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Zonisamide

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Zonisamide
Ball-and-stick model of the zonisamide molecule
Clinical data
Trade namesZonegran, Zonisade
AHFS/Drugs.comMonograph
MedlinePlusa603008
License data
Pregnancy
category
  • AU:D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability~100%[5]
Protein binding40%[5]
MetabolismLiverthroughCYP3A4[5]
Eliminationhalf-life63 hours inplasma[5]
ExcretionKidney(62%); Faeces (3%)[5]
Identifiers
  • benzo[d]isoxazol-3-ylmethanesulfonamide
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.118.526Edit this at Wikidata
Chemical and physical data
FormulaC8H8N2O3S
Molar mass212.22g·mol−1
3D model (JSmol)
Melting point162 °C (324 °F)
  • O=S(=O)(N)Cc2noc1ccccc12
  • InChI=1S/C8H8N2O3S/c9-14(11,12)5-7-6-3-1-2-4-8(6)13-10-7/h1-4H,5H2,(H2,9,11,12)checkY
  • Key:UBQNRHZMVUUOMG-UHFFFAOYSA-NcheckY
(verify)

Zonisamide,sold under the brand nameZonegranamong others, is amedicationused to treat the symptoms ofepilepsyandParkinson's disease.[6][7]Chemically it is asulfonamide.It serves as ananticonvulsantused primarily as anadjunctivetherapy in adults with Parkinson's disease,partial-onset seizures;infantile spasm,mixed seizure types ofLennox–Gastaut syndrome,myoclonicand generalizedtonic clonic seizure.[8]Despite this it is also sometimes used as amonotherapyfor partial-onset seizures.[7][9]

In 2020, it was the 276th most commonly prescribed medication in the United States, with more than 1million prescriptions.[10][11]

Medical uses

[edit]

Epilepsy

[edit]

Zonisamide is approved in the United States,[2][12]and United Kingdom[13]for adjunctive treatment of partial seizures in adults and Japan for both adjunctive and monotherapy for partial seizures (simple, complex, secondarily generalized), generalized (tonic, tonic-clonic (grand mal), and atypical absence) and combined seizures.[14]In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.[9]

Parkinson's disease

[edit]

It has been approved for the treatment of the motor symptoms of Parkinson's disease (PD), as an adjunct tolevodopa,in a few countries such as Japan.[6][7]In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009.[15]In addition, there is clinical evidence that zonisamide in combination with levodopa control of motor symptoms of PD but evidence for the treatment of the non motor symptoms of PD lacking.[16][17]

Adverse effects

[edit]

Adverse effects by incidence:[5][18][19]

Very common (>10% incidence) adverse effects include:

  • Anorexia
  • Somnolence
  • Dizziness
  • Agitation
  • Irritability
  • Confusional state
  • Depression
  • Diplopia
  • Memory impairment
  • Decreased bicarbonate

Common (1–10% incidence) adverse effects include:

Incidence unknown

  • Reproductive toxic effects[20]

Interactions

[edit]

Zonisamide and othercarbonic anhydraseinhibitors such astopiramate,furosemide,andhydrochlorothiazidehave been known to interfere withamobarbital,which has led to inadequate anesthetization during theWada test.[21]Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.[5]

Additionally, the metabolism of zonisamide is inhibited byketoconazole,ciclosporin,miconazole,fluconazoleandcarbamazepine(in descending order of inhibition) due to their effects on theCYP3A4enzyme.[22]

Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.[23]

Mechanism of action

[edit]

Zonisamide is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The precise mechanism by which zonisamide exerts its antiseizure effect is unknown, although it is believed that the drug blockssodiumandT-type calcium channels,which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity).[9]It is also known to be a weakcarbonic anhydraseinhibitor (similarly to the anticonvulsanttopiramate). It is also known to modulateGABAergicandglutamatergicneurotransmission.[9][24][25][26][27]

Pharmacokinetics

[edit]

Absorption

[edit]

Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8–3.9 hours.Bioavailabilityis close to 100% and food has no effect on the bioavailability of zonisamide but may affect the rate of absorption.[28][23]

Metabolism

[edit]

Zonisamide is metabolized mostly by theCYP3A4isoenzyme,but alsoCYP3A7andCYP3A5,[29]to 2-(sulphamoylacetyl)-phenol via reductivecleavageof the 1,2-benzisoxazolering.[30]

History

[edit]

Zonisamide was discovered by Uno and colleagues in 1972[31]and launched byDainippon Sumitomo Pharma(formerly Dainippon Pharmaceutical) in 1989 asExcegranin Japan.[32]It was marketed byÉlanin the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide toEisai Co., Ltd.in 2004.[33]Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)[34]and Europe (starting in Germany and the United Kingdom).[35]

Research

[edit]

Tardive dyskinesia

[edit]

In an open-label trial zonisamide attenuated the symptoms oftardive dyskinesia.[36]

Obesity

[edit]

It has also been studied forobesity[37]with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication.[38][39][40]It was to be sold, when combined withbupropion,under the brand nameEmpatic,until its development was discontinued.[41]

