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Zonisamide
Systematic (IUPAC) name
1,2-benzisoxazole-3-methanesulfonamide
Identifiers
CAS number 68291-97-4
ATC code N03AX15
PubChem 5734
DrugBank APRD00004
Chemical data
Formula C8H8N2O3S 
Mol. mass 212.227 g/mol
Physical data
Melt. point 162 °C (324 °F)
Pharmacokinetic data
Bioavailability  ?
Protein binding 40%
Metabolism Hepatic
Half life 105 hours in red blood cells, 63 hours in plasma
Excretion Renal
Therapeutic considerations
Pregnancy cat. C(US)
Legal status Prescription only
Routes Oral
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Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures for adults; infantile spasm, mixed seizure types of Lennox-Gastaut syndrome, myoclonic, and generalized tonic clonic seizure[1].

Contents

History

Zonisamide was discovered by Uno and colleagues in 1972[2] and launched by Dainippon Sumitomo Pharma (大日本住友製薬 Dainippon Sumitomo Seiyaku?) (formerly Dainippon Pharmaceutical (大日本製薬 Dainippon Seiyaku?)) 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]

Indications

Epilepsy

Zonisamide is approved in the United States,[7] United Kingdom,[8] 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.[9]

Parkinson's

An open trial on zonisamide in seven Parkinson's disease patients had positive results, according to this 2001 report.[10] Since then, it has been reported to treat the resting tremor that other therapies may leave behind.[11] By early November 2005, Dainippon Sumitomo had filed a NDA for the use of zonisamide in Parkinson's disease; it is to be marketed as Tremode.[12]

Obesity

It has also been studied for obesity[13] with significant positive effects on body weight and there are three ongoing clinical trials for this indication.[14][15][16] See Empatic

Migraines

Zonisamide has been studied for and used as a migraine preventative medication, and has also been shown to be effective in some cases of neuropathic pain.

Bipolar depression

It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.[17][18]

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[19] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[20]

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,[21] or by binding allosterically to GABA receptors like the benzodiazepines and muscimol,[22],[23] 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.[24]

Side effects

The most common side effects include drowsiness, loss of appetite, dizziness, headache, nausea, and agitation/irritability. Zonisamide has also been associated with hypohidrosis.[25]

On February 23, 2009 the U.S. Food and Drug Administration (FDA) issued a warning that zonisamide can cause metabolic acidosis in some patients. It is now recommended that serum bicarbonate levels are assessed before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms.[26]

Interactions

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.[27]

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine in descending order.[28]

