Antiepileptic Drugs, 5th Edition

Zonisamide

94

Clinical Efficacy and Use in Epilepsy

Masakazu Seino MD^*

Buichi Fujitani PhD^**

* Honorary President, National Epilepsy Center, Shizuoka, Medical Institute of Neurological Diseases, Shizuoka, Japan

** Department of International Affairs, Dainippon Pharmaceutical Company, Limited, Osaka, Japan

EVIDENCE FROM RANDOMIZED, CONTROLLED CLINICAL TRIALS

Although in the United States zonisamide (ZNS) was not approved for treatment of epilepsy until 2000, initial use in Japan in 1989 has allowed more experience concerning many aspects of efficacy than is available for most new antiepileptic drugs (AEDs) at the time of licensing.

Five randomized, controlled trials on ZNS were performed: three placebo-controlled studies and two comparative studies with active reference drugs, either carbamazepine (CBZ) or valproate (VPA). All of the three placebo-controlled studies were evaluated ZNS for add-on treatment for patients with refractory partial or generalized epileptic seizures. The designs and results of these studies are summarized in Table 94.1.

Schmidt et al. (1) reported the European multicenter, placebo-controlled study of ZNS in adult patients who had four or more partial or generalized seizures per month and were refractory to other existing AEDs, either in monotherapy or in bitherapy. One hundred thirty-nine patients were randomly allocated to the ZNS group (n = 71) or the placebo (PLC) group (n = 68). ZNS was given once a day for 12 weeks in an add-on manner at an average maintenance dosage of 430 mg/day after a 1-month baseline period. Although the study involved patients with either partial or generalized seizures, most of the patients were having complex partial seizures. In patients with complex partial seizures, the median seizure frequency decreased by 27.7% in the ZNS group and increased by 3.9% in the PLC group from baseline (p < .05). Responder rates, defined as percentage of patients whose seizure frequency decreased by 50% or more, decreased by 30.3% in the ZNS group and 12.7% in the PLC group (p < .05). The median daily doses and plasma concentrations of ZNS did not differ between responders and nonresponders (7.8 versus 6.8 mg/kg/day; 17.0 versus 15.2 µg/mL).

A multicenter, double-blind, placebo-controlled study was conducted by Sackellares et al. (2) in the United States under a protocol similar to that used in the study described previously (1). One hundred fifty-two patients (ZNS group, n = 78; PLC group, n = 74) with refractory partial seizures were enrolled in the study, and efficacy was evaluated in 141 patients (ZNS group, n = 69; PLC group, n = 72). After a 2- to 3-month baseline period, ZNS was given twice a day for 12 weeks in an add-on manner, with an average maintenance dosage of 530 mg/day. The median seizure frequency decreased by 29.5% in the ZNS group (n = 69) and increased by 0.8% in the PLC group (n = 72). The difference was statistically significant (p < .05). Responder rates were 26.1% in the ZNS group and 16.7% in the PLC group (p < .05). The final median plasma concentrations of ZNS were 16.9 µg/mL and 13.0 µg/mL in responders and nonresponders, respectively.

The third ZNS trial, a randomized, double-blind, placebo-controlled study, was conducted to assess the efficacy and dose-response characteristics of ZNS as adjunctive therapy for refractory partial seizures (3). After a 4-week baseline period, 203 patients enrolled were randomly allocated to group A (n = 85), group B1 (n = 60), and group B2 (n = 58). Group A patients received placebo, along with their concomitant AEDs, for 12 weeks. At week 13, they were then crossed over to ZNS treatment, starting at a 100-mg/day increment per week to 400 mg/day for the final 5 weeks (weeks 16 to 20). Group B1 patients received 100 mg/day of ZNS for weeks 1 to 5, 200 mg/day during week 6, 300 mg/day during week 7, and 400 mg/day for weeks 8 to 20. Group B2 patients received 100 mg/day of ZNS for week 1, 200 mg/day for weeks 2 to 6, 300 mg/day during week 7, and 400 mg/day for weeks 8 to 20. This unique study protocol allowed parallel comparisons with placebo

