase inhibitors thus exists in controlling the inflammatory component of osteoarthritis. Furthermore, the improvement in the clinical signs and symptoms were maintained even after withdrawal of the NSAID therapy thereby suggesting Sallaki to be effective even when used as a sole therapy One may conclude from the present study that in OA patients once treatment with NSAID and Sallahi is initiated the need to continue with the NSAID is obviated It is preferable to continue w~thSallaki on a long-term basis and gradually reduce the dose of NSAID or use it only intermittently i e during exacerbation of joint paln
148
REFERENCES
1. Chopra, A., Patil, J., et al. The BHIGWAN (India) COPCORD : Meth@ology a d j r s t infomation report. APLAR Journal of Rheumatology 1997; l(1): 145-54. 2. Das, S.K., Ramakrishnan, S. Osteoarthritis:Diagnosis and management. JIRA 1999; 7(4).
139-145.
3. Dequeker, J., Hawkey, C., Kahan, A., .et al. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicm, compared with piroxicam: Resutts of the safety nd eficacy large scale evaluution of COX-inhibiting therapies (SELECT) trial in osteourthritis. Br. J. Rheumatol 1998; 37: 946-5 1 4. Hawkey, C., Kahan, A,, et al. Gas@ointestinaltolerability of meloxicam compared to dzcofenac zn osteoarthritispatients. The International MELISSA Study Group. Br. J. Rheumatol 1998; 37: 937-45. 5. Brandt, K.D. Osteoarthritis: In Fauci AS, Braunwld E, et a1 (Eds): Harrison's Principles of ~ Edition 1998: Vol. 2: pp. 1935-41. Internal medicine 1 4 ed., Mc Graw-Hill. In~rnational 6. Ford-Hutchinson, A. W., et al (1980) Nature. 286,264. 7. Malmsten, C. L.,et al. (1980) Acta Physiol. Scand. 110,449. 8. Bray, M.A., et al. (1981) Br. J. Pharmacology..72, 483. 9. Wedmore, C.V., et al. (1981) Nature. 289,646. 10. Hagers Handbuch der pharmazeut. Praxis (1972) 4& Ed., Vol. 111 pp. 491, Spinger-Verlog, Berlin, Heidelberg New York. 11. Ammon, H.P. T., et al. (1991) Planta Medica. 57,203 - 207. 12.. Singh, G. B., et al. (1 9sb) Agents and Actions. 18, 3 / 4, 407-4 12. 13. Menon, M. K., Kar, A. (1971) Planta Medica. 19, 333 - 341. 14. Atal, C. K., et al. (1980) Ind. J. Parn1.,12,59. 15. Atal, C. K., et al. (1981) Br. J. Pharm., 74, 203. 16. Atal, C. K., et al. (1982) XV IPS (Abstract), Chandigarh. 17. Chandrashekaran A.N., et al. (1995) JIRA, Eflect of ,Sirllaki in the treatmen1 c?f Kheumcrtoid arthritis. Vol. 3 -No. 3, 101-106. 18. Rajagopal, S., et al. (1995) ,JIM, Assessment of the therupeutic ~fll?ct Sallczki (Boswelliu qf serrata) in the treatment of juvenile rheumatoid arthritis. Vol. 3 - No. 3, 107-1 10. 19; Lohokare, S. K. (1995) JIM, A (,'linical Trzal of Ro~wellia Serrata &ScdZuki)in the trecztment of Osteoarthritis. Vol. 3 - No. 3, 113- 116. 20. Bradley, J.D., Brandt, K.D., et al. (,'omparison of an anti-zn$ummatoory &,ye of ib.~dprc?fen, an analgesic dose of ibuprofen and acetaminophen in the treatment patienls with osteo&rthritzsof the knee. N.E.J.M. 1991; 325-87 21. March, L.M., Irwig, L.M., et al. N-of-] trials comparing u non-steroidal antilinflummutory drug andpacetamol on osteoarthritis. B.M. J . 1994,309: 1041. 22. Williams, H.J., Ward, J.R., et al. (.:omparison of naproxen mui acetaminophen in cr two-year study of treatment of osteoarthritis of the knee. Arthritis and rheumatism 1993; 36: 1196 23. Dieppe, P., Cushnagan; J., et .al. A two-yeur placebo controlled trial of non-steroihl untiin$ammatory therapy in osteoarthritis of the knee joint. Br. J. Rheumatology 1993; 32-595.
149
Table I. Nature of cornpla~nt
Complaint ......... Pain in knee joints Pain in hip joints Stiffness in knee joints Stiffness in hip joints ~ i i ' f i c u l in walking and/ or climbing t~
.-,--p--.-.-..-..--
.....
II 42
14 19
.....
.. ..
150
Table 2. Details of the medication Medication T. nimesulide T.meloxicam T.dolonex C.indomethacin C . indocid T. ibuprofen T. dicloram Dose lOOmg b.i.d 15mgb.i.d 20mgo.d 75 mg o.d 25 mg t.i.d 400 mg t.i.d 100mgod No of patients on the medication 18 19 2 1 3
1
The medication described is the one on which the patients had been stabilized for the past onemonth.
151
Table 3. Efficacy results with Sallaki (400 mg) t.i.d. in osteoarthritis

-- -
Clinical Parameters Joint pain Joint tenderness Joint swelling Morning stif'fness Functional impairment Modified KGMC lndex for Physical function criteria Baseline 1.26+ 0.42
109+033 082*027 105*046 114+04 22 3 + 5 86
Mean Score on Week 2 Week 4 0.96 0.4 * 0.66 0.28 *
Week 6 . 0.73 0.39 *
069h033
046*031
046*035
054i028* 07h034* 088%04*
033*029* 047&03* 058*029* 146*653*
034+033* '045*037* 064*043* 16+739*
--
* : significantly different from baseline values atxp

Values are expressed as the mean
* std. deviation of 46 observations
0.05)
152
Table 4. Overall efficacy of the treatment Response Excellent Good Fair Poor Very poor No. reported by Investigator 4 21
16 4 1
Values given are the number of responses reported by the investigator for the 46 enrolled subjects.
1 53
Figure 1: Ef'fect of treatment with Sallaki (400 mg) t.i.d. on the Joint Pain Score of patients with Osteoarthritis
score at (11 .- 0 05) "significantly different from Basel~ne L'ali~esare expressed as the Mean + Std Deviation of 46 observations
154
Figure 2: Effect oftreatment with Sallaki (400 mg) t.i.d. on the. Joint Tenderness Score of patients with Osteoarthritis
--
- .-- - - . . --- . .-- ~ ~
. ..
~
-~ ~- - .. - ---~
T'"
significantly different from Baseline score at (p - 05) 0 : Values are expressed as the Mean + Std Deviation of 46 observations
155
Figure 3: Effect of treatment with Sallaki (400 mg) t:i.d. on the Joint Swelling Score of patients with Osteoarthritis
* : significantly-different from Baseline score at (p < 0.05) Values are expressed as the Mean It Std. Deviation of 46 observations
156
Figure 4: Effect of treatment with Sallaki (400 mg) t.i.d. on the Morning Stiffness Score of patients with Osteoarthritis
* . significantly different from Baseline score at (p < 0.05) Values are expressed as the Mean + Std. Deviation of 46 observations
157
Figure 5: Effect of treatment with Sallaki (400 mg) t.i.d. on the Functional Impairment Score of patients with Osteoarthritis
* . significantly different from Baseline score at (p 0 05) Values are expressed as the Mean + Std Deviation of 46 observations
158
Figure 6: Effect of treatment with Sallaki (400 mg) t.i.d. on the Modified KGMC Index for PhysicalFunction Criteria of patients with Osteoarthritis
* : significantly different from Baseline score at (p < 0.05) Values are expressed as the Mean Std. Deviation of 46 observations
159
DOUBLEBLIND RANDOMIZED CONTROLLED TRIAL OF SALLAKI (600 MG) VS DICLOFENAC (50 MG) IN THE TREATMENT OF RHEUMATOID ARTHRITIS
* Bichile, L S , Rajadhyaksha, A , Kini, S
'
* Author for correspondence Dr.L.S.Bichile M.D. Professor & Head Department of Medicine It Chief Rheumatolgy K.E M. hospital, Parel, M u m b a ~ 400 0 12 Dr A Rajadhyaksha M D Assoc Prof 111 Medlcine K E M hospital, Parel, Mumbai - 400 0 12
Dr. S. Kini M.D Lecturer in Medicine K.E.M. hospital, Parel, Mulnbai
400 0 12
160
ABSTRACT In an open study, fifty patients with primary osteoarthritis of the knee andlor hip were treated with Sallaki8 (400-mg t.i.d) along with the NSAID, which they had been routinely consuming for their disease The duration of the treatment period was four weeks. At the end of the forth week treatment with NSAID was withdrawn and only Sallaki8 (400-mg t.i.d) administered for an additional two week period. The following variables were tested: Joint pain, Joint tenderness, Joint swelling, Morning Stiffness and Functional Impairment for the hip and knee joints. The patients also participated in a questionnaire that included all the thirteen physical hnction criteria of the KGMC Index. A statistically significant improvement in all 'the variables were observed at the Week 2, Week 4 and Week 6 end points. The improvement was thus sustained even after withdrawal of the NSAID therapy. The drug was also well tolerated with no reported incidence of adverse drug reaction
Key words:, Sallaki 8,NSAID, Osteoarthritis
161
INTRODUCTION
Recognition of rheumatoid arthritis as a "medical emergency" led to a change in the therapeutic strategy fiom " go-slow-and-go-low" to "aggressive early treatment" aimed both at symptomatic relief (controlling synovial inflammation) prevention of joint destruction and loss of fknction (modification of the progressive course of the disease). Reasons for the increasing popularity of the aggressive approach were the uncommon natural remissions and the substantial morbidity, work disability, and mortality rates observed in the patients Long term treatment with DC-ARTs/DMARDS is therefore instituted early in the course of the disease before the occurrence of irreversible joint damage. However the use of DCARTsIDMARDS as well as of NSAIDS are associated with a wide spectrum of side effects
'
A recent study on the pattern of adverse drug reaction with NSAIDS, DC-ARTs/DMARDS and steroids on Indian population revealed that gastrointestinal disturbances is the most frequent adverse event and observed in 54 1% of patients Cardiovascular 1 respiratory system abnormalities were observed in about 3 1 88 % of the patients, cutaneous reactions in 2 20 8% and nervous system related symptoms in I 1% of the patients 2
Thus the search for agents with anti-inflammatory and disease modifying potential whose long-term use would not be associated with side effects still continues. The gum resin exudate of Boswellia serrata that has been advocated in the treatment of 'rheumatism in Sushrutha Samhita and Charak Samhita is known to possess remarkable anti3 inflammatory and anti-arthritic effect and to be devoid Of toxicity on prolonged use . Pharmacological studies conducted on the extract of Boswellia serrata to delineate its mode of action revealed the extract to be acting by a mechanism similar to non-steroidal group of antikthritic drugs with the added advantage of it being free fiom side effects and gastric 4 irritation and ulcerogenic activity The extract can inhibit the prodbction of leukothene-type mediators of inflammation at low concentrations and prostaglandin-type mediators of inflammation (the PGF series) at higher 5 concentrations without impairing the PLAz action The extract can also inhibit the expression of 24 hour delayed type hypersensitivity reaction (cell mefliated immunity) and primary humoral response to SRBC in mice (humoral 6 immunity) Marked analgesic effects of rapid onset i.e 30 minutes which lasts for about 2 hours has been 7 obsewed with the non-phenolic extract of Boswell~a serrata These findings suggests that the gum resin exudate of Boswellia 'serrata can play a role in controlling the signs and symptoms of RA by virtue of its anti-inflammatory and analgesic effect and can also prevent the progression of the disease by inhibiting the cell mediated and humoral responses
162
Recent evidence suggests propagation of RA to be an immunologically mediated event with the inflammatory process in the tissue driven by the CD4+ T cells infiltrating the synoviunl. If the extract is able to control the persistent tissue inflammation (i e persistent T cell activity) that is reminiscent of delayed type hypersensitivity reaction occurring in response to soluble antigens or microorganisms, it may help in preventing the progression ofthe disease However before one can claim the superiority of Bo.swell~u .serrutu over conventional drugs on account of the absolute freedom from side effects it is imperative to evaluate ~ t s antiinflammatory and disease modifying potentials in RA patients The crude extract of Ho.vwellru serrutcr resin is available 111 the Intf~anmarket under the trade name "Sallaki" from Gufic Health Care Ltd Well-controlled clinical trials \ ~ t Sallaki ha\ e h been conducted in the past on patients with rheumatoid arthritis and osteoarthrltis Sallaki (400 mg t.i.d) when administered along with anti-inflammatory drugs like aspirin, indomethacin and ibuprofen for a period of six months in patients with rheumatoid arthritis. produced a statistically significant improvement with respect to pain score, number of joints. articular index, swelling score, PIP circumference, grip strength, ESK and CKP. A significant reduction in the rheumatoid factor was observed wh~chseemed to suggest ~ t s probable disease modifying potential ' When Sallah~(400-mg t I d) was assessed for ~ t s therapeut~ceffect in j u ~ e n ~ l~heumdto~d e arthr~tls it demonstrated a potentla1 In produc~tig a remlsslon In the clln~ciil s ~ g n $ 'ind symptoms Besides histologically ~tshoned to produce healing In the svnm [urn bv Inciedsi~le 9 fibrosis aFter sixth month of therapy Sallaki (200-mg t i d) when used in the treatment of osteoarthritls showed encouraging results in early cases having mild pain with no radiological changes In the jcrlnts In the patlents ~clth long-standing disease with moderate to severe radiological changes ~t shomed a fair to pool 10 response Results of the three clinical trials with Sallaki seemed to suggest its efXcacy In relleving the signs and symptoms of rheumatoid arthritis and osteoarthi-itis w~thoutproducrng any side eff'ect eken on long-term use
The results of the previous trials encouraged us to conduct a study where~nthe eflficac? of Sallahl would be compared with the routinely prescribed anti-inf1amnl:ttor-y agents in reliev~ng signs and symptoms of rheumatoid arthritis the
Thus the objective of the present study was to compare the ef'ficacy and tolerance of Sallahr (600 mg t.i.d) with Diclofenac sodium (50 mg t i.d) in providing symptomatic rel~efto patients with rheumatoid arthritis The trial was conducted as a double bllnd randomized parallel group study
163
MATERIAL AND IMETHODS
Patients selection Consecutive patients with active classical or definite rheumatoid arthiitis, according to the American Rheumatism Association (A.R.A.) criteria, attendin8 the Rheurnatology O.P.D. at The patients were includcdif they had K E M Hospital were enrolled into the study atleast four of the seven diagnostic criteria established by the A.R.A. and if their disease state was characterized by the presence of atleast two of the following: 1 duration of morning stiffness of at least 3 hour or more 4 2 atleast six painful or tender joints on motion 3 three inflamed joints 4 erythrocyte sedimentation rate greater that 30 mrnhr as determined by the Westergreen method Patients having developed rheumatoid arthritis before 16 years of age, or thdse with severe disabling arthritis rendering them eligible for surgical intervention or those incapacitated or bedridden were not included in the trial. Patients with ongoing therapy with anticoagulant, hydantoin, dorticosteroids, methotrexate,. gold, penicillamine or lithium or having undergone a thaapy with the same in the previous three months were also not included in the trial Pregnant, lactating women or women at a risk of becoming pregnant were not included. Patients with a history of active peptic ulcer in the preceding six months or bleeding ulcers at any time in the past, or those exhibiting hypersensitivity and / or intolerance to NSAID's including a history of aspirin induced bronchospasm were excluded from the trial. Patients having received any investigational drug in the preceding one-month _or having donated blood in the past three months were also excluded from the trial. Patients with severe renal, hepatic, hemopoetic disease or severe cardiac insufficiency as revealed by laboratory investigations or other tests were also excluded from the trial Previous anti-inflammatory treatment were discontinued for atieast five days prior to initiating the therapy with the investigational drugs and only analgesic therapy with paracetamol was allowed to control symptoms of pain during the wash out period Consumption of other analgesics except paracetamol, antipyretics, tranquilizers, hypnotic, andlor anti-inflammatory drugs were prohibited during the trial to avoid any interference in evaluating the investigational drug treatment The protocol had been reviewed and ratified by the Ethics committee at K.E.M. Hospital. All the patients gave written informed consent before enrollment into the trial. Study Design The study was conducted as a double blind, randomized, paraliel group comparative trial. After the patient satisfied the entry requirements, a complete medical history was taken and a general examination performed The disease activity was measured by counting the number of tender and swollen joints, determining the digital joint circumference, grip strength, duration of morning stiffness, time required to walk 50 feet and VAS score The painhl and
164
swollen joints were scored using a scale of 0, 1, 2 or 3 to evaluate the severity of the inflammatory condition of each joint. The disease activity measurements were conducted during the screening visit, at baseline i e prior to initiating the investigational drug therapy (Week 0), at the end of the first week, second week and thereafter at the fourth week i e the end of the study. Laboratory investigation like ESR, CRP, Rheumatoid factor, blood chemistry, hematological and urine routine were performed at baseline and then repeated at the end of the study i e Week 4 At the end of the study the investigator assessed the overall efficacy and tolerability to the treatment. The dose of Sallaki was (600 mg. t i d) and of Diclofenac sodium (50 mg t I d) divlded morning, afternoon and night The rescue medication paracetamol and the invest~gatlonal drug were provided to the patients at every follaw - up visit At every visit the return tablet count was made to ascertain the compliance to the medication and the paracetamol consumption. The patients were instructed to contact the investigator at any time if they developed an exacerbation of any of the symptoms
Evaluation Procedures
liflicczcy /xzrrzmeter.s The disease activity was assessed at the screening visit, at baseline i.e. Week 0. at Week I . Week 2 and Week 4. The following symptoms were assessed: 1. VAS score: Patients assessment of pain severity during ,day and night was evaluated .using the VAS score. The patient was asked to place a mark on a 10-cm long standarti scale assuming that 0-cm indicated no pain and 10-cm indicated maximum pain. The distance of the point marked from O cm was calculated and recorded in Iiiln. 2. Duration of morning stiffness recorded in minutes 3 . Time to walk 50 feet recordid in minutes. 4. Grip strength in mm Hg: The cuff of a mercury sphygmomanometer was inflated to 20 mm Hg after which the patient was asked to squeeze the cuff to the best of hislher ability and the rise in the level of the mercury was recorded. The mean rise in mm Hg calculated for three tries by each hand was taken as the grip strength) 5. Number of swollen joints: The presence or absence of swelling in the following joints were determined; Temporomandibular ( TM ) Sternoclavicular (SCL), Acromioclavicular (ACL), shoulder, elbow, wrist, Digital interphalangeal (DIP) (2-S), Interphalangeal (IP), Proximal.interphalangeal(PIP) (2-5), Metacarpophalangeal (MCP) (1-S), hip, knee, ankle mortis, ankle tarsus, Metatarsocuneiform (MTC), Sacroiliac (SI) , Interphalangeal L (feet), Proximal interphalangeal PIP (2-5) and Metatrsophalangeal P (MTP) (1 -5). 6 . Swelling score: Swelling in the affected joints was graded as 0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe and a composite swelling score was arrived at by averaging the swelling score of the affected joints.
165
Number of tender joints : The presence or absence of tenderness in the above mentioned jo~ntswere determined 8. Tenderness score Tenderness of the affected joint on palpitation was graded as O= No pain, I= Paln. 2- Pam and wincing, 3= Pain, wincing and withdrawal, 4= Patient d ~ d not allow palpitation and the composite tenderness score was arrived at by averaging the tenderness score o f t h e affected joints. 9 Digital joint circumference. The swelling in the digital joints was evaluated using jeweler's rings (diameter ranging from 10-33 mm). specially des~gned
7.
'She fiillaw~ng porctmeters were also evaluated to determine the efticacy ii'aracetamcil ccmsurnptlon throughout the trial per~od e f o u ~ueeks I I 2 Er~throcytesed~mentat~on (Westergreen method stated In ninilhr) at basel~neand rate Weel-. 4 7 Wlleui~l~~to~d at baselme and Week 4 fact01 -I (' Keact~ce pruteln at basel~ne Week 4 and s oplnlon on efficacy at the coniplet~on the tr~al of graded as f i d l o ~ Ciooti s 10 Pn~est~gittor s~ginticant ~mprc)\ernent,Fair = moderate ~niprovemciitand Poor = no Irnpln~ement
1,abolator~ ~ncest~gatlons 'B'lie following lnvestlgat~onswere conducted at bascl~nc and ~ e p m t c d the tcrm~nat~onf t h e tr~al e Week 4 at o I cvh~teblood cell count t '~lilt Wed blood cell count Hernoplob~n.Complete and d~fferent~al :inalks~s Blood sugal (fkst~ng) Blocrd L I I ~ C I nltrtrper~ Serum creat~nrne 5erurii b~llrub~n, Zs( ' I E . I c~t,il p1citrllis Album~na n d c;lobulin Ln~est~patc~i\ ~ \ \ i ~ ~ c ofl lo\tl,il! tr>le~~rl)~llt\ ,IL . r rlit ~ncestig~tto~ ~ ~ lt11t (l , \ < ~ r toler:ti>~l~ty the ~ n c e s t ~ g a t ~ odrugl on lnterrogiitlng the ~i ec ~ll to r~a ld patient as t luod 1 1 0 S I ~ Cefle~ts.b n ~ r ~ n ~ to {nodel-ate slde ctrects, IJoor = seLcrc \1(1c . effect\ i r,qriliIII: \h, ~tlid~d\c~tl thernln ti0111
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s r z n ~ f i ~ ~ i~l~l'fcrcncc I I I I ~ , I ~ G iil C t~lt'ttment groups and wlth~ntreatment groups for basel~ne ch,tnge frc,m bi~\elineassessment calues at the fourth week ~)l,~niie~i \$[be~oiiip;+~ \%a\ inidde for B)lclofenac sudiuni velsus Sallak~ also ~ ~ t h ~ n (;,ill 15on and c'tel~ lICcjt,l~cnt groups . 11 cc>nlpar1sonswere tested at a s~gn~ficance A level of p - 0 05 In tr~ticr t:i suinmar~ze -I beech tredtnient results, only the mean assessment ti>r bascline thc ' ~ n dthe nie'ln assessment at the end cif the treatment perrod (4 weeks) are presented as Weel (1 !#-ti.4 iespecti\el\. i
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SELECT RESEARCH PAPEha ON EVIDENCE BASED AYURVEDIC DRUGS
166
OBSERVATIONS
Demographics and Patient characteristics Forty-seven patients were enrolled in the study amongst which thirty-thl-ee patients completed the trial (18 on the diclofenac sodium group and 15 on the Sallaki group) The mean age of the patients in the diclofenac sodium group is 37.67 13.5 whi!e the mean age of the patients in the Sallaki group is 43.47 i 13.27. Twenty-six amongst the thil-ty-ttlree patients who completed the trial were females while the remaining six patients were males. The mean duration of the disease in the Sallaki group was 3.09 i- 2.77 years while that I ~ the I diclofenac sodium group was 2 3.9 years and were not significantly difrerent from each other
Clinical Efficacy Results The clinical responses of the patients were determined and the results are as shown In 1 able 1.28~3
VAS score ('otiip~zri.~~t~ and post /rt?utrnen/vcr1iic.s ofpre Both Sallaki and Diclofenac sodium produced very significant improvement in the pat~enl's perception of pain at the 4-week endpoint when compared to baseline. The mean V.4S score for the Sallaki group at Week 4 is 48.57 27.49 that is significantly less (p . 0.05) than the : mean VAS score at baseline of 64 14 + 28.03. Similarly the mean VAS score for the Diclofenac sod~urn group at Week 4 is 44.06 + 25 which is also .sigtiiticantly less ( p . 0 0 5 ) tllan the mean b~seline VAS s.:ore of 57 71 23.7
l )i/Ii,~.c~ti~.e ~ t w Sclllczki and I ) I c I O ~ ~ ~ ~ L I C h~ ~~cn .sodil~tn There was no significant difference between Sallaki and Diclofenac sodium in reduc~ngthc patient's perception of pain. The mean baseline VAS scores for Sallaki and ~iclofenac \\el-e not significantly different from each other Besides the mean absolute difference between tllc pre-treatment and Week 4 VAS score for the Sallaki and Diclofenac sodium group that were 24 63 k 22.9 and 21.42 22.06 respectively were also not significantly different from each other.
G r i p strength
('otn/~cwi.son ofpre czrzdfio.st lrelzfrnentvu1ue.v Both Sallaki and Diclofenac sodium produced non-significant improvement in the grip strength at the 4-week endpoint when compared to baseline The mean grlp strength in the Sallaki group at Week 4 is 82.07 i- 58.15 that is not significantly higher than the rnenn baseline grip strength of 75.14 37.4. Similarly the mean grip strength for the D~clotenac sodium group at Week 4 is 90.74 i 42.9 which is not significantly higher than the rneiiil baseline grip strength of 82.58 44.7.
ll~fferenct! hetweet?Scrllc~ki utzd I)ick!fencrc .sodirrrn There was no significant difference between Sallaki and Diclofenac sodium i n increasing thc grip strength at Week 4. The mean baseline grip strength score for Sallaki and L)rcloltnac were not significantly different from each other. Bes~desthe mean absolute difference between the pre-treatment and Week 4 grip strength score for the Sallaki and D ~ c l o t n a c
167
sodium group that were 39.73 + 37 9 and 23.24 + 18 3 respectively were also not significantly different from each other Duration of morning stiffness
('ompczrzscm ofpre undpost trecztment values Both Sallaki and Diclofenac sodium produced non-significant decrease in the duration of morning stiffness at the 4-week endpoint when compared to baseline The mean duration of morning stiffness for the Sallaki group at Week 4 is 61 93 + 76 46 which is not significantly less than the mean duration of morning stiffness at baseline of 68 36 + 63 2 Similarly the mean duration of morning stiffness for the Dlclofenac sodium group at Week 4 is 51 33 + 59 2 which is not significantly less (p 0 05) than the mean duration of morning stlffness at baseline of 80 88 + 5 l 8 Ihference between Strlluk~ I)rciqfenuc sodzutn und There was no significant dlt'ference between Sallaki and Diclofenac sod~um decreasing the In duration of morning stiffness at Week 4 The mean baseline readings for duration of morning stiffness for Sallaki and Diclofenac were not significantly different from each other Besides the mean absolute difference between the pre-treatment and Week 4 readlnps for duration of morning stlffness for the Sallaki and Dlclofenac sodium group that were 38 53 + 40 29 and 44 84 + 42 7 respectively were also not significantly different from each other
Time to walk 50 feet
('ompczrison of pre tndpost treuttnent values Both Sallaki and Diclofenac sodium produced non-significant decrease in the time required to walk 50 feet at the 4-week endpoint when compared to baseline. The mean time required to walk 50 feet for the Sallaki group at Week 4 is 33.80 5 16.4 which is not significantly less than the mean time required to walk 50 feet at baseline of 35.4 + 19.2. Similarly the mean time required to walk 50 feet for the Diclofenac sodium group at Week 4 is 36.37 + 14.5 wh~chI S not significantly less than the mean time required to walk 50 feet at baseline of 4 3 . 2 6 i 188
1 )l fferencc~ helween Sullukl rznd Dlclofinac sodium , There was no s~gniticant d~fference betwcen Sallakl and Dlclofenac sodlum In decreasing the time requ~redto walk 50 feet at Week 4 The mean baseline value for the time required to walk 50 feet for Sallak~and D~clofenacwere not s~gnlficantlyd~fferentfrom each other Besides the mean absolute difference between the pre-treatment and Week 4 value for the tlme requ~redto walh 50 feet for the Sallak~and Dlclofenac sodium group were 11 98 + 12 3 and 12 47 11 05 respectively and were not s~gnificantly d~fferent from each other
Digital joint circumference
('om/~urzson q'pre undpost treuttnent vu/ues Both Sallaki and Diclofenac sodium produced non-significant decrease in the digital joint circumference at the 4-week endpoint when compared to baseline The mean digital joint circumference for the Sallaki group at Week 4 is 22 8 + 6 4 which is not significantly less (p < 0 05) than the mean digital joint circumference at baseline of 23 2 + 2 86 Similarly the mean digital joint circumference for the Diclofenac sodium group at Week 4 is 23 1 1 h 2.88
which is not significantly different (p < 0 05) from the mean digital joint circumference at baseline of 23.16 + 2.5.
lhfference between Salluk~and Dzclofenac sodzum There was no significant difference between Sallaki and Diclofenac sodium in decreasing the digital joint circumference at Week 4 The mean baseline value for digital jo~utc~rcutiiference for Sallaki and Diclofenac were not significantly different from each other Besides the mean absolute difference between the pre-treatment and Week 4 value for dlg~ial joint circumference for the Sallaki and Diclofenac sodium group were 2 41 + 5 58 and 0 83 i O 87 r~spectively were not significantly different from each other and Number of swollen joints ('ompcrrison of pre ~zndpost treatment i~alues Diclofenac sodium but not Sallaki produced a significant-decrease in the number of swollen joints at the 4-week endpoint when compared fo baseline. The mean score for number of swollen joints for the Sallaki group at Week 4 is 9.5 + 10.1 which is not significantly less than the mean score for number of swollen joints at baseline of 11.42 7.43. 'T'he mean'score for number of swollen joints for the Diclofenac sodium group at Week 4 is 4:63 + 3.88 which is significantly less (p < 0.05) than the mean score for number of swollen joints at baseline ot' 8.44 + 5.9. 1)~firence between SaZlakr and D ~ c !ferric sodium b There was no significant difference between Sallakr and Diclofenac sodium In decreasing the number of swollen joints at Week 4 The mean baseline value for the number of s\\ollen jo~ntsfor Sallaki was 15 21 which is significantly higher than (p 0 05) 7 58. tlic hnseltne value for the number of swollen joints for the D~clofenac group However the mean absolute difference between the pre-treatment and Week 4 value for the number of swollen joints f o ~ the Sallaki and Diclofenac sodium group were 7 59 + 6 I0 and 4 71 5 4 36 respect~\elvand were not significantly different from each other Number of tender joints <:ompcrrisonqf pre and post treatment vali~es Both Sallaki and Diclofenac sodium produced a non-significant decrease in the number of tender joints at the 4-Week endpoint when compared to baseline The mean value for the number of tender joints for the Sallaki group at Week 4 is 14.5* 12.9 which is not significantly less (p < 0.05) than the.mean baseline value for the number of tender joints of 19.79 + 12.5. Similarly the mean value for number of tender joints for the Diclofenac sodium group at Week 4 is 13.88 + 17.1 which is not significantly less (p < 0.05) than the mean baseline value for number of tender joints of 13.88 + 9.2. II~fference between S U / / U czndUzclofen~rc ~Z sodzzltn There was no significant difference between Sallaki and Diclofenac sodium in decreasing the number of tender joints at Week 4 The mean baseline value for the number of tender joints for Sallaki and diclofenac were not significantly different from each other Besides the mean absolute difference between the pre-treatment and Week 4 value for the number of tender joints for the Sallaki and Diclofenac sodium group were 7 56 6 71 and 7 92 8 28 respectively and were not significantly dif'ferent from each other
169
Composite swelling score
('c)m/)~:rlsor~ and post treatment va1zre.s c?fpre Diclofenac sodium but not Sallaki produced a significant decrease in the composite swelling score at the 4-week endpoint when compared to baseline The mean composite swelling score for the Sallaki group at Week 4 is 11 33 k 11 25 which is not significantly less thhn the mean composite swelling score at baseline of 15 33 1 1 The mean composite swelling score for the Diclofenac sodium group at Week 4 is 5 56 4 28 which is significantly less (p 4 0 05) than the mean composite swelling score at baseline of 9 00 + 5 8
/)/fferetlce between A % z / /arzd 1)rclofenuc sodlum ~ There was no significant difference between Sallaki and Diclofenac sodium in decreasing the composite swelling score at Week 4 The mean baseline composite swelling score for Sallaki and Diclofenac sod~um were not significantly different from each other Besides the mean absolute difference between the pre-treatment and Week 4 composite swelling score for the Sallaki and Diclofenac sodium group were 9,25 + 8 9 and 4 71 3 92 respectively and were not significantly different from each other
Composite tenderness score
atzdpos[ treatment vultres Sallaki but not Diclofenac sodium produced a significant decrease in the composite tenderness score at the 4-week endpoint when compared to baseline. The mean Week 4 composite tenderness score for the Sallaki group is 17.71 5 16.6 that is significantly less (p < 0.05) than the mean baseline composite tenderness score of 30.00 + 20.3. Hbwever the mean composite tenderness score for the Diclofenac sodium group at Week 4 is 15.16 14.5 which is not significantly less (p <: 0.05) than the mean composite tenderness score at baseline of 17.05i 14.9.
( 'omp~~rison/)re of
I)rfirrnce betweet1 Strllukz and J)lclJfenuc sdzum There was no significant difference between Sallaki and Diclofenac sodium in decreasing the composite tenderness score at Week 4 The mean baselme composite tenderness score for Sallahl and Dlclofenac sodium were not significantly different from each other Besides the mean absolute difference between the pre-treatment and Week 4 composite tenderness score for the Sallak~ Diclofenac sodium group were 12 59 i 12 5 and i 1 9 2 d 9 85 respectively and and were not significantly different from each other
Erythrocyte sedimentation rate
urdpost treatment values Both Sallaki and Diclofenac sodium produced a non-significant decrease in the ESR at the 4week endpoint when compared to baseline. The mean ESR for the Sallaki group at Week 4 is 39.36 that is not significantly different than the mean ESR at baseline of 38.55. Similarly the mean ESR for the Dic:!;::,.,ac sodium group at Week 4 is 42.13 which is not significantly less than the mean ESR at baseline of 45.4.
Rheumatoid factor and C. reactive protein As the data of very few patients for the above two parameters were available, they were not subjected to statistical analysis.
( i)tnp~rri.sor~ cfpre
Paracetamol consumption
The mean paracetamol consumption throughout the study period (4 weeks) in the Diclofenac sodium group is 49:52 25.7 which is not significantly different from the mean paracetamol consumption in the Sallaki group of 53.28 18.9.
Overall efficacy
The overall efficacy of the treatment amongst the 15 patient who completed the trial with Sallaki and 18 patient who completed the trial with Diclofenac sodium is as shown in Table 6.
Safety Comparison of pre and post treatment laboratory values
No abnormalities in the laboratory tests were observed for both the treatment groups (Table 4, 5). No statistically significant change in the pre and post values for hemoglobin, white blood cell count, fasting blood sugar,-blood urea nitrogen, serum creatinine, serum bilirubin, SGPT, serum proteins albumin and globulin was observed for both the groups.
Comparison of the overall tolerability
The overall tolerability to the treatment amongst the 15 patient who completed the trial with Sallaki and amongst the 18 patient who completed the trial with Diclofenac sodium is as shown in Table 6.
Patients complaint
One patient in the diclofenac sodium group complained of abdominal discomfort for 15 days that was of moderate severity requiring discontinuation of the therapy. Two patients 'complained of GI side effects amongst which one suffereft from dyspepsia for 7 days. One of the patients on therapy with diclofenac sodium complained of piles without bleeding during the last 10 days of treatment. One patient in the Sallaki group complained of dyspepsia of mild severity.
A very good compIiance to the medication was observed for both the groups.
171
DISCUSSION
A total of forty seven patients who Mfilled the diagnostic criteria of classical or definite rheumatoid arthritis were enrolled in the double blind, randomized study to compare the efficacy and tolerability of Sallaki (600 mg) with the routinely prescribed Diclofenac sodium (50 mg) in relieving symptoms of rheumatoid arthritis Eighteen patients completed the trial on Diclofenac sodium and fifteen patients completed the trial on Sallaki. Six patients had lost to follow-up after baseline assessments, four patients after one week and two patients after two weeks of therapy. Two of the patients had to be dropped from the study owing to develepment of adverse drug reaction,.and one patient was dropped after inclusion owing to the detection of-interstitial nephritis.
There is a clear and well-documented evidence of efficacy of diclofenac sodium in the treatment of rheumatoid arthritis. The present study indicates that the eflicacy of Sallaki (600 mg t.i d) is comparable to that of diclofenae sodium (50 mg t i.d) in relieving the symptoms of rheumatoid arthritis This can be concluded from the non-significant difference between Sallaki and jliclofenac sodium in decreasing the duration of morning stiffness, pain severity, number of swollen joints and the scores for swelling and tenderness in the joints. These objective measurements of efficacy were supported by the investigators subjective global evaliration of the patient's response to both the therapies The other two measurements of grip strength and digital joint circumference failed to show any evidence of efficacy. The objective value of both these parameters is subject to V'lfiscussion since they have no direct relationship with the inflammatory state of the joint. Factors such as limited mobility, increased volume and pain may influence grip strength and bone deformity, while exostosis and chronic swelling of the paraarticular structures may also affect the circumference of the digital joints
A realistic approach to estimate the minor or major changes induced by a pharmacological therapy is the patient's hnctional disability. Assessment of the articular index and the functional index are sensitive parameters in evaluating changes induced by treatment. In the present study we observed a statistically significant decrease in the articular index (tenderness score) at the end of the study period i e four weeks in the Sallaki group The decrease in the articular index at the end of the study period in the diclofenac sodium group was however not statistically significant But comparison of the decrease in the tenderness score observed for both the groups revealed them not to be significantly d i f f e ~ n from each t other
The results of the composite swelling score seem to indicate diclofenac sodium to be more efficacious than Sallaki in reducing swelling in the joints. But the baseline swelling score in the Sallaki group was significantly higher than the diclofenac group It was therefore decided to compare the decrease in the swelling score at the end of the study period for the two groups. The two groups were found to be comparable with each other in decreasing the swelling score Thus it may be said that a comparable positive result was obtained with both the treatments
Thus it inay be conctuded ti-om the study that Sallaki does have a role t o play in the pathology o f rheuniatoid arthritis. The pathology o f rheumatoid arthritis evolves over the dul-ation o f tlie disease. The earliest eve18 is a nonspecific inflammatory response initiated b y an i~nlinown stiniulus. Subsequently. an initial. and perhaps specific, response o f CD4+T cell is induced that amplifies and perpetuates tlie intlaniniation. The presence o f activated T cells can induce polyclonal B cell s t i m i ~ l a t ~ o n the local production of rheumatoid factor. As and tissue damage occurs. additional autoantigens are revealed and the nature o f the T cell response broadens ils additional clones ofC1)3-1-T cells are recruited into the inflammatory site. Finall\ as n ~.csultof pel-sistent e\posiIre to tlie inflammatory milieu, the function o f s\novial fibroblasts is altered i ~ n dtlley niay acquire destructive potential that no longer requi~.cs stimulntion fi.oni 1 cells (.II. ~iiac~.opliagcs ' I.' CI~I~IC~III,..clironic infl;criirilatio~i in rlic s!.~io\ ial tissuc and acute inflatnmatory process i n the s\,no\i;~l Iluid c;luses s\\clling. tcndcrness and liniitation o f motion. With persistent i ~ ~ t l ; i ~ i t ~ i i iil \;~rictyof'cli;~r.;ccter.isticdcfi)~.niitics ~~ioti. dckclop. \:or manageinent o f such pi~tients the various tlierapies cnlployed are directed at nonspecific suppression of' the inll;~nin~atory i ~ ~ i ~ ~ ~ i ~ i~xoccss iinc tlie hope o f ameliorating or~olog s\.ml?to~iis preventing progressive damage t o articular structures and 'l'lie constituent o f Sallaki. gum resin c\udiite oi' Boswcllin scrratn is ;I potent inhihi;:;!- .' - . lipoo.;spenase a c t i ~ i t y and can inhibit tlir acutc inllamniatory pl.ocess in the sy,lit.\, i.ii t l u ~ d I ~ i l i i O ~ tof5-I1~~oosygcnasc ~o~i acfivity prc\;cnts the synthesis of' Icucot~.ienc typf: ~i~:li~ntors of ~ntla~n~nntion I;rom tlic family o f Icucotricne-tvpc inediators lcuhotriene B., IS a ,potent s t ~ ~ i i ~ r l ;ol't o ~ . ~ Icucoc\~tcresponses like cll~~ll~)t;~.,is. adhcsiori. supcroside production. ccll cnlc~uni translocation i111d ~.clc;~scol' Ii\;tl~.olytic cnzymcs Additionally. it stimulates ~"nnouncedpl;~sni;c cs~rd;~t~ori o 111 \.i\ 'l'lie tfec~.c;~sc lcndcrncss ill10 S\CCIIIII~.l i ~ i ~ l ill c l i ~ niani1'Cst;ilions o f acute inflammation, may he t l ~ toe inliib~tion ~ tlic o1'5-li~~oo~~\~gcnitse ;lctivity.
It is illso k n o w ~ ifi.om cspcrinicntal studies Iliat I ~ o s w c l l i :serrat;~cicli i ~ i l i ~ bthe delayed ~ it In.persc~cs~t11y react iori i\ I(ccent lindings Iinve suggcstctl tIi;11 the pr.ol)ilgi~tion I< is nn i r l i ~ ~ i ~ ~ ~ i o l o g mediated ol' A ically cicnt. w ~ t l itlic inllaniniatory proccss 111 ~ l i ct~ssuc k i n g c l ~ . ~ c e ~ i tlic ('L)4+T cells by ~ ~ i l i l t ~ . a tllcnsynoviurii 'l'lie 'I'cells p~.otl\~cc variety ol' c y t o L i ~ ~ c s promote B cell r~ g ; I that ~ ~ ~ o l ~ f ' c illid td~fl'C~.c~iti;~tio~i~ ~ i t ~ l ) o d y - l i )cells ~ i ~ ~ i g r;~ ~o~l into i ~ . ~ and tlic~.efi)~.e may promote also If~ c i 1) lccll st in111 ion 'l'lie rcsu Itant ~)~rjcluct 01' i~iiriirrnoglohrrli~~ rheumatoid factor ~ la1 icm and call Icild to 1111111111ico ~ i i ~ >l Ii c .~~ ~ i i ; WI~II C(~I~SCIIII~II~ ~onlplcnient activation and ~ ~ . ~t~o~i c.\i~cc~.l>i~tio~l i n f l a n i ~ ~ i i ~ t o ~ . ~ Oy !lie l)~.otlu~tion oftlic J>I.OCCSS of'a~iapliylatoxins, C3a and C5a, illl(ltllc! cllc111,~tactlc fi1ct01 ('5iiI2 'l'he tissue i~illaniniationIS I-eni~n~sccnt ol'tlclayctl type hypersensitivity reaction occurring i n rcspu~isc ssolublc antigens or ~iiicroorgicnis~iis to illso tllc cylokiries rclcascd by the 'r cells, 11.- I iuid TNI; alpha play an important role by stiniulating the cells ol' the pannus to )~.oducc colla~enaseand other neutral proteases, resulting in bone and cartilage destruction I2 As the extract of U o s \ ~ e \ l i a serrata srin inhibit the delaycd type hypersensitivity reactian i t tnay be proposed that it could play a rote i n preventing the persistent T cell activity and the subsequent cartilage and bone damage. 'I'hus Sallaki may possess disease-modifying potential by preventing tlie progression o f the disease.
In the present study Sallaki was better tolerated than diclofenac sodium as except for on case of mild dyspepsia no other incidence of GI disturbances was -observed. Clinical laboratory studies, performed before and after the study, never showed any pathological modification in both the groups.
CONCLUSION
The result of the study indicates Sallaki and diclofenac sodium to be having comparable efficacy in the treatment of symptoms of rheumatoid arthritis. However Sallaki is better tolerated than diclofenac sodium by the patients. Considering the fact that rheumatoid arthritic patients hav.e demonstrable predisposition for gastric intolerance with antiinflammatory medication, we believe that Sallaki will benefit these arthritic patients who can not otherwise tolerate these anti-inflammatory medications. The result of the present study of Sallaki (600-mg t.i.d) in RA, encourage hrther investigations on the therapeutic potential of the drug in modifying the disease process.
ACKNOWLEDGEMENT
The authors wish to thank Ciufic Healthcare LM1. for providing the drug samples (Sallaki (600 mg) and Diclofenac sodium (50 mg)) for conducting the trial. We are also grateful to Dr Harshad P. Thakur M.D., D.B.M. for carrying out the statistical analysis of the data.
1 74
Table 1. Efficacy resul'ts with Diclofenac sodium (SO mg t.i.d) in rheumatoid arthritis patients Parameter Vas Score
Duration of Morning Stiffness Grip Strength Time to walk 50 ft Digital Joint Circumference Total Swelling Score No. of Swollen Joints Total Tenderness score No. of Tender Joints
Week 0 57.71 k 23.7
Week 4 44.06 i 25
p < 0.05 S
Values are expressed as the mean score std. deviation Number of observations = 18
175
Table 2. Efficacy results with Sallaki (600 mg ti.d) in rheumatoid arthritis patients Parameter Vas Score Week 0 66.14*28.03 Week 4 48.57*27.49
p< 0.05
Durati6n of Morning Stiffness Grip Strength Time to walk 50 ft Digital Joint Circumference Total Swelling Score No. of Swdlen Joints Total Tenderness score No. of Tender Joints
Values are expressed as mean score + std deviation Number of observations = 15
Table 3 Comparison of Diclofenac sodium (50 mg t.i.d) with Sallaki (600 mg t.i.d) therapy in rheumatoid arthritis patients Parameter Diclofenac sodium 21.42A22.06
44.84 k 42.7 23.24
Sallaki
24.63k22.9 38.53 40.29 39.73 f 37.9 11.98 f 12.3 2.41 =t 5.58 9.25 % 8.9 7.59 =t 6.10 12.59 f 12.5
7.56 k 8.28
P
NS
NS NS NS
Vas Score Duration of Morning Stiffness Grip Strength Time to walk 50 ft Digital Joint Circumference Total Swelling Score No. of Swollen Joi-nts Total Tenderness score
* 18.3
12.47k 11.05
0.83 0.82
*
* *
NS
NS
4.71f 3.92 4.71 4.36 11.92f 9.85

7.92 6.71
NS
NS
NS
No. of Tender Joints
Valyes expressed are the mean absolute difference between the Week 0 score and Week 4 score for each parameter Values are expressed as mean std. deviation
177
Table 4. Mean of laboratory tests in 15 patients sumring from RA. given Sallaki (600 m t.i.d) for four weeks Parameter Hemoglobin
WBC Fasting Blood Sugar Blood Urea Nitrogen Serum Creatinine Serum Bilirubin SGPT
Serum Total Protein
Week 0
11.83
* 2.13
Week 4
10.5
* 1.34
p< 0.05
NS
Albumin Globulin
Values are expressed as mean Number of observations = 15
std. deviation
178
Table 5. Mean of laboratory tests in 18 patients suffering from R.A. given Diclofenac sodium (50 mg t.i.d) for four weeks
Parameter Hemoglobin
WBC Fasting Blood Sugar Blood Urea Nitrogen
Week 0
11.81* 1.59 8193.3*2364 87.69 k 29.1 13.87 15.16 29.09 k 13.06
Week 4 12.00 h 1.64

7486.6*2071 89.04k149
p< 0.05
NS
NS
NS NS
NS NS NS
SGPT
Serum Total Protein Albumin Globulin
*3 7 42.27 * 39.5
9.93
* 3.7 * 0.82
7.4 0.92
11.27i13.08 3 . 0 k 1.52 2.2 5 1.64
2 . 6 * 1.31
NS
Values are expressed as mean .t std. deviation Number of observations = 18
--
--
179
Table 6. Overall efficacy and overall tolerability to treatment for four weeks with Sallaki (600 mg t.i.d) and Diclofenac sodium (50 mg t.i.d)
Treatment
Sallaki
Diclofenac
Responses to Overall Efficacy Fair Poor Good 1 7 7

12
Responses to Overall Tolerability Good Fair Poor 2 12 4
Values expressed are the number of patients reporting the responses
SELECT RESEARCH PAPEKS ON EVIDENCE BASED AYURVEDIC DRUGS
180
REFERENCES
I. Malaviya, A.N., Kaushik, P. ''Recent udvances in drug therapy for rheumatoid arthrltis" Journal of Association of Physicians of India September 1999, V01. 47, pp 912-91 7 2. Jhaj, R., Uppal. R, et al. "Adverse drug reactions with anti-rheumatic h g s in a Rheumafology clinic" Journal of Indian Rheumatism Association 1998, Vol. 6 No 1 , pp 3-6. 3. Atal, C.K., et d.Indian Journal of Pharmacology 1980, Vol 12, No 10 pp 59. 4. Singh, G.B., Atal, C.K. "Pharmacology of an extract of salul guggal ex-Boswella serruta, a new non-steroiclal anti-inflammatory agent" Agents and actions 1986, Vol. 18, pp407411. 5. Arnmon, H.P.T., Mack, T., et al. "Inhibition of leukotriene b4 formation m rat pertioneul neutrophils by ethanolrc extract of the gum resin exuhte of -Boswellru serruta" Planta Medica 1991, 57, pp 203-207. 6 Sharma, M.L., Kaul, A,, et al 'lmmunomodulutory activzty of Bo~we[/zcUCZ& (penta~yclic triterpene acids) jkom Boswellia serratu ". Phytotherapy Research, 1996, V O ~ O(2)' p 107-112. 1 7 Menon, M K., Kar, A "Analgesic and psychophurmacologzcul effects of the gum resrn e m ~ h t e -Boswellza serruta " Planta Medica 1971, 19, pp 333-34 1 uf 8 Chandrashekaran A N., et al. "Efect of S'allakz m the treatment of Hheumatozd arthrltis " JIM, 1995, VOI 3 - NO. 3, pp101-106. 9 Rajagopal, S., et al. "Assessment of the therapeutic effect of ";allakz(Boswellru serrataj zn the treutment ofjuvenile rheumatold urthritrs " JIRA, 1995, Vol 3 - No 3, pp 107-110 I0 Lohokare, S. K "A C/inzcal Trzul of Boswellzu Serruta (Sallukl) In the treatment of Osteoarthrztzs." JIRA, 1995, Vol. 3 - No 3, 113-116 11. Arnett, F C. et al. "The American Rheumatism Associatran 1987 revised criterza for the cls,sz$cution qf rheumatold urthntls" Arthritis Rheum 1988 3 1, pp3 15-324 12.Lipsky1 P.E., "Rheumatoid Arthritis" in Harrison's Principles of Internal medicine, 1 4 ' ~ ~dition, Mac Graw Hill Companies, Inc. 1998, pp. 1880-1888
181
August, 20,1999
To, Dr. (Mrs) L.S. Bichile, M.D. Professor and Head Department of Medicine & Chief Rheumatology, K E M Hospital, Parel, Mumbai- 400 012.
Sub: Receipt of the completed case report forms and the drug supply returned by the patients
Dear Dr. Bichile, We gratefully acknowledge the receipt of twenty-two completed case report forms of the patients enrolled in the trial namely "Clinical trial to evaluate the eficacy of Sallaki 600 mg with rheumatoid arthritis" and bearing the patient number (1-10,12-15,17,21-26). in pat~ents Amongst these, 13 case report forms of the patients bearing the patient number as mentioned below are complete for all the follow up visits i e 4 weeks PatientNo 1 , 2 , 3 , 4 , 5 , 6 , 8 , 10, 12, 1 7 , 2 4 8 ~ 2 6 Six of the case report forms of the patients bearing the patient number as mentioned below are not complete for all the follow-ups as the patient's lost to follow-up. Patient No. 9, 13, 14, 15,22,25 Two case report forms as mentioned below have been filled for adverse drug reactions Patient No 7,23 One case report form has stated the patient's discontinuation from the study Patient No. 21. The drugs returned by the patients bearing the patient number (1-10, 12-15, 17) was collected ~ back from the site on 3 0 June, 1999 for subsequent.disposition. The drugs returned by the patients bearing the patient number (21-26) will be collected back from the site for subsequent disposition today. Thanking you once again for your kind cooperation Yours truly, For SPC Interface
Dr. H.S. Parikh M.D.
SELECT RESEARCH PAPERS ON kvIDENCE BASED AYURVEDIC DRUGS
182
To, Dr. (Mrs) L.S. Bichile, M.D. Professor and Head Department of Medicine & Chief Rheumatology, K.E.M. Hospital, Parel, Mumbai- 400 012.
Dear Dr. Bichile, We gratehlly acknowledge the receipt of thirteen completed case report forms of the patients enrolled in the trial namely "Clinical trial to evaluate the eficacy of Sallaki 600 mg in patients with rheumatoid arthritis" and bearing the patient number (1 1, 16, 18-20, 27-34). Amongst these, 12 case report forms ot'the patients bearing the patient number as mentioned below are complete for all the follow up visits i.e. 4 weeks Patient No 1 1, 16, 18, 1 9, 20, 27, 28, 29, 3 1, 32, 33 One of the case report form of the patients bearing the patient number as mentioned below I e not complete for all the follow-ups as the patient lost to follow-up. Patient No. 30 Two case report forms as mentioned below have been filled for adverse drug reactions Patient No. 34, The drugs returned by the patients bearing the patient number (1 1, 16, 18-20, 27-34) will be collected back from the site for subsequent disposition today. Thanking you once again for your kind cooperation Yours truly, For SPC Interface

183
February 25, 2000
To, Dr. (Mrs) L.S. Bichile, M D .. Professor and Head Department of Medicine & Chief Rheumatology, K.E.M Hospital, Parel, Mumbai- 400 0 12.
Dear Dr. Bichile, We gratefully acknowledge the receipt of nine completed case report forms of the patients enrolled in the trial namely "Clinical trial to evaluate the efficacy of Sallaki 600 mg in patients with rheumatoid arthritis" aiid bearing the patient number (35-43). Amongst these, 6 case report forms of the patients bearing the patient number as mentioned below are complete for all the follow up visits i.e. 4 weeks Patient No. 36, 37, 38, 39, 41 & 42 Three of the case report forms of the patients-bearing the patient number as mentioned below are not complete for all the follow-ups as the patient's lost to follow-up. Patient No 3 5 , 40, 43 The drugs returned by the patients bearing the patient number (35-43) will be collected back from the site for subsequent disposition today. Thanking you once again for your kind cooperation. Yours truly, For SPC Interface
184
March 3 1, 2000
To, Dr. (Mrs) L.S. Bichile, M.D. Professor and Head Department of Medicine & Chief Rheumatology, K.E.M. Hospital, Parel, Mumbai- 400 012
Sub: Receipt of the completed case report forms and the drug supply returned by the pa tients
Dear Dr. Bichile, We gratehlly acknowledge the receipt of four completed case report forms of the patients enrolled in the trial namely "Clinical trial to evaluate the efficacy of Sallaki 600 mg in patients with rheumatoid arthritis" and bearing the patient number (44-47). Amongst these, 3 case report forms of the patients bearing the patient number as mentioned below are complete for a 1 the follow up visits i.e. 4 weeks 1 Patient No. 44,45 & 46 Three of the case report forms of the patients bearing the patient number as mentioned below are not complete for all the follow-ups as the patient's lost to follow-up. Patient No. 47 The drugs returned by the patients bearing the patient number (44-47) will be collected back from the site for subsequent disposition today. Thanking you once again for your kind cooperation. Yours truly, For SPC Interface
185
June 28;2000
To, Dr. (Mrs) L.S. Bichile, M.D. Professor and Head Department of Medicine & Chief Wheumatology, K E.M Hospital, Parel, Murnbai- 400 012.
Sub: Receipt of the report of the clinical trial
Dear Dr. B.ichile, We are extremely pleased to receive the report entitled "Double-blind randomized controlled trial of Sallaki (600 mg) vs Diclofenac (50 mg) in the treatment of rheumatoid arthritis" of the clinical trial conducted by your department. We also take this opportunity to once again express our gratitude at receiving 47 completed case report forms of the patient you had enrolled in the trial. We would like to reiterate for your perusal that amongst the 47 patients you had enrolled in the trial, 33 patients completed the four weeks of the trial, 3 reported for adverse drug reaction and 1 1 lost to follow up. The balance payment for the remaining case report forms will be made at the earliest Thanking you once again for the well-conduction of the trial Yours truly,
For SPC Interface
186
Economic and
Medicinal Plant Research
Volume 5
Edited by
H. WAGNER
Institut fur P h a r m ~ u t i s c h e Biologic der Unkmsitiit Miimhn, .lfGn~hcrl, il >st Cennary
NORMAN R. FARNSWORTH
Program for Cqllaborative Research in the Pharmaceutical ;ciencis: College oj Pharmacy, University of Illinois at C k g o , Chicagoy Illinoisy ~h.4
ACADEMIC PRESS
Harcouri B r m Jovanooitlr, Publirhcrs
London San Die New York Boston Sydney okyo Toronto
??
-
187
Guggulipid: a Promising Hypolipidaemic Agent from Gum G uggul (C o m m i ' o r a wightii)

Sznibr Dcpup Director-Gqnd. Indian C Snu Drlhi-1100?9, l n d i ~
cf .\ledical
ILscarrC. .+van .Vale..
1ntroduction ..................................................................................... Ethnomcdical Information on Guggul Cum ..................... :................. A. History of Guggul in jncient Indian .\lcdical Literatlrrc ............. B. Uses o G u g p l in Folk1o.r~ f and Ethnornedicinc ........................... Economic and Pharmacognostic Aspects dGuggul Gum ................. Chemical Investigations oCGuggul Gum ............................................. PhaIIna~~lOgiCid Stud+ ofGuggu1 Gum ............................................. A. Hypolipidaernic Acti\iv of Cuggul Gum ........................................ B. Studies on the hiechanisrn of k d o n of Guggul Gum as 3 . Hypolipidaernic Agent .................................................................... Clinical Studia on Guggul Gum .......................................................... A. Hypolipidacmic Activig ................................................................. B. Clinical Studies on Patients ha\isg lschacmic Heart .......... C. CliScal Studies on Patients ha\ing Hcmiplegia .............................. EKmt of Guggul Gum on C+gulation Fytors and Body \\'eight ......... A. Erect on Body Weight .................................................................. VIII. Other Pharmacological ~ c & i t i r s C u d Gum ............................... of : I S . Toxicity and Side-EfFect$ of G u p l Gum ............................................ S. Concluding Remarh ......................................................................... Acknowledgemer.ts ...............?. ............................................................ Refennca ......................................................................................... Appendix ............................................................................................
Guggulipid, a 'mixture of lipid steroids isblated from the olcogurn resin of Commiphora uqightii (guggul gum) has been available cn the 1ndian market since 1988 as a potent hypolipidaemic agent. The evolution of C. uligltlii gum resin as a hypolipidaemic drug spans insights into the rich kno\\.ledge'and over two decades and offcrs i n ~ r e s t i n g wisdom of the ancient medical systems of India, like Ayumeda. The saga of guggul as a hypolipidaemic agent started in 1964, in a tiny laborator\- of the
189
?hen College of Medical Sciences of the Banaras Hindu Ur.ii.c.i-sit?. (BHL7.:) ir! the holy Indian city of k'aranasi. Prior to this work. p ~ g u lwas:, of . cceurse. well known as an X~ur\.etlic. druz and !\.as \tide!! wed -in the rrrntment ofvarious types ofarthritis. Until then, th~:reic,re.pharm~cological i:l.;dies on guggul a-ere naturally conc:t.ntratc.cl nit\in!>- on the anti:r.tlan~mator?-lantiarthriticactivit!. of the gr1n1 rt.siri, Tt~ch) jxiipidaemic action of the drug \+.asfirst rzportcd in a cioira)l.atr rhesi,: ~r!ir;ril -ElTect.of ar. indigenous drug on disorders of lipid nlc:t'it)oli~rn ,\-itti ??iiLl rzkrenre r . atherosclerosis and obesit)- (m~dorogn)'sut~rnitredro rhc Bsr-\rtrs Hindu ~ n i v e r s i 5%-hich inspired bj. a rather ot)scurc stanza or i.+;ojh (Fig. 1) ~' was i~ Sanskrit. in the well known .A!-unedic treatise Sisi;o!a Sumhita -.--*.MIB.C.) This stanzaq deals in a n estraordinarily lucid and scientific r?anner 1%-ith the aetiolop. pattiogenesis and trearnient o i n k l r l ; and irjociated lipid disorders and their complications. Inspirtd b. this shloka, ! gug.gul \$.as selected fcr screening for its possible h!.polipidaemic activity in laboratory animals as \$-ell as in patients of ohesit?- c d h>-percholestzrolaemia. The story, in fact, actually bagan \\.hen Sat!-avati and
d h m4 a r n a m ~ ~ ~ c t
W
e
& G . l
.mmfw f k h F m m 7-PT ~ \ n m, S F
~ I
\
i )
Ct4 '-'1
1
&
W I I ~ + ~ :
T&fkmmmb: cW&tf+
&dm, & s x r n s r n *,
i r h
rq-lqnw*<
t.bwdm3 i i i i ~ r n ; r r c m -
+ f T 7ek m -
f W m w c r + rn 9 - c q + M l f a ,
$q-1
mrmfl
Ji9?;t
5Rqlqfl4llddwh'~dmit3;)
6, e> J
y? w?T
-qlrqy54~a~<~q*m~~~~~qsz~& ha
u , = M m T m - m - m h - F G 1 Original Sanskrit verse from the Xyun.edic classic Sushru:; .Sam& Im#tra I. Shim: 15; 600 B.C.. which inspired the \-cry first investigation on rhr \1?;n~lipi5cmic u i )o xvt. f g ~ guggvl at B a n a m Hindu University. i'aranasi i.lndiai. (For 3 Ii~rra!mla6M1 of the z
3:
'"
vcrr+
see .4ppendix I . )
190
CLGGULIPIV: A PRO\1ISIYG HYPO!.lRDAEMIC AGENT
Du:trakanaril found n strong ana10,gy txltw.een the ancient concept of Sushrura (600 B.C.) the modern concept of the pathqencsis and of arhcrost1r1-osisand its fatal c,omplications (Fig. 2). T h e English translation of Sr~shruta'cnriEinal reft:rence is given in Appendis I. T h e implications of this a n s l o s ~ (Fig. 2 ) ha\.c been discussed in detail e l s e ~ . h e r ~ . ' - ~
rn~ioroga of
Modern Ancient
Unbclanced, High i n Calories Total tats Scturated Fatty Acids 8 Cholesterol
Sushrutg
Dalhana
Overeating
Shleshmaldh6ra ( ~14isht6h6ra)
+
Lack of Exercise
Sushruta Me:oholism: Hyperlipemia with Cholesterol Lipid4 ipoprotlen
'Amarasa Produced at t k level of
Metabolism
Llpld Deposds (11) Narrow~ng of
Coatlng 8 Obstruct~on of Channels
- Cerebral - Coronary : - ?eri@wral'

'
Hem~pleg~a lschaem~c Heart Disease Gangrene
Many Complicat~onshcludlng W t a V~koras ( w g v a r a n a j ~ f )i Leodlng to Death
FIG. 4 . h a l o g ' d r a ~ n ber~seen andcnt concept of the pathqenais of .Llt&mgo and the the modem concept of the pathogenesis of athrrosclerosis (on the bsis of Daihana's commentary S w h Samhr:~:Smtra Sllwrut: 13; 321.9 ~
191
TG t s t this analogy, urefully planned str~diest\.crc samcc .:ut {over a p e t i d of 2 yearsj on rabbits in x\.tiich i~vpcrliparmis1\-22 znduced by feedirig cholesterol (in hydrogenated vegetable oil). It was thus dmonstrated h r the vrr) first time that, on oral administration. crude g:m gug\gul (watrr estrsct) could not only lottrr sig~liticant!~ semnl cholesterol the (and pi:orpho!ipids) in h>-percho1esterolarr:-,ic rabbits i)ur also p:;.ct.cts these aninlals aqninst cholesterol induced artht.rosclerosis, at the 2 r t y streak siage. The tissue lipids were aho lo\cercld'si~nifiwntly. The TAX: resin also reduced the body weight of the animals.'.' .-4 similar trend to reducc. significantly the serum cholesterol leveis in patients \\.irh obesin 2nd hyperm cholesterolaernia was obsemed in clinical studies with crude ~ c guggul' (Satyavati. 1966). The results of this pioneering work done at BHL7 provoked ccnsiderable Soon, a interest among other Indian scientists at BHU and eIse\\-he~.i.. number of pharmacological and clinic.al srudies \\.ere undertaken on gum suggu! ( C. uightii) with paniculzr referefie to its ti!-polipidaemjc a d related zcti\.itirs. These were soon follo~.ed phytochernical and p h x r ~ c o g n o s t i c by studies. \\.bile some of these studies were initiated under the Composite Drug Research Scheme (CDRS) of the Indian Council of hledici 'Research, others \\.ere canied out independent1)- by various scientists in dEerent parts of India.
11. ETHNOMCDICAL INFORMATION ON GUCCUL CUM A. HISTORY OF GUCGUL IN ANCIENT INDIAN MEDICAL LITERATURE
The earliest reference to the medicinal and rherapeutic properries of guggul is in -4thcln;a v&'** (one of the four \veil-known Vtdm or holy s e p t u r e s of the Hindus), which devotes an entire stanza to the drug (Fs. 3). The English translation of this verse is: G~sease (consumpuon) does ncu diet and thc cu-e n x c r ? f i ~ r sk h O ~ tht d~l~cious ~l odour o the beding Guggd pcnctratu (spre~blf The disehier also fe &ay in i dirccuans from him % h;irscs and deer. 0 Gdg~du! either bon,frorn S h & i or fromthc s a , (I) &ant ).our name d both q!pcs for the rerno\af o diseaxs. f
a-
Detaged description of the varieties; physical qualities. a c t i o ~ uses and , ~ B.C.), indications ofguggul are available in the rreatises o f ~ h a r a l i at' :+300 Siuhmfa (600 B.c.)'*~and \'agbhata1= [Tth century =\.D.) in tbt &sic (or Samhifu) period and also in various Nicphontus (or hledical lexiams) which \\-ere w-ritten between the 12th i d 14th centuries X.D. .A detail& history of guggul. based on Ayunledic literature, has been published.'
192
CUGCULIPID: A PROX,\ISINZ HVPOLlPlDAEhliC AGWT
FIG. 3 Earliest reference available on the medicinal value of guggulu in Athenmuch (Kanda: 19: Sno::~:38).12'
.\bu:The drug is rel'crred ro by the name 'gulgulu', in this \.erse. As was the practict, during thc \.edit period, divinity is c~,nferrcdupor1 plants (Ilkc g lggul) known to have healing p o x * ers.1"
Summaries of r\yun.edic degcription including synonyms, properties, actions and uses of gugqul from various literaq- sources are a~ailable.~-*>'*~ The \vide therapeutic range of guggul and its indications from healing of bone fracture to inflammation, arthritis as well as cardiovascular conditions, obesip- and lipid disorders make it a unique drug in the Ayurvedic matnio medico. Another unique feature of guggul is that major Ayurvedic treatises very emphatically stress that most of the therapeutic properties relating to fat disorders aetributed to the drug relate to 'old' samples of guggul. The fresh gum guggul is said to have the opposite effects, particularly with respect to its effect on obesity and fat disorders. In other words, while a n 'old' sample of guggul is described as highly effective in reducing body weight and lipids, a fresh sample of'the drug is claimed to have the opposite effect of increasing body \veight.6;'251'27NO such information is a\ailable regarding its action on arthritis and other conditions. In clinical practice, however, Ayurvedic physicians have used guggul extensively for centuries in the treatment of arthritis and rclated conditions, mainly in the form of compound preparations. A large n u m b e ~ d such p r e p a t i o n s with guggul as the main ingredient afe n t t n t i d in the Ayurvedic Medical lexicons. Many of these preparations are awihble commercially in India and neighbouring counmes.
B. U E OF GUGGUL IN FOLKLORE AND ETHNOMEDICINE SS

