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At least 19 recordsLinked to original sources
PubMed1986

Biopharmaceutical studies on hydantoin derivatives. V. Pharmacokinetics and pharmacodynamics of 5,5-diphenylhydantoin and 1-benzenesulfonyl-5,5-diphenylhydantoin.

Disposition of 1-benzenesulfonyl-5,5-diphenylhydantoin (II) having a potent anti-inflammatory activity was compared with that of 5,5-diphenylhydantoin (I), an antiepileptic drug, in order to elucidate whether the pharmacodynamic difference between them can be explained by their physicochemical and pharmacokinetic properties. After oral administration of I-14C to rats, radioactivity was distributed in all tissues including the brain, whereas after II-14C administration, the concentrations of radioactivity in most tissues were lower than those in plasma. The results were consistent with the finding obtained by whole-body autoradiography which revealed that after oral administration of II-14C to rats, radioactivity was not transferred into brain but was significantly transferred into inflamed tissues. Brain/plasma concentration ratio of I was about 1.3, whereas that of II was about 0.05. Plasma protein binding of I having pKa value of 8.30 was about 88%, whereas that of II having pKa value of 4.89 was about 99%. The changes in physicochemical properties due to introduction of a benzenesulfonyl group into the hydantoin ring may be responsible for the difference in the disposition between I and II. When II was cerebroventricularly administered to mice, it showed a potent anti-convulsant activity against maximal electroshock seizure, the activity being comparable to that for I. This indicates that the earlier failure to demonstrate the activity of II in a routine screening test for antiepileptic drugs was due to the inability of II to penetrate the blood-brain barrier and to achieve effective concentration in the brain. II was found to inhibit the biosynthesis of prostaglandin. These findings along with the physicochemical properties suggest that although II does not fall structurally under any category of anti-inflammatory drugs the mechanism of action may be similar to that for non-steroidal acidic anti-inflammatory drugs.

Administration, Oral↗
PubMed1981

Neurobiological studies of experimental diphenylhydantoin intoxication. - I. Electron microscopic investigations of the rat cerebellum with chronic diphenylhydantoin intoxication.

The effect of chronic administration of diphenylhydantoin on the fine structures of the rat cerebellum was ultrastructurally investigated. Materials from nine control rats and 16 experimental rats to which 200 to 300 mg/kg b.wt. of diphenylhydantoin was administered orally for 12 months were studied with the light and electron microscopes. The most striking changes were observed in the presynaptic boutons located predominantly in the molecular layer and the neuropil of deep cerebellar nuclei and sometimes in the granule cell layer. The changes consisted of the proliferation of either interconnected tubules 150 to 350 A in diameter associated with membranous scrolls and/or membranous strands separated by a cleft-like space, or parallel tubules about 600 A in diameter with a honeycomb-like architecture in the cross section, and hypertrophy of the boutons. Other alterations were a generalized increase in the density of the axoplasmic matrix, the accumulation of mitochondria, vesicular structures and dense bodies, an increased number of neurofilaments and a decreased number of synaptic vesicles. The axon displayed morphological abnormalities similar to those found in the terminal boutons. Along with the synaptic and axonic changes mentioned above, the perikaryal alterations in the Purkinje cell and in granule cell layers and deep cerebellar nuclei were also found, but they were generally not so prominent so that they were considered to reflect a non-specific reaction to synapto-axonic changes rather than a primary degenerative change. However, in contrast to the neuronal changes, no indication of damage of the glial elements was found, nor were the vascular changes.

Animals↗
PubMed1975

Effects of administration of estrogen or diphenylhydantoin on the kinetics of diphenylhydantoin in man.

The rate of disappearance of 131I-diphenylhydantoin (131I-DPH) from plasma and its hepatic uptake were studied during a control period and after estrogen administration in ten normal human subjects. Four subjects were given DPH and were studied in the same fashion as the estrogen-treated group. After intravenous injection of a tracer dose of 131I-DPH (period of study: 30-150 min after 131I-DPH administration), the estrogen-treated group showed an increase in the plasma half-time, a decrease in the fractional turnover rate, and a decrease in the distribution space of 131I-DPH in comparison with control. The hepatic uptake was decreased in comparison with the control, which may be explained by an increase in the binding capacity of thyroxine-binding globulin (TBG) induced by estrogens. An increase in the distribution space of 131I-DPH was observed in subjects treated with diphenylhydantoin. Consequently, the clearance rate was increased. No change in half-time or in turnover rate was observed. The hepatic uptake in the DPH-treated group was increased in comparison with control. This may be explained by a displacement of 131I-DPH by DPH from the binding sites of TBG. This study showed, therefore, that changes in the binding capacity of TBG are associated with alterations in the peripheral metabolism of 131I-DPH in man.