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for three fixed doses and a final crossover to 400 mg/day for all patients. During weeks 8 to 12, median seizure frequency in patients treated with ZNS at 400 mg (n = 98) decreased by 40.5% from baseline, compared with a 9.0% decrease in the PLC group (n = 72; p < .01). During these weeks, the responder rate for all seizures was 41.8% in patients treated with 400 mg/day of ZNS, compared with 22.2% in the PLC group (p < .05). As for the dose-efficacy relation for ZNS, the median reduction of seizure frequency in patients treated with ZNS at 100 mg/day for weeks 1 to 5 was 24.7%, compared with 8.3% in the PLC group during the same period (p < .05). The median reduction in patients given 200 mg/day ZNS for weeks 2 to 6 was 20.4%, compared with 4.0% in the PLC group (p < .05), and that in patients given 400 mg/day ZNS (weeks 8 to 12) was 40.5%, compared with 9.0% in the PLC group (p < .01). The significant reduction of seizure frequency with ZNS was consistent at dosages of 100, 200, and 400 mg/day.

CONTROLLED, COMPARATIVE STUDY WITH ACTIVE REFERENCE DRUGS

The design and results of two controlled, comparative studies with active reference drugs are summarized in Table 94.2. A double-blind, controlled, comparative study of ZNS with CBZ was carried out by Seino et al. (4). One hundred twenty-three patients with partial seizures, two seizures per month or more, who had been untreated with other AEDs or were refractory to one to three other AEDs, were assigned to the ZNS group (n = 59) or the CBZ group (n = 64). Based on a preclinical study (5) and a preliminary clinical study (6), 100 mg ZNS was equated with 200 mg CBZ. The patients were placed on ZNS (mean dosage = 330 mg/day) or CBZ (mean dosage = 600 mg/day) for 16 weeks. After the 16-week-treatment period, the average frequency of simple or complex partial seizures was reduced by 68.4% in the ZNS group and 46.6% in the CBZ group from baseline. The average frequency of secondarily generalized tonic-clonic seizures also was markedly reduced in the ZNS group (69.7%) and in the CBZ group (70.2%). There were no statistical differences in the reduction of seizure frequency between the two groups. Responder rates were 81.8% in the ZNS group and 70.7% in the CBZ group (not statistically significant). Overall improvement rates in terms of seizure frequency and interseizure condition also were similar for the ZNS group (66.1%) and the CBZ group (65.4%).

GENERALIZED SEIZURES

A controlled study in pediatric patients with generalized seizures was carried out and the efficacy of ZNS was compared with that of VPA (7). Thirty-four patients with convulsive or nonconvulsive generalized seizures, four seizures or more per month, and who were refractory to one to three

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other AEDs, were allocated to the ZNS group (n = 18) or the VPA group (n = 16). The patients were on medication for 8 weeks with ZNS or VPA at the mean daily dosage of 7.3 mg/kg/day or 27.6 mg/kg/day, respectively. Overall improvements rates based on assessment of seizure frequency, electroencephalographic (EEG) findings, and interseizure condition were 50.0% in the ZNS group and 43.8% in the VPA group. The efficacy of ZNS was at least comparable with that of VPA for children with convulsive or nonconvulsive generalized seizures.

EVIDENCE FROM OTHER CLINICAL STUDIES

Noncomparative, Multicenter Studies

Leppik et al. (8) studied the efficacy of ZNS in a noncomparative, multicenter study in the United States. In this study, 167 patients with simple or complex partial seizures, including secondarily generalized tonic-clonic seizures, who were refractory to one to two other AEDs and were having four or more seizures per month, were enrolled. After 12-week baseline period, patients were given ZNS, 50 to 1,100 mg/day, for 16 weeks in an add-on manner. Treatment of patients with ZNS resulted in a significant reduction in seizure frequency per month from 11.5 during baseline to 5.5, or a 51.8% reduction during the final month. At least a 50% reduction in seizure frequency was noted in 41% of all patients, 43.2% of those with complex partial seizures, and 67.5% of those with secondarily generalized tonic-clonic seizures.

