Int. J. Pharm. Sci. Rev. Res., 32(2), May – June 2015; Article No.

24, Pages: 154-156 ISSN 0976 – 044X

Research Article

Spectrophotometric Method for the Simultaneous Determination of Isoniazid and

Rifampicin in Bulk and Tablet Forms

Mohamed A.O. Mohamed, Shaza W. Shantier*, Magdi A. Mohamed, Elrasheed A. GadKariem, Esraa M.O. Ismail
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Khartoum, Sudan.
*Corresponding author’s E-mail: sshantier@yahoo.com

Accepted on: 16-04-2015; Finalized on: 31-05-2015.

ABSTRACT
A spectrophotometric method was developed for the simultaneous determination of Isoniazid (INH) and rifampicin (RIF) in bulk and
dosage forms. The method involved the determination of INH in the presence of rifampicin using two wavelengths (238nm &
337nm). Beer’s law was obeyed in the concentration range 2.5-12.5µg/ml and 5-25µg/ml with good linearity (0.9997 & 0.9999) and
satisfactory limits of detection (0.70 & 0.26µg/ml) for INH and RIF respectively. The accuracy and the precision of the developed
method were confirmed through the statistical comparison of the obtained data with those of the official USP method.
Keywords: INH; Rifampicin; Simultaneous; Spectrophotometry.

INTRODUCTION chromatography8-10 and spectrophotometry11-14.

However, most of these methods are expensive, time

T he world health organization (WHO) ranked

Tuberculosis (TB) as the second leading cause of
death among infectious diseases worldwide. More
than 95% of the TB cases and deaths occur in the third
world countries1. A variety of drugs are used to cure TB,
however, INH (Figure 1) and rifampicin (Figure 2) are the
most active ones2. One of the greatest challenges in
eradicating TB is multidrug resistance TB (MDR-TB)
resulting from resistant strains to INH and/or rifampicin.
The use of counterfeit or substandard drugs is among the
major causes of MDR-TB1.
consuming and, to the best of our knowledge, none of
them had been applied for determination of INH in the
presence of rifampicin.
Therefore, the aim of the present work was to develop a
simple, sensitive and accurate spectrophotometric
method for the simultaneous determination of INH in the
presence of rifampicin.
MATERIALS AND METHODS
Materials and Instruments
INH and rifampicin working standards (99.4% and 99.5%,
respectively) were kindly provided by General Medicines
Company, Sudan. Refalin® tablets (INH USP 150mg +
rifampicin USP 300mg) were purchased from the local
market. Methanol analytical grade was purchased from
ScharlauChemie, Spain.
UV spectrophotometric studies were carried out on
Shimadzu UV-1800ENG240V, (Koyoto, Japan).
Diluent Solvent

Figure 1: Chemical structure of INH Methanol and distilled water were mixed together in the
ratio of 2:1, respectively in order to prepare the diluent
solvent.
Preparation of INH Standard Solution
0.025g of INH working standard was accurately weighed
and dissolved in 20ml diluent solvent. The solution was
then transferred into 100ml volumetric flask and the
volume was completed to mark with the diluent solvent
(250µg/ml; solution A).
Preparation of Rifampicin Standard Solution
Figure 2: Chemical structure of RIF
0.05g of RIF working standard was accurately weighed
Many methods were reported for determination of INH and dissolved in 20ml diluent solvent. The solution was
including chemiluminescence3-5, voltammetry6,7, then transferred into 100ml volumetric flask and the

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Int. J. Pharm. Sci. Rev. Res., 32(2), May – June 2015; Article No. 24, Pages: 154-156 ISSN 0976 – 044X

