Zonisamide
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| Non-proprietary name | Zonisamide | ||||||||||||
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1,2-benzisoxazole-3-methanesulfonamide |
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| Molecular formula | C 8 H 8 N 2 O 3 S | ||||||||||||
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| Molar mass | 212.2 g · mol -1 | ||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||
Zonisamide is a drug from the group of anticonvulsants that is used in the additional treatment of partial epileptic seizures . Zonisamide works by reducing the excitability of nerve cells . As an active ingredient in a drug, zonisamide was first marketed in 1989 by Dainippon in Japan under the name Excegran . Since 2005, zonisamide has also been marketed in the EU and Switzerland under the trade name Zonegran ® .
Clinical information
Approved areas of application
Zonisamide is approved as an add-on therapy for the treatment of adult patients with partial (focal) seizures with or without secondary generalization in the EU and Switzerland.
Type and duration of application
According to the approval, zonisamide can only be used in addition to existing treatment with other anticonvulsants. The drug is taken orally.
Adverse effects (side effects)
Psychological side effects occur most frequently (excitability, irritability, confusion , depression ). There are also diseases of the nervous system ( ataxia , dizziness, memory impairment, drowsiness), diplopia and anorexia . The most serious side effects observed were: allergic reactions, seizures, neuroleptic malignant syndrome, rhabdomyolysis and kidney stones . The very common psychiatric and neurological side effects should make the use of zonisamide more difficult. The frequent occurrence of allergic reactions and the occasional occurrence of kidney stones is related to the material properties of zonisamide (sulfonamide, carbonic anhydrase inhibitor).
Pharmacological properties
Mechanism of action (pharmacodynamics)
The mechanism of action of zonisamide is not fully understood. It appears to act on voltage-dependent sodium and calcium channels and thereby interrupt the synchronized discharge of nerve cells , thereby reducing the spread of convulsive discharges. Zonisamide is also a carbonic anhydrase inhibitor . Carbonic anhydrase inhibitors lead to over-acidification of the tissue and thus also reduce the excitability of nerve cells.
Chemical information
Zonisamide is a benzisoxazole derivative and sulfonamide . It has hardly any chemical similarities to other common anticonvulsants, but like topiramate or sultiam it contains a sulfonamide group. Further structural similarities exist with benzisoxazole derivatives such. B. the neuroleptic risperidone .
History
Zonisamide was synthesized and characterized by Dainippon in the 1970s . The clinical development was initially started in collaboration between Dainippon and Parke-Davis (now part of Pfizer ) and led to the approval of zonisamide in Japan ( Excegran ) in 1989 . Parke-Davis left the collaboration in 1987. The main reason Parke-Davis left was the frequent occurrence of kidney stones . Dainippon continued the development outside of Japan and in 1997 sold the rights outside of Japan to Athena Neuroscience (now part of Elan Corporation ). A registration application submitted in Europe in 1997 was withdrawn by Athena in 1998 due to deficiencies in the registration documents. In 2000 it was approved in the USA . In 2004, Élan transferred the rights for Europe and the USA to Eisai . The approval in Europe followed in 2005, 16 years after the initial approval in Japan.
Studies
The European approval is based on four double-blind, placebo-controlled studies in around 500 patients who received zonisamide once or twice daily for a period of up to 24 weeks. These studies show that sustained efficacy can be expected at doses of 300 to 500 mg / day. Another five open studies on around 700 people over a period of seven years demonstrate long-term safety.
The manufacturer has committed itself to the European approval authority to further investigate the neurological effects in older patients and to a development program for children and adolescents.
Individual evidence
- ↑ a b Data sheet Zonisamide sodium salt from Sigma-Aldrich , accessed on April 26, 2011 ( PDF ).
- ↑ Zonegran European Public Assessment Report (EPAR). European Medicines Agency, accessed January 6, 2016 .
- ↑ Y. Masuda, Y. Utsui, Y. Shiraishi et al .: Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine, and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant or neurotoxic effects in experimental animals. In: Epilepsia. 20, 1979, pp. 623-633. PMID 115675 .
- ↑ MJ Brodie, R. Duncan, H. Vespignani et al .: Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures. In: Epilepsia. 46, 2005, pp. 31-41. PMID 15660766 .