Ono et al. (9) conducted a multicenter, noncomparative clinical study in 538 adult patients with partial seizures (n = 433) or secondarily generalized tonic-clonic seizures (n = 105). ZNS was given in an add-on manner with daily dosage of 6.08 ± 2.89 mg/kg for at least 3 months. The mean duration of administration was 273 days. At the completion of the trial, at least a 50% reduction of seizure frequency was obtained in 254 of 506 patients (50.2%). Overall improvement rates based on assessment of severity and duration of seizures, interseizure condition, and EEG findings were 41.4% (213/514) in all patients, 48.1% (13/27) in those with simple partial seizures, 38.3% (23/60) in those with simple followed by complex partial seizures, 41.2% (98/238) in those with complex partial seizures, and 50% (45/90) in those with secondarily generalized tonic-clonic seizures. There were no statistically significant differences in the overall improvement rates between patients with these seizure types.

Oguni et al. (7) carried out an open-label trial in 393 patients with partial or generalized epilepsies. Patients, either adults or children who were refractory to previous AEDs and in whom the average number of AEDs concomitantly used was 2.8, were given ZNS at a dosage of 2 to 8 mg/kg/day, with an average final dosage at 7.3 mg/kg/day. The overall responder rate was 44.4%. The overall improvement rate based on assessment of severity and duration of seizures, interseizure condition, and EEG findings was 51.0% in all patients. According to seizure types, the overall improvement rates were 50% to 70% in patients with simple or complex partial seizures or secondarily generalized tonic-clonic seizures. Improvement rates in patients with generalized seizures were lower than in those with partial seizures: 47% in patients with generalized tonic-clonic seizures, 31.3% in those with generalized tonic seizures, and 20.0% in those with myoclonic seizures.

Yagi and Seino (10) analyzed the clinical efficacy of ZNS in a total of 1,008 adult and pediatric patients with various epilepsies (605 adults and 403 children), who were enrolled in controlled studies and noncomparative, multicenter studies already cited (4,7,9). Mean daily dosages of ZNS ranged between 5.9 and 8.8 mg/kg, and their mean serum concentrations ranged between 19.6 and 20.7 µg/mL at steady state. The efficacy was assessed by the percentage of patients whose seizure frequency decreased by 50% or more from the baseline with simple or complex seizures, and secondarily generalized tonic-clonic seizures. It also was beneficial for the treatment of convulsive and nonconvulsive generalized seizures and combined seizures, although efficacy rates varied between 26% and 100% by the seizure type (Table 94.3). The responder rate for ZNS also was analyzed according to epileptic syndromes in this study (Table 94.4). ZNS showed efficacy in more than 50% of patients with symptomatic partial epilepsies, including temporal lobe epilepsy, extratemporal lobe epilepsy, and unclassified symptomatic partial epilepsies. As for generalized epilepsies, responder rates to ZNS were 66% in patients with idiopathic generalized epilepsy, 32% in those with Lennox-Gastaut

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syndrome, 22% in those with West's syndrome, and 47% in those with other symptomatic generalized epilepsies. This study suggested that ZNS had a wide spectrum of efficacy for the treatment of patients with various seizure types and syndromes. Supporting the analysis, more than 20 open-label studies demonstrated the efficacy of ZNS in the treatment of adults and children with partial, generalized, or combined seizures in the late 1980s and early 1990s in Japan (11).

