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PubMed2001

High-performance liquid chromatographic assay of zonisamide in human plasma using a non-porous silica column.

A new method for measuring zonisamide (ZNS) in plasma by high-performance liquid chromatography was developed by using a 2-microm reversed-phase non-porous silica column. ZNS in plasma was first purified with a column extraction technique and injected onto the non-porous silica column. Calibration curve was linear over the concentration range of 1-80 microg/ml in plasma. The recoveries of ZNS added to plasma were more than 95.4% with the coefficient of variation less than 9.0%. We developed a rapid routine method using the non-porous silica column that was accurate and improved solvent consumption in the measurement of ZNS.

Anticonvulsants↗
PubMed2000

Zonisamide - induced urinary lithiasis in patients with intractable epilepsy.

We report here three patients with intractable epilepsy who developed urinary lithiasis during zonisamide (ZNS) treatment. Abdominal pain due to left-sided hydronephrosis was the initial symptom in the first patient, and it was resolved after the excretion of a stone. The second patient, who had no specific symptoms, was found to have a thick sludge of calcium phosphate in the bladder when he suffered from aspiration pneumonia and dehydration. The third patient, who had a history of recurrent urinary obstruction, was also found to have a thick sludge of calcium oxalate in the bladder. The urinalysis of the three patients revealed alkaline urine and hypercalciuria. Although their urinary lithiasis was resolved by discontinuation of ZNS and supportive therapy, routine examination of urine parameters such as pH and sediments, and daily urine-output checks are thought to be necessary during treatment with ZNS, especially for patients who are bedridden for a long time and receive multiple antiepileptic drugs.

Adolescent↗
PubMed2001

Zonisamide in West syndrome.

Zonisamide (ZNS), a new antiepileptic drug developed in Japan, is being used as the initial treatment of West syndrome in some Japanese institutes. The reported response rate varied from 20 to 38%. The cryptogenic patients showed a better response than the symptomatic patients. A striking finding was that the response to ZNS is rapid; most of the children who responded did so within 1-2 weeks of starting ZNS at a dose of 4-8 mg/kg/day. No serious side effects have been reported so far. ZNS may be both effective and well tolerated for the initial treatment of selected patients with West syndrome.

Anticonvulsants↗
PubMed1990

Anticonvulsant effects of zonisamide and phenytoin on seizure activity of the feline visual cortex.

The acute anticonvulsant effects of zonisamide (ZNS) and phenytoin (PHT) on seizure activity produced by electrical stimulation of the feline visual cortex were studied. The intravenous administration of ZNS 60 mg/kg reduced kindled generalized seizures into partial seizures, with marked reduction in the afterdischarge duration. ZNS also suppressed focal seizure activity of the visual cortex and produced a dose-related increase in the afterdischarge threshold. The anticonvulsant effect of ZNS (60 mg/kg) was comparable to that of PHT (15 mg/kg) and was observed in the absence of neurological toxicity and background EEG changes. The present findings demonstrated that ZNS possesses potent anticonvulsant action against focal seizure and its secondary generalization from the visual cortex.

Animals↗
PubMed1999

Treatment of infantile spasms with zonisamide.

We determined the efficacy of and tolerability to zonisamide (ZNS) in newly diagnosed patients with infantile spasms. ZNS, 4-20 mg/kg per day, was introduced as an add-on therapy or monotherapy in 27 children with infantile spasms (cryptogenic, 2; symptomatic, 25). The dosage was initially 2-4 mg/kg per day, and then was increased by 2-5 mg/kg every 2-4 days until the seizures disappeared. Nine (33.3%) out of the 27 patients who were administered ZNS exhibited the disappearance of seizures. ZNS was effective in all the cryptogenic cases and seven (28.0%) of the symptomatic cases. The effective daily doses were 5-12.5 mg/kg (mean, 7.8 mg/kg), and the daily dosages were 40-100 mg (mean, 61.1 mg). The steady-state plasma ZNS concentrations were almost within the therapeutic range. The mean time interval between the start of ZNS therapy and the seizure disappearance was 5.0 days. Six (75.0%) of eight effective cases, the exception being one for whom EEG was not performed after the therapy, showed the disappearance of hypsarrhythmia. The recurrence of seizures were observed in four of the nine cases. No adverse reaction to ZNS was noted in any patient. In conclusion, ZNS treatment is considered to be worthwhile trying, for early stage therapy for infantile spasms.

