Zonisamide

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Zonisamide
Zonisamide2DACS.svg
Zonisamide3Dan.gif
Systematic (IUPAC) name
benzo[d]isoxazol-3-ylmethanesulfonamide
Clinical data
Trade names Zonegran
AHFS/Drugs.com monograph
MedlinePlus a603008
Pregnancy cat. D (AU) C (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability ~100%[1]
Protein binding 40%[1]
Metabolism Hepatic through CYP3A4[1]
Half-life 63 hours in plasma[1]
Excretion Renal (62%); Faeces (3%)[1]
Identifiers
CAS number 68291-97-4 YesY
ATC code N03AX15
PubChem CID 5734
DrugBank DB00909
ChemSpider 5532 YesY
UNII 459384H98V YesY
KEGG D00538 YesY
ChEBI CHEBI:10127 YesY
ChEMBL CHEMBL750 YesY
PDB ligand ID ZON (PDBe, RCSB PDB)
Chemical data
Formula C8H8N2O3S 
Mol. mass 212.227 g/mol
Physical data
Melt. point 162 °C (324 °F)
 YesY (what is this?)  (verify)

Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures; infantile spasm, mixed seizure types of Lennox-Gastaut syndrome, myoclonic, and generalized tonic clonic seizure.[2]

Medical uses[edit]

Epilepsy[edit]

Zonisamide is approved in the United States,[3] United Kingdom,[4] and Australia[5] 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.[6] For epilepsy, most studies have used oral zonisamide in daily doses ranging from 200 to 600 milligrams/day, divided in 2 daily doses, adjusted to maintain serum levels of 15 to 40 micrograms/milliliter[7][8][9][10]

Parkinson's[edit]

An open trial on zonisamide in seven Parkinson's disease patients had positive results, according to this 2001 report.[11] Since then, it has been reported to treat the resting tremor that other therapies may leave behind.[12] 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.[13]

Tardive dyskinesia[edit]

In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.[14]

Obesity[edit]

It has also been studied for obesity[15] with significant positive effects on body weight and there are three ongoing clinical trials for this indication.[16][17][18] It is to be sold, when combined with bupropion, under the brand name Empatic.

Migraines[edit]

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[edit]

It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.[19][20]

Adverse effects[edit]

Adverse effects by incidence:[1][21][22]

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:

  • Ecchymosis
  • Hypersensitivity
  • Affect lability
  • Anxiety
  • Insomnia
  • Psychotic disorder* Bradyphrenia
  • Disturbance in attention
  • Nystagmus
  • Paraesthesia
  • Speech disorder
  • Tremor
  • Abdominal pain
  • Constipation
  • Diarrhoea
  • Dyspepsia
  • Nausea
  • Rash
  • Pruritis
  • Alopecia
  • Nephrolithiasis
  • Fatigue
  • Influenza-like illness
  • Pyrexia
  • Oedema peripheral
  • Weight loss

Uncommon (0.1-1% incidence) adverse effects include:

Rare/Very rare (<0.1% incidence) adverse effects include:

Interactions[edit]

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.[23] Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.[1]

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine (in descending order of inhibition) due to their effects on the CYP3A4 enzyme.[24]

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 blocks sodium and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity).[5] It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant, acetazolamide). It is also known to modulate GABAergic and glutamatergic neurotransmission.[5][25][26][27][28]

Pharmacokinetics[edit]

Absorption[edit]

Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8-3.9 hours. Food has no effect on the bioavailability of zonisamide[29]

Metabolism[edit]

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[30] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[31]

History[edit]

Zonisamide was discovered by Uno and colleagues in 1972[32] and launched byDainippon 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.[33] It was marketed by Élan in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide toEisai (エーザイ?) in 2004.[34] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)[35] and Europe (starting in Germany and the United Kingdom).[36]

References[edit]

