| Revision as of 06:04, 21 January 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{drugbox}} (changes to verified fields - added verified revid - updated 'UNII_Ref', 'ChemSpiderID_Ref', 'StdInChI_Ref', 'StdInChIKey_Ref', 'ChEMBL_Ref', 'KEGG_Ref') per [[Misplaced Pages:WikiProject Chemicals/Chembox validation|Chem/Drugbox valid← Previous edit |
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{{Short description|Drug for chronic pain}} |
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{{Drugbox| Verifiedfields = changed |
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{{Use mdy dates|date=April 2013}} |
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| verifiedrevid = 402795513 |
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{{Drugbox |
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| Verifiedfields = changed |
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| IUPAC_name = ? |
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| Watchedfields = changed |
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| image = Ziconotide 1DW5.png |
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| verifiedrevid = 409117228 |
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| image2 = |
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| image = Structural formula of ziconotide.png |
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| width = 250 |
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| width = 250 |
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| image2 = Ziconotide 1DW5.png |
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| CAS_number = 107452-89-1 |
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| width2 = 250 |
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<!--Clinical data --> |
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| pronounce = {{IPAc-en|z|aɪ|ˈ|k|ɒ|n|oʊ|t|aɪ|d}}<br />{{respell|zy|KON|oh|tyd}} |
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| tradename = |
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| Drugs.com = {{drugs.com|monograph|ziconotide}} |
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| MedlinePlus = |
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| DailyMedID = Ziconotide |
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| routes_of_administration = ] – directly into cerebrospinal fluid by a catheter |
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| ATC_prefix = N02 |
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| ATC_prefix = N02 |
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| ATC_suffix = BG08 |
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| ATC_suffix = BG08 |
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| PubChem = 16129690 |
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| DrugBank = ? |
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| legal_US = Rx-only |
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| legal_EU = Rx-only |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| legal_EU_comment = <ref>{{cite web | title=Prialt EPAR | website=European Medicines Agency | date=9 July 2001 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/prialt | access-date=21 June 2024}}</ref> |
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| KEGG = D06363 |
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| legal_status = Rx-only |
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| C=102 | H=172 | N=36 | O=32 | S=7 |
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| molecular_weight = 2639 daltons |
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<!--Pharmacokinetic data--> |
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| bioavailability = 50% |
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| bioavailability = 50% |
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| metabolism = ? |
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| metabolism = |
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| elimination_half-life = 2.9 to 6.5 hours |
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| elimination_half-life = 2.9 to 6.5 hours |
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| excretion = <1% Urine |
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| excretion = <1% urine |
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| pregnancy_US = C |
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<!--Identifiers--> |
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| legal_status = Rx-only |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| routes_of_administration = ] - directly into cerebrospinal fluid by a catheter |
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| CAS_number = 107452-89-1 |
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| IUPHAR_ligand = 2536 |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank = DB06283 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = 7I64C51O16 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D06363 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 1201418 |
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| PubChem = 16135415 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = 17291932 |
