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Introduction to zonisamide.

Zonisamide (Zonegran), a novel antiepileptic drug (AED) approved recently in Europe as adjunctive therapy for refractory partial seizures in adults, has been used extensively in Japan and the United States. A substantial body of clinical experience has accumulated over a 14-year period, allowing the properties and pharmacologic/clinical profiles of zonisamide to be clearly defined. Zonisamide is structurally distinct from other AEDs and has multiple and complementary mechanisms of action, which likely contribute to its efficacy across a broad range of epilepsy types. Zonisamide has a long T1/2 enabling once-daily dosing, linear pharmacokinetics and minimal interaction with other drugs; plasma levels of commonly administered AEDs and oral contraceptives are unaffected by concomitant zonisamide. Effective control of partial seizures (up to 51% decrease in seizure frequency) is attained at doses of >or=300 mg/day, and optimal titration and maintenance dosing schedules have been established. The adverse event profile is well defined; in common with most AEDs, most adverse events are central nervous system-related (e.g. somnolence, dizziness, tiredness). Adverse events may be minimised with appropriate patient management. Zonisamide therefore has many characteristics considered desirable in an AED and represents a valuable addition to the therapeutic options for treating epilepsy in Europe.

Anticonvulsants↗

Efficacy and safety of zonisamide monotherapy in a cohort of children with epilepsy.

The aim of this study was to evaluate the efficacy and safety of zonisamide monotherapy in a cohort of children and adolescents with various types of epilepsy. Retrospective review of charts of our institution from 2001 through 2004 identified 69 children (19 males and 50 females, mean age 13.2 years) with epilepsy on zonisamide monotherapy. Seizure count and side effect profile were maintained during therapy. Sixty-one percent had idiopathic generalized epilepsy, 4% symptomatic generalized epilepsy, and 35% partial-onset epilepsy. Zonisamide was the first-line and second-line monotherapy for 32% and 68% of patients, respectively. The mean duration of follow-up on treatment was 22 months (range 3-48 months). The overall efficacy of zonisamide was 75.4% (> or = 50% seizure frequency reduction: good responders). Sixty-seven percent of good responders became seizure-free. Seventy-nine percent of patients with partial epilepsy and 71% with generalized epilepsy were good responders, of whom 79% and 63% were free of seizure, respectively. Eighteen (26%) patients developed side effects: weight loss (9), cognitive impairment (3), sleepiness (3), dizziness (2), and decreased appetite (1). In seven patients (10%), zonisamide had to be discontinued: four due to side effects and three because of poor seizure control. Zonisamide was demonstrated to be effective as monotherapy in children with epilepsy.

Adolescent↗

Possible induction of systemic lupus erythematosus by zonisamide.

An epileptic male to whom zonisamide and ethosuximide had been administered exhibited fever, pericarditis, pleuritis, arthralgia, and elevated titers of antinuclear antibody and anti-DNA-antibody at 5 years, 11 months of age. It was suggested that zonisamide induced the systemic lupus erythematosus symptoms because the antinuclear antibody titers began to rise after zonisamide was administered, and clinical recovery and a decrease in the anti-DNA-antibody levels promptly followed the discontinuation of the drug. The positive lymphocyte transformation test results against zonisamide further supports the etiologic relationship of the male's lupus and the drug. This first case of zonisamide-induced lupus should alert physicians to the possibility of this serious unwanted effect in patients receiving zonisamide.

Antibodies, Antinuclear↗

Zonisamide prophylaxis in refractory pediatric headache.

INTRODUCTION: Currently, no medications are approved for pediatric headache prophylaxis in the United States. Zonisamide is an antiepileptic drug with preliminary studies suggesting some efficacy in the adult headache population. METHODS: A retrospective chart review was conducted on refractory headache patients in our multidisciplinary Headache Clinic who were treated with zonisamide, an antiepileptic drug, for headache prophylaxis. Records were reviewed for pertinent data including patient history, diagnosis, prior treatment regimens, and zonisamide response, along with headache frequency. RESULTS: Twelve patients were identified (8 girls); mean age was 13.5 years. Eight of the 12 patients had a positive response to zonisamide with greater than 50% reduction in headaches from pretreatment values. CONCLUSION: Zonisamide had some efficacy in headache reduction. It was well tolerated with only minor side effects. Further prospective studies with zonisamide are warranted in refractory pediatric headache patients.

