Zonisamide

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

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History

Zonisamide was discovered by Uno and colleagues in 1972^[1] 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.^[2] 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, Eisai^?) in 2004.^[3] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)^[4] and Europe (starting in Germany and the United Kingdom).^[5]

Indications

Epilepsy

Zonisamide is approved in the United States,^[6] United Kingdom,^[7] 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.^[8]

Parkinson's

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]

Obesity

It has also been studied for obesity^[12] with significant positive effects on body weight and there are three ongoing clinical trials for this indication.^[13][14][15]

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. It has also been used by psychiatrists as a mood stabilizer.^[16][17]

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,^[18] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.^[19]

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,^[20] or by binding allosterically to GABA receptors like the benzodiazepines and muscimol,^[21],[22] 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.^[23]

Side 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.^[24]

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine in descending order.^[25]

References and end notes