VINCA ROSEA

TIM TEACHING FITOMEDICINE

FAKULTAS FARMASI
UNIKA WIDYA MANDALA
SURABAYA
Vinca rosea
Madagascar Periwinkle Vinca alkaloids
Catharanthus roseus is
known as the common or
Madagascar periwinkle,
Formerly classified as
Vinca rosea
Perennial evergreen herb
in Apocynaceae
Originally native to island
of Madagascar
Traditional uses of periwinkle
Used to treat a wide assortment of diseases
In Europe, folk remedy for diabetes for centuries
In India, juice from the leaves to treat wasp stings.
In Hawaii, boiled to make a poultice to stop bleeding.
In China, an astringent, diuretic and cough remedy.
In Central and South America, homemade cold remedy to
ease lung congestion and inflammation and sore throats
Throughout the Caribbean, an flower extract to treat eye
irritation and infections
Interest in Periwinkle
Two groups began independently working on
periwinkle in 1950s when they learned of a tea
Jamaicans were drinking to treat diabetes
Univ of Western Ontario - Beer and Noble -interested in
plant as a possible oral insulin - they isolated alkalod -
vinblastin
Eli Lilly Pharmaceuticals - Svoboda

FARMAKOLOGI
Halucilogenic herbs
Antidiabetes
Antikanker
Herbs Botanical sources
Catnip Nepeta catasia
Juniper Juniperus macropoda
Kava-kava Piper methysicum
Mandrake Mandrogora officinarum
Nutmeg Myristica fragans
Periwinkle Catharanthus roseus
Thorn apple Datura stramomium
Yohimbe Corynanthe yohimbe
Sources: Siegel, R.L., 1976. Herbal intoxication: Psychoactive
effects from herbal cigarettes, tea and capsules. Journal of the
American Medical Association. 236(5): 473 476.
Antidiabetes
Mohammed Fazil Ahmed, Syed Mohammed Kazim,Syed Safiullah Ghori, Syeda Sughra
Mehjabeen, Shaik Rasheed Ahmed, Shaik Mehboob Ali, and Mohammed Ibrahim.
2010. Antidiabetic Activity of Vinca rosea Extracts in Alloxan-Induced Diabetic Rats
International Journal of Endocrinology. 1-6
The coarsely powder whole plant (1 kg) of Vinca rosea Linn was used
for extraction with methanol in soxlate apparatus.
Oral Glucose
Tolerance Test.
Acute Oral Toxicity Studies.
Hyperglicemic rats
Group I was kept as vehicle control which received 5% Tween 80 p.o., Group II
received glucose only,
Group III received methanolic extract 300 mg/kg,
Group IV received methanolic extract 500 mg/kg
Group V and VI received only extracts (300 mg/kg and 500 mg/kg) only in a vehicle

The rats of group III and IV were loaded with glucose (3 g/kg, p.o.) 30 minutes after drug
administration. Blood samples were collected from puncturing the retro orbital sinus just
prior to drug administration, and 30, 90, 150 minutes after loading glucose.
Oral Glucose Tolerance Test
Group I: Normal control (saline).
Group II: Alloxan treated control (150 mg/kg.ip).
Group III: Alloxan (150 mg/kg.ip) + Vinca rosea (Whole plants extract 300 mg/kg, p.o)
Group IV: Alloxan (150 mg/kg.ip) + Vinca rosea (Whole plants extract 500mg/kg, p.o)
Group V: Alloxan (150 mg/kg.ip) + Standard drug, Glibenclamide (5mg/kg, p.o).
Hyperglicemic rats
Groups Colesterol
(mg/dl)

H.D.L
(mg/dl)

L.D.L
(mg/dl)
Creatinine
(mg/dl)
Urea
(mg/dl)
Alkaline
Phosphatase
(mg/dl)

