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Zonisamide

Image:Zonisamide.png

Zonisamide
benzo[d]isoxazol-3-ylmethanesulfonamide
CAS number
68291-97-4		 ATC code
N03AX15
PubChem
5734		 DrugBank
APRD00004
Chemical formula C8H8N2O3S
Molecular weight 212.23
Bioavailability  ?
Metabolism hepatic
Elimination half-life 105 hours in red blood cells, 63 hours in plasma
Time to reach steady state 14 days
Excretion urinary
Pregnancy category USA:C
Legal status Not a controlled substance
Routes of administration Oral

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.[1] 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.[2] Eisai also markets Zonegran® in Asia (China, Taiwan, and fourteen others)[3] and Europe (starting in Germany and the United Kingdom).[4]

Contents

Uses

Approved

Zonisamide is approved in the United States,[5] United Kingdom,[6] for adjunctive treatment of partial seizures in adults and in 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.[7]

Unapproved/Off-Label/Investigational

An open trial on zonisamide in seven Parkinson's disease patients had positive results, according to this 2001 report.[8] Since then, it has been reported to treat the resting tremor that other therapies may leave behind.[9] 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®.[10]

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[11] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[12]

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,[13] or by binding allosterically to GABA receptors like the benzodiazepines and muscimol,[14],[15] 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.[16]

Side effects

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

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.[17]

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, cyclosporin A, miconazole, fluconazole and carbamazepine in descending order.[18]

References and End Notes

  1. ↑ Dainippon Sumitomo Pharma Co., Ltd. (2005). Company History. Company Information. Dainippon Sumitomo Co., Ltd.. URL accessed on 12 November 2005.
  2. ↑ 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. URL accessed on 12 November 2005.
  3. ↑ 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.. URL accessed on 12 November 2005.
  4. ↑ Eisai Co., Ltd. (2005). 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.
  5. ↑ Élan Pharmaceuticals Inc (2003). NDA 20-789/S-001; Zonegran (zonisamide) Capsules 25, 50, 100 mg FDA Approvable Labeling Text - August 22, 2003. (PDF) Zonisamide Approval History. Drugs@FDA. URL accessed on 13 November 2005.
  6. ↑ Eisai Ltd. (2005). Zonegran Summary of Product Characteristics. electronic Medicines Compendium. Medicines.org.uk. URL accessed on 13 November 2005.
  7. ↑ Dainippon Pharmaceutical Co., Ltd. (2004). EXCEGRAN® Tablets 100 mg & EXCEGRAN® Powder 20% (English). URL accessed on March 13, 2006.
  8. ↑ Murata, Miho, Horiuchi Emiko and Kanazawa Ichiro (December 2001). "Zonisamide has beneficial effects on Parkinson's disease patients". Neuroscience Research 41 (4): 397-9. PMID 11755227.
  9. ↑ Nakanishi, I, Kohmoto J, Miwa H, Kondo T (August 2003). "[Effect of zonisamide on resting tremor resistant to antiparkinsonian medication]". No To Shinkei 55 (8): 685-9. PMID 13677302.
  10. ↑ Dainippon Sumitomo Pharma Co., Ltd. (2005). New Drugs in the R&D Pipeline (under development by DSP). (PDF) List of Product Development Project. URL accessed on 21 November 2005.
  11. ↑ Ohmori, S., Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, Kitada M (1998 May 8). "Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells". Biochimica et Biophysica Acta 1380 (3): 297-304. PMID 9555064.
  12. ↑ Stiff, D. D., Robicheau JT, Zemaitis MA. (January 1992). "Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative". Xenobiotica 22 (1): 1-11. PMID 1615700.
  13. ↑ Leppik, Ilo E. (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.
  14. ↑ 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. PMID 1369646.
  15. ↑ Mimaki, T., Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H (1990 March). "[3H]zonisamide binding in rat brain". Medical Journal of Osaka University 39 (1-4): 19-22. PMID 1369647.
  16. ↑ Ueda, Yuto, Doi Taku, Tokumaru Jun, and L. James Willmore (2003 August 19). "Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures". Molecular Brain Research 116 (1-2): 1-6. DOI:10.1016/S0169-328X(03)00183-9.
  17. ↑ Bookheimer, Susan, Schrader, Lara M.; Rausch, Rebecca; Sankar, Raman; Engel, Jerome Jr. (February 2005). "Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications". Epilepsia 46 (2): 236. DOI:10.1111/j.0013-9580.2005.23904.x.
  18. ↑ Nakasa, H., Nakamura H, Ono S, Tsutsui M, Kiuchi M, Ohmori S, Kitada M. (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. PMID 9626925.

External links


Anticonvulsants edit


The content of this page is retrieved from http://en.wikipedia.org/wiki/Zonisamide under GFDL