  1. ^ a b c d e f g "Zonegran® Product Information" (PDF). TGA eBusiness Services. SciGen (Australia) Pty Ltd. 4 April 2013. Retrieved 18 November 2013. 
  2. ^ Comprehensive Pharmacy Review, Leon Shargel, 6th edition, p988
  3. ^ 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. Retrieved {{Subst:Date|2009-08-24|mdy}}. 
  4. ^ Eisai Ltd. (2005). "Zonegran Summary of Product Characteristics". electronic Medicines Compendium. Medicines.org.uk. Retrieved {{Subst:Date|subst=Subst:|2005-11-13|mdy}}. 
  5. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  6. ^ Dainippon Pharmaceutical Co., Ltd. (2004). "EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20%" (PDF). Retrieved {{Subst:Date|subst=Subst:|2006-03-13|mdy}}. 
  7. ^ Shimizu A, Ikoma R, & Shimizu T: Effects and side effects of zonisamide during long-term medication. Curr Ther Res 1990; 47:696-706
  8. ^ Iinuma K, Handa I, Fueki N, et al: Effects of zonisamide (AD-810) on refractory epilepsy in children: special reference to temporal lobe abnormalities. Curr Ther Res 1988; 43:281-282
  9. ^ Sakamoto K, Kurokawa T, Tomita S, et al: Effects of zonisamide in children with epilepsy. Curr Ther Res 1988; 43:378-383
  10. ^ Shimizu A, Yamamoto J, Yamada Y, et al: The antiepileptic effect of zonisamide in patients with refractory seizures. Curr Ther Res 1987; 42:147-155
  11. ^ 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. 
  12. ^ 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. 
  13. ^ Dainippon Sumitomo Pharma Co., Ltd. (2005). "New Drugs in the R&D Pipeline (under development by DSP)" (PDF). List of Product Development Project. Archived from the original on 2006-02-13. Retrieved 2005-11-21. 
  14. ^ Iwata, Y; Irie, S; Uchida, H; Suzuki, T; Watanabe, K; Iwashita, S; Mimura, M (15 April 2012). "Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial". Journal of the Neurological Sciences 315 (1-2): 137–140. doi:10.1016/j.jns.2011.12.010. PMID 22285275. 
  15. ^ 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. 
  16. ^ University of Cincinnati (2005). "Zonegran in the Treatment of Binge Eating Disorder Associated With Obesity". ClinicalTrials.gov. Retrieved 2006-05-04. 
  17. ^ Tuscaloosa Research & Education Advancement Corporation (2005). "Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial". ClinicalTrials.gov. Retrieved 2006-05-04. 
  18. ^ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2006). "Zonisamide for Weight Reduction in Obese Adults". ClinicalTrials.gov. Retrieved 2006-05-04. 
  19. ^ Dr. Brian D. Loftus (2004). "Zonegran". Retrieved 2006-11-29. 
  20. ^ 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. 
  21. ^ "Zonegran 25, 50, 100 mg Hard Capsules". elecronic Medicines Compendium. Eisai Ltd. 8 October 2013. Retrieved 18 November 2013. 
  22. ^ "zonisamide (Rx) - Zonegran". Medscape Reference. WebMD. Retrieved 18 November 2013. 
  23. ^ 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. PMID 15679504. 
  24. ^ 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. 
  25. ^ 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. 
  26. ^ 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. 
  27. ^ 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. 
  28. ^ Ueda, Y; Doi, T; Tokumaru, J; Willmore, J (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. 
  29. ^ http://www.drugbank.ca/drugs/DB00909
  30. ^ 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. doi:10.1016/s0304-4165(97)00156-6. PMID 9555064. 
  31. ^ 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. doi:10.3109/00498259209053097. PMID 1615700. 
  32. ^ 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. Retrieved 2007-11-07. 
  33. ^ Dainippon Sumitomo Pharma Co., Ltd. (2005). "Company History". Company Information. Dainippon Sumitomo Co., Ltd. Archived from the original on 13 February 2006. Retrieved 12 November 2005. 
  34. ^ 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 from the original on 13 February 2006. Retrieved 12 November 2005. 
  35. ^ 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 from the original on 22 February 2006. Retrieved 12 November 2005. 
  36. ^ 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. Retrieved 12 November 2005. 

External links[edit]