Migraine

[edit]

Zonisamide has been studied for and used as amigrainepreventative medication, whentopiramateis either ineffective or cannot be continued due to side effects.[7]

Bipolar depression

[edit]

It has also been usedoff-labelby psychiatrists as a mood stabilizer to treat bipolar depression.[42][43]

References

[edit]
  1. ^"Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017".Therapeutic Goods Administration (TGA).21 June 2022.Retrieved30 March2024.
  2. ^ab"Zonegran- zonisamide capsule".DailyMed.20 August 2021.Archivedfrom the original on 27 January 2021.Retrieved19 July2022.
  3. ^"Zonisade- zonisamide suspension".DailyMed.15 July 2022.Retrieved21 January2023.
  4. ^"Zonegran EPAR".European Medicines Agency.10 March 2005.Retrieved24 May2024.
  5. ^abcdefg"Zonegran Product Information"(PDF).TGA eBusiness Services.SciGen (Australia) Pty Ltd. 4 April 2013.Archivedfrom the original on 15 October 2018.Retrieved18 November2013.
  6. ^abGrover ND, Limaye RP, Gokhale DV, Patil TR (November–December 2013)."Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease".Indian Journal of Pharmacology.45(6): 547–55.doi:10.4103/0253-7613.121266.PMC3847242.PMID24347760.
  7. ^abcdBrayfield A, ed. (8 March 2016)."Zonisamide: Martindale: The Complete Drug Reference".MedicinesComplete.London, UK: Pharmaceutical Press.Archivedfrom the original on 27 August 2021.Retrieved19 August2017.
  8. ^Souney P, Mutnick A, Shargel L (2007).Comprehensive Pharmacy Review(6th ed.). Williams & Wilkins. p. 988.ISBN9780781765619.OCLC869677890.
  9. ^abcdRossi S, ed. (2013).Australian Medicines Handbook(2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.ISBN978-0-9805790-9-3.
  10. ^"The Top 300 of 2020".ClinCalc.Retrieved7 October2022.
  11. ^"Zonisamide - Drug Usage Statistics".ClinCalc.Retrieved7 October2022.
  12. ^"Drug Approval Package: Zonegran (Zonisomide) NDA #20-789".U.S.Food and Drug Administration(FDA).24 December 1999.Archivedfrom the original on 29 March 2021.Retrieved20 July2022.
  13. ^Eisai Ltd. (2005)."Zonegran Summary of Product Characteristics".electronic Medicines Compendium.Medicines.org.uk. Archived fromthe originalon 8 November 2005.Retrieved13 November2005.
  14. ^Dainippon Pharmaceutical Co., Ltd. (2004)."EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20%"(PDF).Archived fromthe original(PDF)on 2007-09-28.Retrieved13 March2006.
  15. ^Murata M, Hasegawa K, Kanazawa I (January 2007). "Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study".Neurology.68(1): 45–50.doi:10.1212/01.wnl.0000250236.75053.16.PMID17200492.S2CID894677.
  16. ^Grover ND, Limaye RP, Gokhale DV, Patil TR (2013)."Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease".Indian Journal of Pharmacology.45(6): 547–55.doi:10.4103/0253-7613.121266.PMC3847242.PMID24347760.
  17. ^Matsunaga S, Kishi T, Iwata N (2017). "Combination Therapy with Zonisamide and Antiparkinson Drugs for Parkinson's Disease: A Meta-Analysis".Journal of Alzheimer's Disease.56(4): 1229–1239.doi:10.3233/JAD-161068.PMID28157097.
  18. ^"Zonegran 25, 50, 100 mg Hard Capsules".electronic Medicines Compendium.Eisai Ltd. 8 October 2013.Archivedfrom the original on 12 January 2015.Retrieved18 November2013.
  19. ^"zonisamide (Rx) - Zonegran".Medscape Reference.WebMD.Archivedfrom the original on 4 December 2013.Retrieved18 November2013.
  20. ^Karaduman AB, Kilic V, Atli-Eklioglu O, Baysal M, Aydogan-Kılıc G, Ucarcan S, et al. (December 2019). "Reproductive toxic effects and possible mechanisms of zonisamide in male rats".Human & Experimental Toxicology.38(12): 1384–1396.Bibcode:2019HETox..38.1384K.doi:10.1177/0960327119871094.PMID31476894.S2CID201804214.
  21. ^Bookheimer S, Schrader LM, Rausch R, Sankar R, Engel J (February 2005)."Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications".Epilepsia.46(2): 236–43.doi:10.1111/j.0013-9580.2005.23904.x.PMID15679504.S2CID20730895.
  22. ^Nakasa H, Nakamura H, Ono S, Tsutsui M, Kiuchi M, Ohmori S, et al. (April 1998)."Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data".European Journal of Clinical Pharmacology.54(2): 177–83.doi:10.1007/s002280050442.PMID9626925.S2CID6508614.
  23. ^ab"Zonegran 25, 50, 100 mg Hard Capsules".Electronic Medicines Compendium (eMC).Archivedfrom the original on 14 February 2019.Retrieved12 April2017.
