DR.SNAKE (The Jungle Medici ine) SAI KRISHNA.G 1 BHAVANI RAMESH.T, PREM KUMAR.P SIMS COLLEGE OF PHARMACY, GUNTUR, A.P, A INDIA. ABSTRACT: The most important reason why snake venom is such a goldmine for thee pharmaceutical industry and drug development is its origin and evolution. It is wrong to assume that all venom components are derived from saliva proteins. Actually, they are mainly mutatedd body proteins. Those bodyy proteins often play a crucial role in physiological processes such as the regulationn of blood pressure, conduction of nerve impulses, immune responsess (the complement system) ), regulation of cardiac rhythm, and others. Snake venom is highly modified saliva. The venom is part of a whole: the apparatus, which is made up of venom glands that synthesize venom; and an injection system, consisting of modified fangs with which to make the t venom penetrate into a prey item or a possible threat or predator. The glands whichh secrete the zootoxins are a modificationn of the parotid salivary gland of other vertebrates, and are usually situated on each side of the head beloww and behind the eye, encapsulated in a muscular sheath. KEYWOARDS: Snake Venom, Pharmaceutical Industry, Drug Development, Saliva Proteins, Blood Pressure, Nerve Impulses, Zootoxins. INTRODUCTION: There are mainly 4 families of snakes are present. They are as follows: 1) Colubridae 2) Atractaspididae 3) Elapidae 4) Viperidae. 1 Addres ss for correspondence: Seetharam nagar, 2nd lane, D.no: 8-22-17, Guntur, A.P, India. Email: sknanu06@gmail.com Cell: 9700444540, 8121166691. ISSN : 0976-285X Vol 4 Issue 3 Jun-Jul 2013 41
Venom is the general term referring to any variety of toxins used by certain types of animals that inject it into their victims by the means of a bite, sting or other sharp body feature. There are four distinct types of venom that act on the body differently. Proteolytic venom dismantles the molecular structure of the area surrounding and including the bite. Hemotoxic venoms act on the heart and cardiovascular system. 3 Neurotoxic venom acts on the nervous system and brain. Cytotoxic venom has a localized action at the site of the bite Snake venom is highly modified saliva. The venom is part of a whole: the apparatus, which is made up of venom glands that synthesize venom; and an injection system, consisting of modified fangs with which to make the venom penetrate into a prey item or a possible threat or predator. The glands which secrete the zootoxins are a modification of the parotid salivary gland of other vertebrates, and are usually situated on each side of the head below and behind the eye, encapsulated in a muscular sheath. The glands have large alveoli in which the synthesized venom is stored before being conveyed by a duct to the base of channeled or tubular fangs, through which it is ejected. Venoms contain more than 20 different compounds, mostly proteins and polypeptides. Snake venom has two main functions: first, the immobilization of prey and second, the digestion of prey. It is a complex mixture of proteins, enzymes, and various other substances. The proteins are responsible for the toxic and lethal effect of the venom and its function is to immobilize prey, enzymes play an important role in the digestion of prey,and various other substances are responsible for important but non-lethal biological effects. Some of the proteins in snake venom are very particular in their effects on various biological functions including blood coagulation, blood pressure regulation, transmission of the nervous or muscular impulse and have turned out to be pharmacological or diagnostic tools or even useful drugs CHEMISTRY: Proteins constitute 90-95% of venom's dry weight and thousands of proteins found in venom, there are toxins, neurotoxins in particular, as well as nontoxic proteins (which also have pharmacological properties), and many enzymes, especially hydrolytic ones, digestive hydrolyses, L-amino acid oxidase, phospholipases, thrombinlike pro-coagulant, and kallikrein-like serine proteases and metalloproteinases include cytotoxins, cardiotoxins, and postsynaptic neurotoxins (such as α-bungarotoxin and α-cobratoxin), Phosphodiesterases interfere with the prey's cardiac system, mainly to lower the blood pressure. Phospholipase A2 causes