Zonisamide Concentrations Research Articles

Alcohol intake decreases brain Zonisamide concentration in inbred EL mice.

This study was undertaken to evaluate the effect of ethanol intake on the anticonvulsive effects of Zonisamide (ZNS), a sulfonamide derivative. EL mice, which are highly susceptible to seizures, were given a 10% ethanol solution ad lib for 1-4 weeks. In mice given ethanol for 4 weeks, seizures were not suppressed by ZNS at a dose of 75 mg kg-1, i.p. Serum ZNS concentrations following ethanol consumption for 1-4 weeks were higher than in untreated mice; however, brain ZNS concentrations following ethanol consumption were lower than those in untreated mice. These results suggest that alcohol intake decreases the brain concentration of ZNS, but not the serum concentration.

血清中ゾニサミド濃度に対する併用抗てんかん薬の影響 非線型モデルにもとずく解析と予測

The effects of coadministrated antiepileptics; carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproic acid (VA), primidone (PD), on the serum zonisamide (ZNS) concentration were investigated. Routine therapeutic drug monitoring data, obtained from 98 epileptic patients who were treated by an oral administration of ZNS, and consisting of 287 serum concentration data at steady-state, were collected. Each ratio (L/D) of the serum level (L) to the daily dose per body weight (D) was used for the analysis.First, the mean values of the L/D ratio of ZNS alone and each coadministrated antiepileptic were calculated. As the values of the ratio obtained from dividing each mean value by that of ZNS alone indicated the degrees of effect on the L/D ratio of ZNS alone, these values are thus considered to be the variation ratios of each coadministrated antiepileptic. Next, all the data were analyzed by the non-linear model under the assumptions that the effect of each coadministrated antiepileptic on the L/D ratio of ZNS alone is independent and multiplicative.(L/D) ZNS (0) is 3.89, and the variation ratios of CBZ, PB, PHT, VA, PD, are estimated as 0.98, 0.90, 0.83, 0.71, 0.77, respectively. The (L/D) ZNS (0) means have no effects on the coadministrated antiepileptics to the L/D ratio of ZNS.(L/D) ZNS (0) was nearly equal to the mean of the L/D ratio of ZNS alone and each variation ratio was also nearly the same as that calculated in the manner described above. These findings thus support the above assumptions that the effect of each coadministrated antiepileptic on the serum ZNS concentration is independent and multiplicative.These variation ratios thus calculated by the non-linear model seemed to be useful indicators for predicting serum ZNS concentration changed in the case of the addition or discontinuance of coadministrated antiepileptics for the treatment of ZNS in epileptic patients.

全自動ＥＬＩＳＡシステムによるゾニサミドおよびハロペリドールの血しょう中濃度測定

A fully automated enzyme immunoassay system, Omni (BIO-TEK Co.) (ELISA system), using Markit-M Excegran and Markit-M Haloperidol (Dainippon Pharmaceutical Co.) was evaluated to determine the concentrations of zonisamide (ZNS) and haloperidol (HP) in human plasma. At first, the within-run (ZNS: n=8, HP: n=10) and the between-run (4 days) precisions of ZNS and HP were examined.The coefficient of the variations in both the within-run and the between-run precisions of HP were below 5.0 and 7.0%, respectively. In contrast, the some values of ZNS were below 6.5 and 8.4%, respectively. A good correlation was observed between this ELISA system and HPLC (r=0.917), which was used to determine the plasma ZNS concentration. In the case of HP, a good correlation was seen between this ELISA system and the manual ELISA method (r=0.978).This method was thus used to monitor the serum levels in patients receiving ZNS or HP therapy. The relationship was observed between the daily dose (mg/kg) and the plasma concentration of the trough level for ZNS and HP, respectively (r=0.750 p<0.001, r=0.669 p<0.001). However, the ratio of the plasma concentration of ZNS and the daily dose increased significantly with aging.

Preliminary report on teratogenic effects of zonisamide in the offspring of treated women with epilepsy.

