Zonisamide: Encyclopedia - Zonisamide

Zonisamide

Zonisamide

Zonisamide (brand name Zonegran®) is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures. It was discovered by researchers at Dainippon Sumitomo Pharma (大日本住友製薬: Dainippon Sumitomo Seiyaku (formerly Dainippon Pharmaceutical (大日本製薬: Dainippon Seiyaku)), who launched it in 1989 as Excegran® in Japan.^[3] It was marketed by Élan in the United States starting in 2000 as Zonegran®, before Élan transferred their interests in zonisamide to Eisai (エーザイ) in 2004.^[4] Eisai also markets Zonegran® in Asia (China, Taiwan, and fourteen others)^[5] and Europe (starting in Germany and the United Kingdom).^[6]

Zonisamide - Uses

Zonisamide - Approved

Zonisamide is approved in the United States,^[7] United Kingdom,^[8] and Japan for adjunctive treatment of partial seizures in adults.

Zonisamide - Unapproved/Off-Label/Investigational

An open trial on zonisamide in seven Parkinson's disease patients had positive results, according to this 2001 report.^[9] Since then, it has been reported to treat the resting tremor that other therapies may leave behind.^[10] By early November of 2005, Dainippon Sumitomo had filed a NDA for the use of zonisamide in Parkinson's disease; it is to be marketed as Tremode®.^[11]

Zonisamide - Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,^[12] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.^[13]

Zonisamide - Mechanism of Action

The exact mechanism of action is not known for zonisamide. According to Leppik, while zonisamide may be a carbonic anhydrase inhibitor like acetazolamide, this is not one of the primary mechanisms of action, which might be blocking repetitive firing of voltage-gated sodium channels and reduction of T-type calcium channel currents,^[14] or by binding allosterically to GABA receptor like the benzodiazepines and muscimol,^[15][16] or increasing the levels of the glutamate transport protein in the brain while decreasing the amount of GABA transport protein, in other words, inhibiting the uptake of the inhibitory neurotransmitter GABA while enhancing the uptake of the excitatory neurotransmitter glutamate.^[17]

Zonisamide - Side Effects

The most common side effects include loss of appetite/weight loss, drowsiness, kidney stones, and dizziness.

Zonisamide - Interactions with Other Medication

Zonisamide and other carbonic anhydrase inhibitors such as topiramate, furosemide, and hydrochlorothiazide have been known to interfere with amobarbital, which has led to inadequate anesthetization during the Wada test.^[18]

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, cyclosporin A, miconazole, fluconazole and carbamazepine in descending order.^[19]

