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PubMed2004

Review of zonisamide development in Japan.

Zonisamide is a benzisoxazole-based compound first synthesized in the early 1970s by the research laboratories of Dainippon Pharmaceutical Company in Osaka, Japan. Identified as an anticonvulsant during exploratory research, zonisamide has since been characterized as having broad-spectrum antiepilepsy and neuroprotective effects. Early clinical studies in Japan demonstrated that zonisamide has a long elimination half-life and is well tolerated; Phase II and III clinical trials established the drug's efficacy and safety for the treatment of partial and generalized seizures. In 1989, zonisamide was approved and marketed in Japan under the trade name of Excegran. Data from postmarketing surveillance studies and clinical observations over 10 years of use have continued to support zonisamide's efficacy and safety, identified its usefulness as monotherapy, and characterized its effectiveness for various seizure types and epilepsy syndromes.

Animals↗
PubMed2006

Long-term efficacy and safety of monotherapy and adjunctive therapy with zonisamide.

The long-term effects of zonisamide as monotherapy or adjunctive therapy were investigated in patients with seizure disorders. One hundred twelve adult neurology patients treated with zonisamide were retrospectively identified through a chart review; 90 patients (n=45 monotherapy, n=45 adjunctive therapy) who received zonisamide for 3 months were included in the efficacy-evaluable population, and all 112 patients were included in the safety population. The average duration of treatment was 24.3 months (range, 3-46 months), and the average zonisamide dosage was 324 mg/day (range, 100-1000 mg/day). Thirty-eight of 90 patients (42%; n=25 monotherapy, n=13 adjunctive therapy) were seizure-free, and an additional 26 patients (29%; n=9 monotherapy, n=17 adjunctive therapy) had 50% seizure frequency reduction at the last follow-up visit. Thirty of 112 patients (27%) reported mild to moderate adverse events, such as weight loss (5.4%), fatigue (4.5%), and sedation (2.7%). Zonisamide, as monotherapy or adjunctive therapy, was a safe, effective, and well-tolerated long-term treatment option in patients with various seizure types.

Adolescent↗
PubMed1997

Zonisamide as a neuroprotective agent in an adult gerbil model of global forebrain ischemia: a histological, in vivo microdialysis and behavioral study.

Brief periods of global cerebral ischemia are known to produce characteristic patterns of neuronal injury both in human studies and in experimental animal models. Ischemic damage to vulnerable areas such as the CA1 sector of the hippocampus is thought to result from excitotoxic amino acid neurotransmission. The objective of this study was to determine the ability of a novel sodium channel blocking compound, zonisamide, to reduce neuronal damage by preventing the ischemia-associated accumulation of extracellular glutamate. Using a gerbil model, animals were subjected to 5 min ischemic insults. Both pre- and post-ischemic drug administration (zonisamide 150 mg/kg) were studied. Histological brain sections were prepared using a silver stain at 7 and 28 days post ischemia. The animals sacrificed at 28 days also underwent behavioral testing using a modified Morris water maze. In vivo microdialysis was performed on a separate group of animals in order to determine the patterns of ischemia-induced glutamate accumulation in the CA1 sector of the hippocampus. Pyramidal cell damage scores in the CA1 region of the hippocampus were significantly reduced in animals pre-treated with zonisamide compared to saline-treated controls, both at 7 days (drug pre-treated: 0.812 +/- 0.28, n = 8; controls: 1.625 +/- 0.24, n = 8; *P < 0.05) and 28 (drug pre-treated: 0.833 +/- 0.22, n = 12; controls: 1.955 +/- 0.26, n = 11; **P < 0.01) days post ischemia. However, animals receiving zonisamide post-treatment did not display significant differences from controls. Behavioral studies also showed significant preservation of function in drug-treated animals. Microdialysis studies confirmed a reduction in glutamate release in drug-treated animals compared to saline-treated controls. Our data suggest that zonisamide is effective in reducing neuronal damage by a mechanism involving decreased ischemia-induced extracellular glutamate accumulation and interruption of excitotoxic pathways.

Animals↗
PubMed2002

Pharmacokinetics of zonisamide in perinatal period.

Zonisamide is widely used for intractable epilepsy and the effects of this drug on fetuses and neonates through the mother taking it for epilepsy need to be clarified. We measured the zonisamide concentration in plasma and breast milk using high-performance liquid chromatography to investigate the transfer of zonisamide through the placenta and breast milk, as well as its pharmacokinetics, in two neonates born to epileptic mothers receiving zonisamide. The transfer rates were 92% via the placenta and 41-57% through the breast milk. The first-order kinetics of zonisamide in the two infants was elimination half-lives of 109 and 61h, respectively.

Adult↗
PubMed1998

Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients.

