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Ziconotide

Clinical data
Routes of administration	Intrathecal - directly into cerebrospinal fluid by a catheter
ATC code	N02BG08 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	50%
Metabolism	?
Elimination half-life	2.9 to 6.5 hours
Excretion	<1% Urine
Identifiers
IUPAC name ?
CAS Number	107452-89-1
PubChem CID	16129690
DrugBank	?
KEGG	D06363
CompTox Dashboard (EPA)	DTXSID60883174
ECHA InfoCard	100.212.174
Chemical and physical data
Formula	C102H172N36O32S7
Molar mass	2639 daltons g·mol
(what is this?)  (verify)

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 an ω-conotoxin peptide.

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

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. Olivera, now a professor of biology in the University of Utah, was inspired by accounts of the deadly effects of these toxins from his childhood in the Philippines. Ziconotide was discovered in the early 1980s by University of Utah research scientist Michael McIntosh, when he was barely out of high school and working with Baldomero Olivera. Ziconotide 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. 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.

Amino Acid Sequence

H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH2

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 (i.e. directly into the spinal fluid). As this is by far the most expensive and invasive method of drug delivery and involves additional risks of its own, 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”.

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 and other signs of dependence 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.

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. Recent incidents suggesting a link between intrathecal ziconotide treatment and increased risk of suicide have led to calls for strict and ongoing psychiatric monitoring of patients to avoid suicide occurring in vulnerable individuals.

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. {{cite journal}}: Unknown parameter |unused_data= ignored (help)CS1 maint: multiple names: authors list (link)
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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
3. "NIGMS -- Findings, September 2002: Secrets of the Killer Snails". 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.
5. ^ McGivern JG (2007). "Ziconotide: a review of its pharmacology and use in the treatment of pain". Neuropsychiatr Dis Treat. 3 (1): 69–85. doi:10.2147/nedt.2007.3.1.69. PMC 2654521. PMID 19300539.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
6. "Medscape". Retrieved 2007-12-21.
7. "U.S. Pharmacist". 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.
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
11. Maier C, Gockel HH, Gruhn K, Krumova EK, Edel MA (2010). "Increased risk of suicide under intrathecal ziconotide treatment? - A warning". Pain. doi:10.1016/j.pain.2010.10.007. PMID 21041028. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

External links

• Manufacturer website
• FDA approves new drug for severe pain, a December 2004 Associated Press article
• Press release announcing FDA approval from Elan
• Ziconotide Effectiveness and Safety Trial in Patients with Chronic Severe Pain

• Analgesics