volume was completed to mark with the diluent solvent wavelength 238nm. This was confirmed by mixing fixed
(500µg/ml; solution B). amount of rifampicin with increased amounts of INH
(Table 1).
Procedures
These findings were used to construct the calibration
Estimation of Wavelengths
curve at 238nm. Equation 1 was solved to calculate
One ml of each solution A and B were transferred to rifampicin serial concentrations from the absorbance
separate 100ml volumetric flasks. In a third 100ml values at 337nm. These concentrations were then
volumetric flask 1 ml of solution A was mixed with 1 ml of substituted in equation 2 to calculate the absorbance
solution B. The volumes of the above solutions were values of INH at 238nm.
completed to marks using the diluent solvent. The
The simultaneous results using wavelengths 238nm and
resultant solutions were scanned between 200-500nm
447nm were found to be less sensitive and less accurate,
range. The wavelengths were determined and their
that is why the determination of INH and RIF was
corresponding specific absorbances were calculated.
obtained from results at 238nm and 337nm.
Calibration Curve
A =A1%1cml Cy …………… Eq. 1 (at 337nm)
Aliquot volumes from solution A (1-5ml) were transferred
Am = (A1%1cm)xl Cx + (A1%1cm)yl Cy ………. Eq. 2 (at 238nm)
into five separate 100ml volumetric flasks. Serial volumes
1%
of solution B (1-5ml) were then added to the above Where: Am is the absorbance of the mixture; A 1cm is the
solutions to obtain mixtures having concentration in the specific absorbances for INH and RIF at 238nm; l is the
ratio of 1:2 (INH: RIF). The volumes were then completed cell path length; CX and CY are the concentrations of INH
to mark using the diluent solvent. Absorbance values and RIF, respectively.
were measured at 238nm, 337nm and 477nm. The
The results obtained for the absorbance values at 238nm
absorbance values obtained at 238nm were plotted
and 337nm are summarized in Table 2.
against the corresponding INH and RIF concentrations.
Table 2: Construction of calibration curve (n=3)
Assay of INH in INH/Rifampicin Combined Tablets
Conc. µg/ml RIF Abs. at RIF Abs. at INH Abs.
An amount of the powdered tablets containing 0.025g Am
(INH+RIF) 337nm 238nm at 238nm
INH was accurately weighed and dissolved in 20ml of the
diluent solvent. The volume was completed to 100ml, 2.5+5 0.276 0.163 0.201 0.075
mixed and filtered. One ml of the filtrate was diluted to 5+10 0.555 0.327 0.404 0.151
100ml and the absorbance of the resultant solution was 7.5+15 0.817 0.488 0.603 0.214
measured at 238nm. The content percent was calculated 10+20 1.094 0.650 0.803 0.291
by direct sample/standard comparison. 12.5+25 1.373 0.816 1.008 0.365
RESULTS AND DISCUSSION R 0.9999 0.9999 0.9997

Table 1: Estimation of Interference Wavelength Analytical Data

RIF INH Abs. at Abs. at Abs. at Beer’s law was obeyed in the concentration range 2.5-
Volume Volume 238nm 337nm 477nm 12.5µg/ml and 5-25µg/ml for INH and rifampicin,
respectively. Table 3 revealed the optical characteristics
1 ml 1 ml 0.339 0.170 0.096 and statistical data for the regression equation of the
1 ml 2 ml 0.459 0.169 0.095 proposed method. The limits of detection (LOD) and
1 ml 3 ml 0.582 0.169 0.094 quantification (LOQ) were calculated using the standard
1 ml 4 ml 0.715 0.172 0.096 deviation of response and the slope of the calibration
16
1 ml 5 ml 0.835 0.172 0.095
curve .
Table 3: Optical characteristics for INH and rifampicin by
The analysis of two or more components in a sample
the proposed method at 238nm
mixture is straightforward if there are regions in the
sample’s spectrum in which each component is the only Proposed method
Parameter
absorbing species. Unfortunately, UV/Vis absorption INH Rifampicin
bands are so broad making it impossible to find Range 2.5-12.5µg/ml 5-25
appropriate wavelengths at which each component of a Slope ± tSb* 0.029 ± (2.70x10 )
-3
0.04 ± (7.0x10 )
-4

mixture absorbs separately15. Intercept ± tSa* 0.0015 ± 0.029 -0.000048 ± 0.015

The UV spectrum of rifampicin showed absorbance at Correlation coefficient 0.9997 0.9999
three wavelengths, namely 238nm, 337nm and 477nm Limit of detection (LOD) 0.70µg/ml 0.26µg/ml
with corresponding specific absorbance values 420.67, Limit of quantification
340.66 and 196.00, respectively. INH was found to 2.33µg/ml 0.86µg/ml
(LOQ)
interfere with rifampicin absorption only at the *= 95% confidence limit of the standard error of slope and intercept

