Hisao Miura

Michaelis-Menten pharmacokinetics of diphenylhydantoin and application in the pediatric age patient

Michaelis-Menten pharmacokinetics were evaluated for diphenylhydantoin given to 104 patients 0.5 to 16 years of age with seizures. A method for individualizing the dosage regimen of DPH for each patient was evaluated retrospectively. The Vmax was inversely related to age (r = 0.552, P less than 0.001) but there was no such relationship for Km. The individual pharmacokinetics were characteristic of that person and could be used to adjust dosage so that toxicity would be avoided. We present a nomogram for adjusting the dosage of DPH in the pediatric age groups.

Long-term effectiveness and side effects of acetazolamide as an adjunct to other anticonvulsants in the treatment of refractory epilepsies

The long-term effectiveness of acetazolamide (AZA) and its side effects, especially the formation of renal calculi, were investigated in a prospective study when AZA was used as an adjunct to other antiepileptic drugs in the treatment of refractory epilepsies. The subjects comprised 37 patients aged from 1 to 17 years (mean age, 8 years and 1 month) whose seizures were hard to control with the use of two or more drugs among sodium valproate, carbamazepine and clonazepam. Thirty-two of the 37 patients were complicated with mental retardation. A daily dose of 10mg/kg of AZA was first administered and then the dosage was increased up to 20mg/kg based on the clinical response and side effects. The maintenance daily dosage of AZA (12.2+/-4.2mg/kg) produced a steady-state plasma concentration of 6.2+/-4.5 microg/ml. Among the 37 patients, complete seizure control for more than 3 years was obtained in four patients. Although there were no significant differences, all of the four patients were classified as having symptomatic localization-related epilepsies. Seizures recurred in five after complete remission for at least 6 months, and six showed >50% decrease in seizure frequency for more than 6 months after the introduction of AZA. Twenty-eight patients, who were taking AZA for 10 months to 14 years (mean, 6 years and 5 months), were examined for the formation of renal calculi. None of them showed evidence of renal calculi. This study reinforces the idea that AZA may be a useful adjunct drug in selected patients with refractory symptomatic localization-related epilepsies.

Pharmacokinetics of rectal diazepam in the prevention of recurrent febrile convulsions

To determine the optimum dosage schedule for intermittent rectal diazepam in suppository form for the prevention of recurrent febrile convulsions, we studied the pharmacokinetics of diazepam administered in repeated rectal doses. The plasma concentration-time data for diazepam on twice repeated rectal dosing with 0.5 mg/kg at 8-hour intervals in six infants showed that therapeutic plasma levels could be attained within 30 minutes and maintained for the first 24 hours. Most of the observed plasma diazepam levels were found to be within +/- one standard deviation of the values calculated from the pharmacokinetic parameters in six other infants with single rectal dosing. Computer-simulated plasma level profile suggested that plasma diazepam levels may reach the toxic range after administration of five or more doses. Twice repeated rectal dosing with 0.5 mg/kg of diazepam in suppository form at 8-hour intervals during the febrile period may be a rational approach for the prevention of recurrent febrile convulsions.

Phenobarbital, primidone and sodium valproate in the prophylaxis of febrile convulsions

Of 196 children with febrile convulsions, 6.9 were placed on phenobarbital, 4-5 mg/kg/day b.i.d., and 32 on primidone, 15-20 mg/kg/day b.i.d. The remaining 95 children were given sodium valproate; the dosage was 20-25 mg/kg/day b.i.d. in 38 of them, 20-25 mg/kg/day t.i.d. in 24 of them, and 30 mg/kg/day b.i.d. in 33 patients. Recurrence rate of febrile convulsions during one year were not statistically different among these five groups. However, the dosage regimen of valproate of 20-25 mg/kg/day b.i.d. was relatively inferior to the other regimens of valproate in the prophylactic effect. This may be explained by the facts that when the same daily dosage of sodium valproate was given, the daily fluctuation of plasma levels was greater with the b.i.d.-regimen than with the t.i.d.-regimen, and that when the dosage interval was the same, the minimum plasma level of the day was lower with the smaller daily dosage regimen than with the larger one.

Radioreceptor assay of clonazepam and diazepam in blood for therapeutic drug monitoring.

Rat cerebral cortex was used to prepare a suspension of benzodiazepine receptors. The suspension was mixed with an extract of specimen and [3H]flunitrazepam. The mixture was filtered through a membrane, and radioactivity on the membrane was measured. Clonazepam concentrations in patient plasma specimens determined by radioreceptor assay and gas-liquid chromatography agreed well. However, diazepam equivalent concentrations determined by radioreceptor assay were close to the sum of diazepam and desmethyldiazepam concentrations determined by high-performance liquid chromatography, as desmethyldiazepam had binding activity for the receptor. This receptor assay method is accurate, simple, requires less than 0.5 ml of plasma, and is therefore suitable for analyzing numerous samples in a short time.