Anticonvulsants↗
PubMed2001

Long-term observations of two siblings with Lafora disease treated with zonisamide.

We have reported long-term clinical follow-up for two siblings with Lafora disease, a brother and sister, one of whom autopsied. Both siblings had repeated attacks of severe myoclonus, tonic and tonic-clonic convulsions, and intractable status epilepticus. The addition of orally administered zonisamide brought about striking effective seizure control for about 12-14 years in both patients, relieving not only myoclonus and generalized tonic-clonic seizures but also intractable status epilepticus.

Adult↗
PubMed2002

Interaction between carbamazepine, zonisamide and voltage-sensitive Ca2+ channel on acetylcholine release in rat frontal cortex.

To clarify the mechanisms of action of antiepileptic drugs (AEDs), carbamazepine (CBZ) and zonisamide (ZNS), on exocytosis mechanisms, the present study determined the concentration-dependent action of CBZ and ZNS, as well as the interaction between these AEDs and voltage-sensitive Ca(2+) channel (VSCC) activity on basal, Ca(2+)- and K(+)-evoked acetylcholine (ACh) release in frontal cortex of freely moving rat using in vivo microdialysis. Perfusion with therapeutic-relevant concentrations of CBZ and ZNS increased basal ACh release, which was regulated by N-type VSCC predominantly and P-type VSCC weakly, whereas supratherapeutic-relevant concentrations of these AEDs reduced this release. The 3.4 mM Ca(2+)-evoked release, which was regulated by N-type VSCC selectively, but not by P-type VSCC, was increased by therapeutic-relevant concentrations of CBZ and ZNS, whereas this release was reduced by supratherapeutic-relevant concentrations of them. The 50 mM K(+)-evoked release, which was regulated by P-type VSCC predominantly and N-type VSCC weakly, was decreased by CBZ and ZNS, in a concentration-dependent manner. These findings indicate that the interplay between enhancement of basal ACh release and reduction of depolarization-related ACh release in the frontal cortex are at least partially involved in a common mechanism of antiepileptic action between CBZ and ZNS.

Acetylcholine↗
PubMed2002

Clobazam shows a different antiepileptic action profile from clonazepam and zonisamide in Ihara epileptic rats.

PURPOSE: Clobazam (CLB, 1,5-benzodiazepine, 1,5-BZP) has been reported to show unique antiepileptic action profile distinguishing from standard 1,4-BZPs. To further elucidate the action profile of CLB, its effects on the abnormal circling fits (ACFs) and generalized tonic-clonic convulsions (GTCs) in Ihara epileptic rats (IERs), a genetically epileptic mutant, were examined in comparison with conventional antiepileptic drugs (AEDs), a 1,4-BZP, clonazepam (CZP) and a non-BZP, zonisamide (ZNS). METHODS: The incidence of ACFs or GTCs in IERs was recorded automatically by the computer-assisted behavior monitoring system (COBAS N-IV) before, during and after the drug treatment period for 5 days in each. The drugs were orally administered twice daily. The daily and total incidences of ACFs or GTCs were calculated every each period in each dose group. The incidences of various behaviors such as feeding, gnawing and scratching recorded simultaneously were used for evaluating the behavioral activity (BA). RESULTS: CLB (30 and 60 mg/kg) prevented the appearance of ACFs and GTCs without affecting BAs. CZP (1 and 3 mg/kg) suppressed the occurrence of ACFs but induced no effect on the incidence of GTCs. Furthermore, it inhibited BAs at the same doses. ZNS (15 mg/kg) suppressed GTCs but little ACFs without affecting BA. CONCLUSION: CLB exhibited a different action profile from CZP and ZNS in a novel epileptic mutant, IERs, and was expected to be a useful AED superior to 1,4-BZPs in clinical practice.

Animals↗
PubMed1998

Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide.

