Severe thrombocytopenia associated with phenytoin and cimetidine therapy

A 67-year-old man developed a sudden onset of severe isolated thrombocytopenia (platelet count, 1000/mm3) after 10 days of phenytoin administration as a prophylactic measure prior to craniotomy. The patient had also been taking cimetidine for 2 months prior to admission. No other hematological complications were noted, and an extensive hematologic investigation was otherwise unremarkable. Rapid resolution of the thrombocytopenia upon discontinuation of phenytoin and cimetidine strongly suggests a drug-induced adverse reaction.     

苯妥英钠缓释片的研制

参照美国药典收载的“延效苯妥英钠胶囊”的体外释放速率,筛选处方,制成苯妥英钠缓释片,并进行体外释放度测定。根据测定结果表明,能达到延效目的,因此,每天只需服药1～2次。     

Subsensitivity to muscimol-induced catalepsy after long-term administration of phenytoin in rats

Male albino rats were injected with 25 mg/kg of phenytoin (PHT) every day for 20 consecutive days and were tested on days 21 and 28 for their response to 1 or 2 mg/kg of muscimol, a GABA receptor agonist. Rats treated with PHT showed a decreased responsiveness to muscimol-induced catalepsy (2 mg/kg) on day 21 but not on day 28. Acutely administered PHT, on the contrary, had a tendency to potentiate muscimol-induced catalepsy. Muscimol-induced catalepsy was not antagonized by acute treatment with bicuculline (0.5–2.0 mg/kg). It is proposed that withdrawal after long-term administration of PHT reduces the sensitivity of a GABA receptor site not sensitive to bicuculline.     

Decrease of Serum Folates in Healthy Male Volunteers Taking Phenytoin

The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20-35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (microgram/ml) of PHT in order to calculate the PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km-1 and Km+5, respectively. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 +/- 21.44% after an average of 24.15 +/- 5.63 days of PHT administration, with a mean steady-state total serum PHT concentration of 8.45 +/- 2.70 micrograms/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 +/- 31.45% and 23.24 +/- 21.24% for Km-1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 +/- 3.34 and 15.84 +/- 7.02 days, and 2.60 +/- 2.18 and 8.64 +/- 3.44 micrograms/ml, for Km-1 and Km+5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Depression by antiparkinson drugs of reserpine rigidity

Summary The effect of metamphetamine, propylhexedrine and biperiden on reserpine rigidity in the rat was assessed in an electromyographical study. For comparison the anticonvulsant agent phenytoin was also included in the investigation. Tonic electromyographical activity during stretch of the calf muscles served as an indicator of rigidity. All drugs tested and their combinations depressed the rigidity elicited by an intravenous injection of a high dose of reserpine.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

The antagonism between reserpine and some antiparkinson drugs in electroseizure

Summary The effects of amphetamine, metamphetamine, propylhexedrine, biperiden and atropine were studied in experiments on electroseizure threshold in rats. In high doses these drugs lowered the threshold of electroseizures and antagonized the threshold lowering produced by reserpine, with the exception of atropine, which enhanced the action of reserpine. Low doses of the drugs and combinations of low doses of metamphetamine, propylhexedrine and biperiden did not influence electroseizure threshold, but inhibited the action of reserpine. The effect of phenytoin on the threshold lowered by reserpine was enhanced by low doses of metamphetamine, propylhexedrine and biperiden. Tetrabenazine caused threshold lowering which was antagonized by metamphetamine, propylhexedrine, biperiden and atropine. Pretreatment with -methyl-p-tyrosine, but not with diethyldithiocarbaminate abolished the effect of high doses of metamphetamine or propylhexedrine on the electroseizure threshold. Inhibition of the formation of DOPA or noradrenaline did not influence the action of reserpine or the antagonism between reserpine and the drugs of the amphetamine group. After a repeated injection of metamphetamine tachyphylaxis developed.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

