Chemistry:Ziconotide
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| Pronunciation | /zaɪˈkɒnoʊtaɪd/ zy-KON-oh-tyd |
| Other names | SNX–111 |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | Intrathecal – directly into cerebrospinal fluid by a catheter |
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| Bioavailability | 50% |
| Elimination half-life | 2.9 to 6.5 hours |
| Excretion | <1% urine |
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| Formula | C102H172N36O32S7 |
| Molar mass | 2639.14 g·mol−1 |
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Ziconotide, sold under the brand name Prialt, also called intrathecal ziconotide (ITZ) because of its administration route, is an atypical analgesic agent for the amelioration of severe and chronic pain. Derived from Conus magus, a cone snail, it is the synthetic form of an ω-conotoxin peptide.[1] It is 1,000 times as powerful as morphine.[citation needed]
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,[2] when he was barely out of high school and working with Baldomero Olivera.[3]
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. Azur Pharma acquired worldwide rights (except Europe) to Prialt in 2010.
Mechanism of action
Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble in methyl t-butyl ether. 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 (i.e. directly into the spinal fluid). As this is 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 the 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] Research is ongoing to determine whether ziconotide can be formulated in a way that would allow it to be administered by less invasive means.[8][9]
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[10] and other signs of dependence[11] 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.[12]
Adverse reactions
The most common side effects are dizziness, nausea, confusion, nystagmus, and headache. Others may include weakness, hypertonia, ataxia, abnormal vision, anorexia, somnolence, unsteadiness on feet, vertigo, urinary retention, pruritus, increased sweating, diarrhea, nausea, vomiting, asthenia, fever, rigors, sinusitis, muscle spasms, myalgia, insomnia, anxiety, amnesia, tremor, memory impairment, and induced psychiatric disorders. Other side effects which are less frequent but still clinically significant include auditory and visual hallucinations, thoughts of suicide, acute kidney failure, atrial fibrillation, cardiovascular accident, sepsis, new or worsening depression, paranoia, disorientation, 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.[13] There is no known antidote.
Structure
Ziconotide is a peptide with the 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 (CKGKGAKCSRLMYDCCTGSCRSGKC-NH2) and contains 3 disulfide bonds (Cys1-Cys16, Cys8-Cys20, and Cys15-Cys25).
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 5,587,454.
References
- ↑ "Prialt solution for infusion - Summary of Product Characteristics (SmPC) - (eMC)" (in en). Electronic Medicines Compendium. January 2017. https://www.medicines.org.uk/emc/product/215.
- ↑ "Isolation and structure of a peptide toxin from the marine snail Conus magus". Arch. Biochem. Biophys. 218 (1): 329–34. 1982. doi:10.1016/0003-9861(82)90351-4. PMID 7149738.
- ↑ "NIGMS – Findings, September 2002: Secrets of the Killer Snails". http://publications.nigms.nih.gov/findings/sept02/snails.html.
- ↑ Miljanich GP (2004). "Ziconotide: neuronal calcium channel blocker for treating severe chronic pain.". Curr Med Chem 11 (23): 3029–40. doi:10.2174/0929867043363884. PMID 15578997.
- ↑ 5.0 5.1 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. PMID 19300539.
- ↑ "Medscape". http://www.medscape.com/viewarticle/510621_7.
- ↑ "U.S. Pharmacist". http://www.uspharmacist.com/index.asp?page=ce/10186/default.htm.
- ↑ "Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers". Scientific Reports 5: 12497. August 2015. doi:10.1038/srep12497. PMID 26234920. Bibcode: 2015NatSR...512497A.
- ↑ "Snail Venom Yields Potent Painkiller, But Delivering The Drug Is Tricky". NPR. 3 August 2015. https://www.npr.org/sections/health-shots/2015/08/03/428990755/snail-venom-yields-potent-painkiller-but-delivering-the-drug-is-tricky.
- ↑ 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.
- ↑ 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. doi:10.5414/cpp44478. PMID 17063978.
- ↑ prialt.com
- ↑ "Increased risk of suicide under intrathecal ziconotide treatment? – A warning". Pain 152 (1): 235–237. October 2010. doi:10.1016/j.pain.2010.10.007. PMID 21041028.
External links
- "Ziconotide". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/ziconotide.
- Clinical trial number NCT00076544 for "Ziconotide Effectiveness and Safety Trial in Patients with Chronic Severe Pain" at ClinicalTrials.gov
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