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At least 19 recordsLinked to original sources
PubMed1992

Pharmacokinetic interaction of zonisamide in rats. Effect of other antiepileptics on zonisamide.

The pharmacokinetics of zonisamide (ZNS) and the effects of phenobarbital (PB), valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) on ZNS kinetics were investigated in rats. The effects of other antiepileptics on the serum protein binding, erythrocyte distribution and metabolism of ZNS were also studied in vitro to elucidate the mechanism of pharmacokinetic interaction of ZNS. ZNS showed a linear disposition kinetics after oral administration of ZNS within the dose examined. Moreover, the pharmacokinetic behaviors of ZNS were not altered after multiple dosing. The decreased t1/2 value of ZNS by PB or CBZ pretreatment and the increased Vd/F value of ZNS by VPA pretreatment were observed, although it showed no marked effect of PHT on ZNS kinetics. The enhanced metabolism of ZNS was observed by PB or CBZ pretreatment from an in vitro metabolism study. The serum protein binding and erythrocyte distribution of ZNS showed no significant change in the presence of other antiepileptics in vitro. These results indicate that the decreased t1/2 value of ZNS is attributable to the enzyme inducing effect of PB or CBZ, and that neither protein binding nor erythrocyte distribution of ZNS could be the reason for the increased Vd/F value of ZNS by VPA coadministration.

Administration, Oral↗
PubMed1987

General pharmacology of the novel antiepileptic compound zonisamide. 1st communication: effects on central nervous system.

The effects of 1,2-benzisoxazole-3-methanesulfonamide (zonisamide, AD-810, CI-912), an antiepileptic compound, on the central nervous system were compared with those of carbamazepine and acetazolamide in experimental animals. 1. Zonisamide at an oral dose of 100 mg/kg was without effect on general behavior in mice except lowerings of pelvic, tail and body positions and ptosis. In rats, zonisamide slightly decreased the body temperature at the same dose. 2. Zonisamide (50 mg/kg p.o.) did not affect spontaneous alteration behavior and active avoidance performance in mice, although it impaired the acquisition of step-down passive avoidance behavior in mice. Carbamazepine (50 mg/kg) deteriorated the spontaneous alternation behavior. 3. Zonisamide (40 mg/kg i.v.) did not affect the relative power of cortical EEGs in gallamine-immobilized cats. Caudate spindles and recruiting responses, induced by electrical stimulation of the head of the caudate nucleus and the ventralis anterior thalamus, respectively, were not affected with the same dose of zonisamide in cats. On the other hand, carbamazepine (5 mg/kg) decreased the beta 2 relative power in the cortex, and enhanced both caudate spindles and recruiting responses. 4. Zonisamide (10 mg/kg i.v.) and carbamazepine (3 mg/kg) showed a tendency to depress the flexor reflex without affecting the neuromuscular transmission in anesthetized cats. 5. The central effects of zonisamide clearly differed from those of acetazolamide. Namely, acetazolamide markedly decreased brain pH at 25 mg/kg i.v., and increased regional cerebral blood flow at 100 mg/kg p.o. in rats. Zonisamide at 50 mg/kg i.v. and 100 mg/kg p.o. did not affect brain pH and regional cerebral blood flow, respectively. In addition, zonisamide (100 mg/kg p.o.) decreased brain contents of dopamine metabolite, DOPAC, with slight increase of a serotonin metabolite, 5-HIAA, in mice, and decreased brain contents of dopamine metabolites, DOPAC and HVA, in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

General pharmacology of the novel antiepileptic compound zonisamide. 2nd communication: effects on cardiovascular, visceral, renal and blood functions.

