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PubMed2005

In vivo evaluation of the effect of zonisamide on the hippocampal redox state during kainic acid-induced seizure status in rats.

The aim in this study is to observe the hippocampal redox state during kainic-acid (KA)-induced seizure status, and examine the effect of systemic preinjection of anticonvulsant zonisamide (ZNS) on the hippocampal redox. To perform under a freely moving state, in vivo microdialysis method was applied to electron paramagnetic resonance (EPR) spectroscopy. Half-life of 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (PCAM), a five-membered ring nitroxide radical, was used for the indicator of the hippocampal antioxidant ability. The changes in EPR signal intensities of PCAM decreased exponentially in all rats used. The average half-lives of PCAM was significantly shorter in the rats pretreated with ZNS than that of control group, and while the average half-lives of PCAM in the perfusate was significantly longer in the rats KA-induced status epilepticus than that of control (P < 0.01). Those of PCAM in the ZNS-pretreated rats followed by KA-injection were almost the same as those of control. These findings indicate that the pretreatment of ZNS increased the antioxidant ability in the hippocampus during KA-induced seizure. This study is the first in vivo evaluation of the antioxidant ability of ZNS as neuroprotective role against the free radicals performed under the condition of freely moving rats during seizure status.

Animals↗
PubMed1996

Relationships between convulsive seizures and serum and brain concentrations of phenobarbital and zonisamide in mutant inbred strain EL mouse.

We evaluated the anticonvulsive effects of phenobarbital (PB) and zonisamide (ZNS) in the EL mouse, a strain that is highly susceptible to seizures. The concentration of each agent was analyzed in the serum and brain. PB suppressed the seizures dose-dependently, whereas even the higher dose of ZNS was ineffective in achieving a complete suppression. Serum and brain concentrations of these two drugs increased in proportion to the higher dose injected intraperitoneally. Brain concentration of PB was lower than the serum concentration, while the brain concentration of ZNS exceeded that in serum. Although serum concentration of ZNS was essential unchanged after the combined administration of PB and ZNS, the concentration of ZNS in brain tended to rise in proportion to the highly dose of PB. Combined administration was more effective than other treatment alone. Results indicated that brain concentration of ZNS especially after concomitant PB administration, were higher than that would be expected from the concentration of ZNS in serum.

Animals↗
PubMed1987

Increasing anticonvulsant effect of AD-810 (zonisamide) in aging BDF1 mice.

The anticonvulsant efficacy of a newly developed anticonvulsant, AD-810 (zonisamide, 3-sulfamoylmethyl-1,2-benzisoxazole) was examined in relation to mouse age in three different age groups of female BDF1 mice (7-, 25- and 29-month-old). The minimal effective concentration (MEC) of AD-810 in both plasma and brain for abolishing the electroshock-induced maximal seizure steadily decreased with age, the 25- and 29-month values being 50 and 30% of respective 7-month values. The observation in the present study was almost identical to previous observations by the authors on phenytoin, phenobarbital and oxazepam. The present results support our previous contention that the dose and plasma concentration of anticonvulsants can (and probably should) be reduced in the elderly regardless of the drug. Since the anticonvulsant mechanism of AD-810 has been reported to differ from those of previously examined drugs (phenobarbital and oxazepam), the results also suggest that the apparent increase in the pharmacological effect of these anticonvulsants may be due to old animals' lowered response capability for seizures rather than a specific age effect on the pharmacological reaction sites for individual anticonvulsants.

Aging↗
PubMed1992

Methodological requirements for clinical trials in refractory epilepsies--our experience with zonisamide.

1. The guidelines for clinical evaluation of antiepileptic drugs (AEDs), proposed by the International League Against Epilepsy in 1989, were scrutinized through our clinical experiences with zonisamide. 2. Seizure type, seizure frequency, number of concomitant AEDs, and type of epilepsy were found to be essential factors in quantitatively determining the efficacy of a new drug. 3. The majority of patients selected according to the guidelines consist inevitably of those with complex partial seizures with or without secondary generalization. Consequently, the efficacy of new AEDs is evaluated mainly in patients with partial seizures, and it is difficult to evaluate their efficacy in those with refractory generalized seizures, either convulsive or nonconvulsive. 4. In order to avoid such predilection, patients with various types of generalized seizures who are taking one or two conventional AEDs should account for 30 to 40% of the total patient population selected for clinical drug trials.

