Zonisamide

Drugbox
IUPAC_name = 1,2-benzisoxazole-3-methanesulfonamide

---

CAS_number=68291-97-4
ATC_prefix=N03
ATC_suffix=AX15
ATC_supplemental=
PubChem=5734
DrugBank=APRD00004
C = 8 | H = 8 | N = 2 | O = 3 | S = 1
molecular_weight = 212.227 g/mol
melting_point = 162
bioavailability= ?
protein_bound = 40%
metabolism = Hepatic
elimination_half-life=105 hours in red blood cells, 63 hours in plasma
excretion = Renal
pregnancy_US = C
legal_status = Rx-only
routes_of_administration= Oral

Zonisamide is a sulfonamide anticonvulsant approved for use as an therapy in adults with partial-onset seizures.

History

Zonisamide was discovered by Uno and colleagues in 1972cite book |last=Shah |first=Jaymin |coauthors=Kent Shellenberger, Daniel M. Canafax |editor=René H. Levy, Richard H. Mattson, Brian S. Meldrum, and Emilio Perrucca (ed.) |title=Antiepileptic Drugs |origyear=1972 |url= |format= |accessdate=2007-11-07 |edition=Fifth |date=2002-06-15 |publisher=Lippincott Williams& Wilkins |location=Philadelphia |isbn=0-7817-2321-3 |oclc= |doi= |id= |pages=873 |chapter=Zonisamide |chapterurl=http://books.google.com/books?id=HAOY0qG-vAYC&pg=PA873&dq=zonisamide+synthesized&sig=iVrgUS51CNUo4qbjPMSt1sQV2pY#PPA873,M1 |quote= ] and launched by nihongo|Dainippon Sumitomo Pharma|大日本住友製薬|Dainippon Sumitomo Seiyaku (formerly nihongo|Dainippon Pharmaceutical|大日本製薬|Dainippon Seiyaku) in 1989 as Excegran in Japan.cite web
author=Dainippon Sumitomo Pharma Co., Ltd.
year=2005 | title=Company History | work=Company Information
publisher=Dainippon Sumitomo Co., Ltd. | url=http://www.ds-pharma.co.jp/english/profile/history.html
accessmonthday=12 November | accessyear=2005] It was marketed by Élan in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to nihongo|Eisai|エーザイ in 2004.cite web
author = Dainippon Pharmaceutical Co., Ltd. | year = 2004 | url = http://www.ds-pharma.co.jp/english/news/dainippon_2004.html
title = Transfer of Rights Agreement for North America and Europe Reached on Zonegran | work = News Releases for Dainippon Pharmaceutical in 2004
publisher = Dainippon Sumitomo Pharma Co., Ltd | accessmonthday=12 November | accessyear = 2005] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)cite web
author=Dainippon Pharmaceutical Co., Ltd.
year = 2005
title = Dainippon Pharmaceutical and Eisai Conclude Agreement for the Development, Manufacture and Marketing of the Anti-Epileptic Agent Zonisamide in Asia | work = Dainippon Pharmaceutical News Releases for 2005 | publisher=Dainippon Sumitomo Pharma Co., Ltd. | url = http://www.ds-pharma.co.jp/english/news/dainippon_2005/no_002.html | accessmonthday=12 November | accessyear = 2005] and Europe (starting in Germany and the United Kingdom).cite web | author=Eisai Co., Ltd.
year=2005 | title=Eisai Announces Launch of Zonegran (zonisamide), Treatment For Epilepsy In the UK and Germany
work=Eisai 2005 News Releases | publisher=Eisai Co., Ltd. | url=http://www.eisai.co.jp/enews/index.html | accessmonthday=12 November | accessyear=2005]

Indications

Epilepsy

Zonisamide is approved in the United States,cite web
author = Élan Pharmaceuticals Inc | year = 2003 | url = http://www.fda.gov/cder/foi/label/2003/20789scm001_zonegran_lbl.pdf
title = NDA 20-789/S-001; Zonegran (zonisamide) Capsules 25, 50, 100 mg FDA Approvable Labeling Text - August 22 2003
format = PDF | work = Zonisamide Approval History
publisher = Food and Drug Administration | accessdate = 2005-11-13] United Kingdom,cite web
author=Eisai Ltd.
year=2005
title=Zonegran Summary of Product Characteristics
work=electronic Medicines Compendium | publisher=Medicines.org.uk
accessdate = 2005-11-13
url=http://emc.medicines.org.uk/] 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.cite web | author = Dainippon Pharmaceutical Co., Ltd. | year = 2004 | url = http://www.e-search.ne.jp/~jpr/PDF/DAINIP03.PDF | title = EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20% (English) | accessdate = 2006-03-13|format=PDF]

Parkinson's

An open trial on zonisamide in seven Parkinson's disease patients had positive results, according to this 2001 report.cite journal
first = Miho
last = Murata
coauthors = Horiuchi Emiko and Kanazawa Ichiro
year = 2001
month = December
title = Zonisamide has beneficial effects on Parkinson's disease patients
journal = Neuroscience Research
volume = 41
issue = 4
pages = 397–9
pmid = 11755227
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=11755227&dopt=ExternalLink
doi = 10.1016/S0168-0102(01)00298-X] Since then, it has been reported to treat the resting tremor that other therapies may leave behind.cite journal
first = I
last = Nakanishi
coauthors = Kohmoto J, Miwa H, Kondo T
year = 2003
month = August
title = [Effect of zonisamide on resting tremor resistant to antiparkinsonian medication]
journal = No To Shinkei
volume = 55
issue = 8
pages = 685–9
pmid = 13677302] 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.cite web
author=Dainippon Sumitomo Pharma Co., Ltd.
year=2005
title=New Drugs in the R&D Pipeline (under development by DSP)
format = PDF | work=List of Product Development Project
url=http://www.ds-pharma.co.jp/english/rd/item.html
accessdate = 2005-11-21]