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| SMILES = CSCC1NC(=O)(CC(C)C)NC(=O)(CCCNC(=N)N)NC(=O)(CO)NC(=O)2CSSC3NC(=O)(CO)NC(=O)CNC(=O)((C)O)NC(=O)(CSSC(N)C(=O)N(CCCCN)C(=O)NCC(=O)N(CCCCN)C(=O)NCC(=O)N(C)C(=O)N(CCCCN)C(=O)N2)NC(=O)(CSSC(C(N)=O)NC(=O)(CCCCN)NC(=O)CNC(=O)(CO)NC(=O)(CCCNC(=N)N)NC3=O)NC(=O)(CC(=O)O)NC(=O)(Cc2ccc(O)cc2)NC1=O |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI = 1S/C102H172N36O32S7/c1-50(2)34-63-91(161)127-62(26-33-171-5)90(160)129-64(35-53-22-24-54(143)25-23-53)92(162)130-65(36-78(148)149)93(163)135-72-48-175-173-45-69(80(108)150)133-86(156)58(18-8-12-29-105)121-76(146)39-117-85(155)66(41-139)131-88(158)61(21-15-32-114-102(111)112)126-96(166)70-46-176-177-47-71(97(167)132-68(43-141)95(165)125-60(87(157)128-63)20-14-31-113-101(109)110)134-89(159)59(19-9-13-30-106)123-81(151)51(3)119-74(144)37-115-83(153)56(16-6-10-27-103)120-75(145)38-116-84(154)57(17-7-11-28-104)124-82(152)55(107)44-172-174-49-73(137-98(72)168)99(169)138-79(52(4)142)100(170)118-40-77(147)122-67(42-140)94(164)136-70/h22-25,50-52,55-73,79,139-143H,6-21,26-49,103-107H2,1-5H3,(H2,108,150)(H,115,153)(H,116,154)(H,117,155)(H,118,170)(H,119,144)(H,120,145)(H,121,146)(H,122,147)(H,123,151)(H,124,152)(H,125,165)(H,126,166)(H,127,161)(H,128,157)(H,129,160)(H,130,162)(H,131,158)(H,132,167)(H,133,156)(H,134,159)(H,135,163)(H,136,164)(H,137,168)(H,138,169)(H,148,149)(H4,109,110,113)(H4,111,112,114)/t51-,52+,55-,56-,57-,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,72-,73-,79-/m0/s1 |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = BPKIMPVREBSLAJ-QTBYCLKRSA-N |
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| synonyms = SNX–111 |
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<!--Chemical data--> |
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| C=102 | H=172 | N=36 | O=32 | S=7 |
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'''Ziconotide''' ('''SNX-111'''; '''Prialt''') is a non-] and non-] ] agent used for the amelioration of severe and ]. Derived from '']'' ("Cone Snail"), it is the ] of an ω-] ].<ref name="pmid17963128">{{cite journal |unused_data=1B69BA326FFE69C3F0A8F227DF8201D0 |author=Skov MJ, Beck JC, de Kater AW, Shopp GM |title=Nonclinical safety of ziconotide: an intrathecal analgesic of a new pharmaceutical class |journal=Int. J. Toxicol. |volume=26 |issue=5 |pages=411–21 |year=2007 |pmid=17963128 |doi=10.1080/10915810701582970 |url=http://www.informaworld.com/openurl?genre=article&doi=10.1080/10915810701582970&magic=pubmed}}</ref> |
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'''Ziconotide''', sold under the brand name '''Prialt''', also called ] ziconotide (ITZ) because of its administration route, is an atypical ] agent for the amelioration of severe and ]. Derived from '']'', a cone snail, it is the ] of an ω-] ].<ref name=UKlabel>{{cite web|title=Prialt solution for infusion - Summary of Product Characteristics (SmPC) - (eMC)|url=https://www.medicines.org.uk/emc/product/215|publisher=Electronic Medicines Compendium|access-date=21 April 2018|language=en|date=January 2017}}</ref> |
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In December 2004 the ] approved ziconotide ] as an infusion into the ] using an ] ]. |
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In December 2004 the ] approved ziconotide ] as an infusion into the ] using an ] ]. |
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== Discovery == |
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==Discovery== |
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Ziconotide is derived from the toxin of the ] species '']''. 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 ]. Olivera, now a professor of biology in the ], 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,<ref name="pmid7149738">{{cite journal |vauthors=McIntosh M, Cruz LJ, Hunkapiller MW, Gray WR, Olivera BM | title = Isolation and structure of a peptide toxin from the marine snail Conus magus | journal = Arch. Biochem. Biophys. | volume = 218 | issue = 1 | pages = 329–34 | year = 1982 | pmid = 7149738 | doi = 10.1016/0003-9861(82)90351-4 }}</ref> when he was barely out of high school and working with Baldomero Olivera.<ref name="titleNIGMS -- Findings, September 2002: Secrets of the Killer Snails">{{cite web |url=http://publications.nigms.nih.gov/findings/sept02/snails.html |title=NIGMS – Findings, September 2002: Secrets of the Killer Snails |access-date=2007-12-21 |archive-date=November 7, 2017 |archive-url=https://web.archive.org/web/20171107113530/https://publications.nigms.nih.gov/findings/sept02/snails.html |url-status=dead }}</ref> |
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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 ] on February 22, 2005. Azur Pharma acquired worldwide rights (except Europe) to Prialt in 2010. |
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Ziconotide is derived from the toxin of the ] species '']''. 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 ]. Olivera, now a professor of biology in the ], 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,<ref name="pmid7149738">{{cite journal | author = McIntosh M, Cruz LJ, Hunkapiller MW, Gray WR, Olivera BM | title = Isolation and structure of a peptide toxin from the marine snail Conus magus | journal = Arch. Biochem. Biophys. | volume = 218 | issue = 1 | pages = 329–34 | year = 1982 | pmid = 7149738 | doi = 10.1016/0003-9861(82)90351-4 }}</ref> when he was barely out of high school and working with Baldomero Olivera.<ref name="titleNIGMS -- Findings, September 2002: Secrets of the Killer Snails">{{cite web |url=http://publications.nigms.nih.gov/findings/sept02/snails.html |title=NIGMS -- Findings, September 2002: Secrets of the Killer Snails |accessdate=2007-12-21 |work=}}</ref> 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 ] on February 22, 2005. |