Adult↗
PubMed1983

Neurobiological studies of experimental diphenylhydantoin intoxication--III. Electron microscopic studies on development and disintegration mechanism of altered axon terminals and synaptic endings in rat cerebellum with chronic diphenylhydantoin intoxication.

The processes of development and disintegration of axonal spheroids were electron microscopically studied in the rat cerebellum with chronic diphenylhydantoin intoxication. According to the severity and character of membrane accumulation, the whole course ranging from development to disintegration of altered axon terminals and synaptic endings in the DPH-intoxicated rat cerebellum was classified into the following four stages--initial, moderate, advanced and terminal. The initial stage was characterized by the appearance of a small number of interconnected tubules 150 to 350 A in diameter in non-enlarged axon terminals and synaptic endings. Usually these tubular structures tended to congregate in a certain part of axoplasm so that there were no intimate relationships between them and ordinary cell organelles. The moderate stage was characterized by an increased number of interconnected tubules in slightly or moderately swollen axon terminals and synaptic endings. The advanced stage was characterized by an extraordinary number of interconnected tubules in extremely highly swollen axon terminals and synaptic endings. Membranous scrolls and/or membranous strands separated by a cleft-like space were also found in an association with interconnected tubules so that the morphological organization of spheroids in the rat cerebellum with chronic DPH intoxication was very analogous to those of infantile neuroaxonal dystrophy. The terminal stage was characterized by the following three axonal events, i.e., rarefaction and coagulation necroses, and phagocytosis of spheroids by glial elements, presumably astrocytic in origin. The formation and fate of such axonal spheroids have not as yet been shown and discussed by electron microscopists. Thus the present paper was the first to reveal the electron microscopic observations suggestive of the details of development and disintegration mechanisms of spheroids by means of animal experimentations.

Animals↗
PubMed1979

Transient hyperkinesia after a single intravenous perfusion of diphenylhydantoin. Report of a case associated with nontoxic plasma levels of diphenylhydantoin.

Transient hyperkinesia was observed in a 16-year-old epileptic and mentally retarded patient after a single intravenous perfusion of diphenylhydantoin (DPH). No clinical signs of DPH intoxication were associated with the movement disorder. Repeated plasma anticonvulsant level determinations never showed toxic concentrations of DPH. Since a few spontaneous episodes of hyperkinesia had been observed before, the DPH intravenous perfusion could have unmasked a preexisting latent movement disorder in our patient. However, neuroradiological investigations failed to demonstrate the existence of any anatomical damage of the basal ganglia, and HVA as well as 5-HIAA levels measured in the CSF with the probenecid technique were within the normal range 2 months after cessation of hyperkinesia. HVA and 5-HIAA levels have also been measured in the CSF during the period with hyperkinesia; the results are discussed with reference to previously published data concerning cerebral monoamine metabolism in drug-treated epileptic patients.

Adolescent↗
PubMed1982

Neurobiological studies of experimental diphenylhydantoin intoxication. II. Electrophysiological and electron microscopic studies of the rat cerebellum with chronic diphenylhydantoin intoxication.

The oral administration of diphenylhydantoin (DPH) for a period of more than nine months produced ataxia and muscle weakness in rats. The cerebellum of rats which were fed food containing DPH for a period of 12 months was studied electrophysiologically and morphologically. In the DPH-administered rats, little facilitation of Purkinje cell responses was elicited by the stimulation of the inferior olive, and a low frequency and a short duration of after-discharges on the cessation of tetani were observed as compared with that of the control rats. The value of the chronaxie of Purkinje cell axons was smaller in the DPH-administered rats than that in the control rats. Withdrawal of an overdose of DPH from the body returned these phenomena to those observed under normal condition, leaving the degeneration of synaptic boutons and some myelinated axons in the cerebellum. The electrophysiological results were well supported by the electron microscopic findings of degenerative presynaptic terminals and the depletion of synaptic vesicles.

Animals↗
PubMed1989

[Comparison of the teratogenic properties manifested in BALB c mice, by diphenylhydantoin and deuterated diphenylhydantoin].

The aim of this study was to investigate the role of an arene oxide pathway in the teratogenicity displayed by DPH, a highly effective antiepileptic agent. This approach was carried out by comparing the teratogene potential of DPH and of p2-H-DPH administrated at days 8, 9 and 12 of gestation. The present findings support the hypothesis that substitution of protium by deuterium at the para position of one of the phenyl rings, which favours an arene oxide pathway, causes an increase in some to the teratogenic effects of DPH.

Abnormalities, Drug-Induced↗