Long-Term Efficacy

Seino and Yagi (10) also analyzed the efficacy of ZNS in 155 patients who were treated for at least 1 year with ZNS in controlled, comparative studies and noncomparative studies conducted in Japan. The responder rates were 75% in patients with simple partial seizures (n = 4), 65% in those with simple partial followed by complex partial seizures (n = 26), 64% in those with complex partial seizures (n = 47), 61% in those with secondarily generalized tonic-clonic seizures (n = 28), 67% in those with generalized tonic-clonic seizures (n = 6), 40% in those with tonic seizures (n = 20), and 50% in those with combined seizures (n = 24). The analysis demonstrated the long-term efficacy of ZNS.

Three open-label trials were completed for assessment of the long-term efficacy of ZNS in the United States. One of these trials, a multicenter study, enrolled 103 patients with partial seizures who were refractory to other AEDs (12). Patients were given ZNS (usually 400 to 600 mg/day) for less than 24 months. The median reduction of seizure frequency and responder rate were 37.6% and 36.4% (35/96) after 5- to 16-week treatment, and those after 5- to 24-month treatment were 45.5% and 42.3% (33/78), respectively.

In the second trial (13), long-term efficacy was investigated in 137 patients with partial seizures who were refractory to other AEDs. ZNS was given for at least 5 months in an add-on fashion, and the dosage did not exceed the smaller of 20 mg/kg/day or the amount producing a plasma concentration of 40 µg/mL. Forty patients were treated with ZNS for longer than 16 months. The overall median seizure frequency was reduced by 64.9% (n = 129). Responder rates were consistently higher than 40% throughout the study period, at 44% (53/120), 46% (44/95), 51% (38/74), and 49% (31/63) during 5- to 7- , 8- to 10-, 11- to 13-, and 14- to 16-month periods, respectively, and 40% (16/40) for more than 16 months.

The third trial (14) was an extension of a U.S. placebo-controlled study (2). A total of 123 patients having documented refractory partial seizures with or without secondary generalization received open-label ZNS therapy (median dosage = 450 mg/day). Of the 123 patients who began open-label therapy, 47 patients received ZNS for at least 12 months, and 40 patients received ZNS for 15 months or more before the study terminated. The median percentage reduction in seizure frequency from the baseline was 50.1% for patients with any kind of partial seizures and 50.8% for those with complex partial seizures only. The responder rate, the percentage of patients who showed a reduction in seizure frequency of at least 50%, ranged from 42.1% to 55.0% according to the treatment period.

Long-term efficacy of ZNS also was shown by Ota et al. (15), Kohsaka et al. (16), Nishiura and Oiwa (17), Kanazawa et al. (18), Wilder et al. (19), Shimizu et al. (20), and Sugahara et al. (21).

ZONISAMIDE MONOTHERAPY

Analysis of 1,008 epileptic patients recruited in controlled studies and multicenter, open-label studies in Japan included 55 patients who were treated with ZNS alone (10). Seventy-two percent of these 55 patients showed at least a 50% reduction of seizure frequency. Kumagai et al. (22) investigated the efficacy and safety of ZNS monotherapy in 44 pediatric patients. ZNS was given for 4 months to 4.5 years (mean treatment period = 1.1 years). The starting dosages were 2 to 4 mg/kg/day and increased to 12 mg/kg/day; unless a satisfactory response was obtained at a previous dose. The seizures completely disappeared in 30 of 38 patients (78.9%) whose efficacy could be evaluated (5/5 in patients with idiopathic generalized epilepsy, 7/8 in those with symptomatic generalized epilepsy, 1/1 in those with idiopathic partial epilepsy, and 17/24 in those with symptomatic partial epilepsy). Hosoda et al. (23) also investigated the efficacy of ZNS monotherapy in 72 pediatric patients with cryptogenic localization-related epilepsies. ZNS at 2 to 8 mg/kg/day was given once daily for 6 to 43 months. During this period, complete seizure control was achieved in 57 of 72 patients (79%), including 8 patients whose dosage was increased at an early stage of the treatment because of seizure recurrence with the initial maintenance dosage. The efficacy of ZNS monotherapy for infantile spasms was reported by Suzuki et al. (24). Eleven newly