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The precision of the developed method was evaluated by dichloroisocyanurate-and trichloroisocyanuric acid-luminol
the results obtained from between-days (reproducibility) chemiluminescence systems. Il Farmaco. 59, 2004, 481-
and within-day data (repeatability) for three 486.
concentrations within the linearity range. The calculated 4. Haghighi B, Bozorgzadeh S. Flow injection
RSD values for both drugs were found to be within the chemiluminescence determination of isoniazid using
accepted limit (less than 2%, Table 4). luminol and silver nanoparticles. Microchemical journal.
95, 2010, 192-197.
Table 4: Precision of the proposed method (n=3)
5. Du J, Lu J. Flow injection chemiluminescence determination
Repeatability (RSD %) Reproducibility (RSD %) of isoniazid using the lucigenin–periodate system.
INH 1.80 1.70 2.00 1.0 0.7 0.8 Luminescence. 21, 2006, 26-30.
Rifampicin 0.25 0.70 0.76 1.4 1.7 1.0 6. Xia HY, Hu XY. Determination of isoniazid using a gold
electrode by differential pulse voltammetry. Analytical
Finally, the proposed method was applied for the Letters. 38, 2005,1405-1414.
determination of INH and RIF in the tablet dosage form.
7. Szlósarczyk M, Piech R, Bator BP, Maślanka A, Opoka W,
The mean content percent of three independent analyses
Krzek J. Voltammetric determination of isoniazid using
for INH and rifampicin were found to be102.0 ± 1.25% cyclic renewable mercury film silver based electrode.
and 100.3 ± 0.46%, respectively; n=3 (Table 5). Pharmaceutica Analytica Acta. 3, 2012, 5.
Table 5: Validation results of the proposed method 8. Khuhawar M, Rind F, Rajper A. High-performance liquid
compared to the official method chromatographic determination of isoniazid, pyrazinamide,
and indomethacin in pharmaceutical preparations. Acta
Content% ± *t cal, *Fcal,
chromatographica. 15, 2005, 269-275.
SD% t(tab) F(tab)

Proposed INH 102.0 ± 1.25 2.76 (2.78) 5.17 (19) 9. Khuhawar MY, Zardari LA. Ethyl chloroformate as a
Method derivatizing reagent for the gas chromatographic
Rifampicin 100.3 ± 0.46 1.76 (2.78) 3.58 (19)
determination of isoniazid and hydrazine in pharmaceutical
Official INH 99.6 ± 0.55 preparations. Analytical sciences. 24, 2008, 1493-1496.
- -
Method Rifampicin 101.3 ± 0.87
10. Khuhawar M, Rind F. High performance liquid
* = t and F calculated and tabulated values chromatographic determination of isoniazid, pyrazinamide
The validity of the method was assessed by comparing and rifampicin in pharmaceutical preparations. Pakistan
journal of pharmaceutical sciences. 18, 1998, 49-54.
the statistical results obtained with those of the official
USP liquid chromatography method. As the calculated t- 11. Oga EF. Spectrophotometric determination of isoniazid in
and F-values were less than tabulated ones, the result of pure and pharmaceuticla formulations using vainillin.
the developed method can be considered as accurate and International Journal of Pharmacy and Pharmaceutical
precise as the liquid chromatographic method. Sciences. 2, 2010, 55-58.

CONCLUSION 12. Elhagi AM, Ben Naji NR, Bensaber SM, Almog TK.
Microwave assistant technique in spectrophotometric
The proposed method was proved to be simple, selective, assay of isoniazid using it’s Schiff’s base derivatives.
precise and sensitive for the determination of INH and International Journal of pharmaceutical sciences and
rifampicin in bulk form and tablet forms. Statistical and research. 4, 2013, 644-649.
analytical validation of the results, using λ = 238 & 13. Naidu KG, Suvardhan K, Kumar SK, Rekha D, Sastry BS,
337nm, confirmed that the simultaneous determination Chiranjeevi P. Simple sensitive spectrophotometric
could be used as an alternative method for the routine determination of isoniazid and ritodrine hydrochloride.
analysis of both drugs in quality control laboratories. Journal of Analytical Chemistry. 60, 2005, 822-827.
REFERENCES 14. Nagaraja P, Srinivasa Murthy K, Yathirajan H.
Spectrophotometric determination of isoniazid with
1. Tuberculosis, Fact Sheet No. 104. [Internet]: WHO; sodium 1, 2-naphthoquinone-4-sulphonate and
[updated October 2014; cited 2014 December, 13]; cetyltrimethyl ammonium bromide. Talanta. 43, 1996,
Available from: 1075-1080.
http://www.who.int/mediacentre/factsheets/fs104/en/ind
ex.html. 15. David Harvey. Modern Analytical Chemistry, McGraw Hill.
2000, 400.
2. Katzung BG, Masters SB, Trevor AJ. Basic and Clinical
Pharmacology. 12th ed. USA: McGraw-Hill Lange; 2012, 16. JC Miller and JN Miller. Statistics and Chemometrics for
839. Analytical Chemistry (fifth ed.) Pearson Education Limited,
UK. 2005, 39–51, 25.
3. Safavi A, Karimi M, Hormozi Nezhad M. Flow-injection
determination of isoniazid using sodium

Source of Support: The authors declare no conflict of interest and the current work was self sponsored, Conflict of Interest: None.

