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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| Pharmacokineticdata | |
| Bioavailability | 50% |
| Eliminationhalf-life | 2.9 to 6.5 hours |
| Excretion | <1% urine |
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| ECHA InfoCard | 100.212.174 |
| Chemical and physical data | |
| Formula | C102H172N36O32S7 |
| Molar mass | 2639.14g·mol−1 |
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Ziconotide,sold under the brand namePrialt,also calledintrathecalziconotide (ITZ) because of its administration route, is an atypicalanalgesicagent for the amelioration of severe andchronic pain.Derived fromConus magus,a cone snail, it is thesynthetic formof an ω-conotoxinpeptide.[2]It is 1,000 times as powerful asmorphine.[citation needed]
In December 2004 theFood and Drug Administrationapproved ziconotidewhen deliveredas an infusion into thecerebrospinal fluidusing anintrathecalpump system.
Discovery[edit]
Ziconotide is derived from the toxin of thecone snailspeciesConus 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 byBaldomero Olivera.Olivera, now a professor of biology in theUniversity 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,[3]when he was barely out of high school and working with Baldomero Olivera.[4]
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 theEuropean Commissionon February 22, 2005. Azur Pharma acquired worldwide rights (except Europe) to Prialt in 2010.
Mechanism of action[edit]
Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble inmethyl t-butyl ether.Ziconotide acts as a selectiveN-type voltage-gated calcium channelblocker.[5][6]This action inhibits the release of pro-nociceptiveneurochemicalslikeglutamate,calcitonin gene-related peptide(CGRP), andsubstance Pin the brain andspinal cord,resulting in pain relief.[6]
Therapeutic use[edit]
Due to the profound side effects or lack of efficacy when delivered through more common routes, such as orally or intravenously, ziconotide must be administeredintrathecally(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,[7]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 systemicanalgesics,adjunctive therapies or ITmorphine".[8]Research is ongoing to determine whether ziconotide can be formulated in a way that would allow it to be administered by less invasive means.[9][10]
However, this must be weighed against the high level ofpain management,both in terms of degree and length, and the apparent lack oftolerance[11]and other signs ofdependence[12]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 preexistingmental disorders(e.g.,psychosis) due to evidence that they are more susceptible to certain severe side effects.[13]
Adverse reactions[edit]
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 visualhallucinations,thoughts of suicide, acute kidney failure,atrial fibrillation,cardiovascular accident,sepsis,new or worsening depression, paranoia, disorientation,meningitis,andseizures.Therefore, it is contraindicated in people with a history ofpsychosis,schizophrenia,clinical depression, andbipolar 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.[14]There is no known antidote.
Structure[edit]
Ziconotide is apeptidewith theamino acidsequence 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 3disulfidebonds (Cys1-Cys16, Cys8-Cys20, and Cys15-Cys25).
Patents[edit]
The drug was patented by Neurex Corp., a U.S. company purchased in 1998 byÉlanCorporation, plc of Ireland. U.S. patents assigned to Elan include5,859,186,5,795,8645,770,690,5,587,454,and5,587,454.
References[edit]
- ^"Prialt EPAR".European Medicines Agency.July 9, 2001.RetrievedJune 21,2024.
- ^"Prialt solution for infusion - Summary of Product Characteristics (SmPC) - (eMC)".Electronic Medicines Compendium. January 2017.RetrievedApril 21,2018.
- ^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.PMID7149738.
- ^"NIGMS – Findings, September 2002: Secrets of the Killer Snails".Archived fromthe originalon November 7, 2017.RetrievedDecember 21,2007.
- ^Miljanich GP (2004). "Ziconotide: neuronal calcium channel blocker for treating severe chronic pain".Curr Med Chem.11(23): 3029–40.doi:10.2174/0929867043363884.PMID15578997.
- ^abMcGivern 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.PMC2654521.PMID19300539.
- ^"Medscape".RetrievedDecember 21,2007.
- ^"U.S. Pharmacist".Archived fromthe originalon September 28, 2007.RetrievedDecember 21,2007.
- ^Anand P, O'Neil A, Lin E, Douglas T, Holford M (August 2015)."Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers".Scientific Reports.5:12497.Bibcode:2015NatSR...512497A.doi:10.1038/srep12497.PMC4522602.PMID26234920.
- ^Palca J (August 3, 2015)."Snail Venom Yields Potent Painkiller, But Delivering The Drug Is Tricky".NPR.RetrievedAugust 5,2015.
- ^Prommer E (2006)."Ziconotide: a new option for refractory pain".Drugs Today.42(6): 369–78.doi:10.1358/dot.2006.42.6.973534.PMID16845440.
- ^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.PMID17063978.
- ^prialt.comArchivedMarch 15, 2006, at theWayback Machine
- ^Maier C, Gockel HH, Gruhn K, Krumova EK, Edel MA (October 2010). "Increased risk of suicide under intrathecal ziconotide treatment? – A warning".Pain.152(1): 235–237.doi:10.1016/j.pain.2010.10.007.PMID21041028.S2CID33370759.
External links[edit]
- Clinical trial numberNCT00076544for "Ziconotide Effectiveness and Safety Trial in Patients with Chronic Severe Pain" atClinicalTrials.gov