Progressive myoclonic epilepsy (PME) syndromes are intractable to most antiepileptic drugs (AED). The course of these diseases, results in almost total dependency due to continuous myoclonias, repeated episodes of status epilepticus, ataxia and dementia. The need for new treatment strategies is therefore imperative. Zonisamide has previously been reported to be effective in two patients with PME. Case reports of seven patients (ages 19-42) with Unverricht-Lundborgs disease (ULD) and one Lafora Body Disease are presented. Zonisamide was given at doses of 100-600 mg/day for a period of 2 to 3 years. Concomitant AEDs were usually valproate and a benzodiazepine. Zonisamide dramatically reduced the amount of myoclonias and generalized seizures. In three of the cases, the initial dramatic effect on myoclonias wore off after 2-4 years of treatment but patients still experienced moderate efficacy for generalized tonic-clonic seizures. The dramatic reduction of stimulus sensitivity for light, touch and startle by zonisamide was sustained in all patients with ULD. Zonisamide may be a useful agent in the treatment of PME. Controlled clinical trials are warranted to further investigate the antiepileptic effects of this drug, in difficult to treat epileptic syndromes.

Adult↗
PubMed1996

Mechanisms of T-type calcium channel blockade by zonisamide.

We investigated the effects of zonisamide, a new antiepileptic drug, on voltage-dependent T-type calcium current (ICa) in cultured neuroblastoma cells of human origin (NB-I). Zonisamide reduced T-type ICa in a concentration-dependent manner without evoking any change in its inactivation kinetics or voltage dependence of action. The mean percent reduction was 38.3 +/- 5.8% at 50 microM. Further, zonisamide shifted the inactivation curve approximately 20 mV negative compared to the control. These resting blocking actions suggest that zonisamide shifts the channel population toward the inactivation state, allowing fewer channels to open during membrane depolarization. The blockade of T-type calcium channels by zonisamide could suppress an important component of inward current that underlies epileptiform cellular bursting, thereby inhibiting the spread of seizure activity.

Anticonvulsants↗
PubMed1986

Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy.

Zonisamide (CI-912) is an experimental antiepileptic drug. Since this drug is to be evaluated initially as an add-on medication, an investigation was conducted to study its kinetics in the presence of two standard antiepileptic drugs. Patients in two groups, one on maintenance phenytoin (PHT) monotherapy and the other on maintenance carbamazepine (CBZ) monotherapy, each received a single dose of four 100-mg capsules of zonisamide; and blood samples were obtained at periodic intervals. Plasma and red blood cell (RBC) concentrations of zonisamide were measured by high performance liquid chromatography. Plasma and RBC areas under the curve produced by single doses of zonisamide in patients receiving CBZ were significantly higher than those receiving PHT (p less than 0.05). Clearance values, although not statistically significantly different, were lower for the CBZ group; and consistent with this, plasma and RBC concentrations decreased more rapidly in the PHT group. The approximate values for t1/2 were 36.4 h in plasma and 54.2 h in RBC for patients treated with CBZ, and 27.1 h in plasma and 35.8 h in RBC for patients treated with PHT. The RBC/plasma ratio varied eightfold within a given curve. These findings suggest that the dosage of zonisamide in epileptic patients might need to be varied depending on the comedication.

Adolescent↗
PubMed2005

Clinical experience with zonisamide monotherapy and adjunctive therapy in children with epilepsy at a tertiary care referral center.

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.

Adolescent↗
PubMed2005

Broad-spectrum efficacy of zonisamide at 12 months in children with intractable epilepsy.

In a retrospective study of 35 children (ages 8 months to 22 years; mean age 9 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of zonisamide therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications, and the number of previous anticonvulsant drugs. Good to excellent seizure control (50-100% reduction) was attained in seven (54%) patients with generalized seizures, two (40%) patients with focal seizures, five (35%) patients with mixed seizures, and one (33%) patient with infantile spasms. In this group of children, the efficacy of zonisamide was comparable for focal, generalized, and mixed seizures. The efficacy of zonisamide was independent of cognitive status. Adverse effects were not associated with a higher mean dose. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of zonisamide and levetiracetam had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of mechanisms of action of zonisamide and levetiracetam and/or their pharmacodynamic interactions.

Adolescent↗
PubMed1994

Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients.

The pharmacokinetics of zonisamide was studied using routine therapeutic drug monitoring data from 68 epileptic patients. The 266 serum concentration data at steady-state after repetitive oral administration were analyzed using the nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose-dependent clearance was used for the pharmacokinetic analysis of zonisamide. The volume of distribution (V) was estimated to be 1.27 l/kg in a typical 33-kg patient, assuming that the bioavailability of orally administered zonisamide is 100%. The maximal daily dose to be cleared (Vmax) and the concentration giving half maximal clearance (a Michaelis-Menten constant) was 27.6 mg/d/kg and 45.9 micrograms/ml, respectively. The parameter of a power function of weight to adjust V and Vmax was estimated to be 0.741. In addition, Vmax for zonisamide appears to be 13% increased in patients receiving carbamazepine concurrently. The population pharmacokinetic parameters of zonisamide will be useful for designing dosage regimens in epileptic patients.

