Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy

PURPOSE: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. METHODS: The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). RESULTS: The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 microg/ml versus 8.1 microg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 microg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 microg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 microg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. CONCLUSIONS: LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.     

Valproic acid in epilepsy: clinical and pharmacological effects.

The antiepileptic drug valproic acid was studied in an open clinical trial as adjunct medication for 23 patients with uncontrolled seizures of a generalized or partial type. Two-thirds of the patients experienced reduction in seizure frequency ranging from 25 to 100%. Extensive testing revealed no evidence of serious systemic toxicity due to the drug. Minor side effects (e.g., nausea, vomiting, or sedation) were usually transient. Sodium valproate syrup and valproic acid in capsules gave equivalent mean low (23.3 microgram/ml) and maximum (42.5 microgram/ml) serum concentrations. The drug had a relatively short half-life of 8.7 hours, necessitating administration in divided daily doses. During initiation of valproate therapy there was evidence of a decline in total serum phenytoin concentration (16.5 to 10.2 microgram/ml; p less than 0.001) while the percentage of free phenytoin increased (10.9 to 20%). The quantity of unbound phenytoin was relatively stable throughout. This observation was interpreted as a drug interaction: valproic acid competed with phenytoin for access to plasma protein binding sites.     

Valproic acid in the treatment of epilepsy with special emphasis on serum level determination (author's transl)]

Valproic acid has become a regular component of antiepileptic therapy. Generally it is used against genetically caused, primary generalized epilepsies with bilateral hypersynchronous neuronal discharges in the EEG. An improvement can also be observed by Valproic acid-treatment for secondary generalized and partial epilepsies. Therapeutic results could possibly be improved through a consideration of the serum concentration of valproic acid. Some of the commercial preparations contain the sodium salt of Valproic acid. The free acid which is quickly absorbed, is released in the stomach (tablet) or in the intestine (dragee). The half life is about 15 to 17 hours (one finds a range of 6 to 20 hours in the literature). In view of the half life, it is recommended that the daily dose should be divided into three single doses. About 84 to 95% of the substance is protein bound. Up to now, clinically relevant observations concerning the displacement of valproic acid from its protein binding are unknown. Recently in in vitro studies a decreased protein binding of valproic acid due to phenylbutazone, salicylic acid, and sulfadimethoxine and vice versa, a displacement of phenobarbital and phenytoin caused by valproic acid could be demonstrated. The therapeutic range of the serum level was between 50 and 120 mcg/ml. Individual patients showed that the dispensed dose did not reliably yield the expected serum levels. The necessary daily dose lies for adults between 600 and 2400 mg, in children between 15 and 150 mg/kg. The wide range of allowable dosis is dependent on whether or not valproic acid is to be given in conjunction with other antiepileptic drugs. When phenobarbital and valproic acid are given in conjunction one should be alert for a rise in the phenobarbital serum level. Results of studies in which valproic acid was combined with several other antiepileptic and psychotropic drugs are reported. The majority of the researchers determine a clear parallelism between clinical improvement and a normalization of the EEG in primary generalized epilepsies with bilateral synchronous 3/sec. spikes and waves. The background activity, determined by visual inspection, is not affected. Few workers discuss the correlation of the side effects of valproic acid and its serum level. Tiredness and impaired function of thrombocytes has been observed to be dependent on the valproic acid plasma level.     

Simultaneous toxicities in a child on multiple anticonvulsants

It is rare to develop simultaneous toxicities while on anticonvulsants. This article presents a 3(1/2)-year-old child on valproic acid, lamotrigine, and phenytoin who developed simultaneous hepatotoxicity and bone marrow toxicity during a parainfluenza virus type 3 infection. These toxicities resolved after the cessation of anticonvulsants, and her seizures were managed acutely with scheduled lorazepam. This article discusses the possibility that simultaneous use of valproic acid, lamotrigine, and phenytoin could give this combination of toxicities and that concurrent viral infection may increase this risk.     

Asterixis associated with sodium valproate

Intoxication with most anticonvulsants can produce asterixis. Asterixis rarely occurs with therapeutic serum anticonvulsant levels. We report two patients with asterixis who were taking valproic acid and had serum levels within the therapeutic range. Neither patient had clinical or laboratory evidence of hepatotoxicity. Only one other patient has been reported with valproate-associated asterixis in the absence of toxic serum drug levels or hepatotoxicity. Asterixis seems to be due to a central effect of the drug unrelated to hepatotoxicity or sedation.     