Adolescent↗
PubMedDate not supplied

Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding.

The influence of co-medication with zonisamide (ZNS) on the serum concentration and protein binding of phenytoin (PHT) and sodium valproate (VPA) was studied in 21 pediatric patients. No significant correlation between the daily ZNS dose, and total serum concentrations, free concentrations or free fractions (FF) of PHT or VPA was observed. The patient study showed that changes in the FF of PHT and VPA were correlated more closely with the serum protein and bilirubin levels than changes in the ZNS dosage. An in vitro study revealed that the addition of ZNS caused decreases in the FF of PHT and VPA. However, these decreases were within the range of measurement error and were negligible. In conclusion, no significant effect of ZNS on the serum concentration or protein binding of PHT or VPA was demonstrated.

Adolescent↗
PubMed1993

Efficacy and safety of zonisamide: results of a multicenter study.

The safety and efficacy of zonisamide (ZNS), a new antiepileptic drug, was tested in 167 adult participants who entered a historical-controlled 16-week open label, multicenter study. The median percent reduction from baseline of partial seizures was 51.8% in the fourth month of the study (baseline median = 11.5 sz/month; treatment weeks 13-16 = 5.5 sz/month). Persons completing the efficacy study successfully were eligible for a long-term safety study; 113 entered this study. Adverse effects involved principally the CNS and were similar to those seen with other antiepileptic drugs. Four persons (3.7%) developed kidney stones and were withdrawn from the study 250-477 days after starting ZNS. Because of the high percentage of kidney stones, development of ZNS was stopped in the United States but was continued in Japan.

Adolescent↗
PubMed1995

Effects of zonisamide on dopaminergic system.

Effects of zonisamide (ZNS) on extracellular dopamine (DA), its precursor 3,4-dihydroxyphenylalanine (DOPA), its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in the striatum as well as hippocampus of freely moving rats were studied. Intracellular DA, DOPA, DOPAC and HVA levels, as well as DOPA accumulation as an index of tyrosine hydroxylase activity in the rat brain in vivo, DA re-uptake in the striatum and hippocampus, and monoamine oxidase (MAO) activities were also determined. Acute administrations of therapeutic ZNS doses (20 and 50 mg/kg) increased striatal extracellular DOPA levels, intracellular striatal and hippocampal DOPA levels, and stimulated DOPA accumulation in both brain regions. ZNS also increased striatal and hippocampal intracellular as well as extracellular DA and HVA levels, but decreased those of DOPAC levels. Chronic (3 weeks) administrations of therapeutic ZNS doses (20 and 50 mg/kg/day) increased intracellular DA, DOPA, DOPAC and HVA levels in striatum and hippocampus. ZNS-induced changes were greater in intracellular levels than in extracellular levels. Acute and chronic supratherapeutic ZNS dose (100 mg/kg) administration decreased intracellular levels of all substances detectable in both brain regions, and inhibited DOPA accumulation. Both subtypes of MAO (type A and type B) activities were weakly inhibited by ZNS. ZNS showed no effect on DA re-uptake in striatum nor in hippocampus. These results suggest that therapeutic ZNS doses increase DOPA accumulation as well as both intracellular and extracellular DA, DOPA and HVA levels. However, such doses also decrease extracellular and intracellular DOPAC levels by enhancing DA synthesis and/or by selectively inhibiting MAO-B activities. In addition, chronic therapeutic ZNS dose administration enhances DA synthesis, which results in increased intracellular DA, its precursor and its metabolites levels. On the other hand, both acute and chronic supratherapeutic ZNS dose administrations inhibit DA turnover. These ZNS effects on DA metabolism are at least partly involved in the mechanisms of action of ZNS.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Zonisamide for West syndrome: a comparison of clinical responses among different titration rate.