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== Mechanism of action == |
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==Mechanism of action== |
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Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble in ]. Ziconotide acts as a selective ] ].<ref name="pmid15578997">{{cite journal| author=Miljanich GP| title=Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. | journal=Curr Med Chem | year= 2004 | volume= 11 | issue= 23 | pages= 3029–40 | pmid=15578997 | doi=10.2174/0929867043363884}}</ref><ref name="pmid19300539">{{cite journal| author=McGivern JG| title=Ziconotide: a review of its pharmacology and use in the treatment of pain. | journal=Neuropsychiatr Dis Treat | year= 2007 | volume= 3 | issue= 1 | pages= 69–85 | pmid=19300539 |
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| pmc=2654521| doi=10.2147/nedt.2007.3.1.69 | doi-access=free }}</ref> This action inhibits the release of pro-] ]s like ], ] (CGRP), and ] in the brain and ], resulting in pain relief.<ref name="pmid19300539"/> |
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==Therapeutic use== |
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Ziconotide acts as a selective ] ].<ref name="pmid15578997">{{cite journal| author=Miljanich GP| title=Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. | journal=Curr Med Chem | year= 2004 | volume= 11 | issue= 23 | pages= 3029–40 | pmid=15578997 }}</ref><ref name="pmid19300539">{{cite journal| author=McGivern JG| title=Ziconotide: a review of its pharmacology and use in the treatment of pain. | journal=Neuropsychiatr Dis Treat | year= 2007 | volume= 3 | issue= 1 | pages= 69–85 | pmid=19300539 |
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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 ]ly (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,<ref>{{cite web |url=http://www.medscape.com/viewarticle/510621_7 |title=Medscape |access-date=2007-12-21 }}</ref> 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 ], adjunctive therapies or IT ]".<ref name="titleU.S. Pharmacist">{{cite web |url=http://www.uspharmacist.com/index.asp?page=ce/10186/default.htm |title=U.S. Pharmacist |access-date=2007-12-21 |archive-date=September 28, 2007 |archive-url=https://web.archive.org/web/20070928021210/http://www.uspharmacist.com/index.asp?page=ce%2F10186%2Fdefault.htm |url-status=dead }}</ref> Research is ongoing to determine whether ziconotide can be formulated in a way that would allow it to be administered by less invasive means.<ref>{{cite journal | vauthors = Anand P, O'Neil A, Lin E, Douglas T, Holford M | title = Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers | journal = Scientific Reports | volume = 5 | pages = 12497 | date = August 2015 | pmid = 26234920 | pmc = 4522602 | doi = 10.1038/srep12497 | bibcode = 2015NatSR...512497A }}</ref><ref>{{cite news| vauthors = Palca J |date=3 August 2015|title=Snail Venom Yields Potent Painkiller, But Delivering The Drug Is Tricky|url=https://www.npr.org/sections/health-shots/2015/08/03/428990755/snail-venom-yields-potent-painkiller-but-delivering-the-drug-is-tricky|newspaper=]|access-date=5 August 2015}}</ref> |
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| url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2654521 | pmc=PMC2654521| doi=10.2147/nedt.2007.3.1.69 }}</ref> This action inhibits the release of pro-] ]s like ], ] (CGRP), and ] in the ] and ], resulting in pain relief.<ref name="pmid19300539"/> |
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However, this must be weighed against the high level of ], both in terms of degree and length, and the apparent lack of ]<ref name="pmid16845440">{{cite journal |author=Prommer E |title=Ziconotide: a new option for refractory pain |journal=Drugs Today |volume=42 |issue=6 |pages=369–78 |year=2006 |pmid=16845440 |doi=10.1358/dot.2006.42.6.973534 |url=http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=973534}}</ref> and other signs of ]<ref name="pmid17063978">{{cite journal |author=Klotz U |title=Ziconotide—a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain—a short review |journal=Int J Clin Pharmacol Ther |volume=44 |issue=10 |pages=478–83 |year=2006 |pmid=17063978 |doi=10.5414/cpp44478}}</ref> 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 ] (e.g., ]) due to evidence that they are more susceptible to certain severe side effects.<ref> {{webarchive |url=https://web.archive.org/web/20060315192710/https://www.prialt.com/downloads/product_information.pdf |date=March 15, 2006 }}</ref> |
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=== Amino Acid Sequence === |
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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 |
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==Adverse reactions== |
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== Therapeutic use == |
