| [Download PDF]
|Year : 2007 | Volume
| Issue : 6 | Page : 260--264
Therapeutic alternatives from venoms and toxins
Shivaji P Gawade
SVERI's College of Pharmacy, Gopalpur-Ranjani Rd, P.B. 54, Pandharpur - 413 304, Solapur, MS, India
Shivaji P Gawade
SVERI«SQ»s College of Pharmacy, Gopalpur-Ranjani Rd, P.B. 54, Pandharpur - 413 304, Solapur, MS
The medicinal value of venoms has been known from ancient times. The active principles in venoms have been extensively investigated for their target specificity. Affinity for the primary sites responsible for lethality and efficacy at extremely low concentrations made these agents valuable tools or surrogates for basic biomedical research. The therapeutic effects of these agents are usually achieved by mechanisms that are different from that of conventional therapeutic agents. In the present paper, nonherbal natural therapeutic alternatives approved by the FDA, those that have undergone extensive clinical evaluation and shown promise in preclinical evaluation, or those that are isolated in pure form or subjected for the treatment to venoms are reviewed. These agents are suggested for the treatment of various diseases, including inflammatory, hematological, autoimmune, infectious, cardiovascular, malignant, neuromuscular, and psychotic diseases.
|How to cite this article:|
Gawade SP. Therapeutic alternatives from venoms and toxins.Indian J Pharmacol 2007;39:260-264
|How to cite this URL:|
Gawade SP. Therapeutic alternatives from venoms and toxins. Indian J Pharmacol [serial online] 2007 [cited 2020 May 28 ];39:260-264
Available from: http://www.ijp-online.com/text.asp?2007/39/6/260/39143
The planet Earth has been blessed with a vast variety of flora and fauna. Most of these still remain uninvestigated in the search for biomolecules with specialized structures and target specificity. Natural nonherbal therapeutic alternatives (NNTA) with proven therapeutic actions would be of immense value for the treatment of age-old diseases. These therapeutic alternatives are atypical therapeutic agents that originate from natural sources and are used for the treatment of diseases when the patient is found to be refractory to the conventional therapies. These agents are effective at extremely low doses and the therapeutic properties exhibited by them are achieved by mechanisms other than that of the known therapies. Venom is a complex mixture of a number of constituents proteins, peptides, enzymes and trace amounts of nonprotein inclusions, which exist in a specialized reservoir, i.e., the venom glands of arthropods and reptiles. These specialized secretions are employed by these creatures to paralyze their prey and its subsequent catabolism. On the other hand, toxin is a homogenous structure that is isolated, extracted, or derived from plant, animal, or microbial sources and has a specific locus of action.
The NNTA, currently under extensive evaluation, come from diverse natural sources, such as marine snail, sea anemone, leech, frog skin, snake venoms, and microbes such as Clostridium botulinum type A. These substances are being evaluated for use in various disease conditions, including inflammatory, hematological, autoimmune, infectious, cardiovascular, malignant, neuromuscular, and psychotic diseases. [Table 1] summarizes the various NNTA that are under extensive evaluation.
The NNTA used for inflammatory pain include, ziconotide, Xen 2174, hannalgesin, epibatidine, Keluoqu tablets, etc.
Ziconotide (2699 Da, 25 aa) is a nonopioid nonsteriodal alternative for pain relief. It is a synthetic analogue derived from omega conotoxin MVII A, which is isolated from the marine snail, Conus magnus . The analgesic action of ziconotide is by blockade of the presynaptic N-type of Ca 2+ channel present on sensory neurons. Ziconotide is used as an intrathecal analgesic in patients refractory to intrathecal opioid or oral opioid therapy. The data from a phase III clinical trial on 1250 patients revealed that ziconotide is devoid of adverse effects such as respiratory depression, tolerance, and the withdrawal syndrome. 
