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A retrospective multicenter study was conducted, designed to evaluate the efficacy and safety of midazolam for the treatment of status epilepticus. The subjects were 358 inpatients who received intravenous midazolam therapy for status epilepticus. The mean age was 48.6 +/- 46.5 months. The underlying disorder was epilepsy in 195 cases, and acute symptomatic diseases in 163 (encephalitis or encephalopathy in 88 cases). Midazolam was administered as a bolus dose (0.25 +/- 0.21 mg/kg), followed if necessary by continuous infusion (0.26 +/- 0.25 mg/kg/hr). The bolus injection was effective in 162 (56.6%) of the 286 cases. In the end, seizure suppression was obtained in 231 cases (64.5% of the total). The effectiveness of midazolam was lower in patients in whom midazolam was initiated more than 3 hours after seizure onset, and this tendency was particularly marked in the epilepsy group. During the treatment period, 10 patients died, but none of these deaths were associated with midazolam therapy. The incidence and types of adverse events were consistent with previously reported data. The present results indicate that midazolam is highly effective for the management of status epilepticus, if used sufficiently early after seizure onset.

症例は、精神遅滞を有する小児期発症の難治性てんかんの26歳の女性で、てんかんは未決定てんかんに分類される。20歳時にvalproic acid、clonazepamに加え、zonisamide (ZNS) を2年余にわたり、1日量400mg (血中濃度36.7μg/ml) まで増量して使用したが、発作の抑制が不十分であった。今回は、phenobarbital (PB) 、phenytoin (PHT) にacetazolamide (AZA) を漸増しながら併用していたが、他にはとくに誘因なく、顔面から始まり約30秒持続する二次性全般化強直間代発作が頻発したため入院した。入院当日よりAZAを中止し、再度ZNSを1日量160mgから導入した。この二次性全般化発作はlidocaineの静注でほぼ消失したが、ZNS服用再開1週後より、覚醒時に間断のない全身性のi舞踏病アテトーゼ様の不随意運動が出現した。この時点の血中濃度は、PB28.5μ9/ml、PHT8.9μg/ml、ZNS5.2μg/mlであった。ZNSによる副作用を疑い、ZNSの投与を中止し、中止後4日目には不随意運動は消失した。

過去に2回以上の部分発作を示す, それまで未治療の潜因性局在関連性てんかん患児45例を対象に, zonisamide (ZNS) を単剤で1日1回の投与を行い, 血中濃度の日内変動 (最高/最低血中濃度比) と年齢的変化を検討した。ZNSの初回維持量は8mg/kg/dayを基準としたが, 最高/最低血中濃度比は1.25±0.13で, 日内の血中濃度は比較的一定に保たれた。さらに, 前述の対象のうち, 調査時まで12カ月以上にわたり経過を観察しえた25例について, ZNS単剤1日1回投与法の臨床効果を血中濃度面から検討した。初回維持量で, 25例中5例で発作が再発し, 3例で眠気が出現したが, 再発例は最低血中濃度が15μg/mll前後の者に多く, 眠気は最高血中濃度が40μg/ml以上の者に出現した。また, ZNS単剤治療を継続した22例中8例では, 治療開始後12カ月の時点で, 脳波上のてんかん発射が消失していた。

We investigated the clinical effects and plasma levels of zonisamide (ZNS) in children with cryptogenic localization-related epilepsies. ZNS is absorbed slowly from the gastrointestinal tract, and its biological half-life is long as compared with that of other common antiepileptic drugs. The peak-to-trough plasma level ratios during a day were as small as 1.28 +/- 0.15 in children taking a daily dose of 8 mg/kg of ZNS once a day as a single drug. The plasma level (microg/ml) to dose (mg/kg/day) ratios estimated by the trough and peak plasma levels both increased with advancing age, but the peak-to-trough plasma level ratios were maintained almost uniformly throughout the pediatric age period. A wide range of the plasma levels was associated with complete freedom from seizures. The range of the plasma levels in patients who did not respond to ZNS was higher than that in the controlled group. However, the clinical effects of ZNS were in agreement with the range of generally accepted therapeutic plasma levels of ZNS, 15-40 microg/ml. Any patient who receives polytherapy is at risk to develop 1 or more drug interactions. Concurrent administration of carbamazepine (CBZ) decreases plasma concentrations of ZNS. However, ZNS does not alter plasma concentrations of CBZ or its primary metabolite, carbamazepine-10,11-epoxide (CBZ-E). It is evident that the concurrent administration of lamotrigine (LTG) affects plasma concentrations of CBZ-E, while plasma CBZ levels remain unaltered. However, the effect of LTG on plasma concentrations of CBZ-E is small, and none of the study patients showed toxic plasma concentrations of CBZ-E or associated clinical toxicity. Drug-protein binding interactions are another source of side effects. A simultaneous administration of valproic acid increases the total plasma CBZ-E levels relative to the CBZ dose associated with the raised free fractions of CBZ and CBZ-E. The high free plasma concentrations of CBZ-E above 1.5 microg/ml may be responsible for the side effects.