Based on small numbers of patients, it is possible to make the following suggestions rather than categorical statements. For myoclonic seizures and epilepsies which are not otherwise specified, valproate seems of proven efficacy. Ethosuximide may be a useful adjunct. The exact place of lamotrigine, which controls some myoclonia and makes them worse in other patients, requires further study. The findings are clearer when specific syndromes are considered. Valproate is the treatment of first choice for benign myoclonic epilepsy in infants, myoclonic astatic epilepsy, epilepsy with myoclonic absences, eyelid myoclonia with absences, juvenile myoclonic epilepsy and progressive myoclonus epilepsy. The addition of ethosuximide to valproate can be helpful to those with myoclonic absences, where this combination appears more beneficial than either valproate or ethosuximide alone and in eyelid myoclonia with absences. Lamotrigine can be effective therapy for juvenile myoclonic epilepsy and eyelid myoclonia with absences when used alone and, in conjunction with other antiepileptic drugs (AED) (usually valproate) for early myoclonic encephalopathy, myoclonic-astatic epilepsy and particularly, epilepsy with myoclonic absences. The myoclonia of infantile neuronal ceroid lipofuscinosis respond to lamotrigine. Severe myoclonic epilepsy of infants usually worsens with lamotrigine, but occasionally, children improve. Zonisamide added to clonazepam and valproate or a barbiturate, can reduce the cascade of myoclonia in progressive myoclonus epilepsies for at least 2 years, but relapse may occur thereafter.

Anticonvulsants↗
PubMed1998

The anticonvulsant zonisamide scavenges free radicals.

Zonisamide (ZNS) is effective in animal models of epilepsy and epileptic patients. The free radical scavenging activities of ZNS were analyzed by using electron spin resonance. ZNS, in the mmolar range, scavenged hydroxyl and nitric oxide radicals in a dose-dependent manner. This suggests that the mechanism of antiepileptic effect of ZNS may involve protection of neurons from free radical damage and stabilization of neuronal membranes.

Anticonvulsants↗
PubMed1999

Biphasic effects of zonisamide on serotonergic system in rat hippocampus.

To study the mechanisms of antiepileptic action of zonisamide (ZNS), we determined the effects of ZNS on extracellular, total levels and re-uptake activity of serotonin (5-HT) in rat striatum and hippocampus. After acute administrations, plasma ZNS concentrations associated with anticonvulsive action (effective concentrations) increased the total levels of 5-HT, its metabolise (5-hydroxyindoleacetic acid: 5-HIAA) and precursor (5-hydroxytryptophan: 5-HTP). After chronic administration of ZNS, effective plasma concentrations also increased the extracellular and total levels of 5-HT, 5-HIAA, and 5-HTP. On the other hand, after both acute and chronic administrations of ZNS, a supra-effective ZNS concentration either decreased or did not affect the total levels of these substances. Therefore, the stimulatory effects of ZNS on the 5-HT system were reduced by an increase in ZNS concentration to supra-effective concentrations. ZNS concentrations of 30-1000 microM did not affect hippocampal 5HT re uptake activity in vitro. These results suggest that ZNS has biphasic effects on the 5-HT system, in that effective concentrations of ZNS enhance and supra-effective concentrations of ZNS reduce the function of the 5-HT system. These biphasic effects of ZNS on the 5-HT system may be involved in the mechanisms of action of the antiepileptic and psychotropic effects, and side effects of ZNS.

5-Hydroxytryptophan↗
PubMed1999

Effects of zonisamide on K+ and Ca2+ evoked release of monoamine as well as K+ evoked intracellular Ca2+ mobilization in rat hippocampus.

To clarify the effects of zonisamide (ZNS) on neurotransmission and intracellular Ca2+ mobilization, both Ca2+ and K+ evoked hippocampal releases of dopamine (DA) and serotonin (5-HT) were determined by in vivo microdialysis, and K+ (25 and 50 mM) evoked elevation of intracellular Ca2+ level was determined by fluorescence microscopy in vitro. Therapeutic concentrations of ZNS had different effects on Ca2+ and K+ evoked release of monoamine. ZNS stimulated Ca2+ evoked monoamine release, while ZNS inhibited K+ evoked monoamine release. ZNS inhibited K+ evoked elevation of hippocampal intracellular Ca2+ levels in a concentration dependent manner. These results suggest that ZNS inhibits the depolarization induced by neuronal excitation, whereas ZNS might enhance the N-type Ca2+ channel activity or N-type Ca2+ channel related exocytosis mechanisms.

Animals↗
PubMed2001

Regional accumulation of 14C-zonisamide in rat brain during kainic acid-induced limbic seizures.