It is an analogue of MrIA X conapeptide isolated from the venom of the marine snail Conus marmoreus . Xen 2174 is more potent, selective and stable than X conapeptide. Xen 2174 has been proved to be safe in phase I clinical trials. It is recommended intrathecally to treat severe and unmanageable pain in cancer patients.  In a phase III clinical trial on 322 patients for 6.5 months, Xen 2174 decreased sweat production in 50% to 80% patients. It is suggested for the treatment of underarm hyperhidrosis (USFDA, July 2004). Intrathecal X conopeptide, Xen 2174 dose dependently alleviated mechanical allodynia in rats with neuropathic and intractable pain. 
It is isolated from the venom of Ophiophagus hannah .  The analgesic action of hannalgesin is by binding to the SS1 or SS2 subunit of the sodium channel, similar to tetrodotoxin and saxitoxin.  In the dose of 16-32 ng/gm by i.p. injection, hannalgesin induced analgesia is without causing neurological and muscular defects. The analgesic action is blocked by naloxone and L-NG-nitro methyl ester. Additionally, hannalgesin produced sedation and muscle relaxation and also induced locomotor activity. 
Epibatidine (C 11 H 13 N 2 C1)  is an alkaloid extracted from the skin of the frog, Epipedobatus tricolor . Epibatidine binds to nicotinic ACh receptors and receptors at the neuromuscular junction. It produced a typical arched tail in mice when injected parenterally. Epibatidine is 200 times more potent than morphine in the relief of pain. ,
Keluoqu tablet is prepared by the incorporation of neurotoxin from the venom of the Chinese cobra. The duration of its analgesic effect is longer lasting (24 h) than that of tramadol (2.5 h). In a clinical trial on 200 patients, the effective rate of analgesia of keluoqu tablet in comparison with tramadol is 88: 72.2%. The side effects of Keluoqu tablet and tramadol recorded during the clinical trial included muscle weakness and constipation, respectively. 
The venom of viperidae and crotalidae primarily exert their lethal action by interference with blood coagulation, either by accelerating the process or by specific delineation of a vital factor that prevents or inhibits the coagulation process. NNTA approved by the FDA, and those undergoing extensive clinical evaluation for the treatment of various hematological diseases, include fibrinolytics, anticoagulants, thrombin inhibitors, platelet aggregation inhibitor and hematological diagnostics etc.
Batroxobin: Batroxobin (43 kDa, 231 aa, 12 cysteines) is a serine protease from Bothrops atrox moojeni venom. It is a thrombin-like enzyme (factor IIa), which inhibits the conversion of fibrinogen to fibrin. Botroxobin is used to study coagulation on patient's blood in the presence of heparin and prothrombin time in the absence of thrombin.  It is used to treat vascular thrombosis. It is also used to monitor fibrinogen levels in patients on heparin therapy. 
Ancrod (Viprinex): Ancrod is a directly-acting defibrinogenating enzyme. The drug prevents clot formation (by cleavage of fibrinogen), reduces blood viscosity, and increases blood flow to ischemic regions. Ancrod is a promising reperfusion agent for the treatment of acute ischemic stroke. Phase 3 clinical trials are underway to confirm its efficacy when used within 6 h of onset of stroke. 
Lepuridin: Lepuridin is a thrombin inhibitor derived by recombinant DNA technology from hirudin, which is isolated from the medicinal leech, Hirudo medicinalis . The antithrombic action of lepuridin is independent of antithrombin. Lepuridin inactivates fibrin-bound thrombin in thrombi. It is used in thromboembolic disease of arterial and venous origin and in thrombosis due to heparin-induced thrombocytopenia. 
Bothrojaracin: Bothrojaracin (27 kDa) is an c-type lectin-like protein from Bothrops jararaca . Bothrojaracin, at a concentration of 1 mg/kg (i.v.), decreased thrombus weight by 95% in rats with venom thrombosis and exhibited 100% protection in mice with thrombin-induced thromboembolism.  The antithrombic action of bothrojaracin is by binding to the two-thrombin anion-binding exosites, exosite I at fibrinogen and exosite II at antithrombin. 