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.

An anticarbamazepine antibody was detected in the serum of a patient with severe carbamazepine-induced serum sickness. We found that the patient's 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.

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.

小児を対象に, 部分発作に対するclonazepam (CZP) 単剤投与の効果を, 脳波所見におよぼす影響とともに, 血中濃度面と合わせて検討した。CZPの初回維持量は0.1mg/kg/dayを基準とした。対象40例中30例では, 14-43ヵ月 (平均24ヵ月) の観察期間中発作が完全に抑制されており, しかもこのうち22例では, CZP投与後6ヵ月の脳波で発作性異常波が消失していた。一方, 6例では発作が再発し, 2例では発作が増強, また他の2例では過動などの副作用が強く, いずれもCZPの単剤投与あるいは継続投与が困難であった。しかし, 有効例とこれら無効例, 発作増強例ならびに副作用出現例で, CZP血中濃度に差を認めなかつた。

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.

Clinical effects and pharmacokinetics of once-a-day pediatric zonisamide (ZNS) monotherapy were investigated in 72 children (range, 3 months to 15 years; mean age, 8 years and 3 months) with cryptogenic localization-related epilepsies with simple, complex, or secondarily generalized partial seizures; none had prior epilepsy treatment. ZNS was initiated at 2mg/kg; daily dosage was doubled at weekly intervals to achieve maintenance dosage (8.0 mg/kg; mean, 7.97 +/- 0.55 mg/kg). Blood samples determined trough and peak plasma levels; levels were 27.0 +/- 9.4 microg/ml and 33.8 +/- 10.8 microg/ml, respectively, with ratios as small as 1.28 +/- 0.15. Plasma level to dose ratios increased with age; peak-to-trough ratios were not age variable. Seizures were not controlled in 23 of 72 patients; low trough plasma levels (approximately 15 microg/ml) were observed. Drowsiness/short attention span in five patients instigated a dosage decrease (peak plasma levels40 microg/ml). During treatment (6-43 months; mean, 27.2 months), seizure control occurred in 57 of 72 patients (79.2%), including eight refractory patients. In 12 patients with uncontrolled seizures and high ZNS levels, carbamazepine (CBZ) was added (BID; mean total dose, 15.1 +/- 3.0 mg/kg) to ZNS (QD; mean dose, 11.1 +/- 2.5 mg/kg); drug interactions were examined.

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.

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.

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.

The Michaelis-Menten pharmacokinetics and bioavailability of phenytoin were evaluated in children. The Vmax was inversely related to age, but there was no such relationship for Km. The fraction excreted in urine as 5-(p-hydroxyphenyl)-5-phenylhydantoin, the main metabolite of phenytoin after oral administration, was not significantly different among the patients aged two months to 16 years; suggesting that no functional difference existed between children and adults that would alter the drug absorption from the gastrointestinal tract. Children on sodium valproate mono-therapy were divided into three different age groups. The daily dose per kilogram of body weight correlated poorly with the plasma concentration in each age group. However, the plasma level to dose ratio increased with the advancement of the group age. Also in children treated only with carbamazepine at daily doses of 10–15 mg/kg body weight, the younger age group achieved the lower steady-state plasma concentrations of carbamazepine. In contrast, the concentration of carbamaze-pine-10, ll-epoxide, the main metabolite of carbamazepine, expressed as a percentage of the parent drug, was higher in the younger age group.