Zonisamide Research Articles

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 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.

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.

Clobazam, oxcarbazepine, tiagabine, topiramate, and other new antiepileptic drugs.

Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK-801, nafimidone, ORG-6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB represent agents that act on the GABA system, and MLM acts on the glycine system. MK-801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium-channel antagonist. OCBZ is a keto analogue of carbamazepine, which is not metabolized to the epoxide and may have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience.

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.

Influence of additional therapy with zonisamide (Excegran) on protein binding and metabolism of carbamazepine.

The influence of comedication with zonisamide (ZNS) on protein binding and carbamazepine (CBZ) metabolism was studied in 16 pediatric epileptic patients. Correlations were evaluated between ZNS daily dose and individual change of level per dose ratio (L/D ratio), free fraction, and carbamazepine-10,11-epoxide/CBZ level ratio (CBZE/CBZ). Statistical significant negative correlation was observed between L/D ratio and ZNS daily dose. Despite alteration in the L/D ratio, the free fraction of CBZ was unaltered in combination with ZNS. To assess the effect of addition of ZNS on CBZ metabolism, the CBZE/CBZ level ratio was compared; this ratio showed a tendency to increase with increase in ZNS dose. Consequently, ZNS is considered to have a significant effect on CBZ metabolism but not on protein binding.

Antiepileptic drugs in development: prospects for the near future.

Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.

ゾニサミドの体内動態と薬物相互作用の検討

Zonisamide (ZNS) is a useful anticonvulsant, but its pharmacokinetic properties are not sufficiently known. We discuss the optimal dosage regimen for ZNS by means of therapeutic drug monitoring (TDM). In our examination of whether the coadministration of other anticonvulsants might affect the serum concentration of ZNS, the following results were obtained: 1) a higher dosage of ZNS was required for the patients under 13 years old than for elderly patients to maintain the similar serum ZNS levels; 2) the serum protein binding rate of ZN.S was less than 40%, indicating serum levels of ZNS might unlikely be affected by coadministration of other protein-binding agents, although when ZNS was administered with valproic acid (VPA), both the binding rates of ZNS and VPA tended to decrease; 3) the serum concentrations linearly correlated with the doses when 10 mg/kg or less was given; 4) the serum ZNS concentration tended to decrease with coadministration of other anticonvulsants such as phenytoin, carbamazepine and phenobarbital, which are known to induce hepatic microsomal enzyme systems; and 5) thus TDM provides useful information on the appropriate dosage adjustments for ZNS.

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.

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

The effects of zonisamide (ZNS) on the pharmacokinetics of phenobarbital (PB), valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) were investigated in rats. Additionally, the influence of ZNS on the serum protein binding, erythrocyte distribution and metabolism of these antiepileptics was studied in vitro. The t 1/2 and AUC values of PB were significantly increased by ZNS coadministration, and a significant decrease in the Vd/F value of PHT was observed after multiple dosing of ZNS. By contrast, ZNS showed no significant effect on VPA and CBZ kinetics. No significant effect of ZNS was observed in the serum protein binding, erythrocyte distribution or metabolism of other antiepileptics. These results suggest that ZNS has little effect on the pharmacokinetic behaviors of other antiepileptic drugs.

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.

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.

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.

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).

Zonisamide: world first launch of Dainippon's anticonvulsant in Japan

Zonisamide: world first launch of Dainippon's anticonvulsant in Japan

Zonisamide: improves about 50% of children with partial or generalised seizures

Zonisamide: improves about 50% of children with partial or generalised seizures