Externally, gum guggul has'no action on unbroken skin but on the abraded skin and mucous membranes, it acts as an astringent and antiseptic.
193
Administered intmallg, it acts as a carminative, antispasmodic, diaphoretic, ccbolic. antisuppurative emmenagogue and I s Tibetan medicine, the plant (C. zightii) mixed with other herbs is u'xd for skin diseases, anaemia oedema, salivation and heaviness of the s t o r ~ c h . ' ~ I11 the lotion Form, guggul is used for ulcers; in gargle form it b used for dental care. in spongy gilrns. tonsilitis, sore throat and related anditions. Fumes from burning g u ~ g u 'l re recommended for hay fmer, n a d catarrh, a lap-ngitis. hrr,nchius. phthisis, et~.".'~."The gum resin is also ~ s e d the in : reamen t o rheumatism, neurological disorders, obesiq and rttzted disr orders. scrofula. slphilis. and skin and urinary dis~rders.'~."
Ill. ECONOMIC AND PHARMACOGNOSTIC A P C S O SET F GUGCUL GUM
.\part from its medicinal and therapeutic uses, the gum resin s f C. wightii ' h .Bhand (syn. C. rnukul) Hooker Stedor. Engl.), Burseraceae. is used as a . binding and disintegrating agent in tablets and also as a suspe~cingand emulsifl~ing agent.I6 It is used widely as an incense and also as a kuative in perfumery. It is also used as a substitute for African Bdellium.' C. urightii (Indian Bdellium) is a much branched Spiny shrub cr a small tree 2-3m high (Fig. 4), found in the arid, rocky. tracts of the states of Rajasthan, Gujarat and Karnataka in India and in the states of Sind and Baluchistan in Pakistan. The main Indian commercial centres of pqgul are the states of Rajasthan (mainly the western region) and Gujawr (Kutch are division) as shown on the map. (Fig. 5). Apart from these regions. ~ 5 e r e a few minor guggul-producing arcas."*" A healthy mature m e yields 250-500 g dry resin of guggul in one collecting season. Pharmacopmtically, the macroscopic characteristics of all the parts of t11e plant h v e been studied." The microscopic features of the young stem, marare stem The development, histochand and leaf have been des~ribed.'~ . ul trastructure of the gum resin ducts of C wightii have also been .~udied.'~ The distribution, cultivation, tapping and collection, marketing ij well as grading of guggul in India have been .extensively reviewed by - 4 9 ct Tbe ant can be prop~gated vegetative means. Recently. iL r farm ~f by neariy 140 acres in Mangliakas in Rajasthan, the Central Cocncil for Research in Ayun-eda ana Siddha (CCRAS) has undertaken cdtivation and propagation of the guggul gum plant. On this farm, attempts are also being made to determine the optimaleethod of tapping to btrtain the maximum yield o the guggul resin, without adversely affecting ttj: health f of the plant. Similar efhrts arc being made by the Department oi Environment and Forests, the Council of Scientific and Industrial Rexarch. e t ~ . ~ - * '
194
GUCGULIPID. A PROMISIN<; I-IYPOLIPIDAEMICAGENT
FIG. 4 Guggul gum (Co-@ra Lucknow.)
u i g u ) am. (courtesy ofCcnrral Drug b e a r c b InSLi~te,
195
G V. SATYAVATI .
FIG 5 Xlap showing the lacAoo d guggul producing states in India. !Reproduced from A d d el.'=)
Tapping of the tree is usually done in the months of So\-ember to January 2nd collection~continuesuntil May-June. For tapping, healthy plants which are over 5 years of age are selected and an incision is made on the bark. A pale yellow aromatic fluid which oozes out through tbt cuts on ulr bark slowly hardem tci form the golden brown or reddish brown~1cogurn.rrsk.of@ The gdn is ready for co1lection 1-2 hrtks aftu, rhe first incision. Subsequent cdlection of the oleogurn resin k made at intervals of approximately 2 weeks during the tapping season.'5 The main adulterants of gum guggul available on the Indian market are the gums of plants like Albiziu kbbeck, Acacia smrgal, Acacia arabuc, BosweIIia srnata, hloringa oki&ra, etcn
196
GUGGULIRD: A PROMISING HYPOLIPIDAEMK AGENT
IV. CHEMICAL INVESTIGATIONS O GUGGUi GUM F
Prior to 1972, the chemical studies done on the gum of C wightii were of the . the routine n-pe incl~rding nature of sugars,23the structure of the degraded and methylation and peridate oxidation studies.25 Chemical studies undertaken on the other parts of the plant were related to the volatile oil,"*16 leaves.?' seed oil'"" and flowers.29 \Vith the discover). of the hypolipidaemic activity of the gum systematic and carefully plannea'chemical investigations were initiated at the National Chemical Laboratory, Pune, in collaboration with the pharmacology team ofthe Central Drug Research Institute, Luckno\%(India). The main aim of these chemical investigations was to isolate and chemicaIIy characterize compound(s) of the gum resin of C. wightii responsible for the hypocholesterolaemic/h~polipaemic activity of the gum resin. For this purpose, a viable separation scheme was evolved by the chemistry team headed by Dr Sukh Dev, first at the National Chemical Laboratorl;. Pune, and later at the Malti-Chem'Research Centre, Vadodara (India,. This scheme on segregation of guggcll is shown in Fig. 6. The ethylacetate soluble portion of gum guggul was found to possess hyplipid?emic as well as anti-inflammatory activity. As the eth>-lacetate insoluble portion representing the carbohydrate gum constituent reported - * found to be toxic, no further studies were earlier by Bose and ~ u p t a ? ~ was ~ undertaken'on this portion. In the next phase, Sukh Dev and colleaguesa6 separated the ethylacetate soluble resin into basic, acid and neutral portions. The neutral portion is responsible for the hypocholesterolaerraic activity, while the acids show anti-inflammatory activity. As the neutral firaction contains several ketones (\\-ith significant hypolipidaemic activity:, this fractirm was further segregated into ketonic and non-ketonic fractions with the aid of semicarbazine-on-silla gel. Although the non-ketonic poi-tion is devoid of any significant hypolipidaemic! activity, it apparently eserts a synergistic action on the pharmacological activity of the ketone, h a i o n . This fraction was therefore fur:her segregated and investigated chemicallj-.% These chemical investigations soon revealed that guggul resin i a s complex mixture of various classes of chemical compounds such as @xis and lipids, diterpenoids and The naturc: d.these compounds is s B o m in Fig. 7 From the benzene phase (constituting 14% of the gum resin) four lignans have been isolated (of which two are new), as well as a waxy solid w-hich i s a mixturc of esters based on homologous long-chain tetrols (and faulic acid) with a unique structure reported for the first time in nature These lignans are structurally similar to phytosphingosines which are present in the cerebroside and ganglioside components of specialized biomembranes.
197
I
Benzene phase 750t0
@
MeOH aq. phase 25%
Ant(-inf lammatory activity Hypocholesterolemic activity Toxic
m A
FIG 6 Sclleme to sllow the chemical segregation proass of guggul gum. ( R c p r m h d from Sukh Dev 36)
The tiexane phase yielded two diterpenoids: cemberene A and rn.zkul01.~ The gum resin of C. wightii proved to be a rich source of steroid- Of the 10 steroids isolated and characterized from the reslli (Fig. $1. four (viz. cholesterol and gugguktemids I, I1 and 111) are C27 steroids. whereas d the others-are pregnanedeuvatives. Among these, (Z)~gygge;ulsbcroat (E)-guggulsterone (together constituting approximately 2% of the gum resin) have been fmnd to be responsible for the hypolipaemic activity. Guggulsterones may offer an economically viable alternative rnatrnal for the synthesis of cortiscosteroids like dexamethasone and b e t a m e r h ~ n e . ~ ~ The stereochemistry of guggul tetrols has also been reported."
198
GUGCULIPID: A PROMlSlNG HYPOLlPlDAEMlC'AGENT
"p%pQ ~ o M
OMc
OMe
GUGGULLIGNAN - I
GUGGULLIGNAN -11
HO
n ol3,15 (minor : n =11,12,14,16,17)
MUKULBL
FIG. 7 The lignans, lipids and diterpenoids isolaicd hwn guggul gum. ( R e p r o d d from S u b Dc\.S)
199
G . V. 5 4 NAVATI
HO
Cholesterol
&
8.2 % (based on
Z - Guggulsterol
Z - Guggulsterone
E-Guggulsterone HO
do
0.4%
h
H,e-QH
GugguLsterol-I1
Guygulsterol-III
")
FIG. 8 Sreroids d a t e d .km gcggcl gJm. (Reproduced from Sukh Dn
Sukh l3ev.jfi has drawn attention to another interesting chemical phenomen~i, revealed by the steroids of guggul in the unique ocaurence of cholesterol along with each of the key intermediates (with the additional oxygenation at C 16) of its catabolism, in sequence, in the same plant tissue (Figs. 9 and 10). The h>polipidaemic activity of ( Z ) - and (E)-guggulsterones has been found ro be quantitatively comparable to that of the total ethylacetate
SELECT RESEARCH PAPERS ON EVTDENCE BASED AYURVEDIC DRUGS
200
-GUGGULIPID: A PRaWlSING HYPOLlPlDAEMlC AGENT
Cholesterol
ow Guggulsterono ZFIG. 9 Biogeneiis of guggul steroids. (Reproduced fro^ Sukh Dcv.")
extract of the gum resin. Furthermore, as the other components of the ethylacetate extract appear to exert a significant synergistic effect with regard to the lipid-lowering activity, detailed phannacologid, toxicalogical and clinical studies were undertaken by the CDRI, Lbckriow, c?neanethylacetate extract standardized to contain 40 g of ( Z ) - and (E)-guggulsterone per 1OOg (on the basis of an estimation by , m a s of high performance liquid chroma\ography). This standard extract i the b s s of s ai the commercially available guggulipid (Guglip marketed by Cipla Ltd, Bombay). The credit for taking the drug to the point of technology transfer to the pharmaceutical industry for the promotion of its commercial viability as a hypolipidaemic agent should be given to the systematic, combined efforts of the chemical team led bv Sukh Dev and the pharmacology team
-
G. '.'.SATYAVATI
icd hv Nit; nnand. Thr various steps of this collaborative investigation ilavt: been elaborated in excellent reviews by Sukh Sporadic interest in the chemistr?. of the gum resin has k n shown by other Indian scientists. 'Thus. two new sterols from the chloroform estract of p q g u l guln (guggulsterol 11' and guggulsterol \I) were isolated and cha~cterizedon the basis of spectral evidence and chemical reaction^.^ Z-Guegulsterone has also been isolated and characterized b! means of ~prcrroscopiciriethods by Tripathi tf al.," who reported that this compound ! enhances iodine uptake b- thyroid in rats.
'J. PHARMACOLOGICAL STUDIES OF GUGGUL G U M

A. HYPOLI~IDAEM~C ACTIVITY OF GUGGUL GUM
The hypollpidaemic activiy of the gum resin and its extracts first demonbeen confirmed by various strated by Satyavati and coworkers.'.%as Indian investigators in several species of animals. Thus, the petrol-soluble fraction (A1 and the alcoholic extracts of the gum resiAi\\-err reported to lo\+-er the serum cholesterol in hypercholesterolaemic chi&.T1.* The alcoholic estract shows a similar effect in rabbits3'."' and domesac pigs.31 The alcoholic estract and a pure steroid ofguggul lowered serum cholesterol in triton treated rats.jO The petroleum ether extract ( h a i o n A) and erhylacetatc estract (fraction B) of gu,ggul gum reduced serum cholesterol, trig&-ceridesand total lipids in hl-perlipidaemic chick^.^' Fraction A and its steroidal fraetion protected r a against isoproterenol induced myocardial ~ infarction." Fraction A also reduced serum cholesterol, trig&-ccrides, total lipids and phospholipids in wstrogen induced hyperlipidaernia in cf,i~ks.~* Fracaon A revealed significant hypolipidaemic effect in Mongolian gerbils, in which hyperlipidaemia was induced by diet.53 In \\bite leghorn chicks, rendered blperlipidaemic by a high-fat diet, the gum resin (3p kg-') given for 1 month in the diet, lowered serum cholesterol f and triglycerides and also reversed, to some extent, the atbcroaclerotic pn>ms in the aorta.% In tritor. induced hyperlipidaqnia induced in presbytis monh-cys, the steroid fractior. ofguggul I~wered total cholested (bs 60.5%), rrigil-cerides I3>'39.4%-1-$fiospholipids and also xion-esterificd f n . acids a) (by -k2.9%),as co.i:;.lred to dofibrate which lowered the same parameters by 47.690. 51.0%, 41.7% and 31,0%, respectively. The steroid h u t i o n of guggul also lowered LDL cholesterol (f6.1%) and VLDL c h o l e s t d (40.6%) significantly. The ratio of HDL cholesterol to total cholesterol in tbc steroid treated monkeys was significantlv higher at all intervals, as compared with the initial values."
202
CCIGGULIPID: A PRO~MISING HYPOLIPIDAEMK AGENT
HO
Pregnenolone
Subsequent to - preliminary studies with \ ariolls fractions of guggul further phmacological investigations attht-eDRf, L p b w a concc-ted maiinly on guggulipid (a standardized 'ed-ylaoetate a m c c supplied by Sukh Dev). In hyperlipidaemic rabbits and rhesus ~tlonkcys, guggulipid led to significant changes in the lipoprotein profile by reducing the serum cholesterol and triglycerides and aliuing .he ratio of HDL to LDL cholesterol, apart from regression of tthemmatous lesions. Guggulipid also afforded partial protection against isoproterenol induced myocardial necrosis in rat^.^'-^'
In another independent study carried out at CDRI, the alcobhc extract of guggul gum administered for 5 days showed only a mild h>pocholesterolaemic action in normal rabbits, whereas Atromida showed a ciqificant lipid low-ering action in these animals. Ascorbic acid, howevci. .did not l. reveal any hyplipidaemic effect at a l To study the effect of thr dmqs on the phagocytic indes of the reticuloendothelial system, radiometric clearance studies with '3'~-labelled human serum albumin were undertaker, The rat? of clearance of '371-labelled protein bound i~dine(PB'~'I) round to br increased in rabbits treated with atromid but not with eitk.rr quygul (alcoholic extract) or ascor\>ic
0. STUDIES ON THE MECHANISM O ACTION O F F GUGGUL GUM AS A HYPOLIPIDAEMIC AGENT

The first study done on gum guggul had suggestedi.' an anion cxchanqe property with bile acid sequestration leading to enhanced escrrcion of cholesterol as one of the possible mechanism of its hypolipidaenx action. Limited efforts have subsequently been made by _a few groups c.5 scientists gum to work out the mechanism of the hypolipidaernic action of the ~ : r ~ m l r~ and its various fractions. Nityanand and ~ a ~ o o have' r e p r e d slight inhibition of cholesrerol biosynthesis in rats by the alcoholic esrsxt and a steroid isolated from this extract, as compared tc Atrornidg -6chlorophenoxyisohutyrate) in liver slices, by acetatell-14c] incorporaric*~.b o n g . the various fractions of C. mukul gum tested in uitro for inhibition oi acetate [I-"'c] incorporation inti cholesterol, the ethylacetate extract. petrol ether extract and the steroid showed inhibition. the steroid fraction revealing maximum i n h i b i t i ~ n . ~ Kinetic studies canied out on the rates of cholesterol turnm-tr (using ( 4 - ' t ] cholesteiol) in \\'istar rats revealed a n enhanced rate ofacretion of cholesterol by fraction A of C. d petroI ether extvct, as -.*eiI as by clofibrate, Fraction .\ also increase the late of removal of cimIcsterol, possibly through the gut. The effect of hction A was similar that of clofibrate in this The ketosteroicl of pl-ggul gum was tested for its effect on th?m .i activity in rats and chicks. The classical proliferah of thc.epithelia1 cr2s and the reduced j3'I uptake under the iduence ofneomercazole was 'cpned to be countered by guggul ketosteroid. The thymid stimulating actkip of the drug was evident from the high 13'1uptake and active vacuolizadon of the colloidal substance.* The ketosteroid (3mgkg-' given for 1 month loweled the serum cholesterol, phospholipids and higlycerides in male u-hireleghorn chicks. The mode of action suggested is rapid degradation of cboksterol by activation of the thyroid.&
204
GUCGULIPID: A PROMISING HYPOLlPlDAEMK AGENT
\%%enthyroid explants of young mice (6- 7 weeks old) were cultivated in media containing melatonin and petroleum ether extract of guggul gum, respectively, the media containing gum guggul extract showed a s i g d c a n t increase in the uptake of 13'1 as well as T3 (triiodothyronine) along with PBI and free thyroxine index, suggesting direct stimulation of thyroid gland by guggul extract. On the basis of these results,.it has even been suggested that gum guggul may be of use in the treatment of hypothyroidism and a\:xiat-d condition^.^' Adrninistra tion of (2)-guggulsterone ( l mg/ 100g) led to an increase in the iodine uptake by thyroid in rats and enhanced the activities of thyroid pcroxidase and protease as well as oxygen consumption by isolated slices of liver and biceps muscle." The dfect of guggulipid on the levels of catecholamine and dopamine @-hydroxylaseactivity of normal and cholesterol fed rabbit tissues was studied. The catecholamine levels and enzyme act~vity were found to be decreased in cholesterol (500 mg kg-') fed rabbits. In nonnal rabbits, pggulipid (lOOmgkg-') causCd a significant increase in, the dopamine 6-hydroxylase activity and catecholarnine levels. It also helped the hypcrcholesterolaemic rabbits to recover the decrease in catecholarnine biosynthesisb8 Studies were next carried out on the effect of guggulipid on the levels of catecholarnine and dopamine B-hydroxylase activity of the brain and heart tissues of rhesus monkeys. The levels of norepinephrine and dopamine and activity of dopamine f3-hydrosylase (the norepinephrine biosynthesis enzyme) increased progressively with an increasing dose of guggulipid (60, 120 and 240mgkg-I). The results suggested that inacase in catecholaminebiosynthesis by guggulipid is one of the possible mechanisms of its hypolipidaemic activity.69 The effect of guggulsterone (mixture of (Z)- and (E)-guggulster~ne isomers) the purified fraction of C. mukul resin, was studied on biogenic monoamine levels and Copamine 0-hydfoxylasr activity of rat brain and heart. Guggulstuone administration to rats led to an inhibition of brain dopamine fl-hydroxylase activity with a marked stimulation of heart both in oitro and in uiw. Catecholamine levels were also similarly inhibited by guggulste..ane, whilst serotonin 2nd histamine con tents ~ e r e enhar.cd in the brain but decreased in the heart. Thus, the results arofirrncd &at alterations in biogenic amines and dopamine $-hydroxyl&c aczivlty may be one of the possible mechanisms of the antilipaemic effect of guggulster~ne.~ In guggulsteronc treated rats (20mg kg-' for 6 days), membrane urperiments showed an increase (90%) of high-aifinity binding. Furthermore, there was a significant decrease ir, the levels of cholesterol (23.5%), phospholipids (25.5%) and triglyceride (34.1%) in membrane lipids of gugsllsterone treated rats.7'
205
The foregoing studies indicate that guggd cxuts its hypolipidaernic action by inhbiting the biosynthesis ofcholestml as well as by promoting rapid degradation and exczetion of cholesterol. Thyroid stimulation, alterations in biogenic amines, high-amnity binding, and anion exchange have been suggested as the mechanisms of hypolipidaunic action of this complex drug.
VI. CLINICAL STUDIES ON CUGCUL C U M

A. HYPOLlPlDAEMlC ACTIVITY
Clinical studies carried out at BHU, Varanasi, showed that gum guggul administered in a dose of 2 g three times daily in patients with obesity andlor hyperlipidaemia not only reduced their serum chde~terol phospholipid and levels but also their body weight.'-49 Following these reports, a number of clinical studies were undertaken by various scientists in difXercnt parts of India which confirmed the lipid lowering ac9vity of gum guggul and a few of its fractions. Thus, fraction A of gum guggul (1.ogday-') administered for 12 weeks was reported to lower suum cholesterol, triglyceridcs. phospholipids and total lipids in 20 patients having hrperlipoproteinaernii. The hypolipidaernic effect of fraction A was found to be better than that of clofibrate administered to 20 Other clinical studies from different part. of India on the hypdipidaernic activity of gum guggul were reported in quick succession, confirming the hgocholesterolaemic activity of gum guggul andlor its fractions Thus, at Madras, a double-blind clinical trial on three groups of 40 obese patients, one treated with crude guggul (2g three times daily), another with fraction A of petroleum ether extract (0.5g thm times dailv) and the third with plaubo, for 21 days sho\ved significant lowering of serum chdaterol by crude guggul and fraction A from the tenth day onwards, which decreased further by day 2.1. The h>-pocholesterolaemiceffxt of the crude drug was found to be higher than that of fraction A in o m study," but a l m t similar in a subsequent report by the same pup.74 In a double-blind cross-over study with placebo canied out at Pariala on 60 obese subjects, crude guggul gum (4g in three divided doses administered d for 4 weeksj revealed a significant El in serum total lipids, cholesterol. uiglycerides and f3-lipoproteins, while no changes were observed in these parameters with placcbo.75 In an open trial carried out on 25 patients (14 males and 1l kmales; aged 40-60 years) having coronary anuy disease (diagnosed on the basis of pmious history of myocardial infarction, ECG findings, serum cholesterol

206
GUGGULIPID: A PROMISING HYPOLlPlDAEMlC ACFh'T
and triglycerides), purified gukggul gum was administered in the form of pills in a dose of 12-16gday-' in four divided dose. for 3 months. The drug not only reduced the serum cholesterol and triglyceride levels but also reversed elecfrocardiDgram (ECG) abnormalities (e.g. T-wave inversion and S-T segrnint depression) 'in 16 patients. Tllerc \\.as also a ieduction in body weight at a rate of 1 kg month-' In a !ong-term clinical study at Sew Dclhi on fraction A of guggul gum ( I .5 dayw') compared wit11 clofibrate (2 g day-') over a mew period of - weeks in 51 and 10 patients of hyperlipvproteinacmia (types 11. 111 and ,J I\'), respectively, both drugs showed highly significant lipid-lowering e&ct on serum cholesterol, as well as triglycerides, 3t all periods of observation (i.e. at an interval of 10 weeks) up to 75 weeks. In three patients with xanthomatosis treated 59th fraction A, there was gradual, but complete, resolution of the lesions in about 40 weeks. 1Vith clofibdte? however, in only one of the three patients of santhomatosis was thm complete res~lution.~~ Kinetic studies with 14-'"c] cholesterol were carried out to elucidate the effect of fraction A of guggul gum in rats and humans. In the first part of the study the effect of the drug was investigated without attaining isotope equilibrium, whereas the second part of the study was done after quilibrium had been attained (i.e. after 40 days in rats and 5 weeks in humans). ! humans, fraction A significantly reduced the serum cholesterol levels and n the cholesterol pool size through: (i) a significant increase in the rate of excretion of cholesterol from the body; and (ii) a mobilization of cholesterol from tissues, as evidenced clinically by resolution of xanthomotosis.~" Faecal sterol studies in 12 patients of hypeilipoproteinaernia showed that fmction A as well as dofibrate enhanced the faecal excretion of s t e r o ~ s . ~ In a double-blind cross-over study of the effects of fraction A of guggul gum (0.5g t h m times daily) and placebo (administered b r . 4 wek) on 38 hypercholesterolaemic subjects at Pondicherry, fraction A led to highly significant reduction in serum ch$estcrol and a significant reduction i ~ i total lipids, triglycerides and non-esterified f ~ t t y acids.m In a clinical study at Sewagram (Wardha), 47 patients were first given placebo for 1 month, followed by the administration of 2g guggul gum three times daily for 3 months. A significnt fa11 in serum chrilesterol was reported at monthly intervals until 3 months after cessation ~Cguggul gum administcation. Serum triglycerides showed reduction only after 2 months ofguggul administration and the reduction lvas maintained during 3 months follow-rtp. Serum plipoproteins revealed significant reduction only after 3 molsths of therapy and during a follow-up of 3 months. This study, however, did not reveal an;. significant alteration in the serum phospholipid level.n
'"
207
An open vial was carried out on a haborninera1 preparation [drogva&i) with five bhasma or ash preparations (of mercury, sulphur, iron. mica and copper), one part of which mixed with tw-o parts of Triphala (i.e. a mixture of Tenninialia drtbuln, T.b/ eand Emblitz of/;indis), three pans of Shilajit (asphalt) and four parts each ofpure guggul gum. Plumbago z&nica and Picrorhiza kurrcm Tt~ii trial was carried out on 101 in&\iduals (69 females and 32 males) with mild (serum cholesterol 200-23:lmg%). moderate (serum cholesterol 2j0-300rng9b) and severe (serum cholestq-01 >300mg%) hypercholesterolaemia, who were treated \\-ith (he drug Awavardhini for three months. The drug w a s administered in the form of tablets (six tablets in three divided doses, i.e. 240g three times dairy). The fafl in serum cholesterol was 23%. 23.4% and 36.4%, kspectivdy, in the three groups. The hypocholesteroIaemic actioa of the compound preparation was attributed not only to guggu1 gum, but also to the other drugs like P k u m which is a kno\r,n ~ h o l a ~ o ~Only. marginal reduction m body . ue ~ weight (which was not sta~isucally significant) was obsened in this ;tudy. In a controlled (single-blind)clinical trial at Pondicherry on obese patients (10% overydeight for height. ape and sex, acwrding to the Index s-the Life Insurance of India), 35 obese individuals (8 males and 27 females received 1.5g of fraction A of guggul gum in three divided doses, while 27 obese subjects (10 males and 1 7 females) received placebo for 4 weeks. There \\.as significant reduction in serum cholesteroi and triglyceride le\-& in the group treated with guggul gum ftaction A. There was no reduction in lipids or fiee fatty acid levels. The reduction in body weight WQS marginal and not statistically significant. No rosic effects or side-effects were ~ k t d . ~ ' ~ o t w a n studied healthy- individuals as well as patients of coronnr). i~~ disease and reported that serum cholestepA and triglyceride la-& were reduced significantly by guggul gum only u r b the initial serum cholesterol levels were higher than 223 mg% in healthy subjects and coronary artery discase patients. f 4 Another open trial compared the &ect o guggul gum ( 3 0 0 ~ of petroleum ether fraction A t\rice daily for 1 mouth) with gariic estact (one garlic pearl twice daily for 1 month) and dofibrate (500rng nrict daily for . h month) on 30 adults with IA\-perlipidaemia,10 in pch group. M~ximum regression_in serum-cholattrol, triglycuidcs. 2nd .JDL cholesre,ul levels was found in t h i group iicei\ing bggul gum, followed by those receiving dofibrate and garlic pearls.g? A double-blind dinical trial was carried out with fraction A d guggul -gum (300 mg capsules three times @ly far 12 weeks) in 51 patients of obesity and compared to placebo (groundnutoil) administered to X patients of obesity with hyperlipidaemia. The goup receiving guggul capsules showed significant reduction in serum cbdcsterol and serum tri@vcerides
208
CUCCULlP1D: A PROMKING HYPOLIPIDAEMIC AGENT after 4 weeks of treatment, which persisted up to 12 weeks. The dect on, serum total Lipids, however, was not consistent, showing reduction afia 4 \veeks with elevation at 8 weeks and again a significant reduction after 12 weeks of drug treatment.@ A for body weight, a significant reduction noted s after 4 weeks was not maintained after 8 atid 12 weeks in this doubI&blind trial. The triceps skinfold thickness, ho~\.e\.er.showed significant rcdAction after 8 and 12 weeks in the group treated with guggul gum. No signi6can~ side-elrects were obse~vedduring the trial." In a long-term (6 months) cross-over clinical trial, guggul gum (@ed according to the ayurvedic method) was administered (1 g three dmes daily) for 3 months, folloning placebo administration for 1 month, in 31 male subjects with hypercholesterolaemia. A significant fall in serum cholesterol and plipoproteins observed at the end of 1 month of guggul gum treatinent persisted 3 months after discontinuation of the drhg. In this study, the reduction in serum triglycerides and free fatty acids mas not statistically significant. Furthermore, there was no erect on serum phpholipids. Similarly, the drug dfd not significantly reduce body weighr even at the end of 3 months, despite a consistent trend for decline in body weight.= As meptioned earlier, the CDRI, Lucknow, undertook, in collaboration with the chemistry team, systematic, pharmacological and clinical studies on various.chemical fractions. After preliminary studies, the CDRI concentrated more on the standard ethylacetate extract fraction designated as guggulipid for pharmacological and clinical studies. Phase 1 (safety) of the study on guggulipid (400 mg three times daily for 4 weeks) was camed out on 21 patients (nine with hypertension,:tk with ischaemic heart disease, two with diabetes, three with diabetes and hyputension, and three with ischaernic'heart disease and hypertension, and one of gout). Phase I1 (efficacy) of the study on guggulipid (j00mg thrcc dmes daily for 12 weeks) was camed out on 19vpatients with primary hypaiipi4aemia (seven with a past history of myocardial infarction, three -.vith angina pectoris, tltree with angina and hypertension. two with hypertension alone, and three with clinical suspicion of coronan- artery disease). Gugplipid \\,as found to be completely safe and devoid of any effect on liver function, blood sugar, blood urea, haernatological parameters or ECG findings In the efficacy study, serum cholesterol and/or trigly~en~ij&f.&e signihcantly lowered in 15 patients, the effect being evident 4 weeks if<& drug administration, The average lowering \\.as 17.5% for c!!olestd and 30.3% for triglycerides. Guggulipid was effective as a hypolipidaemic agent in type I1 B and type'IV hyperlipidaemia and also in familial combined hypercholesterolaemia. Ho\v:ver, tlte drug v-as not effective in familial hyper&ole~terolaemiaas
&ng
209
G V. SATYAVATI
Multicentric clinical trials (phase 111) were then organized by CDRI on guggulipid, on 245 hyperlipidaemia patients at Lucknow. Sew Delhi, Bombay,Jaipur and Bangalore. These trials showed that the hypolipidaemic activity of guggulipid was comparable to that of clofibratc the average reduction in serum cholesterol and triglycerides being 27% a x i 22% with the two drugs, respectively. Kearly 80% of patients (of the 245%responded not related to guggulipid'action. The lipid-:owering effect of guggulipid to age, sex or body 1%-eight." Permission to marker guggulipid \\.as obtained from the I - , . w Controller (India) in June 19&6.a In 1988, Cipla Ltd, Bombay, markcicd the drug o under the name 'Guglip' (on a non-exclusive basis), in thk Fm of 500-mg tablets to be administered three times daily in mixed h y p e r l i m m i a (with serum cholesterol 220 dl-'; and serum triglycerides 170mS&-') hypercholesterdaemia (220 rns dl-') and hypemiglyceraernia (190 %dl)-'). In spite of the commercial availability of guggulipid, some studies are still being undertaken on crude guggul gum. One of the recm: studies on guggul gum (administered in a dose of 4.5g in two di\i& doses for 4 months) in comparison with placebo, in 40 patients with npc I1 hyperlipidaemia (the strum cholesterol levels being 275mgdl-' & above and serum and serum triglycerides above 145mgdl-I), showed s significant decrease in serum total cholesterol, \'LDL and LDL cholarml levels at theweeks 8 and 16, with a sirnultan&us, significant rise in HDL iciralestero~.~~ i n an earlier study rrom the same department, however, it UZI: reported that the drug had no significant hypocholesterolaemic effm in healthy controls and patients of coronary artery disease, although ir decreased platelet adhesiveness and increased fibrinolytic activity in patients of coronary artery diseasew
\$=
mg
B. CLINICAL STUDIES ON PATIENTS HAVING ISCHAEMIC HEART GISEASE For clinical studies on ischaemic heart disease, guggul has L.en used mainly in combination with other herbal drugs and not sin&-. as is the practice with Ayurveciic phgsidms. I n an open -triai on 50 patients of coronary heart disease, a c-ompound preparation comprising q u a 1 quantities of I d a raccmosa (PukLmool) root powder, purified guggul gum and expressedjuice of Bacopa monjl-;' ( Brahmi) was administered in a dose of 6gday-1 (in the form of 500-mg pills) for a period of 6 months. Apart from significz~t reduction in serum cholesterol (32.9%), total lipids (31.6%), triglycirides (41.2%) and free 5try acids (56.9%), there was a significant decrease (38.2%) in the uric a levels at the end of 6 months ucatment with this compound drug. K G changes
210
CUGGULIPID: A PROMISING hYPOLIPIDAEhllC AGENT
showed significant improvement in eight patients (20%), moderate rmprovement in 22 (55%) and no improvemrnt in 10 (25Y0) patients. The improvement in ECG changes \\.as in terms of normalization of ST segment depression and T-wave inversion. There was also significant relief from precordial pain and dyspnoea. .A significant scd~rctiotlin body weight (from 63.5kg to 59.6kg) was also noted after G monrllh of ~reatrnent.~' A combination df the gum resin uf C. tt~ui~tcl and I . rortrnosa (in equal cluantities)'\~as administered to 30 patlenrf of ischdemic heart disease in a doses for ., period o r 4 months. Five of dose of 6gdaY-', in three di\.~ded these patients were declared cured (i.e thry u ere totally devoid of anginal pain and showed regression of serum cholestcl-ol and reversion of ECG to normal pattern). Varying degrees of lmprovernent were observed in 40 patients, whereas in five there \\.as no changt. In a clinical study on 25' patients of ischacmic heart disease (diagnosed on the basis of ECG findings). a con~poundpreparation Pushkara gugglu (comprising equal quantities of powered rcmt of lttula racnnosa and powered !gum resin of C mukul) in the form of capsules. \\.as administered in a dose . of 6gday-' (in three dividel doses) for 3 months. Apart G-om recording clinical signs and symptoms, as well as ECC findings, plasma C-AMP levels were estimated by the radiometric method. Plasma catecholamines, i e. adrenaline and noradrenaline as \cell as serotonin, were estimated by the fluorometric method. Plasma adrenaline levels showed no significant change, whereas noradrenaline and, C-ABIP levels were reduced significantly at the end of treatment with Pushkara guSUgylu. \Vith respect to ECG findings, of the 25 patients there was no improvement in 11 (44%), moderate improvement in 12 (48%), and a significant improvement in two (8%). The improvement was evidenced by a trend towards normalization of ST segment depression and T-wave inversion. In the overall clinical assessment of treatment, the authors reported no change in six patients, reliefofsymptoms in 10 and a high degree of relief (or cure) in :hree pa ti en^. Decrease in noradrenaline was attributed to reduction in sympat:~eticactivity due to a possible $-blocking pmperty of the drug. Reduc:i~n in plasma C-AMP was also attributed ta reduced catecholamine and @-receptoractivity.94
"'vq3
C. CLINICAL STUDIES ON PATIENTS HAVING HEMIMECIA

In an open trial on 25 patients (aged 40-70 years) of hemiplegia (six with recent attacks, nine who had the attack 1 month ago, one with previous histoe of herniplegia and nine patients of paresis or partial herniplegia), it was reported that one patient with a recent attack, two of chose who came after 1 month of the attack, and all niie patients of paresis recovered completely on being treated u-ith 'purified' guggul gum in a dose of
211
12-16~day-I in four divided doses for 3 months. In 10 patients there was improvement but residual paral!.sis persisted. Four patients showed only a slight improvement in their motor function. whereas in one with a history of repeated attacks there'tvas no improvement. Serum cholestud: phosphoLipids, triglycerides and free fatty acids were reduced highly significantly in all the 25 patients.95
V11. EFFECT OF CUCCUL GUM ON COACULATICY FACTORS AND BODY WEIGHT
A. EFFECT O N COAGULATION FACTORS

~ a s o y ~ " n 4Tripathi cf oLWfirst reported that crude guggul and its alcohol soluble fraction decreased serum turbidity and increased the mqulation time and prothrombin time in rabbits as well is in patients w r obesity ih and/or hyperlipidaemia. The effect of crude guggulu as well as the two gumlstemncs ! E and 2 ) on platelet -aggregattion was studied using adenosine diphosphate (1 X 10-'m). The steroid mixture and purified (E)-guggulsteroneand (2)guggulsterone completely inhibited platelet aggregation induced bv ADP, adrcoaline and serotonin. The effect of the two gu&ulsterones ac 1 0 - * ~ f n l concentratian was reponed to be very similar to xhe inhibite- effect of ia dofibrate at the same final w n c e n t r a ~ o n.. ~ When fraction A of guggul gum w s administered (6.4g capnrla twice a daily) for 30 days to 20 healthy individuals and patients of corartery disease each, no significant fallsin the serum cholesterol levels w a s observed in either group, as compared with the initial levels and with rbt control group (which feceived placebo). There was, howevr -.2 significant inaease in serum fibrinolytic activity in both groups treated with fraction -1 along with a fall in the plztelet adhesive index The investigators d shis study therefore concluded that fraction A has a direct action on blood aagdatioil mechanism, which is independent of its action on b l d lipids.g0Inddentallye this is the only clinical study which did not find a lowering d serum cholesterol b) guggul gum (fraction,A). In another study q12tpatienb of ischaemic heart disease compared with 27 m m l s , guggul gum (1.2 g) increased the fibrinolytic activity in patients of ischaemic heart disease, without any significan: effect on platelet aggregationg7 A significantly prolong4 clotting time with no @cant changes in plasma fibrinogen levels in patients of ischaemic h e m disease was reported in another study.= Jain and w\vorker~*.~~ found a significant fall in serum cbdeterol,
212
GUC;GULIPID: A PROMISING HYPOLlPlDAEMlC A E T GN
triglycerides, free fatty acid levcls and @-lipoprotein levels on administration of crude guggul (2g three times daily) for 3 months in 47 hyperlipidaemic patients, but did not observe any effect of the drug on serum phospholipid levels or on bleeding and platelet count.79
B. EFFECT ON BODY WEIGHT
.\I1 the studies carried out at the Institute of Medical Sciences, Banaras Hindu University, ~ a r a n a s i ' . ~ ~ . ~ a significant reduction in body reported !\-eight by guggul gum in animals and in clinical studies. Only one other study reported a significant reduction in body weight and skinfold thickness in a cliniql situation." All other clinical studies reported no significant effect of guggul gum on body weight.73,74.77,78,8'*&4,8j of the investigators Some did find a trend towards reduction in body weight but this treid was not statistically significant. However. Kotiyal et aLe4 reported a significant after 8-12 weeks treatment with reduction in triceps skinfold guggul. The CDRI study on guggulipid reported a total lack of effect on body weight in both animal models and in clinical studies.87 Such reports of an inconsistent effect of guggul gum on body weight requires special comment, particularly in view of the emphatic statements and indications in all the avai!able Ayurvedic treatises that it is only the old sample of guggul that can decrease the body weight and havea beneficial efIect on fat disorders, whereas a new sample of the gum resin is claimed to ha1.e an exactly opposite effect. In view of this, in the initial studies carried out at Banaras Hindu University, Varanasi, special efforts were made to procure (from Gujarat) guggul sahlples which were at least 5 years old. In the case of a l other studies, no information is available as to t e source of l h the drug and its age, conditions of storage and related aspects. The inconsistency in the results obtained with regard to the effect of the drug on body weight could be due to the variation i i the samples of the gum resin (including its age in storage).
thickness
VI 11. OTHER PHARMACOLOGICAL ACTIVITIES OF GUGGUL SUM
Guggul gum is an important ingredient of most of the commercially available Xyurvedic drugs prescribed for arthritis and reldted conditions. Tho drug is used evtensively in India for the treatment of all types of arthritis by Ayurvedic physicians. !t is not surprising, therefore, that early pharmacological studies on this drug concentrated on its anti-inflammatory and antiarthritic activities in
213
@us animal models. 'The action ofguggul against Bmwdte's formaldehyde induced arthritis in albino rats has been reported.'00 The oleoresin of guggul and its fractions were ncsl screened against Browniec's arthritis model and granuloma pouch and cotton pellet tests in normal and bilaterally adrenalectamized albino rats. The oleoresin showed significant antiMammator)- anti antiarrhriric effect in all models at a dose of 12.5rng;lOOg body weight and above. The acid Craction of guggul gum showed thb effect even in the adrenalectomized rats.''' Significant anti-inflammato~and antiarthritic effects of the oleogum resin \Vr,j reparted against canaqenan induced rat paw edema, granuloma pouch as well as adjuvant ~ r t h r i t i s . ' ~ Significant anti-inflammato~/antiarti1riticeffect of a steroid fraction of guggul gum against carragenan edema in rat paw and second* inflammation caused by Freund's adjuvant has been Three coqpound Ayrirvedic preparations (Mahayogaraja guggul, .~laharama and Samccrclpannagaras) were tested for anti-inflammatory acti\ity in rats using the formaline ifiduced arthritis and the granuloma pouch methods. All the three preparations (with guggul gl rn as one of the major iqrcdients) showed a significant anti-inflammatory effect, which was not mediated thrpugh the pituitary-adrenal axis. ''j A promising antifertility effect of the oleogum resin of guggulu and its acid fraction was reported, as evidenced by reduction in.the \ w of the v r uterus, ovaries and cervix of rats with a concomitant ~dcrease tbe slycogen in a d sialic acid levels.'OG
IX. TOXICITY AND SIDE-EFFECTS OF GUGCUL GUM
An emulsion of-gum resin in 5% acacia gum had no significant action on dog heart, bid pressure or respiration. I t h ~ no action on f q heart or d on perfused frog blood vessels.'07 The LDdoof the essential oil of guggul gum in mice was reperz'd to be 705 mg kg-' intraperitoneally and 1669mg kg-' orally. I n t r a p e r i t o d doses of 400 and 600 mg kg-' of the essential oil did not lead to any effbx on *e central nervous system. No analgesic effect or behavioural were obJen.ed and the oil had no action on frpg rcctus aldominis. A dqressant action noted on isolated frog h h r t could be reversad by calcium-'" In clinical studies, (unpurified) crude guggul r e c d e d mild side-effects like skin rashes, diarrhoea, menorrhagia and irregular mensrmation. Skin rashes were easily controlled on withdrawal of the drug aod also by reducing the dose. Purification (shodhanu) of a u d e guggul in T w l a decoction (as recommended by Ayuntedic texts) was found to diminate the Other side-effects reported incidence of side-eKects like skin
'
SELECT RESEARCH PAPERS UN EVIDENCE BASED AYURVEDIC DRUGS
214
werc diarrhoea in three patients, and hiccough, restlessness and apprehension in one patient,63 while mild gastrointestinal irritation \%-asnoted in some ~tudies.'~ Diarrhoea, anorexia, abdominal pain, tilziwria, polyurea and menorrhagia were observed in seven, three and one patient, respectively, in a group of 33 obese individuals who were given crude guggul gum (4g twice daily) for 4 weeks, in a doubleblind cross-over srudy." Iiotiyal ct a1.78181.u4 not report any side-effects on administration of did fraction A of guggul gum for varying periods (4- 12 weeks). Other clinical studies aIso did not report any notable adverse reactions. Guggulipid (the standardized ethylacetate estract) was subjected to fxtensive preclinical toxicity at the CDRI, Luckno\\.. The drug did not reveal any adverse action on liver function, blood urea, or haematological prameters: I t was found to be devoid of any hormonal, central nervous system. cardiovaxular or diuretic effects. In rats, it showed no advase effects in toxiaty studies over a period of 6 months and in teratogdc studies in rats, monkeys and ~ > e a ~ l e s . ~ ' . " ~ Guggulipid administered in (a dose of 400 mg three times daily for 4 u.eeks was r e ~ r t e d be devoid of any adverse effects on liver functiom, to blood sugar, blood urea and haematological parameters in phase I dinical studies.86v!" Khe information brochure on Guglip tablets (manufactured and marketed by Cipla Ltd, Bombay) mentions that the drug is devoid of any a d v a x etfect on the central nervous system or cardiovascular system and has no diuretic effects and that safety evaluation has showed Guglip to be safe in rats. rabbits and rhesus monkeys. It had no embryotosic, fetotoxic or teraeogenic effects. T h e brochure also mentions that Guglip is to be used with caution in hepatic disease impairment and also in gastrointestinal disturbances (ex. diarrhoea, dysentery). Its use in children is not rcawamended, as,dataon the effcct of the drug in children is inadequate.
X. CONCLUDING REMARKS
The hypolipidaemic activity of guggul gum has been a popular topac of manv doctorate theses in different parts of ~ n d i a , ' , ' ~ 9891'3-116,13 These .~~.~ theses represent not only different types of research but also coverdifIknmt branches of modern science and two different systems of me-&cine: r4. -4yurveda ( K a p c/tikit~a)and allopathy or Western medicine (including clinical medicine and pharmacology), phytochemistq, biochemistry, etc. Pespite the large numb& of theses submitted and paperslreports publishtd, there are still a number of unanswered questions and 'grey areas' in tbe profile of guggul gum as a hypolipidaemic agent, which await solution
215
G V. SATYAVATI
Thus, despite attempts by a few scientists to work out the mechanism of

h of the drug, no clear-pt picture has emerged so far, mainly because o the lack of perseverance by any single group in carrying ow in-depth f studies. From an initial simplistic suggestion of an anion e x c h q e propertv, with bile acid sequestration activity /akin to that ofcholestyramine'~ suggested as one of the possible meclianisms for the hypocholesterolaemic action of the gum resin of guggul, to the subsquent studies which suggcsrcrd that the drug not only inhibits cholesterol biosynthesis but also sirnuitaneously enhances cholesterol excretion thr,;ngh :he .gut, no evidence is zvailable of amsistent scientific research by an) qoup on these facets. R e v that the g u m resin lowers P-lipoprotein, increases the HDL cholest&ol w h i k lowering LDL and VLDL choiesterol, that it binds bile acids, along nirh an antililipoiytic action should, in fact, inspire scientists to take up further advanced d,piece together the results of research on the entire gamut so as to o h e biochemical, metabolic, pharmacol~caland therapeutic profile of f this driig, \vh~ch throw light on its \side pharmacological and therapeutic can SPe-m. The studies camed out so far on guc@ gumihavenot addressed themselves to the imponant point referred to in ;\?un~edic literature on its m q u e dual dm on body weight. The inconsistent effect of guggul gum on body weight reported by some authors seems to stem mainly from lack of serious efforts to concentrate on this aspect and also from thk scant attention p a d to the classic description of the action of guggul on body weight. Ven- fat. studies have investigated the effect on skinfold thickless and other paramccers of fat deposition in the body in humans or animal models. Mere r e a d i n g of the body weight a t different points of time, without giving attentioa to other important factors cannot be expected to give an answer to tbt unsolved questio,ns regarding the action of guggul gum on obesity and dated conditions. What is required is IP-deoth metabolic studies under controlled conditions. Furthermore, it is essential to bear in mind the significance of the source and age of the guggul sample being tested. Tbt emphnc claims in Aprvedic literature'*' on the diarnemcally opposite actions ofthe .old9and 'new' samples of guggul (Sushruta Samhita: chih'ts~~~thana) be investigated must seriously by pharmacologists, clinic~ans well as phytochemistr Carefully as planned, .aetabolic and pharmacokinetic smdies in controlled coditions (in animals as well -as- humans) ma? unravel exciting new frorcs of the - ..-- aaion o this i~ckatile f drug. The saga dl'guggul gum, despite its long and tortuous course serves a3 an example of the amazing insights of the ancient Indian medical anhorities like Sruhruta (600 a.C.), while also revealing the complexity of m c h into natural products like guggul, which do not yidd a 'single' actiw principle responsible for their pharmacological and therapeutic profile. The story a
216
GUGCULIPID: A PROMMffi HYPOLlflDAEMlC A G E M
of cguggul gum is thus quite different from that of forskolin (from COLW forskoli), another Indian herb not mentioned ir? the Ayurvedic texts, but estensively investigated globally on account of its unique adenylatc q d a s e activation property.11' The need to'pursue research by means of a mcltidisciplinary approach in the casc of drugs like guggul is evident. Such an approach must t&e into account \various imponderables such as the correct animal models, therapeutic synergism and action with refereme to pro-drugs and irnrnun~~tentiation, antagonism. and other factors which can influence the outcome of m a r c h on natural products.* The number of reviews and status reports published recently on current research into medicinal plants in India bear tedmony to the rekindled interest in research on natural produc~s.8~"8-'nHowever, most research on natural products still continues to be done in,an isolated manner. 119 In contrast to 'ethnomedicine', certain organized systems of medicine like .I\yurveda offer much more than mere remedies or drugs for various diseases. .I\)-urveda, which literally means 'science of life'. thus offers rich concepts basecl on ancient wisdom as illustrated in the case of guggul and its effect 6n lipid metabolism. Apart from guggul, other drugs have been listed by Sushruta for intervention in the pathogenesis of medoroga (Fig. 1 and .ippendi:: I). Ayurvcda also claims to offer a ne-.. way of life throngb its holistic approach.'23 The story of guggul gum should, therefore, be mnsidered as an important milestone in the history of biomedical research, not so much because o the f 'discovery' of guggul gum as a hypolipidaemic q e n t , but more became of the remarkable analogy found between Sushruta's ancient concept of &a and the modem scientific concept of artlierosclerosis. This, by itsdf is a more significant discovev or 'milestone' than that of guggul gum, the drug. A systematic and opcn-minded study of selected chapters of the Ayun-edic Samhitas by modem scientists, in close consultation with th? scholam and 3ystem;may pave the way for many more such physicians of the A j w ~ e d i c 'disco\,eries, and b r i n i t o light the 'hidden' kno\~-ledge and wisdom in these ancient systems of medicine, which eventually can be applied for the benefit of mankind.
ACKNOWLEDGEMENTS
The author ,is grateful to a l the scientists who provided lists of their l publications (along with reprints) on guggul gum, which have been a in d this chapter. Special thanks are due to Dr C. K. Atal and Dr Sukh Dev and to the editors and publishers of Economic Botanr. USA, and the W a n
217
National Science Academy, Xew Delhi, India, for permitting reproduction of figures from their puhlicaripns. The iiuthor is obliged to Dr Nityanand, formerly Dimaor; CDRI. Lucknow, Dr!Mrs) S. Nityanand, formerly Scientist, CDRI, LucLnow, and Dr B.N. Dhawan, presently Director, CDRI, Lucknow, fm permitting access to literature on guggul. including the CDRI ctossier oa gugulipid (submitted to'the Drugs Coritrclller of India), and also for p i d i n g the photograph of the gum guggul plant. Thanks are due to P~of.PIorman Farnsworth, Research Professor of Pharrnacognosy, College of Pharmacy, University of Illinois, Chicago, for scheduling a NAPRALERT search on Comm@hra mukul. T e able aszistance of Dr hladhu Sharma and Ms N w l j Tandon, h ICMR, New Delhi, in collecting reprints and checking the &ces and the patient secretarial assistance of 3lr T. Ramani, Miss Padma Vati and Mrs Harjeet Kaur is also ackno\\-ledged. Shri J. N. Mathur, Sh. R. K. Sharma and Shri S a ~ Praliash who assisted in the preparuioa of the a illustratior~deserve tl anks.
REFERENCES
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CUC'CL:LIRD: A PROMlSlNG HYPOLlPlDAEMK AGENT
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(1981). 42. Bajaj. A.C. a d Sukh Dev. Tefruhafnm 2949 (1982). 38, 43. Kumar, V. and Sukh th.T e 43, 5933 (1987). 44. Sukh Dcv. C w . Sci. 52, 949 (1983). 45. Sukh Dcv, Sd Age 5 , 13 (1987). 46. Pum-hothaman, K.K. and Cahn , S. I d J. Chnn. 14B.802 (1970). 47. Tcpathi, Y.B., Malhotra, 0 P. and Tripathi, S.K. Plrmlo A l d SO. 38 (1984). HI. Xlchta, V.L.., hblhotra, C.L. and Kalrah, N.S. Ind.1. Phyml.,Phamocd. 12, 91 (1968). 49. Sastry. V.V.S. E.;perirnental and di&cal studies on the dea d- dcogum r c h d Cmmiphota d l Engl., on thrombotic phenomena associated ulth hyperlipaania (Snchabyapat). M.D. thais (Doctor dA>un-edic Xledicine). Banaras Hindu University, Varanasi, 1967. 3.Nibanand, S. and Kapoor, N.K, I d . J. Exp. Cffi.'.9, 356 (1971,. 51. Arora. R.B., Diy D., Kapaor, S.C and Sharma. R.C I d . J. frpr Bid. 11. 166 (t973). 52 Gupta. M.,Tripathi, S.N. and Pnsad. B. J. fis. I d . Aftd. 9, 4 (igfi). 53. Ahuja Pyf-MS., Malhotra, S.C. and Tandon, H.D. J. Erp. Bid. 15, 143 (1977). Id. 54. -Baldha, VS., B h i n , V., Ranka, PC. and Mathur, K.hl. J. As=- P b % k u I 29, 13 d (1981). 55. Bhargab3, S K . Plcrnl M d P h ~ l o h .18,68 (1984). e. 3 Nityanand, S. and Kapoor, N.K. Id. J. Erp. Biol. 11, 395 (1973). 3 57 Ni~anand, Asthana, C.P.,Gupta, P P . Kapoor. N.K. and Dha~an,BN. E.L J, S., .. Phamorol. 13, 58 (1981).
219
58 Nityanmd, S.. Gupta. P.P., Astham O.P.. Khan, SA., Sonuni, PN, BJdwa, VS. and Agarwid, S.S. Clinical studia w i t h guggdipid-a new hypolipidwrPic - . 1 1" Rmz&gs o II W l Om f a d ~CTC(YI CIildrol P h d n a d k p a h c s , p. 21. Washington, a DC, 1984. 60. Gopal, K., bran, R,K., Nityanand, S., Cup- P.P.. Hasan, hI., Das, SR, Sinha, N. and Aganval, SS. j. Asroc. PhI d 34,248 (1986). 61- Kapoor, N.K. and Nityanand. S. I d .I. Heart &s. 1 (Suppl. 1). 22 (I-) 62. Pachauri, S.P. and hlukherjee, S.K. I d . J. P w . Allvd Sci. 45, 123 (1971). 63. Malhotrr, S.C. Pharmacological and clinical studia on the dfects of -a &l (guggulu) and dofibnte on certain aspccu of lipid metabolism. Ph.D. t&sis, All India Institute of hfedical Sciences, h'cw Ddhi. 1973. 64. Yalhotra, C. and Ahuja, hI.M.S. Smdia on the rates of cholertad turnover in aperimentally induced hyperlipidaernia in rats- the influence of hypolipkkmic agenu. In P m m d q s o FYI Asia and Ocrania Ca,nrss o f l h b i m l o g y , yol. 11 (cd. . . Rastogi), f GK p. 504 Endocrine Society of India, Chandigarh. 1974. 65. '~ri~athi, Gupta, hI., h-ivedi, L.D. S.N., and Sen,S.P. J. Res. I d M d la, I I (1975). 66. Tripathi, S.N., Gupta, Xi., Sen, S.P. and Udupa, K.N. I d . J. Etp. B i d U.15 (1975). 67. Singtr, A.K., Prasad, G.C. and Tripathi, S.N. dluioll Sd. Lijr 4, 23 (1982). 66- b t a v a , M., Nityanand, S. and Kapoor, N.K. J. Biol. Sd 6, 277 (I*). 69. Srivastava, hf , Nityanand, S. and Kapoor, N.K. Curi. Sci. 53, 1131 (I*). 70. Srivasta--a, and Kapoor, N.K. J. Bbl. Sn. 10. 15 (1986). M. 71. S i h , C. and Kapoor, N.K,Stimulation of low density lipoprotein r e a p o r activin. in ha mer.rbrane ofguggul-sterone treated rats. In PIocudugs of&&& o b b g d ChrnpioLr f I d a , 57th Anrrvol Meeting, CSlR Centre for Biocbcmicah, New Delhi, 9-12 October I-. i2. Slalhotra, S.C. and Ahuja, M.hI.S. I d . J. Altd. Res. 59, 1621 (1971). 73- Kuppurajan, K., Rajagopalan, S.S., Kotawan Rao, T ; Vijayal. A N . and Dwarakanath, C. J. Rrr. I d . M d 8, 1 (1973). 34. Kuppurajan, K., Rajagopalan, S.S., Kotawara Rao, T. and Sitaraman R J. Assoc. AtpLicmr'Id 26, 367 (1978). 75. Shrma, Keuti, Pun, A.S., Sharma, R and P&, S. J. Ru. I d M d hp H o m e . 1 , 132 (1976). 1 76. Upadhyaya, E.N., 'Tripathi, S.N. and Lhvivedi. LD. J. Res. I d Mrd. Y t h c o p . 1 , w 1 1 (1976). 77. h f a b k a , S.C., Ahuja, h1.M.S. and Sundanm, K.R I d . J. Mrd hs. 65, bSi,r)O (1977). 78. Kobiyal, .P.; Bfht, D.B. and Singh, D.S. J. Ru. Id. Mrd. Yoga Haorop. 1 4 11 (1979). 79. Jak, A.P. ICMR Bull. 10, 83 ( 1980). 80. T w i N.S. and Jain, P.C. J . Rrr. Apr cu, 1, 121 (1980). 81. Kotiyal, J.P., Singh, D.S. and Biiht, D.B. J. Rrs. A ~ S i a % a1, 335 (1980b. 82. hfot~ani, H.A. The effect ofguggul (ComnripAma mrPLul) on lipid profile a d -lation in ischemic hean disease. Ph.D. thesis, Nagpur University, Nagpur, 1981. 83. Bddwa, V.S., Ranka, P.C., Rishi, J.P. and Rai, R.R. Rj o& Mcd. J. i 3 (\%I). 84. KatiyaI, J.P., Singh, I. and Bisht, D.B. J. Ru. Apr Si&h 6, M (I=). i3 85. Jab, A P , Gupta, O.P., Harindth, B.C., Taori, C B and Tpgi, KJL Clinicirm .. .. 664 August (1987). 86. Aguwal, R.C., Singh, S.P., Saran, R.K., Das, S.K.. Siha, N., Asthana, OZ, Gupta, P-P, Nityanand, S., Dhawan, B.N. and Apmal, SS. Ina! J. Mrd Ru. 84, Q6 (1986). 87. Nityanand, S. Case history ofguggulipid-ahypdipidaanic agent. AbsF j h rLrirm i? SJ.1Corian a Mrdiriral Plunk a d Spiu, Sracrl, Kana (ds. Han, B.H, Han, D.S., Haa, Y.N. and Wox, W.S.), p. 171 7hc Korean National Commission for UhFSCO and the Natural Product Ruearch Institute, Seoul National University, Seoul 1W.
f
220
GUCGULIPID: A PROMlSlNC HYPOURDAEMK: AGENT

