Koichi Otani

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.

A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans : In vivo evidence for the involvement of CYP3A4 in alprazolam metabolism

To assess the possible involvement of CYP3A4 in the metabolism of alprazolam in vivo.

Effects of zonisamide on extracellular levels of monoamine and its metabolite, and on Ca2+ ependent 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.

Associations Between Risk Factors for Valproate Hepatotoxicity and Altered Valproate Metabolism

Summary: The effects of three risk factors for valproate (VPA) hepatotoxicity (i.e., young age, polypharmacy, and high VPA serum level) on the metabolism of VPA to its monounsaturated metabolites 12‐en‐VPA (2‐en), 3‐en‐VPA (3‐en) and 4‐en‐VPA (4‐en)l were investigated in 106 patients treated with VPA (56 cases of monotherapy and 50 cases of polytherapy). In the monotherapy group, there was a significant negative correlation between age and 4‐en/VPA ratio. In the same group, the 4‐en/VPA ratio showed a significant positive correlation with serum VPA level, while 3‐enIVPA and 2‐enIVPA ratios showed significant negative correlations. In patients > 10 years, the 4‐enlVPA ratio was significantly higher, while the 2‐enIVPA ratio was significantly lower in the polytherapy group than in the monotherapy group. Our results indicate that all three risk factors clearly increase the metabolic conversion of VPA to 4‐en, the most toxic VPA metabolite, and that polytherapy and high VPA serum level result in the inhibited beta‐oxidative metabolism of VPA to 2‐en. These altered VPA metabolic profiles are strikingly similar to the abnormal VPA metabolism previously reported in cases with fatal hepatic failure. Although VPA‐induced fatal hepatotoxicity has been regarded as an idiosyncratic reaction, it is possible that these three factors enhance susceptibility to VPA hepatotoxicity by altering the metabolism of VPA.

Serum folic acid levels in epileptic mothers and their relationship to congenital malformations

Folic acid levels during pregnancy and in pre-pregnancy were determined in 51 epileptic mothers and those of matched controls. The serum folic acid (SF) levels of epileptic mothers were significantly lower than those of controls in all study periods. The SF levels of mothers of malformed offspring were significantly lower than those of mothers of normal offspring in the 1st and 2nd trimesters of pregnancy. These results suggest that SF concentrations are implicated in congenital malformations in the offspring of epileptic mothers.

Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.

The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.

Carbamazepine and Zonisamide Increase Extracellular Dopamine and Serotonin Levels In Vivo, and Carbamazepine Does Not Antagonize Adenosine Effect In Vitro: Mechanisms of Blockade of Seizure Spread

Carbamazepine (CBZ) and zonisamide (ZNS) are effective for the treatment of partial, generalized tonic clonic, and secondary generalized seizures. The object of this paper is to study the common mechanisms of action for both drugs by which a seizure spread is blocked as the understanding of such mechanisms of action may shed some light on the pathogenesis of secondary generalization of seizures. Methods

Relationship between the CYP2D6 genotype and the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine

Abstract The relationship between the cytochrome P450 (CYP) 2D6 genotype and the steady-state plasma concentrations (Css) of trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) was studied in 54 depressed Japanese patients receiving trazodone 150 mg at bedtime. By use of allele-specific PCR analysis, the wild type allele, three mutated alleles causing absent enzyme activity (CYP2D6A, CYP2D6B and CYP2D6D) and one mutated allele causing decreased enzyme activity (CYPZD6 Ch) were identified. The means (ranges) of the Css of trazodone, corrected to the median body weight in 17 cases with no mutated allele, 27 cases with one mutated allele and 10 cases with two mutated alleles, were 556 (281–1115), 643 (302–1362) and 671 (234–1418)u2005ng/ml, respectively, while the values of mCPP were 60 (35–121), 65 (33–99) and 58 (38–112)u2005ng/ml, respectively. Neither the Css of trazodone (Fu2008=u20080.80, Pu2008=u20080.45) nor that of mCPP (Fu2008=u20080.49, Pu2008=u20080.61) significantly differed among the three groups. The present study thus suggests that the CYP2D6 genotype cannot predict the Css of these compounds.

High‐performance Liquid Chromatographic Determination of Trazodone and 1‐m‐Chlorophenylpiperazine with Ultraviolet and Electrochemical Detector

A high‐performance liquid chromatographic (HPLC) assay was developed for the determination of trazodone and its metabolite, 1‐m‐chlorophenylpiperazine (m‐CPP), in plasma.

Is 2‐Propyl‐4‐Pentenoic Acid, a Hepatotoxic Metabolite of Valproate, Responsible for Valproate‐Induced Hyperammonemia?

Summary: To investigate the association between valproate metabolism (VPA) and VPA‐induced hyperammonemia together with the contribution of VPA hepatotoxicity risk factors such as young age, polypharmacy, and high serum VPA levels to VPA‐induced hyperammonemia, plasma ammonia (NH3) levels, serum levels of VPA and its metabolites, and biochemical parameters were determined in 98 patients treated with VPA (53 monopharmacy cases and 45 polypharmacy cases). In monopharmacy patients, plasma NH3 levels did not depend on age, VPA dosage or serum levels. Serum level of 2‐propyl‐4‐pentenoic acid (4‐en) showed a negative correlation with plasma NH3 level in the monopharmacy group. In polypharmacy patients, plasma NH3 levels, serum glutamic pyruvic transaminase, and γ‐glutamyltranspeptidase were significantly higher, while level/dose VPA ratio, 2‐en‐VPA serum level, and bilirubin were significantly lower than those in monopharmacy patients. These results suggest that young age and relatively high VPA serum levels within the therapeutic range were unlikely to be risk factors for common hyperammonemia associated with VPA therapy and that 4‐en was not causally related to this adverse effect. The decreased serum level of 2‐en‐VPA in polypharmacy patients may be a reflection of a certain mitochondrial dysfunction, which might be a mechanism of the increased NH3 levels. The changes in biochemical parameters in polypharmacy patients were considered results of the enzyme‐inducing activity of coadministered antiepileptic drugs (AEDs).