The effects of 1,2-benzisoxazole-3-methanesulfonamide (zonisamide, AD-810, CI-912), an antiepileptic compound, on the cardiovascular, visceral, renal and blood functions were compared with those of carbamazepine and, in part, acetazolamide in experimental animals. 1. Zonisamide (30 mg/kg i.v.) transiently lowered the blood pressure and decreased the blood flows in the carotid and femoral arteries in anesthetized dogs. The effects were 3 times less potent than those of carbamazepine, Zonisamide, when orally administered, did not affect the blood pressure even at 300 mg/kg in conscious rats. 2. Zonisamide little affected the autonomic nervous system even at high doses. In anesthetized cats, contractions of the nictating membrane by electrical stimulation of the cervical sympathetic nerve, pressor responses to norepinephrine, and depressor responses to acetylcholine, all were not modified with zonisamide (100 mg/kg i.v.). In isolated guinea-pig ileum, contractions induced by acetylcholine, histamine and bradykinin were not affected by zonisamide up to a concentration of 10(-3) g/ml zonisamide, although those by serotonin and nicotine were depressed with high concentrations over 10(-5) g/ml. 3. With 100 mg/kg p.o., zonisamide decreased the gastric juice volume and pH in pylorus ligated rats, and depressed gastric emptying in rats, but did not inhibit the intestinal transit of charcoal meal in mice. These effects were less potent than those of carbamazepine. 4. Zonisamide increased the urine volume, pH, and Na+ and K+ concentrations in rats and anesthetized dogs. The renal blood flow and glomerular filtration rate were little changed with the high doses of zonisamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain.

The effects of zonisamide on [3H]flunitrazepam binding and [3H]muscimol binding were studied in Sprague-Dawley rat brain. Specific [3H]flunitrazepam bound was decreased to 64.6 +/- 5.6% (mean +/- SD, n = 5, p < 0.002) and 91.9 +/- 4.0% (p < 0.005) by the addition of 10(-3) M and 10(-4) M zonisamide, respectively. Scatchard plot analysis of [3H]flunitrazepam binding with 10(-3) M of zonisamide revealed an increased Kd value with no change in Bmax. No inhibitory effect of zonisamide was seen on the enhancement of specific [3H]flunitrazepam binding by GABA. As for the effects on GABA receptors, specific [3H]muscimol bound was decreased to 27.7 +/- 10.4% (mean +/- SD, n = 4, p < 0.005) and 68.3 +/- 3.7% (mean +/- SD, n = 4, p < 0.005) by the addition of 10(-3) M and 10(-4) M zonisamide, respectively. Since therapeutic serum level of zonisamide are around 10(-4) M, these results suggest that zonisamide neuropharmacologically interacts with the GABA/benzodiazepine receptor ionophore complex in a manner similar to phenytoin.

Animals↗
PubMedDate not supplied

Metabolism of the anticonvulsant agent zonisamide in the rat.

The metabolism of zonisamide [3-(sulfamoylmethyl)-1,2-benzisoxazole], a new anticonvulsant, has been studied. In rats dosed with [14C]zonisamide (100 mg/kg, ip) 86.5% of the radioactive dose was excreted in the urine over 72 hr. The remainder of the radioactive dose (13.5%) was excreted in the feces over the same time period. Unchanged drug and eight metabolites were isolated from the urine, and the structures of five metabolites were assigned by physicochemical methods. metabolism of zonisamide primarily involves reductive and conjugative mechanisms, with oxidation of this compound being of minor metabolic significance. The percentage of urinary radioactivity accounted for by unmetabolized zonisamide and metabolites is as follows: unmetabolized zonisamide (metabolite 9), 32.8%; metabolite 8 [N-acetyl-3-(sulfamoylmethyl)-1,2-benzisoxazole], 7.7%; unidentified metabolite 7, 2.4%; metabolite 6 (zonisamide glucuronide), 7.6%; metabolite 5 [3-(carboxy)-1,2-benzisoxazole], 5.4%; unidentified metabolite 4, 13.1%; metabolite 3 [2-(sulfamoylacetyl)-phenol glucuronide], 12.6%; unidentified metabolite 2, 3.8%; and metabolite 1 (2-[1-(amino)sulfamoylethyl]phenol sulfate), 2.3%. A total of 87.7% of the 0-24 hr urinary radioactivity was accounted for by unchanged zonisamide and metabolites.

Animals↗
PubMed1988

Chronic toxicity of the anticonvulsant zonisamide in beagle dogs.