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The most common side effects are dizziness, ], confusion, ], and headache. Others may include weakness, ], ], abnormal vision, ], ], unsteadiness on feet, ], urinary retention, pruritus, increased sweating, ], ], vomiting, ], ], rigors, ], muscle spasms, myalgia, ], ], amnesia, ], memory impairment, and induced psychiatric disorders. Other side effects which are less frequent but still clinically significant include auditory and visual ], thoughts of suicide, acute kidney failure, ], cardiovascular accident, ], new or worsening depression, paranoia, disorientation, ], and ]. Therefore, it is contraindicated in people with a history of ], ], clinical depression, and ]. 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.<ref name="pmid21041028">{{cite journal |vauthors=Maier C, Gockel HH, Gruhn K, Krumova EK, Edel MA |title=Increased risk of suicide under intrathecal ziconotide treatment? – A warning |journal=Pain |volume= 152|issue= 1|pages= 235–237|date=October 2010 |pmid=21041028 |doi=10.1016/j.pain.2010.10.007 |s2cid=33370759 }}</ref> There is no known antidote. |
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==Structure== |
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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 ]ly (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,<ref>{{cite web |url=http://www.medscape.com/viewarticle/510621_7 |title=Medscape |accessdate=2007-12-21 |format= |work=}}</ref> 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 ], adjunctive therapies or IT ]”.<ref name="titleU.S. Pharmacist">{{cite web |url=http://www.uspharmacist.com/index.asp?page=ce/10186/default.htm |title=U.S. Pharmacist |accessdate=2007-12-21 |work=}}</ref> |
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Ziconotide is a ] with the ] sequence |
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H-]-]-]-Lys-Gly-]-Lys-Cys-]-]-]-]-]-]-Cys-Cys-]-Gly-]-Cys-Arg-Ser-Gly-Lys-Cys-NH<sub>2</sub> (CKGKGAKCSRLMYDCCTGSCRSGKC-NH2) and contains 3 ] bonds (Cys1-Cys16, Cys8-Cys20, and Cys15-Cys25). |
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==Patents== |
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However, this must be weighed against the high level of ], both in terms of degree and length, and the apparent lack of ]<ref name="pmid16845440">{{cite journal |author=Prommer E |title=Ziconotide: a new option for refractory pain |journal=Drugs Today |volume=42 |issue=6 |pages=369–78 |year=2006 |pmid=16845440 |doi=10.1358/dot.2006.42.6.973534 |url=http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=973534}}</ref> and other signs of ]<ref name="pmid17063978">{{cite journal |author=Klotz U |title=Ziconotide--a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain--a short review |journal=Int J Clin Pharmacol Ther |volume=44 |issue=10 |pages=478–83 |year=2006 |pmid=17063978 |doi=}}</ref> 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 ] (e.g. ]) due to evidence that they are more susceptible to certain severe side effects.<ref></ref> |
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The drug was patented by Neurex Corp., a U.S. company purchased in 1998 by ] Corporation, plc of Ireland. U.S. patents assigned to Elan include {{US patent|5,859,186|5,859,186}}, {{US patent|5,795,864|5,795,864}} {{US patent|5,770,690|5,770,690}}, {{US patent|5,587,454|5,587,454}}, and {{US patent|5,559,095|5,587,454}}. |
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==References== |
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== Adverse reactions == |
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{{Reflist}} |
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==External links== |
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The most common side effects are dizziness, ], confusion, and ]. Others may include weakness, ], ], abnormal vision, ], ], unsteadiness on feet, and memory problems. The most severe, but rare side effects are ], thoughts of ], new or worsening ], ] and ]. Therefore, it is contraindicated in people with a history of ], ], ], and ]. 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.<ref name="pmid21041028">{{cite journal |author=Maier C, Gockel HH, Gruhn K, Krumova EK, Edel MA |title=Increased risk of suicide under intrathecal ziconotide treatment? - A warning |journal=Pain |volume= |issue= |pages= |year=2010 |month=October |pmid=21041028 |doi=10.1016/j.pain.2010.10.007 |url=}}</ref> |
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* {{ClinicalTrialsGov|NCT00076544|Ziconotide Effectiveness and Safety Trial in Patients with Chronic Severe Pain}} |
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== Patents == |
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The drug was patented by Neurex Corp., a U.S. company purchased in ] by ] Corporation, plc of ]. U.S. patents assigned to Elan include 5,859,186, 5,795,864, 5,770,690, 5,587,454, and 5,559,095. |
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== References == |
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{{Reflist|2}} |
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== External links == |
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* |
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* , a December 2004 ] article |
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* from Elan |
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* |
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{{Analgesics}} |
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{{Analgesics}} |
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{{Neuropathic pain and fibromyalgia pharmacotherapies}} |
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{{Calcium channel blockers}} |
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{{Channelergics}} |
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{{Portal bar | Medicine}} |
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