3-Sulfamoylmethyl-l, 2-benzisoxazole, a new type of anticonvulsant drug: Pharmacological profile

Masuda, Y.; Karasawa, Tadahiko; Shiraishi, Yuko; Hori, Misako; Yoshida, Kouichi; Shimizu, Masanao

doi:10.1016/s0021-5198(19)66864-2

Cited by 9 publications

(7 citation statements)

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“…8,9 Zonisamide also blocks seizures induced by maximal electroshock and has variable effects on pentylenetetrazole-induced seizures. 10,11 Consistent with predictions from these in vitro and in vivo studies, zonisamide appears to ameliorate a broad range of seizure types in humans. 12 Its efficacy in controlling partial seizures with or without secondary generalization was demonstrated by two multicenter, randomized, controlled, adjunctive treatment trials in adults.…”

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confidence: 58%

Clinical Experience With Zonisamide Monotherapy and Adjunctive Therapy in Children With Epilepsy at a Tertiary Care Referral Center

2005

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We evaluated our clinical experience with zonisamide, a broad-spectrum antiepileptic drug, in a group of children with predominantly medically refractory epilepsy. A retrospective chart review was conducted on patients at our tertiary referral center following Institutional Review Board approval. Observers documented reports of seizure frequency, and seizure types were identified either clinically or by prior video-electroencephalography monitoring. We identified 68 patients (age range 1.9-18.1 years [median 6.9 years]; male to female ratio 1.3:1) treated with zonisamide for 0.7 to 28.9 months; at the last visit, 22% and 78% were on monotherapy and adjunctive therapy, respectively. The median duration of treatment and maintenance dose at the end of the follow-up were 11.2 months and 8.0 mg/kg/day, respectively. Seizure types included generalized (primary generalized tonic-clonic, myoclonic, tonic, atonic, absence) and partial (simple, complex, and secondarily generalized tonic-clonic seizures); 10 (15%) patients had both partial and generalized seizures. Sixteen (25.8%) patients were seizure free, although five of them were already in remission prior to starting zonisamide. Thirteen (21.0%) patients had a > 50% seizure reduction, 10 (16.1%) patients had a < 50% seizure reduction, 14 (22.6%) had no improvement in baseline seizures, and 9 (14.5%) reported having increased seizures. The latter were mostly associated with dosage alterations in concomitant antiepileptic drugs. Common side effects were central nervous system related, including behavioral or psychiatric (23.5%), cognitive dysfunction (12.0%), and sedation (10.3%). Eleven (16.2%) patients ultimately discontinued zonisamide, but only five were strictly due to side effects. Zonisamide is clinically effective against multiple seizure types in a significant proportion of children with epilepsy across a broad age range. Drug discontinuation as a result of side effects is uncommon.

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supporting

confidence: 58%

Clinical Experience With Zonisamide Monotherapy and Adjunctive Therapy in Children With Epilepsy at a Tertiary Care Referral Center

2005

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“…These results are similar to those reported for zonisamide after 7-day tolerance studies (see ref b) but contrast with the rapid development of tolerance observed with acetazolamide, see ref .…”

Section: Referencessupporting

confidence: 91%

Synthesis and Evaluation of N-(Phenylacetyl)trifluoromethanesulfonamides as Anticonvulsant Agents

et al. 1996

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A series of N-(phenylacetyl)trifluoromethanesulfonamides (3a-g) was prepared according to the Topliss scheme in order to determine if aryl substituents would influence anticonvulsant activity. In initial (phase I) screening and quantitative (phase II) evaluation, all seven compounds exhibited significant activity against MES- and scMet-induced seizures. N-(Phenylacetyl)trifluoromethanesulfonamide (3a) was then advanced through five additional testing phases (phases III-VII). Compound 3a displayed good oral bioavailability, low toxicity, and a larger protective index in mice than the prototype drugs, phenytoin, phenobarbital, valproate, and ethosuximide. Additionally, 3a exhibited a longer time to peak effect in all tests and a greater 24-h margin of safety (HD(50)/ED(50)) than the prototypes. Compound 3a blocked picrotoxin-induced seizures but was ineffective against seizures induced by bicuculline or strychnine. In vitro receptor binding studies revealed that 3a did not displace [(3)H]-labeled gamma-aminobutyric acid or [(3)H]-labeled flunitrazepam, and tolerance did not develop during a 5-day chronic administration.

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“…Zonisamide is classified as a member of the methanesulfonamide group even though it has a sulfamoyl group in common with acetazolamide, an arylsulfonamide analog that also has anticonvulsant properties. 2,3…”

Section: Chemistrymentioning

confidence: 99%

“…However, when zonisamide was compared with acetazolamide in vivo, zonisamide had only weak carbonic anhydrase inhibiting activity, requiring 100-1000 times higher doses than acetazolamide to achieve equivalent inhibition. 3 Thus, carbonic anhydrase inhibition was ruled out as the primary mechanism of action of zonisamide. 2 The presence of a methylene group on zonisamide's side chain may explain the differences in carbonic anhydrase inhibition.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Zonisamide: chemistry, mechanism of action, and pharmacokinetics

Leppik

2004

Seizure

204

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Zonisamide is a synthetic 1,2-benzisoxazole-3-methanesulfonamide with anticonvulsant properties. The sulfamoyl group on zonisamide was expected to suppress seizures in a manner similar to another sulfonamide analogue, acetazolamide, through inhibition of carbonic anhydrase. However, this does not appear to be the primary mechanism of action since zonisamide requires much higher doses than acetazolamide to achieve equivalent titration in vivo. Studies with cultured neurons indicate that zonisamide blocks repetitive firing of voltage-sensitive sodium channels and reduces voltage-sensitive T-type calcium currents without affecting L-type calcium currents. Its dual mechanism of action may explain its efficacy in patients resistant to other antiepileptic drugs (AEDs). Zonisamide has a pharmacokinetic profile favorable for clinical use. It is rapidly and completely absorbed and has a long half-life (63-69h in healthy volunteers) which allows twice-daily, or even once-daily, dosing. Zonisamide is not highly bound to plasma proteins. Consequently, it does not affect protein binding of other highly protein-bound AEDs. Furthermore, zonisamide does not induce its own metabolism and does not induce liver enzymes. However, since zonisamide is metabolized by cytochrome P450, liver enzyme-inducing AEDs will increase zonisamide clearance, and dosage adjustments may be necessary when it is used in combination with certain AEDs.

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3-Sulfamoylmethyl-l, 2-benzisoxazole, a new type of anticonvulsant drug: Pharmacological profile

Cited by 9 publications

References 0 publications

Clinical Experience With Zonisamide Monotherapy and Adjunctive Therapy in Children With Epilepsy at a Tertiary Care Referral Center

Clinical Experience With Zonisamide Monotherapy and Adjunctive Therapy in Children With Epilepsy at a Tertiary Care Referral Center

Synthesis and Evaluation of N-(Phenylacetyl)trifluoromethanesulfonamides as Anticonvulsant Agents

Zonisamide: chemistry, mechanism of action, and pharmacokinetics

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