Normal control
145.36 3.2 36.83 2.5 91.32 1.2 0.54 0.3 31.83 2.2 120 3.2
Diabetic control
271.16 10.5 30.00 1.9 189 12.4 2.4 0.1 62.6 1.8 276 3.6
Alloxan +Whole
plant extract
(300 mg/kg,p.o)
184.32 2.5 34.22 4.3 120.27 1.4 0.98 0.3 43.323.8 146.35 4.9

Alloxan +Whole
plant extract
(500 mg/kg,p.o)
158.46 5.6 36.63 2.1 93.65 3.6 0.60 0.2 32.332.0 135.55 4.9

Alloxan +
glibenclamide
(5 mg/kg)
145.42 5.3 36.73 1.5 92.35 3.1 0.58 0.1 31.244.0 130.75 2.9

Endocrine
Histopathological studies of pancreas: Group I (Control), Group II (Alloxan 150 mg/kg), Group III
(Alloxan + Whole Plant 300 mg/kg)
Endocrine
I
II
Endocrine
II
Endocrine
II
Histopathological studies of pancreas: Group I (Control), Group II (Alloxan 150 mg/kg), Group III
(Alloxan + Whole Plant 300 mg/kg)
The whole plant extracts did not show a consistent effect on
normal blood sugar levels alcoholic whole plant extracts of
Vinca rosea at high dose (500 mg/kg) exhibited significant
antihyperglycemic activity
Effectively reversed the alloxan-induced changes in the blood
sugar level and the beta-cell population in the pancreas.
It also showed a protective effect when it was given prior to
alloxan administration.
The action of whole plant extracts on the pancreatic beta-cells
and absence of acute toxicity may offer a new hope to the
diabetics in future.
These extracts also showed improvement in parameters like body
weight and lipid profile as well as regeneration of cells of
pancreas and so might be of value in diabetes treatment.
Antimitotic Agents
Three distinct classes of antimitotic agents have been
identified thus far.
1.) Taxanes; include: paclitaxel and docetaxel.
2.) Vinca alkaloids; include: vincristine, vinblastine,
vindesine, and vinorelbine.
3.) Colchicine.

All must be administrated via intravenous infusion.

Antimitotic Agents: One Possible
Treatment
Antimitotic agents: Anti-tumor
agents that inhibit the function of
microtubules through the binding
of their subunits or through
direct cessation of their growth.
What are microtubules (MTs)?
Protein polymers formed by a-
Tubulin and B-tubulin
heterodimers that play an
important role in critical cell
functions such as movement,
phagocytosis and axonal
transport. They also play a key
role in the formation of the
mitotic spindle apparatus and
cytokinesis at the end of mitosis.

In normal cells, microtubules are
formed when a cell starts dividing
during mitosis. Once the cell
stops dividing, microtubules are
broken down or destroyed.
The crucial involvement of MTs in
mitosis makes them a prime
target for anti-cancer agents.



Vinca alkaloids
Vinca alkaloids (Indols)
from Vinca rosea
(Catharantus roseus)
MadagaskarPerivinkle
N
H
N
HO
MeO
2
C
MeO
N
R
N
H OCOMe
CO
2
Me
OH
R=-Me: Vinblastin, Velbe
R=-CHO: Vinkristin, Vincristine
N
H
N
MeO
2
C
MeO
N
CH
3
N
H OCOMe
CO
2
Me
OH
Vinorelbine, Navelbine
Binds to microtubuli- Supression of microtubuli dynamics-
Metaphase arrest

Depolymerization of microtubuli high conc.
Vinca Alkaloids (Second Antimitotic Group)