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 Acetylcholinesterase Inhibitors Test Confirmed Myasthenia
Gravis in Psychosis Remitted by Aripiprazole

ANDREEA TEODORESCU1,2, PETRU IFTENI1,2, PAULA PETRIC2, SEBASTIAN TOMA1*, ADRIAN BARACAN1,3*, CLAUDIA GAVRIS1,3,
GHEORGHE G. BALAN4*, VLADIMIR POROCH4,5, ALINA MIHAELA PASCU1
1
Transilvania University of Brasov, Faculty of Medicine, 29 Eroilor Blvd., 500036, Brasov, Romania
2
Clinical Psychiatry and Neurology Hospital Brasov, 18 Mihai Eminescu Str., 500079, Brasov, Romania
3
Clinical Emergency County Hospital Brasov, 25-27 Calea Bucuresti, 500326, Brasaov, Romania
4
Grigore T. Popa University of Medicine and Pharmacy, Faculty of Medicine, 16 Universitatii Str., 700115, Iasi, Romania
5
Regional Institute of Oncology, 2-4 G-ral Berthelot Str., 700483, Iasi, Romania

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease affecting the neuromuscular
junction and causes weakness in the skeletal muscles. The acetylcholine receptor is usually attacked in
skeletal muscles, but other components of neuromuscular junction, such as muscle-specific receptor tyrosine
kinase, may be affected. MG can be life-threatening when the respiratory muscles are involved. The first
symptom in about 2 out of 3 cases is the damage of the extrinsic eye muscles. The condition is treatable, so
an early recognition is needed. Although there have been reports of associations between psychosis and
myasthenia gravis it is unclear if psychotic symptoms in MG are an integral part of the various manifestations
of this disease, or are due to another co-occurring distinct disorder. Sometimes psychotic episodes could
disguise the simptoms of myastenia gravis, and delay the diagnosis.
Keywords: acetylcholinesterase, miostine, myasthenia gravis, psychosis, aripiprazole

Myasthenia gravis (MG) is a relatively uncommon
autoimmune disorder in which autoantibodies
(immunoglobulin G) anti-acetylcholine nicotinic
postsynaptic receptors (AChR) develop in the
neuromuscular junction [1]. In essence, it is an
autoimmune reaction in which anti-AChR antibodies
decrease, in fact, the number of AChR in the postsynaptic
muscle membrane [2].
Patients suffering from this disease experience
muscular weakness and fatigue that impact the quality of
life. The weakness usually affects a specific muscular
group and it’s fluctuant in different days, increases with
activity and improves with rest [3].
According to a recent systematic review of population-
based epidemiological studies, the pooled incidence and
prevalence rates of MG were estimated at 5.4 per million
person/year and 77.7 per million persons, respectively [4].
Although some data about the associations of psychosis
in MG have been reported, it is still unclear whether
psychotic symptoms in MG represent an integral part of
the various manifestations of this disease, or appear
because of other distinct co-existing disorders [5].
Experimental part
A female patient, addressed to the psychiatric
emergency service in 2014 and admited for psychomotor
agitation, perturbing behavior, delusions of persecution,
transformation and prejudice. The general physical
examination was normal. Her family reported that the
bizarre, perturbing behavior started 12 months before
admition, when the patient returned home from university
and they considered behaviour as a consequence of a
possible substance abuse. Despite their efforts the patient
sistematicaly refused to be apointed to a psychiatrist.
The routine admission blood tests, including full blood
count, electrolytes, renal, hepatic and thyroid parameters
were all within normal limits. The patient was also tested
for drugs and the results were negative. Head computed
*email: sebitom2002@yahoo.com; adrianbaracan@yahoo.com; balan.gheo@yahoo.com
tomography (CT) scan reveled a possible right-sided
demyelinating parietal lesion and bilateral cortical-
subcortical atrophy (fig. 1). A magnetic resonance imaging
(MRI) was also reccomended after discharge.
Fig. 1. Head Computed
Tomography (CT): Bilateral
Cortical-Subcortical Atrophy
And Possible Right Parietal
Demyelinayting Lesion
Durring the admision she was treated with haloperidol
10 mg/day with improvement of sympoms but with
extrapiramidal side effects (EPS). The treatment was
switched to aripiprazole 10 mg/day, valproic acid 1000 mg/
day and lorazepam 2mg/day. The new treatment schema
was efficient and safe.
The patient was discharged after 30 days with clinical
global impresion-improvement (CGI-I) score of 2 (much
improved). She returned to work and she was involved in
an international project abroad.
Despite her complains about fatigability, dizziness, and
muscle wickness, these simptoms were considered side
effects of psychotropic medication. She was advised to
gradualy stop valproic acid and lorazepam, but not
aripiprazole because of possible relapse of psychosis.
In 2016 she returned to the first psychiatrist for another
opinion. She was very unstable on her legs, presenting
movement dificulties, visual disturbances, difficulty in
swallowing especially for solid food. The patient was
imediatly sent to the neurology department to be evaluated
for myastenia gravis. At admision, myasthenic muscle
score (Gajdos) [6] was 30 points. After the administration
of oral cholinesterase-inhibitors the score was 60 points

