Transcript Bio445 C. magus and Prialtx

Conus magus and
Ziconotide (Prialt)
Thomas Crowell
S
Conus magus
S “The Magician’s Cone Snail”
(Conus – cone, magus – sorcerer)
S Live along tropical shorelines
especially around coral reefs
S Family Conidae: All members of
this family are predators and use
venom to hunt prey
http://www.uksh.de/uksh_media/Pressemitteilung
en/2010/Juli/livett_coneshell_1-width-1152-height633-view_image-1-called_by-uksh-original_siteuksh-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
S Venom contains neurotoxic peptides known as
“conotoxins”
S 4 types of conotoxins in family Conidae: α, σ, κ, μ,
and ω
S 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/weich
tiere/schnecken/ctxm7a.jpg
Human Interaction with
Conotoxins
S 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.
S 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
S There is no antivenom for any of the conotoxins.
S Conotoxins cause such excruciating pain that even pain
killers, such as morphine, can’t even dull it down. You
HAVE to wait it out.
S 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
S Ziconotide was discovered in the 1980’s through
experimentation with conotoxins and isolation of conotoxin
peptides.
S The specific derived conotoxin is ω-conotoxin MVIIA
caused analgesic effects.
S ω-conotoxin MVIIA is further synthesized to SNX-111 aka
Ziconotide.
S Treatment was originally for patients suffereing from cancer
and AIDS
What is Ziconotide?
S ω-conotoxin MVIIA is
synthesized into drug
Ziconotide.
S Ziconotide is manufactured
by Elan Corporation
S 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
S Ziconotide is a hydrophilic N-type voltage gated
calcium channel blocker
S FDA approved if Ziconotide is administered into
cerebrospinal fluid with an intrathecal catheter.
S The analgesic effects of Ziconotide are 1000x stronger
than morphine and does not exhibit addictive qualities.
Adverse effects of Ziconotide
S The common side effects are nausea, dizziness,
diarrhea, weakness, etc.
S Ziconotide is contraindicated to people that have
mental illnesses such as psychosis or depression.
S 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
S Ziconotide is cleaved by endopeptidases and
exopeptidases at multiple locations.
S Ziconotide is also susceptible to proteolytic cleavage by
peptidases and proteases found in organs.
S 1% of ziconotide is excreted through urine. Many of
the peptide fragments of ziconotide are degraded in the
body.
Further research into
conotoxins
S Further research into Ziconotide to increase the therapeutic index
in hopes of creating an orally-available solution opposed to
treatment through an intrathecal catheter.
S The synthesis of Ziconotide has led to research into marine toxins
and the synthesis of medications from other conotoxins.
S 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
S
http://bioweb.uwlax.edu/bio203/2011/haas_kayl/index.htm
S
http://grimwade.biochem.unimelb.edu.au/cone/about.html
S
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021060s003lbl.pdf
S
http://publications.nigms.nih.gov/findings/sept02/snails.html
S
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
S
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
S
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
S
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
S
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