hemolysis by lysing the phospholipid cell membranes of red blood cells. Amino acid oxidases and proteases are used for digestion. Amino acid oxidase also triggers some other enzymes and is responsible for the yellow color of the venom of some species. Hyaluronidase increases tissue permeability to accelerate absorption of other enzymes into tissues. Some snake venoms carry fasciculins, like the mambas which inhibit cholinesterase to make the prey lose muscle control. Comparison between enzymes and toxins: Enzymes Toxins High Molecular Weight. Variable MW but always < Enzymes. Variable specificity of action. Action on specific receptors. Action on coagulation systems. Action on CV, muscular systems. Activation of complement. Action on neurologic systems. USES OF SNAKE VENOM ANTI VENOM - The first and perhaps the most obvious use of snake venom is the production of anti-venom, the main technique used to produce anti-venom is known as the 'horse serum' method. Here the snake is milked of its venom as illustrated by the image, and then a small non-lethal dose of the venom is injected into a horse. The horse is then given time to produce antibodies to the venom, a sample of blood is removed from the horse and the antibodies are extracted. This anti-venom can now be used to treat patients, although unfortunately a third of patients are allergic to this serum. TREATMENT OF BREAST CANCER - The protein contortrostatin which was extracted from the venom of the Southern Copperhead Viper Agkistrodon contortrix, has been shown to slow the growth of breast cancer cells (implanted into mice) by up to 70%. The protein is cytostatic (it prevents/slow tumor growth) rather than cytotoxic (kills tumor cells). The protein inhibits blood vessel development, the quick formation of which is essential to the rapid growth of tumor cells; this in turn prevents the growth of the tumor. TREATMENT OF BLOOD CLOTS - Ancrod is a substance formulated from the venom of the Malayan pit viper Calloselasma rhodostoma, it inhibits fibrinogen which is involved in the production of fibrin (which forms ISSN : 0976-285X Vol 4 Issue 3 Jun-Jul 2013 42
blood clots). This enzyme is used by the snake to prevent blood clots forming in its prey whilst it is digesting them. This enzyme has played a major role in the development of ACE inhibitors (angiotensin converting enzyme inhibitors) which play a vital role in modern treatment of diseases such as strokes and heart attacks. In recent studies it was shown to improve recovery rates from strokes, 30% of patients given a placebo regained their mental faculties whilst using ancrod 40% did. OTHER AREAS OF INTEREST - There are many other potential areas of research as to the use of snake venom in medicine.for example there has been interest in the use of snake venom to treat Alzheimer's disease due to its ability to destroy nerves, and the potential use to destroy affected brain cells. Other areas of interest include the treatment of viruses as snake venom contain phospholipidases, which break down cell membranes, this could obviously be very useful in destroying viruses but it is very difficult to make this specific to viruses. MEDICAL USES: The dangerous effect of snake venom on humans is well known, but there are also many medicinal uses of snake venom, this specialized saliva: Excessive bleeding: A blood-clotting protein in Taipan venom has been found to stop excessive bleeding during surgery or after major trauma. Stroke: Components of Malayan Pit Viper venom has shown potential for breaking blood clots and treating stroke victims. Neurological diseases: Enzymes from cobra venom may be instrumental to finding cures for Parkinson's disease and Alzheimer's disease. Cancer (various types): An enzyme derived from copperhead venom could be used to treatment for breast cancer. Aging: Yes, some are even used in a commercial wrinkle cream! Snake venoms other compounds: 1.Nerve Growth Factor No enzymatic activity, no toxicity Action: Différenciation of sensitive neuron. 2.Enzymatic inhibitor and activator Bothrajaracine, TSV-PA, factor X inhibitor. 