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Ziconotide
Systematic (IUPAC) name
?
Identifiers
CAS number 107452-89-1
ATC code N02BG08
PubChem 16129690
DrugBank ?
Chemical data
Formula C 102H172N36O32S7  
Mol. mass 2639 daltons
Pharmacokinetic data
Bioavailability 50%
Metabolism  ?
Half life 2.9 to 6.5 hours
Excretion <1% Urine
Therapeutic considerations
Pregnancy cat. C(US)
Legal status Prescription only
Routes Intrathecal - directly into cerebrospinal fluid by a catheter

Ziconotide (SNX-111; Prialt) is a non-opioid and non-NSAID analgesic agent used for the amelioration of severe and chronic pain. Derived from Conus magus ("Cone Snail"), it is the synthetic form of the peptide ω-conotoxin.[1]

In December 2004 the Food and Drug Administration approved ziconotide when delivered as an infusion into the cerebrospinal fluid using an intrathecal pump system.

Contents

Discovery

Ziconotide is derived from the toxin of the cone snail species Conus magus. Scientists have been intrigued by the effects of the thousands of chemicals in marine snail toxins since the initial investigations in the late 1960s by Baldomero Olivera, who remembered the deadly effects from his childhood in the Philippines. Ziconotide was discovered in the early 1980s by Michael McIntosh,[2] at the time barely out of high school and working with Baldomero Olivera. [3] It was developed into an artificially manufactured drug by Elan Corporation. It was approved for sale under the name Prialt by the U.S. Food and Drug Administration on December 28, 2004, and by the European Commission on February 22, 2005.

Mechanism of action

Ziconotide acts as a selective N-type voltage-gated calcium channel blocker.[4][5] This action inhibits the release of pro-nociceptive neurochemicals like glutamate, calcitonin gene-related peptide (CGRP), and substance P in the brain and spinal cord, resulting in pain relief.[5]

Therapeutic use

Due to the profound side effects or lack of efficacy when delivered through more common routes, such as orally or intravenously, ziconotide must be administered intrathecally (directly into the spine). As this is by far the most expensive and invasive method of drug delivery and involves additional risks of its own,[6] ziconotide therapy is generally considered appropriate (as evidenced by the range of use approved by the FDA in US) only for “management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine”.[7]

However, this must be weighed against the high level of pain management, both in terms of degree and length, and the apparent lack of tolerance[8] and other signs of dependence[9] even after extended treatment along with the need for alternatives to other therapies that have not worked for the patient. Ziconotide is also contraindicated for patients with certain preexisting mental disorders (e.g. psychosis) due to evidence that they are more susceptible to certain severe side effects.[10]

Adverse reactions

The most common side effects are dizziness, nausea, confusion, and headache. Others may include weakness, hypertonia, ataxia, abnormal vision, anorexia, somnolence, unsteadiness on feet, and memory problems. The most severe, but rare side effects are hallucinations, thoughts of suicide, new or worsening depression, meningitis and seizures. Therefore, it is contraindicated in people with a history of psychosis, schizophrenia, clinical depression, and bipolar disorder.

Patents

The drug was patented by Neurex Corp., a U.S. company purchased in 1998 by Élan Corporation, plc of Ireland. U.S. patents assigned to Elan include 5,859,186, 5,795,864, 5,770,690, 5,587,454, and 5,559,095.

References

  1. ^ Skov MJ, Beck JC, de Kater AW, Shopp GM (2007). "Nonclinical safety of ziconotide: an intrathecal analgesic of a new pharmaceutical class". Int. J. Toxicol. 26 (5): 411–21. doi:10.1080/10915810701582970. PMID 17963128. http://www.informaworld.com/openurl?genre=article&doi=10.1080/10915810701582970&magic=pubmed.  
  2. ^ McIntosh M, Cruz LJ, Hunkapiller MW, Gray WR, Olivera BM (1982). "Isolation and structure of a peptide toxin from the marine snail Conus magus". Arch. Biochem. Biophys. 218 (1): 329–34. doi:10.1016/0003-9861(82)90351-4. PMID 7149738.  
  3. ^ "NIGMS -- Findings, September 2002: Secrets of the Killer Snails". http://publications.nigms.nih.gov/findings/sept02/snails.html. Retrieved 2007-12-21.  
  4. ^ Miljanich GP (2004). "Ziconotide: neuronal calcium channel blocker for treating severe chronic pain.". Curr Med Chem 11 (23): 3029-40. PMID 15578997. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15578997.  
  5. ^ a b McGivern JG (2007). "Ziconotide: a review of its pharmacology and use in the treatment of pain.". Neuropsychiatr Dis Treat 3 (1): 69-85. PMID 19300539. PMC PMC2654521. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2654521.  
  6. ^ "Medscape". http://www.medscape.com/viewarticle/510621_7. Retrieved 2007-12-21.  
  7. ^ "U.S. Pharmacist". http://www.uspharmacist.com/index.asp?page=ce/10186/default.htm. Retrieved 2007-12-21.  
  8. ^ Prommer E (2006). "Ziconotide: a new option for refractory pain". Drugs Today 42 (6): 369–78. doi:10.1358/dot.2006.42.6.973534. PMID 16845440. http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=973534.  
  9. ^ Klotz U (2006). "Ziconotide--a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain--a short review". Int J Clin Pharmacol Ther 44 (10): 478–83. PMID 17063978.  
  10. ^ prialt.com

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