Venum for Pain

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Slide 1: APPROACHES IN VENOM THERAPY A Project By: Akashdip C. Dhanak (T.Y.B.Pharm) Guided By: Dinesh D. Rishipathak MET’s Institute of Pharmacy; Adgaon, Nashik, 422003


Slide 2: Introduction: Venom is a protein secreted by various reptiles, spiders, & other nocturnal animal which can cause damage to a living tissue. A toxin is a poisonous substance produced by living cells or organisms that are active at very low concentrations. Concept in Therapy: Snake venom is a complex mixture of numerous bioreactive components, such as toxins, enzymes, hormones and growth factors with a wide spectrum of biological activities. Snake venom derived proteins have importance in medicine, pharmacology and in various diagnostic procedures. USE IN: Multiple sclerosis a neuro-degenerative disorder Inhibition of herpes’ virus Anti-retroviral Analgesic Polio Adrenomyeloneuropathy Pseudo rabies infection Semliki Forest Virus infection Employed usually as receptor ligands Anti-viral Anti-tumor Immunomodulatory Modulation of cytokine/hormone release Modulation of neuro-muscular transmission


Slide 3: Mixture of venoms from different species Could prevent/treat monkeys infected with poliovirus Supply Large amount of venoms to Miami University to find vaccins over Polio. Bill Haast’s contribution He 1st Introduce the technique for collection of venom. He Have His Snake farm Known as The Serpentarium in 1946.


Slide 4: Onset of Venom Therapy: In the early part of the last century, cobra venoms were established products mainly for the treatment of severe pain, and also for rheumatism, trigeminal neuralgia, asthma, ocular therapy, and neuroses. Cobra venom has been widely used for decades in China for the treatment of rheumatoid arthritis and cancer. Prior to its use, it is partially denaturated by heating. This process inactivates many of the venom enzymes, although the neurotoxins can retain their toxicity. Such modified venoms proved to be 80% effective in the clinic for the treatment of headache and arthritis pain. In ancient Ayurveda it is noted that snake venom gives painless death (vedanarahit mrutu). The symbol of bowl of hygea should had been concluded due to therapeutic activity of venom.


Slide 5: Applicative approach in venom therapy: Multiple sclerosis & its treatment with alpha-cobra toxin Methods of isolation of alpha cobra toxin Inhibition of Herpes virus by a novel nontoxic protein from cobra venom Modified venom & Its component as an Antiretroviral agent Russell viper venom as potent coagulant


Slide 6: What is Actually Multiple sclerosis (MS)? It is caused by various ways By autoimmune destruction of central nervous system By Herpes virus infection to CNS A French neurologist Jean-Martin Charcoat recognize MS as a Distinct diseases in 1868 Figure 2: MRI FLAIR sequence showing four bright spots (plaques) where multiple sclerosis has damaged myelin in the brain MS affects the areas of the brain and spinal cord known as the white matter, destroying a fatty layer called the myelin sheath, which wraps around nerve fibers and electrically insulates them. Symptoms: Symptoms of MS usually appear in episodic acute periods of worsening (relapses, exacerbations, bouts or attacks), in a gradually-progressive deterioration of neurologic function, or in a combination of both.


Slide 7: Treatment Of MS with a-Cobratoxin: a-Cobratoxin- obtained from all cobra (naja-genus) ideally from Cobra-Naja naja siamensis a-Cobratoxin is a substance of the venom of certain Naja cobras. It is a muscle-type nicotinic acetylcholine receptor (nAChR) antagonist, which causes paralysis by preventing the binding of acetylcholine to the nAChR a-Cobratoxin have some pharmacological actions: Antiviral Activity Immunomodulatory Activity Neuroprotective Activity Neuromodulatory & Analgesic


Slide 8: Antiviral Activity: The first pharmacological activity associated with MN and detoxified cobratoxin (MCTX) related to their antiviral activity. MCTX-HIV & Rabies- Having involvement of the NAchR in viral infection. Immunomodulatory Activity: MCTX-Rsemeblence action of Alpha-Interferon Nicotinic receptors have been detected on T lymphocytes, and, when blocked by BTX & MCTX, Neuroprotective effects: It has reported that the blockade of a-7 NAchR containing receptors inhibits the release of glutamate a known trigger of cell apoptosis. Analgesic Activity: In the rat tail-flick assay, the intracerebroventricular administration of MCTX was not toxic and it produced marked analgesic effects with 1/160 of the systemic dose (10 mg/kg). The involvement of muscarinic and the opioid peptidergic systems in MCTX induced analgesia were examined by pretreatment of animals with atropine or naloxone. Alpha-Cobratoxin


Slide 9: Comparison of the Activities of MS Drugs to MCTX


Slide 10: Inhibition of Herpes Virus By a Novel nontoxic protein from cobra venom It is clear that snake venom proteins have been tested for their antiviral properties. Two decades ago, venoms were tested on a limited scale and for a few viruses, mostly RNA viruses. On isolation of nontoxic protein Herp(Herpes Virus Inhibitor) from the venom of Naja kaouthia cobra snake, which inhibits the infectivity of human herpes viruses in cell cultures under different conditions. This is a first interesting research report that HHV 1 and HHV 2 viruses can be differentiated at the cellular level. Herp itself has no effect on Chang liver, HE or Vero cells up to 50 µg/ml. concentration therefore, it is nontoxic.