Zonisamide - References and End Notes

1. ^  PubChem Substance: Zonisamide National Center for Biotechnology Information.
2. ^  New ATC codes and DDDs WHO Collaborating Centre for Drug Statistics Methodology. Oslo, May 2005
3. ^  Dainippon Sumitomo Pharma Co., Ltd.. Company History. Company Information. Dainippon Sumitomo Co., Ltd.. URL accessed on 12 November 2005.
4. ^  Dainippon Pharmaceutical Co., Ltd. (2004) Transfer of Rights Agreement for North America and Europe Reached on Zonegran^®, News Releases for Dainippon Pharmaceutical in 2004 [online] Dainippon Sumitomo Pharma Co., Ltd.. Available from: http://www.ds-pharma.co.jp/english/news/dainippon_2004.html Accessed on 12 November 2005.
5. ^  Dainippon Pharmaceutical Co., Ltd.. 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.. URL accessed on 12 November 2005.
6. ^  Eisai Co., Ltd.. Eisai Announces Launch of Zonegran(R)(zonisamide), Treatment For Epilepsy In the U.K. and Germany. Eisai 2005 News Releases. Eisai Co., Ltd.. URL accessed on 12 November 2005.
7. ^  Élan Pharmaceuticals Inc. (2003) NDA 20-789/S-001; Zonegran (zonisamide) Capsules 25, 50, 100 mg FDA Approvable Labeling Text - August 22, 2003, Zonisamide Approval History [online] Drugs@FDA. Available from: http://www.fda.gov/cder/foi/label/2003/20789scm001_zonegran_lbl.pdf Accessed on 13 November 2005. (PDF)
8. ^  Eisai Ltd.. Zonegran Summary of Product Characteristics. electronic Medicines Compendium. Medicines.org.uk. URL accessed on 13 November 2005.
9. ^  Murata M, Horiuchi E, Kanazawa I. "Zonisamide has beneficial effects on Parkinson's disease patients." Neuroscience Research. 2001 Dec;41(4):397-9. PMID 11755227 Fulltext
10. ^  Nakanishi I, Kohmoto J, Miwa H, Kondo T. "[Effect of zonisamide on resting tremor resistant to antiparkinsonian medication]" [Article in Japanese] No To Shinkei. 2003 Aug;55(8):685-9. PMID 13677302
11. ^  Dainippon Sumitomo Pharma Co., Ltd.. New Drugs in the R&D Pipeline (under development by DSP). List of Product Development Project. URL accessed on 21 November 2005. (PDF)
12. ^  Ohmori S, Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, Kitada M. "Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells." Biochimica et Biophysica Acta. 1998 May 8;1380(3):297-304. PMID 9555064
13. ^  Stiff DD, Robicheau JT, Zemaitis MA. "Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative." Xenobiotica. 1992 Jan;22(1):1-11. PMID 1615700
14. ^  Leppik IE. "Zonisamide: chemistry, mechanism of action, and pharmacokinetics." Seizure. 2004 Dec;13 Suppl 1:S5-9; discussion S10. PMID 15511691 Fulltext
15. ^  Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H. "Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain." Medical Journal of Osaka University. 1990 Mar;39(1-4):13-7. PMID 1369646
16. ^  Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H. "[3H]zonisamide binding in rat brain." Medical Journal of Osaka University. 1990 Mar;39(1-4):19-22. PMID 1369647
17. ^  Ueda Y, Doi T, Tokumaru J, Willmore LJ. "Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures." Brain Research. Molecular Brain Research. 2003 Aug 19;116(1-2):1-6. PMID 12941455 Fulltext
18. ^  Bookheimer S, Schrader LM, Rausch R, Sankar R, Engel J Jr. "Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications." Epilepsia. Volume 46 Issue 2 Page 236 - February 2005 PMID 15679504 Fulltext
19. ^  Nakasa H, Nakamura H, Ono S, Tsutsui M, Kiuchi M, Ohmori S, Kitada M. "Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data." European Journal of Clinical Pharmacology. 1998 Apr;54(2):177-83. PMID 9626925 Fulltext options

{Lamotrigine}

{Primidone}

{Potassium bromide}

{Paraldehyde}

{Valpromide} {Valnoctamide}

{Topiramate}

{Beclamide}

{Stiripentol}

{Carbamazepine} {Oxcarbazepine}

{Pheneturide} {Phenacemide}

{Gabapentin} {Vigabatrin} {Progabide} {Pregabalin}

{Trimethadione} {Paramethadione} {Ethadione}

{Brivaracetam} {Levetiracetam} {Nefiracetam} {Seletracetam}

{Ethotoin} {Phenytoin} {Mephenytoin} {Fosphenytoin}

{Acetazolamide} {Sultiame} {Methazolamide} {Zonisamide}

{Felbamate} {Meprobamate} {Emylcamate} {Phenprobamate}

{Ethosuximide} {Phensuximide} {Mesuximide}

{Valproic acid} {Sodium valproate} {Valproate semisodium} {Tiagabine}

{Amobarbital} {Aprobarbital} {Butabarbital} {Butalbital} {Hexobarbital} {Mephobarbital} {Pentobarbital} {Phenobarbital} {Phenytoin} {Secobarbital} {Sodium thiopental} {Talbutal} {Thiobarbital}

{Diazepam} {Oxazepam} {Nitrazepam} {Temazepam} {Lorazepam} {Flunitrazepam} {Bromazepam} {Clobazam} {Clonazepam} {Chlordiazepoxide} {Triazolam} {Midazolam} {Alprazolam} {Estazolam} {Quazepam} {Clorazepate} {Medazepam} {Prazepam} {Flurazepam}

Adapted from the Wikipedia article "Zonisamide", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki