Vinca alkaloids

Medicinal use of Catharanthus roseus and its Vinca Alkaloids

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Vinca alkaloids are a subset of drugs obtained from the Madagascar periwinkle plant. They are naturally extracted from the plant, Catharanthus roseus  and have a hypoglycemic as well as cytotoxic effects. They have been used to treat diabetes, high blood pressure and have been used as disinfectants. The vinca alkaloids are also important for being cancer fighters. There are four major vinca alkaloids in clinical use: Vinblastine (VBL), vinorelbine (VRL), vincristine (VCR) and vindesine (VDS). VCR, VBL and VRL have been approved for use in the United States. 

Vinca alkaloids are a subset of drugs obtained from the Madagascar periwinkle plant

Vinflunine is also a new synthetic vinca alkaloid, which has been approved in Europe for the treatment of second‑line transitional cell carcinoma of the urothelium is being developed for other malignancies. Vinca alkaloids are the second‑most‑used class of cancer drugs and will stay among the original cancer therapies.Vinca alkaloids were discovered in the 1950’s by Robert Noble and Charles Beer of Canada

Mechanism of action of Vinca alkaloids cytotoxicity

The vinca alkaloid cytotoxicity is due to the synergy with tubulin and disruption of microtubule function. This occurs mainly in the microtubules comprising the mitotic spindles, causing the arrest of metaphase. There are many other biochemical activities of these alkaloids that may or may not be related to their effect on microtubules. After the treatment of the cells with doses of vinca alkaloids, there doesn’t show any effect on the microtubules. Vinca alkaloids and other antimicrotubule agents have effect on non-malignant as well as malignant cells in the non-mitotic cell division, because microtubules are involved in many non-mitotic functions. 
Vinca alkaloids bind to the receptor sites on tubulin and separate from the taxanes, colchicine, podophyllotoxin and guanosine-5’-triphosphate. Binding occurs rapidly as well as slowly. There exist two vinca alkaloid binding sites per mole of tubulin dimer. There are 16-17 high-affinity binding sites that are located at the end of the microtubule. Binding of the vinca alkaloids to the binding site of tubulin interrupts microtubule segregation, but one of the most important effects of low drug concentration of vinca alkaloid is decrease growth rate and shortening at the assembly end of the microtubule, which cause a “kinetic cap” and suppresses function. 
Vinca alkaloids inhibit malignant angiogenesis in vitro. For example, Vinblastine with concentrations of 0.1 to 1.0 pmol/L blocks endothelial proliferation, chemotaxis and spreading on fibronectin but other fibroblasts and lymphoid tumors remain unaffected at these low concentrations. Low doses of Vinblastine in combination with antibodies against vascular endothelial growth factor increase antitumor response even in tumors resistant to direct cytotoxic effects of drug. Vincristine and related compounds produce destabilization of microtubules by binding to tubulin and blocking the polymerization. 

Catharanthus roseus

Catharanthus roseus which is an important medicinal plant of the family Apocynaceae is used to treat many of the fatal diseases contains a virtual cornucopia of useful alkaloids, used in diabetes, blood pressure, asthma, constipation, and cancer and menetrual problem. There are about two common cultivars of C. roseus which is named on the basis of their flower colour that is the pink flowered “Rosea” and the white flowers “Alba”. Catharanthus roseus which is pridely known as the Madagascar periwinkle is found to be a species of Catharanthus native and also endemic to Madagascar. 
The synonyms of the plant name include Vinca rosea, Ammocallis rosea and Lochnera rosea, other English names occasionally used for the plant include Cape Periwinkle, Rose Periwinkle, Rosy Periwinkle and “Old Maid”. “Periwinkle” or Catharanthus roseus (Family Apocyanaceae), commonly known as “Nayantara” or “Sadabahar”, the word Catharanthus derives from the Greek language meaning “pure flower.” While, roseus means red, rose or rosy.   

Scientific classification
Botanical Name(s): Vinca Rosea (Catharanthus roseus)
Kingdom: Plantae
Division: Magnoliophyta (Flowering plants)
Class: Magnoliopsida (Dicotyledons) 
Order: Gentianales 
Family: Apocynaceae 
Genus: Catharanthus
Species: C. roseus
Anti cancer activity
The anticancer alkaloids Vinblastine and Vincristine are derived from stem and leaf of Catharanthus roseus. These alkaloids have growth inhibition effect to some human tumors. Vinblastine is used experimentally for treatment of neoplasmas and is recommended for Hodgkins disease, chorio carcinoma. Vincristine another alkaloids is used for leukemia in children. Different percentage of the methanolic crude extracts of Catharanthus was found to show the significant anticancer activity against numerous cell types in the in vitro condition and especially greatest activity was found against the multidrug resistant tumor types. Vinblastine is sold as Velban or Vincristine as oncovin. 
Antidiabetic activity 