BACKGROUND: Zonisamide (ZNS) is an antiepileptic drug developed in Japan. Various experimental studies have investigated the effects of ZNS. However, the mechanism of action of ZNS against limbic seizures and secondary generalization is not well-known. We studied ictal regional accumulation of ZNS in the rat brain during kainic acid (KA)-induced limbic status epilepticus. METHODS: Fourteen male Wistar rats underwent a stereotactic operation. For recording the electroencephalogram (EEG), electrodes were placed in the left amygdala (LA), left dorsal hippocampus, and over the left sensorimotor cortex. For microinjection, a stainless steel cannula was also inserted into the LA. Seven days after surgery, rats were anesthetized and a catheter was inserted into the femoral vein. The animals were immobilized and allowed to recover from anesthesia for at least two hours. In eight rats, 1.0 microL (1.0 microg) of KA was injected into the LA, and 1.0 microL of phosphate buffer solution was injected into the LA in six control rats. Sixty minutes after injection, 14C-ZNS was administered intravenously, and an autoradiographic study was done. RESULTS: During limbic status epilepticus, only seizures in the sensorimotor cortex were markedly attenuated a few minutes after 14C-ZNS administration. Additionally, high uptake of 14C-ZNS was noted ipsilaterally in the sensorimotor cortex, parietal cortex and thalamus (lateral portion). In control rats, no EEG change was seen, and distribution of 14C-ZNS was rather homogeneous. CONCLUSIONS: These results suggested that ZNS suppresses secondary generalization of limbic seizures by a direct effect on the cerebral cortex.

Animals↗
PubMed2000

In vivo evaluation of hippocampal anti-oxidant ability of zonisamide in rats.

We evaluated the anti-oxidant property of zonisamide (ZNS) in the rat brain under freely moving conditions by means of in vivo microdialysis of two exogenous nitroxide radicals, 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (carbamoyl-PROXYL) and 3-methoxy carbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (PCAM). Time-dependent changes in the signal intensities of these exogenous nitroxide radicals obtained from the hippocampal perfusates were observed using an X-band ESR spectrometer at 20-min intervals. The ESR signal intensities of nitroxide radicals decreased exponentially in all animals, which indicates that their half-life could be used as a parameter to estimate the decay rate of nitroxide radicals. Nitroxide radicals lose their paramagnetism when exposed to reductants in a biological system. Thus, half-life reflects the in vivo reducing ability. Although the half-life of carbamoyl-PROXYL, which could not pass the blood-brain barrier (BBB), was not changed when compared with the controls, pre-treatment with ZNS significantly shortened the half-life of PCAM, which could pass through the BBB. These findings suggest that the ZNS-induced increase in reducing ability did not occur within the extracellular space, but rather mainly at the neural cell membrane. This study is the first in vivo evaluation of the reducing ability of ZNS in freely moving animals.

Animals↗
PubMed1998

Interaction between Ca2+, K+, carbamazepine and zonisamide on hippocampal extracellular glutamate monitored with a microdialysis electrode.

1. Multiple components of hippocampal glutamate release were examined by study of Ca2+- and K+-evoked hippocampal extracellular glutamate release using an in vivo microdialysis glutamate biosensor in urethane-anaesthetized rats. In addition, the effects of the antiepileptic drugs, carbamazepine (CBZ) and zonisamide (ZNS) perfused through the probe on glutamate release were assessed. 2. Basal glutamate levels were below detection limits (approximately 0.1 microM). An increase in extracellular KCl (from 2.7 to 50 and 100 mM) increased extracellular hippocampal glutamate levels to 9.2+/-1.4 and 20.0+/-2.6 microM, respectively, calculated from the area under curve (AUC) for 60 min. 3. This KCl-evoked glutamate release consisted of three components: an initial transient rise, a late gentle rise, and late multiple phasic transient rises. 4. An increase in or removal of extracellular CaCl2 levels respectively enhanced and reduced the 50 mM KCl-evoked hippocampal glutamate release (AUC for 60 min) from 9.2+/-1.4 to 12.4+/-2.1 and 5.8+/-0.9 microM. 5. Perfusion with 100 microM CBZ or 1 mM ZNS inhibited both the 50 mM KCl-evoked hippocampal glutamate release (AUC for 60 min) from 9.2+/-1.4 to 5.5+/-1.1 and to 5.8+/-1.3 microM, respectively, as well as the stimulatory effects of Ca2+ on KCl-evoked hippocampal glutamate release. 6. These results suggest that both CBZ and ZNS may reduce epileptiform events by inhibiting excitatory glutamatergic transmission.