3.Activity on thrombocytes Agregoserpentines, thrombolectines 4.Cobra Venom Factor Action: activation of complement (+++ C3, C5) 5.Dendropeptins Hormonal role THE USES OF SNAKE VENOM IN ANTIQUITY: In 67 BC, Mithradates suffered a grievous sword slash to the thigh. Bleeding profusely, he hovered near death, but the Agari staunched his wound with serpent venom. Mithradates recovered and led his army to victory. This is the first documented account of using the coagulating effects of miniscule amounts of steppe viper venom to stop severe hemorrhage, an exciting discovery made only recently by scientists in the new field of venomics. The ancient Scythian healers would not be surprised to learn that crystallized venom of steppe vipers from their homeland is now a major export to emergency rooms around the world. SNAKE VENOM TOXINS IN HAEMOSTASIS: Snake venom toxins affecting homeostasis have facilitated extensively the routine assays of haemostatic parameters in the coagulation laboratory. Snake venom thrombin-like enzymes (SVTLE) are used for fibrinogen/fibrinogen breakdown product assay and for the detection of fibrinogen dysfunction. SVTLE are not inhibited by heparin and thus, can be used for assaying anti-thrombin III and other haemostatic variables in heparin-containing samples. Snake venoms are a rich source of prothrombin activators and these are utilized in prothrombin assays, for studying dysprothrombinaemias and for preparing meizothrombin and non-enzyme forms of prothrombin. Other snake venom proteins show promise in the treatment of a range of Haemostatic disorders. SNAKE VENOM AS MEDICATION: What in the 1950s led to the development of Captopril, a drug for the treatment of hypertension, is being continued in an interesting new chapter with the analysis of venom from South American pit vipers and tropical rattlesnakes. A deliberately administered toxic effect in the right amount can actually be beneficial to human health. Snake toxins have a very broad field of potential use, including antibacterial applications, cell growth inhibition, nerve stimulation, blood thinning and clotting. Their effects are also being tested for the treatment of Alzheimer s disease. SNAKE VENOM MAY SLOW CANCER GROWTH: Preliminary research shows a natural compound in some snake venoms may prevent the growth of cancerous tumors, potentially transforming one of nature s deadliest toxins into a curative agent. Snakes use venom to ISSN : 0976-285X Vol 4 Issue 3 Jun-Jul 2013 43
alter biological functions, ACE inhibitors, a class of drugs used to treat high blood pressure and other cardiovascular disorders, were developed from the venom of a Brazilian snake. Main Enzymes of Snake Venom: Type Name Origin Oxydoreductases dehydrogenase lactate L-amino-acid oxidase Catalase Elapidae Transferases Alanine amino transferase Hydrolases Phospholipase A 2 Lysophospholipase Acetylcholinesterase Alkaline phosphatase Acid phosphatase 5'-Nucleotidase Phosphodiesterase Elapidae, Viperidae Elapidae Bothrops atrox Deinagkistrodon acutus PRESENT USES OF SNAKE VENOMS: Now a day s snake venom is used in Different fields such as, Anti-venom sera +++, Research, Homeopathy, Diagnostic & Therapeutic and Toxins. ANTIVENOM SERA: It is most important present use of snake venom. Advantages Drawbacks Specific treatment. Low cost of production. Difficult process of preparation. Adverse effects. DNA VACCINATION: ADN extracted from gland of venom. ADN injected to a plasmid Vaccination strategy (antibodies anti toxins are produced). Cost seems to be competitive So far, early stage of development No recurrent use. This technology seems to be possible. HOMEOPATHY: Venomous compounds like following are used in the homeopathy field: Example: Crotalus Horridus, Naja Tripudians Dose: Small quantities needed. OTHER: Diagnosis and therapeutic A good example is Pentapharm which Diagnosis & therapeutic +++ homeostasis. ISSN : 0976-285X Vol 4 Issue 3 Jun-Jul 2013 44
Example: Reptilase, Protac TOXINS: Venom fractionation: Example: Chromatography, HPLC SM.. POTENTIAL USES OF SNAKE VENOM: Potential Uses of Snake Venom are mainly in three fields: 1) Therapeutics Oncology Cardiology 2) 3) Antibiotic therapy. Homeopathy, Cosmetology. COSMO-VENOMICS This is the field where venom compounds are used in the preparation of cosmetics. Here are some examples with different dosage forms. ISSN : 0976-285X Vol 4 Issue 3 Jun-Jul 2013 45