88. CDhY N w L f . 1, I (I 987). e s et 4 89. Vama, S.K. and W A. I . Md. Rcs. 87. 356 (1988). q d J. 90. B d a , A and Chutturi, S.K. I d J. Med. Rrr. 70, 992 (1979).
91. Shtnna, S.D., Upadhayay, B.N. and Tripathi, S.N J. Katl. In@. M d An 26, 249 (1984). 92. Sfisma, S.D., Gupta, V.K.,Upadhayay, B.N., Tripathi S . S and Tripathi, Y B J..Vdt. .. Is28 .fd A~sor.25. 384 (1983). \e. 93 T n p r h i , S.N., Upadhyaya, B.N., Sharma, S.D., G u p a \ R and Tripathi, Y.B. Arial Sn L/i.4, 9 ( 1984) 9. Shukla. hf., Singh, R D . and Tripthi, S.N. Elfea o an indigenous m p d drug f PushLar guggulu on G A M P and biogmic arnina in ichaernic hearc d i s t s x in nne In R:ctrdings of thr I e a o a Snninur on Clinical P h a t w w ~ l 0 ~ - Drwloping Cmnfrits, Iactnow, r mt nl u 1 u 13- I4 January 1986, p. 157. 95. T r i p t h i , S.N., Upadhyaya, B.N. and Dwiuedi, L.D.Rt-hrm 15, 5 (1980). 96. hlatcr.. L., hlater, hl. and Nityanand S. Planfa Mcd 37, 367 (1979). 37. Bdd-a, V.S., Sharmq R.C.. Ranka, P.C. and Chittom X1.D. R u j a ~ h d J. 19, M 84 * 1980). 98. Tnpachi, S.N. Studies on the use o deoresin guggdu - an indigenous d r q i the f n & d e n of lipid metabolism (with special reference to atherosclerosis and abuisy), Ph D. thesis (Ayurvcda), BanHindu University, \ ' w a i , 1973. 99 S~dhu.L.S., Shanna, Keerti, Pun, A.S. and Prakash, S. J. R t r I d h f d Y a p t . r , n. kl) 11. 16 (1976). IW. G u j d . M.L., Sareen, K., Tangri. K.K., Arnma, h1.K.P 2nd Roy, A.K. Ind. J. J+id. P h o y l . 4, 267 (1960). 101. Santha Kumari, G., Gujral, M.L. and Sareen, K. Id.J ??rszoJ. Phannarol. 8. 36 (1964) 102 Sana\ati, G.V., Raghunathan, K., P a d , D N. and Ratsor. R.S. Rhmaticn 4 141 (1969). 103 Arom R.B., Kapoor, V., Gupta, S.K. and Sharma, R.C. I d . J Erp. B d . 9,403 (1971). 104 Aror;l, R.B., Taneja, V., Sharma, R C . and Gupta, S.K. Id.J. .Lftd. Rrr. 60,929 119T2). 105. Ihandikar, G.K., Gulati, O.D. and Cokhale, S.D. I d J .bled. Ra. 48, 482 (1960). 106 Amma M.K.P., hi;llhotra, N., Sun, R.K., Arya, O.P.. Dani. H.hl. and Sartxn, K bC. J. Erp. Bid. 16, 1021 (1978). 107. Gujral. bl.L., Sareen, K., Reddy, G.S. and Amma, hi.K.P. I d J. McL. Sd 1 , 771 n. 6 (I%?). 108 Bagi. hl.f;., Kakrani, H.K., Kalyani, G.A., Satyanarayana D. and hlanii, F.V.F w 56. 245 (1985) 109. S a w \ a t i , G V. Id. J. h f i . &. 87, 32? (1988). s I I CDRI Dossier on p g g P p i d , Lucknow .i986. 0 1 1 1 Sinanand, S., Asthana, O.P., Agarwal, S.S., Gupta, P.P.. Tangri, A.N.. Dmi. S, b , i 1 and Dhawan, B.N. Tokrance and hypolipidaemic acti\in d guggulipid - the stadrLI ' fracooa of Commifhra d u l . In h u d a g s of H'orld e r n r u e on C!m.cd P J L and A c r ~ ~ b d i c London, 1980. s, 112 P&b. S. Evaluatio~of C. nur&l (gum guggul) in o k i y . M.D, tdKsi Fmjabi Uni\.mit)., Patiah, 1952. 113 Tnpzthi, Y B Studies on the &kt of Cannrijhom mtutul on thmoid function in mu a d .. expcimental animals. Ph.D. thesis (Biochemistry), BaHindu University, V 1983 114 Prasad, R.S. Studies in terpena. Ph.D. h i s , Poona Uni\usity, Pune, 1976. 115 Agarual, R C . Clinical studies on guggulipid, a new h>polipidaemic agent d eQ origin. M.D. thesis (hfedianc), Lucknow Univenity, L u c t w ~ .1982. i 1 G u p t a 0 P. An assessment of the intermittent use of C o n n ~ . ~ a r a 6 nukul in the
221
~ I I ischaemic bevl dirca M D t h i s .. (Ayur~cda),Banaras Hindu University. VarariaG, 1980. 117. D Swr, NJ. and Shah, V. Forskdin-an adenyhte cydue activating drug h m an e IPdirn herb. In EraMmu and dfrduiaal Bka, &d, pp. 1 16. Acdanic h Vol. 11, , London, 1988. t I . Satyavati, G.V. Pharmacnlogy of medicid +nu md other natural p S & in C m l LMd in Prhnrrm~log~ I n h (1975-82) (cd. P.R. Das and B.N. Dk-xn), p. 119 in Indian National Science Aradcmy, Sm Delhi, 1984. 119. Satyamti, G.V. ICAlK Bull. 16. 131 (1986). 120. P a d , C.K. and Dhawan, B . S P h a m a d o g a l studies on Indian m & i d plants. In C Rcsead on r\l~di~ilrol PI& in I d a (cd B . S . Dhawan), p. 45. IJ&D Xaoonal Sr;icna Aadcmy, 1986. 121. Das, P.K., Dasgupta, C . and hlishra, A.R. Clinical studies on medianal p u of India. In C d Rruud on ~ e d t h d PI@& k I& (cd. B.N. Dhaum), p. 72. lpdhn National Science Academy, New Dclhi, 1986. in Sub Dev. Aw. Ind. Nafl. Sri. Acad. 5U. 12 (1988). I23 !haanti. G.V. Ind. J . Mrd. fLs. 76 (Suppl.), 1 (1982). 1%. Viva Bandhu (Ed.). A f b d a ( S d i , 1st FAR 1962. Part IV. F P ~ C1. p. 1919. Vihvahvaranand Ved~c Research Institute, Sadhu Ashram, Hoshiarpur. mnjab, 1962. 125. Dwivcdi, V.N. (Ed.). Bhawpmkorh N i & n f ~ ~ . 3rd cdn, p. 107. hfotikl &narsi Das, &MN, 1924. 1% hfajumdar. R.C. Indian medicine in the h d i c period. In A Cadw H b - t q rf-S&uc in I& (ed. D.M. Bose, S.N. Sen and B.V. Subbarayappa), p. 216. Indian x5md Science Aadcmy, New Delhi, 19i 1 127. SukY&saahi& (600 B.C.), cdn. C h U m a h m m 5, 40-45. p. 412. h i d fSana-i 5th Dy Delhi, 1975. v 128, I'agbhata: Adangahridaya, 1st cdn. Clta.hntra, pp. 40-48, hiotilal B a n d D s Varanasi, z 1963. 129. Charah Samahita (1000 B.C.): C h i k i t u u t k a 26, 156-159 (1941). 130. Satyamti, G.V., Gupta, A.K. and Tandon S. ilfnikkol P W of la&, \-i Indian 11. Cowdl of hfedical Research, New Dw 1987. e 131. Saxena, A. Role ofguggulipid on hyperlipacmia:hlD (General hfedidne) M y Banrras H i u University, India, 1980.
of hypachdeatuolaemia and bypdipacmh
APPENDIX
ENGLISH TRANSLATION OF THE SANSKRIT VERSE I FIG. N
1113
Obesity or wasting of the body, as the case may be. is determined by nw. In x p m o n of Shhhnsq u h bds a sdntary lire and is averse to physical cxmise, who overeats and is.a&brd to dccphg in the daytime, the predominantly sweet-tzaing r which rcsanbia ae. w circulata~throughoutt e. hFrom this s a t - t a s t i n g q p p is brmed-a&land rndsi which contribute to excessive corpulence (olirW/o). The subject rffikrd by obesity exhibits a symptomatology which indudes brcathkssnus, thint, & s u hunger, e x d v e rlapiness, fetid body odour, wheezing while a s l q &den catching of the breath, feeling of inertness of the limbs, heaviness of the t+ and idistinct speech. Due to the sdtncs of the body-fat, the dxse subject i rrndaaa -fit s h my kind of work . He suffers from diminished s a d r i v e ... The nourbbwnt r
n . boverindulges in foods that conduce to the production
..
222
CUGGULIPiD: A PROMISING HYPOLIPIDAEMK AGENT
and growth of tissrres other than the adipose tissue is i m p c d d due to the co\*cringl oxting of the cllannels of internal arculation by fat, thus c~dangeringthe b a k . h obese or cxcessivdy corpulant subject is susceptibk to such ~L-CS as diabetes mdlitur (pramha),frven (jwara), carbuncle (pidaLn), anal fistula ( / i h P J a d r a ) . abscess ( l i d r d i ) , d ~ ~ a rot s n m o u s system (Vpfdhmu), etc., which ma\ terminate in death. The e the lifr-cxpcctancy, in these subjects, is very low. Any diseace in them is apt to take a serious turn (ana cause mmplications) due to the ohstr*:;iun cJ the patb\,.a); and ch~nnels circulation by fat . . .. Hence these subjects akvuld axold the aetidugical of Fncrors dcscribcd If the condition has already occurred. thc suljecrs should br treated H II11 (Lrmulnt~ons u n ~ a i n i n ~ , c among other drugs, Silajrtu. Cu.su:r. C;omutra. Tnphafu. l . i h r a p . Hncnnlnno. .\ladhu. etc., and such food articles (pulz)a,@,.\ludga, Koruwb, Jlonrcrka. L'ddaloka, etc., as well as the resort to physical r x r r c i . ' l',a;ama) and sllmnllng ur fat-rcn~o\ (Itthonn) therapies. ing
Susruta's commentator, Dalhana in his commentary on the above, elimmates the possible 'gastrointestinal' contribution to obesity and focusses attention on the metabolic. phenomena in this condition. Elucidating the implications of the term 'sweet-tasting amarara'. obsenes Dalhana: 'the ploduction of amarasa does not arise ,in obese subjects whose agni is acute (dcepta). In these cases, the digestion of food is as rapid and complete as tl~eirabsorption is quick. The formation of ama at the level of intestipal d~qestion, therefore, does not occur in these cases. To say that obese uld sons \\.hose digestion is 'acute' ptoduce ama ~ ~ ~ ointroduce an element of contradictior~as only an impairment of digestion can produce a m (at this le\.el) tvhich, however, is not the case in obese subjects. The correct ~nterpretation (of Susruta's reference is this regardj is that it is dhatumgi I\ hlch is manda (dull) and, in consequence, a m is produced at the level of [Issue metabolism. In other words, after formation and absorption, the ~~r~rlnrrsa (chyle) not metabolized properly by dhatwagni. This results in the circulation of u metabolized substances (ama),the covering/coating ( d ) of the pathways of circulation and metabolism (margalsrotac) by fat c medax), the predominantly sweet-tasting substances in circulation are con\erted to fat (medas), which alone accumulates in the body. Tissues other than the adipose are, therefore, not nourished and formed. and they deteriorate.'
6 '
1 he term 'rasa' has been defined as the fluid which is ever cir~uEtiiig-r&&&'
the body like a rotating wheel transporting nutrients to and collecting waste
products from the body tissues. In this sense, it resembles the description of. 1,lood plasma, lymph and nutrient pool. The A~urvedicdescription of the article4 of food that conduce to the production of shleshma suggests both proteins and Gts. ,
Tht tam a m refm, among other things, to unripe, immature, undigested or-partly digested. In the context of gastrointestinal digestion, it refers to uneested or inoompietely digested food. At the metabolic l e d , this.term refus to incompletely metabolized nutrients. The term sweet-tasting amrara is reminiscent of the high sugar amtent of the blood as in hyperglycaemia. -SruhaYmeans oily /viscous substances. '.khs' means fat/lipids. The tern 'bah' refers to: (a) body strength, an index of uhic1, is the capacity to do work, both physical and mental; and (b) rcsistana to disease li.&ancatw~'. It comprises two aspects: ri;. antagonism to t virulence k bi t b c , h e ( V+ibalauiro&twam) and the inhibition of the olrrar of the disease ( V m p a &kaoib&tzuam). In the context of obuity, both the aspms of bah are stated to be involved. The term 'aanrorcrro' refers to the chyle formed out of i m p i d digestion. Thc term 'crgnt' refers, at the gastrointestihal level, to factors concgrned with gastrointestinal digestion (jatharaagni),' and at the tissue k n l ( d k t uvogni), $ refers to factors concerned with the metabolism of nutrients.
224
0-15 GENE BANKS FOR MEDICINAL & AROMATIC PUNTS
NEWS-ER
Commiphora wightii Engl. (Gum Guggul)
scientific manner with the etiology, pathogenesis and treatment of obesity and associated lipid disorders and their complications. The story, actually began when a strong analogy was discovered between the ancient concept of medomga of Sushruta (600B.C.) and the modern concept of pathogenesis of The evolution of guggulgum resinas atherosclerosis and its fatal coma hypolipidagmk drug offers inter- plications. Among the therapeutic esting insights into the rich measures prescribed, gum guggul howledge and wisdom of A y ~ ~ e d a vks selected for screening for its the ancient medical system of possible hypolipidaemic acthrity in India. The saga of guggul as a loboratory animals as well as in hypoliiidaemicagent was initiatedin patients of obesity and hyper1964, in a tiny laboratory of the then cholegterolaemia (Sushruta SamCollepe of MedW Sciences of the htta, 600 B.C.). 8anakq Hindu University (BHU) in the holy Indiancity of Vatanmi. Prior Carefully conducted studies in rabto this work, gum guggul was Well bits by Satyavati (1966) demonsknown as an Ayuwedk drug of trated that on oral administfation, choice in the treatment of various gum guggul (water extract) not only types of aecltis. 718 chemicel and lowered the serum and tksue pharmacological studles w guggul cholesterolandplksphdiids levels were also thereforefoarssed, till this but also protected the animals cholesterol-induced time, mainly on the entiinRam- against matorylantlaru~ritic activity of the atherosclerosis at the fatty streak gumvasin. The hypolipidee* ac- stage. Inclinical studies also, similar tion of the drug was first reporled in results were obtained. Followinng a doctorate thesis by Satyavati, tbese pioneeri.ng studies, a large 1966, suBmitted to the BHU which number of experimental and clihical was inspired by a rather obscure studies were undertaken not only at stanza or ehbh ln Sanskrit In the BHU itself but also by different well knownAyurvedic treatise Sush- laboratories/medical colleges and Ntd WnMa(800 8.C.). Thls stmp hospitals in India, confirming these deals in an extraordinarily tucM and results. The Central Drug Research Guggulipid,amixtweof lipidsteroids isolated f m the oleogum w i n of Corn-m wghtli Engl. (guggui gum) is available in the Indian market since 1988 as a potent hypolipidaemic agent. More recently, the drug has been intr6duced in Europe and a few other countries.
and utinz-
225
Numbers 3 & 4
6-15 GEBMAP Newsletter
Instrade (CDRI). Lucknow, took up studies on gum guggul for drug development andfinally, in 1988Jhe drug reachedthe market in the form of N i (mhltvre of two gugp
gulsterones) hypolipkfemic 1991). as an antidrug (Satyavati,
Economic Aspects Guggul Gum
of
Apart from its medicinal and therapeutic uses, the gum resin of C . wightii(AKm. Bhand (syn. C. rnukuf) HookerStedor, Engl.), Burseraceae, is used as a binding and disintegrating agent in tablets and also as a suspending and emulsifying agent. The gum is also used widely as an incense and also as a fixative in perfumery. The gum is also used as a subqitvte for African Bdellium.
Commphon wightii piant /Photo Courtesv Dl
Pharmacognosy of Guggul
C. wiQMii(indianBdellium) is a much branchedspiny shrub or a small tree 2-3m high, found in the arid, rocky tracts of the states of Rajasthan, Gujarat and Karnataka in lndia and in the states of Sind and Baluchistan in Pakistan. The main Indian commercial centres of guggul are the states of Rajasthan (mainly the The distribution, cultivation, tapping westem regibh) and Gujarat (Kutch and collection, marketing as well as division). A healthy mature tree (#w~ocourtesy :~ rJ.R ahen) . ~ommi?ph~la, m Tnmk lurced to MOW ,
yields 250-5009 dry resin of guggu) in one collectina season. Pharmacognostically, the. macroscopic characteristics of all the parts of the plant have been studied. The microscopic features of the young stem, mature stem and leaf have been described. The development, histochemistry and ultrastructure of the gum resin ducts of C, wightii have also been studied.
gradrng of guggul in lndia have been extensively reviewed (Atal et al., 1975). The plant can be propagated by vegetative means. The Central Council f o ~ Research in Ayuweda and Siddha (CCRAS) has undertaken cultivation and propagation of the guggul gum plant n Rajasthan. Attempts are being made to determine the optimal method af tapping to obtain the maxlmum yield of the gugeul without adversely affecting the healthofthe plant by not onlv the CCRAS. but also the ~e~artment Environment and of ~ o k s t s d w ~ e \ h \ . view the . h heterogenyty of gumveld in wd. grown plants. attempts are bBmQ made to produce guggul s t e m $ through In vitro approach at the M.S. University.Baroda. Tapping of the tree is ysually done from November to Januw, whereas collection continues untir'Wy-June. For tapping, healthyplantswhichare over 5 years of age are selected and an incision is made on the bark. A pale yellow aromati fluid that oozed out through the cuts on the bark slowly hardens to form the golden brown o reddish brown oteogum r resinof guggul. The gum is readyfor cd\ectbn 1-2 weeks ' a m the first incision. Subsequent collection of the oleogum resin is ma* at inter-
226
0-15 GEBMAP Newsletter valsof approximately2 weeksduring, attributed to guggul pertain to 'old' samples of guggul. Fresh gum gugthe tapping season (Atal et al., 1975). An improved method of tap- gul, on the contrary, is said to have ping with ehtephon application has the opposite effects, particularlywith been described. This is said to im- respect to obesity and fat disorders. Thus, while an 'old' sampleof guggul prove yields by over 22 times. is described as highly effective in Ethnomedical Aspects of reducing body weight and lipids, a fresh sample of the drug is claimed Gum Guggul to have the opposite effect of inGuggul in Ancient Indian creasingbody weight. No such inforMedical literature mation is available regarding its acThe Atharva Veda (one of the four tion on other conditions like arthritis. holy scriptures of the Hindus) gives the earliest reference to the In clinical practice, however, Ayurmedicinaland therapeutic properties vedic physicians have been using of guggul by devoting an entire stan- guggul extensively for centuries in za to the drug. Detailed description the treatment of arthritis and related of the varieties, physical qualities, conditions, mainly in the form of actions, uses and indicationsof gug- compound preparations. A large gul are available in the famous Ayur- number of such preparations with vedic Samhitas or treatises of guggul as the main ingredient are Charaka (1000 B.C.), Sushruta (600 mentioned in the Ayurvedic medical B.C.) and Vagbhata (7th century lexicons and many of these preparaA.D.) and also in thevarious Nighan- tions are available commercially in tus (or Medical lexicons), written be- lndia and neighbouring countries. It tweenthe 12and 14thcenturiesA.D. is only in recent years (i.e. since the 1970's) that the drug is being used (Satyavati, 1991). by Ayurvedic clinicians as a hypolipMemic/anti-atherosclerotic agent, following the pioneering studies carried out at the BHU.
Numbers 3 & 4 related disorders, scrofula, syphilis, and skin and urinary disorders.
Chemical Investigations of Guggul Gum

With the discovery of the hypolipidaemic activity of the gum resin, systematic; and carefully planned chemical investigations were initiatedat the National Chemical Laboratory (NCL'). Pune in collaboration with the Pharmacology team of the Central Drug Research Institute(CDRI). Lucknow.The main aim of these chemical investigations was to isolate and chemically characterise compound(s) of the gum resin of C. wightii responsible for the hypocholesterolaemiclhypolipaemic activity of the gum resin. For this purpose, a viable separation scheme was evolved by the chemistry team headed by Dr. Sukh Dev, first at the NCL, Purie. and later at the Matti-ChemResearch Centre, Vadodara (India). Guggul resin is a complex mixture of various classes of chemical comditerpounds such as lignans, lip~ds, penoids and steroids. Among these, (3-guggulsterone and (E)-guggulsterone (together constituting apgroximately 2% of the gum resin) hkve been found to be responsible for the hypolipaemic activity. The and hypolipidaemic activity of (Z)(E)-guggulsterones has been found to be quantitatively comparable to that of the total ethylacetate extract of the gum resin. As the other components of the ethylacetate extract appear to exert a significant synergistic effect with regard to the lipidlowering activity, detailed pharmacological, toxicological and clinical studies were undertaken by the CDR1. Lucknow, on an ethyl-acetate extract standardized to pontain 40g of (Z)- and (E)- guggulsterone per 1009 (on the basis of an estimation by means of high performance liquid chromatography). This standard extract Is the basis of the commercially available.guggulipid i lndia and a few other countries.
Ethnomedical Uses of Guggul

Externally, gum guggulhasno action on unbqken skin but on the abraded skin an0 mucous membranes, it acts as an astringent and antiseptic. Administered internally, it acts as a carminative, antispasmodic, diaphoretic, ecbolic, antisuppuratie, emmenagogue and aphrodisiac. In Tibetan medicine, the . plant (C.wightir)mixed with other herbs is used-for skin diseases, anaemia. oedema. salivationand heavinessof the stomach. In the lotion form, guggul is used for ulcers; as a gargle it is used for dental care, in spongy gums, tonsillitis, sore throat and related conditions. Fumes from burning guggul are recommended for hay fever, nasal catarrh, laryngitis, bronchitis, phthisis, etc. The gum resin is also used in the treatment of rheumatism. neurological disorders, obesity and
Commiphonr wightii, crude gum (photo c w r t e s ~ ~ J.R. BheU) Or
The wide therapeutic range of guggul and its indk+ions from healing of bone fracture to inflammation, arthritis as well as cardiovascular conditions, obesity and lipid disorders make it a unique drug in the Ayurvedic materia medica. Another interesting fact is that major Ayurvedic treatises and lexiconsvery ernphatically stress that the therapeutic properties relating to fat disorders
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227
Numbers 3-& 4 - -
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G-15 GEBMAP Newsletter
Pharmacological and Clinical Studies on Guggul Gum

Several doctorate theses and nearly 100 researchpapers have been contributed so far, by research workers in different parts ot India, on the hypolipidaemic activity of gum guggul in animals as well as in human studies following the discovery of its hv~oli~idemictanti-atherisclerotic a&vi&. Clinical studies on gum guggul have also been carried out in patients of ischaemic heart disease and hemiplegia. Studies of gum guggul fractions-on cholesterol biosynthes~s rats and kinetic studies with in 4-C'4 cholesterol in rats and human beings have attempted to work out the mecnanism of hvpolipidaemic action of gum guggul. It appears that guggul exerts its hypolipidemic action by not only inhibiting cholesterol biosynthesis, but also by promoting rapid degradation and exertion of cholesterol. The other mechanisms suggested are thyroid stimulation. An exhaustive review of these studies has been published recently (Satyavati, 1991). Guggul gum 1 an important ins gredient of most of the commercialy available Ayurvedic drugs prescribed for arthritis and related conditions. The drug is used extensively in India for the treatment of all types of arthritis by Ayurvedic physicians. A large number of compound preparations, with guggul as the main inaredient are mentioned in medical leexicons or the ~9urve;dic Nighantus. Among its other pharmacologicalactivities potent antiinflammatory and antiarthritic effects of the oleogum resin has been reported against carragenaninduced rat paw oedema, granuloma pouch as well as adjuvant arthritis. A promising antifertility effect of the oleogum resin of guggul and its acid fraction is reported, as evidenced by reduction in the weight of the uterus, ovaries and cervix of rats with a concomitant increase in the glycogen and sialic acid levels.
The saga of gum guggul as a hypolipidemic agent is unique in the history of research on herbal drugs as it is based on the remarkable insights of ancient A y u ~ e d i iexperts/scholars on the intricate metabolic aspects of a disease like atherosclerosis. In spite of nearly two decadesof researchon the drug, there are several important unresolved questions yet to be answered by modemscientists, with resDect to hvpolipidemic/antiatheroscleroticactivity of gum guggul, includingits exact mechanismof action. he-most major setback to the success story of gum guggul is, however, the dwindling supply of the gum resin from natural soums due to difficulty in cultivation and the need for a long waiting periodfor the collectionof the gum. It is hoped that application of appropriate biotechnological methods may come to the rescue of scientists to resolve this major bottleneck. G.V. Satyavati Senior Deputy Director General Indian Council of M e d i i l Research New Delhi 110029
AM. C.K., Guptr. O.P. and Afw. S.H.1075. Ccnnnd@mm muW: Soum d guOOul h Indian system d medkine. Eco. Bot..
29(3b,208.
C h a m Samhita (1000 B.C.). CMkHasmthana 28,158,1941.
Wyavati. G.V.1966. ERect of an indlgem drug on disorders of lipid metabdhm wllh epecial reference to athetusdemk end obmW Wedofow). Thesis (Doctw of AyurVarenasi.
vadk Medicine). Baneras Hlndu Unlvetany,

Salyavati.G.V. 1991. Guggulipid:a promising hypolipidaemic agent hwn gum guggul (Cam rniphora wight@.In: Economic and Medkinal Plant Research. Volume 5. Plants and TRdC lied Medicine, Ed : H. W a p r 6 N.R. F8m8WOrlh. Academic Press. London. SushNtasamhita (600 B.C.) ' Maanam 15, 32 MotiU Banarsi Das, DelM 1975. p.60
Sukh Dev 1988.Ayuweoa and modem drug developmenl. Proc InbanNatal Sa Acad 54a. i2.
Vaobhata : Astancrahridava 1st edn. UItaitantra p.40. M& Banarsi Das. Varanasi.
1963.
228
T ,,:,i,.~
-.I.... J Mcd Res [B] 94, June 1991, pp !77-185
Multicentric randomized controlled clinical trial of Kshaarasootra (Ayurvedic medicated thread) in the management of fistula-in-ano*
I C M R Collaborating Centresf, Central Biostatistical Monitoring Unitz, Madras & Central Technical Co-ordinating Unit? ICMR, New Delhi
Accepted February 2, 1991
This paper reports the results of a multicentric, randomized controlled trial t o evaluate t h e emcacy of Kshaarasootra (Ayurvedic medicated thread) in the management of fistula-in-ano, in comparison with conventional surgery. This trial w u carried out a t Bombay, Chandigarh, New Delhi a n d Wardha. Complete healing was noted in all 265 patients in the Kshaarasootra series a n d all 237 patients in the surgery series. The median healing time was, however, significantly longer in the Kshaarasbotra series (8 wk) than in the surgery series (4 wk). In both t h e series, the healing time was least for subcutmeous fistula and highest in t h e case of high anal fistula. Patients in both the series are being followed u p for onc year after the completion of treatment, and the recurrence rates, based o n 150 patients in each series ' cent in the surgery series, a significant difference are 4 per cent in the Kshaarasootra series and 11 r (P- 0.03). Transient local hurnirig and increased discharge from the fistulo~rsopening were observed in rnost patients treated with Kshaararootrd. Mild anal incontinence was ohserved in 8 patients trestrd with Kshaarasootra and 13 patients treated with surgery. It is conelodd8 that the long-term outcome with Kshaarasootra is better than with surgery, although the initial healing tirne is longer. Kshaarasootra thus offers an effective, ambulatory and safe alternative treatment for patients with fistula-in-ano. It also constitutes a new drug delivery technique for conditions ltke anal fistula.
Fistula-in-ano is an age old, common condition prevalent all over the world. Considered second to haemorrhoids in importance amongst all anorectal conditions; its prevalence in a London hospital study1 was reported to be 10 per cent of all inpatients and 4 per cent of all new outpatients. A
retrospective study from India* reported anal fistula t o constitute 1.6 per cent of all surgical admissions. Though a benign condition, fistula-inano leads to major physical, psychological arid social problems due t o the persistent discharge through the external opening'. Most of the
*This ;epon was prepared by a sub-comainittee comprising Dr N:K. Shukla. Dr R. Narang, Sh. N.G.K. Nair, Dr S. Radhakrishna and D r G.V. Satyavati. I) Collaborating Centres (According to alphabetical order of the city giving address of the Department. Principal Investigator, Co-Investigator(s), Research staff o f the Collaborating Centres). (I) Bombay : Department of Surgery, Seth G.S. Medical Colle$e: R.D. Bapat; S.I. Nagral; Ashok Hande; Sanjay Kapote. (;I) Chandigarh: Department of Surgery, Post-graduate lnstitute of Medical Education & Research: Kuldip Singh (till March 1987); R.N. Katariya (since April 1987); Rajendra Singh; A.K. Das, G.V.Prakash; R.G. Ray. (;;I) Delhi: Department of Surgery, All India lnstitute of Medical Sciences : M.M. Kapur (till Sept '86); N.K. Shukla (since Sept'86); Anand Kumari Sharma; Rajesh Nanda; Vinay Mishra; Rakesh Kurnar; Girish i Pandey. (iv) Wardha: Department of Surgery, Mahatma Gandhi Institute of Medical Sciences: R. Narang, K.R. ~ o h i (till February 1990); D. Ramesh Babu (since 1990) 2) Central Biostatislical Monitoring Unit, Institute for Research in Medical Statistics, Madras: N.G.K. Nair; P. .layabal; S. Radhakrishna, P.A. Tamby. 3) Central Technical Co-ordinating Unit for ~ r a d i t i o n a l Medicine Research, ICMR Hqrs, New Delhi: G.V. Satyavati and A.K. Gupta.
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229
I \ l > l A S .I MEI) KES [R]. J U N E 1991
fistulae de\relop after rupture inadcquate drainage of pyogenic anorectal abscesses which dcvelop secondary to infection of the cryptic gland' . I Surgical treatment dcmands familiarity of the \urgeon with thc anatomy of the anoiectal region ; t r ~ t l also with the pathogenesis ol' fislula-in-ano. I hc tl-c:~tmcnt usually comprises laying open or completely excising the fistulous track and then ;illow healing O secotidary intention. This y procedure requires hospi1alis:rtion and regular post-operative drcssinp, which is oflcn painful. ('omplcte healing t;tkes from a few weeks to ~nonthh.the chances of recurrence (0.7 to 26.5%) and incidence of anal incontincricc (5 to 40%)) being rather highs. !)eshpande and Sharman.' from the lpstitutc of Medical Sciences, Banaras Hindu ,University ( B H U ) . Val'anasi (India), through their pioneering work, introduced an alternative, non-operative Ayurvedic technique known as Kshaarasootra in the treatment of fistula-in-ano. The method described by the ancient Indian surgeon SushrutaR in his falnous treatise, Sushruta Sarnhira (600 B.C.;- Fig.1) involves insertion, into the fistulous track. of a specially prcpared medicated thread coi~tedwith herbal drugs, and rendered alkaline. In 1984, the Indian Council of Medical Research. New Delhi. revived its research on selectcd thrust areas of traditional medicine, with it rlcw disease-oriented approach and the role of Kshaitci,soorr-;r in the rnanagernellt of fistula-inano was identified as one of the thrust areas >elected. I t was decided to evaluate the efficacy of K.shiracjsoo/r;r in comlxtrison with conventional surgical treatment, through rnulticentric clinical trials. Material & Methods The study was conducted as a prospective. randomized multicentric clinical trial at 4 centres viz., New Delhi, Chandigarh, Wardha and Bombay, using specially devised uniform protocol and proformae, designed with the assistance of a Task Force comprising experts in surgery/ proctology, clinical pharmacology, biostatistics and also reputed Ayurvedic experts. Essentially, the trial aimed to evaluate .the efficacy of Kshaarasootra (the Ayurvedic medicated thread), in comparison with
Fig. I . Original Referencexon Kshaarasootra in.Sushruta Samhrta (600B.C.): Chikitsasthanam: Chapter 17: Shlokas 29-33.
surgery, on (I) ihe healing of the fistulous trackand (ii) recurrence of fistula, after complete healing. All the participating centres were required to 'send regularly, the filled-ill, pre-coded prol'ormae of each patient at monthly intervals t o the Central Biostatistical Monitoring Unit (CBMU) located at the Institute for Research in Medical Statistics, Madras, which verified, computerized and al~alysed the data. Regular ~nonitoringwas done by the CBMU. in collaborat,ion with the Central Technical Co-ordinating Unit (CTCU) for Traditional Medicine Research at the I C M R Headquarters, New Delhi. The d a t a were reviewed and discussed annually (or more frequently, when required) through meetings of Principal-Investigalors, Task Force members/.experts and also the scientists of CBMU and CTCU. Anually, the data were also reviewed by tile l C M R Scientific Advisory Group on Traditional Medicine Research. Preparation and supply o f Kshaarasootra : The Kshaarasootr'a (medicated threads) were prepared according t o the method standardized a t the Dept. of Shalya & Shalakya, lnstitute of MediCal Sciences, Varanasi, through a special Manufacturing Unit set u p for this purpose (under the supervision'of Prof. P.J. Deshpande till 1987 and
SELECT RESEARCH PAPERS C?.' EVXDENCE BASED AYURVEDIC DRUGS
230
CLINICAL TR(ALS ON KASHAARASOOTHA IN ANAL
FISTULA
later with Prof. S.N. Pathak as the officer-incharge). Briefly, the method o f preparing the Kshaarasootras is as follows:The Kshaarasootra was prepared by smearing a surgical linen thread (guage no. 20) with the fresh latex of $nuhi o r Euphorbia neriifolia (a cactus plant) a d a spekially prepared alkaline powder (known as kshaara) from the plant Achy-anthes aspera (Apaamyga) and turmeric powder from the dried rhizomes of Curcuma longs (turmeric, Haridra).
d
I he processing o f the thrhad is done inside a specially designed cabinet for drying the threads. The thread is manually coated first with bhe latex ol' E.nerii/oliir elevon limes, followed by seven coatings of the latex and the ash (Kshaar?) of A.aspera allernari\cl>. and dried. I n thc final ' phase, three coatiiigs o l thr latex and turmcric powder are given alrcriintivcl). -1 he thread thus prepared is sterilised hy cxposing'to ultra \iolci radiation for 15 tilin in the samc cahinei. and placed i n a polythene bag. which is translcrred to a glass tube containing silica get a3 the dcss~citnt. before sealing the tube. I h c p H ol the Kshaarasootra was ensured to he ahot~t c) 75. while the length was abopt 25 cm (Fig. 2).
Each batch of KshaBrasootra prepared ua\ subjected to qualify control, i n tcrnis of pH. tensile strength and other physico-chcnircal paranieters dt the Central Drug Research Institute (CDRI). Lucknow. and also the Departsic111 o l Pharmaceutical Scie~i~s:~.Panjab Udi\ crsit! . Chandigarh. before being sent to the CTCII. L e u Delhi. i n sealed tubes. The CTCU supplied Ilic threads as Gel1 as the clinical trial proformac periodically to the Principal Investigators. Bcfoic the clinical trials started, either the Pr~ncipal 'Investigator (PI) or the Research Officer appointed i n the project was trained in thc applicittion ol Kshaarasootra by @rnf. Deshpande (cither at Varanasi itself or .I: the surgical OPI) o f tlic participating centre\). Whcrmcr thi\ was not possible, an Ayurvedic expert well-versed In tho application of the k ~;raar;.isr)olr;l tcclin~quewa\ associated with the pru,:ct. i t \ a co-invcstigatoi.
t
Fig. 2 . K \ l ~ ; i ; ~ r ; t r r ~ ~ ) l r i ~ (Ayur\.edicmedicated thread) ready for ;~pplic:~tion. Fig.3. Specially dehigned. malleable probes for
;~pplic;!lion 01' Ksh;i;tr;tsc~otr;~.
only the k l l o ~ i n g were considered eligible for inclusion in the randomized clinical trial: Patients with evidence of anal fistula and willing to ( I ) be hospitaltsed for 2 t o 6 wk to undergo surgery; (it) repolt once a week for change of thread (Kshaarasoorra): and (iir) rcport once i n two moiithi lor one year for follow up, after the coii~pletionof treatment. Patients with diabetes, cclrdiova\cular disease. renal disease and cellulitis adlitcent to the dnorectal area were excluded from tlic randomrzed controlled study. The'se patients uric. however. treated with Kshaarasootra and lollowed up under the 'non-randomized group', along w ~ t l ithose pai:ents (in each centre) who. on refused surgery or ins~sted being treated with Ksh:r;~r:i\oorra (Data not included in this paper). After obtaining informed consent. the patients found eligihlc l o r the ccmtrollcd study were randomly allocated. within each centre, to Kshoiir~isootra or surgery groups by sealed
Patients : At each p;tr~icipating ecntrc. patienth attending the surgical proctolcrgical 0E'l)s were subjected to detailed clinicc~lexitmination and
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231
INDIAN J MED RES [B], JUNE 1991
in the subcutaneous and low anal types of fistulae and excision of the track below the anorectal ring along with curetting of the upper track, in case of high anal fistulae. A malleable probe was passed through the track till it came out at the internal opening. Using the probe as a guide, the complete fistulous track along with adjacent tissue was excised as a wedge and the raw area was packed. Post-operatively, the patient was advised regular aseptic dressing with loose packingito allow the wound to heal from the apex. The time required for t k w o u n d to heal completely was recorded for each patient. After' 'healing by either of the treatmew schedules, d l the patients were asked to report once in two months for a period of one year for physical examinatiqn for any complications (including recurrence). For the nl*rpose of this study, recurrence is deiined as leappearancc of the fistula at the same site or at different site, within a period ~f 12 months. The randomized controlled trial comprised 502 patients of fitula-in-ano (between October 1984 and September 1990) drawn from four centres
Fig.4(8).
Probing of the f ~ ~ t u l o utrack preparatory to s application of Kshaarasootra. (b) Change of Ksharrrasootra by the railroad technique.
viz., All India Institute of Medical Sciences, New Delhi (167 patients); Postgraduate Institute of Medical Education and Research. Chandigarh (185 patients); Mahatma Gandhi Institute of Medical Sciences, Wardha (77 patients); and the Seth G.S. Medical College and KEM Hospital, Bombay (73 patients). The pooled results from the 4 centres, based on 265 patients randomized to Ksharirasootra treatment and 237 to surgery arc presented here (Data of non-randomized series of patients treated with Kshaarasootra are not present4 in this communication). Results Condition of patients on admission : In both the Kshaarasootra and surgery series, nearly 90 per cent were males and nearly 50 per cent aged under 30 yr while approximately 40 per cent were aged 3 0 4 yr. Patients from the New Dclhi Centre consti-
232
C L I N I C A L T R I A L S O N KASHAARASOQTRA IN A N A L F I S T U L A
tuted 38 per cent of the Kshayarootra (K) series and 28 per cent of the Surgery (S) series; the corresponding proportions being 36 and 38 per cent at Chandigarh. 14 and 16 per cent at Wardha and 12 and 17 per cent at Bombay. The characteristics of anal fistula, o n admission, are summarised in Table I. Nearly 50 per cent of patients in the K series and 44 per cent in S series had the disease for a t least one year, and about a fourth of the patients in each series had previous anal surgery: The type of fistula was subcutaneous in 29 per cent of the K series and 26 per cent of the S series, low anal in 56 and 61 per cent, and high anal in IS and I4 per cent, respectively. The twp series were also similar with respect to .other characteristics such as the depth ajld shape
-
of the fistula, distance from the anal rnargin and the location of the fistulous opening. In short, the Kshaarasootra patients and the Surgery patients were broadly similar on admission to the clinical trial, in all respects. Speed o f healing o f the fistulous track : Healing took place in all 265 patients subjected to Kshaarasootra and also in all 237 patients subjected to Surgery. However, the healing was relatively slow in patients treated with Kshaarasootra. Thus, the proportion with healing by 12 wk was 68 per cent in the K series. a\ compared ta 89 per cent in the S series (Table 11) -a significant difference (P<0.01). By 40 wk. the proportions became fairly similar, i.e., 92 and 98 per cent respectively. The median healing time was 8.0 wk in Kshaarasootra series and 4.0 wk in the Surgery series (P< 0.0 1 ). In both the series, the speed of heal~ngvaried appreciably with the type of anal fistula (P<0.01). Thus, in the Kshaarasootra series, the median heal~ngtime was 5.0 wk In subcutaneou,c type, 8.0 wk In low anal type and 15.0 wk In hlgh anal type of fistula. The corresponding f~guresIn the Surgery series also showed a slrn~lartrend but were consrsrently lower, viz.. 2.0. 4.5 and 8 0 wk respectively. The difference in median heding t ~ m e between the Kshaarasootra series and the
Table 11: Speed of healing or anal fistula in Kshaar:rsootra and Surgery series T~me Percentage of pallents w ~ t h heal~ng All Types K S Subcuta- 1.ow neous K S K anal H ~ g h anal
S
Tmblc I.Characteristics of the anal fistula on admisslop

Characteristic Percentage of patielits Kshaarasootra (n = 265) Duration ofdzscase(yr). Suigery (n = 237)
<I
1-2 23
49 33 17
56 21
23
26. 61 'r14
Type of fistula :
,
Subcutaneous Low anal High anal
29
56 I5
Depth of fistula (em) :
Shape offutula :
Radial
Curved Straight Others*
Dist8noc from a n d margin (cm) :
<3
5 5
3-4
Location ofthe tiituloous opening : Towards rectum Towards anal canal Others**
63 29 8
70 26 4
75 17 Total number ofpatients
77
18 5
265
237 4.0
77 5.0
61
2.0
149
8.0
144 4.5
39 15.0
32'
Medlan healing time(wk) 8.0
80
**
Bilateral, horse-shoe, ~ o m b i ~ t i o f shapes eic. n Towards a n o - m a 1 ring, i k h i a l tuberosity etc.
K. Kshaarasootra: S. Surgery
233
INDIAN J MED RES [B], JUNE 1991
Surgery series, varied with the type of fistula, being 3.0 wk in subcutaneous type. 3.5 wk in low anal type and 7.0 wk in high anal type. With Side-effects and complications : Kshaarasootra treatment, almost all the patients complained of local burning sensation especially after the ftrst insertion. This lasted usually for a few minutes, and was rarely of a severe nature requiring medication. Increased discharge from the fistulous opening was observed in the first few days in most of the patients, requiring the use of a pad. During one year follow-up, anal incontinence was observed in eight patients (5%) treated with Kshaarasootra and this was mostly of mild type (1.e.. incontinence to flatus or occasio,~ally to liquid faeces) and six of them recovered sphincter control. Recurrent perianal abscesses were seen in ftve patlents and incomplete prolapse of rectum in two patlents. With sutptcal treatment. all the patients had post-opetattve pain lasting for a few days i n d requiring analgesics. During the follow-up. anal incontinence, mostly of mild type, occurred in 13 patients (9%). four of whom recovered sphincter control Recurrent perianal abscess and tncomplete rectal prolapse were observed in five and two patlents rcspecttvely Recurrence . Among the 502 patients who completed treatment. 83 are currently still under follow-up. 122 faded to attend regularly for follow-up. while the remaining 297 completed one yeat follow-up. Among these 297 pattents. recurrence rate was 4, per cent in 155 pattents treated with Kshaarasootra, as compared to l l pet. cent of 142 in the Surgery series(-l .~blc I l l ) . 'lhis difference of 7 per cent was st;ttistically significant (1'- 0.03). The recuricticc rate was not inl'lucnccd by the type of I'ihtula in either scrich (1-able I l l ) . A history of' previous anal surgei.! did not seem to affect the recurrence rate in K.\lr;t;tr-;tstrotr;t series. the proportions wit17 t,idl.t-cncc heing 6 and 3 per cent in those with. and u'ithcut previous surgery ( P > 0.2). On the other Iiatid. in the patients subjected to surgcr!. tlict-c was an appreciable and significant diflkrcncc ( I ' = 0.02). the proportions bring 24 atid 7 pet- cent, iespectively:
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Table 111. Recu~rence rates of anal fisntla in Kshaarmootra and Surgery xrles
f shaarasootra
Surgery
Pat~cntsPatients with Patients Patients with
followed recurrence followed tccurrcncc No. No, % No. No $

Tvpe oflistuta .
Subcotaneous' 1.o~ anal . High anal
32 95
28
3 1
9 1
2
h
0
25 91 26
1 13 2
4 14 8
No. of tracks : S~nglc Multiple

Done Nor dolie
l oral
139 Ih
4 (01
131 I1
14 11 208)
'
47
IOX
3
1
34
108 142
8
8
24
7
11
?
4
IS5
16
i-~gure\ p ~ r e n ~ h c w v In dcnolc 111.11 the than 20 patlents
percentage is based on Ie5s
Discussion Fistula-in-ano is known to be predominantly a disease of men and of middle agev. In the present study also. most of the patients were males the proportion ol male : female being 9:1, as compared to 7: 1 and 12:l in other Indian s t u d i e ~ ~ . ~ ~ . The age distribution of patients of fistula was also The similar to that reported by. other$". incidence of various types of fistulae also corresponded with those reported by o t h e r ~ " ~ ~ - l ' . single track being found in 9 0 per cent and low anal fistula in 59 per cent in the present series. Healing occurred in all the patients treated with either Ksh;torasootra o r surgery. In the earlier study of Deshpande a?d Sharmae. the fistula in three ol 200 patients failed to heal. In other studies on surgical treatment of anal fistula. 0.3 to 5.6 per cent patlent\ failed to heal following \urgeryl' I' I h and most ol the patients who failed high anal fistula or associated to heal had e ~ t h e r anorectal discitself*. In the present study, the healing, rate was sloucr with Kshaarasootra, as compared to surgcry. Thus the proportions with healing by 12 wk were 68 and 89 per cent. but became 92 and 98
SELECT P3SEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS
Cl.INICA1. TR'IALS ON KASHAARASOOTRA IN ANAL FISTULA
per cent by 40 wk. The median healing time was 8 wk for Kshaarasootra. as compared to 4 wk with surgery. This could be due to a slow cauterisation ,pf the track by Ksh;t;tr;tsootr;t. through its herbal ~ngredient\.The mcdiitn healing time was least for ~rhcut;~ncous fistul;~and maximum for high anal f~stitla.Ilcshpande and Sharmah have reported that 92 pel. ccnt of 200 patients healed within 12 \r.k. A wide variation in healing time following \urgcry has been reported. from 4 to 26 wk in low itnal l'ixtula ancl 8 to 52 wk in high anal fistulat. A 1ic;tling rate of 74 per cent is reported" in uncomplicated fistula. within 12 wk of surgery. In the present study. the median healing time lollowing surgery, was 2.0 wk for subcutaneous, 4.5 wk for low anal and 8.0 wk for high anal I'i\tula. K~11;r;rrirsnotra treatment does not require I~Ospitalisation.whereas the average hospital stay following surgery varies from 3 to 16. days'.I4. Patients treated with Krhaarasootra could continue with their normal routine work, and the presence of the thread did not bother them, as was also tlemonstrated earlier hy I>cshpande and Sharrnah. O n the other hand, the mean duration of absence Irom work in surgically treated patients has been I cported to be 49 days'. .I<ccutrence rate over one year follow up was 4 pcr cent in the Kshaarasootra group, as compared 10 I I per cent in the surgery group and this rate was not affected by the type of fistula. Previous nnal burgery. however, adversely affected the recurrence rate in surgically treated patients but not in those treated with Kshaarasootra. Ileshpande and Sharma" reported a recurrence rate of 2 per cent with Kshaarasootra. Surgical treatment of anal fistula is known' to have a recurrence rate ranging from 0.7 to 26.5 per cent, most of the recurrences (7742%) being reported within one year'.l0.l2. High anal fistulae have been reporpd to be associated with higher Incidence of recurrence3, though this was not observed in the present multicentric study. High recurrence after surgery i s mainly due to ~ncomplete laying openlexcision of track and laster union of skin e d p s . Low recurrence of listula treated with Kshilarasootra has been attributed by Deshpande and Sharma' to better
drainage, slow and gradual cutting with simultaneous healing and also complete destruction of the cryptic gland by the caustic action of the thread. Recent advances in surgical techniques and the advent of anal manometry have also led to a reduced rate of recurrence with surgeryI7.l8. Mild anal incontinence was observed in patients treated with Kshaarasootra as also in those treated surgically. In the Kshaarasootra series, the incontinence was transient and perhaps related to the stage of 'cutting through' the anal sphincters by the thread, which.subsequently led t o complete recovery, during follow-up. Deshpande and Sharma7 did not encounter anal incontinence in their series of 50 patients of high anal fistula. Following surgical excision, 5 to 40 per cent incidence of anal incontinence has been reported, mostly of the mild type3.5.tt. High risk of postoperative incontinence to be associated with high anal and complicated fistulae may be like surgical trauma to the attributed' to f a c t ~ r s anal sphincters, sensory nerve damage and, excessive loss of anal skin. In most cases, the damage is permanent, as also observed in 9 of the 13 patients in our series. A lower incidence (3%) of anal incontinence has been reported with the recent use of mucosal advancement technique" following fistulectomy. Misra and Kapurlo recently reported favourable results with a technique involving the passing of a multistrand braided stainless steel wire through the fistulous track, but their series was small (56 patients), and consequently, the recurrence rate of 4 per cent cited by them has an upper 95 per cent limit that is as high as 13 per cent, (as compared to 8% in our series). Moreover, their study did not have a surgery group as control, either concurrent or historic. On the basis of the results of this multicentric, randomized clinical trial, it is concluded that the long-term outcome (in terms of recurrence and anal incontinence) is better with Kshaarasootra than with surgery, even though the initial healing may take l.onger. Similar results with respect to healing and recurrence were obtained with Kshaarasootra treatment in another series of 269 patients who were ineligible for the randomized control study (including those who refused
SELECT RESEARCH PAPERS Oh' EVIDENCE BASED AYURVEDIC DRUGS
235
lNDlAN J MED RES [B]. JUNE 1991
surgery). The data of this series which invoked, in addition to the 4 centres, two others i.b, at Goa and Manipal, have not been given here. The consolidated results of all patients treated with Kshaarasootra (randomized and non-randomized series) with follow-up data will be communicated separately. Kshaarasootra technique can be used in the outpatient department under local anaesthesia, even at the Primary Health Centre level. Patients are ambulatory throughout the period of treatment and do not need regular dressings. The method is also more acceptable than surgery to most patients as it avoids any invasive (surgical) intervention. No systemic side effects were encountered with Kshaarasootra, although transient local effects like slight burning and discomfort were observed. These local effects can be attributed to the caustic nature of the latex and the ash (Kshaara) used in the thread. Another advantage of the technique is that poor risk patients for anaesthesia and surgery can also be subjected to Kshaarasootra treatment safely. As no hospitalisation is required, Kshaarasootra can be more cost-effective than surgery and therefore, more suitable for developing countries with limited resources and facilities for inpatient services. This advantage of Kshaarasootra has also been emphasized by others6.19. Disadvantages of KshaarAsootra include the necessity for weekly l~ospital visits for changing the thread, apart'from local burning sensation and increased discharge. Despitdhese, Kshaarasootra technique offers an effective, ambulatory and safe, alternative treatment for patients with anal fistula. The mechanism of action of Kshaarasootra in healipg the fistulous track has not yet been clearly elucidated. Deshpande considered that the technique served to achieve what he termed as 'chemical' fistulectomy, in contrast to the 'physical' fistulectomy achieved by surgery (P.J. Deshpandepersopal communication, 1985). Among the three ingredients of the thread, the latex of E. neriifoIia is well known in Ayurveda2O for its wound vealing property (applicable in different types of sinuses and fistulae), whereas Achyranthes aspera Kshaara (ash) is considered necessary for ensuring the alkaline (Kshaara) medium, without which the thread is not at ail effective. Curcuma longa or turmeric powder is used as the last coating on the
thread to aid in (I) minimizing the severe local reaction due to the caustic action of the other twr herbal ingredients; and also (il) for its known anti-inflammatory and anti-infective efficacy (P.J Deshpande - personal communication, 1985) Anti-inflammatory2'. anti-bacterial22 and anti-leprosy23 actions of Achyranthes aspera have beep reported and there are a number of reports or; Curcuma longa and its active constituent curcumin. to demonsirate anti-inflarnmaf~ry~'-~~ antiand bacteria128activities. In the case of Kshaarasootra, it appears that the combination of the three herbal ingredients, through the medium of the thread achieves the desired results. The' technique 01 Kshaarasootra therefore constitutes not only a unique drug formulation but also a novel method of drug delivery, most appropriate for healing the fistulous track. Recently, the resulk of preliminary chemical analysis of the thread used in Kshaarasootra have been reported29. In-depth chemical studies on the finished thread as well as the individual ingredients of Kshaarasootra (including quality control and standardization) are in progress jointly at the ICMR Advanced Centres on ( a ) Pharmacological Research on Selected Traditional Remedies at the CDRI, Lucknow; and ( 6 ) Standardization & Quality Control of Traditional Remedies/Natural Products at Panjab University, Chandigarh. The results of these studies will be reported separately. Studies are also under way to determine variation in clinical efficacy and physico-chemical charactetistics of different batches of thread manufactured under strict quality control. Acknowledgment
This report is ded~cated the memory of the late Prof.,P.J. to Deshpande, formerly Head, Department of Shalya. & Shalakya, Institute of Medical Sciences, Banaras H~ndu University, Varanasi(India), who introduced Kshaarasootra to the scientific world and who was closely associated w~thtlic multicentric clinical trials reported here till his untimely.d,drath in August 1987. Prof. Deshpande also prepared several batches of Kshaarasootra uscd in this clinical trial. till 1987. Subsequent t o his demise, Dr S.N. Pathak of the same Institute, took over the manufacturing of the Kshaarasootra (with the help of Sh. Satya Ram, Research Assistant). Useful slrggestions given throughout the period of the study by members of the Task Force on Anal Fistula 'and experts of the ICMR Scientific Advisory Group on Traditional Medicine Research are acknowledged. The
236
CLINICAL TRIALS ON KASHAARASOOTRA IN ANAL FISTULA tinuing interest and advice of Prof. S . C Lahiri. Calcutta: 16. Ewerth. S., Ahlberg. J.. Collste, G. and Holmstrom. R. Fistula-in-ano a 6 year follow up study of 143 operated patients. Acta Chir Scand[Suppl] 482.1 1978) 53. 17. Aguilar. P.S., Plasencia. G.. Hardy. T,(i.. Hartman. R.F. and Stewart, W.R.C. Mucoral advancement in the treatment of anal fistula. Dis Colon Rectum 26 (1985) 496. 18. Pescatori. M.. Maria. G., Anastasia. G. and Rinallo. L. Anal manometry improves the outcome of surgery fur fistula-in-ano. Dis Colon Rectum 32 (1989) 588. 19. Wolffers. I. Ayurvedic treatment for fistula-in-ano. Trop Doct 16 (1986) 44. 20. Sharma. P.V. Dravyaguna vignan, vol. 2. 4th ed. (Chowkhambha Sanskrit Sansthan, Varawsi) I978 p ,432.
IT. B.N. Dhawan. Lucknow: Prof. I.C. Pathak. Chandigarh I Prof. P. Khanduri,, Vellore. in particular, deserve special
ntion. The assistance of Prof. S.S. blanda. Chandigarh
1 Sh. J.P.S. Sarin, CDRI, Lucknow. in standardization of
threads used in the clinical trials. is acknowledged.
Rtlerences
Marks, C.G. and Ritchie, J.K. Anal fistulas at St Marks hospital. Br JSurg 64 (1977) 84. Raghavaiah. N.V. Anal fistula in India. Int Surg 61 (1976) 243. Sainio, P. and Husa, A. Fistula in ano -clinical features and long term results of surgery in 199 adults. Acta Chir Scand 151 (1985) 169.
1.
Parks, A.G., Gordon, P.H. and Hardcastle. J.D. A classification of fistula-in-ano. Br J Surg 63 ( 1976) I.
5. Lilius. H.G. lnvestigltion of human fetal anal ducts and intermuscular glands and a clinical study of I50 patients. Acta Chir Scand 383 [Suppl] (1968) 1.
6. Deshpanie. P.J. and Sharma, K.R. Treatment of fistulain-ano by a new technique. review and follow up of 200 cases. A m J Proctol24 (1973) 49.
7. Deshpande, P.J. and Sharma. K.R. Successful nonopera-
21. Khare. A.K.. Feror Hasan and Sharma. M.K. Antiinflammatory drugs from the plantr. J Sci Res PI Mcd 4 (1983) 4.
22. Basu. N.K.. Xeogi. N.C. and Sri~astava.V:P. Hiological invertigation of Achyranrht'h aspera [.inn. and i t \ constituent achyranthine. J Pr13clnst Chenl29 (1957) 161. 23. Medicinal plants ol' India, vol. I. G.V. Satyabati. M.K. Raina and M. Sharma. Eds (Indian Council of Medical Research. New Delhi) 1976 p 13. 24. Srimal, R.C. and Dhawan, B.N. Pharmacology of diferuloyl methane (Curcumin). a non-steroidal antiinflammatory agent. J Pharrn Pharmacol25 ( 1973) 447. 25. Ikodhar. S.D.. Sethi. K. and Srimal, R.C. Preliminary study on the anti-rheumatic activity of curcumin (diferUloyl methane). Indian J Med Res 71 (1980) 632. 26. Rastogi. R.P. and Dhawan:B.N. Research on medicinal plants at the CDRI. I.ucknow (India). Indian J Med Res 76 .Suppl( 1982) 27. 27. Satyavati. G.V. Pharmacology of medicinal plants and other natural p~oductr. In : C'urrent research in pharmacology in India (1975-82). I'.K. L>as and B.N. Dhawan, Eds (Indian National Science Academy, New Delhi) 1984 p 131. 28. Zutrhi. S.K., Joshi. S.K. and Bokadia. M.M. In vitro anti-microbiol emciency of scrmc csscntiul oil%: Indian .I Med Rrs 64 ( 1976) 854. 29. Ciewali. M.B.. Pilapitiya, U., Hattori, M. and Namha. 7 . Analysis of a thread used in the Kshaarasootra trcatmcnt in the Ayurvedic medicinal system. J Ethnopharrn;1col29 (1990) 199.
live treatment of high rectal fistula. Am J Procrol(1976) 39. 8. Sushruta samhita: Chikitsasthanam: Chapter 17: Shlokas 29-33; 5th ed. (Motilal Banarasi Das, Varanasi. India) 1975 p 456. 9. Goligher, J . Surgery o f t h e anus. rectum and cokm. 5th ed. (Baillier indall. London) 1984 p 181. 10. Misra, M.C. and Kapur. B.M.L. A new nonoperative approach to fistula-in-ano. Br J Surg 75 (1988) 1093. I I. Vasilcvsky. C.A. and Gordon. P.H. Results of treatment d fis!uta-inago. Dis Colon Rectum 2g (1985) 225. 12. Ani, A.N. and Solanke. T.F. Anal fistula - a review of 82 cases. Dis Colon Rectum 14 (1971) 51. 13. Ma7ier. W.P. The treatment and care of anal fistula - a study of 1000 patients. Dis Colon Rectlim 14 (1971) 134. 14. Adams, D. and Kavalcik. P.J. Fistula-in-ano. Surg (iynaecol Obstet IS3 (198 1) 73 1. IS. Hill. J.R. Fistulas and fistulous abscesses in the anorectal region: Personal experience in management. 1);s Colon R e a m 10 ( 1967) 42 1.
Reprint requests: Dr S. Radhakrishna. D i m t o r . Institute lor Re\earch 1n Mcdic;~lS t i ~ t i ~ t ~ c \ . Spurtirnk Kwd. ChNput. Madras 600031
237
TREATMENT OF FISTULA IN A N 0 BY A MEDICATED THREAD-KSI-IARA SUTRA TREATMENT, REVIEW AND FOLLOW UP OF 182 CASES t(enji Tazawal, Shigeru Takemoril, Takuji Fujikawal, Katuya Yamamotol,
fdaszo Hatnri2, Tuneo Namba2, Upali Pilapiriya3, Masao Fujimakil
Introduction
I4ippocra'les 460 B. C. (before Christ) described the use of seton to cure f i s h l a in ano. The first surgical lay open of fistula in ano as practised today was performed in 1337'. Various treatments have been tried to cure fistula in ano inclcding fistulectonly cvitii primary closure and s!tin graftingV4. Some variations in classical operation of lay open have been added by Hanlcy? Parks6. and Goligher7. The routine surgical treatment of fistula in ano srnployecl today i s f i s t u l e c t o ~ ~ i yfistulotoniy 2nd coring out method , fo llowing sphinct~?r-preservingfistulectomys. In spite of the best efforts cven today, the niain problems faced in the treatment of this disease, are : I ) extensive multilation of the ano-rectal and ischio-rectal area which i s a prerequisite for radical cure, 2) prolonged hospitalization, and 3) high raie of recurrence. Thus, in principle the surgiczl treatincnt of f i s h l a in ano has remained the same without much improvement. Moreover, the gatienls also have to suffer economic loss as they h z - ~ c be away fro111 their jobs and the society as a result of to 'prolonged hospitalizaiion and healing time.
--
':
*:
3:
2nd of Department of Surgery, Research Ir~sli.iute for ~ a k h - ~ a k u Toyama Medical & Pharmaceutical , University, 2530 Sugitani Toyama Shi, Toyama, Japan 930-01 Brindaranayake memorial Ayurvedic Research Institute Nawinna, Maharagama, Sri Lanka. Ayurvedic medicine, Indian medicine, Medicated threads.
Key words : Fistula ani,
238
--
The technique adopted i n the present work i s the revival of an age-oi procedure practised by " Sushruta ", the eminent lndian Surgeon9. Man studies have been.published by Ayurvedic surgeohs recently with encouiadnl results for treatment of fistula in ano by use o f ~ s h a r a Sutralo-". This method i s non-operative and belongs t6 the parasurgical group. It invalves the application of a specially prepared medicated thread proce8sed with certain vegetable caustics. This Ayurvedic treatment was recently introduced into Japan from Sri Lanka by U. Pilapitiya, and more than ninety fistula patients weie successfully treated i n our university hospital * I 3 1 4 . In this paper, we describe a review of analysis of 182 patients treated by this method. A l l these :patients have been followed up for a minimum of one year,
Materiala and Methods

These patients either attended (lie outdoor: of the Toyama Medical and Pharmaceutical University or Fujikoshi Hospital with conlplaints of discharging sinus in - the anal region. Unless the extent of the track was very extensive or associated with malignancy, active tuberculosis or severe anaemia, the patients were taken up for the treatment by "Ksharasutra". X detailed history of th.e patient was taken and careful systemic and local examination was done. Rectal examination and probing was done in all cases t o assess the extent and the direction of the -fistula. Standard classification of fistula' in ano as desc~ibed in the modern medical text books was taken into account7. The "Ksharasutra" ' was applied by the method described in earlier paper12. These needed local or spinal anaesthesia, on the first application or subsequent changing of the thread. Patients were advised some analgesics intrarectally on the first day of application, and to wash thoroughly after each defaecation and take warm bath if practicable. After the fistulous track is cut througli, the resulting open wound
was then dressed with oirit~nent. The patients were advised to continue
thei! normal work during the treatment.

239
I. Preparation of Threads :
In this medical procedure, a surgical and medicated thread (Fig. 1) is prepared by U. Pilapitya in following way : first, an' alkaline powder of the plant Achyranthes aspera L. i s produced by cutting the whole into small pieces and burning tkam in a clay or iron pot i n the semiclosed air. The t-ash i s allowed to dissolve i n water and the filtrate is dried over the sun to afford an alkaline powder. Second, a cotton thread i s dipped in latex of Euphorbia antiquorum, L: and in -alkaline ash of Achyranthes aspera alternately fop about seven times and finally coated with1yellow powder of Curcurna dornesteca L.. The thread is then dried In the shade.
II. Selection of Cases :

i n 182 cases of fistula in ano included in the present study, local examination was conducted noting carefully the number, site, distance, discharge, tenderness, induration and the position of internal and external opening. Rectal i n d proctoscopic examination was also done i n each case.
il. Application of KshaTasutra (K.S.) :

A l l patients were advised a rectal wash before the application of K.S.. i-he patient was put in a lithotomy position and the perineum was prepared 4th antiseptic lotions. Depending on the site of fistula, the index finger of he ilght or the left hand was passed into the annal canal and a silver lalleable probe was passed into the fistuluos tract gradually and cautiously ,y the other hand, till it touched the finger in the anal canal. The tip of the probe was brought out of anus, by bending it. A litable length of K.S. was qut and threaded throvgh the eye of the probe. l e probe was brought out of the anus leaving K. S. in the fistulous tract. l e K. S. was moderately tightened and tied out side verge over the anoderm. 1 K. S. is pierced through fistula several times and gradually this 'brings 3 JOU~ healing of the wound.
240
AYU 1
IV
---
-------
I A~igust
Subsequent Changes
A new piece of K. S. was replaced and tied on every 7th day i~ the cases by rail road technique till the last K. S. gradually cut through fistulous tract, leaving a smf'r healing ulcer at the anal verge. Only I c ('. anesthesia was reqir;red for these changes. The length of K. S. taken on each occasion. was measured and recorded. Shortening of the t h ~ ~ , ' removed at each change indiqated the _sliortening of the fistulous t r ~ lntrarectal analgesics were allo,wed in all cases and an3biotic was admi2 stered in all cases for 3 to 4 days, as they had significant discharge of p:
Kohata Sutra Technique in Fiuiula-.in-nno
-----
Healing T (weekj .- ---- .-. 3.4w 4.4W 7.7 W

4.6W
T Ype
Ic ' 45 1I%* 114 I I I ~ ~ 23

mean
h 1
---
Number (case)
- -A
-. .
Excl~ange Cutiing Time (thread) . (clay)
Hos1;italization
(day)
--- - - -
-- - - - -. -
- -
0.5T 1.1T 2.4T
6.1 D 9.1 D 19.5D
8.OD 12.40 29.8D
(182)
1.1T
0.7D
--.-* --a
----
13.OD
I : Subniucous or subcutaneous fistula. * 2 1 1 . : Intersphincteric fistula. * " I I i : Transsphincteric or' high level fistula.
Compal.ison of Operation 2nd Ksharz SuQra
1 _ - -. 1 * I - I-. C .- . -^__ ^
-.*_
Type
Niirnvar (case) operation kshara

34 38 45 114 23
tfospitalizatior~ (day) operation kshara

26.3 29.1 53.7 8.0 12.4 29.8
-
Healing Time (week) operation kshalL

_ r
3.4 4.4
--
I*' I[%2 111~3
---.----
--------
----
- ------ -
8.2 8.2 13.2
7.7
-4-
I : SuSmucous or subcutaneous fistula. *211 : Intersghincteric fiistula. *3111 : Transsphincteric or high level fistula.
241
SELECT RESEARCH PAPERS ON EVIDENCE BASED AY URVEDIC DRUGS
August-19921
[ A Y ~
Follow up
A l l the cases were examined every month for the first 3 months aild f every 3rd month thereafter. Anal defects and recurrences if an):,were recorded. This revival method of K. S. in Japan has been applied in.241 cases of fistula in arro at Jun 1991. Out of 241, 182 cases fol!owed up over 1 year have been studied various angles in order to find out the optimum response of this treatment in a particular group of patients.
..
Follow up study
7 -
in Mshara Sutra (1)

_ I .
----
(182 cases)
1 No. of complication and dysfunction a) pus pocket formation : 7 3.7,z b) mild deformity of anus : I 0.6% c) severe deformity of anus : 0 d) local inflammation : 1 0.6% e) bleeding : 0 f ) stenosis : 0 g) incontinence : 0 ! No: of recurrence
------
9 4.9%
9 4.9%
Follow o p study
in kcshara Sutra (2)

(1 14)
xse) 3mplication
.
(45)
- (23) 5 (21.7%)
4
3
-
(2.2%) - -- ---
(2.6%) 2 0 1
-1s pocket formation ;Id deformity of anus 3 1 inflanlmation

.
0
0
-
1
--
__
--
--
:urrence
----_.
: Subn~ucouaor subcutaneous fistula.

i1 : Intersphincteric fistula. : Transsphincteric or high level fistula.
__ _
_ __ __
.- - - - - - .
(0%)
- ------.-,--
(5.3%)
3 (3,OZ) I
242
AYU J
Result
1 August-1992
Male patients were the usual sufferers (912 : 166/'182). Majority of the cases complained of pain, discharge and swelling in the perianal region. 24.7% (45/182) fistulae were subcutaneous and submucous, 62.6% (114/182) intersphinteric, 12.6% (23/1S2) transsphinteric or high level fistula (Table-I). Table 1 gives the details regarding the number of fistulae, average changes of K.S., average durations of cutting time (in days), average durations of hospitalizhtion (in days) and healing time (in weeks) in various types of fistulas encountered in the present series. Distribution of cutting time in each type was shown in Figure 2. 95.1% (1731182) of the cases had complete cu.re while 4.9% (91482) had recurrence after treatment with K.S. (Table 2). The incontinence of faeces and flatus was not observed in any of the cases. The first application of K.S. was easy in majority of the cases but some had difficulty in cases of high level fistula. But all cases had successful application of K.S. in the fistulous tract. Subsequent application of K.S. was pain in a few cases.
Dfscusslon :
The routine surgical treatment of fistula in ano is also by laying open the tract either by fistulectomy or fistulotoniy in Japan. It was a common observation that incontinence of faeces or stricture of the anal canal are frequent in cases of high level fistula in ano. The high recurrence of fistula in ano i s another common problem. In this study, all the cases were anlbulatory after initial application and subsequent changes of K.S.. A few cases were confine3 to bed for a day or two because of pain. A l l the cases Were traated on in patient basis, but a few patients had to be non-hospitalized as they had come to work after this treatment. The average duration of cutting tinie in this study was six days in cases of subfi~ucous subcutaneous fistula, 9 days in cases of or intersphilicteric f~stulaand <9 days i n cases of transsphincteric or high
level fistula.
SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS 243
The average duration of treatment when compared to conventional surgical treatment of fistula in ano was half week i n submucous, subcutaieous and intersphincteric fistula. In cases of high level fistulae and transsphincteric fistula it was very much less than the hospitalizaiion in days by ;urgical treatment of fistula in ano. Deshpande et a l l 2 had advocated application of K.S. without anes.hesia, But it was observed during the present study that i t was difficult to -pply K.S. without local or spinal anesthesia. The results of treatment in the present study when compared to those $ Deshpande et all are almost similar in clinical course. These authors ?d reported 96.5% and 96%12 cure rate, while in the present study it is lout 95%. The rate of recurrence after conventional treatment of fistula as ported by E c n n ~ . t was 10 cases (8.87:) l~ out of 118 and by Sumikoshi16 was 418 patients (12.42) out of 3370. In the pre'sent series i t was only . Daslipande et a l l 2 and KothiaI7 reported recurrence rate of 3.5% (7 .ses out of 2CO) and 0.8:; (4 cases out of 498) respectively in a 2-9 years ilow up study. The treatment of fistula in ano by K.S. is very simple, easy and safe. ';e chances of recurrence are very much less in properly selected cases pyogenic fistulae in ano excluding horse shoe fistulae. The treatment can 20 be employed to severlly ill patients of hypertension, diabetesr~~ellitis, art disease and Crohn's disease. The suggested mode of action of K.S. is as foll.ows : The K.S. cuts slowly and gradually through the fjstulous tract from apex to the periphery, There is sn ideal simultaneous cutting and healing of the tract and no pocket of pus is allowed to stay back. Tlie causticsI4 l 8 applied on the medicated thread have properly of chemical irriiant and curetting for smooth cutting, and in addition, are antibacterial, antifungal, antiinflammatory and antislough against (Table 3). The K.S, remains in direct contact of the tract and therefore, it
244
chemically curettes out the tract a n d . slougl13 out the epitherial lining, thereby allowing the fistulous tract to cotlapse anu heal under the 'drug deliverly system.
*
The K.S. due to its antibacterial property, dose not allovr bacteria to . . multiply i n the presence of Haridra. The pH value of K.S. (Fig. 3) was towards the alkaline side13 'and thkrefore i t did not allow rectal pathogens to invade the cavity.
REFERENCES :
.I
Perrin W.S. : President's Address : Some landmarks in history of rectal surgery. Proc. Roy. Soc. Med., 25 : 338-346, 1932. Hughes E.S.R.: Primary skin grafting in proctological surgery. Brit. J. Surg. 41 : 639-642, 1953. Khurana C., Saronwale K. C., Gupfa S. P. : Primary skin grafting after fistulectomy in the treatment of fistula in ano. Amer. J. Proctol.,. 23 : 139-152, 1972. Arakawa a,, ~ r j k a w a J. : Split thickness skin graft on granulating wounds follbwing extensive fistulectomy. Dis. Colon. Rectum. 6 : 436-440. 1963. Hanley P. H. : Conservative surgical correction. of horseshoe abscess and fistula. Dis. Colon Rec., 8 : 364-368, .j965. Parks A. G. : The pathogenesis and treatment of fistula in and. Brit.
4
.
6.
. Med. Jc, 1 : 463-469, 1961.
Goligher J. C. : "Surgery of Anus, Rectum and Colon" 1st Edition, Bailliere, Tindall and Cassell, London, 1961, pp. 11 and 174-208.
8 Yoshikawa N., Sasai T. : Operation for anal fistulae. ~astroenterologica~ Surgery, 5 : 1291-1299, 19E2,
245
Deshpande P. 'J. : A review of 40 cases of fistula-in-ano treated with Kshara-sutra. Nagarjun, 10 : 160-168, 1966. Deshpande P. J., .Paathak S. N., Sharma B. N., Singh L. M. : Treatment of fistula-in-ano by Kshara Sutra. J. Res. Ind. Med., 2 : 131-139, 1968. Deshpande P. J , Sharma K. R. : Treatment of fistula-in-ano by a new techniq'uk-Review and follow-bp of 200 cases. Amer. J. Proctol., 24 : 49-60, 1973. ~ e s h p a n d eP. J., Sharrna K. R. : Successful non-operative treatment -of high rectal fistula. Amer. J. Proctol., 27 : 39-47, 1976. Tazawa K., Yamamoto K., Pilapitiya U., el al : Kshara sutra-its attempt and results. Studies on Ayurveda i n Japan, 16: 1693-1699, 1986. Yamanloto K., Tazawa K., Yamashita I., et at : Clinical study of anal fistula treated by Ksllara-sutra: its result and composition analysis. Studies on kyurveda in Japan, 18: i900-1904, 1988. Bennet R. C.: A review of the results of orthodox treatment for anal fistulae. Proc. Roy. Soc. Med., 55., 756-757, 1962.
10
11
12
13
14
15
16 Sumikoshi Y., Okada M., lwadare J., et al : Anatomy and physiology of the anus for the surgical operation of .fistula-in-ano. J. Jpn. Soc. ~ o l o - ~ . r o c t o l .33: 444-447, 1980. ,
17
Kotliia M. B.: Bhagandara-A study of Kshara-Sutra therapy. Studies on Ayurveda in Japan, 17: 1790-1797, 1987. ~ e w a l iM. B., Pilapitiya U., Hattori M., Namba T.: Analysis of a thread used in the Kshara Sutra treatment in the Ayurvedic medicinal system.
18
J. Ethnopharniacol., 29: 199-206,, 1990.