Adolescent↗

Zonisamide in epilepsy: a pilot study.

We compared zonisamide monotherapy (12 weeks) to carbamazepine monotherapy (12 weeks) after phenytoin baseline monotherapy (8 weeks) in an open crossover pilot study of eight adults with uncontrolled partial seizures. Zonisamide had definite antiepileptic activity in five subjects. In two of these, response to zonisamide was superior to that to either phenytoin or carbamazepine. A third subject became seizure free on zonisamide, but had to be withdrawn after 18 days because of mild Stevens-Johnson syndrome. The other three subjects were withdrawn from the study because of drug toxicity, manifested mainly by impaired higher mental function and increased seizures. The best response to zonisamide was at doses approximating 6 mg/kg/day, with plasma levels of 20-30 mg/L. Plasma levels of greater than 30 mg/L usually were associated with toxicity. The pharmacokinetics of zonisamide are complex and nonlinear, with steady-state plasma levels being approximately three times higher than those predicted from a single-dose study.

Adolescent↗

Effects of zonisamide (AD-810) on tungstic acid gel-induced thalamic generalized seizures and conjugated estrogen-induced cortical spike-wave discharges in cats.

Effects of zonisamide (AD-810, CI-912) were examined on tungstic acid gel-induced thalamic generalized seizures and conjugated estrogen-induced cortical spike-wave discharges in gallamine-immobilized cats. Zonisamide prolonged the interictal periods of the generalized seizures by thalamic (centralis lateralis) application of tungstic acid gel (50 microliters) and, at the higher doses, abolished the seizures; its potency was near that of phenobarbital. Zonisamide abolished the spike-wave discharges by cortical (posterior lateralis) application of 2% conjugated estrogens (CE); its potency was stronger than that of dipropylacetate or trimethadione, but slightly less than that of phenytoin, phenobarbital, or carbamazepine. Zonisamide did not affect the posttetanic potentiation of the monosynaptic reflexes (ventral root potentials) in urethane-chloralose-anesthetized spinal rats. From these results, it is suggested that zonisamide suppresses both seizures originating from the thalamus and the cortex through the mechanism differing from that of phenytoin. Zonisamide appears to be effective in primary generalized seizures, especially the grand mal epilepsies, in addition to being effective in cortical epilepsies.

Animals↗

Zonisamide in pediatric epilepsy: review of the Japanese experience.

Zonisamide is a novel anticonvulsant that is structurally and mechanistically unique, compared with other antiepilepsy drugs. Available in Japan and South Korea since 1989, it was approved in the United States in the year 2000 as adjunctive therapy for partial seizures in adults. There has been extensive clinical trial and clinical practice experience with zonisamide therapy in Japanese children. Open-label data from pediatric clinical trials conducted in Japan suggest that zonisamide is well tolerated and effective against partial- and generalized-onset seizures in children. Despite this wealth of open-label data, no formal pharmacokinetic studies and only one well-controlled trial of zonisamide's efficacy and safety in Japanese children have been completed to date. No controlled clinical trials of zonisamide in children have been completed in the United States or Europe. Additional controlled trials in children with partial- or generalized-onset seizures, infantile spasms, and Lennox-Gastaut syndrome are warranted to further delineate zonisamide's broad spectrum of efficacy and tolerability in children.

Adult↗

Pharmacokinetics of zonisamide; saturable distribution into human and rat erythrocytes and into rat brain.

The distribution of zonisamide, a new antiepileptic drug, in erythrocytes and in brain was studied to clarify the factors influencing its distribution in epileptic patients. In both humans and rats, zonisamide was concentrated significantly in erythrocytes in a saturable manner. When the effective concentration of zonisamide in serum was compared with that in blood in nine refractory epileptic patients taking zonisamide chronically, the variation in effective serum concentration was significantly larger than that in blood concentration. In rats, the distribution in the brain also showed saturability. These results suggest that differences in saturable binding to various tissues may contribute to the wide variation that occurs in the effective serum concentration of zonisamide in epileptic patients and that monitoring of the blood concentration of zonisamide may provide useful information for treatment with this drug.

