Hiroaki Yamada

The Effects of Genetic Polymorphisms of CYP2C9 and CYP2C 19 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy: Studies in Stereoselective Hydroxylation and Population Pharmacokinetics

Summary: Purpose: The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed.

Effect of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, major metabolites of phenytoin, on the occurrence of chronic-gingival hyperplasia: in vivo and in vitro study.

The purpose of this study was to assess the possible role of the (R)- and (S)- enantiomers of the phenytoin metabolite p-HPPH in the pathogenesis of gingival hyperplasia (GH). About 98% of circulating p-HPPH is in the (S)-form. There were significant differences between patients with and without GH in (R)-p-HPPH level (0.055 vs 0.042 μg·ml−1), both enantiomer/racemate level ratios, and R/S enantiomeric ratio (0.0313 vs 0.0232); an increase in serum (R)-p-HPPH level was observed in patients with GH. In separate experiments, the effect of p-HPPH enantiomers on the proliferation of the normal human dermal fibroblast was studied. The in vitro study showed that (R)-p-HPPH selectively stimulated fibroblast growth. The results suggest that the least abundant metabolite, (R)-p-HPPH, is the most toxic with respect to gingival hyperplasia.

Interaction of VEGF to gastric low grade MALT lymphoma by Helicobacter heilmannii infection in C57/BL/6 mice

Abstract.Helicobacter heilmannii (Hh) has been clinically reported to have some relation to gastric low grade MALT lymphoma. Recently, we have formed the gastric MALT lymphoma in C57BL/6 mice.Materials and methods:C57BL/6 mice infected with Hh from cynomolgus monkey for more than 6 months were used. The macroscopic, immunohistochemical and electron microscopic observation was performed.Results:MALT lymphoma was formed in almost 100 % of the infected mice. Increased VEGF-A and Flt-3 immunoreactivity was recognized.Conclusion:Hh was shown to be related to the formation of MALT lymphoma and VEGF is suggested to play a role in this lymphoma.

Covalently Attached Porphycene–Ferrocene Dyads: Synthesis, Redox-Switched Emission, and Observation of the Charge-Separated State

Two new porphycenes functionalized with ferrocenyl pendants have been synthesized and characterized spectroscopically and structurally. The porphycene-based emission in porphycene-ferrocene dyads was switched on and off by the reversible control of the ferrocenyl pendant redox states. Transient absorption spectroscopy with a femtosecond laser-pulsed technique has successfully detected the picosecond charge-separated excited state of the dyad upon Q-band excitation of the porphycene ring.

Laughing Attack: A Review and Report of Nine Cases

Laughing attack is an epileptic manifestation of an affective seizure, and pathological laughter is a release phenomenon of the upper control center in diffuse neurological diseases.

ANALYSIS OF THE FACTORS INFLUENCING ANTI-EPILEPTIC DRUG CONCENTRATIONS-VALPROIC ACID

The factors that influence valproic acid (VPA) serum concentrations and level:dose ratios were evaluated, retrospectively, on 51 consecutive routine VPA determinations from 50 chronically treated epileptic patients. The influence of co‐medicated anti‐epileptic drugs (phenytoin, phenobarbital, carbamazepine), alone or in combination, on total and free levels of VPA was studied. Furthermore, the possible influence of certain physiological and/or pathophysiological factors (age, weight, sex and clinical laboratory data) was considered.

ANALYSIS OF THE FACTORS INFLUENCING ANTI‐EPILEPTIC DRUG CONCENTRATIONS‐CARBAMAZEPINE

The factors that influence carbamazepine (CBZ) serum concentrations and levehdose ratios were evaluated retrospectively on 83 consecutive routine CBZ determinations from chronically treated epileptic patients.

A 10-year follow-up study of 97 epileptics.

1) Of 267 patients with epilepsy who were examined in our clinic during the period between 1964 and 1966, 97 were investigated in a 10‐year follow‐up study. The patients were selected according to the following criteria: the age of onset of seizures was 10 years or older and the follow‐up period was 10 years after the onset of seizures. Of the 97 patients, 36 were followed up by mail.

A Five‐Year Follow‐Up Study of 66 Epileptics

A follow‐up study of 66 patients with epilepsy who had been pursued for about five years from onset of seizures was performed. The patients were selected according to the following criteria: the age of onset of seizures was over 10 years old, and medication started a year from the onset.

Hydroxylation of Phenytoin (PHT) and the Cytochrome P450 (CYP) 2C Subfamily

Purpose: Four members of the CYP2C subfamily, CYP2C8, CYP2C9, CYP2C18, and CYP2C19, have been identified in humans, and a number of allelic variants of the CYP2C9, CYP2C18. and CYP2C19 genes associated with metabolic polymorphisms have been reported (Pharmacogenetics) 1994;4:285–99). CYP2C9 is a major enzyme responsible for the formation of 5–(4‐hydroxyphenyl)‐5‐phenylhydantoin (p‐HPPH), a major hydroxylation metabolite of PHT. However, we recently reported that CYP2C19 contributes to the stereoselective hydroxylation of PHT (Br J Clin Pharmacol 1997;43:431–5). To clarify the relation between hydroxylation of PHT and the CYP2C subfamily, we examined their stereoselective para‐hydroxylation properties by using cDNAs expressing CYP2C8, 9, 18, or 19. In addition, the allelic linkage among members of the CYP2C subfamily was evaluated.