Obesity

It has also been studied for obesitycite journal | first = Kishore M. | last = Gadde | coauthors = Deborah M. Franciscy, H. Ryan Wagner, II; K. Ranga R. Krishnan | month = April | year = 2003 | title = Zonisamide for Weight Loss in Obese Adults: A Randomized Controlled Trial | journal = Journal of the American Medical Association | volume = 289 | issue = 14 | pages = 1820–1825 | pmid = 12684361 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12684361&dopt=ExternalLink | doi = 10.1001/jama.289.14.1820] with significant positive effects on body weight and there are three ongoing clinical trials for this indication.cite web | author = University of Cincinnati | year = 2005 | title = Zonegran in the Treatment of Binge Eating Disorder Associated With Obesity | work = ClinicalTrials.gov | url = http://clinicaltrials.gov/show/NCT00221442 | accessdate = 2006-05-04] cite web | author = Tuscaloosa Research & Education Advancement Corporation | year = 2005 | title = Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial | work = ClinicalTrials.gov | url = http://clinicaltrials.gov/show/NCT00203450 | accessdate = 2006-05-04] cite web | author = National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | year = 2006 | title = Zonisamide for Weight Reduction in Obese Adults | work = ClinicalTrials.gov | url = http://clinicaltrials.gov/show/NCT00275834 | accessdate = 2006-05-04]

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.Cite web|url=http://www.loftusmd.com/Articles/AED/zonegran.html|title=Zonegran|accessdate=2006-11-29|year=2004|author=Dr. Brian D. Loftus] [cite journal
first = Hisanori
last = Hasegawa
coauthors =
year = 2004
month = May
title = Utilization of zonisamide in patients with chronic pain or epilepsy refractory to other treatments: a retrospective, open label, uncontrolled study in a VA hospital
journal = Curr Med Research Opinion
volume = 20
issue = 5
pages = 577–580
pmid = 15140322
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=15140322&dopt=ExternalLink
doi = 10.1185/030079904125003313]

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,cite journal
first = S.
last = Ohmori
coauthors = Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, Kitada M
date = 1998 May 8
title = Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells
journal = Biochimica et Biophysica Acta
volume = 1380
issue = 3
pages = 297–304
pmid = 9555064] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.cite journal
first = D. D.
last = Stiff
coauthors = Robicheau JT, Zemaitis MA.
year = 1992
month = January
title = Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative
journal= Xenobiotica
volume = 22
issue = 1
pages = 1–11
pmid = 1615700]

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,cite journal
first = Ilo E.
last = Leppik
year = 2004
month = December
title = Zonisamide: chemistry, mechanism of action, and pharmacokinetics
journal = Seizure
volume = 13
issue = Suppl 1
pages = S5–9; discussion S10
doi = 10.1016/j.seizure.2004.04.016
pmid = 15511691
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=15511691&dopt=ExternalLink] or by binding allosterically to GABA receptors like the benzodiazepines and muscimol,cite journal
first = T.
last = Mimaki
coauthors = Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H
year = 1990
month = March
title = Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain
journal = Medical Journal of Osaka University
volume = 39
issue = 1-4
pages = 13–7
pmid = 1369646] ^,cite journal
first = T.
last = Mimaki
coauthors = Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H
date = March
month = 1990
title = [3H] zonisamide binding in rat brain
journal = Medical Journal of Osaka University
volume = 39
issue = 1-4
pages = 19–22
pmid = 1369647] 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.cite journal
first = Yuto
last = Ueda
coauthors = Doi Taku, Tokumaru Jun, and L. James Willmore
date = 2003 August 19
title = Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures
journal = Molecular Brain Research
volume = 116
issue = 1-2
pages = 1–6
doi = 10.1016/S0169-328X(03)00183-9
pmid = 12941455
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12941455&dopt=ExternalLink]

ide effects

The most common side effects include drowsiness, loss of appetite, dizziness, headache, nausea, and agitation/irritability.

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.cite journal
first = Susan
last = Bookheimer
coauthors = Schrader, Lara M.; Rausch, Rebecca; Sankar, Raman; Engel, Jerome Jr.
year = 2005
month = February
title = Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications
journal = Epilepsia
volume = 46
issue = 2
pages = 236
doi = 10.1111/j.0013-9580.2005.23904.x
url = http://www.blackwell-synergy.com/doi/full/10.1111/j.0013-9580.2005.23904.x]

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine in descending order.cite journal
first = H.
last = Nakasa
coauthors = Nakamura H, Ono S, Tsutsui M, Kiuchi M, Ohmori S, Kitada M.
year = 1998
month = April
title = Prediction of drug-drug interactions of zonisamide metabolism in humans from "in vitro" data
journal = European Journal of Clinical Pharmacology
volume = 54
issue = 2
pages = 177–83
pmid = 9626925
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=9626925&dopt=ExternalLink
doi = 10.1007/s002280050442]

References and end notes

External links

* [http://www.zonegran.com/ Official Zonegran Website]
* [http://med.ds-pharma.co.jp/medicine/ryouiki/seishin/doc/excegran_tabpow_tenpu.pdf Dainippon Sumitomo Prescribing Information for Excegran] (Japanese version)
* [http://www.ds-pharma.co.jp/english/ Official Dainippon Sumitomo Pharma Website] (English version)