Animals↗
PubMed2001

Influences of caffeine to nitric oxide production and zonisamide concentration in the brain of seizure-susceptible EL mice.

To investigate changes of nitric oxide (NO) productions and zonisamide (ZNS) concentrations in the brain of seizure-susceptible EL mice given caffeine orally, mice were given caffeine (600 microg/mL) solution ad libitum as a drinking fluid for 1-3 weeks. Nitric oxide production in the brain was determined by measuring levels of nitrite plus nitrate (NOx). The brain NOx levels of mice treated with caffeine for 3 weeks were significantly higher than the control. Seizures in mice treated with caffeine for 2 and 3 weeks were not suppressed by ZNS at a dose of 75 mg/kg. Serum ZNS concentrations of mice with caffeine intake for 1-3 weeks were higher than in untreated mice. Conversely, brain ZNS concentrations of mice with caffeine intake for the same periods were significantly lower than in untreated mice. These results suggested that caffeine influenced brain NO production and ZNS concentrations in the seizure susceptibility of EL mice.

Animals↗
PubMed2001

Contrasting effects of zonisamide and acetazolamide on amygdaloid kindling in rats.

PURPOSE: Zonisamide (ZNS) and acetazolamide (AZM) are two antiepileptic drugs (AEDs) that differ in clinical efficacy. To elucidate the mechanisms of action of these compounds, we investigated their therapeutic and prophylactic effects in rats by using a kindling model of partial epilepsy. METHODS: Electrodes were implanted into the left amygdala of adult male Wistar rats. The animals were stimulated at the afterdischarge threshold until five stage 5 seizures were induced. The generalized seizure threshold was then determined. Therapeutic effects were examined in rats manifesting successive convulsions with near-threshold stimulation. To test prophylactic effects, drugs were administered intraperitoneally before daily kindling stimulation until the animal had a stage 5 seizure or reached day 18. RESULTS: ZNS (10-40 mg/kg; n=6) suppressed kindled seizures in a dose-dependent manner. Repeated administration for 7 days produced tolerance to anticonvulsive effects. AZM (25-200 mg/kg; n=7) showed limited therapeutic effect, alleviating only the clonic convulsion in stage 5 seizures and reducing afterdischarge duration. Secondary generalization was not significantly suppressed during repeated treatment (50-200 mg/kg; n=6). ZNS, 25 or 40 mg/kg (n=8), significantly retarded seizure development; 15.0 or 17.0 daily stimulations were required to produce a stage 5 seizure. AZM, 50-200 mg/kg (n=6), also retarded seizure development, with 14.0-14.8 stimulations required. CONCLUSIONS: ZNS exhibited modest therapeutic and prophylactic effects, whereas AZM showed mainly prophylactic effects. Hypotheses are presented that may explain the mechanisms of action of these drugs.

Acetazolamide↗
PubMed2000

Psychotic episodes during zonisamide treatment.

Several articles have appeared over the last years devoted to mental side effects during zonisamide (ZNS) treatment. In this study, we were particularly interested in psychotic episodes. Seventy-four epileptic patients with a history of ZNS treatment were surveyed retrospectively over the period spanning 1 March 1984 to 30 June 1994. They were divided into two groups according to the presence or absence of psychotic episodes during ZNS treatment. We analysed various factors pertaining to psychotic episodes during ZNS treatment. Of the 74 patients 14 had psychotic episodes. We found that the incidence of psychotic episodes during ZNS treatment was several times higher than the previously reported prevalence of epileptic psychosis, and that the risk of psychotic episodes was higher in young patients. In 13 patients, psychotic episodes occurred within a few years of commencement of ZNS. In children, obsessive-compulsive symptoms appeared to be related to psychotic episodes. It is important to terminate ZNS as soon as possible if psychotic episodes develop and never restart, even if seizures become worse. It cannot definitely be proved that ZNS causes psychotic episodes, as information on mental side effects during ZNS monotherapy is scant, but it does appear likely that ZNS contributes to psychotic episodes during polytherapy.

Adult↗