Administration, Oral↗
PubMed2004

Effects of the antiepileptics phenytoin and zonisamide on dentin formation and bone mineral density of the mandible in growing rats.

This study was undertaken to examine the effects of the antiepileptics phenytoin and zonisamide on changes in the mineral density of the incisor and bone mineral density (BMD) of the mandibular head, and on the rate of dentin formation using histomorphometric measurements. After repeated administration of phenytoin or zonisamide to male growing rats, the mineral density of the lower incisors and mandibular head were determined by analyzing microradiographs and dentin formation rates were determined by histomorphometric measurements. Results showed a significant decrease in the mean values of BMD of the mandibular head and lower incisors in groups treated with phenytoin or zonisamide compared with the vehicle-treated group (p < 0.05). The percent rates of decrease in mineral density of the incisors for phenytoin and zonisamide were 6.8% and 4.0%, respectively. Phenytoin and zonisamide significantly reduced the dentin formation rate for the mesial and distal areas compared with the vehicle-treated group. Thus, epileptic children who are treated over a long period with antiepileptics, especially at primary school age, should ensure good oral hygiene so as not to suffer bone loss, edentulism or gingival overgrowth.

Animals↗
PubMed1999

The effects of exposure to cigarette smoke on the pharmacokinetics and pharmacodynamics of zonisamide in rats.

The effects of exposure to cigarette smoke on the pharmacokinetics and pharmacodynamics of zonisamide, an antiepileptic drug, were investigated in rats. Absorption of oral zonisamide was significantly inhibited by exposure to cigarette smoke. The Cmax, T1/2 and the area under the plasma concentration-time curve 0-24 values in the cigarette smoke exposure group were significantly lower than those in the control group. Although tonic extension (TE) induced by maximal electroshock was completely blocked by the administration of zonisamide in the control group, 50% of rats showed TE in the cigarette smoke exposure group. Exposure to cigarette smoke influences both the pharmacokinetics and antiepileptic effects of zonisamide. The effects of smoking on epileptic patients using zonisamide warrants further attention.

Animals↗
PubMed2005

Open-label adjunctive zonisamide in the treatment of bipolar disorders: a prospective trial.

BACKGROUND: The response of 62 outpatients with DSM-IV bipolar disorders to open-label adjunctive zonisamide was evaluated in a prospective 8-week acute trial, followed by a 48-week continuation trial, conducted from June 2001 through May 2002. METHOD: During the acute trial, response to zonisamide was assessed weekly for the first 4 weeks and every 2 weeks for the second 4 weeks with the Clinical Global Impressions scale modified for bipolar illness (CGI-BP), the Young Mania Rating Scale (YMRS), and the Inventory for Depressive Symptomatology (IDS). During the continuation trial, patients were assessed with these scales every 4 weeks. Patients' weights and side effects were also evaluated. Outcome measures were analyzed with repeated-measures analyses of variance. RESULTS: Patients with manic symptoms at study entry (N = 34) displayed significant reductions in CGI-BP-Mania Severity and YMRS scores in the acute and continuation (N = 19) trials (p values < .0001 and < .001, respectively). Patients with depressive symptoms at study entry (N = 22) showed significant decreases in CGI-BP-Depression Severity and IDS scores in the acute trial (p values < .001 and < .05, respectively), but only 9 patients entered the continuation trial. Among these 9 patients, maintenance of anti-depressant response was mostly maintained. Initially euthymic patients (N = 6) showed no change in any rating scale scores acutely, but 2 of 4 patients who entered the continuation trial developed depressive symptoms. The 62 patients as a group showed significant weight loss in both trials (p values < .001). However, 20 patients (32%) discontinued zonisamide for worsening mood symptoms. CONCLUSION: Adjunctive zonisamide was associated with beneficial effects on mood and body weight in some patients with bipolar disorders, but was also associated with a high discontinuation rate due to worsening mood symptoms. Double-blind, placebo-controlled studies are necessary to determine zonisamide's thymoleptic properties, if any, in bipolar disorders.

Adult↗
PubMed1990

Effect of zonisamide on serum immunoglobulins.

