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Hospital de Órbigo, Spain

Inoue Y.,Shizuoka Institute of Epilepsy and Neurological Disorders | Ohtsuka Y.,Okayama University of Science | Ikeda H.,ShizuokaInstitute of Epilepsy and Neurological Disorders | Yoshinaga H.,Okayama University | And 13 more authors.
Epilepsy Research

We evaluated outcomes of 56-week stiripentol use with valproate and clobazam for Dravet syndrome. Of 24 patients, 22 experienced stiripentol-related adverse events. No patients discontinued stiripentol due to adverse events. Seizure frequency decreased by ≥50% in 13 patients with 2 remaining seizure-free. Stiripentol adjunctive therapy has a favorable long-term risk-benefit profile. Background: We have previously shown the benefits of short-term add-on stiripentol therapy for Dravet syndrome inadequately controlled by clobazam and valproate in Japanese patients. We report here the outcomes of long-term stiripentol use. Methods: Patients with Dravet syndrome having ≥4 clonic/tonic-clonic seizures per 30 days while on clobazam and valproate (with or without bromide) received add-on stiripentol for 16 weeks. Those benefiting from stiripentol (50. mg/kg/day; up to 2500. mg/day) continued the therapy for additional up to 40 weeks. Responders were defined as those whose clonic/tonic-clonic seizures became ≤50% frequent as compared to baseline. Results: Of 24 patients starting stiripentol, 21 received the drug for >16 weeks and 19 completed the study. At the endpoint, the responder rate was 54%, with 2 patients remaining clonic/tonic-clonic seizure-free. Twenty-two patients experienced stiripentol-related adverse events, with two having severe ones. They included somnolence (79%), loss of appetite (67%), ataxia (58%), and elevated gamma-glutamyltransferase (38%). No adverse events led to study discontinuation, but 19 patients required dose reduction for stiripentol and/or either antiepileptic drug combined. Stiripentol dose reduction was done in 9 patients, mostly due to somnolence or loss of appetite. Conclusions: During adjunctive stiripentol use with clobazam and valproate, careful monitoring for adverse events such as somnolence and loss of appetite is recommended, and dose reduction may become needed for any of the antiepileptics. Despite the need for safety precautions, the durable responses to stiripentol for up to 56 weeks suggest that the drug is effective as an adjunct to clobazam and valproate for the treatment of Dravet syndrome. © 2015 Elsevier B.V. Source

Esaki T.,Kumamoto Saishunso National Hospital
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society

A 69-year-old asymptomatic woman was admitted because of an abnormal chest shadow. Chest X-ray films showed a tumorous shadow behind the heart. Chest CT scans showed an aberrant artery branching from the thoracic aorta and supplying the left basal segment, but the bronchial tree was normal. The left lung vein was normal but wide, and the left lower pulmonary artery could not be observed. Based on these findings, we diagnosed anomalous systemic arterial supply to the normal basal segment of the left lower lobe. Because this patient had a high risk of heart failure and pulmonary hypertension, we decided to perform a left lower lobectomy, but she refused the operation. As this disease is generally found in younger patients, diagnosis in older age, as in the present case, is rare. In this report we also summarize 39 other reports of this disease in Japan. Source

Tanamachi Y.,Kumamoto University | Saruwatari J.,Kumamoto University | Noai M.,Kumamoto University | Kamihashi R.,Kumamoto University | And 8 more authors.
Neuropsychiatric Disease and Treatment

Background: Although patients with moderate intellectual disability (ID) are known to have higher rates of being overweight and obese than those without ID, there are no current data regarding the relationship between ID and weight gain in epilepsy patients treated with valproic acid (VPA). Patients and methods: The possible association between moderate ID and an overweight status at the time of initiation of VPA therapy (baseline) was investigated using a logistic regression analysis in 143 patients with epilepsy. Among the 119 nonoverweight patients at baseline, the longitudinal association between moderate ID and the weight status during VPA therapy was retrospectively examined using a Cox hazards regression analysis and the generalized estimating equations approach, while also paying careful attention to associations with other patient characteristics. Results: The proportion of patients with moderate ID was 52.4% among the 143 study subjects. The presence of moderate ID was not associated with an overweight status at baseline (P=0.762). Among the nonoverweight patients at baseline, 16 subjects were newly diagnosed as being overweight during treatment with VPA (3.6±2.1 years). The presence of moderate ID was significantly associated with the incidence of an overweight status after starting VPA therapy (adjusted hazard ratio =6.72, P=0.007). The patient age at baseline and treatment with co-administered carbamazepine, clobazam, and zonisamide significantly influenced the degree of weight fluctuation during VPA therapy among the patients with moderate ID (P0.001, P0.001, P=0.002, and P=0.028, respectively), whereas only patient age at baseline affected this parameter among the patients without moderate ID (P=0.022). Conclusion: The present findings suggest that the weight status should be carefully monitored in VPA-treated patients with moderate ID, especially those receiving other co-administered antiepileptic drugs that facilitate weight gain, such as carbamazepine. © 2015 Tanamachi et al. Source

Saruwatari J.,Kumamoto University | Ishitsu T.,Kumamoto Saishunso National Hospital | Nakagawa K.,Kumamoto University

Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmacodynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed. +ACY-copy; 2010 by the authors; licensee MDPI, Basel, Switzerland. Source

Saruwatari J.,Kumamoto University | Deguchi M.,Kumamoto University | Yoshimori Y.,Kumamoto University | Noai M.,Kumamoto University | And 8 more authors.
Epilepsy Research

The association between the superoxide dismutase 2 (SOD2) Val16Ala polymorphism and the serum aminotransferase levels was retrospectively investigated in 207 valproic acid-treated patients with epilepsy. The Val/Val genotype tended to show elevated alanine aminotransferase levels (odds ratio = 3.5; P= 0.056). In addition, an elevated γ-glutamyltransferase level was associated with the Val/Val genotype (odds ratio = 3.1; P= 0.022). The SOD2 Val/Val genotype may therefore contribute to a valproic acid-induced elevation in the serum aminotransferase levels. © 2011 Elsevier B.V. Source

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