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diagnosed children with infantile spasms who failed to respond to vitamin B₆ were treated with ZNS at 3 to 10 mg/kg/day. Four of the 11 infants had cessation of spasms and disappearance of hypsarrhythmia within a few days after starting treatment, although two of them relapsed into spasms several weeks after cessation of seizures. Two other patients showed reduction of seizure frequencies, but seizure frequency did not change in the remaining five patients.

ZONISAMIDE THERAPY FOR SPECIFIC SYNDROMES

Progressive Myoclonus Epilepsy and the Antioxidant Effect of Zonisamide

Progressive myoclonus epilepsies (PME) are a group of syndromes mainly consisting of generalized convulsive seizures, fragmentary myoclonus, status epilepticus, ataxia, and progressive dementia. In 1988, Henry et al. (25) first reported dramatic improvement of seizures after treatment with ZNS (8.8 and 10.5 mg/kg/day, respectively) in two patients with PME of the Unverricht- Lundborg type. Later, Kyllerman and Ben-Menachem (26) treated seven cases of PME with ZNS at 100 to 600 mg/day. They demonstrated that it dramatically reduced the number of myoclonus and generalized convulsive seizures in six of seven cases, although the initial effect on myoclonus wore off after 2 to 4 years of the treatment in three of these cases. Yagi and Seino (10) also reported that ZNS monotherapy resulted in the complete disappearance of seizures in one patient having mitochondrial encephalopathy with ragged-red fibers, and a significant improvement in two pediatric patients with other PMEs.

ZNS has been thought to exert its antiepileptic effect through the blockade of the sodium channel (27) and the T-type calcium channel (28). Because other sodium channel blocking agents, such as phenytoin or CBZ, do not improve PME seizures, ZNS seems to exhibit its improving effect on PMEs through its blockade of the T-type calcium channel or some unknown mechanisms. In relation to the therapeutic effect of ZNS on PME, it should be noted that ZNS has a free radical scavenging action, because treatment with N-acetylcysteine, an antioxidant, markedly decreased the frequency of seizures and normalized somatosensory evoked potentials in patients with PME of the Unverricht-Lundborg type (29). ZNS scavenged 1,1-diphenyl-2-picrylhydroxy radicals [DPPH] (30), hydroxyl radicals, and nitric oxide in a concentration-dependent manner in vitro (31), but phenytoin, phenobarbital (PB), VPA, and CBZ did not show DPPH-scavenging action (32). In an in vivo experiment, treatment of rats with ZNS (20 and 100 mg intraperitoneally) prevented the increase of lipid peroxides in the cerebral cortex induced by topical injection of iron solution (30). Taking these findings into consideration, ZNS may, at least partly, exert therapeutic effects on PMEs and other symptomatic generalized epilepsies through its free radical scavenging action in addition to its blocking action on the T-type calcium channel.

Prevention of Postsurgical Seizures

After demonstrating the cerebral protective effect of ZNS in animal models of cerebral ischemia or traumatic head injury, Fukuda and Masuda (33) first tried to treat six craniotomy patients with ZNS and showed its efficacy in five of these patients. Later, Nakamura et al. (34) conducted a randomized, controlled study of ZNS in postoperative seizures using PB as an active placebo. Patients at high risk for seizures (n = 278) who underwent craniotomy for their brain tumors, cerebrovascular diseases, or head injuries were recruited in this study and were randomly assigned to the ZNS group (n = 141) or the PB group (n = 137). ZNS (100 to 400 mg/day) or PB (40 to 160 mg/day) was given from 1 week before to 1 year after the surgery, after which the patients were followed up for 3 years. Occurrence of seizures was recorded in 255 patients (ZNS group, 129; PB group, 126) during the treatment period and in 219 patients (ZNS group, 112; PB group, 107) during follow-up. The incidences of development of epileptic seizures during medication were 5.4% (7/129) and 6.3% (8/126) in the ZNS group and the PB group, respectively (not significant), and during the follow-up period, they were 7.1% (8/112) and 12.1% (13/107), respectively (not significant). Although six patients (5.6%) in the PB group experienced partial seizures during follow-up, none in the ZNS group experienced such seizures (Fisher test; p = .013). In addition to its antiepileptic action, the free radical scavenging action of ZNS may, at least in part, contribute to its preventive effect on postsurgical seizures.