Hypoglycemic activity was found by using the dichloromethane: methanol extract (1:1) of the leaves and twigs of C. roseus plant in streptozotocin induced diabetic rat model at the dose of 500 mg/ kg that has been administered orally for 7 and 15 days. 48.6 and 57.6% hypoglycemic activity was observed and further treatment for a period of 30 days has provided complete protection against STZ challenge (75 mg/kg/i.p.).
Enzymes activities of glycogen synthase, glucose 6-phosphatedehydrogenase, succinate dehydrogenase and malate dehydrogenase were found to be decreased in the liver of diabetic animals which would be significantly improved after treatment with extract at dose 500 mg/kg p.o. for 7 days. Results indicated the increased metabolization of glucose in treated rats with the increased levels of lipid per oxidation. The ethanolic extracts of the leaves and flower of C. roseus

revealed that a dose dependent decreasing of blood sugar is similar to the standard drug. Decreasing of blood sugar in comparable to the standard drug glibenclamide. The hypoglycemic activity of alkaloids isolated from C. roseus have been studied pharmacologically and a remedy derived from the plant has been marketed under the proprietary name Vinculin as a treatment for diabetes.
Anthelminthic activity
Helminthes infections are the chronic illnesses affecting human beings and cattle. Catharanthus roseus was found to be used from the  traditional period as an anthelminthic agent. The anthelminthic property of Catharanthus roseus  has been evaluated by using Pherithema posthuma as an experimental model and with Piperazine citrate as the standard reference. The ethanolic extract of the concentration of 250 mg/ml was found to show the significant anthelminthic activity with death time of 46.33 min whereas the standard drug at 50 mg/ml was found to show the death time of 40.67 min  This investigation supported the ethnomedical claims of Catharanthus roseus as an anthelminthic plant Anti microbial activity
Crude extracts from different parts of the plant was tested for anti bacterial activity. Extract from leaves showed significantly higher efficacy. The anti bacterial activity of the leaf extract of the plant was checked against micro organism like Pseudomonas aeruginosa NCIM2036, Salmonella typhimuruim NCIM2501, Staphylococus aureus NCIM5021 and was found that the extracts could be used as the prophylactic agent in the treatment of many of the disease.
Antioxidant activity 
Free radicals are found to be the fundamental of any biochemical process and hence  represents an essential part of the aerobic life and metabolism and  could show a dual role in our body as both the  deleterious and beneficial species. The antioxidant potential of the ethanolic extracts of the roots of the two varieties of Catharanthus roseus L. namely ‘rosea’(pink flowers) and ‘alba’(white flowers) was obtained by using different systems of assay such as Hydroxyl radical-scavenging activity, superoxide radical-scavenging activity, DPPH radical- scavenging activity and nitric oxide radical inhibition method. The results obtained proved that the  ethanolic extracts of the roots of Periwinkle varieties extracts has exhibited the satisfactory scavenging effect in all the radical scavenging assays in a concentration dependent manner but Catharanthus rosea  was found to possess more antioxidant activity than that of Catharanthus alb
Anti ulcer property
Vincamine and Vindoline alkaloids of the plant showed anti ulcer property. The alkaloid vincamine, present in the plant leaves shows cerebrovasodilatory and neuroprotective activity. The plant leaves proved for anti-ulcer activity against experimentally induced gastric damage in rats. 
Hypotensive property
Extract of leaves of the plant made significant change in hypotensive. The leaves have been known to contain 150 useful alkaloids among other pharmacologically active compounds. Significant antihyperglycemic and hypotensive activity of the leaf extracts (hydroalcoholic or dichloromethane-methanol) have been reported in laboratory animals.
Anti diarrheal property
The anti diarrheal activity of the plant ethanolic leaf extracts   as tested in the wistar rats with castor oil as a experimental diarrhea inducing agent in addition to the pretreatment of the extract. The anti diarrheal effect of ethanolic extracts C. roseus showed the dose dependant inhibition of the castor oil induced diarrhea.

Wound healing property

Rats treated with 100 mg /kg/day of the Catharanthus roseus ethanol extract had high rate of wound contraction significantly decreased epithelization period, significant increase in dry weight and hydroxyproline content of the granulation tissue when compared with the controls. Wound contraction together with increased tensile strength and hydroxyproline content support the use of C. roseus in the management of wound healing.

Hypolipidimic effect
In study, significant anti atherosclerotic activity as suggested by reduction in the serum levels of total cholesterol, triglycerides, LDL-c, VLDLc and histology of aorta, liver and kidney with the leaf juice of Catharanthus roseus (Linn.) G. Donn. could have resulted from the antioxidant effect of flavonoid, and probably, vinpocetine like compound present in leaf juice of Catharanthus roseus (Linn.) G. Donn.

Memory enhancement activity

Vinpocetine has been reported to have a variety of actions that would hypothetically be beneficial in Alzheimer’s disease (AD). The only study investigating this agent in a well-defined cohort of AD patients found no benefit. Meta-analysis of older studies of vinpocetine in poorly-defined dementia populations concluded that there is insufficient evidence to support its clinical use at this time. Vinpocetine has been well tolerated at doses up to 60 mg/d in clinical trials of dementia and stroke, and no significant adverse events. Reference 

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