Influence of Concurrent Administration of Sodium Valproate on the Plasma Concentrations of Carbamazepine and Its Epoxide and Diol Metabolites

Sodium valproate (VPA) and carbamazepine (CBZ) are among the most widely used antiepileptic drugs and when administered together have been reported to present toxic side effects in some patients, despite the plasma levels of both VPA and CBZ remaining within the therapeutic range.8 l4 lB CBZ is extensively metabolized to the active metabolite carbamazepine1 0 , l l -epoxide (CBZ-E) and finally to the inactive 1 0 , l l dihydroxycarbamazepine ( C s Z H ) .l The high plasma concentration of CBZE may be responsible for the side effects.8 l4 l5 In the present study the influence of concurrently administered VPA on the steadystate plasma concentrations of CBZ, CBZ-E and its diol metabolite CBZ-H was investigated in patients receiving CBZ together with VPA, who attended our pediatric seizure clinic.

Immunosuppressive Factors Detected during Convalescence in a Patient with Severe Serum Sickness Induced by Carbamazepine

We report on a patient with severe serum sickness induced by carbamazepine in whom anticarbamazepine IgG antibodies were detected in the serum. The T cells of the patient showed impairment of phytohemagglutinin-induced proliferation, and hypergammaglobulinemia was evident. The clinical features and immunological abnormalities were compatible with immunoblastic lymphadenopathy. Immunosuppressive factors were also detected in the patient. Their molecular weights ranged from 20,000 to 30,000 as evaluated by Sephadex G-200 gel filtration. Such immunosuppressive cytokines were not detected in other patients with carbamazepine allergy who did not develop the clinical manifestations of immunoblastic lymphadenopathy. These results suggest that the T cell functional deficiency of immunoblastic lymphadenopathy is induced by these immunosuppressive cytokines.

The Long-Term Effectiveness of Clonazepam Therapy in the Control of Partial Seizures in Children Difficult to Control with Carbamazepine Monotherapy

The group of patients comprised 28 children aged from 3 to 15 (mean, 9 years and 2 months) with any type of partial seizures, whose seizures were not completely controlled by CBZ monotherapy, in spite of maintaining the plasma levels above 7 pg/ml within the range of therapeutic levels. NO patients showed evidence of mental retardation or other associated neuropsychiatric handicaps (Table 1 ) . A daily dose of 0.025-0.05 mg/kg of CZP was introduced and the dosage was increased to the initial maintenance daily dose of 0.1 mg/kg, if the patient was tolerating. If toxicity developed, the dosage was main-

Developmental and Therapeutic Pharmacology of Antiepileptic Drugs

During the past 10 to 20 years, better results in the treatment of epilepsy have been obtained through the application of pharmacokinetic data to drug therapy of epilepsy. The drug level is not necessarily constant and fluctuations of the level occur during the day, even in the steady state. Sodium valproate (VPA) is rapidly absorbed from the gastrointestinal tract and the biological halflife of VPA is short in relation to the usual dosage interval. Because of the considerable daily fluctuation of the plasma levels as a result, it is necessary to standardize dose schedules and sampling times in evaluating the plasma level of VPA.3 Children on VPA monotherapy taking a daily dose of 2CF30 mg/kg in two divided doses per day were divided into three different age groups. The daily dose per kilogram of body weight correlated poorly with the plasma concentration taken 2 to 4 hours after the morning dose in each age group. However, the plasma level to dose ratio increased with the advancement of the group age. In another group of pediatric patients on VPA receiving in three divided doses per day, the younger children required a higher dose than the older in order to achieve comparable plasma concentrations, similar to what has

An immunodominant haptenic epitope of carbamazepine detected in serum from patients given long-term treatment with carbamazepine without allergic reaction.

An anticarbamazepine antibody was detected in the serum of a patient with severe carbamazepine-induced serum sickness. We found that the patients T cells and IgG antibody recognized an epitope which appeared in subjects showing an allergic reaction, as well as that in subjects who showed no allergic reaction, after long-term carbamazepine therapy. These results show that an anti-carbamazepine immune response does not occur in the majority of subjects who undergo long-term carbamazepine therapy without developing allergic symptoms, although the immunodominant haptenic epitope of carbamazepine is present in their sera.