Fibrolase: Fibrolase is a directly-acting plasminogen activator isolated from Agkistrodon , copperhead snake venom. Fibrolase rapidly lyses clot. It was also able to lyse a carotid artery thrombus rapidly when administered locally in an anesthetized dog. Fibrolase, in combination with known antiplatelet drug is suggested to be more effective thrombolytic alternative.  Fibrolase, a metalloproteinase fibrinolytic agent, which was patented (US patent 7134114) as a novel-acting thrombolytic, is useful for lysis of blood clots in vivo . Unlike streptokinase, fibrolase causes degradation of fibrin and fibrinogen by direct action. 
Platelet aggregation inhibitors
Lebecetin: Lebecetin (29779 Da) is a basic protein (pH 9.9) comprising two alpha and beta subunits. Lebecetin dose dependently inhibited thrombin-induced platelet aggregation. However thromobxane A 2 , U46619, or acachidonic acid-induced platelet aggregation was not inhibited by lebecetin. Lebecetin, by binding to the platelet GPIb/IX receptor system, inhibited ristocetin-induced platelet aggregation in human platelet-rich plasma. 
Ecarin: Ecarin is a metalloproteinase isolated from the venom of Echis carinatus . It is a prothrombin-independent group 1A prothrombin activator. Prothrombin is converted into meizothrombin ecarin. Ecarin is used to facilitate detection of von Willebrand disease. 
RVV X and RVV V enzymes: RVV X and V enzymes are isolated from the venom of Vipera russelli . These enzymes are used to detect von Willbrand disease by determining factors X and V and prothrombin in blood. ,
Pseutarin C: Pseutarin C is a group C prothrombin activator isolated from the venom of Pseudonaja textiles . Pseutarin C converts prothrombin to thrombin by activation of prothombin. The action of pseutarin C is similar to the mammalian factor Xa-Va complex. 
The NNTA to treat autoimmune diseases include Sh K (L5)-amide, cobra drug and basic short chain snake venom neurotoxins like α-bungarotoxin are used as autoimmune diagnostics. 
Sh K (L 5)-amide
Sh K (L5)-amide is a peptide analogue of Sh K toxin generated from the sea anemone, Stichodactyla helianthus . Sh K (L5)-amide selectively blocked the potassium channel Kv 1.3 at very low concentrations. It is a novel immunomodulator, useful to selectively suppress memory T lymphocytes in patients of multiple sclerosis, type I diabetes mellitus, and rheumatoid arthritis. 
Cobra drug (immunokine)
Immunokine nontoxic peptide derived from cobra venom, termed as polypeptide O3 (PPO3) or peptide E (PEP-E), inhibited 90% of HIV infection tropism independently by blocking the chemokine receptors, CCR 5 and CXCR 4. The cobra drug, immunokine peptide, was found safe in clinical trials on HIV patients subjected to different applications. 
Neurotoxins, like α-bungarotoxin, with a strong affinity for muscle acetylcholine receptors have been used to generate acetylcholine receptor antibodies and diagnostically, in the autoimmune disease, myasthenia gravis, which is characterized by the presence of pathogenic antibodies to acetylcholine receptors. 
The NNTA for infectious diseases include, L-amino oxidase, cobra peptide and pandinins.
L-amino oxidase enzyme from the venom of Crotalus adamenteus showed antibacterial activity against Gram-positive bacteria. The venom of Agkistron halys pallus , Bothorops alternatus , and Trimeresurus jerdoni showed antibacterial activity against E. coli and S. aureus . The antibacterial activity of the venom of Pseudechis australis against aeromonas was 70-fold higher than that of tetracycline. ,
Peptides from the venom of Naja atra have been shown to possess antitubercular activity against Mycobacterium tuberculosis . 
Pim 1 (4799.5 Da) and Pim 2 (2612.9) from the venom of Pandinin imperator showed antibacterial activity against B. subtilus and E. coli . The antibacterial activity of pandinins was higher against Gram-positive bacteria than against Gram-negative bacteria. 