Administration, Oral↗

An assessment of zonisamide as an anti-epileptic drug.

A brief review of epilepsy as a disease, anti-epileptic drugs and methods of evaluation of anti-epileptic drugs are presented as a background for assessment of zonisamide, which has been approved by the FDA as add-on therapy for the treatment of partial seizures with or without secondary generalisation in adults. Chemically, zonisamide is classified as a sulphonamide and is unrelated to other anti-epileptic drugs. The mode of action of zonisamide remains unclear, but likely mechanisms are blockade of sodium and T-type calcium channels. It is also shown to have some neuroprotective effect against hypoxia and ischaemia. It has a liner pharmacokinetics with excellent oral bioavailability. Zonisamide has been approved for use in Japan for ten years prior to approval in USA and Europe. 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. The efficacy and safety was confirmed in trials conducted in USA and Europe in adults as well as children. Zonisamide compares favourably with other newly introduced drugs and has the potential for development as a monotherapy for epilepsy.

Adolescent↗

Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative.

1. The metabolism of zonisamide in vitro was characterized through aerobic and anaerobic incubations with rat liver subcellular fractions and cultured gastrointestinal microflora. 2. Zonisamide reacted with rat hepatic microsomal cytochrome P-450 and exhibited a Type I binding spectrum. 3. Metabolism of zonisamide in vitro by hepatic subcellular fractions and cultured gastrointestinal flora produced a single metabolite, 2-(sulphamoylacetyl)-phenol (2-SMAP), by reductive cleavage of the 1,2-benzisoxazole ring. 4. The reductive metabolism of zonisamide was primarily mediated by microsomal cytochrome P-450. The soluble fraction enhanced reduction when combined with the microsomal fraction but itself possessed only weak reductive activity. 5. Reduction of zonisamide by the most enzymically active liver fractions required NADPH, was stimulated by FMN and SKF-525A, and was inhibited by CO or air, as well as by n-octylamine. 6. Unlike their involvement in the reduction of numerous nitro, azo, and N-oxide compounds, cultured aerobic and anaerobic intestinal flora were not principally involved in the reduction of zonisamide.

Animals↗

Rat liver microsomal cytochrome P-450 responsible for reductive metabolism of zonisamide.

The reductive metabolism of 1,2-benzisoxazole-3-methanesulfonamide (zonisamide) to 2-sulfamoylacetylphenol (SMAP) was observed in liver microsomes from female rats, as well as male rats, but the SMAP-producing activity in female rats was 4-fold lower than that found in male rats. In addition, the reductive metabolism of zonisamide in liver microsomes was induced by the treatment of male rats with phenobarbital. However, the SMAP-producing activity did not correlate positively with the amounts of P-450 2B1 and P-450 2C11 immunochemically determined. In contrast, the reductive metabolism of zonisamide was also found to be induced by the pretreatment of male rats with pregnenolone 16 alpha-carbonitrile, triacetyloleandomycin, and dexamethasone. Furthermore, the SMAP-producing activity correlated highly with the amount of P-450 cross-reactive with antihuman P-450 3A4 antibody, suggesting that P-450 3A1/2 may function in the reductive metabolism of zonisamide. In addition, the P-450 PCNa (3A2) exhibited the SMAP-producing activity in a reconstituted system. The antihuman P-450 3A4 antibody inhibited markedly the formation of SMAP from zonisamide in male rat liver microsomes. These results indicate that cytochrome(s) P-450 belonging to P-450 3A subfamily may be predominantly responsible for the reductive metabolism of zonisamide in rat liver microsomes.

Anaerobiosis↗

Safety of 25- and 50-mg capsules in the initiation of zonisamide therapy in patients with epilepsy: an uncontrolled, open-label study.