Figure 1 Preparation of medicated threads : Surgical threads are impregnated 21 times with the sap of Euphorbia antiquorum, the alkaline powder of Achyranthes aspera ,(and the powder of Curcuma dornestica. It takes about 7 days to prepare the thread,
SELECT RESEARCH PAPEXS ON EVIDENCE BASED AYURVEDIC DRUGS
246
AY u1.
k ~ -
. -
[August 1992
_ _ I -
..
Figure
DIt,trihution of duration of cut-through in days (cutting time) in various types, of fistulae. Alktjlinity of Kshara Sutra i n water and normal saline solution at 5" C; tcrnperat"re.
Figure 3
Table
Mor~r~ values, of thread exchanges, duration of cutting time ( ~ 1 1 1 fhiouyh); duration of hospitalization and duration of healing tinlo in various types of fistulae. ~ ~ ,and~,recurrence ~ ~ t i types~ of~ fistulae in ~ ~ l i in various ~ follov~ up stud). C ~
Taare
Table
C l \ ~ , ~ , ,cauterizaiiorl ill niedicated thread of Kshara Sutra. i~~l

* : 111iiin conipouncls isolatecl and cliaractcrizecl for chemical cnut,1\cs,
Figure 1.
{'reparation
of n~.edicvltedthreads : Surgical tlireahs are
impregnated 21 \Irncs with the sap of takes about 7

t l r ~ y y to
Euphorbia antiquorum, the alkaline
powder of A c I \ y ~ r ~ n aspera~ and the powder of Curcunia doniestica. I t tl~~ prepare the thread.
Surgical thread
No. 1-0
Achyranthes Curcuma Eu~horbia
Acpera
Dol\\ostica
A~\tir\uorum
Powder Sap
1
)
Impregnation
21 times in 7 days
'/
Thread medicatvt) with alkali
-
August 19921
[AY u
Figuro 2. Distribution of duration of cut-through in days ( cutting time) in various iypes of fistulae.
Alkalinity of Kshara ~ u t r a in water and normal saline Figure 3. solution at 5'C temperature.
248
AYU ]
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. ,
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t August-IS92
.' r
Table
Chemical c a u t e r i z a l i o n :in m.edicaled l h r e a d knovn as Kshara sutra

I
Haridra
'
.- - a-c -i ~ r-a n l-t l-l n- t
I
*I
I
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- _ - - __ _ _ _ _ _ * CUPtl0l
* *
t r l~ r p c n e c cuphorbol I cycloarlenol~ anllquol A8q dllcrpcnc
1
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'
glucos~des) lnokostcron I ccydys~cro,n a - I j ! q l o ~ d c s. -1 I 7---
1
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---.
-- ---
'*
I
KzCOI
-)
,*turmerane I d i h y d ~ -turmerone a 1 zlneiberenc ptlcllandrcne I cincol I slorct~ pcnbossn I 110 laslum I oxalate
I I 1 I
I
I
I
KCL a c h y r a n t h l n ,I
KO11
a n t i f ungal antiinflammatory Jnl~oxidant anllcoagulatory an t l t ~ c p a l oo x l c t
(:III!HIC'Al. CAUSf l C S
Y)
.F 2 : R
249
Status Report on
Pharmacological Research in India,

1994-1998
Editor
C . ADITHAN, M.D.. P~.D.,

D.N.B., FIMSA., FIPS.
Department of Pharmacology JTPMER,Pondicherry.
INDIAN NATIONAL SCIENCE ACADEMY

Bahadur Shah Zafar Marg, New Delhi-110 002.
250
PHARMACOLOGY OF MEDICINAL PLANTS AND NATURAL PRODUCTS

S.A. DAHANUKAR. R.A KULKARNI, N.N. REGE
Department of Pharmacology &Therapeutics, Seth G.S Medical College 8 KEM Hospital, Parel, Muinbai-400 012
1 Introduction .
In recent times, focus on plant research has increased all over the world and a large body of evidence has collected to show immense potential of medicinalplants used in various traditional~ystems. More than 13,000 plants have been studied during, th'e last 5 year period. The present review aims to compile data generated through the research activity using modern scientific approaches and innovative scientific tools in last 5 year period i.e. 19941998. To facilitate the readers to look at their areas of inter: est more easily, the data in the present review have beenorganised in various sections according to pharmacotogical activities.Two of these sectiodeserve special mention one on nutracedtice; in which research on plants that form a park6f our normal diet has been compiled irrespedfie of activity and the second on phytochemWl studies which are associated with pharmqmfbgical activity. In the rest of the sections, thrnscription on individual plants is followed t?y.thatit'on polyherbalformulations. Polyherbal forrpulations have been included as they are widely *.used, as reflected in the study by Karandikar eta/,' and. the data based on the studies carried out with these i6rmulation.s has been publishedin peerreviewedjournals.
time, probably by stimulation of the hepatic microsomal enzyme system? Similar properties were exextract (PEE) of the roots sleepingtime, probably PEE of the seed of tested for nootropic of Alzheimer's duced lesioningof nuclear basalis magnocellularis). It reversed both, the cognitive deficits and the reduction in cholinergic markers after 2 weeks of treatment. Be&rsal of perturbedcholinergic function Wp p f s to be the'possible mechanism'. Fhe alcoholic extract of Bacopa monniera facilitated of the acquisition, consolidation an-tention memory as seen by its effect on 3 newly acquired behavioural responses in albino rats, vk. foot shock motivated brightness discrimination, active conditioned avoidance and Sidman continuous avoidance responses. Further studies identified the chemical constituent, a mixture of 2 saponins designated as. cbacosides A & B, responsible for the facilitatory effect of Bawpa monniem on learning schedules.The bacosides a l s ~ a f e the retrograde amnesia d produced by moblsatbn induced stress, electroconvulsive shock and scopolamine and enhanced and increasedthe proteinconPhase Iclinical studies have confirmd the s a k of the bacosides in healthy male volunteers at both\shgle and multiple doses adminiqtered over a perioq of 4 weeka. i h e acetone solubld fractiorrof petroleum ether ex' tract of Lawsonia inerrnis (Mehendi) leaves showed significant nootropic effect on the elevated plus maze and passive shock avoidance paradigms.The extract also potentiatedclonidine induced hypothermia and decreased lithium induced head twitches.This indicates that it affects 5HT and noradrenaline mediated
251
2. CNS Active Plants
The scope of CNS active Indian Medicinal Plants in therapeutics has been illustrated in a review article by Vaidya2. The following paragraphs focus on the further work carried out durina the last 5 years.
Various extracts derived from the'seeds of Pongamia pinnata (Karanj) decreased pentobarbitone sleeping
S. A. DAHANUKAR et aL,
behaviour. It had no effect on haloperidol induced doses (10-200 mgkg), when tested in rats. Higher however, did not show anxiolytic catalepsy, thus showing no effect on dopamine me- doses (>400 mg~kg) diated behaviour7. activity15. A lot of attention has been focused on the effect of BR-16A (Mentat), a polyherbalformulation, on learning and memory. It has been shown to augment acquisition and retention of learning in normal rats, as well as in states of cognitive deficits induced by variety of insults including pre-natal undernutrition, post-natal environmental impoverishment, sodium nitrite hypoxia, aluminium, increasing age and electroconvulsive shock (ECS) induced antero-grade and retro-grade a m n e ~ i a ~ Ramteke,et a/," demon.~~. strated that administration of BR-16A to slow learning rats, improved learning (both speed and magnitude) on the Hebb Williams complex maze as compared to control. The results indicated that BR-16, like piracetam, could facilitate learning and memory, and could be categorized as a nootropic agent. Bhardwaj and Srivastaval* have shown that Mentat (designated by them as CIHP Ill), significantly improved the avoidance learning during endurance performance in rats when tested on the Runimex, a circular runaway. The number of stimuli i,e. electrical shocks requiredto induce learning were consid-. erably.reduced in the treated animals. Trasina, a polyherbal formulation, was found to exert significant nootropic effect following 21 days therapy in 2 experimental models of Alzheimer's disease. These models were induced in rats by either injecting colchicine' (15 pglrat) intracerebroventricularly (i.c.v.) or lesioning of nucleus basalis magnocellularis by ibotenic acid (10 pglrat). Trasina improved both memory and levels of various cholinergic, markers like acetylcholine concentration, choline acetyl transferase activity and muscarinic cholinergic receptor binding in frontal cortex and hippocampus of rat brain. Thus its nootropic effect may be attributed to correction of cholinergic dysfunctionls. Pretreatmentwith Memorin (200 mgldaykg), another herbal formulation, was found to attenuate electroconvulsive shock induced retrograde amnesia in rats when tested for passive avoidance learning paradigms in a shuttle box1'. Ethanol extract and cold aqueous infusion of Vitex leucoxyhn (Nirnochi in Tamil) leaf depressed spontaneous motor activity, antagonised d-amphetamine induced sterotypy and oxotremorine induced tremors and shortened the duration of immobility in the behavioural'despair' test in qicel6. Methanolic extract of rhizomes of Nelumbo nucifera (Kamal) was found to cause significant reduction in spontaneous activity, decrease in the exploratory behaviouralpattern by the head dip andY maze tests, muscle relaxant activity and potentiation of pentobarbitone induced sleeping timeq7. Mitra, et a/, l8 have shown that the root powder of Panax ginseng did not affect pentobarbitone sleep time or spontaneous motor activity. Although it potentiated amphetamine induced increase in motility, it atlenuated the other effects of amphetamine, viz. stereotypy and lethality in aggressive mice. Haloperido1catalepsy -potentiated while the behavioural responses of 5-hydroxytryptophanand \-dopawere both attenuated. It exhibited significant aggressioninhibiting effect in doses that had no effect on spontaneous movements. The results have been discussed on the basis of interaction of Panaxginseng with the functioning of various neurotransmitters. All extracts [petroleum ether (PEE), benzene(BE), chloroform (CE), acetone (AE) and ethanol (EE)] of the leaf of Abies pindrow Royle (Silver fir) showed potentiationof pentobarbitone sleeping time i.e. CNS depresbant effect. The PEE, BE, CE and AE (highest effiqcy) showed significant anti-depressantactivity. On the other hand, EE was found to potentiate immobility, suggesting that this fraction is devoid of anti-depressanteffect '*. Ginkgolic acid conjugates (GAC) (6-alkylsalicylates, namely n-tridecyl-, n-pentadecyl-, n-heptadecyl-, npentadecenyl- and-n-heptadecenylsalicylates) isolated from the leaves of Indian Ginkgo bilobaUnn., a PAF antagonist, showed consistent and significant anxiolytic activity. By contrast, EGb 761 and Ginkocer, 2 conjugates which are devoid of GAC, did not evoke significant activity. EGb 761 was found to increase rearing and decrease immobility time only in open field behavi0ur.Thi.s effect may be due to weak antianxiety activity20.
22 Psychoactives ..
The leaf extract of Azadirachta indica (Neem) exhibited anxiolytic effects comparable to diazepam at low
SELECT RESEARCH PAPERS Ol\f EVIDENCE BASED AYURVEDIC DRUGS
252
MEDICINAL PLANTS (NATURAL PRDUCTS)
Administration of BR-16A for 7 days induced dose related anxiolytic effects as assessed by paradigms like the open field and elevated plus maze tests in mice and the social jnteraction andvogel's drink conflict tests in rats. It attenuatedthe increase in rat brain tribulin levels, a putative endocoid anxiety marker footshock induced aggressive behaviour in paired rats but failed to affect clonidine-induced automutilative behaviour. Reduction in swim stress induced immobility in Porsolt's behaviouraldespair test, reduction in escape failures concomitant with an increase in avoidance response in the learned helplessness test and attenuation of muricidal behaviour in rats demonstrated that it poss'esses antidepressant propertiesa.
2.5. Sedatives The non-polar fractions of the leaf of Vernonia species (~ahadevi) Vernonia lasiopusand Vernonia viz. galamensishave been shown to have sedative properties in ratsn.
2.6. Analgesics
Gossypin , a bioflavonoid from the yellow petals of Hibiscus vitifolius (Bhasadwaji), has been shown to have anti-nociceptiveactivity, similar to morphine and involving multineurotransmitter systems, mainly the cholinergic and GABAergic neurotransmitter pathways. Gossypin pre-treatment significantly decreased the development of acute tolerance to morphine induced anti-nociception (acetic acid induced writhing 2.3. Agents attenuating dependence assay). Thus, it is a potential candidate for clinical Chronic treatment with the root extract of Withania trials as an analgesic with the advantages of lack of somnifera (Ashwagandha) attenuated the develop- tolerance and dependence liability2'. ment of tolerance and also the development of dependence to morphine in mice. By itself, Withania Suppression of acetic acid writhing was seen with both the ethanol extract and cold aqueous infusion somnifera showed no analgesic effectD. of Vitex leucoxylonj6. 2.4. Anticonvulsants Azadirachta indica showed analgesic properties in In a study carried out by Manocha, eta/", Ginkgo mice. Pre-treatment with the opioid antagonist, bilobadecreasedthe protective effect of sodium valnaloxone and central noradrenaline depletor, proate and carbamazepine against picrotoxinas well DSP-4, attenuated the analgesia whereas the seroas strychnine induced convulsions in mice. Further tonin synthesis inhibitor, PCPA, potentiatedthe same, studies showed that pre-treatmentwith Ginkgo biloba suggesting that both central and peripheral mechaextract potentiated the convulsions produced by nisms and complex neural pathways (opioidand non'picrotoxinand strychnine, indicating the involvement opioid i.e. monoaminergic) may be involved in this of GABAergic system and chloride channels (for effectn. picrotoxin) and modulation of action of the glycine neurotransmitter(for strychnine) by Ginkgo bilobaZ4. Cerpegin, a novel furopyridine alkaloid isolated from Pafiax ginseng was shown to have no anticonvulsant action, nor did it potentiate the anticonvulsant effects of phenobarbitone and diazepam1'. Chronic administration of BR-16A was found to protect against pentylenetetrazole (PTZ) induced kindling in mice, demonstrating the role of GABA receptor in PTZ induced kindling and protection by BR-16A by its interaction with these receptorszs. Caffeine intake has been shown to increase the plasma half- life (2-fold) and reduce the bioavailability by 32% of carbamazepine in normal human volunteers. No interaction was seen with sodium valproate. These results indicate the need for restriction of xanthinetcaffeine consumption in patients on carbamazepine therapp. Ceropegia juncea Roxb. (Bhutumbi), has shown an analgesic effect (not involving the opioid pathway) against acetic acid induced writhing in miceu. Using the same model in rats, significant analgesic activity was detected in leaf and seed of Vernonia lasiopus and Vernonia galamensis and alc.ohol1c extract of Ochna obtusata(Kanakchampak)stem barka. Panax ginsengexhibitedanti-nociceptive activity and potentiated the anti-nociceptive activity of both pentazocine and aspirinia. The PEE, BE and EE of the roots of Pongamia pinnatashowed significant analgesic effect in the tail flick tesP.The PEE and direct EE of the seeds also showedssignificant analgesic activity at doses higher than 100 mgl kg.
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Different extracts of Abies pindrow Royle leaf (PEE,BE,CE,AE and EE) showed significant analgesic effect in the hot wire inducedtail flic! response in rats. Possible mechanism of action could be its inhibitory effect on PAF and prostaglandins as this plant contains phyto-constituentssuch as flavonoids and terpenoidstS. Alcotiolic extract of the roots of Clerodendron semtum (Bharanji) showed significant analgesic activity in micen.
2.7. Anti-inflammatory agents
The BE was effective in carrageeninbut not the PGE, model of inflammation. The anti-inflammatory property appears to reside mainly in the intermediatepolar constituents and not in lipophilic or extremely polar constituentsn. The PEE and CE of the seeds of Pongamiapinnata showed potent acute anti-inflammatory effect whereas the aqueous suspension showed pro-inflammatory effects. Further stvdies have shown that maximum anti-inflammatory effect was seen in the bradykiniri induced oedema model with the direct EEw. Possible mechanism of action could be inhibition of prostaglandinsynthesis and decreasedcapillary permeability. PEE and AE inhibited histamine and 5- hydroxytryptamine induced inflammationprobably by their lipophilic constituents preventing the early stages of inflammation. However, the fractions were not effectiveagainst Freund's adjuvant arthritic model.The latter finding indicates that the plant may not be effective in rheumatoidarthritis. All extracts of Abies pindrow Royle leaf showed antiinflammatory effect in various animal models of inflammation such as carrageenin induced paw oedema, granuloma pouch and Freund's adjuvant arthritis. Chemical analysis indicated the presence of glycosides and steroids in the PEE and BE and terpenoids and flavonoids in the AE and EE. Flavonoids and'terpenoids are polar substances effective in acute inflammationwhereas glycosides and steroids are non-polarsubstances effective inchronic inflammationm.
The ethanolic extradof the leaf of Vitex leucoxyIon showed significant inhibition of carrageenin paw oedema and granulation tissue formation in ratsqs. The aqueous suspensionof dried latex of Calotropis procera (Arka) showed anti-inflammatory property when tested in the carrageeninand formaiin induced rat paw oedema modelp. The roots and leaves of Butea frondosa (Palash) were evaluated for ocular anti-inflammatoryactivity in rabbits.The results showed that the gel formulatian of Butea frondosa leaves, prepared using a commercially available, pluronic F-127, reduced the intraocular pressure, decreased leucocytosis and miosis and. was comparable to flubiproten geP. The triglyceride fraction of oil of Ocimum sanctum (Tulsi) offered higher protection against carrageenin induced paw oedema in rats and acetic acid induced writhing in mice, as comparedto the fixed oilU. Fixed oil of 0cimum.sanctumand linolenic acid were found to possess significant anti-inflammatory activity against PGE,, leukotriene and arachidonic acid induced paw oedema. The anti-inflammatory activity of linolenic acid present in the fixed oil of Ocimum sanctum was probably due to Mockade of both, the cyclo-oxygenase and lipo-oxygenase pathways of arachidonic acid metabolism".
The methanolic extracts of the flowers of Michelia champam Linn. (Champaka), lxora brachiata Roxb (Rasna) and Rhynchosia cana Willd were found to possess'significant anti-inflammatoryactivity against cotton pellet induced subacute inflammation in rats. The latter 2 drugs showed higher activity as compared to Michelia champaca.They also reduced the protein content, acid phosphatase, glutamate pyruAlcoholic extract of Ochna obtusatastembark dem- vate transaminase and glutamate oxaloacetate onstrated potent anti-inflammatory effects in the rat transaminase activities in the liver and serum. These paw oedema and cotton pellet granuloma modelsn. properties are probably due to the presence of flavonoids in the flowers of these plantsq. All extracts of the root of Pongamiapinnata showed significant anti-inflammatory activity (compared to The methanolic extract of the aerial part of Sida phenylbutatone) in carrageenin and PGE, induced hombifolia(Atibala) showed significant oedema supoedema models. Possible mechanism of action could pressant activity in the carrageenin induced paw be prostaglandininhibition, especiallyby EE and AE. oedema model in rats. Probable mechanism of
254
MEDICINALPLANTS (NANRALPRDUCTS) action may be due to its inhibitory effects on release to be a less gastrotoxic anti-inflammatory agent as of mediators of inflammation such as histamine, 5- compared to other non-steroidal anti-inflammatory hydroxytryptamine, bradykinin etfl. agentsu. Gmelina asiatica(Gopabhadra) root powder was effective in reducing the oedema in the carrageenininduced rat paw oedema model of acute inflammation. When tested against the cotton pellet granuloma model of chronic inflammation, it not only reduced the weight of the granuloma but also the lipid peroxide content of granuloma exudate and h e r and gamma-glutamyltranspeptidase in the granuioma. It also normalisedserum albumin and serum acid and alkaline phosphatase levels. Probablemechanism of its anti-inflammatoryeffect may be its anti-proliferative, anti-oxidative and lysosomal membran'e stabilising effectsu. Studies have shown that, the methanol extract of Nelumbo nucifera rhizome as well as the steroidal triterpenoid isolated f rom it (betulinic acid), possessed significant anti-inflammatory activity when evaluated in the carrageenin and B-hydroxytryptamine induced rat paw edema models.The effects produced were comparableto that of phenylbutazone and dexamethasoneu. The water soluble part of the alcoholic extract of Azadirachta indicaexertedsig7ificant anti-inflammatory activity in the cotton pellet granuloma assay in rats. Levels of various biochemical parameters studied in cotton pellet exudate were also found to be decreased vk. DNA, RNA, lipid peroxide, acid phosphatase and alkaline phosphatase suggesting the mechanism for the anti-inflammatory effect of Azadirachta indicau. Alcoholic extract of the roots of Clerodendron serraturhshowed significant anti-inflammatoryactivity in the carrageenin induced paw oedema and cotton pellet granuloma models in ratss. The aqueous extract of Gymnema sylvestre leaves showed significant anti-inflammatory activity in the carraseenin induced rat paw oedema and mouse peritineat ascitis models..~, however, did not inhibit granuloma formation and related biochemical indicese such as bhO~proiine and cOmlagen. seen (as in the pith granuloma model) thus indicating that it did not interfere in the normal healing process. In addition, the extract did not affect the integrity of the gastric mucosa, even at high doses, thus appearing Sandhika, an Ayurvedic drug used in the treatment of rheumatoidarthritis showed significant anti-inflammatory activity when tested against carrageenin induced paw oedema and cotton pellet granuloma. Possible mechanism of action could be by free radical scavenging activitp. Treatment with Ease, a polyherbal formulation, significantlyduced Freund's adjuvant-induced nonestablished and established arthritis in rats. In vitm too, it provided significant protection against protein denaturation and RBC membrane damage and exhibited significant proteinase inhibitory action, thus indicating its possible use a$ an anti-arthriticm. Jigrine, another poiyherbaiformulation, exhibited antiinflammatory activity against carrageenin induced acute inflammation but not against cotton pellet granuloma (subacute inflammation). Effect on biochemical parameters suggested that the mechanism of its anti-inflammatory effect could be in its antioxidant and membrane stabilising effect".
2.8. Antipyretics
The ethanolic extracts of Ailanthus excelsa (Mahanimba), Toddalia asiatica (Kanchana) and Araucaria bidwilli (Monkey puzzle) showed moderate to significant degree of antipyretic activity in an experimental rat model of 20% yeast suspension inAndrographis elongata duced hyperthermia4@. showed more potent antipyretic activity when compared to Andrographis paniculata (Kalmegha)=. Methanolic extract of rporne of Nelumbo nucifera produced a significant dose dependent lowering of body temperature in normal rats and antipyretic effect in pyretic rats Rhynchosia cana showed significant antipyretic activity in ratsm. Alcoholic extract of the roots of Clerodendron serratum showed significant antipyretic activity following typhoidTAB vaccination in rabbitsn. mqantiWretic activity of TBR-002, a lation, was found to be almost equal to paracetamol in a rat model of pyrexia induced by su~cutaneous injection of yeast suspenoionu. As against these antipyretic plants, Panax ginseng showed hyperthermic effect and attenuated the
255
hypothermic response of reserpine and BHTP in- of GTE on neuromuscular junctions was found to be duced hyperthermia in animals1@. similar to that of GTE suggesting that the crude polyphenol content of GTE-W~S active constituthe 2.9. Neurotransmitter modulation ent responsiblefor its effect on neuromuscular iunclnvestiaation of the neurochemical effects of differ- tionu. ent fu&rial toxins elaborated from Fusariummonili- Beta-adrenoreceptormediatedtracheal relaxationor form and Fusariumoryspo~m showed that Fusarium the decreased responsiveness of the tracheal smooth monilifofmhad irreversible and nonspecific MA0 in- muscle induced by down-regulation of receptorswith hibitory activity comparable to nialamide*. terbutaline in guinea pigs was unaffected by Abana, Studies on the effect of BR-16A on adrenergic and dopaminergic functioning in rats showed that it did not interferewith or, -adrenergic and dopamine autoreceptor functioning. However, its effects on mqbility in the open field test following challenge with clonidine or apomorphine showed that it enhanced dopamine post-synaptic receptor activity*.
3 piants modulatlng autonomic and autacoid ac. tivity
a herbomineral formulation: This is probably due to lack of Abana's effects on B-receptorsof the airway. However, pretreatment with Abana increased potassium chloride-inducedcontractionsand increasedthe sensitivity to the relaxant effects of isoprenaline, terbutaline and aminophyllinefollowing such contractions, probably by enhancing membrane permeability to calcium ionss.
4. CVS active plants
Over the years,.the trend to evaluate agents modulating autonomic and autacoid activity is declining. However, importanceof using certain methodobgies like isolated tissue experiments to gather preliminary data regarding interactionof a plant product with host receptor systems remains unquestionable. Following are some of the attempts in this direction. . The effects of stem extract of Cuscuta reflexa (Amarvalli) resembled those of acetylcholine when tested on isolated rabbit ileum, frog rectus abdominis and heart and these effects were blocked by atropine. Effect of the extract on isolated frog rectus abdominis muscle was blocked by pancuronium and potentiated by neostigmine". Hot water extract of Camellia sinensis (Green tea leaf extract, GTE) had a facilitatory effedt at lower concentrations and a wralvtic effect at hiaher concentrations on skeleto~oto;function but d i n o t have any effect on direct twitch responses or on acetylcholine and KC1induced contractures of denervated rat diaphragm. In addition it antagonised the submaximal paralytic effect of d-tubocurarine and decamethonium.The effects of GTE were nullified in Since nifedthe presence of magn$sium~chloride. ipine reduced GTE-inducedfacilitation as well as inhibition of twitch responses, it has been suggested that GTE might act on Ca2* channels at the skeletomotorjunction.The effect of crude polyphenol
Researchin cardiovascular~harmacolog~ Past in the few Years has been mainly focused on agents with h~~oli~idaemic Properties and plant drugs are no exCeption.This section describesvarious agents that have been evaluated for their effect on the cardiovascular system.
4. Anticoagulant
,.
The petroleum ether and methanolic extracts of the leaf and oleoresin of Araucaria bidwilliishowedmarginal delaying effect on bleeding and clotting times at 1 hour interval in mbbits when tested usingWrightls and Dukes capillary tube methodn.
4.2. Hypolipidaemics
The ethanol extract and coicfaqueous infusion of Vita leuco~lon lowered serum total cholesterol levleaf els in mice1'. Gugulipid (an active principle of Commiphera mukul) is an agent that has been widely investigatedfor its hypolipidaemic activity. Co-administrationof gugulipid with propranololor diltiazem in normalvolunteers was found to decrease the bioavailability of both drugsu. Dried flowers of Adenocalymma alliaceumwhen fed at 2% levelfor 6 weeks to hypercholeste[olaemic rats, lowered serum cholesterol levels significantly, lowering the absorption of dietary cholesterol from the intestinesm.
256
MEDICINALPLANTS (NATURAL PRDUCTS) Semecarpus anacardium (Bhallatak, nut shell) extract also exhibited hypocholesterolemicaction and prevented cholesterol induced atherorna in hypercholesterolaemic rabbits3@. Similarly, Terminalia belerica (Bibhitak) reduced the levels of lipids in experimentally induced hypercholesterolaemiain rabbits. There was also a significant decrease in liver and heart liiddl. hypertensive animals, thus suggesting that it produces effects against ethinyl oestradiol induced hypertension by its syrnpatholyti~~property".
4.4. ACE (angiotensin converting enzyme) inhibitors
Seventy- five species of traditional medicinal plants belonging to 42 families have been investigated for their ability to inhibit the angiotensin converting enAdministration of ethanolic extract (50% vh) of Plum- zyme. Of these, 4 species were found to possess a bag0 zeylanica(Chitrak) root, alone and in combina- high ACE inhibiting ability and were low in their tantion with vitamin E, significantlyreduced serum total nin content@'. cholesterol, LDL cholesterol and triglyceride levels in experimentally induced hyperlipidaemic rabbitsa. However, DwivediNpointed out that the ethanolic ax- Rutin, a flavonoid, obtained from the plant, Sophora tract of Plumbagozeylanica root alone and with vita- japonica, markedly reduced the infait size and premin E lowered HDL cholesterol levels as well. Hence, vented the loss of theiR'wave in anaesthetized rats he has advised caution about its use in patients and subjected to coronary artery lig8tion. It, however, had confirmation of these findings through larger sample no effect on heart rate and systolic blood pressure. It also reducedthe ligaiion-inducedincrease in serum size studies. malonyldialdehyde levels and prevented the loss of Administration of cell culture extract of Hemidesmus glutathioneperoxidaseactivity. Rutin inhibited, in MID, indicus(Sariva) in rats also receiving an atherogenic luminol-induced chemiluminescence of rat PMN's, diet prevented hypercholesterolaemia~. thus indicating that its beneficial effect is probably due to its ability to impair the generation of reactive oxygen species". Preparationof the whole plant of Phyllanthusamarus (Bhuiamalaki) was administeredto 9 mild hyperten- 4.6. Positive ionotropics sive subjects for 10 days. The results suggest that it Vaidya70in his editorial, had raised4he issue on the is a potential diuretic, hypotensive and hypoglycemic, controversiesthat exist regarding ionotropic action9 drug for humansu. of Terminalia arjuna(Arjuna).Though there are studHydroalcoholic leaf extract of Azadirachta indica ies proving positive icnotroplc effects of this plant, caused a dose-dependent hypotensive effect. It did some scientists have observed negative ionotropic not alter the force of contraction or heart rate at low and chronotroplc effects as well. Hence, he had addoses in isolatedfrog heart, but caused a temporary vised more detailed experimental and clinical studies on the plant and its active principle. Data of placardiac arrest in diastolic at high dosesw. cebo-controlled clinical studies carried out subseThe petroleum ether extract of Abies pindrow leaf quently with this plant is presented below. showed significant hypotensive effect in anaestheWhen the bark extract of Terminalia arjunawas comtized dogs1*. pared to placebo in 12 patients with refractory CCF Treatment with Abana, a polyherbal formulation, in in a phase II clinical trial, it was observed that treatnormotensive rats produced significant lowering of ment with Terminalia arjuna was associated with an blood pressure. enhancement of vaso-pressor re- improvementin symptoms and signs of heart failure, sponses to low dose of noradrenaline (with no effect improvement in the NYHA class (from IV & Ill), deon dopamine $ hydroxylase activity) and no effect crease in echo-left ventricular end-diastolic and endon the vaso-depressor responses of acetylcholine systolic volumes indbes, increase in the left ventricuand isoprenaline. It, however, protected against lar stroke volume index and increase in left ventricuethinyl oestradiol induced hypertension and in- lar ejection fraction at the end of 2 weeks. Long term creased dopamine $ hydroxylass activity in these therapy (i.e. 24 months) too showed continued
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improvement in the signs and symptoms, effort tol- and Hirnachalol, a sesquiterpene alcohol, derived erance and NYHA class among the . patients7'. from the hexane soluble extract of the wood of Cedrus deodan (deodar) #, were found to possess signifiDwiiedi and JauhanR studied the effects of bark stem cant anti-allergic activity comparaMe to disodiurn powder of aquna, as to placebo, cromoglycatewhen tested in the experiments\ modon angina pectoris, CCF and left ventricular mass in els of passive cutaneous and mast cell 12 patients of myocardial infarctionwith angina and/ degranulation in rats. or ischaemic cardiomyopathy. Their findings indicate the potentialof Terminalia arjuna improving left ven- Similarly, hot aqueous extract of the bark of ~ l b i u i a tricular ejection fraction and reducing left ventricular lebbeck(Shirish)was found to possess anti-allergic properties in experimentalmodel of passivecutanemass in coronary artery disease. ous anaphylaxis and mast cell stabilization activit)rl. 5. Plants acting on respiratory system 7. Hypoglycemic plants Methanolic extracts of Drymaria cordata wilU and Leucas lavandulaefolia (Dronapushpi) were investi- A preparation of the whole plant of Phyllanthus effects in 9 gated for their effects on a cough model hduced by maruswas found to have hy~oglycemic sulfur dioxide gas in mice. Both exhibited significant human subjects, 4 of whom were diabeticsu. I anti-tussive activity, comparable to that of codeine n vitmstudies carried out by Rizvi haveshown phosphate and increasing concentrations .showed that epicatechin, an active constituent of Pte-rpus better inhibition of coughn7'. marsupium (Vijaysar)exerted a protective effect on Solanurn xanthocarpum (Kantakari) and Solanurn e~ythrocyte osmotic fmgility, similar to insulin, but by trilobatum(Alarka), the plants mentioned in Siddha, a different parametersof In streptozotocin induced diabetic rats, of the 3 imhave been shown (FVCl FEV** PEFR FEF25- portant phenolic constituents of the heartwood of pulmonary 75%) in asthmatic subjects with mild-moderate pterocarpus (vir.pterosupin, marsupin asthmaT5. and pterostilbene) marsupin and pterostilbene significantly lowered the blood glucose levels and the 6. Apt[-allergic plants metformin''. The Ethanolic extract of Vitex negundo(Nirgundi)of was effects were compsirable Pferocar~us marsupium found to inhibit immunologicallyinduced degranulation of mast cells better than that wt compound has been further evaluated in a multicentric (4 ceni, 40180. It also inhibited be oedema during active paw tres) flexible-doseopen trial in newly-diagnosedpaNair and saraf further stud- tients of non-insulin-dependentdiabetes rnellitusu. n anaphylaxis.in ied their effects on mediator release and smooth Control of blood glucose (both fasting and post-pranlevels) was in 67 of 97 patients (69%) muscle contractions of sensitized and non-sensitized dial was 2 g guinea pig trachea using antigen and compound 481 Studied in l2 weeks and the Optimum Of the extract. HbA1c decreas$ signifi80 respectively.The extract significantly innibitedboth n the initialand later sustained phases of trachea\con- cantly. No significant change was observed i the levelslipids. ' Of tractions.The initial phase was primarily due to histamine release which was blocked by the extrad (con- The chloroform elutedfraction O the petroleumether f firmed in guinea pig ileal studies).The latter phase extract of the root bark of Salacia oblonga Wall was due to release of lipid mediators from arachi- (Ponkoranti) and a fluorescent compound separated donic acid. Inhibitionof the latter phase may be sec- from it (by TLC) demonstrated hypoglycemicpotency ondary to inhibition of arachidonic acid by the eth- in rats when compared to tolbutamideM. anolic extract. The alcoholic extract of lnula racemosa
'
Arbortristoside A & C, derived from the alcoholic ex- (Pushkarmula)loweredblood glucose and enhanced tract of the seeds of NyctanthusaI;bortri~tis(Parijat)~, glycogen in rats. However, there was no increase liver two diterpenes, andrographolide and neoadro- in plasma insulin levels nor an increase in the degrapholide, isolated fromAndmgraphispaniculatam, gree of degranulation of beta cells of pancreas. Its
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MEDICINAL PLANTS (NATURAL PRDUCTS) action may be at the peripheral level by potentiating cept in rats with severe pancreatic damage, SW1 showed better blood glucose lowering effect cominsulin sensitiviv. pared to tolbutamide. Hot water extract of Camellia sinensis(Black tea leaf) significantly reduced the blood glucose level and was Ocimum album (Holy basil) leaves significantly defound to possess both preventive and curative ef- creased the fasting and post-prandialblood glucose fects in streptozotocin induced diabetic rats". levels in patients with NlDDM in a randomized, placebo-controlled, crossover, single blind triaP. AdminThe leaf extract of Azadirachta indica had no effect istration of Ocimum sanctum leaf powderto normal per se, on the peripheral utilization of glucose (de- and diabetic rats for a period of one month resulted termined by intravenous glucose tolerance tests) and in a significant reduction in fasting blood sugar, uronic on hepatic glycogen in normal and streptozotocin acid, total amino acids, total cholesterol, triglycerinduced diabetic rats. However, it blockedthe effects ide, phospholipidsand total lipids. Total cholesterol, of epinephrine on glucose metabolism and reduc- Jriglyceride and total lipids were significantly lowered tion in peripheral glucose utilization in diabetic rats in the liver, kidney and heart. They indicate the and to some extent in normal rats, indicative of an hypoglycemic and hypolipidemic effect of Ocimum anti-hyperglycemicpotential of the planta8. , sanctum in diabetic rats". Leaf extract of Aegle marmelos(Bilva) was found to Chronic administration of Prunus amygdalus (AloV significantly reverse the raised K, values, but n t , mond) seeds and its proportionatefractions viz. devalues of the enzyme malate dehydrogenase, an fatted seed and oil to rabbits demonstrated a definite important enzyme in glucose metabolism, in strep- hypoglycemic effect.The active factor seems to be a tozotocin induced diabetic rats. Alteration in the quali- non-oil fraction which is only partly soluble in ethyl tative and quantitative nature of the enzyme has been ethePs. .suggested to contribute to the pathological state of diabetes. The leaf extract was also effective in re- Significant hypoglycemic effect was observed with storing blood glucose and body weight to normal 1500 mgkg dose of juice of leaves of Lantana camara valuesw. In another studyw, leaf extract of Aegle in ratss. marmelos significantly reversed the altered (histo- The protective effect of Capparis decidua(Karir) paylogical and ultrastructural) parameters in tissues af der on oxidative stress and diabetes in alloxan instreptozotocin induceddiabetic rats seen by light and duced diabetic rats has been evaluated. The data electron microscopy to near normal and improved indicatethat Capparis decidua may have a potential the functional state of pancreatic beta cells. The use as an anti-diabetic agent, especially in chronic hypoglycemic effects of this plant drug thus appears cases as it helps in lowering the oxidative stress in t o be mediated through regeneration of damaged diabetes0'. pancreas. Dubey eta/," studied the effect of D-400, a polyherbal Oral administration of the methanolic extract (but not formulation, on blood glucose, blood urea and sethe water extract) of aerial parts of Artemisia pallens rum creatinine in alloxan-induceddiabetic rabbits. D(Daman) led to significant blood glucose lowering in 400 significantly prevented the rise in blood urea and glucbse fed hyperglycemic and alloxan induced dia- serum creatinine levels at the end of 36 weeks, thus betic rats. Increased peripheral utilisation of glucose showing promise against alloxan induced renal damis probably the mechanism responsible. Inhibition age.The rise in blood sugar too in the treated group of renal proximal tubular reabsorptionof glucose may was lower than the saline control. Further studies by also contributee'. Saxena et a1 ga compared the ef- Dhawan eta/," demonstrated that D-400, in diabetic fects pf mode of action of 3 structurally different rats, not only brought the raised blood glucose levhypoglycemic agents, tolbutamide, centpiperalonand els to within normal limits and raised the suppressed a swerchirin- containing fraction (SW1) from the plant glycogen levels, but also brought towards normal, Swertia chirata(Chirayata) in normal and streptozo- the decreasedI4Cglucose uptake by liver slices in in tocin induced mild and severe diabetes in rats. Ex- vitro studies.
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Trasina, an Ayurvedic herbal formulation, significantly 9. Plants promoting skin and bone healing reduced streptozotocin induced hyperglycemia and also attenuated streptozotocin induced decrease in Methanolic extract of Cissus quadrangularis superoxide dismutase activity of pancreatic islet cells (Asthishunkala) promoted the healing process of experimentally fractured radius-ulna of dogs as eviin male Charles Foster idtstw. denced by radiologicaland histopathologicalexami8. Anti- and pro-fertiliy plants nationsl".The treated group also exhibited a reduc- . tion in serum calcium kvels as compared to saline The second areawhich has been widely worked upon animals. in the field of endocrinology is the reproductive sys-Intra-dermal administrationof the essential oils from tern. the leaves of Eucalyptus hybrid and seeds of Seseli extract Of Bupleurum marginaturn was indicum increasedcutaneous capillary permeability found to have significantoestrogenic activity as seen when tested in blue treated rabbits. This efby the increased uterine weight and early opening fect may be beneficial in their probable wound healand cornificationof vagina in immature rats and his- ing activitylq. toloaical features of the uteruslol. Topical application of aqueous extract of latex of Praneem vilci, a highly purified oil of Azadirachta EuphonSia neriifolia (Nivadung) facilitated the healindicaseed, was found to be safe when administered ing of surgically produced cutaneous wounds in as a single intra-uterine instillation in 18 healthy guinea pigs as evidenced by an increase in tensile tubectomised women. No untoward effects were ob- strength, DNA content, epithelialisation and angioserved. The menstrual pattern and ovulatory status genesislw. remained unaltered and the endometrial biopsy was normal. In 10 of the above women who had also re- Only the aqueous extract suspension in 5% propylceived the HSD-hCG vaccine, co-administration of ene glycol of Centenella asiaticaas compared to the Praneemvilci did not prevent the antibody response other extracts (viz. alcoholic, petroleum ether, The leaves of Azadirachta chloroform, propylene glycol and glycosidal extract) to HSD-hCG vaccine1@. indica were found to have a reversible, anti-andro- promoted wound healing in experimentally induced open woundson topic.al administrationin rats as evigenic'properties in male rats1". denced by the increase in collagen content and thickEthanolic extract of Trichopus zeylanicum ness of epith$iumtoB. However, Suguna et dem(Arogyapacha in Tamil) leaf, when administered to onstrated that the alcoholic extract (oral and topical) male mice was found to stimulate sexual behaviour of Centenella asiatica improved the rate of wound as evidenced by an increase in number of mounts healing in rats. Sunilkumar etal,ltt showed that topiand mating performance. Chronic administration of cal administration of the aqueous extract increased the drug was more effective than a single dose.The cellular proliferation, promotedcollagen synthesis at pups fathered by drug treated mice were also found the wound site as evidenced by the increase in DNA, to be normal with respect to foetal growth, litter size protein and collagen content of granulartion tissue and sex ratioto4. and in tensile strength. The treated wound epithelialised faster and the rate of wound contracBenzene extract of Hibiscus rosea sinensis (Jaswand) flowers showed differing results when tion was higher as compared to control. Among the administered to adult and immature mice. In the various formulations (ointment,cream and gel) of the adults, it resulted in an irregular estrous cycle with aqueous extract, the process of healing was better prolonged estrous and metaestrous. An increase in with the gel formulation. the atretic follicles and absence of corpora lutea indicated the antiovulatory effect of the extract. However, in immature mice, the extract showed oestrogenic activity as seen by the early opening of the vagina. premature cornification of vaginal epithelium and increase in uterine weightto5. The extracts of four plants i.e. the leaves of Aloe Vera, root and root bark of Aegle marmelos and Moring oleifera and leaves of Trdaxprocumbeswere foun to promote wound healing in both normal an1 irnmunocompromised(steroidtreated) rats in a space wound model. The plants increased not only lysyl
SELYCT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS
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MEDICINAL PLANTS (NATURAL PRDUCTS) oxidase activity but also, protein and nucleic acid con- 12. Cytoprotective plants tent in the granuloma tissue thus indicating that the plants probably exert their action at the cellular (nu- 12.1. Ulcero- protectives clear) level. The plants also increased the tensile 12.1.1. Gastric and duodenal ulcers strength of the granuloma tissue probably as a result of the increase in the glycosaminoglycan con- The alcoholic, oleoresin and petroleum ether extracts 'tent.Thus the plants not onlv hastened normal heal- of leaf of Araucaria bidwillii showed moderate deing, but also reversed steroid depressed healing v2. gree of ulcero-protective activity in pylorus ligated rat model of gastric ulcerations8. Sunder vati, an Ayurvedic formulation was effective in the treatment of acne vulgaris as seen by the sig- Leaf and seed extracts of Vernonia lasiopusand Vernificant reduction in lesion count in patients with this nonia galamensis had antiulcerogenic effects when tested using either hydrochloric acid or ethanol as condition"'. the necrotising agent in rats2'. 10. Plants acting o n genito-urinary system The protective effect of hot water extract of black tea Ethanolic extract of Ammannia baccifera (Camellia sinensis) was demonstrate on ulcers in(Bhatjambol) was found to be effective in reducing duced in rats by various ulcerogens (NSAIDs, ethathe formation of urinary stones (prophylactic) as well nol, reserpine, 5-HT, histamine) and by cold restraint as dissolving pre-formed ones (curative) that were stress 5-HT and histamine. It altered the acid and induced by implantation of zinc discs in the urinary peptic activity of gastric secretionMn. bladders of rats. The stones formed were mainly of All four sitavirya plants viz. Sa!avari (Asparagus magnesium ammonium phosphate with traces of racemosus:fresh root juice, 1250 mg/kg),Yastimadhu calcium oxalate.Treatment with Ammannia baccifera (Glycerrhizaglabra: water decoction of root, 600 mgl also significantly reduced calcium and magnesium kg), Kutaja (Holorrhena antidysentrica : wafer levels114. decoctions of bark, 400 mglkg) and Aswattha (water decoctions of bark, 500 mglky) were were found to Lupeol and a number of its derivatives derived from have ulcero-protective effects against 2 hr cold reCrateva nurvala (Varun) were found to possess sigstraint stress ulcers, pylorus ligation-induced gastric nificant an!i-hyperoxaluric and anti-hypercalciuric and cystearnine-induced duodenal ulcers in rdts. activity when tested in rats against hydroxyprolii-le However, they were ineffective against acute aspiinduced hyperoxaluria and calci~rial"~. rin-induced gastric ulcers'1g. 11. Gastro-intestinal pro- and anti-kinetic plants All exqracts of the seeds of Pongamiapinnatashowed significant anti-ulcerogenic effect in fasting mice3.The The methanolic extract of rhizomes of Nelumbo nucifera showed significant inhibitory activity against petroleum ether(PEE), benzene and ethanolic(EE) extracts of the root of the same plant showed significastor oil induced diarrhoea and PGE, induced cant anti-ulcerogenic effect in the pylorus ligated rat entero-pooling in rats. It also showed significant reulcer model. The EE but not PEE decreased acid duction of gastro-intestinal motility in rats, thus indipepsin secretion and increased mucus secretion. cating its efficacy as an anti-diarrhoea1 agent116. PEE showed significant CNS deoression as menThree different dosage formulations (aqueous extract, tioned earlier, this probably relievjng stress induced dry powder and incinerated powder) of Emblica ulceration4. officinalis (Amalki) were evaluated for their effect on gastro-intestinal motility at different dose levels (210,420 and 840 mglkg) in mice. The dry powder and the aqueous extract showed pro-kinetic effect at all the 3 dose levels.The incinerated powder at lower doses, showed pro-kinetic effect, whereas at higher doses, it decreased gastro-intestinal motility"'. Bergenin and norbergenin, two isocoumarins, isolated from the leaves and roots of 'Flueggea microcarpa and luvangetin, a pyranocoumarin isolated from the seeds of Aegle rnarmelosCorrea, gave significant protection against pylorus ligation- and aspirin-inducedgastric ulcers in rats and cold restraintinduced gastric ulcers in rats and guinea pigs. The
S. A. DAHANUKAR at a/.,
gastro-protectiveeffects of bergenin and norbergenin could be due to increased prostaglandin production as demonstrated using human colonic mucosal incubates.This mechanismwas not responsible for the observed effects of luvangetinas it did not affect prostaglandin productioniz0. Ail extracts (petroleum ether, benzene, chloroform, acetone and ethanolic) of Abies pindrowleaf showed ulcero-protective effect in a model of cold ,restraint stress because of their anti-stress effects. The extracts contained terpenoids and flavonoids which were shown to have marked inhibitoryeffect on PAF. Flavonoids have also been shown to increase mucus secretion, prostaglandin synthesis and'blood flowye. Pretreatment wlth the aqueous extract of Emblica officinalisprotected against ethanol- induced and cold restraintinduced gastric damage in rats (evaluated by the Evan's blue method) 'I7. Cauvery 100, a polyherbalformulation, showed antiulcerogenic activity when tested against indomethacin induced ulcers in rats. It decreased the raised hexosamine and sialic acid levels in the ulcertowards normal, increased pepsin activity and gastrin levels and increased the uptake of titnted thymidine into the~lcer area, as compared to untreated animalsf2'. Similarly, another polyherbal formulation, UL-409, demonstrated significant anti-ulcerogenic activity in three experimental studies carried out separately by Mitra et a1 lZf. Vanisree et a1 lP and Kulkarni and Goel1%.
work related to hepato-protective effects of various formulations available in the Indian market. Bhatt and Bhattln have not only compiled the informationavailable regarding the studies on various promising plant drugs from India but also have discussed !he problems and pitfalls pertaining to this research. Some of the agents worth mentioning are as follows: Tinospora cordifolia, a plant which has been shown to decrease fibrosis in rats, induced by CCI,, was to significantly improved the' suppressed Kupffer cell function in another rat model of chronic liver damage induced by heterologous serum. This raises the possibility that anti-fibrotic effect of Tinospora cordifolia is mediated through activation of kupffer cells'". When administered during the pre-operatwe period to patients with obstructive jaundice, it was found to decrease the post-operative morbidity and mortality (due to sepsis and liver cell failure). This was associated with bolstering of phagocytic and intracellular killing capacities of polymorphonuclear tells.Though Tinospora cordifolia was found to significantly decrease the complications associated with pre-operative biliary decompression viz. sepsis and immunosuppression, the prognosis was found to better when Tinospora cordifoliawas instituted alone in preoperative period. These findings focus on the need to alter the preoperative management protocol for obstructive jaundice, by replacing the age-old procedure of biliary decompression by an immunomodulator129. basis for improved prognosis apThe pears to be the reduction in the incidence of endotoxaemia, as revealed from the stud\es in the rat model of cholestasis wherein Tinospora codifolia was found to decrease the mortality in cholestatic rats. Earlier the therapy following cholestasis, better were .the resultslm. Picroliv is a standardised preparatio6 of irioid glycosides, picroside-1 and kutkoside obtained from Picorrhiza kurroa. Both picroliv and silymarin, a flavolignan component of Silyburn marianum seeds were shown to stimulate liver regenerationin the early . stages when evaluated on partially hepatectomised rats. Both the drugs increased the levels of DNA, RNA, protein and ch~lesterol'~'.
12.1.2.Ulcerativecolitis
Gupta et a1 lZs studied the protective effect of Boswellia serrata in patients suffering from (grade II and Ill) ulcerative colitis. The stool characteristics along with histopathological, scan microscopical changes in rectal biopsies and blood parameters (haemoglobin, serum iron, calcium, phosphorus,proteins, total leukocytes and eosinophils) improved following treatment with Boswellia serrata gum resin preparation; the results being similar to sulfasalazine.
Picroliv administration in rats followio~ exposure to Two reviews have been published which cover most alcohol resulted in lowering of various biochemical of the works carried out in this field. Vaidya etal, Is parametersof liver and serum that were elevated with have reviewed the experimental and clinical research alcohol con~umption'~.protected against ethanol It
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(40%) induced toxicity in isolated rat hepatocyteslJf. lation Kumaryasava were found to stimulate de-
I also showed a dose dependent hepatoprotective effect against oxytetracycline induced hepatic damage in ratslM.The protective effect of picroliv against hepatic damage caused by Plasmodium bergheiinfection in Mastomys cauchawas studied by Ramesh et alia5.Treatment with this drug significantly reversed the changes in lipid metabolism induced by Plasmodium berghei. It reactivatedthe plasma and liver lipolytic enzymes, stimulated the binding of LDL with the liver receptors and enhanced the faecal excretidn of bile acids, thus resulting in a return of circulatory lipoproteins towards normal.
pressed hepatic enzyme activities such as hepatic arginase, cathepsin 6, acid phosphatase and ribonuclease in CCI, induced liver damage indicating that these drugs have a protective effect on hepatic enzyme activityq4'
Liv. 100 is an improvisedherbal formulationof Liv52. In an in vitro study combination of Liv52 and Livl00 reduced the peroxidation effect of hydrogen peroxide in rat liver homogenate. The protective effect of these drugs was attributed to the enhanced supply of reduced glutathione that inhibited the deleterious process of lipid peroxidation.This suggested the antiSantra et a/,'% demonstrated that treatment with oxidant potential of Liv. 52 and Liv. 100'". SimultanPicrorrhiza kurroa in carbon tetrachloride treated eous administrationof Liv-100with the anti-tubercumice significantly reversed the altered serum ALT, lar drugs, INH, rifampicin and pyrazinamide showed AST, liver GSH, total thiol, glucose 6 phosphate significant protection against hepato-toxic effects of dehydrogenase (GGPD), catalase and membrane the anti-tubercular drugs in ratsi*. ATPase levels. Histopathological lebound Na+/K+ sions of liver and lipid peroxidation were also signifi- The hepato-protective effect of Jigrine, an Unani cantly less in drug treated animals. Probable mecha- polypharmaceuticalherbal formulationcontaining 14 nism of action of Picrorrhiza kurroaappears to be its medicinal plants, was evaluated in 3 models of heeffect as a free radical scavenger and inhibitor of li- patic damage induced by either alcohol, carbon tetrachlorideor paracetamolin rats. Jigrine significantly pid peroxidation of liver plasma membrane. reduced the increased serum transaminases, biThe diterpenes, andrographolide, andrographiside lirubin, prothrombintime and liver lipid peroxide conand neoandrographolide,isolated from Andrographis tent and also improved the histopathological findings. paniculatademonstrated anti-oxidant effects in CCI, The authors have attributed its hepato-protectiveeftreated mice. Neoandrographolide was as effective fect to its anti-oxidant property1". Further studies caras silymarin with respect to its effects on reduced ried out on Jigrinc by the same group showed that it glutathione, glutathione 5-transferase, glutathione also reduced the levels of gamma-GTP,triglycerides peroxidase and superoxide dismutase and lipid and lipid peroxides in the liver, confirming its mernperoxidation whereas andrographiside had mainly brane stabilising and antioxidant proper tie^'^^. anti-lipoperoxidant activity'". Administration of the aqueous extract of Andrographis paniculatato mice The importance of morphological features and time suffering from liver damage induced by hexachloro- of collection of raw material-canbe understoodfrom cyclohexane (BHC) that ultimately leads to tumor for- a study conducted by Rawat eta/,'& at the National mation, significantly lowered the raised enzymes Botanical Research Institute.The effect of seasons, (SGPT, SGOT, alkaline phosphatase) and raised the root thickness and dosage forms (aqueous or powlowered protein concentration. The results confirm der) on the hepato-protective activity of Boerrhavia the hepato-protective property of Andrographis diffusa (Punarnava)was evaluated in thioacetamide paniculata and suggest its probable role in delaying intoxicated rats. Results showed that aqueous extract of roots of diameter 1-3 cms, collected in May the hepatic tumorigenic conditioni3*. (Summer) exhibited marked protection as deterhlined Administration of Liv-52, a polyherbal formulation, by assessing serum enz)';nes viz. SGOT, SGPT, ACP significantly improved ethanol metabolism in a rat and ALP, but not GLDH and bilirubin. Furthermore, It also model of chronic alcohol administrati~n'~~. pre- the studies have shown that the aqueous form of the vented lipid peroxidation in CCI, induced liver dam- drug has more hepato-protective activity than the age as seen by a significant decrease in malondial- powder form, probably due to better absorption of dehyde content". Both, Liv-52 and another formu- the liquid form.
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A novel non-invasive parameter has been developed for by Visweswaram et al, la screening of drugs that may protect against CCI, induced hepatotoxicity in rats. In these rats, urinary excretion of ascorbic acid is reduced. Measurement of urinary excretion of ascorbic acid thus serves as a parameterfor hepatoprotective effect of a drug.
equimolar concentrationsof sitoindosidesVII-X and withaferin A induced a dose-related increase in superoxide dismutase, catalase and glutathione peroxide activities in rat brain frontal cortex and striatum, comparableto deprenyl, a known antioxidantIs2.
Oral administration of anti-oxidants viz. curcumin, ellagic acid, bixin and alpha-tocopherol significantly Hepatoprotectiveeffects of other medicinal plants that decreased lung collagen hydroxyproline and thus y have been evaluated in various models of liver dis- lung fibrosis in rats following whole b ~ d irradiation. They also lowered serum and liver lipid peroxidation eases are given in Table 1. and liver superoxide dismutase activity and increased catalase activity-Theyalso decreased the frequency The protective effect of Ernblica officinalisin experi- of micronucleatedpolychromatic erythrocytes seen mentally induced acute necrotising pancreatitis in after whole body irradiation in mice1=. dogs has been evaluated by Thorat et al, IU. Emblica The water extract of leaf of Ocimumsantumwas more officinalis inhibited the increase in serum amylase effective and less toxic, as compared to aqueous caused by pancreatitis. Microscopical examination ethanol extract, in improving the survival rate in mice, showed that the acinar cell damage and total inflam- when administeredintra-peritoneally before a whole matory score was significantly less in dogs pretreated body exposure to 11Gy of 60 Co gamma radiation. with Emblica officinalis. Tee intra-peritoneal route gave the best protection as compared to intra-muscular, intra-venousor oral routesIY. Withania somnifera prevented mylosuppression induced bv one or more of the following 3 compounds, cycloph~sphamide, azathioprine or prednisolone, as Leaves of Ocimum sanctum delayed the onset as seen by a significant increase in haemoglobin cont well as the subsequent maturation of cataract sigcentration, RBC and WBC counts, platelet count and nificantly in 2 models of cataract i.e. galactosamic body weight and hemolytic antibody responses to cataract in rats and naphthalenecataract in rabbits1". human erythrocytesiq. 12.7.Membrane stabilizers The leaf and root extracts of Vernonia lasiopus and Oral administration of Rasayana group of drugs (from Vernonia galamensisdemonstratedprominent in vitro Ayurveda) were found to significantly increase total membrane stabilising property as determined by the WBC count. bone marrow cellularitv. natural killer cell percentage inhibition of RBC lysis n. and antibddy dependent cellula; cytotoxicity in gamma radiation exposed mice. Rasayana'sreduced 13. Plahts protecting against oxidative sfress radiation induced lipid peroxidationin liver1*. 13.1. UV light induced Methanolic extract (75%) of Withania somnifera (a plant belongingto the Rasayana group of drugs) sig- Sobatum, purified from the plant Solanum trlobatum nificantly increased the WBC count in normal Balblc (Alarka) showed significant protectionin vitro against mice and reducedthe leucopenia induced by suble- UV light induced damage by free radicals on the bacthal dose of gamma radiatioct It 4so increased bone teria Salmonella typhimurium. Similarly, it also promarrow cellularity and normalised the ratio of tected against superoxide production that was gennormochromatic to polychromatic erythrocytes fol- erated by the reaction of photoreduced riboflavin and lowing radiation. Withania somnifera probably exerts oxygen1%. 13.2. Cumene hydroperoxideinduced its effects by stimulating stem.cell Active principles of Withania somniferaconsisting of Tamra-bhasma, an organo-mineral compound from
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MEDICINAL PLANTS (NATURAL PRDUCTS) Ayurveda, showed significant protection against tion of reduced glutathione, but at higher concentracumene hydroperoxide inducedlipid peroxidationand tions, it enhanced the rate of oxidation. lowered reduced glutathione and superoxide dismutase levels in rat Liver homogenate. It also sig- 14. Chemotherapeutic plant products nificantly reducedmalondealdehyde (MDA) levels. No Plants which have shown anti-microbial, anti-fungal, alterations in biochemical and histopathologicalpa- anti-viral, anti-protozoal and anti-helminthic effects rameters was noted.The rssults thus suggested that have been described in this section. Standard astamra bhasma is a potent anti-oxidant drug and can says have been used by various investigators and be used in the management of lipid peroxidationln. most of the work has carried out in vitro. Similarly, Sandhika, an Ayurvedic drug was evalu- 14.1. Anti-microbialagents : ated in vitro using the same model (cumene hydroperoxide) and showed significant antioxidant Clausenol, a carbazole alkaloid, isolated from an alcoholic extract of the stem bark of Clausena anisata activip. was found to be active against gram positive and 13.3. Iron induced 'gram negative bacteria and fungitg1.
Anti-peroxidative property of Nardostachys jatamanasi(Jatamanasi) was tested in vitro by using iron induced lipid peroxidation in rat liver homogenate.The degree of peroxidation was quantitated by thiobarbituric acid reactive substance (TBARS) con? tent. Both the hexane and alcoholic extracts provided protection against lipid peroxidation(the hexanefraction was more potent) suggesting that the plant does have anti-oxidantacti\,itylm. Rubiadin, a dihydroxy anthraquinone, isolated from alcoholic extract of Rubia cordifolia (rnanjistha) demonstrated significant anti-oxidant property as it prevented lipid peroxidation induced by FeSO, and t-butylhydroperoxide (t-BHP) in a dose depended manner.The percent inhibitionwas more in the case of Fez+induced lipid peroxidation. The anti-oxidant property of the preparation has been found to be better than that of EDTA, mannitol, Vitamin E and pbenzoquinonel". The potential of Bacopa monniera as an antioxidant l The was studied by Tripathi e a/, lM. effect of the alcoholic and hexane fractions of Bacopa monniera on FeSO, and cumene hydroperoxide induced lipid peroxidation was studied. The alcoholic fraction showed greater protection against both that inducers and the results were comparable to known antioxidants like vitamin C. Probable mechanism of action could be through metal chelation at the initiation level and also as a chain breaker suggesting that Bacopa monniera is a potent anti-oxidant. The responses with Bacopa monniera were found to be dose-dependent. At low doses, it only slightly protected the auto-oxidation and FeSO, induced oxida-
Substantialanti-microbial, anti-fungal and moderate insecticidal, sporicidal and cytotoxic activities were observed with the hexane extract of the stem bark of Amona glabra. Chromatographicfractionation of the stem led to the isolation of kaur-16-en-19-oicacid, which was found to be largely responsible for the biological activities The alcoholic extract of dry nuts of Semecarpus anacardium(Bhal1atak)showed bactericidal activity in vitro against 3 gram negative strains (Escherichia coli, Salmonella typhi and Proteus vulgaris) and 2 gram positive strair?s (Staphylococcus aureus and Corynebacteriumdiphtheriae). Subsequent studies have shown that the alcoholic extracts of different parts of the plant (leaves, twigs, green fruit) also possess anti-bacterialproperties, especially the leaf extract. No derrnatoxic effect (irritant property) was observed in the mouse skin irritant.assaytb3. No anti-bacterial activity with any extract of either the root or seeds of Pongamia pinnatawas noted3.'. The acetone and alcoholic extracts of the leaves of Cassia alata showed significant in vitro anti-bactea ial activity against Staphylococcus aureus, coagulase positive Sfaphylococcusaureus, Bacillussubtilis, Bacillus cereus, Bacillus stearothermophilus, Escherichia coli, Salmonella typhi and Salmonella. dysentriae. In addition, the alcoholic extract also inhibited growth of Klebsiella pneumoniaewhereasthe acetone extract inhibited the growth of Vibrio cholerael". Due to a lack of ideal diffusion and evaporation from the surface it is generally difficult to assess the
265
anti-bacterialpropertiesof aromatic oils derived from plants using the agar cup and disc diffusion methods. Hence, Agnihotri and Vaidya lU to develhave oped a novel approach to study the anti-bacterial property of certain plants like Eugenia caryophyllus, Thymus vulgaris, Cinnamonum zeylanium and Cuminum cyminum. Volatile components of the hexane extracts of these plants were tested against standard gram positive an6 gram negative bacteria grown on agar slants and the results were expressed as percentage inhibitionof the area of the slants. Of the 4 Plants selected, Thymus vulgaris had the most prominent anti-bacterial activity.
Ricinus communis (Erand) (75%) and Lawsonia inermis (74.33%) while the minimum activity was exhibited by Jatropha curcas (lOO/~). The essential oil isolated from the leaves of Aegle marmelos exhibited significant anti-fungal a c t i h against different fungal isolates and 100% inhibition of spore germination of all the tested fungi when eval'uated~~in~ the spore germination assay. Kinetic studies showed that the inhibition was both concentration as well as time dependenttn.
Four compounds have been isolated from an extract preparedfrom the fruit rind of Terminalia belerica viz. termilignan, thannilignan (both lignans), 7-hydroxy14.2. Anti-fungalagents 3',4'-(methylenedioxy) flavone and anolignan B. All The ethanolic extract of Azadirachta indica leaves possessed demonstrable anti-HIV-1, anti-malarial, demonstrated much more significant anti- and anti-fungal activity in vitro172.1n. dermatophytic activity as compared to the aqueous extract, when tested in vitro agains?88 clinical iso- The natural xanthones isolated from the fruit hulls of lates of dermatophytes using the agar dilution tech- Garcinia mangostana showed good inhibitory activnique.The MIC90 of ethanolic extract was 100 pg/ml ity against the three phytopathogenicfungi, Fusarium whereas that of aqueous extract was 500 pglmllw. vasinfectum, Alternaria tenuis, and Dreschlera oryzae. Substitution in the A and C rinqs in the deFour Siddha drugs viz Nandhi mezhugh, Parangi rivatives of mangostin obtained by has been shown pattai choornam, Erasa kenthi mezhugu and Vaan to modify the bioactivities of the compound^"^. mezhugu (in order of efficacy) were found to have significant anti-fungalactivity when tested against 14 The petroleum ether, chloroform, acetone and ethanol ( 5 ) extracts of the leaves of Cassia alafaalso 9O strains of Candida albicansl". showed significantin vitro anti-fungal activity against Essential oil obtained from the herb of Santolina various fungi viz. Aspergillus niger; R. japonicum, chamaecyparissus showed significant anti-fungal Candida albicans, C. tropiathis and R. g l ~ t i n i s ~ ~ ~ . activity both in vitro (against 13 strains of Candida albicans) and in vivo (experimentally induced vagi- The root of Withania somnifera was found to be efnal and systemic candidiasis in mice)16', It also fective in prolonging the survival of Balblc mice inshowed activity against experimentally induced su- fected intravenously with Apergillus fumigatus. This perficial cutaneous mycoses in guinea pigs by the protective activity is probably due to the observed hair root invasion testq6*. Anti-bacterial activity was increase in phagocytosis and intracellular killing caalso observed as seen by its inhibitory effects on the pacity of peritoneal macrophages induced by treatgrowth of Staphylococcus aureus, Bacillus subtitis, ment with Withania somnifera, thus suggesting that the plant has the potential to activate macrophage BaciNus caerus and Escherichia coli. function in infectious states176. Rai 170screened 17-medicinalplants against the test pathogen, Pestalotiopsis mangiferaeand the results 14.3. Anti-viralagents revealed that 14 plants had anti-mycotic activity Although initial studies by Thyagarajan et a/, In with whereas 3-plants, vir 4rgemone mexicana, Phyllanthus amarus showed promising results in Caesalpinia bonducelraand Casia fistulaaccelerated Hepatitis B carriers, further studies have demonthe growth of the pathogen. Maximum antimycotic strated that the plant does not clear the hepatitis B activity was shown by Eucalyptusglobulus(88%) and surface antigen (HbsAg) in asymptomatic carriers of Catharanthus roseus (88%) followed by Ocimum the antigen17'. However, recently, in an in vitrostudy, sanctum (85.50%), Azadirachta indica (84.66%), the aqueous extract of Phyllanthus amarus was
MEDICINAL PLANTS (NATURAL PRDUCTS) . Table 1 Illustrates the other plants that have been evaluated in various models of liver diseases and the parameters selected for their evaluation. PlanWPlant derived agents (Author) Methanolic extracts of the seeds of Apium graveolens Linn. and Hygrophiliaauriculata H Damaging agent (Animals)
) ) rats Thioacetamide )
Parameters of evaluation Uver functlon tests (AST, ALT, alkaline phosphatase, sorbitol dehydrogenase. glutamate dehydrogenase and.bilirubin). Hepatic triglycerides, Histopathology. Liver function tests, Histopathology. Hepatic total lipids, triglycerides, phospholipids, free fatty acids Liver function tests, Liver glycogen content. Serum cholesterol. Histopathology. Liver function tests, Histopathology. Liver function tests, Histopathology. Liver function tests (AST, ALT). Blood and hepatic giutathione levels. Hepatic lipid peroxide content Histopathology. . Liver function tests
Paracetamd
50% alcoholic extrad of
Phyllanthus embljca and its isolate. q~ercetin~~~ Garlic oilsm Swertia chiratSn
Country made liquor ingestion (rats). Paracetamd (mice) Radioc?lcium (micer CCI, (rats)
Ethyl acetate extract of Acacia catechu (katha) 2n Leaf extract of Glycosmis pentaphylf13 Propolis. a natural resin produced by honey bees, rich in flavonoids2" Powdered roots and aerial parts of Sjda rt~ombifolia their ague and Plant leaf suspension and methanolic extract of Trichopus ~ e y l a n i c u 3 ~ Methanolic extract of Tiichopus zeyianicus 27s
CCI, (rats) CCI, (rats) Alcohol and CCI, (rats)
C I paracetambl and C, rifampicin (rats) Paracetamol (rats)
Liver function tests. Histopathology. . Hepatic and lipid peroxide contents. Cholerectic activity
Normal rats
incubatedwith the Alexandar ceH line, a human hepatocellular carcinoma derived cell line which has the property of secretingthe Hepatitis B surface antigen (HbsAg) in the supernatant. The results demonstrated that Phyllanthus amarus was effective in inhibiting the secretion of HbsAg for 48 hrs thus proving its anti-hepatitis B virus property at the cellular level1m.
-.
Glycyrrhkaglabra (Yasthimadhu) was tested against RNA viruses like the Chandripura virus, Measles virus, Polio vaccine viruses type 1,2 and 3, Polio wild type viruses 1, 2 and 3 as well as DNA viruses like the Herpes type 1 and 2 viruses in vitro. It inhibited the DNA virus plaque formation at lower concentrations (0.608 mM) while the RNA viruses were inhibited at higher concentrations (1.216 mM) Im.
I8l
Glycyrrhizin, a triterpenoid glycoside obtained from Premanathan et a/,
carried out in vitro screening
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S. A. DAHANUKAR at a / ,
of mangrove plant extracts for anti-immunodeficiency virus activity. HIV infected MT4 cells were incubated with the extract and anti-viral activity was detected using tetrazolium-based colorimetric assay. Seven extractswere found to be effectivefive of which (bark of Rhizophora mucronataand leaves of Excoecaria agallocha, Ceriops decandra, Rhizophora apiculata, Rhizophoralamarckit) completely inhibitedthe virus adsorption to the cells.
14.4.Anti-protozoal agents 14.4.1. Antimalarial :
14.5. Anthelminthic agents