MODE OF USE

Indications

ZNS has been commercially available since 1989 in Japan and since 1992 in Korea. It was approved in the United States in March 2000. Based on its wide-spectrum clinical antiepileptic efficacy as demonstrated by controlled and open-label trials in Japan (4,7,9,10), ZNS monotherapy or adjunctive therapy is approved in adults and children with the following types of seizures in Japan and Korea:

1. Partial seizures: simple or complex partial seizures, and secondarily generalized tonic-clonic seizures
2. Generalized seizures: tonic-clonic seizures, tonic seizures, and atypical absence seizures
3. Mixed seizures: combinations of the aforementioned generalized seizures

On the other hand, in the United States, ZNS is indicated as adjunctive therapy in partial seizures in adults (16

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years of age or older) based on efficacy demonstrated by the placebo-controlled studies in the United States and Europe (1, 2, 3). Efficacy of ZNS as monotherapy or in pediatric patients is being evaluated in the United States and Europe. As mentioned previously, ZNS improved seizures in patients with PMEs (10,25,26).

Dosing Recommendations

ZNS is available in a 100-mg tablet and a 200-mg/g powder formulations in Japan, a 100-mg tablet formulation in Korea, and a 100-mg capsule formulation in the United States. The drug can be used for treatment in children and adults in Japan and Korea, but its use is limited to adults in the United States. Safety in infants younger than 1 year of age has not been established. As for the elderly, 328 patients older than 65 years of age were recorded in postmarketing surveillance in Japan (35), but no systematic studies have been performed in the elderly patient population. Treatment should be started in elderly patients at the lowest dosage of the therapeutic range.

Initial Dosage

The recommended initial adult dosage is 100 mg/day in the United States and 100 to 200 mg/day in Japan and Korea. For children older than 1 year of age, the recommended initial dosage is 2 to 4 mg/kg/day in Japan and Korea.

Titration Rate

In adult patients, the dosage should be increased if necessary to 200 to 400 mg/day, with every 100-mg increase at an interval of 2 weeks or longer in the United States, whereas a 1- to 2-week interval is acceptable in Japan and Korea because it requires approximately 2 weeks to attain a new steady-state plasma concentration of ZNS (36). In children, the dosage should be increased to 4 to 8 mg/kg/day at the interval of 1 to 2 weeks in Japan and Korea. A gradual increase of dosage may reduce adverse drug events.

Maintenance Dosage

The usual maintenance dosage of ZNS is 200 to 400 mg/day for adults and 4 to 8 mg/kg/day for children. Therapeutic plasma concentrations were reported to be 10 to 20 µg/mL or approximately 20 µg/mL (1,2,7,10).

Maximum Dosage

The approved highest dosage is 600 mg/day for adults and 12 mg/kg/day for children in Japan.

CURRENT ROLE IN EPILEPSY MANAGEMENT

ZNS is an important addition to the ranks of available AEDs. It has proven efficacy in adults and children for a wide variety of partial and generalized seizures since it was launched in 1989 in Japan. Many studies demonstrated the efficacy of ZNS in the treatment of simple and complex partial seizures, and secondarily generalized tonic-clonic seizures. For generalized seizures, efficacy was demonstrated in patients with atypical absence tonic, atonic, myoclonic, or clonic seizures. It also is effective in the treatment of infantile spasms or West's syndrome, and tonic and atypical absence seizures in Lennox-Gastaut syndrome. Some investigators reported the dramatic improvement of seizures in patients with PME.