OBJECTIVE: This study was designed to assess the safety of 25- and 50-mg dosage strengths of zonisamide for initial titration in patients with epilepsy. RESEARCH DESIGN AND METHODS: This phase 3, multicenter, open-label, uncontrolled study conducted at 26 study sites in the United States included male and female patients with epilepsy >or= 12 years of age. After a screening visit, subjects began zonisamide therapy at a dosage depending on their body weight. Zonisamide was titrated to 100 mg/day. MAIN OUTCOME MEASURES: At the study's conclusion, information regarding adverse events (AEs) and body weight was recorded. RESULTS: One hundred forty-three subjects enrolled and received at least one zonisamide dose. Of these subjects, 125 reached at least the 100-mg dosage before terminating the study. Eighty-two subjects (57.3%) experienced at least one AE. Most commonly reported AEs included headache, somnolence, asthenia, rhinitis, nausea, and rash. No significant change in patient body weight was noted during the study (95% confidence interval: -0.1, 0.6). CONCLUSIONS: Study limitations include the open-label design and the lack of direct comparison between lower (25- and 50-mg) and higher (100-mg) starting dosages. Despite these limitations, the 25- and 50-mg zonisamide dosage formulations were well tolerated in this study.

Adult↗

Effects of zonisamide on extracellular levels of monoamine and its metabolite, and on Ca2+ dependent dopamine release.

The effects of zonisamide (3-sulfamoylmethyl-1,2-benzisoxazole), a novel anticonvulsant, on extracellular levels of monoamine and its metabolite in the striatum and hippocampus, and Ca2+ dependent monoamine release in the striatum of freely moving rats were studied by microdialysis. Zonisamide increased dopamine, homovanillic acid and 5-hydroxyindoleacetic acid, and decreased 3,4-dihydroxyphenylacetic acid in the rat striatum. However, zonisamide showed no effect on Ca2+ dependent dopamine release in the rat striatum. In the hippocampus, zonisamide increased dopamine, homovanillic acid, serotonin and 5-hydroxyindoleacetic acid and decreased 3,4-dihydroxyphenylacetic acid. The present results suggest that zonisamide facilitates dopaminergic and serotoninergic neurotransmission but does not affect Ca2+ dependent dopamine release within therapeutic plasma concentrations.

3,4-Dihydroxyphenylacetic Acid↗

Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex.

We investigated the effect of zonisamide, a new antiepileptic drug, on voltage-dependent Ca2+ currents in cultured neurons of rat cerebral cortex. Whole-cell voltage-clamp recordings demonstrated at least two distinct voltage-dependent Ca2+ currents: (1) a low-threshold, rapidly inactivating component, T-type Ca2+ current, which is sensitive to 100 microM Ni2+, and (2) a high-threshold, slowly inactivating (long-lasting) component, L-type Ca2+ current. Zonisamide, a new anticonvulsant effective against maximal electroshock (MES) seizures in mice reduced T-type Ca2+ current in a dose-dependent manner. The mean percentage of reduction was 59.5 +/- 7.2% at 500 microM, but zonisamide had no effect on L-type Ca2+ current. A methylated analog of zonisamide, which is ineffective against MES seizures in mice, was tested at a concentration of 500 microM, and reduced neither T-type nor L-type Ca2+ current. These findings suggest that the effects of zonisamide against MES seizures might occur through the reduction of T-type Ca2+ current. Because drugs that are effective against MES seizures are thought to prevent seizure discharge spread, T-type Ca2+ channels could underlie a cellular mechanism of spreading activity in epileptic seizures.

Action Potentials↗

Zonisamide: physician and patient experiences.