We wished to assess the risk of teratogenicity of zonisamide (ZNS) in humans. Pregnant epileptic women treated with ZNS and their offspring were prospectively monitored from June 1989 to December 1994. The outcome of pregnancy and status of neonates were examined based on the same standardized protocol. Twenty-six offspring exposed to ZNS with or without other antiepileptic drugs (AEDs) were studied. Malformations were detected in 2 offspring (7.7%) exposed to ZNS polypharmacy. Anencephaly was detected in one case at 16 weeks of gestation (case 1, artificial abortion), and atrial septal defect was detected in another case at 37 weeks of gestation (case 2, delivery by cesarean section). Serum concentrations of ZNS during the first trimester of pregnancy were 6.1 micrograms/ml in case 1 and 6.3 micrograms/ml in case 2; in both cases, the levels were below the therapeutic concentration range of ZNS. Teratogenic effects of ZNS were not clearly defined from these results since malformations were detected in two polypharmacy cases but not in four monopharmacy cases. The present data do not indicate that the risk of ZNS teratogenicity is greater than that of other conventional AEDs. However, such risk cannot be neglected even at therapeutic dosages or concentrations of ZNS, especially in patients receiving poly-pharmacy.

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 essentially unchanged after the combined administration of PB and ZNS, the concentration of ZNS in brain tended to rise in proportion to the higher 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.

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 essentially unchanged after the combined administration of PB and ZNS, the concentration of ZNS in brain tended to rise in proportion to the higher 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.

The necessity of adjusting the dosage of zonisamide when coadministered with other anti-epileptic drugs.

Zonisamide (ZNS), a new anti-epileptic drug that exhibits a wide anti-epileptic spectrum, is commonly prescribed concomitantly with other anti-epileptic drugs. The interaction between ZNS and other anti-epileptic drugs was investigated in epileptic patients. The steady state plasma levels of all the anti-epileptic drugs were measured by high-performance liquid chromatography. The concomitant administration of phenobarbital (PB), phenytoin (PHT), or carbamazepine (CBZ) with ZNS significantly decreased the ratio of the steady state plasma concentration to the administered dose (C/D ratio) of ZNS, whereas clonazepam (CZP) and valproic acid (VPA) when administered concomitantly with ZNS did not change the C/D ratio. Significant negative correlations were observed between the C/D ratio of ZNS and the doses of PB, PHT, CBZ, and VPA. On the other hand, the ratio of the plasma concentration of carbamazepine-10,11-epoxide (CBZ-E), the major active metabolite of CBZ, to the plasma concentration of CBZ was significantly decreased by concomitant administration with ZNS, indicating that ZNS inhibits the metabolism of CBZ. These findings show that when ZNS is administered concomitantly with these anti-epileptic drugs, it is necessary to monitor the plasma concentration of ZNS in order to adjust its dosage.

Effects of Zonisamide on BAEP, SSEP and P300

The effects of zonisamide on BAEP, SSEP and P300 were studied. The subjects were 12 patients (4 men and 8 women) with untreated epilepsy. Their ages ranged from 16 to 59 years, with a mean of 26.3 +/- 12.0 years. The daily dose of zonisamide was between 200 mg. to 600 mg. (2 to 6 tablets, 2.9 +/- 1.1 tablets on average). The serum concentrations of zonisamide ranged from 11.4 to 32.5 micrograms/ml, with a mean of 18.7 +/- 8.5 micrograms/ml 1 year after administration. Central conduction time and latency in BAEP and SSEP and amplitude, response time and latency in P300 were investigated. There were no significant differences in any of the tests. Zonisamide did not affect any of these evoked responses and may be less toxic to the central nervous system than other antiepileptic drugs.

血しょう中ゾニサミド濃度に及ぼす併用薬の影響

Zonisamide (ZNS), a new antiepileptic drug which features a wide antiepileptic spectrum, is commonly prescribed concomitantly with other drugs. However, there appears to be little data on the drug interaction of ZNS with other coadministered drugs. Concentrations of ZNS and co-medications in plasma were measured simultaneously by HPLC. The ratio of plasma concentration to the administered dose of ZNS in the monotherapy was significantly higher than that in the polytherapy (P>0.05). When co-medications numbered more than two, the ratio was significantly decreased compared with ZNS alone, indicating the possibility that co-medications induce decreases in plasma concentration of ZNS. The present findings provide useful information that the monitoring of plasma concentration of ZNS is needed to adjust dosage regiments of ZNS in the polytherapy.