The Vincas work through their ability to bind to the B-tubulin subunit of
microtubules, blocking their ability to polymerize with the a-tubulin
subunit to form complete microtubules. This causes the cell cycle to
arrest in metaphase because, in absence of an intact mitotic spindle,
duplicated chromosomes cannot align along the division plate. The
ultimate fate of such cells is to undergo apoptosis.
The Vinca alkaloids are all derived from the Madagascan periwinkle plant,
Vinca rosea. The plant was reputed to be useful in the treatment of
diabetes. Attempts to verify the antidiabetic properties of the plants
extracts in the 1950s led instead to the discovery and isolation of
vinblastine.
Scientists first observed its anticancer properties in a lab in 1962 with the
observation of regression of lymphocytic leukemia in rats.
Several years later, the successful purification of the plants alkaloids
yielded three other active dimers: vincristine, vinorelbine, vinrosidine.
- Vinca (Catharanthus) Alkaloids
Occurrence:
Catharanthus or Vinca is the dried whole plant of
Catharanthus roseus G. Don (or Vinca rosea L), Fam.
Apocynaceae.
It contains about 150 alkaloids, the most important are
vinblastine and vincristine.
More alkaloids in periwinkle
Overall 70 alkaloids have been identified in
periwinkle with various uses
anticancer properties
lower blood sugar levels
hemostatics (arrest bleeding)
reserpine and serpentine - tranquilizers

Classification:
1- Monomeric Alkaloids:
These are alkaloids that contain either indole or indoline:
Indole monomers e.g. Catharanthine
Indoline monomers e.g. Vindoline and Vincamine.

2- Dimeric Alkaloids:
Homogenic dimmers: Composed of two indole or indoline
monomers.
Mixed dimmers: One indole and one indoline monomers e.g.
Vincristine and Vinblastine.



1- Monomeric Alkaloids:

Vincamine
Enhances the cerebral blood flow, facilitate cerebral circulation
metabolism and increase general activity. Vincamine is used in
cerebral vascular deficiency and atherosclerosis in elderly
patients.
N
N
H
C
2
H
5
OH
H
3
COOC
N
N
H
H
3
COOC
C
2
H
5
N
N
CH
3
COOCH
3
OH
H
3
COOC
Vincamine
Catharanthine Vindoline
2- Dimeric Alkaloids:
Mixed dimmers
These are dimeric alkaloids having indole and indoline (dihydro-
indole) nuclei e.g. Vinblastine and Vincristine

Vinblastine and Vincristine
They occur in very minute amounts in Vinca (0.003- 0.005); 500 Kg of the plant
yield only 1 gm of vincristine.

They are very important for cancer treatment.

Vincristine is more active but isolated in smaller amounts than Vinblastine.
Vinblastine can be converted to vincristine chemically or by microbial
transformation using Streptomyces albogriseolu . !!!

Structures:
Vinblastine (Vincaleukoblastine) is produced by coupling of Catharanthine and
Vindoline.
Vincristine (leurocristine) has CHO istead of CH
3
in the vindoline part of Vinblastine.
N
N
R
COOCH
3
OH
H
3
COOC
N
N
H
H
3
COOC
HO
R=CH
3
Vinblastine
R=CHO Vincristine
Uses :
Vinblastine is used for treatment of Hodgkin's disease
(Pseudoleukemia or Lymphatic anaemia) and carcinoma resistant
to other therapy.

Vincristine has a cytotoxic effect .It is useful in the treatment of
leukemia in children, small cell lung cancer, cervical and vaginal
cancers.

Mechanism:
Both alkaloids are Antimetabolites interfere with the syntheses of
Desoxyribonucleic acids.
Vinca Alkaloids: Vincristine
Vincristine [Oncovin]
Useful in the treatment of: pediatric
leukemias and lymphomas, non-
Hodgkins lymphoma, neuroblastoma
and rhabdomyosarcoma.
Better tolerated by children than
adults.
Side effects: myelosuppression,
hyponatremia, numbness/tingling of
extremities, loss of deep tendon
reflexes, and loss of motor function.
Intrathecal administration results in
fatal central neurotoxicity.