This study evaluates information regarding physician and patient experiences with zonisamide obtained from the early access and support for epilepsy (EASE) program. Both physicians and patients completed initiation questionnaires regarding seizure history and antiepileptic drug (AED) use. Physicians were advised to initiate zonisamide at 100 mg/day and titrate either to a clinical response or a maximum dosage of 600 mg/day. After > or = 2 months of zonisamide therapy, physicians and patients were asked to complete follow-up questionnaires that included questions regarding seizure frequency, seizure severity, and quality of life. Initiation questionnaires and follow-up questionnaires were submitted by 80 physicians for 163 patients. According to these data, seizure control, functional status, and other symptoms of epilepsy were improved in 57.4% (93/162), 37.1% (59/159), and 30.6% (48/157) of patients, respectively. Physicians intended to continue zonisamide therapy in 77.4% (123/159) of patients. Ninety-six patients submitted both initiation and follow-up questionnaires. Seizure control, seizure severity, and quality of life were improved in 53.6% (45/84), 58.8% (50/85), and 62.1% (54/87) of patients, respectively. These patients, most of whom were refractory to other AEDs, generally had positive experiences with zonisamide.

Adolescent↗

Practical prescribing and long-term efficacy and safety of zonisamide.

Long-term efficacy, tolerability and safety of antiepileptic drug (AED) therapy is essential given the chronic nature of epilepsy. Zonisamide (Zonegran), a novel AED with a broad range of mechanisms of action contributing to its antiseizure efficacy, has been evaluated extensively for the long-term management of epilepsy. Open-label extension studies in the United States and Europe suggest continued efficacy of zonisamide in long-term treatment without development of adverse events further to those seen in registration studies. Baseline seizure frequency is reduced by approximately 40-70% during long-term treatment for up to 2 years, and 30-50% of patients attain >or=50% reduction in seizure frequency across all categories of seizure and durations of treatment. Preliminary data indicate a progressive decline in seizure frequency with continued zonisamide treatment. Zonisamide is well tolerated in long-term use, with a trend towards decreasing incidence of generally mild adverse events over time and a low rate of withdrawal during chronic use. Nephrolithiasis and other serious adverse events are infrequent, and can be minimised by appropriate management and patient education. This profile of maintained efficacy, tolerability and safety during sustained administration in combination with other AEDs supports zonisamide as a valuable adjunctive agent in the long-term management of refractory partial epilepsy.

Adolescent↗

Zonisamide monotherapy for epilepsy in children and young adults.

Several of the newer antiepilepsy drugs have not been tested as monotherapy in controlled trials. Zonisamide is a broad-spectrum antiepilepsy drug indicated for the adjunctive treatment of partial seizures in adults. However, several small, open-label studies have indicated that it may be safe and effective as monotherapy. The present chart review study was conducted to evaluate the safety and effectiveness of zonisamide monotherapy in a pediatric and young adult patient group. Patient records at the Blue Bird Circle Clinic for Pediatric Neurology were reviewed to identify patients receiving zonisamide monotherapy. Efficacy was assessed from seizure diaries and patients' subjective evaluations. Safety and tolerability were evaluated by analysis of adverse events and change in body weight. The study included 131 patients aged 1 to 21.8 years with a broad spectrum of seizure types and epilepsy syndromes. A total of 101 patients (77.1%) achieved a 50% or greater decrease in seizure frequency, including 39 patients who achieved seizure freedom. Zonisamide monotherapy was well tolerated, with three patients (2.3%) discontinuing for adverse events. These results support open-label studies from Japan reporting that zonisamide monotherapy is safe and effective in pediatric and young adult patients.

Adolescent↗

Use of zonisamide in pediatric patients.

Zonisamide is a broad-spectrum antiepilepsy drug approved in the United States for the adjunctive treatment of partial seizures in adults with epilepsy. Studies in Japan have established zonisamide as effective and safe for use in children, but there is limited information from the United States concerning its use in pediatric patients. This chart-review study was conducted to evaluate the efficacy, safety, and appropriate dosage of zonisamide for treating seizures in pediatric and adolescent patients. Charts of 50 pediatric patients (mean age 9.1 years, range 9 months to 20 years) who received zonisamide were evaluated for demographic characteristics, seizure types, dosage (mean = 15.8 mg/kg/day), response, concurrent medications, and adverse events. After treatment, 8 patients were seizure-free, and 11 others had > or =50% improvement in seizure control, including 11 of the 28 patients for whom treatment with six or more antiepileptic drugs was insufficient. Thirty-one patients experienced at least one adverse event while receiving zonisamide, and 14 discontinued as a result.

Adolescent↗