We administered zonisamide (ZNS) to patients with West syndrome in different titration protocols and compared their short-term therapeutic effects. We designed three protocols to raise the serum ZNS concentration (SZC): (1) increase the dose in three steps, from 3 to 10 mg/kg every 3 days, (2) increase the dose from 5 to 10 mg/kg over 3-7 days, and (3) start with 10 mg/kg and maintain this dosage for 2 weeks. The subjects were 23 infants with West syndrome, 8 of whom comprised the 1st group, 5 the 2nd group, and the remaining 10, the 3rd group. As a result, excellent and good effects were obtained in a total of seven patients (30.4%) and one patient, respectively (1/8 in the 1st step-up group, 3/5 in the 2nd step-up group, and 4/10 in the 3rd group). The maximum SZC was higher in the excellent and good effect groups (n=8; 32.0+/-8.0 microg/ml) than in the ineffective group (n=15; 22.4+/-8.2 microg/ml) (P<0.05). The period of time required for cessation of spasms appeared shorter in the 3rd group (n=4; mean=5.7 days) than in the 1st and 2nd groups (n=4; mean=10.3 days). There were few side effects except for transient hyperthermia and gastrointestinal symptoms. Our new protocol of starting with 10 mg/kg of ZNS can be introduced safely and make a therapeutic judgment feasible within 2 weeks.

Anticonvulsants↗
PubMed2005

Zonisamide at clinically relevant concentrations inhibits field EPSP but not presynaptic fiber volley in rat frontal cortex.

We investigated the effect of Zonisamide (ZNS), a newer anti-epileptic drug, on field potentials and neuropropagation in rat frontal cortex, with the aid of the 64-channel multi-electrode dish (MED64) system. The amplitude and propagation of field potentials were expressed dimensionally in the MED64 system. ZNS (3-100 microM) inhibited the amplitude and propagation of field excitatory postsynaptic potentials (fEPSP) in a concentration dependent manner. In contrast, ZNS could not suppress the amplitude and propagation of the presynaptic fiber volley (PrV) at clinically relevant concentrations (10-30 microM). Stimulating dependency with reduction fEPSP was seen in the presence of ZNS at clinically relevant concentrations, but not with PrV. The reduction of fEPSP amplitude was not accompanied by a change in paired-pulse facilitation. These data suggest that at clinically relevant concentrations of ZNS, the suppression of neuronal propagation is at least partially due to the postsynaptic mechanism, probably through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Action Potentials↗
PubMed2005

Effects of zonisamide on neurotransmitter exocytosis associated with ryanodine receptors.

To clarify the antiepileptic and neuroprotective actions of zonisamide (ZNS), we determined acute effects of ZNS on exocytosis of GABA and glutamate associated with ryanodine-receptor (Ryr) in rat hippocampus using microdialysis. ZNS increased basal GABA release concentration-dependently without affecting basal glutamate release; however, K(+)-evoked glutamate and GABA releases were reduced by ZNS concentration-dependently. Inhibition of Ryr reduced K(+)-evoked GABA and glutamate releases without affecting their basal releases. Ryanodine affected GABA and glutamate releases biphasic concentration-dependently: lower concentration of ryanodine increased both basal and K(+)-evoked releases of GABA and glutamate, whereas higher concentration reduced them. The therapeutically relevant concentration of ZNS inhibited ryanodine-induced GABA and glutamate releases, and abolished the inflection point in concentration-response curve for ryanodine on neurotransmitter exocytosis. These data suggest that ZNS elevates seizure threshold via enhancement of GABAergic transmission during resting stage. ZNS inhibits propagation of epileptic hyperexcitability and Ryr-associated neuronal damage during neuronal hyperexcitable stage. These demonstrations indicate that the indirect inhibition of Ryr activities by ZNS during neuronal hyperexcitability appear to be involved in the mechanisms of action of antiepileptic and neuroprotective actions of ZNS.

Animals↗
PubMed2006

Interactions between zonisamide and conventional antiepileptic drugs in the mouse maximal electroshock test model.

Despite the major advances in antiepileptic drug (AED) therapeutics, about one third of patients with epilepsy still do not have adequate seizure control with currently available AEDs when prescribed as monotherapy. Typically, in this setting polytherapy with two or more AEDs is used. Zonisamide (ZNS) is a new AED effective in the treatment of refractory epilepsy and since it is only prescribed in polytherapy regimens, its interactions with other AEDs is of particular importance. The aim of this study was to isobolographically determine interactions between ZNS and four conventional AEDs: carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA), in the mouse maximal electroshock (MES)-induced seizure model. The total brain concentrations of conventional AEDs and ZNS were measured with immunofluorescence and high-pressure liquid chromatography (HPLC), respectively, in order to determine any pharmacokinetic contribution in any observed interactions. With isobolography, synergistic interactions were observed for the combination of ZNS plus VPA and ZNS plus PHT at the fixed-ratio of 1:1, while additivity was observed for their combinations at the remaining dose ratios of 1:3 and 3:1. In contrast, the interactions between ZNS and PB and between ZNS and CBZ, applied at the fixed-ratios of 1:3, 1:1 and 3:1 proved to be additive. None of these AED combinations were associated with motor and long-term memory impairment. Furthermore, whilst brain AED concentrations were unaffected by ZNS, PHT significantly increased and PB reduced brain ZNS concentrations. Thus, the resultant interactions between ZNS and PHT and between ZNZ and PB were consequent to both pharmacodynamic and pharmacokinetic components. Finally, one can conclude that because of the synergistic pharmacodynamic interaction between ZNS and VPA, this combination might be useful in clinical practice.