Effects of exogenous factors on the cerebral glutathione in rodents

Since glutathione is thought to be involved in cerebral functions, changes in the glutathione level imply modulations of the neurotransmission in addition to all the known effects of GSH. It was investigated whether alterations of the cerebral glutathione can be induced by consumption of GSH, by inhibition or stimulation of the synthesis of GSH, or by an inhibition of the re-reduction of the oxidized glutathione. Aminophenazone, propyphenazone, acetaminophen, phenytoin, morphine and nitrofurantoin, known to deplete hepatic GSH, had no effects on cerebral GSH. Diethyl maleate (0.6 ml/kg) decreased the cerebral content of GSH and GSSG in adult rats as well as in fetuses. The depletion of the cerebral GSH caused by diethyl maleate treatment for 4 days was followed by an increase up to 125% and a subsequent return to the normal level after 1 week. In rats starved up to 71 h deficiency of exogenous amino acids caused only a minimal or no decrease in cerebral GSH. The specific inhibitor of the gamma-glutamylcysteine synthetase BSO only depleted GSH in the brain of young mice following the repeated s. c. administration of a high dose (890 mg/kg). After cobaltous chloride (20 mg/kg; twice a day for 2 or 4 days) the GSH level in the brain was unchanged. In vivo inhibition of the cerebral glutathione reductase was caused by ammonium metavanadate (12.5 mg/kg; three times a week for 6 weeks). Nitrofurantoin (150 mg/kg) had no effect. After lomustine (10 mg/kg) a minimal increase in glutathione reductase was found, but simultaneously also an increase in GSSG and of the ratio GSSG/total glutathione.     

Direct effects of diphenylhydantoin (phenytoin) on the ion-transporting ATPases of cultured osteoblast-like cells

Diphenylhydantoin (phenytoin) added to cultures of osteoblast-like cells at a concentration of 10 microM, at the high end of the therapeutic range in plasma of unbound phenytoin (4-8 microM), caused reductions in Na+, K+-ATPase and alkaline phosphatase activities and increases in Ca2+-ATPase and HCO3--ATPase activities in homogenates of whole cells and in subcellular fractions of cultured osteoblast-like cells. These data suggest that, if these changes occur in vivo, the osteomalacia associated with treatment with diphenylhydantoin may be mediated in part by direct effects on the ability of bone cells to transport ions.     

Phenytoin Blocks the Reversal of a Classically Conditioned Discriminative Eyeblink Response in Rabbits

Summary: Purpose: Cognitive deficits associated with chronic treatment with phenytoin (PHT) have been reported. PHT blocks transfer from a signaled appetitive bar press to an active avoidance response in rats. We investigated the effects of PHT and the prodrug fosphenytoin in rabbits required to learn a discrimination and reversal of a classical eyeblink conditioning paradigm.
Methods: Before drug treatment was started, rabbits were trained to produce a discriminated eyeblink response. PHT (n = 7) was administered centrally or the prodrug fosphenytoin (n = 2) was given systemically. Control animals were similarly treated centrally with either saline (n = 3) or no drug treatment (n = 13). Rabbits were then challenged with a stimulus reversal while being maintained on the respective drug.
Results: On the first day of reversal training, control animals typically displayed high response rates to both tones, followed by a reduction in responsiveness to the new conditioned stimulus (CS-) in the ensuing days. In contrast, PHT-treated animals failed to suppress responsiveness to the new CS-.
Conclusions: The response patterns observed are similar to those observed in rabbits with hippocampal ablations, leading us to suggest that the adverse effects of phenytoin may be due to actions in the hippocampus.     

Immunofluorescent evidence for a specific binding site for phenytoin in the cerebellum

The regional distribution of phenytoin in the brains of experimental animals was studied using the indirect fluorescent antibody technique. Using antibodies directed against phenytoin, we observed a specific pattern of staining the Purkinje and granule cell layers of the cerebellum. An identical pattern of staining was seen in phenytoin-treated and untreated animals. Several control procedures and studies indicated that the observed pattern was not caused by nonspecific staining or autofluorescence. The distinctive staining pattern obtained using this technique can be attributed to the high molecular specificity of antigen-antibody reactions and a discrete binding site for phenytoin in the vicinity of cerebellar Purkinje and granule cells.