The chronic toxicity of the new anticonvulsant drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was evaluated in a detailed 52-week study in which dose levels of 0, 10, 30 and 75 mg/kg/day were administered orally in gelatin capsules to groups of five Beagle dogs per sex. Potential toxicity was based on the effects of zonisamide on body weight and food consumption; clinical and ophthalmic examinations; electrocardiography and heart rates; clinical biochemistry, hematology and urinalysis determinations; organ weights and gross and histopathologic evaluations; electron microscopy of high dose and control male dogs; and plasma zonisamide concentrations. Zonisamide was relatively well tolerated during the study. In animals given 75 mg/kg/day, early body weight losses occurred and therefore, from Weeks 2 and 3 until study termination, for males and females respectively, the high dose was given as two equal portions (i.e., 37.5 mg/kg each) approximately 3-4 hr apart. Clinical laboratory analyses in the dogs given 75 mg/kg revealed a small but statistically significant decrease in plasma albumin concentration and a small increase in alkaline phosphatase activity. In animals given 75 mg/kg, liver weights were increased and a brownish discoloration of the liver was noted grossly at necropsy. No significant light microscopic changes were evident; however, electron microscopic evaluation of the liver tissue from the 5 male dogs given 75 mg/kg revealed the presence of concentric lamellae of paired smooth membranes which were not seen in control animals. At the 10 and 30 mg/kg dose levels, plasma zonisamide concentrations reached steady-state and were proportional to dose, but at 75 mg/kg, plasma levels were disproportionately higher and never achieved steady-state. The results of this study indicated that at the high dose level of 75 mg/kg, chronic administration of zonisamide had a mild effect on the liver, particularly the endoplasmic reticulum.

Administration, Oral↗
PubMedDate not supplied

Zonisamide in epilepsy: a pilot study.

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

Adolescent↗
PubMedDate not supplied

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

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

Animals↗
PubMed1992

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

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

Administration, Oral↗
PubMed1992

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

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

Animals↗
PubMed1992

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

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

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

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

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

Action Potentials↗
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↗
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↗
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↗
PubMedDate not supplied

Zonisamide (CI-912) and cognition: results from preliminary study.

Nine patients with refractory partial seizures were evaluated in a pilot study of a new anticonvulsant compound, zonisamide (1,2-benzisoxazole-3-methanesulfonamide; CI-912). Cognitive functioning was evaluated prior to treatment with zonisamide and repeated after 12 and 24 weeks of treatment with zonisamide. At minimum steady-state plasma concentrations greater than 30 micrograms/ml, zonisamide appeared to affect specific cognitive functions such as acquisition and consolidation of new information. Previously learned material, such as vocabulary, and psychomotor performance were not affected. Verbal learning was affected, while visual-perceptual learning was unimpaired. These cognitive effects were observed in the absence of the usual clinical signs and symptoms of toxicity. A linear relationship was found between impairment of cognitive abilities and the minimum plasma concentration (r = -0.73; p less than 0.05). Findings also suggest the development of tolerance to the adverse cognitive effects.

Adult↗
PubMed1990

[3H]zonisamide binding in rat brain.

We previously reported that zonisamide inhibits both [3H]flunitrazepam and [3H]muscimol binding in rat brain. In the present study, [3H]zonisamide was found to bind in a saturable fashion to the crude synaptosomal fraction of whole rat brain. Linear regression analysis of the binding data in the Scatchard plot indicated a Kd of 90 nM, and a maximal binding capacity of 1.40 x 10(3) fmol/mg protein. Displacement studies revealed an inhibitory effect of clonazepam and an enhancement effect of GABA on specific [3H]zonisamide binding. These results suggest that specific [3H]zonisamide binding sites may have a tight correlationship with benzodiazepine receptors in rat brain.

Animals↗
PubMed1992

Formation of reductive metabolite, 2-sulfamoylacetylphenol, from zonisamide in rat liver microsomes.

Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was metabolized to its reductive product, 2-sulfamoylacetylphenol, in rat liver microsomes under anaerobic conditions. The rate of NADPH-dependent reaction was much more rapid than that of NADH-dependent reaction. Furthermore, synergistic effect of NADH on NADPH-dependent reaction was not observed. The optimal formation of 2-sulfamoylacetylphenol from zonisamide in the presence of NADPH was observed around pH 7.0. Cimetidine showed an inhibitory effect on the formation of 2-sulfamoylacetylphenol in a dose-dependent manner. The reductive metabolism of zonisamide was almost completely inhibited by carbon monoxide, and was increased by pretreatment of rats with phenobarbital and pregnenolone 16 alpha-carbonitrile but not by pretreatment with ethanol, 3-methylcholanthrene and imidazole. These results suggest that phenobarbital- and pregnenolone 16 alpha-carbonitrile-inducible form(s) of cytochrome P-450 is responsible for the reductive metabolism of zonisamide to 2-sulfamoylacetylphenol in rat liver microsomes.

Anaerobiosis↗