The NNTA to treat cardiac failure and hypertension are the bufodienolides and BPP9a, respectively.
Bufodienolides are glycosides isolated from the venom of the Central Asian green toad, Bufo viridis laur. There are six different glycosides, namely, gamabufotulin, arenobufugin, telcocinobufagin, marinobufagin, bufaregonin and bufalin. The cardiotonic action of the bufodienolides is probably by the inhibition of endogenous myocardial Na + -K + -ATPase. Bufodienolides increased the force of contraction and to some extent, the heart rate. Frog atrial trabecular contractions are also increased with the rise in the slow calcium current. The yield of bufodienolide is 30% of the total venom, i.e., 70 mg/toad. The bufodienolides are NNTA to stropanthin K, celanidum, and digitoxinum. 
BPP9a, a nanopeptide bradykinin potentiator with angiotensin converting enzyme-inhibiting action, was isolated from the venom of Bothrops jararaca .  BPP9a was synthesised at Squibb Corporation as Teprotide® , a parenteral product. BPP9a was further developed as an oral ACE inhibitor, captopril-an antihypertensive alternative for the treatment of renovascular hypertension. 
The NNTA for the treatment of malignant diseases include salmosin, rhodostamin, contortrostatin, toxin-28, and dr-CT-1.
Salmosin is a disintegrin comprising a Arg-Gly-Asp sequence, isolated from the venom of the Korean snake Agkistrodon halys brevicaudus . Salmosin acts by blocking the function of α2β3 integrin.  Salmosin suppressed tumor progression by strongly inhibiting tumor-derived angiogenesis, adherence and proliferation of tumor cells. Maintenance of drug levels in antiangiogenic cancer therapy through liposome delivery of the salmosin gene for in vivo expression has been investigated. 
Rhodostomin is a disintegrin from the venom of Calloselasma rhodostoma . Rhodostomin inhibited angiogenesis induced by basic fibroblast growth factor and suppressed murine melanoma B16-F10 tumor growth.  The antiangiogenic effect of rhodostomin is related to integrin αν β3 blockade.
Contorstrostatin, a disintegrin isolated from Agkistrodon contortrix contortrix , strongly inhibited the adhesion of human metastatic melanoma (M-24 met) to extracellular matrix and in vivo , lung colonization by M-24 met cells.  Contorstrostatin inhibited tumor growth and angiogenesis and prolonged the survival of mice with glioma.  Intravenous liposomal delivery of contorstrostatin was shown to be promising for human breast cancer therapy as it has a longer half life. It gets accumulated in the tumor cells and is devoid of platelet reactivity. Liposomal delivery of contorstrostatin does not respond to the immune system. 
Toxin CM-28, a protein toxin from the venom of Vipera russelli and BM-T2, a nonprotein toxin from the skin of Bufo melanostictus , showed pronounced reduction in proliferation of the cancer cell cultures U937 and K562. In microscopical observations, both the toxins revealed membrane blebbing and nuclear fragmentation. BM-T2 decreased PCNA expression and exhibited cytotoxicity by MTT assay. ,
dr-CT-1 (7.2 KDa), a heat-stable protein from Daboia russelli russelli venom, showed significant decrease in EAC cells in vivo and on human leukemic cell lines (U937 and K 562) in vitro ; there was also significant prolongation of survival in mice. The antiproliferative action of the drug is evident from the reduction in MTT values. The apoptic effects of the drug is confirmed by observations of membrane blebbing, perforations, nuclear fragmentation, and cell cycle arrest in G 1 phase. 
Botulinum toxin type A (Botox)
Botox is injected locally in the limbs to treat generalized spastic disorders like cerebral palsy and can produce prolonged and persistent improvement, lasting several weeks.  Intramuscular injection of Botulinum toxin type A is used to treat involuntary muscle contractions (FDA approval, 1989). A cosmetic product of Botulinum toxin A, BOTOX® , is used to treat moderate to severe frown lines between the brows (FDA approval, 2002). 