14.5-1. Anti-Nematodes
Kumar et a1ln studied the mechanism of action has of palasonin, the active principle of Butea frondosa seeds onAscaridia gallL Palasonin inhibited glucose uptakeand depletedthe glycogen content1" and thus the possible mechanism of A anthelminthic action s may be relatedto inhibition of energy metabolism. Both aqueous and alcoholic extracts of the leavesof SencionudicaulisBuch Hamwere found to exert antifilarial activity ,when tested against Setaria cervi (Nematoda Filarioidea).The effective concentrations differed for the aqueous and alcoholic extracts suggesting the presenceof a cuticularpermeabilitybarrier. Both extracts also demonstrated micro-filaricidal action in vitro.Their anti-filarial responses were similar to diethylcarbamazinein that they too did not block the stimulant effeot of acetylcholine on the wormlu.
Ethanolic and petroleum extracts of Artemisia japonica, Artemisia maritimia and Arlemisia nilegaricawere tested for anti-malarial activity, both in vivo and in vitro. In vivo studies were carried out in Balblc mice using the Rane test wherein all the compounds prolonged the survival time of the mice. In vitro, all 3 compounds inhibited schisont maturation in chloroquine sensitive strains of Plasmodium falciCo-administrationof Rbgulipid, a herbal formulation, parum'=. *with diethylcarbamazine therapy to patients sufferBall shaped wood scrappings soaked in 5% Neem ing from filariasis was found to decrease chyluria ir oil (Azadirachtaindica) diluted in acetone and placed these patients1". in water storage overhead tanks controlledthe breedMustafa et allwinjectedthe excretory-secretojpoding of Anopheles stephensiandAedes aegyptiin45 ucts released by the adult Setaria cervi, a bovine days1*'. Similarly, application of a cream of filarial parasite, into rabbits to raise polyvalentantiAzadimchta indicaon exposed body parts at the rate bodies.The$eantibodies can be used to detect circuof 2.0 gm/person significantly protected against lating antigens in sera by counter immuno-electroAedes, Culex and Anopheles musquitoe biesIu. phoresis and serve as a diagnostic test for filariasis. The methanolic extract of Swertia chimta was found to inhibit the catalytic activity of topoisomerase Ienzyme of Leishmania donovani. On subjecting the extract to fractionation, it yielded 3 secoiridoid glycosides, amarogentin, amarohwerin and sweroside of which amacogentin was found to be a potent inhibitor of topoisomerase I and exerted its effect by interactingwith the enzyme, thus preventing binary complex formation1-.
14.5.2. Anti-Trematode (fluke) The root tuber extract of Flemingia vestita, an indigenous medicinal plant in Meghalaya, exhibited antihelminthicactivity in vitro, against 2 species of flukes, Artyfechinostomum sufrartyfex and Fasciolopsis buski. It caused paralysis in both the spedes. Stereoscanning observations on the tegumental surfaces revealed sloughing off of most of the spines or their deformation and wrinkling and rupture of the general tegument1". 14.5.3. Agents with molluscicidalactivity
Crude 50% ethanolic extract of Parthenium hysterophorus flowers exhibited trypanocidal activy nsm ip evansi both in vitro and in ity against 7aoo a vim. Toxicity was seen only at 1g / kg doselm.
The leaf, bark, cake and oil of Azadirachta indicaand synthetic pesticides derived from the plant domonstrated both, dose and time dependent, molluscicidal activity when tested against the snails, Lymnaga
acuminata and'lndoplanorbis exustus. The cidal effect of pure azadirachtinwas greaterthen that of the synthetic mollusci~ides~~.
15. Anti-mutagenic plants
thymidine uptake studies, thus demonstrating its anti- ' cancer The anti-tumor effect of the crude extract of Centella asiatica as well as its ~artially purified fraction was studied in both, in vitro short and long term chemosensitivity test systems and in vivo tumor models. The purified fraction inhibited the proliferation of transformed cell lines of Ehrlich ascites tumor cells and Dalton's lymphoma ascites tumor cells more significantlythan the crude extract. It also significantly suppressed the multiplication of mouse lung fibroblast cells in long term culture. In vivo administration of both extracts retarded the development of solid and ascites tumors and increased the lifespan of the tumor bearing mice.Tritiated thymidine, uridine and leucine incorporation assays suggest that the purified fraction acts directly on DNA synthesis1". The methanol eluted fraction of the petroleum ether extract of the root bark of Salacia otilonga Wall showed 100% cytotoxicity on Ehrlich ascites tumor cellsM. Fresh root suspension of Janakia arayalpathra exhibited strong anti-tumor effects in mice challenged with Ehrlich Ascitic Carcinoma (EAC) cells. It prolongedthe survival of all mice and protecteda number of mice from tumor growth, probably by enhancing the activity of the immune systemtgg.
Punark, a mixture of solvent extracts of natural products, namely turmeric (Curcuma tonga), betel leaf (Piperbetel) and catechu (Acacia catechu) protected against benzo (a) pyrene inducedchromosomaldamage in human lymphocytes in vitro '=. Alcoholic extracts of tumeric oil (TD) and tumeric oleoresin (TOR) showed anti-mutageniceffect in vitro.They also demonstrated chemoprotective effect in lymphocytes of normal healthy subjects in vitrowhen tested against benzo (a) pyrene induced DNA damage. In vivo the extracts reduced DNA damage (cytogenetic damage) in oral mucosalcells of patients with oral submucous Water, oil and alcoholic extracts of nuts of Semecarpus anacardiumwere found to be anti-mutagenic when tested against benzo (a) pyrene (BZP) in the bacterial test system using Salmonella typhimurium strainsTA98 andTA100. The water ex. tract was less-effectiveas compared to the oil and alcoholic extracts. In addition, the water and alcoholic extracts showed anti-mutaginic effect when tested in lymphocyte cultures of normal healthy volunteers'". Ellagic acid, a fraction isolatedfrom Terminalia arju'na has been evaluated for it anti-mutagenic potential in TA98 and TA100 strains of Salmonella typhimurium against direct and indirect - acting mutagens. The f.raction was quite effective against S9-dependent 2AF while it showed moderate effect against NPDigg.
16. Anti-cancer plants
Withaferin A, a steroidal lactone isolated from the roots of Withania somnifera, reduced survival of V79 cells in a dose-dependent manner.The applicability of this drug as a radiosensitizer in cancer therapy needs to be exploredzo0. Banerjee etal, have studied the modulatory influence of the alcoholic'extract of leaves of Ocimum sanctum on various enzyme levels in the liver, lung and stomach of mouse. Oral treatment with the extract significantlyelevatedthe activities of cytochrome P450, cytochrome b5, arylhydrocarbon hydroxylase and glutathione S-transferaseenzvmes. all of which are important in the detoxificationof carcinogens as well as mutagens. Moreover, it also significantly elevated extra-hepatic glutathione S-transferase and reducedglutathione levels in the liver, lung and stomach. These observations suggest that the leaf extract or its active principles may have a potential role in the chemoprevention of chemicalcarcinogenesis.
The potential role of various plants in cancer therapy as either a direct anti-canceragent, chemopreventive agent, radiosensitizer or immunity enhancer is presented in the following paragraphs. Evaluation of the in vitro anti-cancer effects of bioflavonoids, viz. quercelon, catechin, luteolin and rutin against human carcinoma of larynx (Hep-2) and sarcoma 180 (S-180) cell lines showed that only luteolinand quercetin inhibited the proliferationof the cells. Luteolin caused depletion of glutathione in the cells and a decline in DNA synthesis, as seen by 3H
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S1W S. A DAHANUKAR et EL.
Studies conducted by Rao eta/, have shown that pergularinine (PgL) and tylophorinidine (TPD) isolated from Pergulada pallida are potently toxic and inhibit the growth of Lactobacillus leichmannii cells by binding to thymidylate synthetase.The binding led to significant inhibitionof thymidylate synthetase activity making them potential anti-tumor agents.
lighted the therapeutic potential of immunomodulatory angets from plant products. They have evaluated Indian medicinal plants for immunomodulatory activityz0'. The authors have also reviewed the Ayurvedic concepts of preventive health care. A list of Ayurvedic medicinal plants showing immunomodulatoryactivity has been provided which includes agents like Withania somnifera, Allium sativum, Petroleum ether.extract of Hygrophilic spinosa ex- Azadirachta indica, Piper longum, Asparagus hibitedanti-tumor activity in Ehlrich ascitic carcinoma racemosus, Glycyrrhiza glpbra, Aloe vera, Gmelina and sarcoma 160 bearing mice MS. arborea and Tinospora cordifolia. Aqueous extract of Podophyllumhexandrum, a herb Thatte and Dahanukar, *0 have described how clues from the Himalayas, demonstrated significant anti- from the description of ancient writings can lead to tumor effects when drug was tested in strainlA'mice the development of new immunostimulatoryagents. carrying solid tumors developed by transplanting The experiments carried out to prove the rasayana Ehrlich ascites tumor cells. Radioprotective effects concept of Ayuweda have demonstrated that Asparawere also seen when the drug was administrated to gus racemosus, Tinospora cordifolia and Withania mice before whole body lethal irradiation of 10 GyzM. somnifera protected animals against infections in The chemopreventive efficacy of Trianthema portulacastrum L.Aizoaceae was tested in male Sprague-Dawley rats. Hepatocarcinogenesis was induced by the potent carcinogen diethylnitrosoamine (DENA).Treatment of the rats with aqueous, ethanolic and chloroform fractions of the plant extract at a dose of 100 mgtkg once daily reduced the incidence, numerical preponderance, multiplicity and size distributipn. of visible neoplastic nodules. Morphometric evaluation of focal lesions showed a reduction in number of altered liver cell foci per square centimeter as well as of average area of individual lesion. A decrease in the percentage of liver parenchyma occupied by foci seems to suggest the anti-carcinogenic potential d the plant extract in DENA-induced f hepatocarcinogenesiszM. Pretreatmentwith Ocimum sanctumleaf extract followed by the addition of 7,12-dimethylbenzIa1anthracene (DMBA) significantly blocked the formation of DMBA-DNA adducts in primary cultures of rat hepatocytesin vitro.The viability of the cells was not adversely affected by the extractm.
17. Immune active plants
normal and immunosuppressed states induced by hemisplenectomy or surgery2j0.These plants also produced leucocytosiswith predominant neutrophilia and prevented, to varying degrees, the leucopenia induced by cyclophosphomide. They were found to activate the polymorphonuclear and monocyte-macrophage systems. Only those rasayanas which produced sweet (madhur) vipaka (Tinospora cordifolia, Asparagus racemosus, Emblica officinalis, Terminalia chebula and Withania somnifera) were found to stimulate the reticulo-endothelial system, but not those like Acorus calamus, Commiphora mukuland Picorrhiza kurroa, which produced bitter (katu) vipakaZt0. Among the immunostimulant rasayanas, Tinospora cordlfolia has been extensivelvstudied bv Dahanukar et a1z,ql. It has been found td activate ihe mononuclear cells to release cytokines like GMCSF m2 and IL-1 in a dose dependent manner "O. Whole aqueous extract of Tinospora cordifolia, standardized using HPTLC, has been evaluated as an adjuvant in clinicalconditions like obstructivejaundice, tuberculosis and cancer chemotherapy and has been found to increase the efficacy of conventional therapyti0. Active principles of Tinospora cordifolia were found to possess anticomplementaryand immunomodulatory activities. Syringin (TC-4) and cocdiol (TC-7) inhibited the in vitro immunohaemolysis of antibody coated sheep erythrocytes by guinea pig serum by inhibiting the C3-convertase of the classical
Modulation of the immune response through stimulation or suppression may help in maintaining a disease free state. Agents that activate host defence mechanisms in the presence of an impairedimmune responsiveness can provide supportive therapy to conventional chemotherapy. Upadhyap7 has high-
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complement pathway.The compounds also gave rise to significant increases in IgG antibodies in serum. Both humoraland cell-mediatedimmunity were dosedependently enhanced. Macrophage activation was reportedfor cordioside (TC-2), cordiofoliosideA (TC5) and cordiol (TC-7) and this activation was more pronouncedwith increasing incubation times21a.
to have irnmunostimulatory properties in mice. It stimulated an increase in humoral antibody titres and also of antibody secreting spleen cells in the plaque forming cells assay following immunisationwith sheep erythrocytes. It also increasedthe number of perito- . neat macrophages and produced an increase in delayed hypersensitivity reaction in mice lge.
The effect of Asparagus racemosus, Tinospora The alkaloidal fraction of Boerrhiva diffusa significordifolia, Withania somnifera and Picorrhiza kurroa cantly restoredthe suppressed humoral response in on macrophage function obtained from mice treated stressed rats as observed by Mungantiwar et a1,218 with the carcinogen, ochratoxin (OTA) was evaluated wherein Boerrhiva diffusaincreasedthe suppressed with by ~hule~~l'.~reatment these plants significantly antibody titres following immunizationby sheep RBCs attenuated the OTA-induceds u ~ ~ r e s s i o nchemo- in rats subjected to restraint stress. It also signifiof tactic activity as well as IL-1 arid TNF-a production cantly reversed the depleted adrenal cortisol level by macrophages. Moreover, Withania somnifera po- and the elevated plasma cortisol level in the stressed rats, thus appearing to have a corticosteroidsparing tentiated 'macrophage chemotaxis and ~ s ~ a r a $ u s racemosus induced excessive production of TNF-a effect in experimental stress.. as compared to controls. Immune-21, a polyherbal natural'product, has been Ray etaI2l5 demonstrated that ovalbumin immunized shown to exhibit significant irnmunopotentiatingand mice treated with Azadirachta indicaleaf extract had immuno-prophylactic activity, both in vitro and in higher IgG and IgM levels and anti-ovalbumin anti- vivdq9. body titres as compared to control (humoral response). Azadirachta indica also induced cell medi- 18. Adaptogens ated response as seen from the enhancement of Adaptogen is a term used to describe agents that macrophage migration inhibition and footpad thick- increase the nonspecific resistance of organisms ness. These findings were supported by Ansari against a variety of stressors. A recent review on etal, n6.They found that Azadirachta indicapotenti- adaptogens, 211 describes the developments taking ated the antibody titres following typhoid H. antigen place in this field and the problems associated in'the immunisation and induced delayed hypersensitivity evaluation of adaptogens. following administration of tuberculin and DNCB to animals. In human volunteers, it stimulated humoral In a series of experiments the whole, aqueous standimmunity by increasing antibody levels and cell me- ardised extracts of Tinospora cordifolia, Asparagus diated immunity by increasing total lymphocyte and racemosus. Emblica officinAlis. Withania somnifera. T-cell count in 21 days. Piper longum and Terminalia chebula, were admin: istered orally to experimental animals, in a dose exOral pretreatment with leaf extract of Azadirachta trapolated from the human dose.These animals were indicareversedthe inhibitory effect of restraint stress exposedto a variety of biological, physical and chemion formation of anti-sheep RBC antibody titres in cal stressors.The plants were found to offer protecrats immunized with sheep RBC and also the intion against these stressor9I1.All the plants reversed crease in foot pad thickness. It reversed the DDT the effects of cisplatin on gastric emptying, while induced suppression of antibody response and leuTinospora cordifoliaand Asparagus racemosusalso cocyte migration inhibition in tetanus toxoid immunormalised cisplatin induced intestinal hyper-motilnized rats. Restraint stress dong with administration ity, complying to the definition of an adaptogen.They of DDT in subthreshold doses resulted in an inhibiwere found to be safe in both acute and subacute tion of the immune response. Azadirachta indica attoxicity studies. All of them produced immunostimutenuated the immunotoxicity of environmental and lation211. The type of extract (methanolic extract of xenobiotic stressorsm7. Withania somniferawas more active) and time of adRoot suspension of Janakia arayalpathrawas found ministration (the best effects were observed only if
SELECT RESEARCH PAPERS ON EVIDENCE BASED A URVEDIC DRUGS Y
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S102 S. A. DAHANUKAR et aL,
given as pre-treatment) also influenced the effects. o f these plants Emblica officinalis strengthened the defense mechanisms against free radical damage inducedduring stress.The effect of ErnWica officinalis appeared to depend on the ability of target tissues to synthesize prostaglandins. On the other hand, gastroprotective effect of Tinospora cordifolia was probably mediated through a predominantly immunostimulant mechanismas the protectionwas found to disappear on blocking the macrophage function. In normal mice, high doses of Tinospora cordifolia significantly increased apoptosis in bone marrow cells. The therapeutic doses (100-200 mglkg) were devoid of such effect. However, at the same therapeutic doses, it inducedapoptosis in malignant cells, but protected the normal bone marrow from apoptosis induced by cyclophosphamide. This variable effect of Tinospora cordifolia (of increasing or decreasing apoptosis) depending on the stressor (either cancer or cyclophosphamide) as well as the cell type (S180 or bone marrow cells) suggests its true potential as an adaptogen. It is of further interest to note that Tinospora cordifoliaincreases the bone marrow proliferative fractions at 100 and 200 mglkg doses thus leading to leucocytosis. If the dose is increased, apoptosis is observed and the leucocytosis is blunted. This apparent paradox may be due to its effects on c-myc.'a gene that causes both proliferation as well as induces apoptosis depending on the environment. It is exciting thus to hypothesise that Tinospora cordifolia may be producing some of its effects via activation of c-myc and inducing'genotypic'adaptation. Ocirnum sanctum, known to have antistress properties, was,recently studied by Sembulingam et al, 220 for its antistress effects against a different type of stress Le. noise pollution, in rats. The ethanolic extract of Ocimum sanctum reversed the changes in plasma levels of corticosterone induced by exposure to both acute and chronic noise stress, indicating the antistress property of the plant against noise. Studies have been reported in the literature to explore the possible mechanisms responsible for adaptogenic effect. For example, Panax ginseng did not modify brain and hypothalamic 5HT levels in unstressed rats, however, it attenuated restraint stress induced elevation of 5HT levelsa.
19. Nutraceutics
This is an emerging field of therapy. As we come to the end of this millennium, more and more people are getting health conscious and are looking at dietary substances for preventive or curative effects. Support towards this line of thinking from the scientific field is described in the follcwing paragraphs.
19.1. lndian spinach (Beta vulgaris)
Dietary consumption of green vegetables has been associated with protection against mutagenic and clastogenic activity of genotoxicants. Chlorophyll, present in all green plants, has been suggested to be the principal factor involved. Sarkar et a/,2a compared the clastogenic or anticlastogenic effects of crude aqueous extract of leaf of Indian spinach, (Beta vulgaris L. var. benghalensis Hort.) and equivalent amounts of chlorophyll extracted from leaf, purified chlorophyll and chlorophyllin (a sodium copper derivative). After treatment for 7 days, the mice were administered potassium dichromate, a known metallic clastogen and sacrificed 24 hrs later. Cytogenetic end points were chromosomal aberrations and damaged cells. Results showed that both crude leaf extract and chlorophyllin were nonclastoqenic and reduced the clastogenic effects of dichromate. However, chlorophyllwas clastogenic.The protective effect of the crude leaf extract was attributed to the total effect of the interaction between the different components within the leaf extract, thus neutralising the clastogenic effects of chlorophyll.
19.2.Karela (Momordia charantia)
Substitution of groundnut oil with palmolein in cereal based lactovegetarian diets provides about 30% of total fa4 calories, doubles the saturated fatty acids and reduces by half the linoleic acid confent. The hypoglycemic activity of the alcoholic extract of the pulp of Momordia charantia (Karela) was evaluated in 3 experimental models of diabetes. In the normal glucose primed rat model, it decreased plasma glucose that was not accompanied by increase in insulin secretion. No evidence of tachyphylaxis to its effects on repeated dosing was found. In streptozotocin induced diabetic rats, it improved glucose tolerance and significantly reduced plasma glucose. The extract also increased the rate of glycogen synthesis fromt4C-glucose by 4-5 fold in the liver of
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MEDICINAL PLANTS (NATURAL PRDUCTS) normal rats. All the results suggest that the mecha- 19.5.Fenuareek(Traonel1afoenum araecum) . nism of action of Momordia chF,hntiacould be partly Administration of unroasted and roasted powdered attributedto increased glucose utilisation liver in the forms of seeds of figonella foenum graecum (fenurather than an insulin secretion effectP5. areekl to alloxan induced diabetic rats Droduced a 19.3.Edible oils signif;cant fall in various serum lipids like total cholesterol, LDL andVLDL cholesterol and triglycerides Ghafoorunissaet al, studied the effects of the subin normal rats and in addition, increased HDL thostitution of palmolein oil for ground nut oil on selected lesterol in diabetic rats2ag. cardi~vascular factors and membrane furictions risk in middle aged subjects.The effects were essentially 19.6. Curry leaf (Murraya Koenigii) and Mustard similar with both treatment regimes.This studv indi- (Brassica iuncea) cates that palm oil may not the deleterious effects associated with saturated fatty acids=. The Whole curry leaf (Murraya Koenigil) and mustard author further explained that the tocols present in (Brassicajuncea) fed to rats at doses equal to norpalm oil are natural biological anti-oxidantssand can mal human 'intake did not cause any adverse effect therefore augment the anti-oxidant potentialof Indian on food efficiency ratio, haernatologicalparameters, diets. Also, red palm oil is the richest natural source liver and renal function tests, fibrin level and of carotenes (especially beta-carotene) which are glycosylated haemoglobin. No histopathological powerful biological anti-oxidants and hence, red palm changes were observed in the livePo. Both, plants oil can be used to preventvitamin A deficiencywhich showed significant hypoglycemicaction in rats. There was an increase in the concentration of hepatic glyis widespread in India. cogen and glycogenesis and a decrease in glycogA study conducted by Kumar, ruled out the asso- enolysis and gluconeogenesis ciation of increased incidence of coronary heart disease (CHD) with the high consumption of coconut The status of lipid peroxidation was investigated in and coconut oil in Kerala. Since their consumptionof rats fed Murraya Koenigiiand Brassicajuncea. Concoconut and coconut oil and saturatedfats and found centration of malondialdehydeshowed a significant that both groups did not differ in 32 CHD patients decrease, while hydroperoxides and conjugated dienes were significantly increased in liver and heart and 16 age and sex matched healthy controls. of both the experimental aroups. Superoxide 19.4.Turmeric (Curcuma lonaa) dismutase and c'atalase activiiv was found to be in-. creased in liver and heart of bdth the spices adminCurcumin (from Curcuma longa) protected against istered groups. Glutathione levels in liver, heart and decrease in heart rate and blood pressure and biokidney were lowered in rats administered these spechemical changes in cat heart 'Oronary artery cies. Glutathione reductase, glutathione peroxidase ligation. Italso prevented the elevation Of MDA and glutathioneS-transferaseactivity showed a sharp tent and lactatedehydrogenaserelease in the ischae- increase in the experi?lental group to the mic zone. However, it did not prevent the increase in controls2n. myeloperoxidase activity, indicating that curcumin protects against ischaemia induced chanaes bv in- 19.7. Mint leaf (Mentha s~icata) creasing the antioxidant defense Mint leaf has been shown to have significant stimuDeshpandeet a/, 226 demonstratedthat both pre-treat- latory effect on the lipase activity of pancreas and ment as well as concurrent treatment of turmeric intestinal mucosa in rats. It also stimulated intestinal extract in CCI, treated rats caused a reduction in amylase activity2=. It, however, had no effect on bile cholesterol, bilirubin, SGOT, SGPT and alkaline phos- secretion and its composition. phatase activity; concurrent treatment offering more 19.8. Onion (Allium cepa) significant protection. The anti-mutagenic activity of Curcurnin has already Augusti2" in his review on the therapeutic values of been described under the section 'Anti-mutagenic onion (Allium cepa) and garlic (Allium sativum), has plants'. discussed the presence of many sulfur containing
273
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A DAHANUKAR et a/.,
active principles mainly in the form of cysteine de- 19.10. Ginger (Zingiber officinalis) rivatives in onion and garlic, that are responsible for the various biological activities such as anti-diabetic, The acetone and 50% alcoholic extracts of Zingiber antibiotic, hypocholesterolaemic and fibrinolyticm officinalis (ginger) exhibited significant anti-emetic activitv with the acetone extract beina more effective than ihe ethanolic extract against thesis induced 19.9. Garlic (Allium sativum) by 3 mgkg cisplatin in healthy mongrel dogszN.These S-allyl cysteine sulfoxide, isolatedfrom garlic (Allium findings suggest that ginger could be an effective and sativum)* has been shown to be as active as gugulipid cheap anti-emetic adjunct to cancer chemotherapy. in controlling hypercholestermia, obesity and derangement of enzyme activities in cholesteroldiet fed 19.11.Nutmeg (Myristica fragrans) . rats.The beneficial effects are partly due to its inhibitory effects on transaminases, alkaline phosphatase, Myristica fragrans(nutmeg) seed cxtract administralipogenic enzymes and HMG CoA reductase and tion to hypercholesterolemic rabbits reduced both partly due to stimulatory effects on plasmaJecithin- total and LDL cholesterol, lowered the cholesterol1 cholesterol acyl ttansferase lipolytic enzymes and phospholipid ratio and elevated the decreased HDLfecal excretion of sterols and bile acidsm. Further ratio significantly. This extract also prevented the studies by these authorsm showed that the treat- accumulation of cholesterol, phospholipids and ment also reversed the lipid peroxidation and triglycerides in liver, heart and aorta and dissolved decrease in reduced glutathione levels, Superoxide atheromatous plaques of aorta. Fecal excretion of dismutase and catalase activities in cholesterol fed cholesterol and phospholipid were significantly increased in these rabbitsz4'. rats. extract Of M rsi a yi tc fragrans Garlic oil stimulated lipase activity only in the intesti- The rial mucosa and reduced pancreatic trypsin and thy- strated significant hypolipidaemic effects in experimotrypsin activities. Like mint, garlic also did not show mentally induced hyperlipidaemia in rabbits. It lowered the lipoprotein lipid levels, total cholesterol, LDL any effect on bile secretion and compositionm. cholesterol and triglycerides. HDL cholesterol was Garlic protein diet or daily administration of garlic oil not significantly affected. Total cholesterol:HDL and ta 2% cholesterol fed rats controlled significantly the LDL: HDL ratios were also significantly lowered. It increases in sulphated glycosaminoglycans in their loweredthe level ofiotal cholesterol in the heart and heart and aorta. However, hyaluronic acid level in- liver and demonstrated platelet antiaggregatory accreased. UDPG dehydrogenase decreased and sev- tivity2". era1 degrading enzymes increased in the aorta on treatment.The effects of treatment were just the re- 19.'2. (Piper nigrurn and longurn) verse in liver.The high percentage of cysteine in garlic Piperine, [1-[5-[1,3-benzodioxol-5-yl]-1-0xo-2,4, Protein and the reactive disulphide group in the oil pentadienyl] piperidine], a pungent alkaloid present in Piper nigrurn Linn, and Piper longurn Linn. has may be responsible for their beneficial effectsa7. 60th garlic protein (16% of diet) and $arlic oil (100 been shown to enhance the bioavailabilifyof various mgtkglday) exhibited significant lipid lowering effects structurally and therapeutically diverse drugs.Data in rats fed with cholesterol diet. The hypolipidemic obtained from intestinal everted sacs studies sugaction is primarily due to a decrease in hepatic gest that piperine is absorbed very fast across the cholesterogenesls in the treated rats. Even though intestinal barrier through the transcellular pathway. It garlic oil was found to be more effective, the garlic may act as an apolar molecule and form apolar cornprotein is more palatable and free from an obnox- Plex with drugs and solutes. It may modulate membrane dynamics due to its easy partitioningthus helpious smellw. ing in efficient permeability across the barrierszu. Administration of water soluble proteins of garlic to Trikatu, a combination alcohol fed rats caused a significant increase in However, in another studyzd4, antiperoxide activity and decrease in activity of glu- of Piperlongurn, Piper nigrurnandZinglber officinalis tathione peroxidase and gluthathione S-trans- was found to decrease the bioavailability ot isoniazid ferasP. in rabbits as measured by the alteiation of peak
274
MEDICINALPLANTS (NATURALPRDUCTS) plasma concentration (C,) curve (AUC). levels and area under methoxy-3-methylcarbazole and 1.6-dimethoxy-3methyl carbazole, respectively, from physical and chemical evidence and syn!hesis. Clausenol was 19.13. Betel leaf (Piper betle) found to be active against gram-positive and gramThe influence of &o varieties of betel leaf (Piperbetle negative bacteria and fWJfim. . . Linn.) namely, the pungent Mysore and non-pungent 20.2. lebbeck Ambadi, was examined on digestive enzymes of pancreas and intestinal mucosa and on bile secretion in Three main saponins named albiziasaponins A, B experimental rats. The results indicated that while and C were isolated from the bark of Albizia lebbeck these betel leaves do not influence bile secretion and and their structures were established through speccomposition, they have a significant stirnulatory in- tral analyses. These may be responsible for the fluence on pancreatic lipase activity. The Ambadi antiallergic properties of Albizia lebbeckZ4'. variety of betel leaf has a positive stimulatory influence on intestinal digestive enzymes, especially 20.3-ocimumsanctum lipiise, amylase and disaccharidases whereas a slight ' Gas liquid chromatographic analysis of fixed oil of lowering in the activity of these intestinal enZytlleS Ocimum sanctum revealed the presence of five fatty was seen when Mysore variety of betel leaf was ad- acids (stearic, palmitic, oleic, Iinoleic and linolenic ministered.The latter variety also had a negative ef- acids) which in further studies, demonstrated signififect on pancreatic amylase. Further, both the betel cant anti-inflammatoryactivityJ53. leaf varieties have shown decreasing influence on pancreatic trypsin and chymotrypsin a c t i v i t i e ~ ~ ~ . 20.4. BacoPa monnier'
a
The anti-mutagenic potential has already been de- Chemical characterization of the plant, Bacopa monniem has been carried out by Garai et alzWNg. scribed earlier in this chapter. Three new dammarane-type triterpenoid saponins, 19.14. Mowrah (Madhuca latifolia) bacopasaponins A,B and C and a new damtype pseudojujubogenin glycoside* bacOpa Mowrah (Madhuca latjfolia) seeds are used as aniSaponin D have been isolated and identified by ma1feed as they 40-50% edible fat and the transand contains saponins besides protein and high level s~ectroscOpic of formations. carbohydrates.However, the seeds were found to be toxic when administered to young and adult rats at levels of 10 to 40% in diet. The animals showed marked inhibition of feed intake and loss of body weight resulting in mortalities. Histopathological examination revealed a gradation of damage from slight erosion of the tip of villi of intestinal mucous membrane tacomplete necrosis and destruction of it, with increasing amounts of mowrah seed meal in diets. The other significant change was a severe vacuolar degeneration of kidney tubular cellszu.
20.5. Cerpegia juncea
From the chloroformextract of finely chopped, shade dried whole plant of Cer~egia luncea cerpegin has been derived which is the active principle responsible for its analgesic propertiesJ0.
20.6. Ochna obtusata '
Column chromatographyof chloroform extract shadedried and powdered stem bark of Ochna obtusata afforded an orange compound, crystallisedfrom ac20. ~h~tdchernistr~ etone which gave elemental analysis, IR, UV, HNMR Following are some of the studies carried out to find and MS data corresponding to Prezewalskinone-B. This is probably the active principle that is responsiout the active principle of plants. ble for the analgesic and anti-inflammatory proper20.1. Clausena anisata ties of the plantZ5O.
Two new carbozole alkaloids, designated as 20.7. Camelliasinensis clausenol and clausenine, were isolated from alcoholic extract of the stem bark of Clausena anisata. Air-dried roots of Camellia sinensis were extraTheir structures were established as 1-hydroxy-6- cted by percolation with methanol at ambient
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S. A D H N K R et el., AAUA
temperature. Sobnt extraction, chromatography and hydrolysis procedures progressively yielded 3-0-p D-glucopyranoso-a-spinasterol.Further studies will have to be carried out to correlate these principles with the pharmacological (hypoglycaemic and ukeroprotective) activities of the plantm.
20.8. Phytolectins
plants (Araucaria bidwilli, Brachylepsis nervosa), plants with analgesic activity (Araucaria bidwilli, Brynopsis lacinosa, Cyclea peltata, lp~moea obscura, Mirabilis jalappa. Santolina chamaeccyparissus, Stephania japonica), anti-inflammatory plants (A. boustanianum, Araucana bidwiIIi, Bauhinia variegate, lberis amara, lpomoea obscura, Mirabilis jalappa, Santolina chamoeccyparissus,Stephania
Lectins are structurally diterse, carbohydrate binding proteins that bind reversibly to specific mono-or oligosaccharides. They are being used by the biomedical scientists and biochemists in blood typing and stimulation of cell for chromosome analysis and gene mapping, in cell separation, identification of complex glycoproteins and typing bacteria. Cell tatgeting by lectins in cancer therapy is still in its infancy. Sengupta et a/, ZP have reviewed the potential of these biomolecules in medicine.
jaPOnd, Thunbe~ia fmgrans), antiPYretic plants (Araucaria bidwilli, Malvastrum commandelianum, Rumexnepalensis, Santdlena chamaeccyparissus, Stephamiajaponic~m, Toddalia asiatica), plants with local anaesthetic activity (Mirabilis jalappa), plants affecting~ 1 0 0 t h muscle (relaxant effect) (Amucaria bidwilli, Bauhinia wriegata, Brachylepsis nervosa, Calotropis gigantea, Cardiospermum helicacabum, ImPomea obscura, hlalvastrum commandelianum; Melianthus major, Rubia cordifolia, Stephania japonica, Thunbergia fragmns), chemotherapeutic Lectin activities in roots, nodules, Stems and leaves agents (Brachylepsis nervosa, Calotropis gigantea, of 1-6 week old Peanut Plant (A.h.Ypogaea) were lpornoeaobscura), plants modulating fertility (Ailanchecked by erythrocyte (human and rabbit) aggluti- -thus excelsea), CVS active plants (Cystisus scoparnation and sugar inhibition assays. Human and rab- ius, cystisus scoparius), diuretic plants (cystisus bit erythrocyte agglutinating activities Were specifi- scoparius, Sida cordifolja, Toddalja asiafica), tally inhibited by lactoselcellobiose(SLII) and me- ulceroprotectives (Araucaria bidwilli, Malvastrum thy1 al~ha-mannoside respectively. Seed em- coromandelianum, Santolina chamaeccyparissus), bvos and cotyledons agglutinated f~euraminidase anti-diarrhoea1plants (Bauhinia variegata, Ipomoea treated human erythrocytes and that activity was in- obscura, Malothriaperpusilla, Thunbergia fragrans), hibited by T-disaccharide. In the roots of field grown haemostatic plants (A houstanjanum, Toddalia plants SLI was the major activity, while nodules asiatica) and effect on biochemical parameters showed both activities (SLI and SLII). Specific ac- (Amarantus spinosus). tivities of SLI and SLll were maximal in stem tissue conducted ethnomedical field and minimal hypocotyl. Actively growing tissues con- Bhandary, et al, n 69 tajned mote SLll activity in comparison to the ma- study O 98 medicinal preparations, in~~lvingSpe ture tissues. Immunological tests indicated that all ties of Plants. used by the Siddis of Uttara Kannada the vegetative tissue lectins are serologically re- in the state of Karnataka.Their findings include 40 hitherto unknown medicinal uses of known medicilatedm. nal plants. Among these, the use of the stem sap of 21. Miscellaneous Calamus thwaitesii as an antifertility drug, and the 21.1. Reviews on medicinalplants use of the flowers of lchnocarpus frutescensandthe rhizome of Hedychium coronarium in the treatment It beyond the scope ofthis chapter to IustiB review of diabetesare noteworthy.Awal w have dearticles that have been published in the last 5 years. scribed the results extractsscientific endeavours in of their of 266 botanically idenFor the benefit of the readers, the articles are sum- which the alcoholic
in the fol'Owing paragraphs. An interested reader may refer to them for detailed information.
Suresh, et a/, have investigated the phytochemical and pharmacological activities of 25 medicinal plants, commonly used by the tribals of Nilgiris, using various experimental models viz., CNS-active
sied plant materials from 222
species were tested for various biological activities including chemotherapeutic and pharmacological.~i~hty-nine extracts were shown to possess biological activity. Follow-up studies have been carried out on some of these plants with confirmed activity. The active
SELECT RESEARCH PAPERS a?; EVIDENCE BASED AYURVEDIC DRUGS
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MEDICINAL PLANTS (NATURAL PRDUCTS) principles and resultsof these studies have also been discussed.The chemistry, pharmacology and traditional medicinal uses of various Vernonia species, also called as sahadevf, (viz. Vernonia cinerea, Vernonia anthehelmintica, Vernonia amygdalina, Vernonia lasopiusetc.) have been reviewed by Johri and SingW. Pharmacoepidemiologicalsurvey carried out by Karandikar et al,' in adults over 60 years of age revealed that about 47% of the elderly population uses herbal drugs.The main reasonfor herbal drug usage is the belief that these drugs have lesser side effects. Sharathchandraand Balakrishnamurthv have studied the mode of action of Cleistanlhuscollinus, a toxic plant that is frequently implicated in poisoning. Cleistanthuscollinuscauses depletion of thioVthiol containing enzymes in most organs which results in its toxicity. Thiol compounds may act as antidotes.
Administration of the juice of Lantana camara leaves to rats resulted in a significant reduction in the total protein, globulin, absolute lymphocyte count and percent lymphocytecount. Significant increase in the relativeweights of adrenals was also observed. High doses (1500 mg/kg) significantly inhibited granuloNazarine, et al, 'U have screened two hundred and matous tissue formation in rats, similar to cyclophossixty extracts from marine organisms collectedfrom .phamidem. thewestern & Easterncoastsof India, Lakshadweep and the Andaman and Nicobar Islands, for their ef- The polyherbal drug, Prostina, recommendedfor use fects on 3 isolated tissues of the guinea pig namely, in benign prostatic hypertrophy showed no toxic efthe ileum, the uterus and the atrium with the aim of fects as seen on morphological, gross behaviour, detecting any anti-spasmodic, oxytocic. uterine re- body weight changes and histopathological, biolaxant, ionotropic and antiarrhythmic activity. Anti- chemical and haematological changes in rats upto spasmodic activity was observed in 22 extracts, ec- doses of 450 mglkg, which is 15 times higher than bolic activity (spontaneous contractions in isolated the recommended dosP1. uterus) in 59 samples, uterine relaxant activity in 16 22. Elemental analysis of plants drugs/formula. samples and antihistaminic and anti-SHT activity in tions 6 samples. Various Indian medicinal plants viz. Ocimum sanc21.2. Toxicity studies tum, Tinospora cordifolia, Azadimchta indica, Nerium andicum(Kanher) and Acorus calamus (Vacha) were Toxicity studiestarevealed that LD50 of the ethanol ~ extract of V i t leucawylonleaf was more than 3 glkg analysed for the presence of minor and trace elewhereas that of the cold aqueous infusion was 1050 ments by instrumental neutron activation analysis mgkg. L , of the ethanolic extracts was found to (INAA). Concentrations of 13 elements were deterD be 1 gmlkg for Ailanthus excelsa, 350 mglkg for mined. Zinc, manganese, and sodium were signifiToddalia asiaticaand 250 mgikg for Araucaria bidwilli cantly higher in Ocimum sanctum leaves while zinc was higher in Azadimchta indica leaves. The theram oral administration, in rats4@. peutic significance of these plants in restoring ionic Cerpegin, a furopyridine alkaloid isolated from the balance has been discussed by the authorsm. chloroformextract of Ceropegiajuncea was found to In a similar study, specific parts of several plants be toxic at doses above 400 mg/kg and the mice (fruits, leaves, stem, bark and roots) often used as showed excitation, irritability, convulsions and respimedicines in the Indian Ayurvedic system have been ratory paralysisw. analysed by Singh and Gargm for 20 elements (As, The effect of multiple doses of the petroleum ether Ba, Br, Ca, CI, Co, Cr, Cu, Fe, K, Mn, Mo, Na, P, Rb, extract of Hygrophilia spinosaon the haematological Sb, Sc, Se, Sr and Zn) by employing INAA.The samand biochemical parameters and hepatorenalfunc- ples were irradiated with thermal neutrons in a nutions of normal mice was evaluatep. The results clear reactor and the induced activity was counted showed that weekly moderate to high dose levels using high resolution gamma ray spectrometry. Most (above 40 mg/kg) and daily high dose (8 mg/kg) af- of the medicinal herbs have been found to be rich in fected liver and kidney functions and metabolic and one or more of the elements under study. Similarly, haematologicalparameters. Lower doses did not al- elemental analysis of some herbal plants used in the control of diabetes has been done by the techniques ter them.
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of Neutron Activation Analysis (NAA) and Atomic Absorption Spectroscopy(AAS). The elements Mn, Na, CI, Al, Cu, Pb, Nl. Cr, Cd. Fe, Ca, Zn and Hg were found to be present in different plants in various proportionsl".
23. Modem correlates for standardisation
Wih the advances in cellular biology, a shift towards studyingchanges in cytosolic enzyme atiiities, DNA patterns and genetic control has been observed rather than concentrating merely on the gross effects induced by the plant drugs, In addition to the proper utilization of technological advances, a logical interpretationof the codifiedlanguage of traditional medicine also becomes a necessity in order to further promote research in this field. The work done on rasayana group of plantsa\ is a good example of the above statement. Here, the authors have attempted to interprete the word 'rasayana'in mddern scientific terminology and have , taken into considerationthe advocated uses for this groupof plants as per Ayurvedic textbooks while de'signing their research protocol.This understanding triggered the subsequent research work that was aimed at evaluating the immunostimulant potential of the rasayana group of plants and now, we have indigenousimmunostimulants available, at affordable rates, in,the Indian market.
An attempt has been made by Uchil eta/" to develop a battery of standardization tests using mpdern technotogy for commonly used organometallic preparations (bhasmas) and comparethem with the Ayurvedic tests. Seven preparations of copper bhasma manufactured by different companies were screened using both the methods. The results revealed that on6 3 preparations could fulfil at least 3 of 4 criteria as described in Ayurvedic textbooks. However, all of them differ with respect to particle size, bulk densities, copper content and presence of chemical groups and complexes when tested using modern correlates. None of them showed presence of elemental copper. These data reveal the necessitv of deve\oomentot modern correlates for standardisation of kyurvedic formulationto add precision However, there is a flip side too: to quality control, to detect false claims and adulteraVery few articles published in the last 5 years have tion and to predict their adverse drug reactions. provided adequate information on the procedures adapted by the researchersfor quality assurance of 24. Conclusion the plant products. Any publication related to phyWe see a definite change in the pattern research topharmacology should ideally provide on the on medicinal plants. Our findings are listed below : authenticationand standardisationof the plant prodThere is a growing interest in correlating phytochemi- ucts. cal constituents of a plant with its pharmacological ~ oall the research areas selected by the scientists t activbau3". Scientists have even started correlat- relevant to needs of our country. Infectionslike ing the botanical properties of plants with their phar- tuberculosis, malaria, diarrhoea, AIDS and malnutrimacological activity as seen from the work On tion are some of the major problems of our country. Rawat et a la. In future, more co-ordinated multi- H 1 ~ these areas have not been extensivelyex~ ~ ~ ~ ~ dimensional research aimed at correlatingbotanical ploied. and phytochemical properties to specific pharmacoMajority of the drugs are at the experimental stage logical activities is expected. and have to still undergo clinical trials. In 1982, In terms of pharmacological activity, more attention Dr.Satyavati had expressedneed for well planned. has been paid CNS-actives cytoprOtectivel clinical studies. 16 years later, the status has not immunOmOdulafors and plant changed. There is still a paucity of clinical products. Nutraceutics have Opened up an which are carried out in controlled, dounew field for exploration and, in the near future, di- ble blind manner. etary modulation of diseases may emerge as an alternative mode of therapy. At the sametime a de- Today, concurrent consumption of drugs from differcreasing trend has been noticed towards evaluation ent discipllis is a common finding.Very few studies, of plants for their effects on the autonomic nervous however, address the problem of drug interactions, system or fertility control. if any. In view of this, two studies documenting
SELECT RESEARCH PAPERS G;i ZVIDENCE BASED AYURVEDIC DRUGS
interaction of plant drugs with modern medicine are important from the clinician's point of v i e w . Similarly, the documented data on adverse drug reactions of plant drugs is also sparse.
psychotropic herbal formulation, on cognitive deficits induced by prenatal undernutrition, postnatal environmental impoverishment and hypoxia In rats. Indian J Exp Biol 1994;32:31-6.
9.
A relevant point that arose while compiling this data and needs mentionis the needfor documentation of research activities and publications of results, jourwhether positive or negative, in peer-reQiewed nals. Although, work carried out on traditional medicine is presented in conferences and is available in the conference abstract books (data of which may or may not be complete) or published in local journals, these are not peer-reviewedand moreover this data is accessible to a select few. This results in lacunae whilejudging the current status of researchon traditional medicine and leads to a false impressionthat not enough researchis being carried out in this field. Hence, networkingof the various researchactivities carried out by different scientists has now become . the need of the hour in order to provide information about and access to research work done in different laboratories of the country.
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Karandikar SM, Pandit VA. Kulkarni SD. Pharmaco-epidemiological study of use of herbal medicines in the elderly i Pune. Bharati Vidyapeeth Bulletin 1997;1:9-11. n Vaidya AB.The status and scope of lndian medicinal plants acting on central nervous system. lndian J Pharmacol 7997;29:S340-3.
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+
140. ZlauddinM, Phansalkar N, Patki P, Diwanay S, Patwardhan B. Studies on the immunomodulatory effects of Ashwagandha. J Elhnopharmeed 1996;50:89-78. 150. Kumar P Kuttan R. Kuttan G. Radioprotective effects of , Resayanas. lndian J Exp B i d 1996;34:848-50. 151. Kuttan G Use of Withania somnihta Dunal as an adjuvant . during radiation therapy. lndian J Ewp B i d 1996;34:854-6. 152. BhattacharyaSK. Satyan KS. Ghosal S. Anxiolytic actlvity of glycwvithanolidesfrom Withank, somnifera IndianJ Exp Bid 1997;35:236-9. 153. Thresiamrna KC, Qeorge J, Kuttan R. Protective effect of curcumin, ellagic acid and bixln on radiath induced toxIclty. Indian J Exp B i d 1996;34:845-7. 154. Devl PU, Qaneaoundari A Radioprotectiw effect of leaf cuctnct of Indian medicinal plant Odmrm sanctum. lndian J Bid 199J;33:205-8.
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223. Sarkar S, Pranava M, Marita R. Demonstration of the hypoglycemic action of Momordica chamntiain a validated animal model of diabetes. Pharmacd Res 1996;33:1-4. 224. Ghafoorunissa. Reddy V. Sesikaran B. Palmolein and groundnut oil have compdrable effects on blood lipids and platelet aggregation in healthy \ndian subiects. Liplds 1995;30:1163-9. 225. Ghatoorunlssa. Nutritionaland health implications of palm oil in lndian diets. lndian J Med Res 1995;102:233-40. 226. Kumar PD.The role of coconut and coconut oil in coronary heart disease in Kerala. South India. Trop Dmt 1997;27: 215-7.
212. Thatte UM. Rao SG, Dahanukar SA. Tinospom wrdifolia induces colony stimulating activity in serum. J Fbstgrad 227. Dikshit M, Rastogi L. Shukla R Srimal RC. Prevention of , Med,1994;40:202-3. ischaemia-induced blochemical changes by curcumin and quinidine i n cat heart. lndian J Med Res 1995:101:31-5. 213. Kapil A. Sharma S lmmunopotentiating compounds from . Tinospom cordI1Wia J Ethnophamcd 1997;58:89-95. 228. Deshpande UR. Gadre SG, Raste AS, et a/. Protective 214. Dhuley JN. Effect of some Indian herbs on macmphage effect of turmeric (Cunwne longa L.) extract on carbon
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230. Khan BA, Abraham A. Leelama S. Haematological and hlstological studies after curry leaf ( M u m koenuori) and mustard (Bmssiy juncea) feeding in rats. lndian J Med Res 1995;102:184-7. 231. Khan BA, Abraham A. Leelamma S. Hypoglycemic action of Murreya koenigii(cuny leaf) and Brassicajuncea (mustard): mechanism of action. Indian J Biochem Biophys 1995:32:106-8. 232. Khan BA. Abraham A. Leelamma S. Role of Mlrrraya koenigii(curry leaf) and Brassicajuncea (Mustard) in lipid peroxidation. lndian J Physiol Pharmacd 1996;40:155-8. 233. SharathchandraJNN. Patel K. SrinivasanK. Digestive enzymes of rat pancreas and small Intestine in response to orally administered mint (Mentha spicata) leaf and garlic (Allium satiwm) oil. lndian J Pharmacd 1995;27:156-60. 234. hgusti KT. Therapeutic values of onion (Allium cepe L.1 and garlic (Allium SativUm L.). Ind'ien J EW Biol lgg6; 34:634-40. 242. Ram A. Lauria ? Gupta R. Sharma VN. Hypoliiidaemic I effect of Myristica tragrans fruit extract in rabbits. J Elhnopharmacd 1996;55:49-53. 243. Khajuria 4. Zutshi U. Bedi KL. Permeability characteristics of piperine on oral absorption an active alkaloid from peppers and a bloavailability enhancer. lndian J Exp Biol 1998;36:46-50.
244. Karen RS, BhargavaVK. Garg SK. Effect of Trikatu (Piperlne) of the pharmacokinetic profile of isoniazid In rabbits. lndian J Pharmaooll998;30:254-6. 245. Prabhu MS, Plate1 K. Saraswathi G. Srinivasan K. Effpct of orally administered betel leaf (Piper belle Linn.) on digestive enzyme9 of pancreas and intestinal muwsa and on bile production in rats. lndian J Exp B i d 1995;33:7526. 246. Cherlan KM. Gandhl VM. Mulky MJ. Toxicological evaluation of mowrah (Madhuca latitblia Macbride) seed meal. lndian J Exp B i d 1996;34:61-5. 247. Pal BC. Achari B, Yoshikawa K. Arihara S. Saponins from Albizla lebbeck. Phytochem 1995;38:1287-91. 248. Ga&i $, Mahato SB, K, Yemasaki K. Qammaranetype triterpenoid saponins from Bacopa monniera. Phytochem 1996;42:815-20.
Ohtad
235. Sheela CG. Augusti KT. Effects of S-ally( cysteine sulfoxide from A~~~~~ sativum Linn and gugulipid on some 249. Garai S, Mahato SB. Ohtani K.Yamasaki K. Bawpasaponin D a pseudojujubogeninglycoside from Bacopa monniem. enzymes and fecal excretions of bile acids and sterols in Phytochemistry 1996;43:447-9. cholesterol fed rats. Indian J Exp Biol 1995;33:749-51..
..
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250. SivaprakasamP, Viswanathan S, Thirugnanasambantham P, et al. Przewalskinone-B from the stem bark of Obhna obtusata. J lndian Chem Soc 1997;74:165-7
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282 Samudralwar DL. Garg AN. Minor and trace elemental determl~tlon the Indian herbal and other medidnal in
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NS. PardeddBM. Analydr of some herbal plants from India used in the control of diabetesmeUitus by NAA and M S techniques. Appl Radfat /sot 1997;48:1059-82.
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275. Subramoniarn A, Evans DA. Rajasekharan S, Pushpanqadan I? Hepatoprotective activity of T-us zeylenicus extract agalnst paracetamol-induced hepatic damage in rats. Indian J Expt Bld 1998;36:385-9.
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288
Pharmacology of NIedicioal Plants and other Natural Products

G. V. SATYAVATl
Indian Council of Medical Researcl't, .Insari .Arngar, . h A Delhi-110 029 .
Following tile pioneering and monumental work of Sir Ram Nath Cliopra and colleagues in the early part of this century, there has been a tremendous upsurge of interest and research in the field of indigenous drugs in India. Inspite of a large number of studies undertaken on different aspects of medicinal plants, these researches have been Inore in the nature of independent efforts confined to ind~vidualscientists rJr groups of scientists, without a systematic attempt to co-ordinate the work 'it1 its entirety. Any review of literature in this area, therefore, is fraught with difficulties ofspace and time encountered in compiling material from such widely varying journals and other publications. A deliberate effort to carry out an integrated, coordinated research on ~nedicinal plants selected after careful discussion and consultation with reputed Ayurvedic/Unani physicians was made for the filst time in India by the Indian Council of Medical Research (ICMR) ill 1964, through the Composite Drug Research Scheme (CDRS). This was a unique experiment and during the five years course of this scheme, in operation under the ICAlR, nearly 10 plants out of 58 initially selected for the study, had reached an advanced stage of investigation (ICMR Bulletin, 1972). &n April, 1970 this scheme was transferred to the then newly constituted Central Council for Research in Indian Medicine and Homoeopathy (CCKIMH), New Delhi. The Central Drug Research Iilstitute (CDRI), Lucknow, has also been engaged in research on plants. Earlier, plants to be studied were selected mainly on the basis of their actual use in the traditional systems of medicine. But after 1963 CDRI felt the need to have a more broad-based screening of plants for biological activity by including a number of plants on which no information was available in the traditional systems of medicine. By this means nearly 2000 plants have been so fa1 screened by the CDKI, revealing various types of pharmacological activities irr these plants. These results'have been published in a series of articles {Dhar et of., 1968, 1973, 1974; Bhakuni et a/., 1969, 1971; Dhawan c l nl., 1 9 7 7 , 1980 ; Setty et al., 1976, 1977, Raatogi and Dhawan, 1982).
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289
G . V. SATYAVA'I'I
The present report is a review of the published literature on phaxmacology of medicinal plants between 1975-81. I.
Plant. with CNS activity
,/
There has been considerable interest in plants showin3 CNS actiyity. At the CDRI, Lucknow, a large number of plants have been showh to have CNS depressant activity. Important among these are Pntkirlsonia acukata (Rao, ct a / . , 1979a), Acacia aurirulofornnl (Sahai et al., 1N O ) , and Dysoxylum bitacctarifcrum (Singh etal., 19i6c). Other plants reported to have CNS depressant effect are Cjmbopogm citratus essential oil (Seth ct al., 1976), Fcronia limonin root (Patel st a!., 1982)) Elaaocar~s ganitrus fruits (Battacharya at al., 1973a), Ippmaa carnca leaves (Bhattacharya ct al., 1975c), Piper r~igrum leaves (Sridharan et al., 1978), t ylophorine from Tylophora indlca (Gopalakrirhnan ct of., 1979), total alkaloids of Stephania wightii (Naziniuddeen ct a l . , 1 980) and biflavonoids isolated from Taxus baccata leaves (Vohra et al., 1980). Anticonvulsant activity was found in the roots of Cichorium intibus ( Jindal et ul., 1975). Neuromuscular blocking activity similar to that of' d-tubocurarine, but milder in degree, was demonstrated in a quaternary alkaloid isocwulidins isolated from the leaves of Cocculus kurifolius (Kar et al., 1977a). Essential oil of Psoralca corq.lifoliashowed a direci stimulant effect on skeletal muscle similar to that of caffeire (Zutshi and Bhagwat, 1977). Local anaesthetic activity has been reported in Euphorbia ncrqolio (Lahon el al., 19i9) and Zizyphus jujuba (Sahu and Das, 1975). A new triterpenic acid isolated from Corchorw daplesms has been found to have analgesic and an tipyretic activity (Vohora ct d.,198 1). Morus indica showed potent local anaesthetic and analgesic activity (Barman ct a!., 1980) and Dcsmodium potycurpum only analgesic activity (Wahi ct al., 1975). Epistephanine from Stephania hernandijiolia revealed significant adrenergic neuron blocking?ictivity (Ray et al., 1979a). Tranquillising activity has been reported in Conwluulus plrnicaulis in animals (Singh et al., 1977b) and in clinical studies (Singh and Mehta, 1977). coronarium and H. ~fiicatum revealed Essential oil of the rfiizomes of Had~hium mild tranquillising action in ratr (Dixit and Varrna, 1979). , . Nuciferine is a dopamine receptor antagonist with pharmacologic profile similar to that of chlorpromazine but its Hofman degradation product atherosperminine showed effects associated with d o p a h e receptor stimulation (Bhattacharya et al., 1978). Bacopa monniera Linn., Clycywhize glabra Linn, Conuolwluc pluricwlis and Tinospora cordwia (four plants described in Ayurveda as "Mcdh~eRcfrapma" drugs) decreased the acetylcholine content of whole brain and cortex in stressed rats. The histamine content was lowered in the whole brain but raised in the cortex (Singh et of., 1979b). CVithania somnifera showed beneficial effects in 30 patients of anxiety lleurpsis (Singh and Malviya, 1978). In rats, its extract potentiated barbi.
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PHARMACOLOGY O F MEDIClNAL PLANTS
turate hypnosis, induced depletion of acetylcholine and catecholamu~es axld l an increase in sel otonin and histamine levels in wlrolc L ain (Sing11 c! ol., 1979a). A series of studies has been carried out on the interaction 01 cannabis with CKS depressants (Singh st al., 1978e ; Ghosh and Uhattacharya, 1979b) and copper (Singh and Das, 1978) ; on tolerance (Singh and Ilas, 1977) and on mechanism of anticonvulran t (Singh and Das, I975 ; Ghoah and Battacharya, 1978) and hypothermic activity (Singh and Das, 1976) and potentiation of morphine analgesia by callnabis (Ghosh ail3 Bhattacll~rya, 1979b). There studies at the Banaras Hindu University have confirmed that, in the rat, most of the CNS activity of cannabis is serotonin-mediated (Gliosli and Bhattacharya, 1980 ; Ghosh et al., 1980b). Cannabis led to significant hyperglycemia and concomitant fall in liver glycogen in rats (Soni and Gupta, 1978). A single inhalation of marijualla fumes by rats released acetylcholine from the brain into the blood, while .preventing the release of serotonin and catecholamine. Prolonged inhalation showed inhibition of act tylcholine release from the brain with simult?aneous activation of xrotonin and catechoIamine release (Sing11et a/., 1980a). A study on cognitive functions in chronic cannabis users (lid not reveal any difference between the useri and non-users (Ray rt al., 1979). Clinical study in volunteers on the effrct of chronic cannabis use did not reveal any serious harmful eEects. Wi!hdrawal symptoms were reported by the majority of subjects (Singh st a/., 1981). Significant psychopharmacologicd activity has been demonstrated in the epimeric pair of 4-methoxyindolc alkaloid^ isolated from Alstonia vencnata bark (Bhattacharya ct al., 1975b). MAO-inhibitor activity lias also been reported in echitovenidine, the major fruit alkaloid of A. vetlenata (Bhattacharya and Ray, 1976), anJ strictamine an indole alkaloid isolated from Ustonia scholaris flowers (Bhattacharya et al., 1979). Strictamine is considered to be the biogenic precursor of picntnine. Whilst picrimine is reported to be a cencral nervous system dqprtssant (Dutta ct al., 1976), strictamine exhibits anti-depressant activity (Bhattacharya ct al., 1979). Tranquillisiag effect comparable to chlorpromazine wae found in Lufa hrbrrosa extract tested in rats with septa1 lesions (Karanth rt al., 1976). Rats treated for 37 days with CclostnrrpaniGulota seed oil showed an enhanced learning and memory process (Karanth rt al., 1980, 1981). An Ayurvedic compound comprising Cmtrlla osiatica (Mandookafiarni), G~~nhizaglabra, Dhari&aitara tailarn revealed anxiolytic effcct in rats (Srinivasan rt J.,1981) In a double blind clinical trial, CenbNa asiatica powder did not show any &t. on the general mental ability of normal children (Kuppurajm rt al., 1978). In a comparative study between Bacoja monirra (Bruhmi) and Mandookaparni (CcntrNa asiatica), which are often treated as synonymous.by many Ayurvedic physicians-both plants showed significant
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291
C . V. SATYAVATI
psychotropic action in rats. Bacoba monicra was, however, more potent (Sing11 et 'nl., 1975~). A double blind clinical comparison was carried out in patients suffering fiom various types of schizophrenia (Unmada), on the effect of Tagara (Vaferiana spccics) *, chlorpromazine and a cornpound preparation Brahmadiyoga, comprising 6 plants including Tagara, Brahmi (Centella asiatica), Vocha (Acorur calamus), Sarpagandfia (Rauwolfia scrpcntina), Kushtha (Saussurea lappa) and Jatamansi (Nardostachys jatamansi). While Brolrmadiyoga showed better effect than Tagara alone, chlorpromazine was superior to both (Mahal ct al., 1976).
11.
Plants with activity on tho cardiovascular system
1. Hypotctl~iuc cardiotonic agents and A large number of plants have been screened and found to have mild to moderate degrce of hypotensive activity. At the CDRI, Lucknow, over 60 plants have been found to have cardlovascular system (CVS) activity, 57 of them being hypotensive and three showing cardiotonic activity. Coleonol, a direrpene isolated from Colcus forskohlii is the most promising hypotensive agent (Dubey et al., 1981). Crotosparine, the N-methyl derivative of a proaporphine base from Croton sparsiflorus has been reported to have good hypotensive activity (Rastogi ana Dhawan, 1982). Asclepin, a new cardenolide from Asclepias curclssavica has been shown to have cardiotonic activity in cats and guinea pigs, comparable to digoxin and ouabain with a better margin of safety (Patnaik and Dhawan, 1978; Patnaik and Kohler, 1978). Buddleja asiatica ahowed persistent' hypotensive activity in cats and dogs whichwas found to be due to an alpha-receptor antagonistic action (Singh et al, 1980e). Er).thri,ra variegata (Chatterjee ct af., 1981), HibGcus rosa sinerlsis (Dwivedi ct al., 19771, Sapindus trifoliatur (Singh et al., 1978d), Piper aurantiacum (Singamma e t al., 1978), Tiliacora raccmosa (Guha ct al., 1976), Anchusa strigosa (Mahipal ct of., 1977) and Eclipta alba (Gupta at a/., 1976) were other plants which showed significant hypotensive activity. E . alba also had a myocardial depressant effect. Tribulus tcrrcstris (Seth and Jagadeesh, 1976), Nerium indicum (Singh el al., 1978a) and Cundrbita maxima (Lahon ct al., 1978) showed cardiotonic effect. Mollugo ceruiana showed sustained inotropic effect perhaps mediated through autonomic receptors (Bansina th ct al., 1980).
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2 . IIy+olipidemic agents Ever since the first experiments on crude gum guggul which 4emonstrated l~y~olipidelnic effect in the oleoresin (Satyavati, 1966; Satyava ti ct al., I969), considerableinterest has been evinced not only in gum guggul (Comm;I,hora mukul) itself but other plants which might have similar effect. Systematic studies at the CDRI,Lucknow, have shown hypolipidemic activity in three
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*Exact Uotat~icalname . ~tbe plant uaed not apecitierl. f
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292
steroid constituents of C. mukul (Nityanand and Kapur, i973; Xityanand etal., 1981). Hypolipidemic effect was confirmecl in the ethyl acetate fraction of C. mukul (gum g u g u l ) in rats (Nityanand and Kapoor, 1975), in fraction 'A' ofprtroleuln ether extract in male gerbils (Ahuja rt d., 1977) and in a ketosteroid fraction in cl1ick.i (Tripathi et al., 1975b). Clinically, in a double blind trial, Malhotra et 01. (1977) and later Kotiyal ct al. (1979) reported a hypolipidemic activity comparable to that of clofibrate in the fraction ' A ' of C. naukul in patients with Type 11 l~yperlipoproteinemip. The drug also rhowed an anticoagulant activity (Mester et al., 1979). Bordia and Chuttani (1979) reported an increase in fibrinolytic activity and a decline in ptatelet on adhesive index without s;gr~ificanteff~ct serum cholesterol in patient, of coronary artery d~sease as well as healthy individuals with lraction '' of A C. mukul. Guggulrpid, a srandardised resin fiaction of C. mukul, lowered serum cholesterol and triglyceriies in healtliy male volunteers (Nityanand kt al., 1980). It is now under phase I1 clinics! studies. Onion was found to have hypolipidemic effect in patients of ischaunic heart disease (Shar ma et at., 1977) and normal subjects of the Jain community (Sainani el al., 1979). However, in allother study, 0nion.administration.did not show arry change in tlie blood chulesterol, fibrinogen and fibriuolytic activity onion was not found (Sharma and Sharma, 1976). In experimental ~nirnals, to have any esect on experimental atherosclerosis in rabbits (Jain, 1976; Sharma and Sharma, 197b) but was found to prevent atherosclerotic changes in r rats, similar to garlic ( K u r n ~ ct al., 1979) and also to decrease myocardial necrosis following isoprenaline in rats (Saxena et al., 1979). Garlic prctreatment has been shown to reduce serum cholesterol in rabbib (Jain, 1976) and rats (Pushpendran 61 al., 1980) and to protect rats against isopnnalineGarlic extract feeding in induced myocardial necrosis (Saxena et al., 198 rats prolonged the clotting time, bleeding time and recalcification time but led to a rise in peptic activity and mucin content of the gastric juice (Kumar et al., 1 981 ). Clinically, raw garlic has been reported to lower the blood cholesterol in 'normal subjects (Bhushan rt al., 1979; Sainani ct al., 1979). The essential oil of asafoetida (Fertda o s o f e t i d a ) showed significant protection against fat-iuduced increase in plasma fibrinogen and decrease in coagulation time and a fibrinolytic activity in healthy human volunteers (Bordia and Arora, 1975). Pkrocarpus rnarsupium showed hy pocholesterolemic eKect in normal rabbits (Pandey and Sharma, 1978). A significant lowering of endogenous cholesterol level has been observed in rats fed capsaicin (Sambaiah ct al., 1978). Double blind clinical study was carried out on obcse subjects with Ajush-55 (comprising h-aiuki, Triphala, Guggulu, Chitrakomula, Shilajafu and many mineral preparation). It revealed a consistent hypotensive effect
1).
293
without effecting the body weight or serum lipids (Kuppurajan et al., 19UOa). A vasoconstlictor effect has been found in Albizzia lebbeck (Tripathi and Das, 1976) and an atherosclerotic effect in c u m i ~seeds by Rao rt al. (1979b). Fruit extracts of Emblica OJJicinalis and Terminalia belrrica (two components of the well known 'Trt$hala' of Ayurveda) p~otectedalbino rats against myocardial necrosis induced by isoproterenol (T'ariq el al., 1977). Plumbagin (2-methyl, 5-hydrdxy 1 : 4 naphthoquinone) is reported to have anticoagulant and Rathinam, 1978). Pharmacology of solasonine, activity (San~hakumari a glycoalkaloid from Sdanum surratsase has been s~udicd (Basu and Lahiri, 1977).
1 1 Plants with antifertility activity 1.
Research on Indian plants with antifertility activity has been exhaustively reviewed recently (Chaudhury and Haq, 1980a, b; Kamboj and Dhawan, 1931, 1982). Documented clinical data on antifertility plants is, however, very meagre. 1. Plants with antifertility effect in the femalr Twenty eight plants and about the sarne number of isolated materials have been reported to have shown anti-implantation (interceptive) activity, 5 plants have shown anti-ovulatory activity. (Kamboj 8: Dhawan, 1982). Chaudhury and Haq (1980a) listed 11 plants with 103% antifertility activity in one species of animal or the other, and other plants had over 60% activity (Chaudhury and Haq 1980b). ICamboj and Dhawan (1982), on the other hand, listed 16 plants as more active antifertility age~its. Sc~eening 32 botanically identified plant materials showed significant of antifertily activity in only Abrusprscatorius seeds, Ananas comosus unripe fruit, M~rin~apterygospnna root and Tsrminalia arjuna bark. Ethanol extract of Cychorium inpbis showed significant resorptive activity (Prakash and Mathur, 1976). Alcollolic extract of Cuminium gminum seed and Hyptis suavtolrns leaves showed potent antifertility activity while Dolichos bflorus seeds and Trianthema pentandra leaves were devoid of such activity (Garg, 3 976 j Of 201 extracts of 36 plants screened, 9 extracts of 7 plants viz. Butm monospuma seeds, Curcuma longa rhizomes, DUUCUJ carota seeds, Embelra ribes roots and Sapindus trifolialus seeds, showed significant antifertility effect (Garg el a!., 1978). Anti-implantation activity in mice was found in petroleum ether and chloroform extracts of Abroma augwta root, benzene extract of Achyrantls aspcra stem bark and Sssbania aeglyptica flowers and alcoliol extract of Woodfordta fmtirosa Aowers (Pakrashi et a / . , 1975). A. auplrrta also showed abortifacient activity.
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PHARMACOLOGY O :AIEDICINAL PLANTS I
Extracts of Annona squamost weds and C u m l a reJkxa whole plant and the alcoholic attract of iota la ria juncca seeds showed antifertility effect, w h e t w roots of Butta vulgaris, Trianthcma portdacaslrum and bark of Morirtga olciJira did not show any antifertility erect (Rao ct d.,1979~). ArisWochia indica root has been studied in great detail by Pakrashi and co-workers. 'Antifertility activity was demonstrated ki the root extract (Pakrashi t t al., 1976) and its active constituents, arhtolic acid (Pakrashi and Chakraborti, 1978a), its methyl ester (Pakrashi and Saha, 1978), sesquiterpene (Pakrashi and Saha, 1977) and#-coumaric acid (Pakrashi and Pakrashi, 1978). Both aristolic acid (Pakrashi and Chakraborty, 1978b) and the sesquiterpene (Pakrashi and Chakraborti, 1977) showed anti-estrogenic activity. The methyl ester, however, Icd to liver and kidney damage in mice (Pakrashi and Saha, 1979). Ethanol and benzene extracts of Artaboty odoratiuimu.r fresh leaves were found to disrupt the normal estrus cycle in rats (Prakash and Mathur, 1977) and prolong the dlestrus stage (Prakash, 1978a). Anti-e, trogenic activity reported in rats (Prakash 1978b) was confided in the ethanol and benzene extracts (Prakash, 1979). Con trovenial results have been reported with extracts of Dapcrrs caruta seeds. Anti-implantation activity reported by ~ a and colleagues (Garg, r ~ 1975;Garg ct al., 1978) and Sharina st al. (i976) have not been 'confirmed by Prakash ct al. (197P) or Kamboj and Dhawan (1982). Rerultr of studies on Embrlia ribts arc also equivocal. Em belin (2 : 5 dihydroxy-3-undecyl-4:4 * benzoquinane) isolated f o Embclia rrbes seeds rm was effective in rats in one series of study. (Radhakrishnan and Alam, 1975; Krishnaswami and Purushottaman, 1980b), but not in another (Kholkute st al., i978a) although antifertility effect was found, in this study, in the petroleum ether and methanol extracts of the plant. Further, ernbelin did not reveal any estrogenicor antiestrogenicaction (Krishnaswamiand Purushottaman, 1980b). . Seshadri rt al. (19 78) observed that biochemically embelin seems to share some but not all the e k t s of antiestrogenic compounds. Prrkash and Mathur (1979) found an estrogenic activity in a 50% ethanol extract of the plant at a low dare. A combined preparation of Embrlb nbss, Piper iongum and Borax (Carbhani varanaurhadham) recommended by Ayurvedic practitioners enhanced the uterine alkaline phosphatase activity in rats and guinea pigs (Raman rt a1.,,1916) given in a dose of 0.5 g twice daily from the 5th to 20th day but did not have any intcrceptive effect m 7 women volunteers (Joshi t t ai,, 1977). Piprr longurn fruits alone revealed only marginal antifertility activity in rats. When mixed with E. nbes, however, it inhibited pregnancy in 80% of rats (Kholkute et al., 1979a). Hibi.rcus rosa n'ntnds, benzene extract, showed significant antifertijity activity in rats (Kholkute rt al., 1976);with a dose dependent antiestrogenic activity (Kholkute and Udupa, 1976a) and perhaps altered the estrogen295
progesterone balance (Kholkute and Udupa, 1956b). The compounds isolated l i l t . benzene extract (cyanidin, que~cctin and hent~iacontanc) were clcvoid of any anti-lertility effect (Kholkute and Udupa, 1978), although tlie mother liquor showed activity. The flowers but not leaves and stem of 11. rosa stnensis showed significant antifertility activity (La1 el al., 1976; Kliolkute et al., 1977). Oleanolic acid 3-B glucoside isolated from Randia dumetorium showed anti-implantatioll activity in rats and was found to be anti-estrogenic in action (Pillai rt al., 1977). l'lumbagin (2-methyl-5-hydroxy, 1, 4 naptl1aqu;none) isolated from Plurnbugo zglanica showed significant anti-implantation, anti-ovvlatory and abortifacient activity without any teratogenic effect in rats. Alcoholic extract of Lygodrurn Jlexosum, a plant u s ~ dby an Adivasi population in Maharnshtra, showed antifertility activity in rats, mice and rabbits, by exerting its effect on the zygote and/or blastocyst (Gaitonde and Mabajan, 1980). illalvavlucyscoti,tattii flowers caused degenerative changes i l l the ovary afgsrbils alongwith a decrease in the RNA, protein, sialic acid and glycogen con tents o rhe pterus and vagina (Dixit, 197711). Sida carpinifolia (methanol f extract) and Podocarpus brev~oliirs(chloroforni extract), showed antitertility clrcct in rats (Kholkute et al., 1978b). Laccardia locca (Laksha)-had an 'ulti-implantation elfect in rats. I t revealed an anti-uterotropic effect without an anti-estrogenic activity (Gllosh ef al., 1980a). ~Iyush-17, compound Ayurvedic preparation containing Saraca rndico, a rlreca catechu, Coccus lacca, gold and sugar evinced anti-implantation effect in I ats. Among its ingredients, Saraca indica and its phenolic glycoside (p,) have been shown to be a highly potent uterine stimulant (Satyavati, 1970a,b), u~hereas Areca catechu has also been r e p ~ r t e d to have anti-implantation effect (Chaudhury and Haq, 1980b).
fiom
lle~lzcne extract of Achyranfhes aspera showed 100 per cent abortifacient effect in the rabbit at a single dose of 50 mglkg. I t had no estrogenic, antiestrogenic or androgenic effect in mice (Pakrashi and Bhattacharya, 1977). I'hysalin-X Iron1 Physalis minima had significant abortifacient effect in rats (bfahana et al., 1979). A flavanone glycoside from Curculigo orchioides was found to be a powerful uterine stimulant in several species (Sharma et al., 1975). Larica papaya (unripe fruits) showed abortifacient activity in rats (Gopalkri~tlnanand liajasekharasetty, 1978). Steroids isolated from Ananas comosus (unripe fruits and juice) exerted abortificient effect in mice (Pakrashi and Ijaqan, 1976), whe~:administered during 6-7 days of gestation (Pakrashi and Chnkravarti, 1970). I t has been suggested that the compound acts by exer-
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PHARMACOLOGY OF MEDICINAL PLANTS
ting anti-lutebtrophic activity (Pakrashi and Chakrabarty, 1981). It revealed anti-ovulatory activity i n rabbits (Pakrashi and Chakrabarty, 1978). Vasicine, an alkaloid isolated from Adhatoda vasica showed potent uterotonic activity partially mediated through prostaglandins (Gupta et ul., 1977b). I t exerted an abortifacient effect in guinea pigs but not in rats (Gupta et al.; 1978). Vasicine potentiated prostaglandin-induced uterine contractions in rats (La1 and Sharma, 1981). Ruteafrondosa flowers and Caesalipinia bonducella seeds showrd estrogenic effect in rats (Tewari el al., 197fia). Arjunalone, a new flavonoid from Tarminalia arjuna has shown oxytocic activity (Sharma at d.,1982) whereas Coronaridine froni Tabarnoemontano hcyncano showed anti-implantation activity along with estrogenic activity (Mehrotra acd Kamboj, 1978). AntifibrinoIytic activity in the roots and phenolic glycoside (punamavoside) of Borrrhavia dzJiusa has been found useful in controlling uterine bleeding in monkeys (Srivastava st al., 1980). From the husk of Plantago ouata (Isapgol) a new cerbical dilator (Isaptent) has been developed by the CDRI, Lucknow (Khanna et al., 1980). Isaptent has been found to compare very favourably with the imported laminaria tent in efficacy and safcty and is much cheaper (IChlR, 1982).
3. Plan!$ with lactogmic and anti-lashgenic activities S tigmaaterol (as well as an el .e: .iaction) isolated from L.efitadenia raticulata showed significant lactogenic effect in rats (Anjaria rt al., 1975). Lactogcnic~galactogogue effect of Asfiaragur racmusus roots has been wcll documented (Satyavati at al., 1976). Bandaging the breasts with +mine flowers to suppress. lactation is a common practice among women in Kerala. A s p d y carried out on lactating micc showed that contact with jasmine (jusminum pubucais) flowers led to suppression of milk production with involution of the mammary gland. Even exposure to the smell of thtse flowers induced similar changes although to a lesser drgree (Abraham el d., 1979).
4. Contraception in the male
Aristolochia indka root (chloroform fraction) rcvealcd an antispermatogenetic effect ( Pakrashi and Pakrashi, 1977). and its derivative p-coumaric acid showed an anti-prolactin effect in male mice (rakrashi rt al., 1979). Azadirachln indica leaves showcd an antifertility activity in the male mice f which was not due to inhibition o spcrma~ogencsis(Deihpande st al. 1980). Embafh ribes fruits administered to male bonnet m~nkeys for 3 months reduced the circulating testosterone levels without affecting normal sperrnatogenesis (Purandare et al., 1979). The aqueous and alcoholic extracts of E. n b t s fruits did nDt reveal any toxic effect on the male reproductive organs in rats (Seshadri rt al., 1980). Antispermatogenetic effect of the flower extract of Hibiscus rosa sinenst3 was demonstrated in Rhinopama ki--a n6n-ac$'otd bat (Singhvi and Lal,
,
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1980). Malvavircus conzattii flower extract revealed potent anti-spcrmatogenetic activity in gerbils and house rats (Dixit, 1977a), dogs (Dixit et al., 1978) and albino mice (Verma ct of., 1980). Cannabis extract showed consistent adverse cffe~tson the testicular function in the mice (Dixit and Lohiya, 1975), pigeon (Vyas and Singh, 1976) and toad :Dixit rt al., 1977). Spermicidal activity in a number of plants has been investigatedin detail at the CDRI, Lucknow. Spermicidal saponins from Sapindw mukrossi fruit, Schlrjbra copitota, Pittosporum nilghcrensc and Polemoniurn comuleum have been characterized (Setty st a[., 1976, 1977). Plant extracts with semen .-~amlating property have been taken up for in depth study at the CDRI, Lucknow.
IV. Phnts with hypoglycemic activity

