Evolution of juvenile myoclonic epilepsy treated from the outset with sodium valproate.
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Sodium valproate (VPA) is considered the first choice drug in juvenile myoclonic epilepsy (JME). We have analysed the long-term evolution of 22 patients treated from the outset with VPA. The following inclusion criteria were applied: (1) unequivocal diagnosis of JME; (2) treatment should be initiated with VPA monotherapy; and (3) follow-up for more than 5 years. Twenty-two patients (15 females, seven males) were studied and their EEG recordings were analysed. Their mean age was 28 years (range: 20-40 years) and their mean follow-up was 7.7 years (range: 5-17 years). Four of them suffered persistent seizures despite optimal VPA dosage and needed the addition of a second drug (lamotrigine in three cases, clobazam in one case). All of our patients who continued their treatment are seizure-free. VPA effectively controlled all seizures in 80% of patients. The discontinuation of drug therapy lead to a very high rate of relapses. With accurate diagnosis and appropriate therapy, seizures in JME can be effectively controlled. VPA is a very effective antiepileptic drug in controlling the seizures of JME, but many patients relapse after VPA discontinuation. Thus, JME may require lifelong therapy. (+info)
In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9).
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AIMS: To evaluate the potency and specificity of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes. METHODS: Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform specific marker reactions were measured: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1) and midazolam 1'-hydroxylase (CYP3A4). RESULTS: Valproic acid competitively inhibited CYP2C9 activity with a Ki value of 600 microM. In addition, valproic acid slightly inhibited CYP2C19 activity (Ki = 8553 microM, mixed inhibition) and CYP3A4 activity (Ki = 7975 microM, competitive inhibition). The inhibition of CYP2A6 activity by valproic acid was time-, concentration- and NADPH-dependent (KI = 9150 microM, Kinact=0.048 min(-1)), consistent with mechanism-based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed. CONCLUSIONS: Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co-administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in significant drug interactions. (+info)
Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.
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Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy. (+info)
Evaluation of interaction between valproate and baclofen in the formalin test in mice.
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Valproate and baclofen dose-dependently inhibited both phases of the formalin test. Combination of valproate and baclofen exerted the additive antinociceptive effect on both phases of the formalin test. (+info)
Previous prolonged clonic seizures diminish antiepileptic activity of valproate against pentetrazol-evoked convulsions.
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Prolonged seizures may alter the brain function in numerous ways. It is conceivable that they might lead to modifications of seizure susceptibility or anticonvulsive drug efficacy, however, only limited data address this issue. Therefore, we have decided to estimate the antiepileptic activity of drugs interfering with GABA-ergic neurotransmission in mice subjected to prolonged clonic seizures 2 weeks before, using pentetrazol test. The activity of valproate, but not diazepam or phenobarbital, was diminished in animals following repetitive clonic seizures. It might be hypothesized that in humans suffering from epilepsy, prolonged seizures in the past might contribute to the lowered efficacy of valproic acid later on. (+info)
Morphological changes in the testis after long-term valproate treatment in male Wistar rats.
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Uncertainty exists about the effect of antiepileptic drugs on gonadal function. In females, long-term valproate treatment has been shown to induce endocrine disturbances and an increased number of ovarian cysts. The aim of the present study was to investigate whether valproate can also induce morphological changes in the testis of male animals. In addition, possible morphological changes in the liver, heart, lungs, lymphatic nodes, pancreas, kidney or brain were studied. The carcinogenic implications were evaluated by the measurement of p53. Male Wistar rats were fed perorally with valproate mixture 200 mg kg(-1)(n= 15) or 400 mg kg(-1)(n= 20), or control solution (n= 15) twice daily for 90 days. Serum concentrations measured 4-6 hours after the last dose were 105 and 404 micromol l(-1)in low- and high-dose valproate treated animals respectively. There was a highly significant, 51% decrease (P< 0.001) in testicular weight in the high-dose treated valproate rats with no changes in the other groups. There was widespread testicular atrophy with histologically verified spermatogenic arrest in 15/20 of the high-dose valproate treated animals. No changes in the testis were seen in the low-dose valproate treated rats, nor in the control rats. There were no morphological changes in the other investigated organs. None of the groups showed over-expression of p53. In conclusion, a dose-dependent effect of chronic valproate treatment was found on testicular morphology in rats. Caution must be taken before these results can be applied to humans. (+info)
Video game epilepsy.
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Reflex epilepsy is the commonest form of epilepsy in which seizures are provoked by specific external stimulus. Photosensitive reflex epilepsy is provoked by environmental flicker stimuli. Video game epilepsy is considered to be its variant or a pattern sensitive epilepsy. The mean age of onset is around puberty and boys suffer more commonly as they are more inclined to play video games. Television set or computer screen is the commonest precipitants. The treatment remains the removal of the offending stimulus along with drug therapy. Long term prognosis in these patients is better as photosensitivity gradually declines with increasing age. We present two such case of epilepsy induced by video game. (+info)
Epi-inositol regulates expression of the yeast INO1 gene encoding inositol-1-P synthase.
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Myo-inositol exerts behavioral effects in animal models of psychiatric disorders and is effective in clinical trials in psychiatric patients. Interestingly, epi-inositol exerts behavioral effects similar to myo-inositol, even though epi-inositol is not a substrate for synthesis of phosphatidylinositol. We postulated that the behavioral effects of epi-inositol may be due to its effects on gene expression. Yeast INO1expression was measured in northern blots. INM1 was determined by beta-galactosidase activity in a strain containing the fusion gene INM1-lacZintegrated into the genome. Epi-inositol affects regulation of expression of the INO1 gene (encoding inositol-1-P synthase), even though it cannot support growth of an inositol auxotroph (suggesting that, as in mammalian cells, it is not incorporated into phosphatidylinositol). Like myo-inositol, although to a lesser extent, epi-inositol causes a significant reduction in INO1 expression, and reverses the lithium- or valproate-induced increase in INO1 expression. However, it does not affect regulation of INM1 (encoding inositol monophosphatase), the expression of which is up-regulated by myo-inositol. The observed regulatory effects of epi-inositol on expression of the most highly regulated gene in the inositol biosynthetic pathway may help to explain how this inositol isomer can exert behavioral effects without being incorporated into phosphatidylinositol. (+info)