ACKNOWLEDGMENT: With due respect to the almighty god, MY PARENTS and my siblings, I would like too thank my college i.e., SIMS college of pharmacy for permitting me too do this review work. I thank the publishers of International Journal of Pharmaceutical and Biological Research Here I would like to specify my source of the context in the article i.e., the internet, which helped me for putting fourth this article in front of many people around the t world. CONCLUSION: It is concluded that snake venom toxins may serve as a starting materiall for drug design to combat several pathophysiological problems such as cardiovascular disorders, neurological problems, and cancerr therapy. Though several peoplee feared regarding snake venomous compounds, they are natural biological resources that contain several components that could treat many disorders. The therapeutic potential off snake venom extends from C.N.S and C.V.S to chemotherapy. The extension of this basic activity can be narrow down to alleviate many chronic and life threatening disease and disorder is near to possible. Very V few clinical studies aree available and theree is a need for extensive research programs to clinically work-out for the above mentioned areas, with a view to develop newer drugs to combat human suffering and death globally. REFERENCES: [1] Snake venom components and their cross-reactivity: a review. B J Berger, A R Bhatti in Biochemistry B andd cell biology Biochimie et biologie cellulaire (1989). [2] POTENTIAL USE OF SNAKE VENOM COMPONENTS IN CANCER TREATMENT Dan Vivas, Rosioo Inga, Armando Yarlequé in Rev Peru Med Exp Salud Publica (2012). [3] Action of snake venom components on the haemostatic system. R A Hutton, D A Warrell in Blood Reviews (1993). [4] Raman spectra of some snake venom components. T Takamatsu, I Harada, K Hayashi in Biochimica B et Biophysica Acta (1980). [5] Integrins as Antimetastatic Targets of RGD-Independen nt Snake Venom Components in Liver Metastasis1 Felix Rosenow, Rainer Ossig, Dorit Thormeyer, Peter Gasmann, Kerstin Schlüter, Georg Brunner, et al. in Neoplasia New York Ny (2008). [6] BBC News Online Network, Scientists target breast cancer with snake venom, August 26, 1998, accessed athttp://news.bbc.co.uk/1/hi/health/159054.stm [7] CNN..com, FDA approves â super aspirinâ for certain heart patients, May 15, 1998, accessed a athttp://www.cnn.com/health/9805/ /15/super.aspirin/index.html [8] Lake,, Stan, Pit vipers: friend or foe?, The Cold Bloodedd News, newsletter of the Coloradoo Herpetological Society, Vol. 32,, No. 4; April 2005 and accessed at http://webspinners.com/coloherp/cb-news/vol-32/cbn-0504/pitvipers.php [9] Natural Toxins Research Center, NTRC Kids, accessed at http://ntrc.tamuk.edu/kids.htm [10] Natural Toxins Research Center, NTRC Snakes, accessed at http://ntrc.tamuk.edu/download.htm. [11] Finn, R. (2001) Snake venom protein paralyzes cancer cells. Journal of the National Cancer Institute, 93(4) ), 261-62. [12] Minea, R., Swenson S, Costa F., Chen T.C., & Marklandd F.S. (2005). Development of a novel n recombinant disintegrin, contortrostatin, as an effective anti-tumor and anti-angiogenic agent. Pathophysioogy of lhaemostasis andd Thrombosis,34( (4-5), 177-83. [13] Krishna, B. (2002). Structure Function relationship of muscarinic toxin MT. Retrieved fromhttp://crisp.cit.nih.gov/crisp/crisp_lib.getdoc?textkey=6436341& &p_grant_num=2s06gm050695 080016&p_query=(toxin)&ticket=54141676&p_audit_session_id=285710852&p_audit_score=91&p_audit_numfound=2& &p_keyword s=toxin [14] Patlak, M. (2003). From viperâ s venom to drug design: treating hypertension, FASEB Breakthroughs in Bioscience. Retrieved from http://www.fasebj.org/cgi/reprint/ /18/3/421e. [15] Rosamone, W., Flegal, K., Friday, G., Furie, F K, Go, A., Greenlund, K ett al. (2007). Heartt disease and stroke statisticsâ 2007 update. Circulation, 115, 69-171. [16] Hawgood, B.J., & Reid, H.A. (1998) OBE MD: investigation and treatment of snake bite, Toxicon, 36(3), 431-46. Sherman, D.G., & Ancrod, C. (2002) Current Medical Research and Opinion.. (18), 48-52. [17] Medscape Medical News. (2000). Ancrod shown to have favorable effect for treating acute stroke. [18] FDA. Integrellin consumer information. Retrieved from m http://www.fda.gov/cder/consumerinfo/druginfo/integril.htm. ISSN : 0976-285X Vol 4 Issue 3 Jun-Jul 2013 46