2952 http://www.revistadechimie.ro REV.CHIM.(Bucharest)♦ 68 ♦ No. 12 ♦ 2017


Fig. 2. Chest X-Ray
with the improvement of proximal muscle strength and
the improvement of ocular movements (table 1).
The chest X-ray excluded a thymoma (fig. 2).
Blood tests were positive for rheumatoid factor, and
negative for lupus cells. Other laboratory tests, including
complete blood count (CBC), ionogram, biochemistry were
all in normal range. Based on the clinical, paraclinical and
laborator y results the patient was diagnosed with
myasthenia gravis. She was advised to continue treatment
with neostigmine.
Results and discussions
Myasthenia gravis often appears with other autoimmune
diseases such as thyroid disease, polymyositis/
dermatomyositis, systemic lupus er ythematosus,
rheumatoid arthritis, cardiomyositis, subclinical heart
dysfunction, and cancer [7-9].
Psychosis in MG is very rare [5] and there were no case
reports with psychosis preceding MG. In only one study the
authors have shown a high prevalence of psychiatric
disorders in MG, especially depressive and anxiety
disorders, in comparison to what is expected in the general
population.
In Huntington’s disease, psychotic manifestations are
usually rare, and may occur mostly in patients who are
already demented [10, 11] Psychiatric symptoms are
present in another neurodegenerative disorders and my
delayed identification and treatment [12].
In Parkinson’s disease (PD) researchers are increasingly
attending to and characterizing the non-motor symptoms
of the disease such as depression, apathy, dementia and
psychosis. Psychosis in PD is characterized by
hallucinations (mostly visual), and delusions and may
occur in 20–40% [13, 14].
In dementia psychotic symptoms are frequent and occur
mostly in the moderate phase. Halucinations and delusions
are the componenets of the chalenging behaioour and
REV.CHIM.(Bucharest)♦ 68 ♦ No. 12 ♦ 2017 http://www.revistadechimie.ro
Table 1
GAJDOS SCORE
requaring admission and treatment with antipsychotics
and institutionalization [15, 16].
Another unusual presentation of MG could be an acute
respiratory failure because of severe respiratory muscles
weakness [17]. As the patients present severe dispnea
and chest pain, pulmonary embolism could be suspected.
A spiral CT, and, more cost-effective, biological markers,
as brain natriuretic peptide (BNP) assay can rull out this
critical life-threatening condition [17-19].
Oxidative stress has also been reported in MG [20]. This
could be demonstrate by assessing oxidative modification
of some serum proteins [20, 21]. No independent
parameters of oxidative damage estimation were tested
in our case. Demonstrating of systemic oxidative stress
could suggest therapeutic use of antioxidants as an
adjuvant treatment, improving the evolution and quality of
life in MG [20, 22].
Conclusions
Psychosis in myasthenia gravis is rare condition. In our
case, the psychotic episode was so important that it was
initially considered as a first episode of schizophrenia. The
patient followed treatment for 2 years as recommended.
Under treatment with antipsychotic the patient was
recovered but this was a major factor in delayed
identification and treatment of myasthenia gravis.
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Manuscript received: 24.06.2017
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