Although the indications for ZNS are limited to adjunctive therapy for adult patients with refractory partial epilepsy in the United States, studies on its use as monotherapy and in pediatric patients are under way.

Seizure Relapse on Withdrawal

Because an abrupt reduction or discontinuation of dosage may precipitate relapse of seizures or even status epilepticus in patients who have taken the drug for a prolonged period, the dosage should be reduced gradually, with particular caution in patients with intractable seizures.

REFERENCES

1. Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res1993;15:67-73.
2. Sackellares CJ, Ramsay RE, Wilder BJ, et al. Controlled clinical trial of zonisamide: an effective adjunctive treatment for refractory partial seizures. Files of Dainippon Pharmaceutical Co., Ltd. (#912 US) Osaka, Japan, 1997.
3. Faught E, Ayala R, Montouris GG, et al. Randomized controlled trial of zonisamide for the treatment of refractory partial onset seizures. Neurology2001;7:1777-1779.
4. Seino M, Ohkuma T, Miyasaka M, et al. Efficacy evaluation of AD-810: results of a double blind comparison with carbamazepine [in Japanese]. J Clin Exp Med1988;144:275-291.
5. Kakegawa N. An experimental study on the modes of appearance and disappearance of suppressive effect of antiepileptic drugs on kindled seizure [in Japanese]. Psychiatr Neurol Jpn1986;88: 81-98.
6. Wilensky AJ, Friel PN, Ojemann L, et al. Zonisamide in epilepsy: a pilot study. Epilepsia1985;26:212-220.
7. Oguni H, Hayashi K, Fukuyama Y, et al. Phase III clinical study of the new antiepileptic drug, AD-810 (zonisamide), in patients with childhood epilepsy [in Japanese]. Jpn J Pediatr1988;42: 439-450.
8. Leppik IE, Willmore LJ, Homan RW, et al. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res1993;14: 165-173.