In the last few years, hypoglycemic activity has been reported in a number of plants viz. Allium crpa or onion (Mathew and Augusti, 1975; Augusti, 1976; Gupta et al., 1 9 7 7 ~Arb18 murmlos (Vyas et a[., 1979), Crewia )~ asiatica (Pakrashi and Mukherji, 1976), Coccinia ir~dica & A and Coccinia indica W vor palmata (Pillai ct a(., 198Oa). <ingiber nJzcitlals (Sharma and Shukla, 19771, Ficus bcngabnsis (August, 1975),Gtitiamomurn tamala, inufa racemosa, Terminalia belm'ca (Tripathi et al. 1979~), Cyanropsis tetragonoloba (Pillai et al., 19tOc) and Pferocarpus marsufiium (Chakravarti et al., 1980). Clinical efficacy of the crude drug waq demonstrated in Cinnamomum tumala (Chandola rf of., 1980a), Clrrodendron phlomides (Bhattacharya and Bajpai, -1 975), Pterocarpus marnrpium (Rajasekharan and Tuli, 1976) and onion extract (Sharma et a1 , 1977a). A rise in plasma insulin with a simultaneous Fall in blood sugar was demonstrated in patients of diabetes mellitus treated with Ctnnamomum tamala (Chandola et. al., 198%). The CDRI, Lucknow, has recently reported hypoglycemic action in Dipteracanthus prostratus, Pterocarpus santalinus, Rhur chinensis and Trichoson~hes palmatu (Rastogi and n 1 wan, 1982). A number of leguminou9 plants of the 1a Acacia family have also been found to evince hypoglycemic activity in expe;imental diabetes (Singh st al., 1975a, 1976a; Singh and Bhaqdwaj 1975; Singhal ct al., 1982). Azadirachta indica showed hypoglycemic as well as anti-hypergl y cemic effects in dogs with adrenaline-induced and glucose-induccd hyperglycemia (Satyanaraya~~a blurthy et el., 1978). Of all the plants tested so far, P~trocarpus marsupium and its active cornponent, (-) -epicatechin (a flavonoid), seem to be ofgreat interest and potentiality, on account o f a no7,el antidiabetic mechanism promoting regenera tion of the beta cells of the pancreas (Chakravar~i al., 1980, 1981 ct a?1 '.
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PHARMACOLOGY OF MEDICINAL P U T S
V. P l u t s with antibuterll, aathelmintic, antifungal and antiviral activities

1. Antibacterial actwity In oilro anti-bacterial activity against pathogenic gram positive and gram negative bacteria was reported in the essential oils of several plants viz. Nigtfla sativa (Agarwal et al., 1979), Oenarrthcjawffica (Sharma rt al., 1980), C'bopogon species, ~naphliscontrota, Hedychiwn sjnkatum, Sdvia lanata and <ingiber ofuinak (Slnha et al., 1977), Cwcuma longa, Laggrro aurita, Blumc~mcmbrancea, Cp~nJioadloris, Cythoclmr &rat#, Palma rosa and Psorolea torylfolia (Zutshi et al., 1976). Aty1osol-a new .substituted biphenyl isolated from Aiylosia trinuvia showed antibacterial effect (Tripathi tt al., 1977, 1978a), whereas from Evodia 1u.r~-ankendo,two alkaloids with antibacterial activity have heen isolated (Rastogi and Dhawan, 1982). Plumbagin (5-hydraxy, 2-methyl, 1-4 napthoquinone) revealed anticancer, antibacterial and antifGgal activities (Krishnaswami and Purushottaman, 1980). Crude extract' of Allium sativum (garlic) had anti-bacterial effect against gram-positive and gram-negative bacteria in vitro and gram negative bacteria in the intestinal tract of poultry (Sharma et dl., 197713). It significarltly inhbited the growth as well as production of enterotoxin in Eschcrichio coli (Kumar and Sharrna, 1982). &rbcrine inhibited chokra toxin-induced fluid accummulation in the ligated ileal loop of adult rabbits (Caitonde et al., 1975). It caused potent and prolonged inhibition of the cholera tmin-ir$uced subcutaneous inflammation in rats (Akhtar et d., 1977). Further studies showed that i t could inhibit cholera toxin induced diarrhoea and fluid accummulation in the gastromtestinal tract ofadult raw (Sabir st a/., 1977).
2. Antlulmintic actioiry
Carica P4P(qa, Sapindus tt$oiiahrs,
Butro frondosa and Mimordia charantia
showed anthelqintic action against Ascaridia gaNi i n v~tro (Jawahar La1 et al.,
1976). A striu of plants belonging to different families have been screened in vitro against human round worms (Ascaru lumbrtcoides), revealing potent f activity in p h t r o 'the <ingibnaceae family ( Raj, 1975). Berberine hydrochloride showed potent anthelmintic effect against Sypharia obvelata in rnice in vim (Sighal, 1976). Clinically, Ncem leaves (Mdia azadiraca) were found to be effective against b u w n ascariasis (Singh ct al., 1980d) and Caesalpinia crisfa seeds were effective against human ambebiasis (Tewari et al., 1978).
3. A n t i f i p l octivitt Ether and chlorofbrm extracts of Mwnaprurimr seeds and CurIonga stem w u c found to be fungistatic, while the ether extract of Shsrea robusta win, c h b m f m extract of A&irqchta indica and Pmgamia glabra were fun$SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS 299
lcidal (Mishra and Sahu, 1977). Essential oils of Curclfnra aromolica (Rao, 1976), curcurnu caesia ( ~ a n a j e and Nigam, 1976) and Cuivuma augustijJa (Banerjre e and Nigam, 1977)and the rhizornesof Curnrma amada (Ghoshet al. 1980~) showed p t e n t an ti-fungal activity in oitro. An tifungal constituer.t of Alpinia &in'tiarum has been characterised as a flavonoid (Ray and Mazumdar, 1976). ~Cacsilr alata (Radhakrishnan rt a[., 1976) and Saussurra Ia@a(Ray and Mazurndar, 1977) showed potent an tifungal activity. Schiwallin, a saponin from Schima wallichii (Chandel at al., 1978, 1980) and cmodin f r ~ m Rumrx mardimus (Agarwal st at., 1976) wcre shown'to be antifungal constituents. Inula racemosa yielded a number ofanti-dermatophytic constituents, i. e. lactones, alantolactone and isoalantolactone (Tripathi et al. 1978b). Arnebin from Arnabia nobilis and lactones from many plana sllnwed antifungal activity against experimental fuhgal infection in guinea ,ip,arnebin being more potent (Wahab ct at., 1982).
Antiviral activiw At the CDRI, Lucknow, antiviral activity has been confirmed in several plants,, p i t . , Acacin ouricul~rmis,Aglaia ro~burghiana, Briddia retusa, Cattia jstula, C. auricuIaLa, Cynoden dactylon, Grewia hirsuta, Otaa p o h m a , Psychotria tnmcata, Vanda parviflora and <ingiber capitaturn (Rastogi and Dhawan, 1982). Interferon like substances responsible for antiviral activity have been reported in nearly 17% plants screened at the CDRI. Antiviral activity was found in plants of 14 major genera vir. Acacia, Argyrsia, Ficus, Grewia, Ipomoca, Lima, Euphorbia, Pipa, Polygonum, Solanum, Simplocos, Q I U T G U S , ? ~ ~ ziqphns (Babbat rt at., 1982a). Berberine chloride eye ddPs (0.2 %) adtninistered f a 2 weeks revealed a curative' effect in clinically positive cases of trachoma (Babbar et.al., 1982 b). Berberine sulphate also protected chick embryos against the lethal effect of trachoma organisms (Sabir ct al., 1976).
4.
Plants with anticancer activity Active constituents of 10 plants active against one or more o^ the tumora tested at CDRt, Lucknow have been isolated, characterised and biologidly evaluated. Of these, Amabin-1 from Arnebia nobrlis inhibited mouse leukemia and rat Walker carcinosarcoma (Katti at of., 1979). Celsioside, r saponin from Crhia coromandeliana has sllown high activity in Walker carcinosarcoma system but is toxic in the mouse leukemia system (Cupta' et al., 1979a). Antileukemic constituents from Tithonia tagitiflora (Pal rt al., 1976) and 0thbiologicaliy actiGe anti-tumor agents from Cocculus p~ndulns, Rg&o and Tephrosia candi& have also b u n characterized at the CDRI,Lucknow (Dhawan and Rastogi, 1982). Other plants which have shown va$ng degrees of anti-tumor activity are Alliurn cspa (Yerkar ct d., 11'81), Lrm p iu ~ilgherrense (Garg and Khanna, 1979), Rubia cordifoliaIAdwankarat of., 19791, Srnvcorpur m~cardinm(Chitnis rt al., 1980), Ematamia k p 8 0 ~ (Chitnis i t al., 1979), Rhozp sticta (Mukhapadhyay at d., 1981) and. Dh-s m a ( H a m rt al., 1981). 300
M.
PHARMACOLOGY OF MEDICINAL PLANTS
Anti-viral.and anti-tumor activities of CassiaJistula, Aghia roxburghiana and <ingiber capitanum have been attributed to the presence of interferon-like proteins in them (Babbar et ol., 19i9). Cytotoxic effect in mice of different degrees and nature has been reported in sesquiterpene lactone component of Parthenium hys~crophorus(Vaidya et al., 1978) and in plumbagin from Plumbag0 rosea in chick cmhryos.
VII. Plants with ha ti-in&mmatory, activities
analgesic and
-ti-p~etic
During the perioJ under review, analgesic and anti-inflammatory activity has been reported in a number of plants viz. Acanthus illic~oltus (Agshikar et al., 1979), Berginia ligulata (Gehlot el al., 19751, CaloPhyllum inophyllum and its xanthones (Gopalakrishnan, 1980a) as also a coumarin derivative-calo~~hyllide (Bhalla rt al., 19801, xanthone from Mmu/mso (Gopalakrishr an ct o f . , 1980a), bavachinin from Psoralea coryl~orta (Anand el al., 1978), Tin~spor,~ cordifolia (Shah. and Pandya, 1976; Pendse et d., 1977) aud a compour:d preparation (Am'tarishtam) with 7. cordfolia as the main ingredient (Pillai et al., 1980b). Curcumin (diferuloyl methane), in a double blind clinical trial on patients of 'definites rheumatoid arthritis, showed significant improvement, comparable to phenylbu tazont (Deodhar rt al., 1980). Gossypin reduced initial as well as late phases of rat paw oedcma induced by carrageenin (Pafmar and Ghosh, 1980). N p k h sfeliata (Singh i t al., 1977a1, Hibi~cus rosa JinmEiS, Nmmm indinm (glycaide), With& somnifcra (Singh et o f . , 1978b) and embelin from Embrlie ribs (Gupta t t d , . 1977a) showed potent analgesic, anti-pyretic and anti.inflammatory activities in rats and mice. Berberine was shown to inhibit local inflammation induced by cholera toxin in rat by means of a selective antagonim (Akbtar et al., 1977). Immunosuppressive action was demonstrated in mangostin from Garcinia mangostat~a and t~lophorine from Tylo@ora indica (Oopalirluirhnan st al., 1980b, c). The CDRI, Lucknow, has reported anti-inflammatory activity in 29 plants (Rastogi and Dhawan, 1982). The beneficial effect of Semecarpus anacmdium administered in rLe form of milk extract in various inflammatory conditions has been tonfirmed in patients of rheumatoid arthriti~ (Tripathi st al., 19;9). Ayurveda descrities the drug ' R m a ' as the drug of choice for the treatment of arthritic conditions. The exact identity of Rosna, however, is not clear. Six such plants used as Hnsna were screened against formalin arthritis in rats and all of them revealed anti-inflammatory activity of varying degrees. Alpinia galanga was found to be the most potent followed by P l u c k lancrolaia, Vanda roxburghii, and T-fophora indica (Sharma and S h a m , 1977). A Siddha drug Linga chendooram prepared out of cinnabar showed significant antipyretic activity in rats, but ~Qina"iindgericor anti-in&mmatory activity (Ghosh cf 4., 1979~).
301
WII. Planta with and-dcer activity

Reports on the effect of curcumin on the gastric muwsa and secretion to evince ulcaogenic (Gupta et al., 1980; Prasad et al., 1976) as well as anti-~llceractivities (Sinha ct al., 1975). Nimbidin from Mtlia azadirachtu (Pillai ct al., 1978a), extracts of Ocimrm sawturn (Bhargava and Singh, 1981), blilhania somtuzd~a (Singh et al., 1982) and Altingia excelsa (Singh et al., 198Cb). revealed anti-stress or adaptogcnic properties. Triterhnoids (ulsolic acid and lupeol) from a number of Indian plants belonging to S a ptaceaelsapindaceae famil) evinced anti-ulcer activity in rats subjected to restraint stress (Gupta et al., 1981). Alcoholic extract of T8ctona grandis significantly inhibited restraint ulcers in rats and histamineinduced ulcers in guinea pigs (Pandey ct al., 1982). Amlaki Rasayana (Varma et al., 1977) and Amlaki (Emblica 4fuinalis) (Chawla et al., 1982) have been found to provide relief in dyspepsia (ulcer and non ulcer).
?ire equivocal. Curcumin has been thus reported
I . Plants with X
'
spasmolytic/antispasmodic activity
Spasmolytic or antispasmodic activity of varying degrees has been reported in a number of plants vir. Inula racmsa (Singh at al., 1976b, 1980c), Card-&a turgida (Chaturvedi et al., 1976), Hedy~~hium spica~um( Sharma 1975), Tinasflora cordifalia (Patcl el al., 1978) and Daucus carota (Gambir et al., 1979). Among these, Claumarin-a new coumarin' from Clawen a pmtaph~l/a(Patnaik et a!., 1978) and srsquiterpenoids from Cedrus dsodara (Kar et al., 1975; Puri et al., 1975) have been found to be highly potcnt. Allohimachalol was found to be the most potent as a spasmolytic (Puri et d.,1975) among sesquiterpenes from C. deodara. Tyloflhra indica has been studied extensively for its effect in bronchial asthma, since the initial reports of (Shivpuri c t a f . ) 1968. Alcoholic extract of and total alki~loids T. indica showed non-specific antispasmodic action on isolated tissues (Dhananjayam et al., 1975) and branchodilator and an tibronchoconstriction effect in guinea pig ileum (Gupta, 1975). A q w u s extract of T.indaca prevented albumin-induced anaphylaxis in guinea pigs, modified the Schultz-Dale reaction and caused leucopet~iain dogs (Haranath and Shyamala Kumari, 1975), indicating :in immunosuppressive effect The bronchodilator, membrane-stabilizing and immunosuppressive efFect of T indica was confirmed in rat lung perfusion experiments (Nayampalli and . indica have yielded equivocal ' Sheth, 1979). Recent clinical studies on 7. results (Gupta st al., 1979; Gore stal., 1980). Leaves of Acorur calamas (Chandra, 1980) and AcalHh indua (Rarnan at al., 1979), .Curma longa powder fried in ghee (Jain rt d., 1979) and H1d9hium spicatum rhizome (Chaturvedi and Sharma, 1975) brought about significant relief in bronchospasrn and other clinical signs and symptoms in patients of bronchi J a s t h m .
'
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PHARMACOLOGY O F MEDICINAL PLANTS
Albizcia kbbeck has batxi subjected to detailed study with respect to its anti-asthmatic and anti-allergic activities, apart from general pharmacological studies (Tripathi et al., 1977). I t protected sensitized guinea pigs against hone serum antigen (Tripathi and Das, 1977), had a significant cromoglycatc-like action on the mast cells and appeared to also inhibit the early proccu of sensitization and synthesis of reaginic-type antibodies (Tripathi st al., 1979a). It also significantly inhibited, in vitro, PHA-induced hlrutogenic response of human lymphocytes and in sensitized guinea pigs, it marked1y reduced the secretion of the macrophage .migration inhibitor (Tripathi et al., 1979b). Solanum xanthocarpum in a clinical trial on respiratory diseases showed sigm'ficant improvement in cough and expectoration without any significant reduction in airwav resistance (Jain, 1980). X. Plintm with diuretic activity Diuretic activity has been reported in extracts of Cllrdiosperrnum hiicacabrm (Santakumari st ol., 1981), Mimosa pdica (Pill~i al., 1978b) and Tinospora tt cordiqfolia (Singh ct a/., 1975b). C u m i s tripnus exhibited a do:e-dependm t saliuretic effect, without affecting fhe potassium excretion (Naik rt of., 1981). ~iuretic activi~y Vitladinia australis has been attributed to vittadinoside-a of sterol glucoside isolated from the plant (Kar st al., 1977b). Apart from a diuretic ftavone glycoside from Millingtonia hortsnsis (Kar rt al., 1975), three new coumarins and an alkaloid wit11 diuretic activity have been isolated from Toddalia asiaticc (Rastogi and Dhawah, 1982). Craeta~a nurvala has been shown to be an Ayurvedic drug of choice in the treatment of various urinal y disorders and particularly helps in the migra~ion stone and in preventing of atony of bladder, following prostatectomy (Deshpande st al., 1982).
XI. Plant. acting on hepatic fmnctions The Indian traditional systems of medicine claim to offer usehl
remedies for a variety of hepatic diseases. Among the plants investigated in recent yeara, Luja echinata (Lauria st al., 1976), JVymphaca stcllata, IVithania somnifcra (Singh et al., 1978c), Indigojira tznctoria (Anand ct al., 1979) and Ricinus communis (Natu st al., 1977) have shown protection against carbon tetrachloride (CC1,)-induced hepatic injury in rats. Nympham stellab, Wirlhnia somnifrra, Indigofcra tinctoria and Andrographics panicu/ah (Chaudhuri, 1978) increased the bile flow and liver weight, suggesting a ' stimulation of the microsoma1 enzymes cf the liver. In case of Ricinus commmis, the fresh leaves had better effect than their' cold aqueous extract on the glycoside isolated from the plant (Natu et al., 1977). Among the compound preparations tested, Liv-52, protected r a u against CC1,-induced necrosis of the liver (Singh d d., 197%~).Livcrgcn, a compound preparation (contaming Andrugraphis paninrlata), also had an effect SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS
303
s&lar to the plant A. ~ c u l a t a - i t s main ingredient (Chaudhuri, 1978), on the bile flow and liver weight in rats. ' A double blmd clinical trial of Aro4.a wardhani, a well known Ayurvedic compound prepmation, in patients of acute viral hepatitis showed significant improvement in clinical and biochemical parameten after 2 w& of treatment (An tarkar et al., 1980). The main ipgredien t of A r o p w a r h i is the plant Picrorhita kurroa (Rutki). Kantikar rt at. (1976), however, did not find any protective effect in the alcoholic extract of Picrorhita kurroa against CC1,-induced hcpatoxicity in rats Kutkin, the bitter glucoside of P. kurroa and its constithtent organic acids (cinnamic and vanillic acids) showed significant choleetric activity in dog$ and a laxative activity in rats, (Das st al., 1976). Luffa ecchinata fruit juice administered as nasal drops to patients of viral hepatitis led to a reduction in serum bilirubin and SSPT, along with substan tial relief in clinical symptoms lika anorexia and malaise. There was profuse rhinorrhoea following instillation of L. echinata drops in the nose, the nasal ~ecretions containing 1.6-5.5 mg% bilirubin (Vaidya st al., 1976). 111 a pilot study, two well known medicinal plants ' EcI$h alba and Phyllanthus niruri inactivated hepatitis surface B antigen (HBs Ag) in oitro (Thyagarajan et al., 1982). A random survey of Ayurvedic literature resulted in a list of nearly 90 plant expected to be beneficial in the treatment of liver diseases (Satyavati, 1978). This seems to be a highly interesting and promiring field of research which might throw valuable leads in the pharmacology and therapeutics of liver diseases.
X! I.
Plants with adrptogenic and other activities
Certain drugs classified in Ayurveda as '~asGana' have been tested clinical study, for their effect on the process of ageing. I11 a cont~*olled Wilhania somnifera root powder administered in milk for one year showed significant improvement in several parameters in human volunteers aged 50-59 years, as compared to placebo (Kuppurajan et ol., 1980a). In a double blind clinical trial with milk fortified with Withunia somniftm (Ashwagandha) alone, and a combination of W. somnifera and Rocnhavia d i b a (Punamava) to norm11 children (8-12 years of age), Ash ragundho showed a significant increase in body weight, total proteins and mean corpuscular haemoglobin conccntration (Venkatraghavan d al., 1980). Punarnava whole plant paw ler pro.not'ed a pojitive rritrogen b4ance. growth and also longevity in albino rats on stock diet which was not so marked in animals on a low protein diet (Rajagopalan el al., 1977). Gcniforte-an Ayurvedic compound preparation, with Chavanaprash* as the major ingredient, administered for 1 year was reported to be effective
*Chavan~rashis a well-known Ayur:.edic ratorativc to& o&inalir as the main ingredient,
and r c j u v e ~ ~ r En#lica with
304
PHARMACOLOGY OF AIEDICIKAL PLANTS
in delaying the pathological changes characteristic of senile maculopathies in 36 ophthalmic patients (Albal and Chandorkar, 198,1), Two plants, Bauhinia variegatrr (Kachavar) and Jalkwnbhi (botanical identity not specified), were found to have beneficial eft'ect in experimental goitre in rats (Veena Kumari el al., 1975). The dried kernels of Myisticafrograns (nutmeg) seeds showed a marked inhibitory effect on thr biosyrithesis of prostaglandins by die rat kidneys in vivo and in uirro (Misra et al., 1978). This s ~ u d y supports the earlier reports that nutmeg might act, like iiidomethacin, by inhibiting prostaglandin synthesis (Fawell et ctl., 1973). The bioavailability of vasicine and sparteine were reported to be enhanced by the addition of Piper longunt (Atal, 1979). P9rr chaba was found to enhance thc bioavailability of sulphadiazine and tetracycline (Atal cl al., 1980). 111 a cliiiical study or1 human volunteers, however, by the addition of Trikati-a combination of Piper nigrum, Pi* chaba and Ziruibrr oflcinalis the bioavailability of rifampicin was not increased {Dahanukar et al., 1982).
XIII. Am overview The foregoisg brief accouiit of rescarch on mrQicinai plants in India in the past few years highlights certain important points and trends:1. As in the past, there has been greater emphasis on a search for plants with CNS activity, (.VSactivity and antifertility activity, followed by those with anticancer, hypoglycemic, anti-inflammatory and antimicrobial activities and others. 2. Scteening of plants for their pharmacological effect using a n h l models was continued and to a large extent standardiscd in major laboratories. yowever, the situation regarding well-planned clinical studies of plant poducts continues to be disappointing. 3. Others seem to be undertaking studies largely on individual initiatives. In spite of all these efforts, however, the ultimate goal of providing potent, inexpensive and safer drugs for most diseases encountered in our country still remains (o be achieved. Certain important snd useful lea&, however, have cet tainly been obtained during the years under review. T o mention a few examples, there is the CDRI work on identification and characterisation of chemical cor~stitutentsof plants withepromising biological activity such as coleonol -a diterpenoid from Coleus forshhki with hypotensive activity; spasmolytic sesquiterpcnes from Gdrw deudro and spermicidal saponins &om several plants. The major bottleneck, however, is the lack of clinical follow-up of the leads obtained by painstaking research. 4. The novel mode ot' antidiabetic activity of Pkrocar~us marsupium, the immuno-suppressive effect of Albizzin kbbrck, the consistent hypolipidemic activity of Commiphnra rnukul are but a few examples of success achieved iu exploring the pharmaco~ogical basis of the traditional clinical use of these plants in therapeutics.
305
Lack o organised libratwe srrrury and ruvicw f Subsequent to the monumental publications of Sir R. N. Chopra (Chopra
et al., 1956, 1958) and Dr. K. M. Ndkarni (1954), [here had been no con-
certed etforts till recently to collect and publish the results of all scientific studies carried out on .medicinal plants. Mith a view tomeet the longfelt need the ICMR brought out the first volume of a comprehensive monograph on Medicinal Plants of India (Vol. I) in 1976 (Sqyavati et al., 1976). The second and third volu~nes of this monograph are now under preparation, The entire research on medicinal plants at "CDKI, Lucknow, has also been reviewed very rece~itly Rastogi and Dhawan (1982). Some by major global traditional practices have been reviewed recenly by Satyavati (1982 a).
Plioritics in m a r c h on natural products As stressed earlier, in order to achieve results within a reasonably short period, it would be desirable to have a "need based approach to research on traditional drugs including screening of plants for biological activit)". This was the objective of a ~ H Regional Group which met recently O (1980). Rexarch efforts could thus be directed to finding remedies ( i ) for the so called "Refractory Diseases" i e. those for which modern medicine has not been able tc; offer, so far, a satisfactory or lasting remedy, and (ii) as supplementary measurer .t? well-established chemotherapy. Well-known mlmples of Refractory Diseases are cancer, rheumatoid arthilitis and allied conditions, disorders with an allergic cornpone11t iu their etiology (s.g. bronchial asthma, skin allergies, eczema, psoriasis, ctc.), liver disorders (including viral hepatitis), viral disease like polionzyelitis and herpes zoster, urolithiasis, obesity, hyperlipidaeinia and atherosclerosis, metabolic disorders like diabetes mellitus, peptic ulcer, cerebrovascular disorders like hemiplegia and paraplegia, malabsorption syndromes including ulctrativt colitis, ep.lepsy, mental disorders including psychos,is, anxiety neurosl, stress disorders, drug dependence, ctc. Toxicity of indigenous drugs is another area which has been largely neglected. While it is argued that there is no need for preclinical toxicity studies, whul these drugs are used in clinical practice as per traditional l dosage form, the situation calls for a serious re-appraisal. ~ l active principles ofplants and natural products must be subject to thk same stringent toxicity studies as for synthetic drugs. Further, it is extremely important to realize that the same ethical considerations in human research which are relevant and obligatory for modern naedicine should be applicable to research on medicinal plants and natural products (Satyavati, 1982b). Acknowledgement
I a n grateful for tile prompt and enthusiastic support of all the.pharmaSELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS
306
cologists who, responded by sending a list of their publications (and also reprints) on medicinal plants and other natural products. Thanks arc due to L)r. Ashok Gupta, Research Officer*and Miss Neeta Varshucy, Scientific Documentation Assistatt, Icdian Council of Medical Research, New Delhi, for help in collecting the ~elevantliterature and bibliography. Secretarial assistance by bhri Rakesh K. Bhatnagar is also gratefully .cknowledged. ,
Eke m e rm
A b r k , M., Sarada Wi, N. and Shcda, R. (1979). Indian 3. hIcd. Hcs., 69,88-92. Ad-, M. K., Chitnis, M. P., Khandalekar, D. D. and Bhadsavale, C. G. (1980). Indim 3. exp. Bwl., 18, 102-1 Agarwal, J. S., Rastogi, R. P. and Srivastava, 0. (1976). Cum. Ssi.,45, 619-620. P. AgxwJ, R., Khuya, M.D. and Shrivastava, R., (1979). Indran 3. urp, Bwl., 17, 1264-1265. Agshikar, N. V.,Naik, V. R., Abr,3ham,G. J. S. ,Reddy, C. V. G .,Naqvi, S. W. A. and Mittal, . P. K. (1979). Indian 3. up. Biol., 17, 1257-1258. Ahuja, M. M. S.,Whotra, S. C. and Tanda?, H. D. (1977). Indian J. txp. Bwl., 15,143-145. Akhtar, M.H., Sabir, M.-and Bhidt, N. K . (1977). I n d h 3. Mcd. R t s . , 65, 133-141. A l b d , M. V. and chandorkar, A. G. (1981). Indian 3. Physwl. Pharrnacol., 25,97. A-d, K. K., Sharms, M. L., Singh B. and Ray Ghatak, B. J. (1978). I n d h 3. ex). Biol., 16, 1216-1217. Anand, K. K., Chand C. 311d Ray Ghatek, l3. J. (19i9). I,dion J. c ~ f i 6wl. 17, G&:-CL7. Anjcia,J. V., Varia, M. R.,Janakiramall, K. and Gulat~, D. (1975). Indian 3. r e . Biol., 0. 13, 448449. Antrtpr, D. S., Vaidya, A.B., Doshi, J. C.,Attavale, A. V., Vixchoo, K.S.. Natebr, hi. R ., Tathed, P. S., Vijay-i, R. and Kalre, N. (1980). Indim 3. Med. Rcs., 72, 588-593. Atal, C. K. (1979). I. D. M. A. Bulletin, 10, 483. At.11, C. K., UYlavalan, R., Nighajkiir, R.,Sareen, A. N. ;uld Gupta, 0. (1980). Indaon P. Dnrgs, 17, 266-268. Augusti, K. T. (1975). Indian 3. Physwl. Pharmatd., 19,218-220. Augurti, K. T. (1976). Indian J.,cxp. Bwl., 14, 110-112. Babbar, 0. P.,Bajgai;S. K.,Chowdhury, B. L.and Khan, S. K. (1979). IndimJ. exp. Biol., 17,45 1-454. Babbar, 0. Joshi, M. N. and Madan, A. R. (1982a). Indian 3. Med. Rts., 76 (Suppl.). P., 54-65. Babbar, 0. Chhatwal, V. K., Ray, I. B. and hfehra, M. K. (1982b). Indian 3. Mcd. Rcs., P., 76 (SUPPI.), 83-88 Banwja, A.and Kigam, S. S. (1976). Itdianj. Mtd. Rts., 64, 13181321. B.mjrr, A. and Nigam, S. S. (1977). Indian 3. Phurma. ,39, 143.145. Rumrj&, A., and Nigarn, S. S. (1978). Indian 3. Mtd. Rcs., 68,864-866. Barman, T. K.,Chatthpe, G. K., Nagchaudhuri, A. K. and Pal, S. P. (1980). Indian J. Pharmd.,12,237-241. &su,eA. and M i , S. C. (1977). I n d b 3. exp. Biol., 15, 2&5-289. Bh&w,D. S.,Dhar, M. L.,Dhar, M. M. ,Dhawan, 3.N.,Gupta, B. and Srimal, R.C . (1971). Indiu 3. eM. Bwl,, 9, 91-102. Bkiku~i, S., Dhar; M. L., Dhv, M. h l . , Dhawan, B. N. and hfehrotra, B. N. (1969). D. Indian J . e x .! Biol., 7, 250-262. Bhdk, T. N., Saxena, R. C. Nigam, S. K., h l i s n , G. and Rhargava K. P. (1980). Indian J . Md.Rrc.,72,762-765. m v a , K. P. and Singh, N. (198 1). Indian 3. Med. h., 443-45 1 73,
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PHARMACOLOGY OF MEDICINAL PLANTS ~mmkum&,P, Rathinam, K. and Santhakumari, G. (1977). Indian J. Med. Ru., 65, 829. . 838. Purandue, T V., Kholkute, S. D., Curjar, A., Joshi, U. M.,Datta treya-murty, B., Sheth, . A. R., Swamy, X. R., Jayaraman, S. and Munshi, S. R. (1979). Indian 3. exp. Bwl., 17,935-936. Puri, V. N., Kxr, K., Patwik, G. K., Dhwan, B. N., Kulshreshb, D. K.and ~artog?,R.P. (1975). Indian 3. exp. Bid., 13,369-370. Puahpendran, C. K. Dewuagayarn, T. P. A,, Buleji, A. and Eapen J. (1980). Zndion 3. exp. Bbl., 18, 8 5 M . Radhakrishnan, N., Namsveni,R., Uma, R. and Thyagarajan, R. (1976). J . Ru. ZnWon Med. rw ~ i . 11.70-74. , Radhakrishnan, N. and Alam M. M. (1975). India 3. exp. Biol.,U, 70-73. K. (1975). Indian 3. P w l . Phamad., 19 47-49. Rajagopalan, S. S.,Appa Rao, M. V. R., Koteswara RRO,T. and Sitaraman, R. (1977) . Ni,N,229-27. R+jasekharan, S. and Tuli, S. N. (1975). 3. Rcs. Indian Med. roga Homan.,ll,9-15. Raman, K. G.,Bhardwaj, T. P. R.and Pushothaman, K. K. (1979). J. Ru. I n d h Med. Med. Toga Homoeo., 14, 81-86. Raman, G., Munshi, S. R. and Rao, S+ta, S. (1976). Indian 3. Med. Res.,64, 959-962. Rao, J. T. (1976). Indian 3. Phmmocol., 38,53-54. Rao, M. N. A., Mukheji, K.C.,Patnaik, G. K. and RaatogiR. P. (1979a). Indhn h g s , 17, 43-46. Rao, K. V,, Das, N. S., Pabhakam Rao, P. and Singamma, M. (1979b). I n d h 3. P a w l . , 11, 29. Rao, V. S. N.,Dasaradhan, P. and Krishnaiah, K. S. (1979cj. Indian3. Med. Res.,70,517-529. Raatogi, R. P. and Dhawan ,B. N. (1982). Zndion 3. Med. Rcs., 76 (Sucpl.) , 2-7-45. Ray, A.B.,Chatt-dhyay, S.,Tripathi, R. M., Gambhir, S. S. and Dan, P. K. (1979a). Pat M a b , 35,167. lnd Ray, P. G. and Majumdar, S. K. (1976). Indiun J. exp. Bwl., 14,712. Ray, P. G. and Majumdar, S. K. (1977). Indian 3. exp. Bwl., IS, 334. Ray, R.,Rabhu, G. G., Mohan, D.,Nath, L. M. and Neki, J. S. (1979b). Inch'& 3. Med. Re., 69,996-1000. S3bir, M., M a w , V. N., Mabapatra L. N., Bhide, N. K. (1976). Indian J. Med. Res., 64, 1160-1 167. e. Sab'u,M., AJ&tar, M. H. and Bhide, N.K. (1977). Indian3. M d Res,,65,305-313. S h i , R . , Aganval, S. K.and Rastogi, R. P. (1980). PhHochemirv, 19,1560-1562. Sahu, N. C. and Dar, B. N. (1975). . . JRu. Indian Med., lO,29-33. S h n i , G. S., Desai, D. B., Garhe, N. H.,Natu, S, M., Pise, D. V. and Sainani, P. G . (1979) I& J. Med. Ru., 69,776-780. Samb~iah, Satyaanaryana, M. N. and Rao, M. V. L. (1978). Nutr. Report Id.,18,521. K. Santhskumlri, G., Pillai, N. R., Nair, R. B. (1981). 3. Sci. Ru. P h s Med.,2,32. Sznthakumari, G. and Rathianam, K. (1978). Indian 3. exp. Bwl., 16,485-487. S~tyavati, V. (1966). Thais for the Degree of Doctor of AyurPedic Medicine, G. Brnarar Hindu Univenity, Varanasi. &-ti, G. V. (1978). Paper presented at the Symposium on Life Sciences (Under Ancient ImighM & Modrm Discoveries)-Nav Delhi, hfay, 1978. Sawvati, G. V. (1982a). Indian 3. Med. Res., 76 (Suppl.) ,1-26. Satyavati,G. V. (1928b). Indian Paediatr., 19,201. Satyavati,G. V., m m t h , C..and Tripathi, S. N. (1969). Indim,3. Med.&.,57, 1950. Satyavati, G. V., h a d , D. N., Sen, S. P. and Das, P. K. (1970a). Indian J. Med. Res., 58,
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Tripathi, V. D., A g d , S. K. Stivaatatn, 0 ,P., and Rmtogi R.P (1978b). I d h .

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Traditional M6diCinr.
Pharmacology of Medicinal Plants*

G.K. PATNAIK & B.N. DHAWAN Division of Pharn~acology, Central Drug Research lnstifute, M.G. Marg, Lucknow-226 001 Medicinal plants have continued to be an area of major scientific interest with the lndian investigators and a large amount of literatu~ has been published 3 in addition to some excellent reviews. The long awaite7iVol. 2 of "Medicinal Plants of India" (Satyavati eta/., 1987) is a welcome addi;.on and hopefully the (1 final volume will also be available soon. Mehrotra and cl~lleagues 987) pubPlants" containing lished a compendium to the "Glossary of lndian Medicir~al updated botanical nomenclature of the medicinal plants. Panda and colleagues published comprehensive reviews on hepatoprotective (Handa et a/., 1986) and anti-inflammatory plants (Chawla et a/., 1987) where the lndian contributions have been adequately covered. Dhawan edited a multiauthor review on status of medicinal plants research in India (Dhawan, 1986). . lnspite of a large number of publications a very small number of plants has been clinically evaluated. In the present review the plants have been classified according to thsir pharmacological activities. Some plants, therefore, appear in more than one section. Under each section if any plant has been clinically evaluated it is reported in the beginning followed by plants from which active consbtuents have been isolated and evaluated. The plants, where only crude extracts, fractions or powdered plant material has been used, are dealt with at the end. A broad based screening of lndian plants for a wide range of biological :ctivities is being continued at the Central Drug Research Institute. The results of 870 more plant species were reported during the period (Aswal et a/., 1984a,b; Abraham et a/., 1986). The investigation showed that many crude extracts had promising activity and fractions of 168 plants confirmed various biological activities. Details of these have been provided at appropriate places in the following pages. The list of plants where activity could be confirmed in a fraction is given at the end of each section. Efforts have been made to cover all published papers containing significant new data. The abstracts have not been considered due to constraints of space and paucity of data in such reports. If we have missed any important papers we crave authors indulgence and would appreciate if the lapses are brought to our notice.
,
,
Anti-inflammatory activity
A large number of plants has been tested for antiinfiamrnat~r~ activity and as many as 39 plants have shown promising activity. Unfortunately in most cases work has been restricted to the crude extracts and in many cases only preliminary findings have been reported. The active principle has been identified in a fewsases only.
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G. K. Patnaik & 6. Dhawan N. Curcumin is the active constituent of Curcunia longa and has been evaluated clinically as well as its mechanism of action has been analysed. Curcumin produced stabilization of lysosomal membrane and caused uncoupling of oxidative phosphorylation. It also caused stimulation of the adrenals resulting in the release of endogenous corticoids. Like other non-steroidal anti-inflammatory agents it inhibited the synthesis of prostaglandins (Srivastava and Srimal, 1985). The study, thus shows that curcumin has multiple sites of action accounting for its anti-inflan- ma tory activity. In adtiion it produced a dose related antithrombotic effect in mice (Srivastava et a/., 1985). The antithronibotic effect appears to Le due to its antiplatelet aggregation activity. Anti-inflammatory doses of curi,umin cause either inhibition of platelet cyclooxygenase or by some unknown mechanism inhibit the release of TXbwithout inhibiting the generation of PGI, in rats (Srivastava et a/., 1986). In view of these interesting activities it may be clinically evaluated in patients with arterial thrombotic events and requiring antiarthritic therapy. A review of the pharma-cology and clinical trial of Curcun~alonga has been published (Srimal and Dhawan, 1985). Curucumin inhibited the actwty of some proteolytic enzymes' (Soudamini, 1988). By doing so it can reduce the cell damage produced by these enzymes. The active anti-inflammatory compounds isolated from Indian plants have diverse chemical structures. A flavonoid from the alcoholic extract of central wood of Acacia catechu showed potent anti-inflammatory activity in rats (Chakravarthy etal., 1983), Extracts of the rhizome of Hedychium spicatum showed marked anti-inflammatoiy activity against carrageenin induced oedeina in mice and rats. The hexane-soluble extract was found to be the most active fraction. A furanoid hedychenone isolated from this fraction showed marked activity and had a lower ulcerogenic index than with phenylbutazone (Srimal et a/., 1984). The aqueous extract of the leaves of Delonix eleta produced a dose dependent inhibition of carrageenin-induced rat foot oedema (Sethuraman and Sulochana, 1986). The activity appears to be due to the presence of rutin and quercetin-3-galactoside in the plant. A glycosidal fraction of Acacia farnesiana also inhibited the carrageenin oedema in rzts (Trivedi et a/., 1986). 3-Pglucoside isolated from the alcoholic extracts of the seeds of Randia dumatorum possessed significant anti-inflammatoryactivity in the exudative and proliferative phases of inflammation in rats (Ghosh etal., 1983). Gangetin, a pterocarpan, from the hexane extract of the root of Desmodium gangeticum also had significant anti-inflammatory activity in the above mentioned test system ( ~ h o s h and Anandkumar, 1983). The stem bark of Symplocos spicata yielded tr-spinasteroi which showed a significant activity a ~ i n s acute inflammation t induced by carrageenin in rats. It was more potent than phenyl-butazone but less active than betamethasone (Frotan etal., 1983). The crude extract of the flowers of Wrightia tinctoria showed anti-inflammatory activity in the same model. A 3-0-rhamnose-glucoside (rutin) was isolated from this extract and shown to be responsible for the anti-inflammatory activity (Sethuraman et a/., 1984). The sodium salt and acetyl derivative of anacardic acid isolated from leaves of Rhus seminalata showed significant anti- inflammatory activity against
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Pharmacology of Medicinal Flants carrageenin-induced acute inflammation and analges~cactivity in rats. The compounds exhibited a profile of activity associated wit!; attenuation of central prostaglandin acbvrty. The effect of these cornpounds on ':NS was also studied (Bhattacharya et a/., 1987b). The hexane extract of Euphorbia acaulis showed a! ,'i-inflammatory activity in acute and chronic inflammatory models in mice ai7.j rats by i.p. and p.0. routes. The activity has been compared with phenylt .~tazone (Singh et a/., 1984). A rnacked antiarthritic activity of adjuvant-induc,.d arthritis indicates its of possible usefulness in arthritic patients. The alcoholic .-?xtract the leaves of Nyctanthes arbortristis possessed significant anti-inflamnatory activity in a number of acute, subacute and chronic inflammatory mc.lels in rats including imrnunologically induced arthritis (Saxena et a/., 1984). t-.:i components of the inflammatory process are equally suppressed by the extract. The Ayurvedic use of the plant is justified by these studies. However, the active constituent needs to be isolated and characterised. showed antiThe aqueous extract of stem of Polygonuni glabru~i? inflammatory activity like betamethasone (Singh et al.. 1 9 8 5 ~ )The study is . quite preliminary and needs further detailed evaluation. The petroleum ether extract of Phyllanthus fraternus (0.5-2 gikg s.c.) has anti-inflammatory activity in rats comparable to 25 mgkg of aspirin (Hukeri et a/., 1985). Alcoholic extract of the leaves of Withania sonrnifera (1 gl; 1) was found to be eq~~iactive 50 to mglkg of phenylbutazone and 10 mglkg of hydrocortisone agaiqst sub-acute inflammation in mice (Sudhir et a/., 1986). The root powder (1 glkg) significantly reduced the serum a-2-macroglobulin and increased the synthesis of total serum protein in carrageenin-induced inflarnmation in rats (Agarwal et a/., 1985). The activity simulates that of nonsterokL-4 anti-inflammatory drugs. Alcoholic extracts of Crataeva nurvala fed orally has shown anti-inflammatory activity by the granuloma pouch method (CCRAS Report, 1986). The whole nut, pericarp and endocarp of Sernecarpus anacardiun~ (Bhallataka) were tested for anti-inflammatory activity in rats. The whole nut decoction was most eftectke. The nut had no immuno-suppressive activity. In an open clinical trial in rheumatoid arthritic patients, 5-10 g of hhallataka showed complete remission in 40% patients, another 40% showed major improvement and the rest minor improvement (Upadhyay et al., 1986). The nut merits further chemical and pharmacological studies. Ninety per cent ethanolic extract and aqueous extract of Strobilanthes heyneanus produced biochemical changes in the serum and liver of rats similar to phenylbutazone. The aqueous extract also decreased the level of adrenal ascorbic acid (Nair et al., 1985). The results indicate that the plant has effect on enzymes and metabolites involved in inflammation. Eclipta alba was found to possess moderate anti-inflammatory activity against carrageenin-induced paw oedema in rats (Chandra et a/., 1987). Aqueous extract of the whole plant of Cuscuta chinensis showed significant inhibition of carrageenin-induced oedema in rats. The extract also possessed a cholinergic activity (Nisa eta/., 1985). The activity coilld be due to the presence of sterolttriterpenoids or flavonoids known to possess anti-inflammatory activity. The extract of Salai
319
G. K. Patnaik & 6.N.
haw an
guggul (Boswellia serrata) exhibited marked anti-inflammatory activity in carrageenin-induced oedema in rats. The effect was equally marked in the adrenalectornizedanimals. It was devoid of ulcerngenic effect and had a very high LD,value by oral and i.p. routes (Singh and Atal, 1986). The nonsteroidal mechanism of action with no ulcerogenic activity provides the plant with an advantage over other drugs. In rats extracts of Leucas aspera exhibited significant anti-inflammatory activity (Reddi et a/., 1986). Oral administration of coconut oil extract of rhizome of Acorus calamus and leaves of Ocimum sanctum and 0 imum bascilrcum produced anti-inflammatory activity in acute t as well as chronkc models of inflammation in rats. The effect was decreased by adrenalectamy (Varde et a/., 1988). Other investigators have also reported that extract and aqueous suspension of Ocimum sanctum showed antiinflammatory activity against carrageenin and croton oil-induced oedema in rats. It also exhibited aspirin like analgesic and antipyretic properties (Godhwani et a\., 1987). The preliminary findings provide a rationale for the use o i Ule plant in Ayurvedic system of medicine. The alcoholic extract of Triphala, a powder mixture of Embelica officina/is, Terminalia bellerica and Terminalia chebula, produced significant anti-inflammatory effect against carrageenininduced paw oederna in rats. Commiphora mukul petroleum ether extract also showed a similar activity (Sharma eta/., 1988). There was no additwe effect of the two preparations, contrary to the common belief. Various extracts of Vitex negundo showed anti-inflammatory activity alongwith CNS activity (Ravishankar et a/., 1986). Most of the plants need dose dependent study. Several of these merit fufiher chemical and pharmacological investigations including elucidation of the mechanism of action. Anti-inflammatory activ-itywas also confirmed in the fractions of Antidesma gerardiana, Casimiroa edulis (Aswal et a/., 1984a); Dictamnus albus, Helenia elliptica, Leptorhabdosparvitlora and Viburnum odoratissirnus (Abraham et a/., 1986). Further work is being carried out to isolate the active constituents.
Analgesic and antipyretic activities