Inverse correlation of valproic acid serum concentrations and quality of life in adolescents with epilepsy

BACKGROUND: Correlation between steady-state serum concentrations of antiepileptic drugs and both seizure control and adverse drug reactions frequency (two major determinants of quality of life in patients with epilepsy) is still matter of controversy. OBJECTIVE: The aim of our study was to investigate whether a correlation exists between steady-state serum concentration of valproic acid and quality of life in adolescent patients with epilepsy. METHOD: Twenty-one adolescent patients with epilepsy, treated with valproic acid for more than 6 months entered the study. On two occasions, 3 months apart, both through and 2-h-after-the-dose serum concentrations of valproic acid were measured, as well as quality of life, using QOLIE-AD-48 for adolescents. Adverse drug reactions and seizure control were also recorded. RESULTS: Significant inverse correlation between through serum concentrations of valproic acid and total QOLIE-AD-48 scores was observed, together with correlation between through serum concentrations and adverse drug reactions frequency. The scores of memory/concentration and physical functioning QOLIEAD-48 domains were significantly and inversely correlated with through serum concentrations. CONCLUSION: Our study suggests that therapeutic monitoring of valproic acid serum concentrations could be useful predictor and marker of the most important epilepsy treatment outcome--quality of life.     

Valproic acid improves psychotic agitation without influencing plasma risperidone levels in schizophrenic patients

OBJECTIVE: To investigate the effect of valproic acid on plasma levels of risperidone and its active metabolite, 9-hydroxyrisperidone under steady state conditions in 12 schizophrenic patients. METHODS: The efficacy and tolerability for the combination treatment of valproic acid and risperidone were examined. RESULTS: The addition of valproic acid to risperidone significantly reduced total scores of PANSS positive symptoms, especially excitement and hostility scores, but did not change SAS scores. Addition of valproic acid did not alter plasma concentrations of risperidone or 9-hydroxyrisperidone or active moiety, and the risperidone/9-hydroxyrisperidone ratio. The combination of valproic acid with risperidone decreased plasma levels of HVA, but not those of MHPG; additionally, treatment with this combination was found to reduce dopaminergic activity. CONCLUSION: These results suggest that the addition of valproic acid to risperidone is both effective and well tolerated for treating excitement and impulsiveness in schizophrenic patients without influencing the metabolism of risperidone, and treatment with valproic acid and risperidone.     

Rapid infusion of sodium valproate in acutely ill children

The purpose of this study was to investigate the clinical safety of sodium valproate and total and unbound valproic acid plasma concentrations after rapid infusion in hospitalized, acutely ill children. Four children (5-15 years) completed the study. Sodium valproate doses (8.3-15.4 mg/kg) were administered in 相似文献   

Thyroid hormones in epileptic children receiving carbamazepine and valproic acid

Carbamazepine and valproic acid are effective antiepileptic drugs for treating many types of epilepsy. Although they are well tolerated, many effects on endocrine function have been reported. Changes in serum thyroid hormones levels in 37 children with epilepsy during carbamazepine and valproic acid therapy were analyzed, and the thyroid hormone concentration after thyrotropin-releasing hormone test was evaluated. Serum thyroxine and free thyroxine levels were significantly lower in patients treated with carbamazepine and carbamazepine plus valproic acid than in the control subjects; serum thyroxine and free thyroxine concentrations were unaffected by valproic acid monotherapy. Serum triiodothyronine and free triiodothyronine concentrations were similar in the three groups of patients studied. Thyroid-stimulating hormone serum levels were normal in all patients, and the thyrotropin responses to the thyrotropin-releasing hormone were similar to control group. Our data suggest that children treated with carbamazepine may have subclinical signs of hypothyroidism, and these changes are more evident if carbamazepine is given in association with valproic acid, while no alteration in thyroid hormones can be found with valproic acid monotherapy. Thyroid-stimulating hormone and thyrotropin-releasing hormone levels do not seem to be affected by these drugs, suggesting that hypothalamic function is not affected in these children.