The NNTA snake venomoids POVRVP, POECVP, and POESVP are central nervous system depressants, antidepressants, and stimulants with a wide spectrum of neuro- and psycho-pharmacological properties.
Snake venomoids 
POVRVP: A photooxidised product, POVRVP was generated by exposure of Vipera russelli venom to UV radiation (37°C, 15 min) in the presence of methylene blue. In preclinical evaluation in experimental animal models, POVRVP showed sedative, analgesic, and anti-inflammatory actions and decreased locomotor activity.  POVRVP also showed cardiac stimulant properties on isolated rat heart perfusion and shortened human plasma clotting time (unpublished observation, 2004-2005). Stability and subacute toxicity studies have shown that POVRVP is viable for 3 months. It is a NNTA for the treatment of chronic psychotic hyperactive disorders. POECVP (UVR, 37°C, 90 min), from Echis carinatus venom, showed antidepressant and nootropic properties, , and POESVP (UVR, 37°C, 30 min) from Enhydrina schistosa venom showed central nervous system stimulant, analgesic, anticoagulant nootropic and properties.  POECVP and POESVP are NNTA for chronic psychotic depressive disorders.
Remedies from snake venoms have been reported for the treatment of illnesses in the ancient literature of Charaka, Sushruta, and Vagbhata. However, extensive investigation on these natural leads for the generation of valuable pharmaceutical product is realized only in the last four decades, after a bradykinin-potentiating nanopeptide from Bothrops jararaca venom, with ACE-inhibitory action, was introduced as a natural alternative for the treatment of renovascular hypertension. The area of NNTAs is scanty, largely unattended and extremely expensive. However, these natural substances can offer cure for the disease conditions of tomorrow, which may not respond to currently available therapy.
The paper was presented in the poster session of 39 th Annual Conference of Indian Pharmacological Society, Department of Pharmacology, SMS Medical College, Jaipur, Dec.21-23, 2006. The support and encouragement of Prof. B.P. Ronge, Secretary, Shri Vittal Education and Research Institute, and Principal, College of Engineering, Pandharpur is gratefully acknowledged.
|1||Milijanich GP. Ziconotide: Neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem 2004;23:29-40.|
|2||Lewis R. Venomics to drugs: The Xen 2174 story: Abstract: 15 th world congress on animal, plant and microbial toxins. Univ Strathclyde: Glasgow, UK; July 23- 28, 2006. p. 86.|
|3||Nielsen CK, Lewis RJ, Alewood D, Drinkwater R, Palant E, Patterson M, et al. Anti-allodynic efficacy of the c-conopeptide, Xen2174, in rats with neuropathic pain. Pain 2005;118:112-24.|
|4||Pu XC, Wong PT, Gopalkrishnakone P. A novel analgesic toxin from the venom of king cobra Ophiophagus hannah . Toxicon 1995;33:1425-31.|
|5||Hay F, Shun K, Ku B. Analgesia composition and method. US Patent 6780866. Available from: http://www.patentstorm.us.|
|6||Chlor E. Epibatidine: A natural poison with painkilling potential: Chlorine online information resource. Available from: http://www.euchlor.org/epibatidine. October 2007.|
|7||Daly J. Eptibatidine, Natural frog poison with a surprising benefits to humans. Dr John Daly NIH: USA. Available from: http:// www.chm.bris.ac.uk.|
|8||Badio B, Daly HC. Epibatidine: A potent analgesic and nicotinic agonist. Mol Pharmacol 1994;45:563-9.|