Vincristine
Marketed as Oncovin
Serum half-life of about 85 hours.
Used mainly to treat acute leukemia,
rhabdomyosarcoma, neuroblastoma, Hodgkin's
disease and other lymphomas
Also Wilms' tumor (80%) and Burkitt's lymphoma
(50%), when used in combination with other
drugs
Neurotoxicity is the dose limiting factor (it can
cause damage to the peripheral nervous system)
Side effects of vincristine
Same as those found with vinblastine
Nervous system problems such as sensory
impairment
Breathing problems or lung spasms shortly after the
drug is administered
Secondary cancers if they receive the drug along with
other anticancer drugs that are known to be
carcinogens
Severe birth defects in animal tests
Vinca Alkaloids: Vinblastine
Vinblastine [Velban] was
the first of the Vincas to be
used in the treatment of
cancer.
Useful in the treatment of:
bladder and testicular
cancers, Kaposis sarcoma,
neuroblastoma and
Hodgkins disease.
Side effects include:
leukopenia, GI disturbances,
cellulitis, phlebitis.

Vinblastine
Marketed as Velban
Half-life in the bloodstream of 24 hours
Vinblastine is mainly useful for treating Hodgkin's
disease, lymphocytic lymphoma, histiocytic
lymphoma, advanced testicular cancer, advanced
breast cancer, Kaposi's sarcoma
Another action: It also seems to fight cancer by
interfering with glutamic acid metabolism
Side effects of vinblastine
Side effects include hair loss, nausea, lowered
blood cell counts, headache, stomach pain,
numbness, constipation and mouth sores
Bone marrow damage is the typical dose-
limiting factor
Caused severe birth defects in lab animals so
not used on pregnant patients
Semisynthetic derivatives:

Vindesine:
It is used for treatment of acute lymphoid
leukemia in children.



Vinorelbine:
It is an oral anticancer with broader activity and
lower neurotoxicity than vinblastine.
N
N
CH
3
COOCH
3
OH
H
2
NOC
N
N
H
H
3
COOC
HO
N
N
CH
3
COOCH
3
OH
H
3
COOC
N
N
H
H
3
COOC
HO
Vinca Alkaloids: Vinorelbine
Vinorelbine [Navelbine]
Used in the treatment of:
lung carcinoma, breast
cancer.
Side effects include:
granulocytopenia,
thrombocytopenia,
myelosuppression, and less
neurotoxicity than all of the
other Vincas.


Vinca Alkaloids:
Vindesine
Vindesine [Eldisine]
Useful in the treatment
of: breast and lung
cancer, leukemia.
Side effects:
immunodeficiency,
anemia, myalgia,
fatigue, mouth ulcers,
GI upset.

Vindesine -semi synthetic
Marketed as Eldisine and Fildesin
Serum half-life of about 24 hours
Mainly to treat melanoma and lung cancers
(carcinomas) and, with other drugs, to treat
uterine cancers
Toxicity and side effects are similar to those of
vinblastine
Vinorelbine - semi-synthetic
Marketed as Navelbine
Approved for non-small cell lung cancer and breast
cancer usually in combination with other drugs
Clinical trials on-going as a treatment for ovarian,
cervical, prostrate and other cancers
Seems to have a wider range of antitumor activity
than the other vinca alkaloids
Side effects include diarrhea, nausea, hair loss,
leukopenia
Mode of action of vinca alkaloids
Vinblastine, vincristine, and two semi-synthetic
derivatives (vindesine and vinorelbine) all have the
same mode of action
Inhibit mitosis in metaphase by binding tubulin
Vinca Alkaloids: Complicating Factors
Resistance to the Vinca alkaloids comes in the form of cross-
resistance due to the structural similarity of the four
compounds, and their antitumor effects are blocked by
multidrug resistance in which tumor cells become cross-
resistant to a wide variety of agents after exposure to a single
drug. Resistant cells can also display chromosomal
abnormalities consistent with gene amplification, and these
cells contain increased levels of the P-glycoprotein. Other
forms of resistance stem from mutations in B-tubulin that
prevent the binding of the inhibitors to their target.
Also, because of the heavy concentration of microtubules in
the brain and the drugs disruption of this, patients treated
with Vinca alkaloids can experience severe neurotoxicity.

Tests for identification:

1-Vanillin /HCl reagent gives with:
Vinblastine a pink color.
Vincristine an orange-yellow color.
2-Van-Urk's reagent:
Reddish-brown color.