As in the case of anti-inflammatoly activity compounds of diverse chemical structures have been isolated from plants and shown to have analgesic activity. In other cases crude.extracts have exhibited analgesic andlor antipyretic activity. Some of the plants showing anti-inflammatory activity have been tested for analgesic activity as well. The alkaloidal fraction of the leaves of Solanum melongena have a marked I, . analgesic activity with a mild CNS depressant action (Vohora et ? 1984a). The analgesic activity seems to be of non-narcotic type. The active principle needs to be identified. The tked oil obtained from the petroleum ether extract of the roots of Abutdon indicum containing a number of higher fatty acids like linoleic, oleic: stearic, palmitic, caprylic etc., showed analgesic activity against z a t i c acid-induced writhing in mice but was less potent than aspirin. It was devoid of
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D gross CNS effects and had a high L , value (Bagi et a/., 1984, 1985a). Potassium embelate which was prepared from embelin, a paraquinone derived from the plant Embelia ribes, when administered by oral CS well as parenteral I analgesic acbvity in rats a, d mice comparable routes showed a centrally act~ng to morphine (Atal et el., 1984). The oleanoiic acid 3-p-glcl -.aside isolated from the alcoholic extract of the seeds of Randia dumatorunsshowed significant analgesia against thermal stimuli in rats. It was devoid if antipyretic activity, but had anti-inflammatory activity (Ghosh et a/., 1983). Semilar activities were seen with the Pterocarpan isolated from the roots (hexane extract) of Desmodium gangeticum (Ghosh and Anandkumar , 1983). Certain bioflavonoids, chrysin, morin and rotin showed analgesic activity c 3amanathan etal., with 1985) had opioid-like activity, whereas a role for interacti~~n arachidonic acid metabolism like aspirin is suggested for the other two compounds. Gossipin (Gossypium indicum) is known to possess analgesic activity through opiate receptors. lntracerebroventricular administration of calcium significantly reduced the analgesia. Further, repeated administration of gossipin did not change its analgesic potency in mice indicating the absence of tolerance (Vswanathan etal., 1985). The opioid-like analgesic activity of gossipin without development of tolerance merits a detailed evaluation of selective activity on different types of opiate receptors and the possibility of using it as a morphine substitute. The benzene extracts of Hedychium spicatum (Srimal et el., 1984), ethanolic extracts of Trianthema potrulacastrum and Cissus quadrangularis (Singh et a/., 1984) showed aspirin-like analgesic activity ( ~ k b aetal., 1984). r In addition to the anti-inflammatory activity, aqueous extract of the stem of Polygonurn glabrunt showed morphine-like analgesic activity. It also had a cholinergic and histamine-like action (Singh et a/., 1985~). The defatted extract of Tribulus terrestris enhanced morphine induced analgesia (Prakash et a/., 1985). Presence of 2 carboline alkaloids harmine and harmaline has been established in this extract. Petroleum ether extract of Phyllanthus fratemus (0.5-2 glkg s.c.) had analgesic activity in mice comparable to 25 mglkg of aspirin (Hukeri et al., 1985). Various extracts of seeds of Vitex negundo (Ravishankac et a/., 1986) and aqueous extract of Cuscuta chinensis (Akbar et al., 1985) also shoded analgesic activity apart from other CNS activity. Trianthema portulacastrum, in addition, possessed significant antipyretic activity against yeast-induced pyrexia, which merits further exploitation (Vohora et al.,l984b). Alcoholic extract of Woodfordia fruticosa showed antipyretic effect against TAB vaccine-induced pyrexia in rats (Alam et a/., 1986). The methanol extract and aqueous suspension of Ocimum sanctum had aspirin-like analgesic and antipyretic properties (Godhwani et al., 1987). Most of the above plants showing aspirin like activity should be evaluated for their antipyretic property. In many plants, detailed evaluation of the analgesic activity including the mechanism of action need to be elucidated. Many plants have shown promising activity. Their active principles should be isolated.
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G.K. Patnaik & 8.N. Dhawan
Antiallergic/antihistaminic activity
\
Treatment of asthma and other allergic diseases had been a major problem. Many drugs are recommended in the tradition21 system. However, most of these have given only symptomatic relief. A number of plants were tested for antiallergic activity and in some cases the active principle was identified. Quercetin isolated from Allium cepa exhibited bronchodilatory effect (Handa etal., 1983) and inhibited mast cell degranulation in sensitized rats similar to disodium chromoglycate (Johri eta/., 1985). Tlre latter effect could he due to a membrane stabilizing property. The use of Allium cepa in asthma may be attributed to the presence of quercetin. A similar effect on mast cells was also observed with the crude extract of seeds of Albizia lebbeck and a saponin isolated from the plant (Johri et el., 1985). Biochemical and histochemical studies of adrenal medulla of guinea pigs indicate that administration of Albizia lebbeck reduces the release of catechoiamines in response to histamine (Tripathi etal., 1983). Apart from the membrane stabilizing property, the above qctivity could also be due to an increase in the production of histaminase or histamine receptor blocking acbvity. These properties provide possible rationale for the use of the plant in the treatment of bronchial asthma. Chelidonic acid isolated from Cassia spectabilis showed antiallergic activity comparable to disodium chromoglycate, as tested by the passive peritoneal anaphylaxis method in rats (Mallaiah e l a/., 1984). Dimethyl chelidonate was found to be less active than chelidonic acid. The pure alkaloid extracted from Tinospora malabarcia markedly enhanced the anti-SRBC antibody titre. It significantly inhibited antigen-induced histamine release from the peritoneal mast cells of sensitized rats in vitro (Bhattacharya et a/. 1986). The beneficial effects of Tinospora could be because of an increase in the levels of IgG and IgM i~nmunoglobulins decrease in the mediators of hypersensitivity reactions. and In the isolated guinea pig lung preparation the glycosidal fraction ofpcacia farnesiana (2-10 mg) increased the outflow per se and antagonized the histamine-induced bronchial constriction. It also showed a vasodilatory effect in the hind limb perfusion test in dogs (Trivedi etal., 1986). The dried fruit of Piperlongurn reduced the passive cutaneous anaphylaxis in rats and prevented antigen-induced bronchial spasm in guinea pigs. It had, however, no significant effect on the histamine content of lungs, trachea and intestine or on histamine release by antigens (Dahanukar and Karandikar, 1984). The results provide an explanation for the traditional use of the plant in the porphylaxis of asthma. The steam distilled extract of fresh leaves of Ocimum sanctum was found to enhance anti-SRBC haemagglutination titre and IgE antibody titre. It significantly.inhibited the antigen-induced histamine release from the peritoneal m a ~cells of sensitized rats in vitro and also antagonized t responses to various $pasmogens on isolated guinea pig ileum. The plant extract appears to modulate humoral immune responses and it may be acting at several steps in the immune mechanism which needs further elucidation (Mediratta et ?I., 1988). The aqueous and alcoholic extracts of leaves of Rumex
Pharmacology of Medicinal Plants nepalensis showed antihistaminic and anticholinergic activity. The alcohol~c extract, in particular, was more potent (Agan,tgal et al., ' 985). The use of the plant in local allergic conditions may be attributed to the a:;tihistaminic property. Further study and fractionation of the alcoholic extrac: to isolate the active pri~ciple needed. In addition to the anti-inflammatory sctivity Leucas aspera is extracts prevented mast cell degranulation in rats (Redd; et al., 1986). On the other hand the intracutaneous skin test with the polle i grains of Prosopis luliflora and in vitio test showed signs of histamine release and allergic responses (Thakur and Sharrna, 1987).
Hypolipidaemic activity
Comrniphora mukul continues to be the most investigated plant for hypolipidaernic activity. Gugulipid, obtained from the gum resin of Commiphora mukul, feeding producsd a dose-dependent increase 'in the levels of noradrenaline and dopamine and in the activity of DBH in monkeys (Srivastava et .a/.. 1984). These findings suggest the possible lipid lowering mechanism of gugulipid. In the phase I clinical trial gugulipid was found to be completely safe. The efficacy was evaluated ir?Phase II trial in 19 patients of primary.hyperlipidaemia. It showed significant lowering of !:holesterol and/or trigly-cerides in 15 patients. All patients with familial combined hyperlipidaernia responded to the drug, while patients with familial hypercholesteraemia did not respond (Agarwal et al., 1986). This shows the action of guggul in selective patients. In another clinical study effect of gugul was seen in patients of hyperlipidaernia. The drug was found to be safe and it .markedly lowered the various lipid fractions known to be artherogenic along with a significant rise in HDL chokesterol (Verma and Bordia, 1988). Gugulipid is now being marketed as a new drug. In Il3' prelabelled mice thyroid gland culture, petroleum ether extract of Comminphora mukul significantly increased the turnover of radio-activity. Hypertrophy and hyperplasia of the thyroid gland was also observed (Singh et a/;, 1985a). This indicates that the hypolipidaemic plant can be used in the treatment of thyroid diseases. Yograj guggul (mixture of 27 plants) exhibited more marked immunodepressant effect than guggul (Commiphora mukul) (Shukla etal., 1986). Biochemical studies in rats indicate that Salai guggul (~oswellia'serrata) extracts showed hypolipidaemic activity through inhibition of cholesterol biosynthesis in the liver as with clofibrate (Zutshi etal, 1986). The powdered pulp of fruits'of Embelica ofiicinalis significantly reduced the serum cholesterol and atherosclerosis in cholesterol-fed rabbits (Thakur and Mandal, 1984). Fronl. Cicer arktinurn the antistress and antihyperlipidaemic principle was isolated and identified as pangamic acid. (Singh et a/., 1983). Fiw per cent ethanolic extract of seeds of Alfalfa (Medieago sativa) showed significant antiatherosclerotic effect assessed by the estimation of glycogen, cholesterol, triglyceride and phospholipid contents of cardiac and liver tissue. The effect was similar to clofibrate (Dixit and Joshi 1985) which could be due to decrease in intestinal absorption and increase in bile acid secretion and could be due to saponin content in the seed. The action is, however, encouraging. The
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G.K. Patnaik & &N. Dhawan
alcoholic extract also prevented the development of plaque formation and hyperlipidaemia in cholesterol fed rabbits (Dixit et a/., 1986). A significant hypolipidaemic activity was shown by Atylosia scarabaeoides in the primary screening tests (Prakash et a/., 1985). Commercial Guar seeds (Cymopsis tefragonoloba) were fed orally to guinea pigs in diet (40%. Feeding for 30 days reduced total blood cholesterol and sugar in normal and alloxan-induced diabetic animals (Srivastava et a/., 1987). Dly seed powder of Carum capticum fed orally (1% in food) for 4 weeks to rabbits significantly lowered the serum cholesterol, triglyceride and phospholipd levels. Tbc?serum cholesterolbinding reserve and HDL cholesterol showed a continuous rising pattern from the very first week (Agarwal and Pant, 1986), which indicates the potentiality of the plant as a drug. In rats intramuscular administratioit of Thevetia neriifolia significantly reduced the blood glucose, serum protein and cholesterol and elevated alkaline phosphatase (Goswami and Dutta, 1985). Further, the glycoside extract of Thevetia nen'ifolia in albino et rats stimulated synthesis of blood SLP by the osteoblast cells ( ~ o s w a m i a/., 1986). The hypothesis needs to be confirmed. In the bind brain and pituitary marked increase in ALP was als6 seen. This could be due to some trigger of release mechanism after administration of glycoside. The ethanolic extract of Aloe barbadensis fed for 2 months to dogs not only lowered the lipoproteinwt ih atherogenic properties (GLDL and LDL) but also increased the cholesterol concentration of HDL fraction which has been shown to be an important independent antiatherosclerotic factor (Dixit and Jain, 1985). In the alloxaninduced diabetic rats filtered juice of fresh red gram seeds (Cajanus cajan) was found to be hypocholesterolemic (Giri et el., 1986). The alcoholic extract of Nepeta hindostana at a dose of 20 mglkglday produced marked hypocholestremic effect in pigs. In addition, the histopathology of myocardial infarction suggested a beneficial effect of the plant (Arora, 1987). Jammun seed (Eugenia cumini) extract administered for 2 weeks to rats in addition to showing the antidiabetic effect also reduced markedly the serum cholesterol and serum triglyceride levels (Giri eta/., 1985). The active principle, however, needs to be isolated. Administration of water and ether extracts of bitter gourd (Momordica charantia) powder caused a significant fall in serum cholesterol levels simultaneously with its hypoglycaemic effect. The extracts also had a lowering effect on the body weight (Upadhayay and Pant,1986). Cabbage (Brasica var capitula) oil (100 mgikg p.0. for 30 days) produced a lowering of blood sugar and tissue cholesterol and triglyceride contents in rats (Tarfa et a/., 1988). The effect could be due to the presence of methyl cystein sulphoxide whose antihypercholesterolemic effect is known. However,the active principle needs to be isolated. Two glkg of raw garlic (Allium sativum) fed to rabbits for 30 days, on the other hand, produced a significant increase in serum cholesterol level associated with unwanted cardiac changes in ECG which were reversible on withdrawal of garlic (Gupta e l el., 1987). It will be difficult to postulate any ill effect of garlic in humans as the daily use is usually much less. However, excess use may be harmful.
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Pharmacology o f ~ e d i c i n a l Plants
Hypogiycaemic activity
Several plants which were investigatzd for hypolipidaemic activity were also assessed for hypoglycaemic activity and some plants hi~ve exhibited both effects. Plants used extensively in the traditional systems of medicine have continued to receive greater attention. A flavonoid from the ethanolic extract of wood of Acacr. I catechu showed hypoglycaemic activity (Chakravarthy et a/., 1983). Ethylaceiate extract of stem of Tinospora cordifolia showed a moderate blood sugar Lowering activity in rabbits (Mahajan and Jolly. 1985). Guar seed (Cymposis tctragonoloba) was fed orally to guinea pigs in diet (40%). Feeding for 30 d,!ys reduced total cholesterol and sugar in normal and alloxan-induced irabetic animals (Srivastava eta/., 1987). The hypoglycaemic effect of the plant may be due-to a d~recteffect (due to aminoacids content) or reduction in insulin requirement (due to galactomannan content). Different extracts of seeds of Trigonella foenumgraecurn showed significant blood glucose lowering effect in rabbits. The alkaloid-rich fraction was found to be the most active as tested by the glucose tolerance test (Jain et a/., 1987). The activity is promising and the plant needs special attention. Cabbage oil (Brasica var capitula) feeding to rats produced a good effect (Tarfa et al., 1988). reduction of blood sugar apart from hypolipida~mic In addition to the hypolipidaemic effect Jammun (Eugenia cumini) seed extrat administered for two weeks to alloxan-induced diabetic rats markedly reduced the blood sugar level (Giri et a/., 1985). In the alloxan-induced diabetic rats,'red gram (Gajanus cajan) was found to be hypoglycaemic and hypocholesteraemic. It also lowered the blood urea level. It was found to be non-toxic and had no adverse side effects (Giri et a/., 1986). This may be included in the diet of the diabetic. The effect of, water and ether extracts of bitter gourd (Momordica charantia) administered for 7, 14 and 21 days to albino rabbis revealed that no significant hypoglycaemia could be atained in the first week. From the second week, however, the effect became evident and at the end of third week it became most prominent. The plant also had a hypolipidaemic property (Upadhayaya and Pant, 1986). Dried leaf powder of Gymnema sybestre regulated the blood sugar \evels in alloxan-induced diabetic rats (Shanmugasundararn et a/., 1983). The extract produced blood sugar homoeostasis and increased the activity of the enzyme affording the utilization of glucose by insulin-dependent pathways. The pathological changes initiated in liver during hyperglycaemia are revesed by the extract. The herb is used in the control of diabetes rnellitus. The aqueous extract of the leaf antagonized hyperglycaemia in moderately diacetic rats and the effect persisted beyond 2 months after its discontinuation. It had, however, no effect in severe diabetic rats except for prolongation of survival time in the toxic group of animals (Srivastava et al., 1986). The drug induced longevity could be due to its known cardiotonic and adaptogepic characteristics produced by increasing resistance and immunity in diabetic animals. However, the exact mechanism needs elucidation. The hypoglycaemic action could be explained
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in the light of earlier reports of prevention of hypoglycaemic response of the anterior pituitary gland. Alcoholic extract of Hamiltonia suaveolens root produced significant reduction in blood sugar in normal and a less marked fall in alloxan treated rats. Similar results were observed in normal rabbits, dogs, and monkeys. The ethylacetate fraction showed an equipotent activity in normal rats. One month chronic toxicity study showed no untoward effect (Desai and Bhide.1985). Significant hypogiycaemia was observed with Afylosia scerabaeo!des (Singhal et a/., 1985). Aaueous extract of seeds of Tephrosk purpurea (60 mgkg p.0.) showed hypoglycaemic activity in normal and alloxanirduced diabetic rabbits. The effect was found to be less than that with tolbutamide in diabetic animals. The seeds were more active than the plant (Rahman et al., 1985) In rabbits aqueous suspension of seeds of Syzygium cunlini led to reduction in blood sugar level. In alloxan-treated diabetic rats the decrease was much less (Nair and Santhakumari, 1986). The mechanism of action seems to be extra-pancreatic. The crushed leaves of Munaya koenigii exhibited hypoglycaemic activity in fasting normal rabbits during the first hour itself. Simi\ar response was seen in glucose tolerance study in rabbits. ,In human volunteers a peak fall in blood sugar (25%) at 50 mglkg dose was seen 3 hour after. medication. In alloxan-induced diabetic rats the peak fall in blood sugar was seen at the fifth hour (Shanthakumari et a1.,1985). Different fractions of Swertia chirata showed blood sugar lowering activity in albino rats (Chandrasekar et al., 1987;Mukherjee and Mukherjee,l987). However, the hexane fraction was found to be most active. Probably it contains the active constituents. The fraction needs further chemical exploitation and the mechanism o f action needs to be established. The water-soluble fractions of different extracts of leaf of Bougainvillea spectabilis exhibited blood sugar lowering effects in the streptozotocin-induced diabetic rats (Sarkar et a/., 1986). Aqueous extract of a powdered indigenous preparation containing a mixture of 12 plants showed significant hypoglycaemic activity in normal and alloxan- induced diabetic dogs and alloxaninduced diabetic rats (Ainbpure etal., 1985). The individual plants need to be tested to identify the best plant and its active principle. Hypoglycaemic activity was confirmed in the fractions of the following plants: Trichosanthes dioica (Aswal et a/., 1984b), Dqdonea viscosa (Aswal et al., 1984a) and Echinops echinitus (Abraham etal., 1986). Work is being carried out to identify the active principles.
Hypotensive activity
The plants tested mostly have shown moderate to short duration of action. The experiments were done in normotensive animals. The active plants need to be tested in hypertensive animal models. The water insoluble alcoholic extract of fruits of Wthenia coagulans showed a prolonged fall in blood pressure in dogs. It also had a cardiodepressant effect (Budhiraja et a/., 1987). The effect seems to be direct. However, a new withanolide was isolated from the fruits which had a structural
SELECT RESEARCH PAPERS du EVIDENCE BASED AYURVEDIC DRUGS l '
Phannacology o f Medicinal Plants resemblance with the aglycones. The compound produced a mild hypotensive effect in mediated through cholinergic receptors. A carc:iodepressant effect was also noticed (Budhiraja et a/., 1983j. Work on the plailt Coleus forskohlii led to the isolation of the hypotensive principle forskolin, which appeared initially to be an isomer of coleonol, a diterpene. The two are possibly identical compounds. It possessed antihypertensive, positive'inotrop;::, platelet aggregation inhibitory and adenylate cyclase activating proper ti:.:^ (DeSouza et al., 1983). Scoparone a naturally occurring coumarin (6,7-di~ ;methyl esculetin) in the aerial parts of Artemesia scoparia produced a marked hypotensive effect with immediate onset and lasting for 2 to 5 hours in normote:,isive anaesthetized or conscious animals. It had a good oral absorption (S-iarma, 1985). The hypotensive mechanism seems to be partly central anri partly peripheral (Sharma, 1988). The effect of scoparone on tissue catecholamine content revealed that the hypotensive activity is independent of catecholamine lowering action (Sharma, 1987). Glycosides of Abrus precatorius produced a transient rise of blood pressure associated with a fall which could be attributed to rnyocardial depressant action (Basu et a/., 1985). Essential oil of the whole plant Blumea menlbranacea produced a marked and long lasting hypotensive effect in anaesthetized dogs (Mehta et a/., 1986). The mechanism seems to be a direct vasodilation and cardiodepressant action. It had also a CNS depressant effect. However, no dose-response study was done. The active principlealso. needs to be identified. The ethanolic extract of the pulp (pericarp of fruit) of Balanites roxbiirghii showed a moderate,hypotensive effect in anaesthetized dogs and.less marked effect in cats (Rao et a1.,1986). It seemed to be mediated centrally. The aqueous extracts of Kalanchoe integra and seeds of Canavalia virosa (Mukhopadhyay et a/., 1986) also showed hypotensive activity in addition to other pharmacological effects. The alcoholic extracts of Picrorhiza kurrooa, Tecomella undulata, so la nun^ nigruh and Cichoriom intybus which are used in the management of liver disorders, showed hypotensive effect in dogs (Panday, 1985). Hypotensive activity was confirmed in anaesthetized animals in the fraction of the following plants:Eucalyptus globulus, Euphorbia madden;, Lpon~oea pescaprae, Phyllanthus gardnerianus, Prirvula denticulata, Tamarix ericoides (Aswal et al.,l984b); Coscinium fenestratum, Phytolacca acinosa (Aswal et al.. 1984a); Acacia raddiata, Etrgenia magnifolia and Tibouchitla serl~idecandra (Abraham etal., 1986). Chemical and pharmacological work is in progress to , isolate the active constituents of these plants.
Cardiac .stimulant activity

L i e work has been done in this area. Only one plant has shown promising cardiotonic activity but A needs detailed evaluation. Epicatechin isolated from the bark of Pterocarpus marsupium showed a cardiostimulant effect, on frog heart, mediated by adrenoceptors. A hyperglycaemic activity was also noticed in higher doses in normal rats (Chakraborthy and Gode, 1985). Apart from the
G.K. Patnaik & B.N. Dhawan

hypotensive activity forskolin (isolated from Coleus forskohlir) also showed positive inotropic effect (DeSouza et a/., 1983). A glycosidal fraction of the whole inotropic effect on frog heart (Vohora plant Corchorus tn'dens produced p~sitive eta/., 1983). Study on the cardiovascular effects of "Rooh-afza" an indigenous preparation indicated that this mixture 0f.a number of natural .products selectively improved the coronary blood flow in laboratory animals (Gulaii et aL, 1985).
Diuretic activity
A nomocr of plant extracts showed promising diuretic activity. At the moment it is r:ot possible to ascertain whether this could be due to the presence of naturally occurring inorganic salts. The active material should be desalted and 'tested'. Moreover the potassium sparing nature of the plants should be established before considering them for development as drugs. A good diuretic actiwty was observed with the saponins isolated from Vigna sinensis, Vigna radiata and Vigna mungo (Sood and Bajpai, 1985). The drug "Narikel lavan" (from Cocos nucifera) produced a.diuretic activity in rats (Shukla et a1.,1985). Detailed investigationis, however, required including an elucidation of the mechanism of action. A number of plants have confirmed diuretic activity in various fractions. These are:Meconopsis aculeata, Pentapanax parasiticus, Pulicaria angustifolia, Uncaria macrophylla, Vicia pallida (Aswal et el., 1984b); Clerodendron paniculatum, Pogosten~on pubescens, Sansevieria trifasciata (Aswal et a/., 1984a): ~naphalis' n~arcescens,Elaecarpus munronii, Nepeta erisotachya, Samadera indica and Senecio corymbosus (Abraham et al,, 1986). Further . chemical and pharmacological work is being carried out to isolate the active principles and to establish the mode of action.
Hepataprotective activity
In most of the experiments carbon tetrachloride (CCI,) was used as an agent to induce hepatic damage in rats in different doses and for variable duration. The damage simulated viral hepatitis, fatty infiltration and cirrhosis. Ethanolic extract of the rhizomes of Picrorhiza kurrooa exhibited potent hepatoprotective activity in rats and mastomys .The active principle was identified as an iridoid glycoside mixture, kutkin. The kutkibfree fractions of the extract had no hepatoprotectwe activity, rather they aggravated the toxicity. Kutkin had significant activity against hepatic damage induced by galactosamine in rats and against Plasmodium berghei in mastomys, and appears to be a promisilig lead (Ansari et a/., 1988). The 50% etha~olic extract of roots and leaves of the plant Phyllanthus niruri had hepatoprotective effect on alcohol-induced liver damage on nonhepatectomized and partially hepatectomized rats (Agrawal et' a/., 1986). However, the hexane extract of the aerial parts of Phyllanthus niruri yielded triacontanal, phyllanthin and hypophyllanthin. Phyllanthin and hyp~phyllanthin
'
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328

protected against CCI, and galactosamine induced cytotoxicity in primary cultured rat hepatocytes, while triaronta::~: was protctctive against galactosamine-induced toxicity (Syamasundar et a/., 1985). Ttae study was done with 0.01 to 1% concentration and only GPT activity was studi~ The overall effects d. of the crude drug could be mediated due to the above =onstituents. The chronic type of damage induced by CCI, ..vas prevented by (+) cyanidanol, the active principle of Acacia catechu. It h o lever, failed to prevent ~ the acute type of damage in rats (Rege et al., 1984b). The compound restricted the fibrosis (Nirmal et al., 1985) but had nc effect on the regression of parenchyma. Therefore, the necrotic tissue was found o persist. Cyanidanol might act as a fibrinolytic agent. The mode of action n( ?ds further study. 3-p-hydroxy~2,3-dihydrowithanolide obtained from :ne fruits of Withania F coagulans was found to possess marked hepatoprotectivc effect against CC14induced toxicity as evident by biochemical and histopathological studies It was found to be more active than hyqrocortisone (Budhiraja et a/., 1986). The possible mechanism could be like glucocorticoids es the compound is steroidal in nature. The acute type of liver damage was not prevented by Tinospora cordifolia but the chronic type was prevented. The plant prevented the fibrous changes and promoted regeneration of parenchymal tissue (Rege et a/.,1984a). Aggrevation of acute ,damaqcould have occur; ed either by acceleration of metabolism of CCI, leading to production of free radicals or by accumulation of the metabolites. Prevention of fibrosis by the plant could be due to an action of the immune process. This needs further study. Alcoholic extract of the stem of this plant showed hepatoprotective effect in mice, rats and rabbits against CCI, (Singh et a/., 1984a). Since CCI, produces cell membrane damage, it can be postulatedthat Tinospora cordifolia might act through membrane s!abili-zation. The Ayurvedic use of the plant in liver ailments seems to be logical. The dry fruit powder of Piper longunl had no effect against the acute damage nor against the cirrhotic changes induced by CCI,. The regression process was, however, improved by the plant by restricting fibrosis (Rege et a/., 1984~). Piperlongurn is included in Ayurvedic medicines against liver ailments, but it seems to have no beneficial effect per se. Aqueous extract of the above plants (Tinospora cordifolia, Piper longum (+) cyanidanot from Acacia catechu) administered orally did not show hepatoprotective effect in CC14-inducedacute damage in animals, rather they caused aggravation of this damage. However, prolonged treatment with Piper longum (8-12 weeks) led to normalization of parenchymal damage. Tinospora cordifolia improved the regression pattern and restricted fibrosis (Nirmal et.al., 1985). The aqueous leaf extract (0.5 g k g p.o.x6 days) of Andrograpt5.s paniculata showed a significant hepatoprotective activity in CC1,-induced hepatotoxicity in rabbits as indicated by a reduction of serum asparate amino-transferase and alanine aminotransferase and the histopathological examination of liver tissue. The effect was, however, less marked than Liv-52 (Dwivedi et al., 1986). The herbal drug "Livol" composed of Boerhaavia diffusa, Solanum nigrum, Tenninalia atjuna and Citrullus colocynthis administered orally to dogs exhibited
G.K. Patneik & B.N. Dhawan

hepatoprotective activity as judged by the biochemical parameters (Pandey et a/.,1985) The individual plants should be evaluated and the identification of the active principle in each plant si~ouldbe given importance. The CCI, induced hepatotoxicity in rats was counteracted by Eclipta alba in addition to its anti-inflammatory activity (Chandra et a/., 1987). Alcoholic extract of the leaves of Whania somnifera (1 glkg) possessed a hepatofirotective effect against CCI,-induced toxicity in mice and was equipotent to 10 my/kg of hydrocortisone. This plant also showed a potent antiinflammatory activity (Sudhir etal., 1986). It seems that the two properties may be complimentary.
Spasmolytic activity
Due to the rigid control over poppy cultivation alternatir!e plant sources of obtaining spasmolytic agents are being explored out world wide. This led to the testing of various plants for spasmolytic activity. Many plants are also tested as they were reported to possess this activity in the traditional use. Active constituents have been isolated from sevekal plants and evaluated in detail but unfortunately none of them scores over papaverine. The aerial parts of Corydalis meifolia yielded 13-methyl-tetrahydroprotoberberin (Cavidine) which showed a nonspecific spasmolytic activity by both parenteral and oral routes (Patnaik etal., 1984). It was found to be less potent than papaverine. Because of its good yield this novel compound merits chemical exploitation for improvement of biological activity. The 50% ethanol extract of the aerial parts of Heracleum thomsoni showed promising spasmolytic activity. Several coumarins were responsible for the activii. Among these angelicin was found to be most active (Khan etal., 1986). The coumarins were also isolated from the hexane and ethyl acetate fractions. Angelicin showed nonspecific spasomolytic activity in a variety of in vivo and in vitro test models and was also found to be orally active. It was almost equipotent to papaverine. It relaxed the smooth muscles of gastro-intestinal, biliary, urinary, and vascular systems in several species (Patnaik et a/., uterine respi~atory 1985, 1987a). Rheum webbianum also showed a good spasmo\ytic activity. The active principle was identified to be desoxyrhaponitigenin (Patnaik et a/., 1987b). The ethanolic extract of Cbusena anisata had spasmolytic activity in vitro. After further fractionation the active principles were identified as some novel furanocoumarins. Amongst these ansolactone was found to be the most potent and possessed good oral absorption (Lakshmi etal., 1987). Maxima isoflavone isolated from Tephrosia maxima showed nonspecific antispasmodic activrty in vifm Vaximum activity was observed with isofalvona G but R was less active than papaverine (RamMurthy ef a/., 1986). The saponin isolated from Madhuca indica and characterized as protobasic acid showed moderate spasmolytic activity on isolated guinea pig ileum preparation. The glycosides obtained from Symplocos spicata (Frotan et a/., 1983), and Corchorus hidens (Vohora etal., 1983), saponins isolated from Vigna sinensis, Vigna ~adiata and Vigna mungo (Sood and Bajpai, 1985), the cold aqueous extract of Kalanchoe
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Pharmacology o f Medkinal Plants integra (Varma et al., 1986) and essential 011from Pseudosorghum (Mehta et al., 1983) showed varying degrees of smooth muscle relaxant activity. Spasmolytic activity of a number of plant extracts was confirmed in the subsequent fractions. The plants are:Clausena indica, Corydah's meifolia, Dalbergia sisso and Rheum webbianum (Aswal et al., 1984b): Axyris amaranthoides, Coelogyne ovalis, Desmodium pseudotriquetrum and Thermopsis barbata (Aswal e t al., 1984a); Fraxinus xanthoxyloides, Milletia splendens, Saussurea albessns, Setlecio kunthianus and Toddalia asiatica (Abraham et al., 1986). Further fractionation and isolation of the active principles in the more promising plants is being carried out.
Antigastric ulcer activity

A significantamount ofdata has been reported on the antiulcer activity of banana fruit. The active variety is Muss spaientum var paradisica. The banana pulp powdar fed orally daily in a dose of 500 mglkg increased mucosal resistance as evident by significant increase in the (3H)-thymidine incorporation into mucosal cell DNA, increase in total carbohydrate content of gastric rnucosa, decrease in gastric juice DNA and protein and increase in carbohydrateiprotein ratio of gastric juice. Aspirin produced an opoosite effect (Mukhopadhyay et a/., 1987). The study suggests that the ulcer healing property of banana is by strengthening the mucosal barrier. The antiulcerogenic effect of banzna powder was also studied against aspirin-induced gastric ulcer. The potent effect seems to be again due to strengthening of the mucosal barrier. The study further indicates that the antiulcerogenic principle appears to be present in the unripe fruit and varies from season to season and place to place in the subcontinent (Goel et a/., 1985). The material is under clinical evaluation. Several steryl and acylsteryl glycosides (sitoindosides I , 11, Ill and IV) have been isolated from Musaparadisica (Ghosal and Saini, 1984; Ghosal, 1985). Sitoindoside IV augmented the synthesis cf PGI, like compounds in the gastric mucosal tissue of rat (Bhattacharya and Ghosal, 1987). The antiulcer activity of the plant could be mediated via the cytoprotective effect of PGI,-like compounds. Sioindoside IV in a dose of 100-400 uglmouse, administered for 3-7 days, produced signifi9,ant mobilization and activation of peritoneal macrophages (Chattopadhyaya et a/., 1987). This indicates probible immunostimulant activity of the ptant which needs further evaluation. Nimbidin (40 mglkg i.v.) the bitter principle from the oil of ,Azadirachta indica seed kernel, suppressed the basal as well as the histamine and carbachol stimulated gastric acid output in rats. The effect resembles that of histamine H2 receptor antagonists (Pillai and Santhakumari, 1985). The mechanism of action needs showed good further elucidation. Aqueous extract of the bark of Ficus ~acemosa anti-gastric secretory and antiulcer activity in rats. It stimulated the mucopolysaccharide secretion and inhibited the acid secretion (Pate1 and Vasavada, 1985). The results are promising and the plant needs further study.
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G.K. Patnaik & 0.N Dhawan .
CNS activity
A large number of plants were investigated for CNS activity. But, except for Bacopa monnieri and Fumaria indica attempts were not made to isolate the active principle. Majority of the plants, however, showed CNS depressant qctivity. The activity of the memory improving plant Bacopa monnieri has been.shown to be due to 2 saponemBarcside A and B (Singh and Dhawan, 1985). It had a facilitory effect on the newly acquired behaviour. It improved acquisition and consolidation (retention) and it detayed the extinction of the labile behaviour. The mechanism of the facilitatory action needs further investigation. The findings confirm the traditional use of the plant to improve performance in various learning situations. Fumariline, a spirobenzyl isoquinoline alkaloid isolated from seeds of Fumaria indica showed a dose (10-15 mgkg i.p.) dependent CNS depressant acthnty including anticonvulsant activity in rats. The compoulid, however, has no significant muscle relaxant activity (Kumar et al., 1986). Methanolic extract of Morus hdica produced a CNS depressant action in mice and the motor protile resembled a minor transquilizer but without muscle relaxation and anticonvulsant property (Pal etal., 1983). The essential oil from Pseudosorghum grass showed a mild tranquillizing action (Mt?hta et al.. 1983). The alkaloidal fraction obtained from the alcoholic extract of Triantheme portulacastrum (Vohora et el., 1984b), roots of Salvia haemetodes (Akbar et al., 1984), a crude glycoside fraction of Corchorus tridens (Vohora et a/.,1983), aqueous extract of Kalanchoe integra (Varma et a/., 1986), Cuscuta chinensis (Akbar et a1.,1985). Chloroform fraction of Syzygiurn cumini (Chakraborty et al., 1986), leaf (Ravishankar et al., 1985) and seed (Ravi-' shankar et al,'1986) extract of Vitex negundo and leaf extract of Azadirachta indica (Singh et a/., 1987) showed varying degree of CNS depressant activity validating their traditional use. CNS depressant activity as judged from significant potcintiation of barbitai sodium hypnosis in mice was also confirmed in various fractions of the following plants:Zingiberroseum (Aswal etal., 1984b), Cissampelos pareira, Desmodium pseudotriquetrum, Saccharum oficinarun~,Scrophularia koelzii (Aswal et a/,, 1984a); Etinocarpusnimonii and Hippophae thamnoicies (Abraham et el., 1986). Work'is being continued in the above plants to isolate and characteke the active principles.
Adaptogenic activity
Following the increased use of Panax ginseng and related species as adaptogenic agents there has been a lot of interest in the plants used in the Indian systems of medicine, particularly in the Ayurveda as Rasayanas. However, during the period under review limited work has been done an such plants and only three plants showed promising activity. Aswagandha, an Ayurvedic d ~ obtained from the roots of pthania somnifera, showed positive g anabolic effects (Varma, 1983). Two new acylsterylglucosides sitoindoside Vlt
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Pharmacology o f Medcinal Plants and Vlll isolated from the roots of Withania somnifera produced marked antistress activity in a number of test models. The activity was also potentiated by Withaferin-A, a common withanolide. The compounds had low toxicity (Bhattacharya eta/.,1987a). From Cicerarietinuni the stamina building and antistress principle has been isolated and identified as pangamic acid (d-gluconodirnethyl aminoacetic acid) (Singh et el., 1983). An Ayurvedic formulation "Alert" containing oil of Celastrus paniculatus inhibited glycogenolysis in the muscle fibre of rats. It reduced depletion of liver glycogen after swimming bouts in rats. This suggests possible antistress property of the plant as described in the Ayurveda (Kakrani et el., 1985). It is necessary to systematically study these plants employing a battery of tcst systems and to initiate developmental studies with the more promising agents.
Anticancer activity
Many plant materials have shown encouraging antitumor and cytotoxic activity in cancerous cells. However, all of these need further study to evaluate their specific* by testing these also on the normal healthy cells. An orange coloured oil obtained from the petroleum ether extract and a resinous material from the methanol extract of the nuts of Semicarpus anacardium weie found to possess antitumor property against P388 lymphocytic leukaemia in mice (Indap etal., 1983). Two closely related major constituents of Semicarpus anacardiunl, Bhilwanol-A and Bhilwanol-0, have been isolated and found to possess mild anticancer activity against P388 lymphocybc leukaemia in mice (Gudgaon etal., 1985). A cytotoxic effect of the oil of this plant is also reported (Pathak etal., 1983). The acetylattd oil per se did not have any activity but markedly potentiated the antitumour activity of different groups of anticancer drugs against P388 and sarcoma 180 systems in animals (Indap et al., 1986). The effect could be attributed to an increase in cell membrane permeabnility to the specific group of molecules. However, a detailed study to establish the mode of action is needed. The plant seems to have promising potentialw. The sesquiterpene lactone perthenin, isolated from Parthenium hysterophorus, was studied for its cytotoxic effect in vitro using cultured bovine kidney cells. It was found to inhibit macromolecular synthesis. At luglml concentration there was 50% inhibition in RNA. DNA and protein synthesis. It also markedly inhibited toe activity of key cellular enzymes (Narasimhan et al., 1985). The compound seems to have a potential antitumour activity for which it needs further evdmtion partidularly for the specific activity. Plumbagin isolated from the bark of Plumbego rosea and Plumbargo zeylanica regressed experimental tumor (Purushottaman et a1.,1985). Echitmine chloride isolated from Alostonia scholaris showed a dosedependent regression of methyl cholanthrene-induced fibrosarcoma in rats. At higher doses it was active against P388 lymphocytic leukaemia (Mohan et al., 1985). The compound needs detailed toxicity study at differenr dose levels on other tissues to ascertain the specific anticancer activity.
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G.K. Patnaik & 0.N Dhawan .
Ethanolii extract of Curcuma longa and an ointment of curcumin produced marked symptomatic relief in patientswith ex?ernal cancerous lesions (Kuttan et al., 1986). Further, curcurnin was found to be cytotoxic to Dalton's lymphoma cells in v i h . It was also found to inhibit the growth of Chinese hamster ovary cells (S~udamini Kuttan, 1986). The antitumor property of curcumin needs and futther study. The inhibition of mitochondria1enzymes involved in a-tivation of carcinogens also needs to be evaluated. Several plants have been investigated for their effects on the Dalton's sdi tumor. A purified material (presumably a flavone glycoside) isolated from lxorajavanicawas st~idied its effects on solid tumor development in mice for (Nair and Panikkal, 1988). It completely prevented the formation of tumor and arrested further growth in the already formed tumor. The glycoside deserves further evaluation. An Ayurvedic drug containing the flowers of Ixora coccinea was found to retard the development of tumor and arrest the development of already formed Dalton's lymphoma as solid tumor in experimental animals (Panikkar et a/., 1986). The methanolic extract of seeds of Carum bulbocastrum produced complete cytotoxic effect on Dalton's lymphoma (John and Panikkar, 1988). A peptide of mol. wt. 5000 isolated from Mistletoe extract (Viscum album) reduced the solid tumor induced by Dalton's lymphoma ascites tumor cells . on mice. The peptide was not cytotoxic to normal lymphocytes which indicates a cell dependent toxicity (Kuttan et a/., 1988). The aqueous extract of the flowers of Crotus sativus also showed cytotoxic activity against Dalton's lymphoma in mice3(Panikkarand Majella, 1986). Alcoholic extract of whole plant Withania somn#era prevented the development of adenomas in lungs of mice induced by urethane. The extract also prevented the urethane induced decrease in body weight, mortality, leucopaenia and lymphopaenia (Singh et a/., 1986). The plant extract seems to induce a stategf nonspecific increase in resistance. Elaborate biochemical and immunological studies are indicated to provide further data. A number of plants have confirmed anticancer activity in their subsequent fractions as tested against human epidermoid carcinoma of n-asopharynxin tissue cultureand P388 lymphocyticleukaemia in mice (Aswal bt al., 1984b). These are: Agave americana, Ampelocissus tomentosa, Carpesium abrotanioides, Casearia ovata, Cassine glauca, Coleus caninus, Costus sativum, Cudrania cochinchinensis, Cyanotis cristata, Cyathea khasayana, Diplazium esculentum, Dysophylla crassicaulis, Euphorbia maddeni, Gossypium herbaceljm, Hyptis suaveolens, lnula cuspidata. lpomoea nil, Jatropha glandulifera,Junipenrs indica, Leea n~mphylla, Oplismenus burmannii, Pollia subsum bellata, Scirpus erectus and Thalictmm cultraturn.
Anti-infective activity
Many plant extracts have been tested for antibacterial, antifungal, clntivira) and antihelminthic activity, but only a few have shown promising activity.
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Pham~acology Medicinal Plants of The essential oil obtained from the leaves of Elsholtzia poljdracha showed ankcterial activity in vitro against 0. anthracis. V. cholerae, C. welchii, S. typhi, P. aeruginosa and S. lutea (Chaturvedi and Saxena, 1985). It also showed potent antifungal activity against plant pathogeniz fungi A. nidulans, A. niger and F. oxysporum (Chaturvedi et el., 1987). The alcoholic extract of leaf of Ocin~umsandun~ dilution) completely inhibited the growth of strains of M. (1:l tuberculosis (Reddy et el., 1986). The ethanolic and aqueous extracts of Phyllanthus Ratemus and Jatropha glandulifera showed antibacterial and antifungal activity. The alcoholic extract in addition had antiviral activity against Hepajitis B surface antigen (Ramachandani and Chungath, 1987). The essential oil of the root of Uvaria narum exhibited good antimicrobial and antihelminthic acti\ntyin v b (Nanda et a/., 1986). Several sesquiterpenes were isolated from the oil. The activity could be due to these sesquiterpenes. The aqueous extract of leaf of Eucalyptus laceolatus possessed strong antifungal activity against F. solani. M. chinereus, C. lunata, P.bubaki and A. sclerotiorum (Barde, 1985). The oil obtained from the leaves of lnula cuspidata showed marked antifungal activity against pathogenic fungi, in particular against A. fumigatus, in vitro (Chauhan and Saxena, 1985). Various extracts of seeds of Vernonia enthelmintica possessed significant activity against A. lumbricoides and H nane. The alcoholic extract was most potent (Singh et a/., 1985d). An . indigenous drug formulation containing onion (Allium cepa), garlic (Alljum sativum), lemon (Citrus linlon) and turmeric (Curcuma longa) and seeds of Abrus precatorious completely eliminated scabies in pigs (Dwivedi and Sharma, 1985). Many of the above plants are used in Ayurvedic medicines. Some of these need further evaluation including isolation of the active principles. Fractions of Crotalaria modurensis (Aswal et a/., 1984b), Coscinium fenestratum (Aswal et a/., 1984a), Azadirachta indica (Abraham et a/., 1986) confirmed antifungal activity. Fractions of Eucalyptus globulus (Aswal et a/., 1984b), Coscinium fenestratum (Aswal et el., 1984a), Lespedeza stenocerpa (Abraham et a/., 1986) confirmed antibacterial activity. Fractions of Carex obscura, Shopera robusta (Aswal et al., 1984a), Terminalia cheubla, Hippophae salicifolia, Syzygium megacarpus (Abraham et el., 1986) were confirmed for antiviral activii and antihelminthic activity was confirmed in fractions of Lycium barbarum (Aswal et a/., I 984b).
Antifertility activity
A review of work done upto 1981 has been published (Kamboj and Dhawan, 1982). Subsequent data from 1983 onwards on some promising plantsshowing activity in male and female animals are summarized below. The work on anti-implantation plants has been reviewed by Kamboj (1988). Various Investigators have used different species of animals and periods of drug administration. However, it is advisable to utilise standard procedures of assay (like WHO ME protocols) to draw valid conclusions and to permit evaluation of relative efficacy.
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G.K. Patnaik d B.N. .Dhawen
Plants active .in fernale:.A large number of plant extracts have shown antifertility activity in female animals, but only in 3 plants the active prindple has been identified. Most of the plants, however, possessed estrogenic activity and, therefore, have little clinical potential. Administered orally 1-5 days post coitum, to female rats the ethanolic extract and hexane, benzene and chloroform fractions of Ferulajaeschkeana prevented pregnancy. The active principle was identified as a new coumarin, ferujol.hsingle administrationof ferujol(0.6 mgkg) on day 1,2 or 3 postcoitum prevented pregnancy significantly (Singh et a/., 1985b). It was active during the preimplantation period. The compound has potent estrogenic activity which could be responsible for its contraceptive effect. Vicolide B a sesquiterpene ladone isolatedfrom Viooa indica showed marked reduction in litter size in rats treated with 50, 100 mglkg p.0. for days 8-14 or days 14-21 post coitum. The effect may be due to antiestrogenic activity or due to a direct embryo-toxicity. It was found to be devoid of progestationalactivity (Susan et el., 1986). Further, the aqueous extract of the whole plant administered in 98 or 56 times the human dose (as used by the tribal people, in Bihar) in subacute toxicity study in rats and rabbits was found to be safe as judged by biochemical and other parameters. The ethanolic extract of the aerial parts of Caesalpinia decapitata administered p.0. on days 1-8 post coitum in female hamster exhibited significant contraceptive activity but was devoid of any estrogenic activity. Further fractionation revealed that the activity was localized in the butanol and aqueous fractions (Keshri et a/., 1988). A combination of alcoholic extracts of Azadirachta indica (leaf and stem), Piper longum (fruit), mbclia ribes (harries) and Gossypium indicum (seeds) considerably prolonged the diestrus phase of female rats (Reddy et el., 1984; Kokate et el., 1987). Ei nbelin, isolated from Embelia ribes, increased the uterine weight, total protein, total solid and ACP activity but decreased the RNA content, glycogen and ALP activity in ovariectomized rats. No biochemical changeswere observed in prcrgressive primed rats (Prakash et a/., 1986a). The results suggest that estrogenic property of the substance may be responsible for the antifertility activity of Embelia ribes. The alcoholic extract of Hibiscus rosa-sinensis controlled60% fertility in rats. The surviving foetuses showed neonatal defects. In a dose of 270 mglkg p.a. it caused 70% reduction in weight of foetus (Sethi et el., 1986). The alcoholic extracts of seed of Annona squamosa and pulp of Xeromphiq spinosa significantly prevented pregnancy in animals (Saluja and Dantani,l984). Prakash and co-workers screened 20 medicinal plants for antifertility activity rn female rats (Praksh eta1.,1986b). Among these 50% ethanolic extract of Dupatriumjunceum, Puemria tuberose and Rubus ecs pu It ili inhibited pregnanoy. .Estrogenic andlor antiestrogenic activity was observed in several plants. Some of these also exhibited antifertility activity of varyin($ degree. Acetone extract of the seeds of Foeniculumvulgare showed a dosedependent increase in the weight, nucleic acid and protein concentration inthe cervix and vagina of castrated female rats (Annusuya et a/., 1988). The results of the study suggest the anabolic nature as well as the estrogen-like effect of the plant,
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Pharmacologyof Medicinal Plants Neerp oil (Azadrachta indice) administered intravaginally and p.0. showed 80% foetal resorption activity in female rats (Lal et a/.. 1986). At the higher dose there was mortality indicating toxicity but even then there was incomplete antifertility effect. Similar antifertility activity was also observed by administering neem oil on selected days of pregnancy in female rats (Lal et al., 1987). The material seems .to have little clinical potential. The fractions of Leipiium capitatum exhibited estrogenic activity (Singh et a/., 1984~). Aqueous extract of the root of Moringa oleifera produced both estrogenic as well as antiestrogenic effects in rats (Chattopadhyay et a/., 1987). This could be due to the peresence of several constituentsin the extract. Hence isolation of the active constituents is neded to substantiate the reported use of the plant as an antifertility agent. The butanolic extract of Pueraria tuberose showed estrogenic activity in female rats as evident by biochemical and histological stud~es (Shukla etal., 1987a, b). Petrol and alcoholic extract of the seeds of Daucus carota administered orally showed mild antifertility effect when given 1-10 days post pregnancy in rats (Lal et a/., 1986). It was found to have estrogenic activity (Kaliwal and Ahmed, 1987). The water soluble alcoholic extract obtained from defatted powdered seed kernel of Balanites roxburghii showed antiovulatory antioesrus effects and inhibited sperm motility in rats and rabbits (Shukla et al., 1986). The butanol fraction of the aeriai parts of Acharanthes aspera given on 1-5 day of pregnancy in rats prevented pregnancy. It also showed a marked estrogenic activity (Wadhwa etal., 1986). Antifertility activity was also confirmed in fractions of Bupleurum marginaturn, Chonemorpha fragrans, Pluchea lanceolata, Pulicaria angustifolia, lpomoee pescarpae, Zingiber roseurn (Aswal et al., 1984b); Cacia farnesiana, Lepidium capitatum, Loniera japonica, Juniperus communis (Aswal et a/., 1984a) and Moringa pterygosperriia (Abraham et al., 1986). Oxytocic activity in rats was confirmed in the fractions of the following plants.Amorphophallus cor~ipanulatus, Codonopsis ovata, Deutzia corybose, Ephedra geradiana, Geranium lucidum. Gnaphalium pensylvanicum, Hippophae rhamnoides, Vicoa vestita, (Aswal et a/., 1984a); Luffa echinata, Polemonium coeruleum, Thalictrum cultraturn (Aswal et al., 1984b); Berberis pseudumbellata, Hippophae salicifolia, Lespedezajuncea, Lespedeza stenocaropa and Polygonup nepalense (Abraham etal., 1986). Most of these plants were, however, ineffective in causing abortion in pregnant animals. Isolation of the active constituents in selected plants is in progress. Plants active in male: Gossypol (Thespesia populnea) given in doses of 20, 30 and 40 mglkglday in male rats produced marked degenerative changes in the gonads. Besides testes. epididymis was also affected by tQe compound (Kaur et a/., 1988). Plumbagin isolated from the roots of Plumbago zeylanica administered daily for 60 days caused selective testicular lesions in male dogs. A reduction in the weight of testes and epididymis was observed. Inhibition of androgen dependent structures was also noticed (Bhargava, 1984). Intramuscular administration of saponin rich fraction isolated from the fruits of Sapindus triioliatus daily for 2 months caused reduction in the weight of testes
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G.K. Patnafk 6 B.N. Dhawan
and epkilidymis, inhibition of spermatogenesis and alteration in epididymal
t s u (Bhargava, 1986). The effects suggest decreased production and supply ise
of androgens. The mechanism of action needs to be worked out in detail. The aqueous solution of kernel powder of Semecamus anacardium markedly affected the fertivi in rats. \t caused reversible arrest of .spermatogenesis. However, it produced severe testicular lesions like vacuoSiaiion, nuclear pyknosis, katyorrhexis and atrophy of leydig cells (Singh, 1987). Oral' feeding seeds also produced a marked of 50% ethanolic extract of Syzyghm cc~m'i androgen deficiency in male r a b b i and rats (Sinha et el., 1986). The flower extract of Mahtavisucus conzatti also arrested spermatogenesis and led to atrophy of secondary sex organs (Pakrashi et at., 1985). Any agent affecting leydii cell function cannot be used as male contraceptive and hence it seems that there i no positive lead in this area available so far. s
Other pharmacological activities

A quarternary alkaloid isolated from Co~culuslaurifolius possessed marked neuromuscular blocking activity of nondepolarizing type like dtubocurarine. It had a prompt onset of action and a reversible effect but the duration of action was too -long for any possible therapeutic usefulness (Mukherjee et a/., 1984). Gindarinin hydrochloride an alkaloid of Stephanie glabra possessed local anaesthetic activity like procaine (Mahatma et a/., 1986). The compound was devoid of surface anaesthetic property which may be a disadvantage. The alcoholic extract of Crataeva nurvala (Varuna) given for 36 days significantly reducedthe size of arb;fidlaly produced urinory bladder stone in rats (Report CCRAS, 1986). The plant needs further evaluation, However, Aerva lanata did not affect formation or dissolution of phosphate type urinary stones in rats (Gurumatfhava Rao et a/., 1985). In rabbits root powder of lnula recemosa and Saussurea lappa administered orally showed PGE, like kctivity in aortic tissue. Nigella sativa seeds administered to goats increased the milk production substantially. The galactagogue activiG in agalactia was noticed as the seed causea a sustained rise in the milk yield v ~ h a n Panwar, 1987). The plant may be beneficial and clinically in the management of agalactia.
Concluding remarks
\
This survey shows that a large number of plants has been screened for diverse type of biological activities. There has been limited follow-up studies and in a few cases only an a&e constituent or even an active standardised fraction been obtained. Very few detailed studii have been done with pure compounds. On the contrary chemical constituents have been isolated from a large number of Indian plants but most of these have not been biologically evaluated and,
338
therefore, not included in this review. It is, therefore, necessary to evolve a comprehensive strategy to biologically evaluate isolated compounds and to quickly undertake precllnical developmental studies if new drugs are to be obtained from this important source in a reasonable time frame. Another major limitation in majority of studies has been lack of botanical authentication and any details of place and time of coliection of plant materials in most of the papers. This is absolutely essential to ensure reproducibility of results and to reduce prcblems in follow-up studies. There have been serious discussions to evolve an? utilise alternate strategies in development of new therapeutic aids from plants used in traditional systems of Indian medicine due to limited success, the long time and expenses involved in studies reveiwed above. The lndian Council of Medical Research has started a large project by initiating controlled clinical studies on selected plants in diseases where satisfactory modern drugs are not available e.g. filaria, ~nfective hepatitis, bronchial asthma, etc. ICMR has already got promising data on use of Ksharsootra in treatment of anal fistula (G.V. Satyavati, personal communicatioi ) and other trials are continuing. There is a concommitant follow-up of the plant materials selected for chemical and pr~armacological these studies. The progress of this project will be watched witk interest. What should be thestrategy for the future? It will be neces ,ary to define priority areas and to concentrate developing new drugs from Indian plants in these conditions with a concerted multipronged effort. These areas should fertility include priority areas for health care in India like malaria, Iei~hm:~niasis, control and diseases for which no satisfactory drugs are avaiiab'?, like liver displants and orders, allergy, stress and memory despair. Carefully selec~ed specific test modelsshould be employed in these cases. 'Eff~~rts need to be strengthened in studies of marine flora and fauna also! The data on the plants discussed in :?is review have been summarised as activity wise in Table 1 for ready reference
Table 1 Pharmacological Activity Present it: Different Plants

Name of the Plant Activity kefnrences
Adaptogenic
Celastrus paniculatus Cicer arietinum Withania somnifera
Analgesic
Abutilon indicum Cissus quadranoularis Cuscuta chinensis
Kakrani et a/., 1985 Singh e a/.,1983 f Bhattacharya et al., 1987a Varma et a/.,1983 Bagi et a/., 1984, 1985 Singh et a/., 1984d Akbar et al., 1985
G.K. Patnaik 8 6.N. Dhawan

contd
...jTable I)
Desmodium gangeticum Embelia ribes Gossypium indjcum Hedychium spicatum Ocinwm sanctum Phyllunthus fraternus Polygonum glabrum Randia dumatorum Rhus semialata Salvia haematodes Solanum melongena Trianthema portulacastrum Tribulus terrestris Vitex negundo Acasia farnesiana Albizia lebbeck Allium cepa Cessia+spectabilis Leucas aspera Ocilnum sanctum Piper longum Prosopis juliflora Rumex nepalensis Tinospora malabarics
Ghosh and Ananda

Kumar. 1983 Atal et el., 1984 Vswanathan et a/., 1985 Srimal et el., 1984 Godhwani et a/., 1987 Hukerj et a/., 1985 Singh etal., 198% Ghosh et a/., 1983 Bhattacharya et a/., 1987b Akbar et a/., 1984 V ~ h o r a a/., 1984a et Vohora etal., 1984b Prakash et al.;1985 Ravishanker et aL, 1986 Trivedi et al., 1984 Johri et a/., 1985 Tripathi et al., 1983 Handa et a/., 1983 Johri et al., t985 Mallaiah et a/., 1984 Reddy et a/., 1986 Medirata et el., 1986 Dahanukar and Karandikar, 1984 Thakur 8 Sharrna, 1987 Agarwal et a/., 1985 Bhattacharya e el., 19% f Aswal et a/.. 1984b Mohana et a/., 1985 Aswal et al., 1984b Aswal et al., 1984b John and Panikkar,1988 Aswal et a!., 1984b Aswal et al., 1984b Aswal d a/., 1984b Panikkar and Maiella, 1986 Aswal et a \ , 1984b Kuttan et a/.. 1986
Anticancer
Agave americana Alstonia scholaris Ampelocissus tomentosa Carpesium abrotaniodes Carum bulbocastrum Casearia ovata Cassine glauca Coleus caninus Crotus sativus Cudrania cochinchinnesis Curcuma longa
340

contd ... (Table 1)
Cvanotis crfstata Cyathea khasvana Diplazium esculanlum Dysophylla crassicaulis Euphorbia maddeni Gossypium herbaceurn Hyptis suaveolens lnula cuspidata lpomoea nil lxora coccinea lxora javancia Jatropha glandulifera Juniperus indica Lee*arnacrophyl/a Oplismenus buramanni Parthenium hysterophorus Plumbago rosea Plunibago zevulanica Poollia subumebellata Scirpus erectus Semicarpus anacardium
Thalictrum culfratum Viscurn album Withania somniferi Antifertility
Soudamini and Kuttan, 1986 Aswal et a/., 1984b Aswal et a/., 1984b Aswal et a/., 1984b Aswal et a/., 1984b Aswal et a/., 1984b Aswal et a/., 1984b Aswal et a/., 1984b Aswal et at., 1984b Panikkar st a/., 1986 Nair and Panikkar, 1988 Aswal et a/.. 1984b Aswal et a/., 1984b Aswal et a/., 1984b Aswal e l a/., 1984b Narasirrbhan et a/.,1985 Purush Ahaman, 1985 Purush ,~thaman, 1985 Aswal dt a/., 1984b Aswal et a/., 1984b Gudg-lon et a/., 1985 lndap eial., 1983,1986 Pha:. k et a/.; 1983 Aswal et a/., 1984b Kuttan et al., 1988b Singh et a/., 1986
Acacia farnesiana Aswal et a/., 1984a Achyranthes aspera Wadhwa et a/., 1986 Amorphophallus campannlaiils Aswal et a/., 1984a Annona sqnemosa dt':ria and Dantani, 1984 Azadirachta indica Kokate et a/., 1987 Lal et al., 1986, 1987 Reddy et a/., 1984 Balanites roxburghii Shukla eta/., 1986b Berberis pseudumbellata Abraham et a/., :986 Bupleurum marginatum Aswal et a/., 1984b Caesalpinia decapitata Keshri et a/., 1988 Chonemorpha fragrans Aswal et al., 1984b Codonopsis ovata Aswal et a/., 1984c Daucus carota Kaliwal and Ahmed, 1987
----
341
contd;.. (Table 1)
Deutzia corymbosa Dupatriumjunceum Embelia ribes Eghedra gerardiana Ferula jaeschkeana Foeniculum vulgare Geranium lucidum Gnaphaliumpensylvanicun~ Hibiscus rosasinensis Hippophae rhamnoides Hippophae salicifolia lponloea pescaprae Juniperus communis Lepidium capitatum Lespedeza juncea Lespedeza stenocarpa Lonicerajaponica Luffa echinata Malvaviscus conzatii Moringa oleifera svn. Moringa pterygosperma Piper longum Pluchea lanceolata Plumbago zeylanica Polemonium coeruleum Polycjonum nepalense F'ifsraria tuberosa Pulicaria anqustifolia Rubus ellipticus Sapindus trifoliatus Semicarpus anacardium Syzigium cumini Thalictrum cultratum Thespesia populnea Wcoa indica Xeromphis spinosa Zingiber roseum Lal et el., 1986 Aswal et a/., 1084c Prakash et a/., 1986b Prakash et el., 1986a Reddy et a/., 1984 Aswal et a/., 1984c Singh et a/., 1985b Annusuya et a/., 1988 Aswal et el., 1984c Aswal et a/., 1984c Sethi et a/., 1986 Aswal et a/., 1984c Abraham et a/., 1986 Aswal et al., 1984b Aswal et a/., 1984a Aswal et a/., 1984a Singh et al., 1984c Abraham et el., 1986 Aswal et al., 1984a Aswal et a/., 1984b Prakash et al., 1985 Shukla et a/., 1987b Abraham et a/., 1986 Reddy et al., 1984 Aswal et al., 1984b Bhargava, 1984 Aswal et al., 1984b Abraham et a/., 1986 Prakash et a/., 1986b Shukla et al., 1987a,c Aswal et a/., 1984b Prakash et a/., 1986b Bhargava, 1986 Singh, 1987 Sinha et a/., 1986 ASWT'a a/., 1984b t Kaur et el., 1988 Walia et a/., 1986 Gandhi etal., 1985 Susan et el., 1986 Saluia and Dantani, 1984 Aswal etal., '1984b
342
Phamacology of Medicinal Plants

contd.. (Table 1) Antigastric ulcer
Azadirachta indica
Pillai and Santhakumari, 1985 Ficus racemose Patel and Vasvada, 1985 and Musa sapientum var paradisic Bhattacharya Ghosal, 1987 Chattopadhyav et a/., 1987 Ghosal, 1985 Ghosal and Saini, 1984
Allium cepe Allium sativum Abrus precatorius Azadirachta indlca Carex obscura Citrus Iimon Cosdnium fenestratum Crotalaria madurensis ElshoMie polystrache Eucalyptus globuls Eucalyptus lanceolatus Hippophae salicifoic. lnula cuspidata Jatropha glandulifera Lespedera stenocarpa Lycium barbarum Ocimum sanctum Phyllanthus fraternus Shoera robusta Syzygium megacarpum Terminalia chebula Uvaria narurn Vernonia anthelmintica Acacia catechu Acacia femesiana
Antiinflammatory
Dwivedi and Sharma, 1985 Dwivedi and Sharrna, 1985 Dwivedi8 Sharrna. 1985 Abraham eta!., 1986 Aswal et a , 1984a 1 Dwivedi a; ,d Sharma, 1985 Aswal et :I/., 1984a Aswal et d., 1984b Chatunrelli and Saxena, 1985 Chaturv~:diet al., 1987 Aswal :'a/., 1984b Barde, 1985 Abraham et a/., 1986 Chauhan and Saxena, 1985 Rarnachandani 8 Chungath, 1987 Aswal et a/.,1984b A s L ; ~ a!., 1984b et Reddi et a/., 1986 Ramachandani & Chungath, 1987 Aswal et el., 1984a Abrahem et a/., 1986 Abraham et a/., 1986 Nanda et a/., 1986 Singh et el., 1985b Chakravarthy et a/., 1983 Trivedi et a/., 1986.
343
G.K Patnaik & B.N..D~: Nan
contd
... (Table 1)
Acorus calamus Antidesma geranliana Boswellia serrate Casimiroa edulis Clerodendron inenne Comiphora mukul Cordia obligua Crataeva nurvala Curcuma longa
Cuscuta chinensis Datrrra stramonium Delonix elate ~esmodium gangeticum Dictamnus albus Eclipta alba Embelica oficinalis Euphorbia acaulis Halenia elliptica Hedychium spicatum Lawsonia inermis Lepforhabdos parvifldra Leucas aspera !Vyctanthes arbor-tristis Oci~num bascilicum Ocimum sanctum Phyllanthus fratemus Polygonum glabrum Randia dumetorum Rhus semialata Semicarpus anacardium Strobilanthes heyneanus Symplocos spicatd .. Terminalia bellercia Terminalia chebula Viburnum odoratissimum
Varde et a / , 1988 Aswal et a/., 1984a . Singh et a/., 1986 Aswal et a/., 1984a Somasundararn et el., 1986 Sharma et al., 1988 Agnihotri et a/., 1987 Report CCRAE, 1986 Srimal& Dhawan,1985 Srivastava and Srirnal, 1985 Srivastava et a/., 1985, 1986a Nisa et al., 1985 Uma et a/.,1985 Sethuraman and Sulochana, 1986 Ghosh and Anandakumar, 1983 Abraham et a/.. 1986 Chandra etal., 1987 Sharma et a/., 1988 Singh et al., 1984b Abraham et a/.; 1986 Srimal et a/., 1984 Gupta et a/., 1986 Abraham et al., 1986 Reddy et al., 1986 Saxena et el., 1984 Varde et a/., 1988 Godhwani et a/., 1987 Varde et a/., 1988 Hkeri et al., 1985 Singh et a/., 1985c Ghosh et a/., 1983 Bhattacharya et al.,l987 Upadhayay et a/., 1986 Nair et a/., 1985 Fortan et a/., 1983 Sharma et a/., 1988 Sharma et al., 1988 Abraham et a/., 1986
344
contd (Table 1)
Vitex negundo
Wmhtiria fcndoria Withania somnifera Ravishankar et a/., 1985,1986 Sethuraman eta/..1984 Anbalagan and Sadique,
1985.
...
Sudhir et al. , 1986 Antipyretic Ocimum sanctum Trianthema portulacastrum Woodfordia fruticosa Aerva lanata Crataeva nurvala Cardiostimulant Coleus forskohlii Corchorus tridens Pterocerpus .marsupium Godhwani eta/., 1987 Vohora et a/., 1984b Alam et a/., 1986 Gurumadhava Rao et a/., 1985 Report CCRAS, 1986
Antiurolithiatic
CNS
DeSouza et a/., 1983 Vohora eta!., 1983 Chakravarthy and Gode, 1985 Ruh-afia Gulati et a/., 1085 Azadirachta indica Singh et a/., 1987 Bacopa monnieri Singh & Dhawan,1985 Canavalia virosa Mukhopadhayay etal., 1986 Cissampc?louspareira Aswal et a/., 1984a Corhorus tridens Vohora et a/., 1983 Cuscuta chinensis Akbar et a/., 1985 Desmodum pseudotriquetrum Aswal et el.. 1984a Erinocarpus nimonii Abraham etal., 1986 Fumaria indica Kumar et a/,, 1086 Hippophae rhamnoides Abraham et a/., 1986 Kalanchoe integra Varma et a/., 1986 Morus indica Pal eta/., 1983 Pseudosorghum Mehta et a/., 1983 Saccharom oficinarum Aswal et at., 1984a Salvia haematodes Akbar et a/., 1984 Scrophularia koelzii Aswal et a/., 1984a Solanum melongena Vohora etal., 1984a Syzygium cumini Chakraborty et a/., 1986 Trianthema protulacastrum Vohora et a/., 1984b Tribulus terrestris Prakash et a/., I 985 Vigna mango Sood et at., 1985 Vigna radiata Sood e! al.. 1985
-
345
G.K. Patnaik 8 B.N. Dhowan

contd (Table 1)
Vigne sinensis Vitex negundo Sood et a/., 1985 Ravishankar et a/.,1985, 1986 Aswal et al., 1984b Aswal et a/., 1984a Abraham et a/., 1986 Aswal, et a/. 1984a Aswal et a/. 1984a Aswal et a/. 1984a Shukla et a/., 1985 Abraham et a/., 1986 Asi4al et al., 1984b Abraham et a/., 1986 Aswal et al., 1984b Aswal et a/., 1984a Aswal et al., 1984b Abram et a/., 1986 Aswal et a/., 1984a Abraham et a/., 1986 Aswal et al., 1984b Sood et al., 1985 Sood et el., 1985 Sood et al., 1985
Vihan and Panwar. 1987
...
Diuretic
Zingiber roseurn Acacia tortilis Anaphalis marcescens Antidesma menasu Carduus nutans Clerodendronpaniculatum Cocos nucifera Naeocarpus rnunronii Meconopsis aculeala Nepeta erisotachya Pentapanax parasiticus Pogostemon pubescens Publicaria anqustifolia Samadera indica Sensevieria tifasciata Senbecio corymbosus Uncaria macrophylla Vigna mungo Vigna radiata Vigna sinensis Nigella satjva Acacia catechu Andrographis paniculata Boerhaavia diffusa Citrullus colocynthis Eclipta alba Phyllanthus niruri Picrorhiza kumoa Piper longum Solanum nigrum Tern~inalie ariuna Tinospora cordifolia
Galactopoetic Hepatoprotective
W!hania coaqulans 'Wthania somnifera
Nirinal et a/., 1985 Rege et el., 1984b Dwivedi et a/., 1986 Pandey et al., 1985 Pandey etal., 1985 Chandra et a/., 1987 Agrawal et a/., 1986 Symasundar etal., 1985 Ansari et a/., 1988 Nirrqa! et al., 1985 Rege et al., 1984c Pandey et el., 1985 Pandey et a/., 1985 Nirmal et a/,, 1985 Rege et a/., 1984a Singh et a/., 1984a Budhiraja et al., 1986 Sudhir et a/., 1986
346
contd
...(Table 1)
Acacia catechu Atylosia scarabaeoides Bougainvillea spectabilis Brasica varcapitula Cajanus cajan Cymposis tetragonoloba Dodonea viscosa Echinops echinitus Eugenia cumini Gymnema sylvestre
Chakravarthy et a/., 1983 Singhal et a/., 1985 Sarker et al., 1986 Tarfa et al., 1988 Giri et a/., 1986 Srivastava et a/., 1987 Aswal et a/., 1984a Abraham et a/., 1986 Giri et a/., 1985 Shanmugasundaram, 1983 Srivastava et a/., 1986b Desai and Bhide, 1985 Upadhayay and Pant, 1986 Santhaku~nari et a/., 1985 Chandrasekar et a / , 1987 Mukherjee and Mukherjee, 1987 Nair and Santhakumar~, 1986 Rahman et a/., 1985 Mahajan and Jolly, 1985 Aswal et a/., 1984b Jain et a/., 1987 Dixit and Sinha, 1985 Gupta et al., 1987 Mirhadi and Singh, 1986. 1987 Dixit and Jain, 1985 Singhal et al., 1985 Zutshi et al., 1986 Tarfa et al.. 1988 Giri et a/., 1986 Aganval and Pant, 1986 Singh et a/., 1983 Agawal et a/., 1986 Shukla et al., 1986a Singh et a/., 1985a
Hypoglycaernic
Han~iltonia suaveolens Momordica charantia Murraya koeniqii Swertia chirata
Svzygium cumuni Tephrosia puruprea Tinospora cordifolia Trichosanthes dioica Trigonella foenum-graecum
Hypolipidaernic
Allium sativam
Aloe barbabadei~sis Atylosia scarabaeoides Boswellia serrata Brassia capitata Cajanus cajan Carurum capticurn Cicer arietinun~ Commiphora mukul
347
G.K. Patnaik 8 B.N. Dhawen

contd.. (Table 1)
Cymposis tetragonolobe Embelice oIlicinelis Eugenia cumin1 Medicaqo sativa MomomUca carantia Nepeta hindostena Thevetia neriifolia
Srivastava et a/., 1984 Verrna and Bordia, 1988 Srivastava et el., 1987 Thakur and Mandal, 1984 Giri et a/., 1985 Dixit and Joshi, 1985, 1986 Upac:iyay and Pant, 1986 Arora, 1987 Goswami and Dutta, 1985 Abraham et a/., 1986 Basu et a/., 1985 Sharma, 1985,1988 Rao et a/. 1986 Mehta et el., 1986 Mukhopadhayay et a/., 1986 Pandey, 1985 DeSouza et a/., 1983 Aswal et al. , 1984a Aswal et al. , 1984b Aswal et a/., 1984b Abraham et el., I986 Aswal et a/., 1 984 b Varma et el., 1986 Aswal et a/., 1984b Aswal et al., 1984a Pandey, 1985 Aswal et a/., 1984b Pandey, 1985 Aswal et a/., 1984b Pandey, 1985 Abraham et a\.,l986 Budhiraja et a/., 1983, 1987
Hypotensive
Acacia raddiane Abrus precatorius Artemisia scoparia Balanites roxburghii Blumee membranacea Canavalia virosa Cichorium intybus Coleus forskohlii Coscinium fenestratum Eucalyptus golbulus Euphorbia maddnei Eugenia manqifolia lpomoea pes-caprae Kalanchoe integra Phy!lanthus gardnerianus Phytolacca acinosa Picrorhiza kurrooa Primula denticulata Solanum nigrum Tamarix ericoides Tecomella undulata Tibouchina semidecandra Withania coaqulans
Local anaesthetic Muscle relaxant
Stephania glabra Cocculus laurifolius
Mahatma et al., 1986 Mukherjee et 3 1384 ! ,

348
contd
...(Table 1 )
Axyris emerenthoides Clausena anisata Clausena indica Coelogyne ovalis Corcorus tridens Corydalis meifolia Dalbergia sisso Desmodium pseudotriuetrum Fraxinus xanthoxyloides Heracleum thomsoni Kalanchoe integra Mudhuka 'indica Philletia splendens Pseudosorghum Rheum webbianum Saussurea albescens Senecio kunthianus Sy~r~plocos spictara Tephrosia maxima Thennopsis barbata Toddalia asatica Vigna nlungo
Vjg;~a radiata
Spasmolytic
Vigna sinensis
Aswal et el., 1984a. Lakxhmi et al., 1987 Aswal et a/.,1984a Aswal et al., 1984a Vohora et al.. 1983 Aswal et al. , 1984b Patnaik et a/., 1984 Aswal et a/., 1984b Aswal et a/., 1984a Abraham et a/., 1986 Khan et a/,,1986 Patnaik et a/., 1985 Varma et al., 1986 Banerii et a/., 1985 Abraham et al., 1986 Mehta et al., 1983 Aswal et a/., 1984b Patnaik, et a/., 1987b Abraham etal., 1986 Abraham et a/., 1986 Frotan et al., 1983 Ram Murthy etal., 1986 Aswal et al., 1984a Abraham et a/., 1986 Sood 8 Bajpai, 1985 Sood 8 Bajpai, 1985 Sood 8 Bajpai, 1985
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..
Added In the proof
355
Jolrt..
Res. Ind. Med., Yoga SL Honroeo. 11 :(2?11976
VI J A Y S A K , PTERO CARPUS MARSUPIUM, IN T H E TREATMENT OF MADHUMEHA (DIABETESMELLITUS)

