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Ziconotide

April 11, 2024

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]

Ziconotide
Clinical data
Pronunciation/zaɪˈkɒnoʊtaɪd/
zy-KON-oh-tyd
Other namesSNX–111
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intrathecal – directly into cerebrospinal fluid by a catheter
ATC code
Legal status
Legal status
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability50%
Elimination half-life2.9 to 6.5 hours
Excretion<1% urine
Identifiers
CAS Number
  • 107452-89-1 Y
PubChem CID
  • 16135415
IUPHAR/BPS
  • 2536
ChemSpider
  • 17291932 N
UNII
  • 7I64C51O16
KEGG
  • D06363 Y
ChEMBL
  • ChEMBL1201418 N
CompTox Dashboard (EPA)
  • DTXSID60883174
ECHA InfoCard100.212.174
Chemical and physical data
FormulaC102H172N36O32S7
Molar mass2639.14 g·mol−1
3D model (JSmol)
  • Interactive image
  • CSCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CO)NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CSSC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N2)NC(=O)[C@H](CSSC[C@@H](C(N)=O)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC3=O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](Cc2ccc(O)cc2)NC1=O
  • InChI=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 N
  • Key:BPKIMPVREBSLAJ-QTBYCLKRSA-N N
 NY (what is this?)  (verify)

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 edit

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 edit

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 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 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 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 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 edit

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 edit

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 edit

  1. ^ "Prialt solution for infusion - Summary of Product Characteristics (SmPC) - (eMC)". Electronic Medicines Compendium. January 2017. Retrieved April 21, 2018.
  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". Retrieved December 21, 2007.
  4. ^ 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. ^ 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. doi:10.2147/nedt.2007.3.1.69. PMC 2654521. PMID 19300539.
  6. ^ "Medscape". Retrieved December 21, 2007.
  7. ^ "U.S. Pharmacist". Retrieved December 21, 2007.
  8. ^ 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. PMC 4522602. PMID 26234920.
  9. ^ Palca J (August 3, 2015). "Snail Venom Yields Potent Painkiller, But Delivering The Drug Is Tricky". NPR. Retrieved August 5, 2015.
  10. ^ 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.
  11. ^ 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.
  12. ^ prialt.com March 15, 2006, at the Wayback Machine
  13. ^ 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. PMID 21041028. S2CID 33370759.

External links edit

  • "Ziconotide". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT00076544 for "Ziconotide Effectiveness and Safety Trial in Patients with Chronic Severe Pain" at ClinicalTrials.gov

April 11, 2024
ziconotide, sold, under, brand, name, prialt, also, called, intrathecal, ziconotide, because, administration, route, atypical, analgesic, agent, amelioration, severe, chronic, pain, derived, from, conus, magus, cone, snail, synthetic, form, conotoxin, peptide,. 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 w conotoxin peptide 1 It is 1 000 times as powerful as morphine citation needed ZiconotideClinical dataPronunciation z aɪ ˈ k ɒ n oʊ t aɪ d zy KON oh tydOther namesSNX 111AHFS Drugs comMonographLicense dataEU EMA by INN US DailyMed ZiconotideRoutes ofadministrationIntrathecal directly into cerebrospinal fluid by a catheterATC codeN02BG08 WHO Legal statusLegal statusUS only EU Rx only In general Prescription only Pharmacokinetic dataBioavailability50 Elimination half life2 9 to 6 5 hoursExcretion lt 1 urineIdentifiersCAS Number107452 89 1 YPubChem CID16135415IUPHAR BPS2536ChemSpider17291932 NUNII7I64C51O16KEGGD06363 YChEMBLChEMBL1201418 NCompTox Dashboard EPA DTXSID60883174ECHA InfoCard100 212 174Chemical and physical dataFormulaC 102H 172N 36O 32S 7Molar mass2639 14 g mol 13D model JSmol Interactive imageSMILES CSCC C H 1NC O C H CC C C NC O C H CCCNC N N NC O C H CO NC O C H 2CSSC C H 3NC O C H CO NC O CNC O C H C H C O NC O C H CSSC C H N C O N C H CCCCN C O NCC O N C H CCCCN C O NCC O N C H C C O N C H CCCCN C O N2 NC O C H CSSC C H C N O NC O C H CCCCN NC O CNC O C H CO NC O C H CCCNC N N NC3 O NC O C H CC O O NC O C H Cc2ccc O cc2 NC1 OInChI InChI 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 NKey BPKIMPVREBSLAJ QTBYCLKRSA N N N Y what is this verify 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 1 Discovery 2 Mechanism of action 3 Therapeutic use 4 Adverse reactions 5 Structure 6 Patents 7 References 8 External linksDiscovery editZiconotide 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 editZiconotide 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 editDue 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 editThe 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 editZiconotide 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 editThe drug was patented by Neurex Corp a U S company purchased in 1998 by Elan 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 edit Prialt solution for infusion Summary of Product Characteristics SmPC eMC Electronic Medicines Compendium January 2017 Retrieved April 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 PMID 7149738 NIGMS Findings September 2002 Secrets of the Killer Snails Retrieved December 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 PMID 15578997 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 doi 10 2147 nedt 2007 3 1 69 PMC 2654521 PMID 19300539 Medscape Retrieved December 21 2007 U S Pharmacist Retrieved December 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 PMC 4522602 PMID 26234920 Palca J August 3 2015 Snail Venom Yields Potent Painkiller But Delivering The Drug Is Tricky NPR Retrieved August 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 PMID 16845440 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 Archived March 15 2006 at the Wayback 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 PMID 21041028 S2CID 33370759 External links edit Ziconotide Drug Information Portal U S National Library of Medicine Clinical trial number NCT00076544 for Ziconotide Effectiveness and Safety Trial in Patients with Chronic Severe Pain at ClinicalTrials gov Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Ziconotide amp oldid 1214759425, wikipedia, wiki, book, books, library,

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