|9||Xiong Y, Wang W, Yang L, Zhang G, Xu Y, Zhu H, et al. Analgesic effect of cobra venom neurotoxin and Keluoqu tablet. 13 th World Congress of IST: Paris, France; Sept 18-22, 2000. p. 20.|
|10||Bell WR Jr. De-dibrigenating enzymes. Drugs 1997;54:18-31.|
|11||Stocker KF, Meier J. Thrombin like snake venom enzymes in hemostasis and animal venoms. In: Prikle H, Markland FS, editors. Marcel Dekker Inc: NY; 1988. pp. 67-84.|
|12||Levy DE. Clinical development, UTI, Investigational drug being persued for the treatment of Ischaemic stroke. Neuroprotection news 31.05.07 Neurobiological Technologies Inc. [Last Accessed on 2007 May 31]. Available from: http://www.ntii.com.|
|13||Kwaan HC, Samama MM. Anticoagulant drugs: An unupdate. Expert Rev Cardiovasc Ther 2004;2:511-22.|
|14||Zingali RB, Ferreira MS, Assafim M, Frattani FS, Monterio RQ. Bothrojaracin, a Bothrops jararaca snake venom derived (Pro) Thrombin inhibitor, as an antithrobolic molecule. Pathophysiol Haemost Thromb 2005;34:160-3.|
|15||Zingali RB, Castro HC, Monterio RQ, Assafirm M, Bon C. Structural and pharmacological studies of bothrojaracin or (pro) thrombin action. Abstract:15 th World Congress of animal, plant and microbial. Toxins,Glasgow, University of Strathclyde: UK; 2006. p. 64.|
|16||Markland FS, Friedricks GS, Pe Witt SR, Luchesi BR. Thrombolytic effects of recombinant fibrolase or APSAC in a canine model of carotid artery thrombosis. Circulation 1994;90:2448-56.|
|17||Mann MB, Li H, Boone TC. Methods for the treatment of thrombosis. US Patent No. 7195903, 2007. Available from: http://www.patentstorm.us.|
|18||Sarray S, Srairi N, Luis J, Marvaldi J, Marvaldi J, El Ayeb M, et al. Lebecetin, C-lectin protein from the venom of Macrovipera lebetina that inhibits platelet aggregation and adhesion of cancerous cells. Haemostasis 2001;31:173-6.|
|19||Schiek A, Kornalik F, Habermann E. The prothrombin activating principle from Echis carinatus venom. Preparation and Biochemical properties. Naunyn Schweidebergs Arch Pharmacol 1972;272:402-16.|
|20||Rosing J, Govers-Riemslag JW, Yukelson L, Tans G. Factor V activation and inactivation by venom proteases. Haemostasis 2001;31:241-6.|
|21||Tans G, Rosing J. Snake venom activators of factor X: An overview. Haemostasis 2001;31:225-33.|
|22||Rao VS, Kini MR. Pseutarin C, a prothrombin activator from Pseudonaja textilis venom: Its structural and functional similarity to mammalian coagulation factor Xa-Va complex. Thromb Haemost 2002;88:611-9.|
|23||Beeton C, Pennington MW, Singh S, Nugent D, Crossley G, Khaytin I, et al. Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Mol Pharmacol 2005;67:1369-81.|
|24||Patterson B. DR Newswire, Phylomed Corporation: Florida; 2000. Available from: http://www.phylomed.com.|
|25||Chu NS. Contribution of snake venom toxin to Myasthenia gravis : The discovery of a bungarotoxin in Taiwan. J Hist Neurosci 2005;14:138-48.|
|26||Stocker JF, Trayner Jr. The action of various venoms on E. coli . J Appl Bacterial 1986;61:383-8.|
|27||Stabeli RG, Marcussi S, Carlos GB, Pietro RC, Selistre-de-Araújo HS, Giglio JR, et al. Platelet aggregation and antibacterial effects of an L- Amino oxidase purified from snake venom. Bioorg Med Chem 2004;12:2881-6.|
|28||Corzo G, Escoubas P, Villegas E, Barnham KJ, He W, Norton RS, et al. Characterization of unique amphipathic antimicrobial peptides from venom of the scorpion Pandinus imperator . Biochem J 2001;359:35-45.|
|29||Krylov VN. Study of cardiotonic effects of venom of the green toad Bufo viridis . J Eur Biochem Physiol 2002;38:223-8.|