A CLINICAL TRIAL
S..RAJASEKHARANe and S. 3. TULI*::

(
C.R. E. Unit of CCRIMH,Government Ayrirvedic Cc;llege, Jarnn~ti( J & K ) )
[ Received for publication on' M e !7, I975 ]
lntroductioa From the beginning of history, Ayurveda, a part of Veda gave a good clinical descripcion about Prameha (anomalies of urinary disorders) including hiadhumeha (diabetes mellitus). According to-palaeograhy, the ancient Ayurvedic masters like Charaka (3000 BC-500 BC), Su~hruta'(2200 RC-600 BC), Vagabhatta (500 BC-900 AD) and Madhava (700 A C ) bad given a detailed clinical description of twenty varieties of Prameha as well as Pramehapideka (inflammatory conditions in diabetes). They have also zuggested the treatment of Pramehapideka by antiseptic, clesnsing, healing procedure or surgery. According to the intensity of the disease and pature of the p a t i ~ n tthey adopted "Panchakarma therapy" and advised strict "HitAhar- Vihar" (diet and physical exercise). Many centuries back the Chinese, Japanese acd Arabic writings also indicated the the disorders of urinary exeretion i n ~ l u d i n g sweetness of urine. One OF, the famous Roman physician, Artacus of Cappodocia (AD 30-90) was the first to introduce the name "diabetes". Recently there has been much interest in "nonketotic diabetic coma" and many attempts have been made to
explain it (Watkins et al, 1970,. Several e?idemiolo_eical studies have pointed out the importance of environmeai i~ determining the prevalence of diabetes (Jamtt, 1970). The genesis of diabetes .caused 3y viruses is established by a group of G e r an resear~ chers who creat6d a type of vir-as which destroys islets of langerhans in the pancrezs with a high degree of selectivity from x mutant of ihe enctphalomyocarditis virus.12 Capsule Vijaysar is p r e p ~ t e dfrom Pferocarpus marsupium (Beejak), a common tree growing in central and southern pass of India and Sree Lanka (Cevlone). Beejak, Pethsar, F?thasaiaL, Bendookapuspa, ~ c i ~ a l Sarjak, r,' A ~ a n a are the Sanskrit synonyms of the etc. Pterocarpus-marsupium Roxb. Zhavamisra (16th century A D )has described it as a useful medicine for Prameha. Wood of tbe Prerocarpus marsupium is used as astringent, tonic, for external application in i d a m m a tion and headache etc. (Chopra et al, 1936). Sharma (i959) has m'cntioned in his text-book f'Dravyagmavigyana" about the Karma (action) of Plerocarpus marsupium especially Abhyantara Pachana SamsthcrSthmbhaniya, Mutra Vaha Samsthan-Mutra szmgrs: haniya, and Mehahar. Trivedi (1971.) and
* Rcscarch Assistant
** Officer-ineharge and Principal

356
Rajaseklrnran arid Tuli
Shah e t a ! , (1972) ha-e carried out some chemical investigations of the heartwood of Pterocarpus marsrrpiirrn Roxb. Shah et a1.(1972)have isolated some c h ~ m i c a investil gations of the heartwood of Pferocarplis marsupirim Roxb. Shah et al, (1972) have isolated some flavalroid compounds. From pharmacological investigation of one of these compounds, named Bianol, they found that it has no anthelmintic activity on earthworms, no significant effect on blood pressure and respiration of dog. The study of the hypoglycemic effect of this substance according to them, is under progress. Materials and Methods The raw materials (heartwood of Pterocarpus marsupiurn) was obtained from the following S. M. P.' Units-Govt. Central Pharmacy, Jayanagar, Banglore; Govt. Ayurveda College and Hospital, Gwalior; Govt. Ayurveda College Pharmacy, Rajapipala; and Govt. Ayurveda College, Patna. Capsule Vijaysar was p r e ~ a r e d from the heartwood of Pterocarpus mar~upiurn. Heartwood of Pterocarpus marsupiurn is taken, wash:d i n pure aqueous solution, chipped, 'cruched well, .dipped into pure aqueous solution in the-ratio of 1 : 16 (Kilogram) by weight. It is boded over a \low fire, reduced to one-fourth in volume, filtered through a clean cloth and boiled. The Ghana-satva (extract) obtained is reduced to the Rasakriya Pak, dried under penumbra and powdered. This powder is weighed (250 ~milligrams) and filled into capsules. Capsule Vijaysar was administered to the patients in different ddses based upon their stamina ( ~ a l a ) .age (Vaya) and intensity of the disease (Rogadhikya). For the clinickl trial the 'patients'' hLtory, clinical featuies,
urinary fndings and blood sugar tests were taken. Out of the total number of the patients 35 cases were selected for detailed study. Table 1 presents the details of the patients. Out of 35 patients, 6 were hereditary cases (age group 20-39,2 cases; male 40-49, 2 cases; 1 male and 1 female; 60 and above, 2 cases females). Results Tables 2, 3 and 4 present the details of the administration s f capsule Vijaysar with Iaimkashaya (of heartwood in 35 selected patients. .From a perusal of these Tables, we may lind that the clinical trial of capsule Vijaysar with Himkashaya has considerable effect in reducing the three cardinal sy mptoms of Madhlimeha (diabetes mellitus) i. e. Prabhut Mutrata (polyurea), Atipipasa (polydipsea), Atikshudha (polyphagia). A summary of a case in which the administration of capsule Vijaysar showed marked effect in reducing the three cardinal symptoms of diabetes mellitus is briefly presented below
Tfie details of the patients according t o age a'nd sex.
*ge Group 20- 39 40-59
Number of Patients 5 18 12
35
Male
Female
5 9
7 21
9 5
60 and above TOTAI-:
14
'
357
Pterocarpus nlorsupiunt in the treatment of Afadliunreha
TABLE 2 Effect of the Capsule vijavsar in reducing the three cardinal symptoms
Response Group Complaints No. of cases Good Fair Poor
1.
2. 3.
Prabhutmutra (Polyurea) Atipipasa (Polydipsea) Atikshuda (Polyphagia) TOTAL :
30
25
20 17 14 51
6
3
4
5
25 80
6
15
5 14
TABLE 3. The effect of the Gzpsule Vijaysar on urine sugar Urine No. of Response Group Sugar % cases Good Fair Poor
3.
Above 3
Nil
- - -
TABLE 4 The effect of the Capsule Vijaysar on blood sugar (fustina) Blood Sugar No. of Response cases Good Fair Poor
'
1. 121mg./lOOml. to 2 ( , 0 ~ ~ , / ~ 0 16 ~ ~ . ~
11
2. 201mg.1100mI. to 300mg.1100ml. 7 3. 301mg./100ml. & above Nil TOTAL : 23
A female. aged 45 years, a house-wife came under observation owing to Daurbalya (general debility), pain in legs, on 16-6-73 with the complaints of sleeplessness (Nidranash), polyurea, polydipsea and polyphagia of four years' duration. But only one'yeor back she was found a diabetic. Her urine sugar was 1.25%, fasting blood sugar was I50 mg./100 mi. According to the doctor's advice initially she had taken 20 days' insulin therapy. After the insulin thCrapy the doctor advised her to take tab. Diabenese, 1 daily. Last few months she did not take any medicine. According to the observation on 16-6-73 her urine sugar was 0.75%, fasting blood sugar was 110 mg. / 100 ml. She is married and has three children. There is no family history of diabetes mellitus. Weight 52 kg., temperature was normal, pulse 761 minute regular, all peripheral pulsations were normal. Blood pressure was 125 85 mm, Hg : cardiovascular and respiratory systems , showed no abnormality. She was treated with Capsule Vijaysar (250 mg. weight) 2 T.D.S. with Himkashaya of the heartwood of Vijaysar. She was advised very strict Ahar-Vihar (diet and pbysical exercise); The graph (Figs. 1 and 2) shows the effect of the medicine. in reducing Grihit Jal Rashi (water-in-take), Mutra Rashi (urine output) and Mutravisarjana-krama (fuequency of micturation) of the above patient. After one month's regular administration of the Capsule Vijaysar the patient was found tb have recovered from all the diabetic symptoms. Urine sugar was reduced fram 0.75% t o
~
- - ,
15
normal and weight was increased from 52 kg. to 53.5 kilogram. Thus the clinical effect of the drug shows that it helps'in reducing the sugar percentage of urine gradually, but in blood sugar it docs not show much successful effect, Table 3
SELECT RESEARCH PAPERS O N EVIDENCE BASED AYURVEDIC DRUGS
358
Rajasekharan and Tuli

shows the effect.of .tEe capsule Vijaysar on urine add Table 4 On blood Sugar
(fasting).
FIGUSE.1. WATERdN-TAKE
$
E
(AFTER TREATMENT) FIG.t
:
o
W
3-
Another case in which the administration of the Vijaysar Capsule helped 'in reducins urine sugar and blood sugar [fasting) percentages is briefly described below :-A male, aged 38 years, a police constable came under observation ou 2-5-74 with complaints of polyuren, polydipsea, polyphagia and burning sensation (occasionally) of four years' duration. Urine sugar was 1% and fasting blood 'sugar was 180 mg.1100 ml. Initially (four years back), he had taken tab. diabtnese. For the last few months he did not take any medicine. His father was a diabetic patient, he is married and has three children. Other family members are all very healthy. The patient was having normal health, weight 69 kg., pulse 74lminute regular, all peripheral pulsations were ' normal, blood pressure was 125185 mm. Hg:. Cardiovascular and respiratory systems showed no abnormality. He was given the treatment for one month, dose three capsule T. D. S. with Himkashaya with s t ~ i c Ahart Vihar (diet and physical exertion). Table 5 shows the effect of the medicine in the patient. From a perusal of the Table it may be observed that the treatment is effective in reducing the sugar percentage in urine and blood. TABLE 5 The efecr o the Capsule Vijaysar In reducing f the urine sugar and blood sugar ( F B S ) percentage ( Weekly records)
Alter treatment
D '11 Z
\r
1st 2nd 3rd 4th 5th Before Treatment week week week week week
a
0
,
Urine Sugar 1%
1% 0.75% 0.25%
-Nil
Nil
4 . k ;s
;-%
OATE OF OBSERvAT'ON INWEEKS (AFTER TREATMENTr
FF.B.S. 171mg/ 160rng/'l~0mg/115mgr 180mg/ 100ml. 100m1. 100mI.. 100ml. 1OOml.
359
Pterocarpus marsupiuna in 1he'lrhbli~elf~'oj~~adit~~t~~c1ra

General observations of the administration of Capsule Vijaysar in diflerent patients are given below : Primary stages of diabetes mellitus (Nava cases) and in healthy patients Capsule Vijaysar showed encollraging effects in reducing all the diabetic symptoms gradually. Regular administration of the Himkashaya with. in Capsule Vijaysar was found to be eflect~ve reducing Atipipasa ( polydipsea ) in some chronic diabetic patients. It was 0bserve.d that Capsule Vijaysar produced minimal side elfects. Satisfactory results were not obtained in the following types of cases : (i) Chronic diabetic patients, (ii) Diabetic patients with other complications (Upadravavyadhi's), (iii) Old and debilitated cases, (iv) Hereditary cases (Except one). It is further observed that Madhumeha patients who were used to the insulin therapy or modkrn oral anti-diabetic drugs for a long time did not show significant response. It was also observed from the trials that those patients who did non rigidly follow, the diet and physical exercise (Hit-Ahar-Vihar) had not shown any response to Vijaysar Capsule. The age of onset of t h e diabetic manifestation in majority of the cases is in between the age group of 40 to 60 years. progress was observed. Regular administration of' Himkashaya on some chronic,and. . age-old cases, helped in reducing ~ t i p i p a s a .(polydipsea). Some patitnts however objected . . to the bit.ter .taste of the Himkashaya and as such sonie work is to be undertaken to make the same acceptable to the patients. primary' failure Casbiibted in the patients who vrere addicted t a insulin therapy or modern oral anti-diabetic drugs from a longer period. This drug also proved incft'ective on those who inherited diabetic character and also on chronic and debriitatcd patients. ~oncfus~dn From the above clinical trial, the therapeutic effect of Capsule Vijaysar was found to be- 61) Meha-har (anti-diabetic), (ii I Sthambbaniya (astringent) especially in ~ b h ~ a % t a r Pachan - Samsthan, (iii) Mutraa samgrahaniya. The regular administration of the drug helps in gradually reducing the urine sugar percentage. To a certain extent i t also helps in reducing the blood sugar percentage. Further observations are still in progress.
. ACKNOWLEDGEMENT
The authors are very much grateful to Dr.
P.N.V. Kurup, Director, Central Council for
Research in Indian Medicine and Homoeopathy, New Delhi, for providing the facilities. Discussion The senior authors are also thankful to From the clinical trial carried out in this EX-officer-inkhare&, Dr. S. C. Sankhyadhar, unit, it was found that Capsule Vijaysar is Clinical Research Enquiry, Government effective as Meha-har (anti-diabetic), Stham- ~ y u i v e d '. College, Jammu, for his many a bhaniya (astringent) especially Abhayantara helpful suggestions and encouragements, Pachan Samsthan, and ~ u t r a s a m g r a h a - dur'tliinks are also due to the four S. M. P. niya. However, the effectiveness of t h e JJnits,iC(:RIMH!, (Govt. central Pharmacy, drug is related to the various factors like ~ a ~ a n i ~~a n g l o r eGo'vt. Ayurveda College ar , , Kala, Vaya Satmya and Asatmya. Hereditary and Hospital, Gwalior, Govt. Ayurveda cases studied through Capsule Vijaysar College Pharmacy. Rajpipala, Govt. Ayurtherapy recorded some temporary relief veda College, Patna) for supplying us the except in one case) and no other remarkable heartwood of Pterocarpus marsupturn.
Rajasekharatl and Tuli
1. Astanga Hridayn
(1957)
2. Best, C. A .
(1966)
Nid3dnstha'nam. Chapter 10, Clilhitsastllanam, ~ l i a $ t e r13, Ed. by ~ h o w k h u m b a Vid!a Bhawnn, Va~nnasl.' Epoclts in the lilsto~ of d1'1betes i n '.D~abetes". y Ed. by R o b ~ r H. W i l l i a ~ i ~M. D., Hofber Medit s, Cnl b i i i i i o i i , Harpar and Row, Publishers: Dokutarii Company Ltd., Japan. Bislingratnn Shri Brahma Sanhar Shzs:ri, Ed. by ~hO\vklla&ba Sanskrit Series. Glossary of Indian Medicinal Plants, C. S. I. R. Publications, New Delhj. ChnraL? Sam11ita;Volun~e 111 (English). Chikitsasthauam, chapter 6, Ed. by Shri Gulabkunverba, Ayurvedic Society, Jamnagar. Clraraha Sarnhita, Vo1.11 (English', Sutrnsthanam, Chrrpter 17 (78-121), Nidanasthanam, Chapter 4, E d by S h r i Gulabkunverba, Ayurvedic Society Jamn,., "as.
Q
4.
Chopra, R.N., Nayyar, S.L. and Chopra, 1.C. (1966)

( 1949)
5. Charnkn
7.
Jarrett, R.J.
(1970) (1966)
'Lessons of epidemiology of diabetes', British M e d ~ c a Journal, Vol. 1 1 pp. 210 - 271. l 1, Comentator, Vidyan S Janardhanan Pillai (Sararthndeepika Vyakyan in Malayalam), Ed. by Sree Rarna Vilasam Press, Quilorr, pp. 213-235. Dravyaguna Vigyan, pp. 519-20, Ed. by Chowkhamba Vidya Bliawan, Chowk, Banaras. Bianol, Further studies on Heartwood of Pterocarpus marsupiurn, "Nagarjun", Vol. XV, No. 11. Nidnnasthanam, Chapter 6. Chikitsasthanam, Chapters 11, 12, 13, Ed. by Athridev, Dr. Bhaskar Govind Genaker, Shri La1 Chandji Vaidya, Moti La1 Banarasi Dass, Varanasi. "Nagarjun", July, p. 43. "Ketonaemia in uncontrolled diabetes mellitus", Fritish Medical Journal, Vol. 111, pp. 5 2 - 2 3 .
8. hladhvanidann
9. Sharma, P.V.
(1956)
10. Shah, B.K., Nnik, H.B., , Trivedi, B. A., a n d Thakur, V.M. (1972) 11. Sushruta Samhitn. (1960)
12. .virus induced din betes(l972) . . 13. Watkins, P. J., k i l l , D. M., Fitzgerald, h.1.C. and Mal!ins, J.M. (1970,,.
SELECT RESEARCH PAPERS ON EVIDE-WE BASED AYURVEDIC DRUGS
361
Pterocarpw n ~ a r s ~ i yiin~the~lrenf/lfentof Man'l~toirelra o ~
E=i;l ur ~ i - 4
iililian J Med Res 108, July 1998, pp 24-29
Flexible dose open trial of Vijayasar in cases of newly-diagnosed non-insulin-dependent diabetes mellitus
Indian Council of Medical Research (ICMR) Collaborating Centres', Central Biostatistical Monitoring Unit', Chennai di Central Technical Co-ordinating Unit', ICMR, New Delhi
Accepted June 29, 1998
A flexible dose open trial was undertaken in four centres in India to evaluate the efficacy o f an Ayurvedic drug V~ayasar(Pterocarpus marsup~um)in the treatment of newly-diagnoyd o r untreated non-insulin dependent diabetes mellitus (NIDDM). 12 wk, control o f bleod glucose (both fasting By ,and postprandial levels) had been attained in 67 (69%) of 97 patients studied, and the dose on whic control wna attained was 2 g of the extract in about 73 per cent of tbe patients, 3 g id about 16 pe cent and 4 g i n 10 per cent of the patients. Four patients had to be withdrawn from treatment due to excwively high postprandial blood glucose levels. Among the 93 patienta wbo completed 12 wk o f treatment, both the fasting and postprandial blood glucose levels fell signifiuatly (P < 0.001). by 32 and 45 mJdl at 12 wk from the initial means of 151 and 216 mgldl respectively. I l l r r n HbA,c decreased significantly (P < 0.001) to 9.4 per cent at 12 wk from the initial meai of 9.8 per cent No significant, change w.s obsewd in the mean levels of lipids. Other laboratory parameters remained stableduring the designated treatment period of 12 wk. Also, no side-effects were reported. Heme. it is concluded that Vdaycrrar is useful in the treatment of newly-diagnosed or untreated mild NIDDM ptients.
Key wiirds Flexible .dose open trial
- non-insulin-dependent dtabetes mellltus - Perocarpus mumuprum

used by Ayurvedic physicians to treat diabetes mellitus and is expected to have a role specifically in the treatment of NIDDM. Experimental ~tudieson pgayasar by various
workers1-lohave d e m o n s t r d the hypoglycaemirz
The therapeutic pptions in the treatment of noninsuliwdependent diabetes mellitus (NIDDM) include dietary modification, oral hypoglycaemics and imulin.Numerous claims have been made of a variety of traditional remedies for the cure of diabetes; one sus;h is .Vijayasar (Prerocarpus marsupiz~m) which is
I.
2.
3.
Collabarating Centres [According to alphabetical order of the c ~ t y givlng address o f the Department, Principal rnvestigator(s). Co-lnvestigator(s). Research staff of the Collaborating Cenlre]. (I) Chennai : Department of D~abetology,Madras Medical College : V. Sesh~ah. Sundaram, R.S. Hpr~haran, Venhataraman; K. Suresh, I Periyandavar, P. Sunitha; S. Rajalakshmi. A. S. . f i i ) Cuttuck : Department o f Endocrinology, S.C.B. Medical College : K.C. Samal; S. Manju. ( r r r ) Kottayam : Department o f Medicine. Medical College Hospital : R.V. Jayakumar; Sam Philip. (rv) New Delhi . Sitaram Bhartia Institute of Science w d research : M.M.S. Ahuja*; A.S. Lato Gtntral Biostatistical Monitoring Unit. Institute for Resqrch In Medical Statistics, Chennai : S. Radhakrishna, P. layabal, Paul A. Tamby. B. Kishore Kumar, V. Selvaraj, A.K. Mathai, R. Kausalya and T. Daniel Rajasekar Cefitrsl Te~hnical Co-ordinating Unit for Traditional Med~c~nc Research, ICMR Hqrs. New Delhi : A.K. Gupta and Nandini K. Kumar 'since deceased
TpwlOF YIJAYASR W NlDDM CASES
action in animals. Clinical studies undertaken on V j y a heart~oodll-~~, fi~oyarar iumr the barki4, and water stored in a tumbler made from the Yijayapur heartwood" have shown ehco~aging antidiabetic action. The hypoglycaemic effects have been attributed to various active principles in Yjayarm. An active principle (-) epicatechin isolated from the bark of P.marsupium was found to have proactive and restorative effects in alloxan induced dikbetic ratsi6,though it could not be reproduced by Kolb et all7. However, Ahmad et alia have shown that (-) epicatechin increases the CAMP content of the islets which is associated with increased insulin release, conversion of proinsulin to insulin and cathepsin & activity in mature and immature rat islets in vitro. Other insulin-like effects on glucose metabolism and on osmotic fragility of red cells though probably through a distinct receptor have bean demonstrated by other investigatorsi9-. Moreover, other rcfiva principles are being discovered like the t h m phenolic constituents marsupsin, ptorosupin and pterostilbene which have heen shown to significantly reduce the blood glucose levels in hyperglycaemia induced by streptozotecin, which was comparabk to that of metformin2'. Thus, there isxnsiderabte experimental evideace to show that Vijayasar has antidiabetic action but there is a paucity bf well conducted clinical trials b conclusively document the antidiabetic effect of Vijayasar in NIDDM patients. This prompted the Indian Council of Medical Research (TCMR) to undertake a clinical trial at four c e n m acroSs the country. The main objective of the trial was to assess the antidiabeticeffect of Vijuyrum in t w s of control of blood glucose levels and glycosylatedhaemoglobin (HbA,c) in newlydiagnosed or mtreatd NIDDM p4tienis in a Phase I1 apen trial. It was also proposed toabtain informationmgaiding side-effects/toxicity of the drug, if any,
Mtdical College, Chennai; S.C.B. h4edical Colltge, Cuttack; and Medical College Hospital, Kottayam. Newly-diagnosed or untreated NIDDM patients aged between 35 and 60 yr who gave written informed consent we* recruited for the trial. Presence of any less systemic diseases, body mass index (BMI) than 19, pregnancy or lactation were considered as contraindications for inclusion in the trial. Informatjon on general clinical history and dietary pattern was obtained. Complete physical examination and relevant laboratory investigations were done on all eligible patients. The patients weie prescribed diet therapy for a month comprising 60-65 per cent of carbohydrate, 10- 15 per cent of protein and.25-30 per cent of unsaturated fat in the total calorie intake; one-fifth beingtaken at breakfast and the rest equally at lunch and dinner. Mild diabetics with fasting blood glucose from 120 to 180 mg/dl and postprandial blood glucose from 18Q to 250 rng/dl (both venous whole blood) at the end of diet therapy were admitted t~ treatment with Yijayasur. Tke trial tet e t rimn period was 12 wk. Patients
wem instructed to attend the clinic for assessment
The uniform protocol and proformaa, trial design, drpg, dosage and other relevant aspwts were decided bnExpert Group. The trial wis initiated in Janwry a 1993.and the intake was tsnninated.in M r h 1995. ac The trial was tonductal at the Sitaram Bhartia Institateo Science and Reseuch, Now Dolhi; Madras f
and for collecting drugs weekly until the blood glucose was control!ed and fortnightly thereafter. Vijoyos~ to be self-administered daily in two was divided doses, half-an-hour before a meal. Patients were started with a daily dosage of 2,g of the exttact for the first 4 wk. At the end oc this' period, if the blood glucose was not controlled (i.e., fasting blood glucose level was 2 120 mgtdl or postprandial blood 11 glucose level was 2 110 mgtdl), the daily dosage was increased to 3 g of the extract for the next 4 wk. If the blood glucose was not centrolled by the end of this period also, the daily dosage w e increased to 4 g of the extract for the next 4 wk. If the blood glucos~ was not controlled even with this dose, the patient was declared as a 'failure of treatments with VQqyasm, and withdrawn from the study. During treatment, if the blood glucose was controlled by 2 or 3gdwe, that dose wascontinued for the rest of the treatment period of 12 wk. Weekly assessments were scheduled for the first four weeks and if blood glucose was brouet under coatrol, subsequent assessments were done fortnightly. If not controlled, the dosage was
364
INDiAN J MED RES, N L Y 1998
increased and the assessments continued to be done levels were assessed by using Student's and H ~ A , C 't' test and the 95 per cent confidence intervals were weekly. While blood glucose estimations were done computed. The statistical significance of difference at every visit, haemogram, liver function tests and in proportions was determined by undertaking chirenal function tests weredone only once in four square test with continuity $&ection. weeks. Estimation of electrolytes, glycosylated haemoglobin (HbA,c) and lipids were carried out at the end of diet therapy and at the end of 12 wk of treatment. Blood glucose was estimated by the In all, 223 patients were admitted to diet therapy method of Winckers and Jacobs using 0-toluidinP at the end of which blood glucose was still not or glucose oxidation GOD3 and ~ b ~ , c the ~ controlled in 159 (Table I). Of these, 124 had fasting - b colorimetricz4 or ion exchange resin2' methods. bload glucose from 120-180 mgtdl and postprandial External quality control of these estimations were blood glucose from 180-250 mg/dl and were initiated done with Christian Medical College, Vellora. on treatment with Vijayasar. However, 1 4 (19%) dropped out of the trial at various time points during During the trial period, patients were instructed to the 12 wk treatment period (there were no specific avoid the use of other drugs for any ailment or for complaints made by these patients, nor did their anything unusual without consulting the treating initial mean levels differ from those in patients who physician. To avoid adverse impact of any dietary continued treatment throughout), and three others aberrations, the recommended dietary schedule was were excludedfrom analysis (Table I). The progress strongly advocated. If a pcitient developed any major of the remaining 97 patients is described below in ailment or side-effects, helshe was withdrawn from detail. an4a thorough investigation was undertaken to study assess'if the symptoms were drug-related. If at any At 12 wk, control of fasting blood glucose was time during treatment, the postprandiat blood glucose observed in 72 per cent and postprandial blood level exseeded 300 mgldl on two consecutive glucose in 75 per cent of the patients (Table 11). occasions within a period of nne week, the patient was withdrawn from the study and termed as 'failure Table I. Patients in the study of treatmerlt' with Vijayusar.
The Vijayasar raw material was collected from Matinala, Mervai range, Mekal hills, Madhya Pradesh during November 1992. Vijaymar,an extract (dried aqueous decoctton) of the bark of P. marsupium, was manufactured and packaged by the ICMR Centre for Advanced Research on Standardization, Quality Control and Formulation of Selected Traditional Remedies/Natural Products, Chandigarh, presently located at Jammu. The approximate yield from the raw material was 8-10 per cent. The voucher specimen had k e n deposited in the herbarium of the Central Drug Research Institute (CDRI), Lucknow. The drug was supplied to the centres through the ICMR Central Biostatistical Monitoring Unit (CBM Unit) for Traditional Medicine Research, Chennai. The CBM Unit distributed drugs to the participating centres, scrutinized the data collected, and undertook data processing and statistical analysis.
Statistical. analysis : Changes in the blood glucose
Status
No.
Admittcd to diet thaapy 223 Dropout during did therapy 15 7 Blood glucose levels controlled 49 22 by did therapy Diet therapy completed, but blood glucose not controlled 159 71 Not eligible for study, due to high blood glucose levels* 35 g 124 Admitted to d ~ trial k V u t during chmothernpy 24 1 Excluded.from analysisi Withdrawn from study* 2 Number in analysis 97 fasting level > 180 mddl andlor postpmndial level > 250 mgldl +On accountof non-adherencetothe protocol (dosagenot increased to 3 gat 4 wk although his bbbd glucose was not controlled by 2 s dose). @ one patient developed severe itching and the other developed periodontal abscess requiring nugay'
365
TRIAL.OF VMAYASAR l NIDDM CASES N
Control of both fasting and postprandial levels was attained in 69 per ceht of the patients; t6e dose required for control was 2 g in 49 patients (by 4 wk), 3g in I I patients (by 8 wk) and 4g in the remaining 7 patients (by 12 wk). In the case of HbA,c, only 7 per cent of the patients attained control by 12 wk; their mean initial and final HbA,c values were 8.6 and 8.2 per cent, respectively. Four of the 97 patients had to be withdrawn from treatment because their postprandial blood glucose exceeded 300 rngldl on two consecutive occasions within a week. Among the remaining 93 patients who completed the stipulated 12 wk of treatment, the mean fasting and postprandial levels steadily decreased significantly from the initial values of 151 and 216 mgldl to 119 and 171 mgtdl, respectively, by 12 wk of treatment (Table 111). The HbA,c estimation could be done initially and at the end of 12 wk of treatment for only 67 patients. There was a decrease in the level for 54 patients, increase for 8 patients and
Table 11. Control of blood glucose and HbA,c at I2 wk Parameter Total patients in analysis 97 97 97 67 Control attained* No. Ye
Blood glucose Fasting Postprandial (PP) Fasting and PP HbA,c 70 73 67

72
'15 69
5 *defined as < 120 mgldl for fasting blood glucose < 180 mddl for postprandial blood glucose; and < 8.5 per cent for HbA,c
no change for the remaining 5 patients. In the*group as a whole, the mean HbA,c level decreased from 9.8 to 9.4 per cent by 12 wk of treatment (P < 0.001). The correlation coefficient between the initial and post-treatment HbA,c values was 0.60. A similar picture was observed for the 54 patients, in whom the HbA,c level had-decreased. Also, no relationship was faund between the dose of Vijayasar and the changes observed in the HbA,c levels. Of the three cardinal symptoms of diabetes mellitus, a marked reduction was observed in polyuria, all 10'patients with initial polyuria had complete relief. The other two symptoms, viz., polyphagia and polydipsia were initially present in 21 and 7 patients, and disappeared altogether in 14 and 7 patients, respectively, by 12 wk of treatment. An attempt was made to measure the quality of life on a three-point scale for three parameters viz., capacity to do work (fatigue), sense of well-being and optimization of weight (tending towards normal weight). By the end of treatment, it was found that 35, 26 and 16 per cent, respectively, showed improvement in these three parameters. There was no change in the mean cholesterol level at the end of 12 wk of treatment andthe decreases in triglycetides (5%) and high density lipoproteins (4%) were very small and non-significant statistically. Other biochemical parameters such as serum glutamic oxaloacetictransaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were virtuall'y unaltered. Also, there was no appreciable change in the mean body weight of the patients ocer the 12 wk period. None of the patients reported any side-effects ascribable to Vijayakar.
Table 1 1 Mean blood glucose and HbA c levels during treatment in patients who completed 12 wk of treatment* 1. Parameter No. of patients Initial Blood glucose (mgldl) Fasting
Postprandial
Mean SD
At4wk
At8wk
At 12 wk
Mean decrease by 12wk
95% C1 for mean decrease
93 93 67
151*17.3 216U1.5 9.tU1.0
13W7.6 18B35.4 Not done
12Oi31.0 172i26.3 Not done
lls23.0 171i29.1 9.4i0.9
32'
45'
27-36 40-5 1 0.2-0.7
HbA,c (%)
0.4'
* excluding four patients who were withdrawn from treatment because their postprandial blood glucose levels exceeded 300 mg/dl on two
consecutive occasions within a week
P
0.001 as cornbared to the initial value
366
INDIAN 1 MED RES,JULY 1998
Discussion In a preliminary clinical trial on 14 diabetic patients, Sepaha and Bose" found that the extract of the Vijayasur heart-wood appeared to be effective in reducing blood glucose in only one patient. However, Pandey and Sharma14reported a reduction of 16 mg/ dl in the fasting blood glucose level from an initial mean of 191 mgldl among 12 diabetics treated with Vijayasardecoction prepared daily, 4 02s. thrice daily for seven days. Increased tolerance to glucose was also observed in this study. In a clinical trial of 35 patients, Rajasekharan and Tulil*reported that regular administration of Vijayasar heart-wood extract for 8 wk gradually reduced the urine sugar and the fasting blood glucose, The response was classified by the authors as fair or good in 56 per cent of the patients in terms of urine sugar and in 34 per cent in terms of fasting blood glucose. In contrast, in a pilot trial conducted by the ICMR at the All India Institute of Medical Sciences, New Delhi, among 18 NIDDM patients treated for three months with Vijayasar in a fixed daily dosage of 2 g, eight patients (44%) attained control of both fasting and postprandial blood glucose (unpublished results).
In the present study, substantial symptomatic relief was noticed in thi three cardinal symptoms of diabetes mellitus, as also by pandey and sharma14. However, the quality of life measured On a threepoint scale with Parameters such as capacity to do work (fatigue), sense of well-being and optimization of weight did ,lot show much improvement; in fact, there was no change in the quality of life in majority of patients. H~~ocholesterolaemic was effect not found in patients with diabetes mellitus in this study. in contrast to the findings in healthy rabbitsz6
significance. This small reduction may probably be due to the shorter duration of the trial treatment. Vijayasar has had a significant therapeutic effect, in terms of lowering the blood gluc6se level in NIDDM patients. The virtual absence of hypoglycaemia in the study subjects reflects its relative safety, even in a large dosage of 4 g per day. It may therefore be concluded that Vogyasar is useful in the treatment of newly-diagnosed or untreated NIDDM patients. The conclusion, however, is currently restricted to mild diabetics, i.e., those with fasting blood glucose level between 120 and 180 mg/ dl and postprandial blood glucose level between 180 and 250 mgtdl. To extend the above conclusion to all NIDDM cases, and to assess the relative efficacy of Vijyasar vis-a-vis an allopathic drug, a controlled comparative, randomized, flexible dose multicentric trial has been initiated at four centres, and the findings of this trial will be reported in due course. Acknowledgment
We gratefully acknowledge the pivotal role played by Dr G.V. Satyavati, former Director-General, ICMR. as the coordinator of thenew disease-orientedresearch on herbal drugs. Weacknowledge useful suggestions given throughout the period of the study by Members ofthe Task Forcc on Diabetes Mellitus and Expcrtsof the ICMRScientific Advisory Group forTraditional Medicine Research. We further acknowledge the sustained interest and advice of Prof. h j i t Roy Chaudhury, New Delhi; Prof. B.N. Dhawan, Lucknow; Dr K. Raghunathan, Faridabad; Prof P.K. Das. Meerut during the conduct of the trial. We would like to specially acknowledge the tireless efforts of Prof. S.S. Handa, ahm mu in the standardization. manufacture and supply of trial drugs. The services rendered by Dr B.N. Mehrotrs, former Head, Botany Division. CDRJ, Lucknow in identifying and procuring the plant material is acknowledged. Assistance rendered by Ms. Neeraj Tandon and Dr Madhu Sharma ofMonograph Unit on Medicinal plants ofIndia, lCMR HQs, in the premtion ofbibliography on v~~~~~~ acknowledged, Dr is also M.D. Guptc, Officer-in-Charge, CBMU, scrutinized the manuscriot and made useful &mments. t in all^, we thank the patients who had participated in the trial.
This study has shown that control of blood glucose (both fasting and postprandial) could be achieved in 67 of 93 newly-diagnosed or untreated NIDDM patients, and in about 73 per cent ofthese patients the required daily dose was 2g of Vijayasar (P. ntarsupium). Only 10 per cent of the patients needed a higher dose of 4g per day, which was well tolerated. However, with respect to HbAlc, only 7 per cent of the patients attained control by 12 wk. Also, the 0.4 per cent reduction in the mean HbA,c level, though statistically significant, may not have clinical
References
I. Ojha KN, Paramji RP,Venkatachalam K. A preliminary note on the action of Pterocarpus marsuprum Roxb. on bled sugar. fndran J Pharmacy 1949; 11 : 188 Joglekar GV, Chaudhary NY, Aiman R. Effect of indigenous plant-extracts on glucose-absorption in mice. lndran J Physlol Pharmucol 1959; 3 : 76-7. Gupta SS. Effect of Cymnema sylvestre and Pterocarpus marsupiuni on glucose tolerance in albino rats. Indian J Med Sci 1963: 17 : 501-5.
2.
3.
SELECT RESEARCH PAPERS O N EVIDENCE BASED AYURVEDIC DRUGS
367
TRIAL OF VIJA Y S R IN NIDDM CASES AA 4. Trivedi CP. Observations on the dlect of some indigenous drugs on blood sugar level of nomul and diabetic rabbits. Indian J t'hysiol Pharmmd 1963; 7 : 11-2. Shah DS. A preliminary study of the hypoglycscmic action of hearWood ofPlercrarpusmarsupium Roxb. IndianJMed R u I%% 55 : 166-8. Sliti AQ, Shiniie S Kavishwar WK, Gupta SR. Some aspects , of phytochemisby and hypoglycacmic actions ofPtcrcrapx maraupiw (Papilionaccae). J Rex Indian Med 1971; 6 : 2057. ' Pande MC, Shanna PV. Hypoglycaernic CReci of bark of Pterocurpw marst +urn Roxb. (Boaka) on alloxan induced diabetes. W S u r g 1976; 16 : 9-1 1. Chakravarthy B k Gupta S. Gambhir SS, GodcKD. Pancreatic k t a a l l regeneration A novel antidiabetic mechanism of Pterocarplcr marsupium Roxb. Indian JPharmacol1980; I2 : 123-9. Apte IC. Vnishwanar IP, Khannade B, Jadhav SN. Studies on antihypcrglycwicactivity of some indigenous plants. Indian Drugs 1988; 25 : 461-3. A h d F, K h d i P, Khan MM, Chaubcy M, Rsstogi A Y Ki@ai JR. Hypglyeacmicactivity ofherocorpwmarsupiw wood. JEthanopharmacd 1991; 35 : 71-5. sCpshaGC.~SN.CIinicalobsuvationsontheantidiabcuc pmpcnia of Ptemarpusmarruptum and Eugeniajombola~. J Indian Med AssoC 1956; 27 : 388-94. R a j w h a n n S. Tuli SN. Viioyruar, Pter0capx m ~ u p i W in the treatment ofmadhumeha (diabetes rnellitus) -A clinical trid. J Res Indian Med Yoga Homeop 1976; I / @ : 9-14. of Ojha J K ~ d HS, ~ h im PV. H~poglycaemic S Pterocarpw marmpium Roxh. Tijoyrum). JRes I d a n Med Yogo Horncop 1978; 13 : 126. Pandcy MC. Shanna PV. Hypoglycecmic effect of bark of PterocarPus Roxb, ( ~ ~ : A ) h MedSurg 1975: 25 :21-4. Kdar P, Ch.krabarti CH.Blood sugar, blood ureaand serum lipids as influenced by Gurmar preparation, Pterocarptu marsupium and Tamarfndu~i d c a in diabctca mallips. Mahara.shtra Med J 1981; 28 : 165-9. 16. Chakravanhy BY OuptlS, Gambhir SS, OodeKD. Panmatic bnaccll regeneration in rats by (-)epicatechin. LMcn 1981; s : 75960. 17. Kolb H, Kicsel U, Greulich B, Van Der BO& I. Lack of antidiabetic effectof (-) epicatechin. L.amxt 1982; i : 1303-4. 18. Ahmad F, Khdid P, Khan MM,paaogi AK, Chaubey M, Kidwai JR. Effect of (-) epiubchin on CAMPwntcnt, insulin relase and wnvcrSion of pmiwul'in to insulin in immature andmhvcratislctsmv1ho.lnd1~J~B1ol1991;29:516 20. 19. Ahmad F, Khalid P, Khan MM. Rastogi A h Kidwai JR. Insulin like activity of epicatechin. Acta Diabetol Lutina 1989: 26 :291-300. 20. Rizvi SI, Zaid MA, Suhail M. Insulin-mimctic effect of (-) epicatechin on osmotic fingility ofhuman erythrocytes. Indian Bid 1995; 33 : 791-2.
5.
6.
7.
8.
Jw
lo.
21. Manickam M. AntihypergJymic activity of phenolics ' o m Ptercrarpur marsupium. JNanvol Products I W , 60 : 60910.
22. Varlcy H. Gowenlock AH, Bell M. Practrcd clmtcal biochembtry. 5th ed. London : William Heinemann Medical Books, t980.
LI.
12.
23, Schmidt FH :Methoden dcr Harn-und Blutzu&crbcstimmung I1 Blutzuekcr. In :Pfeiffcr EF, editor, f@ndhch das d i a k t a ntellihu. Munich :IF Lchmanns Valag, 1971 : 938. 24, parkcr KM, ~ ~JD, D~ cOsu H~ ~ ~ d ~ lDE,, ~ J, l RL, Improved wlorimctric assay for glywsylated hemoglobin. Clin Chem 1981;27 : 669-72. 25. Bum HF.Evaluation ofglywsylPtcd hemoglobin in diabetic patients. Diabetes 1981; 30 : 613-7. 26. Pandcy MC, Shama PV. Hypocholcstaolaunic effect of bark of Pterocapa nuvsupium Roxb. (Byah) -An experimental study.J Res Indian Mrd Yoga Hmeop 1978; 13 : 137-9. ~ ~ i ~
13.
14.
15.
Reprmn! requestx : The dffiwin-chargc, CmPal Biostatlst~cdMonitoring Unit, lnstrtute for Rescarth in Medical S q l t c etpls ICMR, Spur Tank Rod, CheCpvt, Chennai 600031
1ndia" J Mcd Re4 108, July 1998, pp 24-29
Flexible dose open trial of Yijayaar in cases of newly-diagoscd~non-insu~in-k~en&~ diabetes mellitus
Indian Council of Medical Resenrch (ICh@ Collaborating Centres. Central Bit.z&,-a Monitoring Unit, Chennai & Central Technical Co-ordinating Unit, ICMif New Leihi
In the sixth para unde: ~1aterinl'g;i~ethods (page No. 261, the second-sentence T q , an extract (dried aqueous decoctio'n) of the bark of P.marsupium, ....should read as ' %, an extract (dried aqueous decoction) of the heartwood of P. mmupium,.,.
- - -
368
Joun~nl o/lDninrind .Sym/don Ainltng-11
Val.
I6 No. 4 Orc&
/ YYX
Managing Morphine-Induced Constipation: A Colltrolled Comparison of an Ayurvedic . Formulation and Senna

I? R Ramcsll, K Surcsh Kumar, M. K. Rajagopal, P Ualacliandnn and I? K Warner .
Pain and Polliatiur Cure Clinic (K.S.X., M.RR), Glicui Medical Col+, Voidyo S b (RR R., R 0.. RK.W). Kotlakkal. Krrala, Indin o
I
Glicul, Indk, and Arya
Cotirlipalion is a frequenl cawe o/distress in aduattced canm A paUiatiue care crt~il in Krrala, a so~itlrern state o/lndia, co~tductcd controlled trial cont/raring a liquid Ayuruedic n (hnkl) pre/.~aratioa (hiisrakasncliam) w i t a convn~lional laxaliue table1 (Sofsm) in the ~~~c~nagmttct~t o olrioicl-ittdtrce cur~sli/rn[iun pafio~ts ad~attcedcnncn: Wough them f it1 with A was,no ~tatisticnlly signijica~rt dij/cretcce itt the a/r/rarettl degree o laxative action bclcucot the f tluo, the rrsul& itidicnlc that tkwr111al1 volu* o/lhe drug requ~rcd/orflecliue laxatiue aclion. tl~e tolerable taste, the once-daily dose, the ac~e/,tabk side c/jrcl projik, and the 141ucost tnake hlisrakasricl~anln good cl~oice /orpro/)/~ylaxir 111 ol~ioid-induced co?ufi,balion. T e e is a hr ~. .~ rtccd /o~.fi~.lltn sttrr1it.s rrjAjurutrlir:atrciici~~m pnllinlirw cart. ,I Pain Symptom Manage in 199S;16:240-244. 8 U.S. CnnccrlJaiirI&lieJCo~nrrillcc;19995'.
Key Words Cancer care, conrtijmlior~, u~otphi~te, alternative medicine, Ayurveda
Zi~kadtcctiort
Constipation is a frcqucnt causc of distress
in advanced canccr.' It is gcncrally tiiultifacto-
3.75 ml per 15 ml emulsion) are botli costly (Ils. 51 per 100 nll and Rs. 23 per 20C 1111 rcspcctively*) and are required in relatively large v o l ~ m c s .Many patienu find them unpalat~ able. As a part of an ongoing eITort to seleit a tilore ideal prcparation, an attempt has bcc~r made to study tllc cfIicacy af an Ayurvedic prcparation. Ayurveda is tlrc most popular indigenous lndian system of medicine, in wliicli materials mainly of plant or animal origin arc used for preparing decoctions. p o ~ ~ d e r~lrrtli. s. cated oils, pills, or otller mcdicincs. Mirrahnel~antis a centuries-old Ayu~ucdic liquid puqativc cor~raining kinds c Ilcrbs. 21 d castor oil. ghec. and anilk. A clinical tri;ll !*.:I\ u~idcrtakcn wit11 ~ l ~ i s prc1)aratiocl to dctcl-nlillc iu c f k c t OII ol~ioid-induced co~~stipatioti. l'lic
-. -
rial in origin and niay bc caused by poor 'dict, dccrcascd activity, local discasc, and drugsnotably opioids.' In tlie I'ain and Palliative Care Clinic at tlie Calicut Medical Collegc. 30% of patients have head and neck caliccr and associated dysphagia. Most of the patients arc bcry poor and arc not ablc to buy drugs regularly. For sucli paticnu, a clleap, sniall-volumc liquid laxative would bc prefcrablc. !+owever, liquid laxadvcs like lactulose and crcrnaffin (milk of magnesia 11.25 rnl. liq. parallill Adclres~ rq~rint requests to: 1)r. 1'. l<.ILIIIICSII~ Alya Vai~lya Sala. Kotukkal (1'. 0.). ~ ~ I ; I I I I I ; I 1)ist.. 676 M II~ 503, Kcrala, Illdin.
0 US. Canccr I'ain
Kclicl Co~a~~~il~ce. 1998
Publiil~cd Elscvicr. Ncw Yort New York by
369
7bbL I Exclt~.io~~ Criteria

IttVattu
i'atic~tuwitlt i t t a r t i t t a l obrtrucciott I'aticttu alrcady on laxativcr l'aiiclru r l ~ arc co~t,tipateclcvctr kforc o
a~td clritdrc~t
tl~c irttakc or ~norplti~lc I'aticnu already utldcrgoing Aptncdic tltcral)y as sonte nrcdicincc may Ilavc a laxarivc action I'alicttu wlto rcfuse i~tfok~ttcd coarcnt
aini was to conrparc efficacy o f Mirrahuru/ram wid1 that o f a cor~vcntional laxative. Sofscm ublec, i t 1 tllc trlatragccitctrc ol o l i o i d - i ~ i d u y t x l coirstipation in p a t i c n u wit11 advanced catrccr.
ill4
Tl~c study was conducted o n p a d c n u witli advanced carlccr aged 15 years a n d o l d e r wlio le wcrc started or1 oral n ~ o r p l i i ~ f o r ~ l r cfirst tirtic an,d \wlio gave i ~ r f o r l n e d consent. T i l e cxclusion criteria arc'givcn illTablc 1. Fifty patic11u wcrc ~:r~rdortrly allocalcd t o tllc two siudy groups (25 c a c l ~ ) b y drawing lots (saiirplirrg with rcl>lacctnc~ri). l ~ c T dif'rcrcncc betwccn llrc plrysical forr~tso f c l ~ ctwo drugs ~rcccssitatcda n o p c ~ rtrial rather t l ~ a i ra double-blind study, as lias bccn d o n e in sinrilar otlrcr studies.' Lasativcs wcrc g i v c ~ as a prol
?blL 2
~>liylacticIilcasurc to tile p a t i e n u wllu wcrc s c a d on oral t t ~ o r p l l i ~ lQr l l i c lint cirnc. c O C g r o u p rcccivcd Murahurneham (TaMc 4 : I ) tlrc o t h e r g r o u p reccivcd S o f s c m b l e u (puri~ ficd ~ n ~ c ix ~ n c t mg c o ~ l t l i n i n g12 m g a GO SCI~II~ g l ~ c ~ ~ i asecalci;m d s salts). ~ 1 1 cdiairioser. d e r n q r a p l ~ i c s n d drugs administcrcd a t o tire study patients are describcd.in Tables 3a at1J Sb. l l r c qudy p e r i o d was I4 days. T l i c hxati:cs wcce adriiit~istcrcdi n tlircc steps (Tablc 4). Step 1was given first a n d t h e n followvcd rap&tively by stcp 2 and stcp 3 if t l ~ c previous stcp lailcd. AII i t ~ t c t v a lo 2 days w s ~ I l o v v c dbel a iwcctl steps. v i e paticnts wcrc c x a i ~ l i n c d every 3 days d u r i n g the first wcck a n d qp.die last day o f tlie second week. Each day's bowel movcmcntc wcre recorded ill a spccilic f o n n a t in accordance wit11 dre critcria given in Tablc 5. Tliesc criteria were set o n the basis o f subjectivc feeling o f satisfaction, in view o f the fact .that 111e cxpcctaiion a n d acliievemeni~of bocvcl movcmcnt a r c widely varying par;~rncters.~
E i g l ~ t y c r c c n t (N = 20) o f tlic p a t i c n b in p tltc Mirmkatnef~am group a n d 64% (N = IG) o f d i c . p a ~ i e n u d i e Sofscna'group cornplctcd the it1 study. Of tlrosc wlio c o m p l c i c d tlte study. 85%
I n g e d i c ~ ~o frhitrah(I~~dan? L
Sanskrit rtntttc
Ituuttical
J I C I
Wt.
(me)
Pippali
Amnlnhi Urahhn
Sjama Danthi
Lhavonfht
Kraduka Ku~arani Sadhoni Charm~lahua

Swrncutrkm
Co&ht Sikha~i
lhjani
Chinnnmh~t h'arnttjo U!~rhntrlti V~nthi~hhatha

Ilnlt~~rtn
Pipnbngurn Linn. Phylbnrhur d l u n I,itr~r. V U u uinfia Litltr. Opmulina turplrhum (L~IIII.) S i h Mallso (wltitc) 8al<o~prmum nwntanum (Willd.) MucU.- k g . (1)urificd) jafmpha cum- Linn. A m caluhu Linn. ,-lid lurpvrhum(Linn.) S i l n hfuu?, (black) Uiraria #cmafcd t i ~ ~ a . Acacia sirmafa (Lour.) Mcrr. A ~ n mexicane L~III~. r Cucvmu trigunw Roxb. Achytanlhu orpna 1.intt. Cu:urrumalonga Liaa. 7i'nospracordi/dia (\Clilld.) hlicrs c x 1la1k.l.kTl~ot~tr fJan#amia& h a Vcttt.
A r p r h a spcdio~e Swcc.~
780 780
7110
780 708 780
780
780
780
780 780 780 780 7W 780 780
780
780
7W 78U
fBI,
Sip*
7X&httnvi1khnl,hale
Ciuiefiluln I~IIII. Mninp ohftra 1a nr. Saccharurn ~Jficr~tnrum 1jrt11. Ctofon rigbum I.ittrt. (purified)
'100 ml of r t ~ c mcdiiit*c i s prrparcd by 11ac rnlrontirr protcvin~ tlw k . a i n g i t c ~ n s x c d a z t c r r i t l l per. 8: d in milk bOa ml: castor uil50 mi; slur W ml.
370
group L)iag~icnu Carcinoi~la ollrlng Carcinoma o l tongue Carcinoma ot breast Carcinoma olesopl~agus Carcinoma oloropharynx Carcinoma or tonsil Hcpatocellular carcinoma Mulitple m)rloma Carcinoma of onry Carcinoma orcelvix Carcinoma of check Carcinoma of pehir Acuk myelogenous leukemia
Age distributiol~
Y J S 1
~""1'
7 J 3 2 2 0
I
3
I 2 I
0 I
0
I
S
2
0 I
0 I -
0 25
I 4
4
25
c10 91-40 4 1-50 51-60 GI-70,

Sex distribution
I 2 d
25 17
A
II B
6 -
10
25
Male Fcnialc
25
10 25
15
rrGshctoiy Imwvcl II~OVCI~~C~ILS. ~ l l ~ c s ic t r c s I p fuggcst a tl.cnd it1 favor of Muraknute/~atr~ fro111 tlic p o i n t o f view of cmucy, cvcn d ~ o u g l tlic l difkrcllcc. is 1101statistically significant ( P > O.Z;,clli-square test). bong dlosc w i t h satisfactory k w c l movcnicnu. 47% (N 8) fro111 t l ~ c M i r r u k a s t J ~ a m g r o and 45% (N5: 5) f r o m tllc u~ Sofseua g r o u p h a d satisfaclory bowel moveci\cnts will1 step 1. Twentynine p c r c c n i (N = 5) from d l c MinokaJnJlomgroup a n d 55% (13= 6 ) froill thc Sofsena group h a d satisfactory bowcl nfbvcnicni wit11 s r p 2, a n d 24% (N= 4) from the Mirrahasneham group a n d n o n e fro111 tlie Sofsena g r o u p h a d satisfactory boivel movcment w i t h stcp 3 (Table 6). Details o f tllosc cases with unsatisfactory bowel movements are given in Tablc7. A m o n g .those who did n o t P m p l e t e the study, o n e f r o m the hfisdam&rn g r o u p a n d four f r o m the Sofsena group d r o p p e d o u t duc to irregular laxative administration. T w o f r o m LII? Misrakainelranr died d u r i n g the coursc of Ole study. Tvvo each from. b o t l i tlic groups were lost t o follow-up. t+orplline was witlidrawn from two patients in the Sofsena group a n d tllesc patients were d r o p p c d fro111 tli: study. O n e f r o m the Sokena g r o u p dropped out as I l e was getting good bowel m o v c m e n l widlout laxative (Table 8).
( N = 17) o f the hlirrakariuhain g r o u p a n d 69% ( N = 11) o f the Sofsena g r o u p h a d satisfactory bowel movements, a n d 15% (N= 3) a n d 31% (N= 5) o f the respective groups did n o t have
Talk 36
DkcusSioff
Ayulveda literally means thc science of liic and,the positive and negative aspects o f life are
DNS Taken by Study Patients

Nurnbcr of patienu MisraLas~~ehai~~ group Morphinc dosc/24 br I5 mg 50 mg 45 mg GO mg Otlrcr n~cdicatior~s Par.rccranrol L)iclole~~ac rodiurt~ hlr~oclo~~rainiclc Aii~itri~~tylinc Ranitidir~e Ilalopcridol I'rcdnirolor~c Dicyclo~ai~~c Dosc/24 2-5 R
Irr
&;blscnn group
9 10
2
4 -
12
0
I , -
25
9 I2
25
10
1 SO r t ~ ~
II
10-50 III~ 17.5-25 iiog

500
III~
20
1 S
1
19
J
4 4 I
1
2.5 ing 10-20 ing 20 inc
37 1
cxl~hincdl i a ulliquc \ ~ a y tliis scicncc. Illc i in lircl.;~turc 1 1 tllc ~)ri~iciplcs ~)l-:icticcs 0 ;uncl of Ayurvctla arc writtc11in tlic classical 1-lintlu language of Sanskrit an J arc fiatcd to 400 U.C.G Ayuweda liar, csscri~all~, cornpo~icnu; two (i) t l ~ c Svnrilravtirhn (I~caltl~y rnarr's r c g i ~ ~ ~ c n ) , tvhicli dcals \Jitli t l ~ c orderly upkccp of Iicaltll and (ii) Alhurnvrithn (paticrit's rcgi~iicn). wliicl~is all about tlic eradication of discascs. Ayuwcda pcrccivcs man as an intcgral part of naturc and its approacl~to uvcll-bcirig is pllilosopl~ical principle ant1 liolistic in tccliniquc. in Evc~y ailrnclit is coricci\.ccl as a psycl~osotnatic nlanifcstation and its cradication is fttnctional and h e g r n t i v e , mltcr d r a ~ isytrlptomatlc or factorial. kvcly 1iuni;tn bcini is iccn to ocpupy. constitiltiorially, a unique state of tlircc basic bodily hurnors (Vntn. Pitlo, and K@ha). Any upset occurring to this nasccrit state of balance is manifested as an ailmcnt arid rlic tllcrapy is dircctcd to rcgai~l :rigitla\ starc. .i.llis is tltc: tllc ~ ~ c a s atlint it is co~~irnorily n swtcd t l ~ a tthe Ayurvcclic tr.c;tLrlrcnt is lor t l ~ c paticnt and not for tllc ailr~iclit. Tl~us, tl~crapy rllc rrlay vary for different paticnts displaying the sanic sylnp toms. This priticiplc was coniprorniscd ill dic use of tlic sarnc Ayuneedic laxative for all pa-
~novc~ncnt:
a. wit side
9. . cffccu (tnurca. vorrlltlng, and colic)

I'IIII~ t lodc~arc
h. ~ ~ ~ I I Oside CKCCU I I I S : ~ t i s r a c t o ~ ~ IIIOVCIIICIII LXIWCI wit11 sidc ciTccu
I
P
ticnu oli oral ~ i i o r p l t i ~ ~ c bccausc a scientific cvaluariorl o r tllc drug using modcrt~ i ~ c ~ l i a i l ~ ology'h~andatcd t ~ c a ~ s l con~promisc.. Afurnkasrrclurm is a ccnturics~ld combinatiim used in Aylllvcda as a purgati\.e in constipated padcnts. TIlc Inode of processing, tile ingrcdicnrs and 1115 indications for this formulation arc' dcscribcd ill a classic A y u y d i c litcmture callcd Asl~fnngahridajan~' wlticl~.& about 1300 ycars old and is in the olficial FormularyP T h e ir~dividualirigredienu arc dcscribcd wid^ botanical and Ayun.cdic dcuils in a recent public a t i o ~ i .Altl~ougl~ ~ used as a 'pucgativc" i l l A)vrvcda, tlte present study evaluated small closis of hfisraknsitel~nm a larati\,c. S o f s e ~ ~aa , as lrccly a\ailablc stirntrlant laxa~ivc co~uliionly used in Irldia, was c~nployed the cornparator. as PaGc~iuw l ~ o had regular bo\rcl riiovclnctits wit11 Afisrkostlelraa~wcrc also satisfied \\+it11its easy adl~~inisrtatiori. it is a liquitl prcparaAs lion tilat c . be usctl ili a srnnll rlosc 1 2 . 7 1 to 1 0 ~ 1111).i t was well acccptcd by tlie patielits who ircrc bcncfirtcd by it. especially tliosc \ \ * i r l ~ clyspl~agiafroni head and luck lesions. Tlic latency of action of Sofscna is 6 1 2 hours.t0 compared to a n observed latency pcriod of 4-6 hours in t l ~ case of ~lurknsntlrnrn. c Tllc cost of 2.5 rill Alicraltnsr~el~o~~~ d1a11115. 1 , ~ 0 1 1 1 is lcsg o;l~ctl( J 1:s. 1.W) f19r I r i ...;: :;r..!,:i:t rlo~c. ~ Sol[ g f scna tablct. 'l'ltc ~~aticrtrs not col~lplai~i tlld abort1 tllc tnstc bf tlic laxative. Mir,ilta~t~cltam appcar-s to be acil11g as ;i sti~riulnrit laxativc. T l ~ c pliar~uacokincticsa ~ i d pl~artriacodparriics o irs compo~rencs not clearly C arc u ~ ~ d c r s t o o d . is assut~rcdillat dle combir~aIt tion of tllc 21 I~erbstogether with castor oil, !uilk. ; u ~ d l ~ c c g \~toduccs ctlcciivcl laxliivc tlic
372
I h w ~ h al. tf
Vd. 16 No. 4 Oclolrr IY98
'Ibblc 7
Details of Cases will1 Utrultfactory Bowel Move~rienLs
7bMc8 Details of Drormuu fro181llle Study
Reas011
a) Vornitcd in step I
and colic* b) N bowel movement o even wid1 step Sb Toul Jee art for dexription.
I
S
5
5
'All nix c W were m a n q e d mlh rcpcatcd u x ol bisacodd supporilor). and glycerine enema..
Irregular luurivc admintcncion Dead8 N follow-up o Morpl~inc-dll~dnwn Good bowel rnuovcelertt nid~out laxatkc Toul
action in tliis small dose. In comparison, castor oil, o n its own, is unpalatable and not as eKec. tivc, as it nccds higher adult dosage.11 It was interesting to note diat 4 of dlc 17 patienu (24%) wlio exhibited satisfactory r e d u in tlic Misraharnel~a~n group took it only once in twp or tlirce days. Anecdotcdly, I~igllcr doses (1020 mi) of tile Misrakariiclrlnm have acliievcd rcsulfs in patients w l ~ o Imuo lrot s c s p d c d LO convenlional laxatives at all. Two patients in tlie Mirrakariieha?n group stopped tlie laxative aftcr tlic first dose. cornplaining of nausea, vomiting, and colicky pain. 'I'llcy did riot liavc bowel rriovcrr~c~it tliat wit11 dose. One oPthesc patienu had carcinoma of the tdnjil and responded well to bisacodyl5-10 mg at niglit, whcrcas the o t l ~ c rpaticlil wlio had hcpatoccllular carcinoma, continued vomiting eveh aftcr stopping Mirrakameltam. dcspite anticmctics. Slic stopped vomiting aftcr discontinuing the low dose of morphine (2.5 mg q4h) that shc was m%ing. It is tentatively concludcd from tl~isstud\that hlirtal~nrncharr~ the potential to bc uscd II;U as an allertlate rllenpcutic tool for niandging tnorpl~inc-inducccl constipation aid part of pallialivc carc of pticnLr with atlmnhd cancer. Vicwcd from tlic perspective of palatability, cgsl cflectivencss, and low sidc eifcct profile, dlc Toniiuladorr appcars to bc a good clioicc Furtlicr rigorous studics arc riccdcd to cstab lisll tlic prcli~riinary results prcscntcd iierc.
cuuioris and guidarice during tlic study arid wliilc prcpariug ll1c manuscript. Tllcy also h a n k tlic paticnu. volu~itecrs. n d stafT of tlic e l'alliativc Care Clinic lor ttlcir cxcclpain a r ~ d l c ~ isupport to the study. Thanks arc also duc t KO Dr. T.S. Murali and Dr. .C. f l ~ ~ ~ a r i k uTory tt Mrs. I'rccsuggestions arid to Mrs. Si~.asivatliy, tlla Kanicsli, and Mr. P:M. Vasudcva~i sccrefor larial support.
JE.
1. Twycross RC. Lack SA. Control ol aiiriicn~ary symptoms in far advanced cancer. Edinburgli: Clturcllill Livingstorre. 198G. 2. Sykes N. I'rog I'nlliaGvc Csrc 199k.i:170. 3, Sykes NP. A~volut~tec~ for tllc colr~pariri~odel son of laxatives in opioid-rclatedconstipation.J I'ain Symptom Manage 1996;11:363.' 4. Sykes NP. A clinical comparisori ol laxative iri a I~ospice. Palliative Med 1991;5:307. ConncU Ah4, Iiilton C. Irvine G.Lennardrjones MisicwicrJ. Variation in bowel Iiabit i r i two p o p uladon sa~i~plcs. hied J 1965:ll 1095. Br 6. Ullisl~agrac~~a S~~sl.utll~ KL. sa11111im. I ( E n Vo1. glisli translation). C l i ~ ~ l k l i ; ~ iS Zb ~ S ~ secics. ~: I I C~I 'Varanari, 1991.
4.
.Ilic autliors cxl)~.css~licirsiriccrc gratitude .

to Dr. Kobct t 'l'wycr~ossfor tlrc vcry ttscfi11 dis-
9. Warricr I'K Nhnbiar VPK. hrnal~kuiiyC. Indi211rnedici~nlI ) ~ ; ~ ~ I I w - . I C I , I I I I ) C I ~ ~ ~ I I IofI 500 S ~ I C ~ cics. i r i 5 %YALIIIICS,~ ~ l Oric~itL O I I ~ I I ~ ; I I ~ Cl~c lai: Ltcl.. 1993-1996. Forr~~ul~ry. No. 18:ti7. 1989. 10. Uritislr Natio~bal
I I . UI itisli ~ a t i o l ~F l I I I I I I1989, No. 18:G6 aV ~~L~,
373

Herbal Formulation Improves Memory Components

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SELECT RESEARCH PAPERS ON EVIDENCE BASED DRUGS IN AYURVEDA J

Date :0152001 Place: New Delhi

(Dr. G. Veluchamy) Director, Central Council for Research in A y u ~ e d a and Siddha

TITLE OF THE STUDY

IMMUNOMODULATORS AND ADAPTOGENS

Adaptogens in High Mountains

Membrane Integrity Changes at High Terrestrial Altitudes (with Geriforle - Himalaya)

1I Endurance Enhancement in Adverse Environment

Guggulipid : a Promising Hypolipiadaemic Agent from Gum Guggul (Commiphora wighlii)

Commiphora wightii Engl. (Gum Guggul)

Managing Morphine-Induced Constipation : A Controlled Comparison of an Ayun'edic Formulation and Senna

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o To evaluate the efficacy of the preparation containing five herbal ingredients in

Sensory perception Central integration and processing Overall sensorimotor coordination

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EFFECT OF LEARNING ON THE TEST BATTERIES

Session Sesvon Servon Session

cannot improve further

PLACEBO GRP UTEST GRP

: SIGNIFICANT DIFFERENCE FROM THE DAY 0 SCORE AT PC 0.001.

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IMMEDIATE VERBAL RECOGNITION (IVR)

DELAYED VERBAL RECOGNITION (DVR)

FIGURE RECOGNITION (FR)

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DIGIT SPAN (DS)

ns : NON-SlGNlFlCANT DIFFERENCE FROM PLACEBO

: SIGNIFICANT DIFFERENCE FROM THE DAY 0 SCORE AT PC 0.03

VISUAL REACTION RATIO

: NONSIGNIFICANT DIFFERENCE FROM PLACEBO

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1. Within treatment group paired T Test

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CFF showed no effect.

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lndian Journal of Pharmacology 1997; 29: S359-5365

NEUROPSYCHOPHARMACOLOGICAL EFFECTS OF THE AYURVEDIC

KEY WORDS Nsolropic

Correspondcncc: B.N. Dhaw

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SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS

(m)is anenualedby bacoride. f a ) .

,' 0 . 0 1 compared to 1) .. p.O.01 far compued lo ~ far

p.O.01 la$ compared lo 3)

SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS

H.K. SINGH /\NO B.N. OHAWAN

retenlion as cnmpared lo the controls (

The ECS induced amnesia (

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a. p*O.Ol (as compared to 1) . 1~;31 pc0.01 (as compared to 4)

The results of the investigation using these three

SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS

H.K. SINGH AND B.N. OHAWAN

SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS

SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS

H.K. SlNGH AND B.N. OHAWAN

CALORIC RESTRICTION MAY EXTEND THE LIFE AND HEALTH

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Phamawpsychoecologia (1990). 3,47-52

B.S. Guptd, K.N. ~ldtrpd

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SELECT RESEARCH PAPERS ON EVIDENCE BASED AYURVEDIC DRUGS

Comparison Initial vs ARn 5 y s p > 0.05 p>0.05 p<O.OOI p>0.05