Hiroyuki Shirai

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.

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-

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.

Long-term prognosis of epilepsies developing after starting intermittent rectal diazepam therapy for prevention of recurrent febrile convulsions: a further study

onset of febrile seizures had EEG abnormalities before 3 years of age. Discussion. The observation of epileptiform EEG abnormalities before epilepsy onset was associated with no family history of febrile seizures within second-degree relatives, higher age at epilepsy onset, longer period between febrile seizures and epilepsy onset, and neurological abnormalities before the onset of febrile seizures. The centroparietal area was the most frequent focus in patients with, while the frontal area was most frequent in those without, EEG abnormalities before epilepsy onset. The degree of maturity and the location of the irritable brain lesion were closely related to the development of epileptiform EEG abnormalities.

Long-term prognosis of West syndrome treated with the combination of ACTH and clonazepam

tion. Her developmental milestones were normal. She had two episodes of febrile convulsions between 1 and 2 years of age. Her family history revealed that her 29-year-old aunt suffered from frequent dystonic attacks from 8 years of age. At the age of 8, the patient began to have brief dystonic attacks induced by sudden movements. The attacks were always stereotyped and mainly involved the right side of her body. Immediately before the attacks, she felt ‘numbness’ in her right upper limb and trunk. She gradually bent her head with the right arm extended backwards and her face grimacing. During the attacks, her consciousness was clear. The duration of the attacks ranged from 5 to 10 s. The frequency of the attacks ranged from 10 to 20 times per day. Neurological examination on admission revealed no abnormalities. Blood chemistry, brain computed tomography and magnetic resonance imaging were normal. Interictal EEG revealed mild slow-wave dysrhythmia in awake records but no abnormalities in sleep records. EEG recorded with a telemeter during attacks showed two diffuse 4 Hz spike and wave bursts lasting for 4 s followed by muscle contraction artifacts. The patient was treated with 120 mg (4 mg/kg) of carbamazepine. There is now almost complete control of the attacks. Discussion: There are two possible explanations for the pathophysiology of PKC: an epileptogenic or an extrapyramida1 tract disorder. In this case, we suspect that the PKC is related to the epileptogenic mechanism.

The effect of concurrent rectal administration of an antipyretic on the rectal absorption of diazeppam suppositories: a pharmacokinetic study in children with febrile convulsions

Benign epilepsy of children with complex partial seizures following febrile convulsions Kazuyoshi Watanabe, Izumi Takahashi, Tamiko Negoro, Kosaburo Aso and Kiyokuni Miura (Department of Pediatrics, Nagoya University School of Medicine, Nagoya, Japan) This study was presented for discussion to the meeting by invitation of the meeting organizer, although the study is already published as an original article in Seizure 1993;2:57-61.

Probability of developing epilepsies after starting intermittent therapy with rectal diazepam suppositories for prevention of recurrent febrile convulsions

CBZ-H. The daily dose of CBZ in 26 patients receiving CBZ together with VPA (mean age: 12 years, 9 months) and that in the other 71 patients receiving CBZ alone (mean: 9 years, 1 month) were 11.0 + 3.0 mg/kg and 11.0 + 4.0 mg/kg, respectively. The daily dose of VPA in the patients treated with CBZ and VPA was 22.1 + 6.3 mg/kg. The plasma levels of CBZ and its metabolites were measured by means of high-performance liquid chromatography, and those of VPA by TDX ®. The plasma concentrations of CBZ, CBZ-E, and CBZ-H in patients treated with both CBZ and VPA were 7.46 + 1.82 ~tg/ml, 1.93 + 0.91 ktg/ml, and 1.47 _+ 0.59 ~tg/ml; those in patients treated solely with CBZ were 7.43 + 2.07 Ixg/ml, 1.28 + 0.55 ktg/ml, and 1.74 _+ 0.63 Bg/ml, respectively. It is evident that the mean plasma levels of CBZ-E and CBZ-E/CBZ ratio were significantly higher in the patients treated with CBZ and VPA than in those treated with CBZ alone. Conversely, the plasma CBZ-H/CBZ-E ratio was significantly lower in the former group than in the latter group. The plasma concentration in the group of patients treated with both CBZ and VPA was 75.81 + 15.57 ~g/ml. It has been shown that the concurrent administration of VPA raises the plasma CBZ-E level, while the plasma CBZ level remains unaltered. Our study indicates that VPA impairs the elimination of CBZ-E by inhibiting its conversion to CBZ-H. The high plasma concentration of CBZ-E may be responsible for toxic side effects in some patients.

Effectiveness and plasma levels of sodium valproate monotherapy in the treatment of epilepsies in children: a further study.

The patients comprised 60 previously untreated children between 3 months and 14 years old (mean, 7) with any of the symptomatic localization-related epilepsies, idiopathic or symptomatic generalized epilepsies, who had been newly referred to our pediatric seizure clinic. Fifteen patients had symptomatic localization-related epilepsies, 37 had idiopathic generalized epilepsies and the other 8 patients showed symptomatic generalized epilepsies. A daily dose of 30mg/kg of VPA was introduced, and the dosage was prescribed in two divided doses per day. The plasma levels selected for the study were determined 6 weeks after starting or increasing the maintenance dosage, and all blood samples were taken 2 to 4 hours after the morning dose.