References

  1. ^ Comprehensive Pharmacy Review, Leon Shargel, 6th edition, p988
  2. ^ Shah, Jaymin; Kent Shellenberger, Daniel M. Canafax (2002-06-15) [1972]. "Zonisamide". in René H. Levy, Richard H. Mattson, Brian S. Meldrum, and Emilio Perrucca (ed.). Antiepileptic Drugs (Fifth ed.). Philadelphia: Lippincott Williams & Wilkins. p. 873. ISBN 0-7817-2321-3. http://books.google.com/books?id=HAOY0qG-vAYC&pg=PA873&dq=zonisamide+synthesized&sig=iVrgUS51CNUo4qbjPMSt1sQV2pY#PPA873,M1. Retrieved 2007-11-07. 
  3. ^ Dainippon Sumitomo Pharma Co., Ltd. (2005). "Company History". Company Information. Dainippon Sumitomo Co., Ltd.. http://www.ds-pharma.co.jp/english/profile/history.html. Retrieved 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. Dainippon Sumitomo Pharma Co., Ltd. http://www.ds-pharma.co.jp/english/news/dainippon_2004.html. Retrieved 12 November 2005. 
  5. ^ 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.. http://www.ds-pharma.co.jp/english/news/dainippon_2005/no_002.html. Retrieved 12 November 2005. 
  6. ^ 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.. http://www.eisai.co.jp/enews/index.html. Retrieved 12 November 2005. 
  7. ^ Élan Pharmaceuticals Inc ({{Subst:Date|subst=Subst:|2003-08-22|mdy}}). "NDA 20-789/S-001; Zonegran (zonisamide) Capsules 25, 50, 100 mg FDA Approvable Labeling Text" (PDF). Zonisamide Approval History. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20789scm001_zonegran_lbl.pdf. Retrieved {{Subst:Date|2009-08-24|mdy}}. 
  8. ^ Eisai Ltd. (2005). "Zonegran Summary of Product Characteristics". electronic Medicines Compendium. Medicines.org.uk. http://emc.medicines.org.uk/. Retrieved {{Subst:Date|subst=Subst:|2005-11-13|mdy}}. 
  9. ^ Dainippon Pharmaceutical Co., Ltd. (2004). "EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20%" (PDF). http://www.e-search.ne.jp/~jpr/PDF/DAINIP03.PDF. Retrieved {{Subst:Date|subst=Subst:|2006-03-13|mdy}}. 
  10. ^ Murata, Miho; Horiuchi Emiko and Kanazawa Ichiro (December 2001). "Zonisamide has beneficial effects on Parkinson's disease patients". Neuroscience Research 41 (4): 397–9. doi:10.1016/S0168-0102(01)00298-X. PMID 11755227. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=11755227&dopt=ExternalLink. 
  11. ^ 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. 
  12. ^ Dainippon Sumitomo Pharma Co., Ltd. (2005). "New Drugs in the R&D Pipeline (under development by DSP)" (PDF). List of Product Development Project. http://www.ds-pharma.co.jp/english/rd/item.html. Retrieved 2005-11-21. 
  13. ^ Gadde, Kishore M.; Deborah M. Franciscy, H. Ryan Wagner, II; K. Ranga R. Krishnan (April 2003). "Zonisamide for Weight Loss in Obese Adults: A Randomized Controlled Trial". Journal of the American Medical Association 289 (14): 1820–1825. doi:10.1001/jama.289.14.1820. PMID 12684361. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12684361&dopt=ExternalLink. 
  14. ^ University of Cincinnati (2005). "Zonegran in the Treatment of Binge Eating Disorder Associated With Obesity". ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT00221442. Retrieved 2006-05-04. 
  15. ^ Tuscaloosa Research & Education Advancement Corporation (2005). "Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial". ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT00203450. Retrieved 2006-05-04. 
  16. ^ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2006). "Zonisamide for Weight Reduction in Obese Adults". ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT00275834. Retrieved 2006-05-04. 
  17. ^ Dr. Brian D. Loftus (2004). "Zonegran". http://www.bellaireneurology.com/seizure/epil_trt_zonegran.html. Retrieved 2006-11-29. 
  18. ^ Hasegawa, Hisanori (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". Curr Med Research Opinion 20 (5): 577–580. doi:10.1185/030079904125003313. PMID 15140322. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=15140322&dopt=ExternalLink. 
  19. ^ Ohmori, S.; Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, Kitada M (1998-05-08). "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. 
  20. ^ 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. 
  21. ^ 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. PMID 15511691. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=15511691&dopt=ExternalLink. 
  22. ^ 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. 
  23. ^ 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. PMID 1369647. 
  24. ^ Ueda, Yuto; Doi Taku, Tokumaru Jun, and L. James Willmore (2003-08-19). "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. PMID 12941455. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12941455&dopt=ExternalLink. 
  25. ^ Miller JL, Hurley HJ (2007). "Diseases of the Eccrine and Apocrine Sweat Glands". in Bolognia, Jean L.. Dermatology. St. Louis: Mosby. pp. 539. ISBN 1-4160-2999-0. 
  26. ^ "FDA alert-Zonisamide". February 23, 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm095251.htm. Retrieved February 24, 2009. 
  27. ^ 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. http://www.blackwell-synergy.com/doi/full/10.1111/j.0013-9580.2005.23904.x. 
  28. ^ 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. doi:10.1007/s002280050442. PMID 9626925. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=9626925&dopt=ExternalLink. 

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