Conus magus and Ziconotide (Prialt) Thomas Crowell

Conus magus “The Magician’s Cone Snail” (Conus – cone, magus – sorcerer) Live along tropical shorelines especially around coral reefs Family Conidae: All members of this family are predators and use venom to hunt prey http://www.uksh.de/uksh_media/Pressemitteilungen/2010/Juli/livett_coneshell_1-width-1152-height-633-view_image-1-called_by-uksh-original_site-uksh-original_page-19586.jpg

Conidae venom Video: Conus magus catching prey with stinging apparatus. http://grimwade.biochem.unimelb.edu.au/cone/index1.html

Conidae venom Venom contains neurotoxic peptides known as “conotoxins” 4 types of conotoxins in family Conidae: α, σ, κ, μ, and ω Conus magus use ω-conotoxin. This specific conotoxin blocks N-type voltage dependent calcium channels which cause paralysis and analgesic effects in prey

Mechanism of Action Extracelllular Ca2+ is blocked by ω-conotoxin Suppresses Na+ and Ca2+ currents through Ca2+ channels Blockade of Ca2+ channels occur 10 – 15 minutes within injection into extracellular fluid http://molluscs.at/images/weichtiere/schnecken/ctxm7a.jpg

Human Interaction with Conotoxins ω-conotoxins of the Conus magus snail cause pain equivalent to a bee sting but in extreme cases can cause paralysis. There have not been any recorded deaths directly related to Conus magus stings. α, σ, κ, μ conotoxins are more toxic. Their effects when injected into a human being results in paralysis, hours of excruciating pain, and/or death.

Treatment after Exposure to Conotoxins There is no antivenom for any of the conotoxins. Conotoxins cause such excruciating pain that even pain killers, such as morphine, can’t even dull it down. You HAVE to wait it out. Individuals stung by Conus geographics have described the pain to be so severe that the thought of death would be a blessing from the pain.

Origins of Ziconotide Ziconotide was discovered in the 1980’s through experimentation with conotoxins and isolation of conotoxin peptides. The specific derived conotoxin is ω-conotoxin MVIIA caused analgesic effects. ω-conotoxin MVIIA is further synthesized to SNX-111 aka Ziconotide. Treatment was originally for patients suffereing from cancer and AIDS

What is Ziconotide? ω-conotoxin MVIIA is synthesized into drug Ziconotide. Ziconotide is manufactured by Elan Corporation It is sold under the commercial name Prialt (Primary alternative to opioid based pain medications). http://upload.wikimedia.org/wikipedia/commons/f/f9/Ziconotide_1DW5.png

Characteristics and Therapeutic Effects of Ziconotide Ziconotide is a hydrophilic N-type voltage gated calcium channel blocker FDA approved if Ziconotide is administered into cerebrospinal fluid with an intrathecal catheter. The analgesic effects of Ziconotide are 1000x stronger than morphine and does not exhibit addictive qualities.

Adverse effects of Ziconotide The common side effects are nausea, dizziness, diarrhea, weakness, etc. Ziconotide is contraindicated to people that have mental illnesses such as psychosis or depression. There is a suggested link between ziconotide treatment and increased suicidal thoughts.

Exposure Pathway of Ziconotide Ziconotide is administered through an interthecal infusion catheter The Ziconotide travels through the spinal fluid and blocks N-type voltage gated Ca2+ Channels at the dorsal horn of the spinal cord.

Metabolism of Ziconotide Ziconotide is cleaved by endopeptidases and exopeptidases at multiple locations. Ziconotide is also susceptible to proteolytic cleavage by peptidases and proteases found in organs. 1% of ziconotide is excreted through urine. Many of the peptide fragments of ziconotide are degraded in the body.

Further research into conotoxins Further research into Ziconotide to increase the therapeutic index in hopes of creating an orally-available solution opposed to treatment through an intrathecal catheter. The synthesis of Ziconotide has led to research into marine toxins and the synthesis of medications from other conotoxins. Research into cyclization of conotoxins to improve biopharmaceutical properties by making the conotoxin less susceptible to proteolysis by proteases: http://www.sciencedirect.com/science/article/pii/S00410101100 04204

References http://bioweb.uwlax.edu/bio203/2011/haas_kayl/index.htm http://grimwade.biochem.unimelb.edu.au/cone/about.html http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021060s003lbl.pdf http://publications.nigms.nih.gov/findings/sept02/snails.html Adams, D. J., Alewood, P. F., Craik, D. J., Drinkwater, R. D., and Lewis, R. J. 1999. Conotoxins and Their Potential Pharmaceutical Applications. Drug Development Research. Vol.46 Iss. 3-4: pp. 219-234 McGivern, J. G. 2007. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatri Dis Treat. Vol. 3, Iss 1: pp. 69-85 Jain, K. K. 2000. An evaluation of intrathecal ziconotide for the treatment of pain of chronic pain. Expert Opin Investig Drugs. Vol. 9, Iss 10: pp. 2403-2410 Savtchenko, A. N. and Verkhratsky, A. N. 1990. Omega-Conotoxin Blockade of Calcium Currents in Cultured Neonatal Rat Cardiomyocytes: Different Action on EGTA-Modified Calcium Channels. Gen. Physiol. Biophys. Vol. 9: pp. 147-166 Winquist, R. J., Pan, J. Q., Gribkoff, V.K. Use dependent blockade of Cav2.2 voltage-gated calcium channels for neuropathic pain. Biochem Pharmacol., Vol 70: pp. 489 - 499