Animals↗
PubMed2006

Simultaneous determination of zonisamide, carbamazepine and carbamazepine-10,11-epoxide in infant serum by high-performance liquid chromatography.

This study developed a simple method for the simultaneous determination of zonisamide (ZNS), carbamazepine (CBZ) and its active metabolite, carbamazepine-10,11-epoxide (CBZE) in infant serum using reversed-phase high-performance liquid chromatograph (HPLC). The method involves a single-step protein precipitation procedure that uses no solid-phase or liquid-liquid extraction. The HPLC separation was carried out on a Cadenza CD-C18 column (3 microm, 4.6 mm x 150 mm) with potassium phosphate buffer (pH 4.6; 25 mM)-methanol-acetonitrile (65:20:15 (v/v/v)) as a mobile phase at a 1.0 ml/min flow rate: ZNS was detectable using a UV detector at 235 nm, and both CBZ and CBZE were at 215 nm. The quantification limits were established in accordance with each therapeutic range at 2.5 microg/ml for ZNS, 0.5 microg/ml for CBZ, and 0.25 microg/ml for CBZE. The respective coefficients of variation were 1.3-6.0% and 2.2-7.7% for the intra- and inter-assay.

Anticonvulsants↗
PubMed2005

Differential effects of vigabatrin and zonisamide on the neuropeptide Y system in the hippocampus of seizure prone gerbil.

Changed neuropeptide Y (NPY) system in the hippocampus has been reported in various experimental epileptic models. However, there have been little data concerning the alteration in the NPY system in the epileptic hippocampus following treatment of anti-epileptic drugs (AEDs). In the present study, therefore, we performed analyses of effects of vigabatrin (VGB) and zonisamide (ZNS) treatment on the NPY system in the hippocampus of the seizure sensitive (SS) gerbils. In SS gerbil, NPY immunoreactivity in the hippocampus was lower than that in seizure resistant gerbil. Following VGB treatment, the number of NPY immunoreactive neurons and NPY mRNA expression were increased in the hilus and the hippocampus proper. In contrast, ZNS treatment markedly elevated only the density of NPY immunoreactive fibers in the dentate gyrus, not in the hippocampus proper, as compared with saline-treated animals. These patterns were observed in the dose-dependent manners. These findings suggest that AEDs treatments may distinctly affect the NPY system in the SS gerbil hippocampus.

Animals↗
PubMed2005

Effect of zonisamide on essential tremor: a pilot crossover study in comparison with arotinolol.

We performed a pilot, crossover trial of zonisamide (ZNS) on essential tremor patients. Patients were randomly selected to start either ZNS or arotinolol treatment for 2 weeks. After a washout period, the patients were switched to an alternative drug. The assessment of tremor was carried out using the Fahn-Tolosa-Marin's clinical rating scale for tremor at baseline and 2 weeks after administration of each drug. There was a significant improvement after ZNS and arotinolol administration compared with the baseline. There was no significant difference in the antitremor effect between ZNS and arotinolol; however, ZNS was more effective for tremors of cranial nerve areas. Although the number of enrolled patients was limited in the present study, this open-label pilot study suggests that ZNS may have a therapeutic potential for essential tremor. A controlled trial of this drug in the future would be valuable.

Adrenergic alpha-Antagonists↗
PubMed2004

Zonisamide monotherapy with once-daily dosing in children with cryptogenic localization-related epilepsies: clinical effects and pharmacokinetic studies.