  24. ^Leppik IE (December 2004)."Zonisamide: chemistry, mechanism of action, and pharmacokinetics".Seizure.13(Suppl 1): S5–9, discussion S10.doi:10.1016/j.seizure.2004.04.016.PMID15511691.S2CID13458791.
  25. ^Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H (March 1990). "Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain".Medical Journal of Osaka University.39(1–4): 13–7.PMID1369646.
  26. ^Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H (March 1990). "[3H]zonisamide binding in rat brain".Medical Journal of Osaka University.39(1–4): 19–22.PMID1369647.
  27. ^Ueda Y, Doi T, Tokumaru J, Willmore LJ (August 2003). "Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures".Brain Research. Molecular Brain Research.116(1–2): 1–6.doi:10.1016/S0169-328X(03)00183-9.PMID12941455.
  28. ^"Zonisamide".www.drugbank.ca.Archivedfrom the original on 2019-01-31.Retrieved2019-01-31.
  29. ^Ohmori S, Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, et al. (May 1998). "Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells".Biochimica et Biophysica Acta (BBA) - General Subjects.1380(3): 297–304.doi:10.1016/s0304-4165(97)00156-6.PMID9555064.
  30. ^Stiff DD, Robicheau JT, Zemaitis MA (January 1992). "Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative".Xenobiotica.22(1): 1–11.doi:10.3109/00498259209053097.PMID1615700.
  31. ^Shah J, Kent S, Daniel MC (2002-06-15) [1972]."Zonisamide".In René H, Levy RH, Brian SM, Perrucca E (eds.).Antiepileptic Drugs(Fifth ed.). Philadelphia: Lippincott Williams & Wilkins. p. 873.ISBN0-7817-2321-3.Archivedfrom the original on 2021-08-27.Retrieved2007-11-07.
  32. ^Dainippon Sumitomo Pharma Co. Ltd. (2005)."Company History".Company Information.Dainippon Sumitomo Co., Ltd. Archived fromthe originalon 13 February 2006.Retrieved12 November2005.
  33. ^Dainippon Pharmaceutical Co. Ltd. (2004)."Transfer of Rights Agreement for North America and Europe Reached on Zonegran".News Releases for Dainippon Pharmaceutical in 2004.Dainippon Sumitomo Pharma Co., Ltd. Archived fromthe originalon 13 February 2006.Retrieved12 November2005.
  34. ^Dainippon Pharmaceutical Co. Ltd. (2005)."Dainippon Pharmaceutical and Eisai Conclude Agreement for the Development, Manufacture and Marketing of the Anti-Epileptic Agent Zonisamide in Asia".Dainippon Pharmaceutical News Releases for 2005.Dainippon Sumitomo Pharma Co., Ltd. Archived fromthe originalon 22 February 2006.Retrieved12 November2005.
  35. ^Eisai Co. Ltd. (2005)."Eisai Announces Launch of Zonegran (zonisamide), Treatment For Epilepsy In the UK and Germany".Eisai 2005 News Releases.Eisai Co., Ltd. Archived fromthe originalon 2005-10-28.Retrieved12 November2005.
  36. ^Iwata Y, Irie S, Uchida H, Suzuki T, Watanabe K, Iwashita S, et al. (April 2012). "Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial".Journal of the Neurological Sciences.315(1–2): 137–40.doi:10.1016/j.jns.2011.12.010.PMID22285275.S2CID460261.
  37. ^Gadde KM, Franciscy DM, Wagner HR, Krishnan KR (April 2003). "Zonisamide for weight loss in obese adults: a randomized controlled trial".JAMA.289(14): 1820–5.doi:10.1001/jama.289.14.1820.PMID12684361.
  38. ^University of Cincinnati (2005)."Zonegran in the Treatment of Binge Eating Disorder Associated With Obesity".ClinicalTrials.gov.Archivedfrom the original on 2006-10-13.Retrieved2006-05-04.
  39. ^Tuscaloosa Research, Education Advancement Corporation (2005)."Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial".ClinicalTrials.gov.Archivedfrom the original on 2007-05-04.Retrieved2006-05-04.
  40. ^National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2006)."Zonisamide for Weight Reduction in Obese Adults".ClinicalTrials.gov.Archivedfrom the original on 2006-10-11.Retrieved2006-05-04.
  41. ^"Bupropion/zonisamide".AdisInsight.Springer. 20 May 2017.Archivedfrom the original on 19 August 2017.Retrieved19 August2017.
  42. ^Loftus BD (2004)."Zonegran".Archivedfrom the original on 2008-10-23.Retrieved2006-11-29.
  43. ^Hasegawa H (May 2004). "Utilization of zonisamide in patients with chronic pain or epilepsy refractory to other treatments: a retrospective, open label, uncontrolled study in a VA hospital".Current Medical Research and Opinion.20(5): 577–80.doi:10.1185/030079904125003313.PMID15140322.S2CID43580909.
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