Zonisamide reduces hypoxic-ischemic brain damage in neonatal rats irrespective of its anticonvulsive effect

The neuroprotective effect of a novel anticonvulsant, zonisamide, was investigated in neonatal rats with hypoxic-ischemic brain damage. Rats underwent left carotid ligation followed by hypoxic exposure (8% O 2) for 2.5 h. When zonisamide (75 mg/kg) was administered i.p. 1 h before hypoxia, it reduced the cortical infarction volume to 6 ± 5% (mean ± S.E.M.) from 68 ± 7% in vehicle-treated controls and the striatal volume to 8 ± 4% from 78 ± 7%. Zonisamide also reduced neuronal necrosis in 5 hippocampal regions (the dentate gyrus, CA4, CA3, CA1, and the subiculum). The plasma zonisamide concentration before and after hypoxia was 47.9 ± 2.0 μg/ml and 42.3±3.9 μg/ml, respectively. Epidural electrodes were implanted in 6 pups one day before hypoxia-ischemia. Electroencephalograms were recorded during hypoxia-ischemia in rats given zonisamide or vehicle before the insult. The intensity of seizure activities was similar in the zonisamide-treated pups and the vehicle-treated controls. These findings demonstrate that zonisamide reduces neonatal hypoxic-ischemic brain damage and that this protective effect does not depend on its anticonvulsant action.

Concentrations of Zonisamide in Serum, Free Fraction, Mixed Saliva and Cerebrospinal Fluid in Epileptic Children Treated with Monotherapy

Concentrations of Zonisamide in Serum, Free Fraction, Mixed Saliva and Cerebrospinal Fluid in Epileptic Children Treated with Monotherapy

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.

Factors influencing serum concentration of zonisamide in epileptic patients.

The relationship between daily dose and serum concentration of zonisamide (ZNS) and the effects of patient age on the serum level/dose (L/D) ratio for ZNS were studied in epileptic patients (mean age +/- S.D. = 10.6 +/- 6.2 years) who chronically received ZNS. The influence of phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ) and valproic acid (VPA) on the serum protein binding of ZNS in vitro and the correlation between total and unbound serum levels of ZNS in patients were also examined. Significant correlations were obtained between daily dose per body weight or per body surface area and serum level of ZNS. The correlation coefficient of the latter was higher than that of the former. There was no effect of age on the L/D ratio on the basis of body surface area, whereas that on the basis of body weight increased significantly with age. No significant increase in the free fraction of ZNS was observed in the presence of PHT, PB and CBZ except VPA in vitro. There were significant correlations between total and unbound serum levels of ZNS in the two patient groups coadministered with and without VPA. Although the free fraction of ZNS in the former was significantly higher than that of the latter, the increase was small. These results suggest that dosage regimens on the basis of body surface area would be more accurate than those on a body weight basis and that there is little effect of other antiepileptics on the serum protein binding of ZNS.

Competitive binding enzyme immunoassay for zonisamide, a new antiepileptic drug, with selected paired-enzyme labeled antigen and antibody

We assessed the competitive binding between zonisamide (ZNS) in serum samples and beta-galactosidase-labeled ZNS derivatives, using competing antibodies to ZNS derivatives, and selected the best enzyme-labeled antigen and antibody for accurate enzyme immunoassay (EIA) of ZNS in serum without interference from its metabolites or from other antiepileptic drugs. This EIA, based on use of antibody linked to bacterial cell walls, has advantages over HPLC in simplicity, speed (50 samples per hour), and lack of requirement for special equipment. The concentrations of ZNS in serum as measured by the EIA correlated well with those by HPLC (n = 33, r = 0.977).

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 μg/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 (10μg/ml) were applied.

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 consurnption; 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 nectropsy. 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.

Cheonic Toxicity of the Anticonvulsant Zonisamide in Beagle Dogs

Chronic Toxicity of the Anticonvulsant Zonisamide in Beagle Dogs. Walker, R. M., Di-Fonzo, C. J., Barsoum, N. J., Smith, G. S., and Macallum, G. E. 1988. Fundam. Appl. Toxicol 11, 333–342. 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. Qinical 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.