Clinical effects and pharmacokinetics of once-a-day pediatric zonisamide (ZNS) monotherapy were investigated in 72 children (range, 3 months to 15 years; mean age, 8 years and 3 months) with cryptogenic localization-related epilepsies with simple, complex, or secondarily generalized partial seizures; none had prior epilepsy treatment. ZNS was initiated at 2mg/kg; daily dosage was doubled at weekly intervals to achieve maintenance dosage (8.0 mg/kg; mean, 7.97 +/- 0.55 mg/kg). Blood samples determined trough and peak plasma levels; levels were 27.0 +/- 9.4 microg/ml and 33.8 +/- 10.8 microg/ml, respectively, with ratios as small as 1.28 +/- 0.15. Plasma level to dose ratios increased with age; peak-to-trough ratios were not age variable. Seizures were not controlled in 23 of 72 patients; low trough plasma levels (approximately 15 microg/ml) were observed. Drowsiness/short attention span in five patients instigated a dosage decrease (peak plasma levels >40 microg/ml). During treatment (6-43 months; mean, 27.2 months), seizure control occurred in 57 of 72 patients (79.2%), including eight refractory patients. In 12 patients with uncontrolled seizures and high ZNS levels, carbamazepine (CBZ) was added (BID; mean total dose, 15.1 +/- 3.0 mg/kg) to ZNS (QD; mean dose, 11.1 +/- 2.5 mg/kg); drug interactions were examined.

Adolescent↗
PubMed2003

Effects of valproate, phenytoin, and zonisamide on clonic and tonic seizures induced by acute and repeated exposure of mice to flurothyl.

The effects of valproate (VPA), zonisamide (ZNS), and phenytoin (PHT) on flurothyl (FE)-induced generalized seizure were investigated in mice. In the FE kindling model, eight daily FE-induced generalized clonic seizures followed by a 28-day stimulation-free interval converted the type of seizure expressed in response to FE from clonic to tonic. In an acute FE trial experiment, the latencies of clonic and tonic seizures were prolonged significantly and dose-dependently by the administration of VPA. ZNS and PHT did not show any effect on the latencies of tonic seizure. When the same three drugs were administered to mice daily for 8 days prior to the FE trial, changes in the seizure phenotypes from clonic to tonic seizure were significantly inhibited by VPA and ZNS, but not by PHT. These results suggest that VPA and ZNS possess significant antiepileptogenic properties. PHT apparently does not share this property to the same degree in the present FE-induced model.

Animals↗
PubMed2001

Zonisamide has beneficial effects on Parkinson's disease patients.

Zonisamide (ZNS) is a generally well tolerated anticonvulsant that has beneficial effects on Parkinson's disease (PD). ZNS (300 mg/day) given to a patient with PD who incidentally had convulsive attacks, ameliorated the attacks and, surprisingly, his parkinsonian symptoms. We, therefore, carried out an open trial of ZNS on nine patients with PD. Patients were given 50-200 mg/day ZNS in addition to their anti-PD drugs. Seven clearly showed lessening of symptoms, especially wearing-off. We speculate that long lasting activation of dopamine synthesis by ZNS ameliorates parkinsonian symptoms, in particular wearing-off.

Aged↗
PubMed2003

Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures.

Epileptiform discharges and behavioral seizures may be the consequences of excess excitation associated with the neurotransmitter glutamate, or from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are terminated by the action of transporter proteins that remove amino acids from the synaptic cleft. Excitation initiated by the synaptic release of glutamate is attenuated by the action of glial transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), and the neuronal transporter excitatory amino-acid carrier-1 (EAAC-1). GABA is removed from synaptic regions by the action of the transporters proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). In this experiment, albino rats with chronic, spontaneous recurrent seizures induced by the amygdalar injection of FeCl3 were treated for 14 days with zonisamide (ZNS) (40 mg/kg, i.p.). Control animals underwent saline injection into the same amygdalar regions. Treatment control for both groups of intracerebrally injected animals was i.p. injection of equal volumes of saline. Western blotting was used to measure the quantity of glutamate and GABA transporters in hippocampus and frontal cortex. ZNS caused increase in the quantity of EAAC-1 protein in hippocampus and cortex and down regulation of the GABA transporter GAT-1. These changes occurred in both experimental and ZNS treated control animals. These data show that the molecular effect of ZNS, with up-regulation of EAAC-1 and decreased production of GABA transporters, should result in increased tissue and synaptic concentrations of GABA. Although many antiepileptic drugs have effects on ion channels when measured in vitro our study suggests that additional mechanisms of action may be operant. Molecular effects on regulation of transporter proteins may aid in understanding epileptogenesis and inform investigators about future design and development of drugs to treat epilepsy.

Amino Acid Transport System X-AG↗