Medicinal effect of zonisamide for seizures

2018-08-18

Introduction 

Zonisamide, sold as brand name Zonegran, is a derivative of 3-(sulfamoylmethyl)-l,2-benzisoxazole. It is a member of novel class of anticonvulsants, and has been proven effective in the treatment of epilepsy, Parkinson's disease, tardive dyskinesia, obesity, migraine and bipolar depression. Its efficacy and safety in the treatment of partial seizures were established in three pivotal clinical trials in the United States and Europe.

Pharmacologic action

A broad mechanistic profile has been exhibited by zonisamide in various animal studies. At the presynaptic level, it increases the release of γ-aminobutyric acid (GABA), while decreasing glutamate release and also acts by prolongation of the inactive state of voltage gated sodium and calcium channels. Although the precise molecular mechanism of action is not known, it has been suggested that zonisamide appears to protect neurons from oxidative damage and to stabilize the neuronal membrane. In another study, zonisamide has shown neuroprotection by increasing glutathione (GSH) levels and enhanced proliferation of astroglial cells. The involvement of apoptosis has been identified as the major mechanism responsible for seizures-induced neuronal death. Caspases play a key role in initiation as well as execution of the apoptotic cell death pathway. Seizures-induced mitochondrial damage results in cytochrome-C release, which in turn attaches to apoptotic protease activating factor-1 (Apaf-1) and triggers caspase-9 (an initiator caspase) activation. Activated caspase-9 further activates executioner caspase-3 and -7.

Function

Zonisamide is an approved antiepileptic drug for the treatment of refractory partial seizures. Clinical experience with zonisamide in Japan has documented its efficacy in the treatment of partial seizures (partial-onset generalised tonic-clonic, simple partial and/or complex partial seizures), and to a more variable extent, generalised tonic-clonic, generalised tonic (mainly seen in symptomatic generalised epilepsies including Lennox-Gastaut Syndrome) and compound/combination seizures (including those refractory to treatment with other antiepileptic drugs). Zonisamide has demonstrated efficacy equivalent to that of carbamazepine in patients with (mainly) partial seizures, and to that of valproic acid in a small study of children (n=32) with generalised seizures.

Pharmacokinetics and metabolism

Zonisamide has a 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. Urinalysis has revealed that zonisamide undergoes biotransformation by acetylation and also cleavage of the isoxazole ring followed by conjugation with glucuronic acid.

References

1. Baldeep Kumar, Bikash MedhiEmail, Manish Modi, Biman Saikia, Savita Verma Attri, Ajay Patial. A mechanistic approach to explore the neuroprotective potential of zonisamide in seizures. Inflammopharmacol, 2018, 1-7.

2. Giuseppina De Simone, Anna Di Fiore, Valeria Menchise, Carlo Pedone, Jochen Antel, Angela Casini, Andrea Scozzafava, Michael Wurl, Claudiu T. Supuran. Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies. Bioorganic & Medicinal Chemistry Letters, 2005, 15, 2315-2320.

3. Angus Wilfong, Rebecca Schultz. Zonisamide for absence seizures. Epilepsy Research, 2005, 64, 31-34.

4. Neeta D. Grover, Ramachandra P. Limaye, Dilip V. Gokhale, Tatyasaheb R. Patil. Zonisamide: A review of the clinical and experimental evidence for its use in Parkinson's disease. Indian Journal of Pharmacology, 2013, 45(6), 547-553.

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