Zonisamide (AD-810) was additionally administered to 19 patients with refractory epilepsy who had been receiving multiple antiepileptic drugs and the effect of zonisamide on serum immunoglobulins was investigated. Zonisamide was administered in daily dose of 200-700 mg (mean 389 mg) for the period of 82-1,470 days (mean 863 days). The serum levels of IgG, IgA and IgM were determined before administration and at intervals of 3 or 6 months over the period of a maximum of 48 months after initiation of administration. There was no significant change in immunoglobulin levels at any time after initiation of zonisamide treatment as compared with the pretreatment levels. No significant correlation was found between the dose or serum concentration of zonisamide and the immunoglobulin levels.

Adolescent↗
PubMed1993

Characterization of human liver microsomal cytochrome P450 involved in the reductive metabolism of zonisamide.

Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was metabolized to 2-sulfamoylacetylphenol (SMAP) in human liver microsomes under anaerobic conditions. The formation of SMAP was remarkably inhibited by cimetidine, n-octylamine, ketoconazole, and carbon monoxide, indicating that a cytochrome P450 is involved in the metabolism of zonisamide to SMAP in human liver microsomes. The SMAP-producing activity did not correlate with the spectrally determined amount of cytochrome P450. In contrast, the SMAP-producing activity from zonisamide correlated closely with the activity of testosterone 6 beta-hydroxylase (r2 = 0.96) and correlated slightly but significantly with the activity of imipramine 2-hydroxylase (r2 = 0.28), but not with those of aniline hydroxylase (r2 = 0.09) or benzphetamine N-demethylase (r2 = 0.20). In addition, immunoquantitation of cytochrome P450 enzymes in 21 human liver microsomal samples revealed that SMAP formation correlated closely with the amount of P450 3A enzyme and correlated moderately well with that of P450 2D6 but not with that of P450 2C enzyme in human liver microsomes. P450 3A4 exhibited SMAP-producing activity in a reconstituted monooxygenase system. The metabolism of zonisamide to SMAP was almost completely inhibited by anti-P450 3A4 antibody but not by anti-P450 2C9 or anti-P450 2D6 antibodies, suggesting that the amount of P450 3A enzyme may be a major factor influencing the level of metabolism of zonisamide to SMAP in human liver microsomes.

Anticonvulsants↗
PubMed2003

Treatment of chronic pain with zonisamide.

Mechanistic similarities underlying neuropathic pain and epilepsy suggest that anticonvulsants can be used for treating neuropathic pain. This open-label prospective study assesses the use of zonisamide in patients with chronic neuropathic pain. Fifty-five patients were initiated on zonisamide, given 100 mg every fourth night and titrated to a stable maintenance dosage (mean=285 mg/d, range=100 to 700 mg/d). Patients rated their pain on a 0 to 10 scale in pain diaries. After > or =3 months on a stable maintenance zonisamide dosage, pain ratings were compared with baseline. Adverse events (AEs) were monitored. Forty-two patients had efficacy data available. Fifteen patients (35.7%) had a >50% improvement in daily pain scores; 10 patients (23.8%) had a 25% to 50% improvement. Zonisamide was well tolerated; only 5 patients discontinued for AEs (drowsiness, nausea, and itching). These results suggest that zonisamide may be useful for treating neuropathic pain. Further investigation in double-blind, placebo-controlled trials is warranted.

Journal Article↗
PubMed2007

Simultaneous determination of lamotrigine, zonisamide, and carbamazepine in human plasma by high-performance liquid chromatography.

A high-performance liquid chromatography assay with ultraviolet detection was developed for the simultaneous determination of the anti-epileptic drugs lamotrigine, carbamazepine and zonisamide in human plasma and serum. Lamotrigine, carbamazepine, zonisamide and the internal standard chloramphenicol were extracted from serum or plasma using liquid-liquid extraction under alkaline conditions into an organic solvent. The method was linear in the range 1-30 microg/mL for lamotrigine, 2-20 microg/mL for carbamazepine, and 1-40 microg/mL for zonisamide. Within- and between-run precision studies demonstrated coefficient of variation <10% at all tested concentrations. Other anti-epileptic medications tested did not interfere with the assay. The method is appropriate for determining lamotrigine, carbamazepine and zonisamide serum or plasma concentrations for therapeutic monitoring.

Adult↗
PubMedDate not supplied

Blockade of sustained repetitive action potentials in cultured spinal cord neurons by zonisamide (AD 810, CI 912), a novel anticonvulsant.

Zonisamide is a novel anticonvulsant that prevents seizures in laboratory animals and in man. Zonisamide (3 micrograms/ml and above) blocked the sustained firing of action potentials induced by depolarizing steps of current injected across the membrane of intracellularly recorded spinal cord neurons. Responses to GABA and glutamate were not altered by zonisamide, and spontaneous synaptically evoked activity was not reduced until higher concentrations of zonisamide (10 micrograms/ml) were applied.

Action Potentials↗