|30||Ferreira SH, Bartelt DC, Greene LJ. Isolation of bradykinin-potentiating peptides from Bothrops jararaca venom. Biochemistry 1970;9:2583-93.|
|31||Cushman DW, Ondetti MA. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension 1991;17:589-92.|
|32||Kim DS, Chung KH, King IC. Antitumor agent comprising salmosin as an active ingredient. U.S.Patent (No.6537551, March 25, 2003). Available from: http://www.patentstorm.us/patents.|
|33||Kim SI, Kim KS, Kim HS, Kim DS, Jang Y, Chung KH, et al. Inhibitory effects of the salmosin gene transfer by cationic liposomes on the progression of B16BL6 tumors. Cancer Res 2003:63:6458-62.|
|34||Yeoh CH, Peng HC, Yang RS, Huang TS. Rhodostomin, a snake venom disintegrin, inhibits angiogenesis elicited by basic fibroblast growth factor and suppresses tumor growth by a selective av β 3 blockade of endothelial cells. Mol Pharma 2001;59:1333-42.|
|35||Trikha M, Tves A, De Clerck, Markland FS. Cantorstrostatin, a snake venom disintigrin, inhibits B1 integrin mediated human metastatic melanoma cell adhesion and blocks experimental metastasis. Cancer Res 1994;54:4993-8.|
|36||Pyrko P, Wang W, Markland FS, Swenson SD, Schmitmeler S, Schonthal AH, et al. The role of contorstrostatin, a snake venom disintigrin in the inhibition of tumor progression and prolongation of survival in a rodent glioma model. Neurosurg 2005;103:526-37.|
|37||Swenson S, Costa F, Minea R, Sherwin RP, Renst W, Fujii G, et al. Intravenous liposomal delivery of the venom disintgrin contortrostatin limits breast cancer progression. Mol Cancer Ther 2004;3:499-511.|
|38||Gomes A. Amphibian Jacket (Skin): A treasure house for drug development. 38 th Annual Conference of IPS. Dec. 28-30, Madras Medical College, Chennai, India. Abstract: Indian J Pharmacol 2005;59:S-18.|
|39||Shubashree RC Gomes A. Antineoplastic protein toxin (Toxin CN-28) from Vipera russelli venom. 38 th Annual Conference of IPS, Dec. 28-30, Madras Medical College, Chennai, India. Abstract: Indian J Pharmacol 2005;59:S-55.|
|40||Gomes A, Choudhury SR, Saha A, Mishra R, Giri B, Biswas AK, et al. A heat stable protein toxin (dr CT-1) from the Indian Viper ( Daboia russelli russelli ) venom having antiproliferative cytotoxic and apoptic activities. Toxicon 2007;49:46-56.|
|41||White PF, Katzung BG. Skeletal muscle relaxants. Section 27, pp 444. In: Basic and Clinical Pharmacology, Katzung BG, editor. 9 th ed. McGraw Hill: International Edition; 2004.|
|42||Botox: Available from http:// www.consumerhealthdigest.com. [Last cited on 2006 Dec 12].|
|43||Gawade SP. Snakoid instead of Venomoid. J Venoms Anim Toxins Inclu Trop Dis 2007;13:430.|
|44||Gawade SP, Sankar A. Pharmaco-photodynamics of photooxidised Russell's viper venom product generated using UV radiation in the presence of methylene blue. Indian J Pharm Edu Res 2007;41:121-8.|
|45||Gawade SP, Prasher S. Pharmaco-photodynamics of photooxidised venom product generated using UV sensitized methylene blue. Indian J Pharm Edu 2004;38:81-6.|
|46||Mohana C. Evaluation of UV sensitised photooxidised venom product of Echis carinatus for learning, memory and stress behavior in rats: Psychopharmacological studies. M.Pharm (II) Pharmacology, Dissertation RGUHS: Bangalore, Karnataka; 2005.|
|47||Gawade SP. Pharmaco-photodynamics of snake venom proteins. In: Shier WT, Tu AT, editors. Toxin reviews. Journal of Toxicology. McGraw-Hill: New York; 2007 (In press).|