VINCA ROSEA

VINCA ROSEATIM TEACHING FITOMEDICINEFAKULTAS FARMASIUNIKA WIDYA MANDALA SURABAYA

Vinca roseaMadagascar Periwinkle Vinca alkaloidsCatharanthus roseus is known as the common or Madagascar periwinkle,Formerly classified as Vinca roseaPerennial evergreen herb in ApocynaceaeOriginally native to island of Madagascar

Vinca Rosea masuk famili apa3

Traditional uses of periwinkleUsed to treat a wide assortment of diseasesIn Europe, folk remedy for diabetes for centuriesIn 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 throatsThroughout the Caribbean, an flower extract to treat eye irritation and infectionsInterest in PeriwinkleTwo groups began independently working on periwinkle in 1950s when they learned of a tea Jamaicans were drinking to treat diabetesUniv of Western Ontario - Beer and Noble -interested in plant as a possible oral insulin - they isolated alkalod - vinblastinEli Lilly Pharmaceuticals - Svoboda

FARMAKOLOGIHalucilogenic herbsAntidiabetes Antikanker

Herbs Botanical sources Catnip Nepeta catasiaJuniper Juniperus macropodaKava-kava Piper methysicumMandrake Mandrogora officinarumNutmeg Myristica fragansPeriwinkle Catharanthus roseusThorn appleDatura stramomiumYohimbe 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. 1-6The 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 ratsGroup 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 TestGroup 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 GroupsColesterol(mg/dl)

H.D.L(mg/dl)

L.D.L(mg/dl) Creatinine (mg/dl) Urea(mg/dl)AlkalinePhosphatase(mg/dl)

Normal control145.36 3.236.83 2.591.32 1.20.54 0.3 31.83 2.2120 3.2Diabetic control271.16 10.530.00 1.9 189 12.42.4 0.1 62.6 1.8 276 3.6Alloxan +Wholeplant extract(300 mg/kg,p.o)184.32 2.5 34.22 4.3 120.27 1.4 0.98 0.343.323.8146.35 4.9

Alloxan +Wholeplant extract(500 mg/kg,p.o)158.46 5.6 36.63 2.193.65 3.6 0.60 0.2 32.332.0 135.55 4.9

Alloxan +glibenclamide(5 mg/kg)145.42 5.336.73 1.5 92.35 3.1 0.58 0.1 31.244.0 130.75 2.9

EndocrineHistopathological studies of pancreas: Group I (Control), Group II (Alloxan 150 mg/kg), Group III (Alloxan + Whole Plant 300 mg/kg)

EndocrineIII15

EndocrineIIEndocrineIIHistopathological 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.Mekanisme vinca rosea pada sel pankreas17Antimitotic 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

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 periwinkleOverall 70 alkaloids have been identified in periwinkle with various usesanticancer propertieslower blood sugar levels hemostatics (arrest bleeding) reserpine and serpentine - tranquilizersClassification:1- Monomeric Alkaloids:These are alkaloids that contain either indole or indoline:Indole monomers e.g. CatharanthineIndoline 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:

VincamineEnhances the cerebral blood flow, facilitate cerebral circulation metabolism and increase general activity. Vincamine is used in cerebral vascular deficiency and atherosclerosis in elderly patients.

2- Dimeric Alkaloids: Mixed dimmersThese are dimeric alkaloids having indole and indoline (dihydro-indole) nuclei e.g. Vinblastine and Vincristine

Vinblastine and VincristineThey 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 . !!!

Kalimat terakhir yg aku kasih tanda seru26Structures:Vinblastine (Vincaleukoblastine) is produced by coupling of Catharanthine and Vindoline.Vincristine (leurocristine) has CHO istead of CH3 in the vindoline part of Vinblastine.

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.Slide ini penting28

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 dapat menyebabkan Neurotoxicity30VincristineMarketed as OncovinSerum 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 drugsNeurotoxicity is the dose limiting factor (it can cause damage to the peripheral nervous system)Side effects of vincristineSame as those found with vinblastine Nervous system problems such as sensory impairment Breathing problems or lung spasms shortly after the drug is administeredSecondary cancers if they receive the drug along with other anticancer drugs that are known to be carcinogensSevere birth defects in animal testsVinca 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.

VinblastineMarketed as Velban Half-life in the bloodstream of 24 hoursVinblastine is mainly useful for treating Hodgkin's disease, lymphocytic lymphoma, histiocytic lymphoma, advanced testicular cancer, advanced breast cancer, Kaposi's sarcomaAnother action: It also seems to fight cancer by interfering with glutamic acid metabolismSide effects of vinblastineSide effects include hair loss, nausea, lowered blood cell counts, headache, stomach pain, numbness, constipation and mouth soresBone marrow damage is the typical dose-limiting factorCaused 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.

Vindesine&Vinorelbine merupakan derivative semisynthetic37Vinca 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:VindesineVindesine [Eldisine]Useful in the treatment of: breast and lung cancer, leukemia.Side effects: immunodeficiency, anemia, myalgia, fatigue, mouth ulcers, GI upset.

Vindesine -semi syntheticMarketed 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 cancersToxicity and side effects are similar to those of vinblastine Vinorelbine - semi-syntheticMarketed as NavelbineApproved for non-small cell lung cancer and breast cancer usually in combination with other drugsClinical trials on-going as a treatment for ovarian, cervical, prostrate and other cancersSeems to have a wider range of antitumor activity than the other vinca alkaloidsSide effects include diarrhea, nausea, hair loss, leukopenia Mode of action of vinca alkaloidsVinblastine, vincristine, and two semi-synthetic derivatives (vindesine and vinorelbine) all have the same mode of actionInhibit mitosis in metaphase by binding tubulinSlide ini penting43Vinca 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.