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9. Ono T, Yagi K, Seino M. Clinical efficacy and safety of a new antiepileptic drug, zonisamide: a multi-institutional phase three study [in Japanese]. Clin Psychiatry1988;30:471-482.
10. Yagi K, Seino M. Methodological requirement for clinical trials in refractory epilepsies: our experience with zonisamide. Prog Neuropsychopharmacol Biol Psychiatry1992;16:79-85.
11. Peters DH, Sorkin EM. Zonisamide, a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs1993;45:760-787.
12. Arlt G, Barkley GL, Bergen D, et al. Baseline controlled safety and efficacy evaluation of zonisamide in the treatment of seizures in medically refractory patients. Files of Dainippon Pharmaceutical Co., Ltd., (#810-920). Osaka, Japan.
13. Dinner S, Fromm G, Homan R, et al. Efficacy and safety report of the extended phase of a baseline-controlled 16-week multicenter study of the efficacy and safety of zonisamide (CI-912) in medically refractory patients with seizures. Files of Dainippon Pharmaceutical Co., Ltd., (#Baseline Contr-Ext). Osaka, Japan.
14. Sackellares CJ, Donofrio PD, Berent S, et al. Overall report of the extended phase of multicenter placebo-controlled double blind study of the efficacy and safety of zonisamide (CI-912) in the complex partial seizures in medically refractory patients (USA). Files of Dainippon Pharmaceutical Co., Ltd., (#912-US-Ext). Osaka, Japan.
15. Ota Y, Nakane Y, Hironaka I, et al. Therapeutic effect of zonisamide (AD-810, ZNS) on refractory partial epilepsy [in Japanese]. J Clin Ther Med1987;3[Suppl]:1079-1087.
16. Kohsaka M, Sumi T, Hiba T, et al. The long term treatment of zonisamide for epileptic patients with intractable epilepsy [in Japanese]. J Clin Ther Med1987;3[Suppl]:1343-1352.
17. Nishiura N, Oiwa N. Clinical study of a new antiepileptic drug, AD-810 (zonisamide): long-term use in intractable patients [in Japanese]. Jpn Pharmacol Ther1987; 15:4217-4223.
18. Kanazawa O, Sengoku A, Kawai I. Experiences of zonisamide treatment on adults and children with refractory epilepsy: follow up for more than 1 year. J Jpn Epilept Soc1990;8:29-38.
19. Wilder BJ, Sackellares JC, Wilensky AJ, et al. Zonisamide as long-term treatment for refractory partial and generalized tonic-clonic seizures. Neurology1987;37[Suppl 1]:351-352.
20. Simizu A, Ikoma R, Shimizu T. Effects and side effects of zonisamide during long-term medication. Curr Ther Res Clin Exp1990;47:696-706.
21. Sugihara H, Yoneyama K, Kamo C, et al. Long-term clinical efficacy of zonisamide in patients with symptomatic epilepsies [in Japanese]. Jpn Pharmacol Ther1992;20:4657-4661.
22. Kumagai N, Seki T, Yamawaki H, et al. Monotherapy for childhood epilepsies with zonisamide. Jpn J Psychiatr Neurol1991;45: 357-359.
23. Hosoda N, Miura H, Takanashi S, et al. Once-daily dose of zonisamide monotherapy in the control of partial seizures in children with cryptogenic localization-related epilepsies: clinical efficacy and their pharmacokinetic basis. Jpn J Psychiatr Neurol1994;48: 335-337.
24. Suzuki Y, Nagai T, Ono J, et al. Zonisamide monotherapy in newly diagnosed infantile spasms. Epilepsia1997;38:1035-1038.
25. Henry TR, Leppik IE, Robert J, et al. Progressive myoclonus epilepsy treated with zonisamide. Neurology1988;38:928-931.
26. Kyllerman M, Ben-Menachem E. Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients. Epilepsy Res1998;29:109-114.
27. Schauf CL. Zonisamide enhances slow sodium inactivation in Myxicola. Brain Res1987;413:185-188.
28. Suzuki S, Kawakami K, Nishimura S, et al. Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex. Epilepsy Res1992;12:21-27.
29. Hurd RW, Wilder BJ, Wendell R, et al. Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine. Neurology1996;47:1264-1268.
30. Komatsu M, Okamura Y, Hiramatu M. Free radical scavenging activity of zonisamide and its inhibitory effect on lipid peroxide formation in iron-induced epileptogenic foci of rats. Neuroscience1995;21:23-29.
31. Mori A, Noda Y, Packer L. The anticonvulsant zonisamide scavenges free radicals. Epilepsy Res1998;30:153-158.
32. Hiramarsu M, Komatsu M, Shi M. Free radical scavenging activity of anti-convulsants on in vivo study of iron-induced epileptogenic foci of rats [in Japanese]. Annu Rep Jpn Epilepsy Res Found1997;9:91-96.
33. Fukuda M, Masuda Y. Cerebral protective effect of zonisamide and its clinical experience on post operative seizures [in Japanese]. Jpn Pharmacol Ther1991;19:2011-2018.
34. Nakamura N, Ishijima B, Mayanagi Y. A randomized controlled trial of zonisamide in postoperative epilepsy: a report of the cooperative group study. Jpn J Neurosurg1999;8:647-656.
35. Report of post marketing surveillance of excegran: II general survey. Dainippon Pharmaceutical Co., Ltd., Osaka, Japan, 1997.
36. Ito T, Yamaguchi T, Miyazaki H, et al. Pharmacokinetic studies of AD-810, a new antiepileptic compound: phase I trials. Arzneimittelforschung1982;32:1581-1586.