Slide 11: Result: The results showed that the replication of HHV 1 and HHV 2 was inhibited in the presence of 5 µg/ml of Herp in Chang liver cells. The results showed that on treating HE(human Embryo line) and Vero cells with 5µg/ml of Herp overnight, made them susceptible to HHV 2 infection but not to HHV 1, as no inhibition of HHV 1 was observed. The results showed that the CPE(cytopathic effect) of HHV 1 isolates was not affected by overnight pretreatment of Vero cells with 5 µg/ml of Herp.


Slide 12: Approach As An Antiretroviral Agent : MCTX having its antiretroviral activity due to-Molecular mimicry; alpha-neurotoxin with HIV gp120 sequence homology. MCTX act post-synaptically and result in blockade of nerve transmission due to their affinity for the nicotinic acetylcho­line receptor (nAchR). nAchR molecule- is a pentamer composed of 1. two alpha subunits, 2.one beta, 3. one gamma 4.one delta subunit CTX prevents further nerve damage Denervation/loss of signaling results in loss of receptors. Blockade increases receptor density. a7 block may enhance signal transduction if acetylcholine has negative action May cross react with muscarinic receptors


Slide 13: Russell Viper Venom As Potent coagulant: Russell's viper- Daboia russelli The species was named in honor of Dr. Patrick Russell After Bite Death from septicaemia, respiratory or cardiac failure may occur 1 to 14 days post-bite or even later. Because this venom is so effective at inducing thrombosis, it has been incorporated into an in vitro diagnostic test for blood clotting that is widely used in hospital laboratories. This Venom Has Great effect on the blood coagulation cascade.


Slide 15: Factor X Needs Protease Enzyme to potentiate the metalloproteinase complex forming reaction resulting in Prothrombin to thrombin conversion. EDTA-Ca Complex –Potentiate by RVV-X Prothrombin Activator: Daboia russelli- Venom - Prothrombin Activator- 4 Groups Group 1- convert Prothrombin to meizothrombin with activity insensitive to the presence of the non-enzymatic prothrombinase complex cofactors (CaCL2, factor V and phospholipid) Group 2&3- Cleave both peptide bond in prothrombin to thrombin conversion GR2-stimulate phospholipid & Factor Va in presence of Ca+ GR3-stimulate CaCl2 & phospholipid Group 4- proteases that cleave prothrombin into non-active precursor forms of thrombin rather than converting prothrombin into the enzymatically active products. Thrombin like enzyme: Mimics the action of TLE


Slide 17: Conclusion: Venom & Toxins is A great source of enzyme, protein & amino-acid gives therapeutical action on living organism; so many biopharmaceutical companies now have great interest in Toxinology.


Slide 18: References: ‘Bill Haast’ available via http://en.wikipedia.org/wiki/ Paul F. Reid ‘Alpha-Cobra toxin as a Possible Therapy for Multiple Sclerosis: A Review of the literature Leading to Its Development for This Application’ Critical Reviews in Immunology, 27(4), 291-302, (2007) ‘Venom & Toxin’ available via http://en.wikipedia.org/wiki/ ‘Multiple sclerosis’ available via http://en.wikipedia.org/wiki/ ‘Multiple sclerosis’ available via http://www.esperanzapeptide.net/ Rosati G "The prevalence of multiple sclerosis in the world: an update". Neurol. Sci. 22 (2): 117 (2001). ‘Cobra-Naja naja siamensis’ available via http://www.latoxan.com/ ‘Cobra-Naja naja siamensis’ available via http://sbsweb.bangor.ac.uk/ Christian Betzel, Gudrun Lange, Gour P. Pal, Keith S. Wilson, Alfred Maelickej and Wolfram Saenger; ‘The Refined Crystal Structure of a-Cobratoxin from Naja naja siamensis at 2.4-A Resolution’, 266,( 32) 21530-32, (1991) Lipps, B. V., Biological and immunological properties of nerve growth factor from snake venoms. J. Nat. Toxins 7, 121-130, 1998. Lipps, B. V., Novel snake venom proteins cytolytic to cancer cells in vitro and in vivo. J. Venom. Anim. Toxins 5, 172-183, 1999. Lipps, B. V.,. Nontoxic inhibitor to RNA viruses isolated from the venom of Australian taipan snake. Acta Virologica (accepted) 2001. Paul f. Reid & Laurence A. Raymond United state patent application publication - Application no. 11/217,713 1-6 pub. Date: Apr 27,2006 ‘Russell's viper- Daboia russelli’ available via http://en.wikipedia.org/wiki/ ‘Blood Coagulation’ available via http://nic.sav.sk/ ‘Blood Coagulation’ available via http://en.wikipedia.org/wiki/ ‘Dr. Bryan Grieg Fry’ available via www.venomdoc.com Hiroyuki Takeya, Shinji Nishida, Toshiyuki Miyata, Soh-ichiro Kawada, Yukari Saisaka, Takashi Morita, and Sadaaki Iwanaga ‘Coagulation Factor X Activating Enzyme from Russell’s Viper Venom (RVV-X)’; 267(20), 14109-1411,(1992)


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