Effect of phenytoin on protein binding of valproic acid.

In vitro experiments using the equilibrium dialysis technique were performed to determine the binding of valproic acid to plasma components in the absence and presence of therapeutic concentrations of phenytoin. The free fraction of valproic acid was found to be dependent on the total valproic acid concentration. Phenytoin did not influence valproic acid protein binding.     

Effects of combined administration of zonisamide and valproic acid or phenytoin to nitric oxide production, monoamines and zonisamide concentrations in the brain of seizure-susceptible EL mice

This study was undertaken to elucidate the anticonvulsive effects of zonisamide (ZNS: 25, 50, and 75 mg/kg, intraperitoneal [i.p.]), which was coadministered with valproic acid (VPA: 25, 50, and 100 mg/kg, i.p.), or phenytoin (PHT: 10, 25, and 50 mg/kg, i.p.) to ZNS concentration, nitric oxide metabolites (NOx levels), and monoamines in the brain of the EL mouse, a strain highly susceptible to seizures. NOx levels were obtained from measuring of combined level of nitrite plus nitrate. Coadministration of ZNS with VPA or PHT suppressed convulsive seizures more effectively than with treatment of ZNS alone. Both serum and brain concentrations of ZNS tended to increase as the dose of VPA or PHT was increased. While coadministrations of ZNS (75 mg/kg) and VPA or PHT at any dose did not change brain and serum NOx levels, those altered brain monoamine contents. These results suggested that anticonvulsive effect of coadministrations of ZNS and VPA or PHT were caused by changes of monoamines rather than changes of NO metabolites.     

Effects of acute valproic acid administration on carnitine plasma concentrations in epileptic patients

Serial plasma samples collected after an acute administration of valproic acid, (VPA, 15 mg/kg as oral solution) in epileptic patients were selected for this study. The plasma samples were selected from three different groups of patients; patients on phenobarbital and phenytoin with clinical VPA intolerance (group A); patients on phenobarbital and phenytoin without clinical VPA toxicity (group B); and patients without phenobarbital and phenytoin and without clinical VPA toxicity (group C). Plasma samples from 6 patients per group were analyzed for carnitines and ammonia. Ammonia levels during acute study increased significantly (P less than 0.05) in patients who experienced VPA intolerance, while no changes were found in the other patients. After acute VPA administration, total carnitine was unchanged but free carnitine was decreased (P less than 0.05) and carnitine esters were increased (P less than 0.05) in all groups of patients studied. No difference in carnitine profiles was seen between patients with or without evidence of VPA administration has an important effect on carnitine metabolism. However, unlike the acute effect on ammonia metabolism, this acute effect does not seem to be correlated with any associated antiepileptic therapy, nor does it predict clinical VPA intolerance.     

Relationship between plasma concentrations of valproic acid and hepatotoxicity in patients receiving high doses

IntroductionValproic acid (VPA) is an anticonvulsivant drug widely prescribed in the treatment of many forms of generalized epilepsy. In literature, the incidence of liver damage induced by AVP is 0.01%. It is potentialized by the combination therapy (phenobarbital, carbamazepine). Severe hepatotoxicity is rare and appears to be independent of dose and to cause a high mortality.MethodsThe aim of our study was to evaluate the relationship between plasma concentrations of AVP and the occurrence of side effects especially hepatotoxicity in patients receiving high doses of AVP.ResultsIn this period, 425 plasmatic AVP monitoring were carried out in our laboratory. From 128 patients treated by high doses of AVP, only 73 were included in this study. Our work showed that adverse effects in epileptics under high doses of AVP was related to the association of the AVP with other antiepileptic in particular carbamazépine, phenobarbital and benzodiazepines rather than supra-therapeutic plasmatic concentrations of AVP. The association of AVP to major antiepileptics (carbamazépine and or phenobarbital) does not seem to generate an increase in the plasmatic concentration of AVP, which was not associated with a greater risque of adverse effects.ConclusionConsequently, clinical signs of liver toxicity may be present in AVP concentrations generally considered in the therapeutic range especially when used in high doses and or combined with antiepileptic drugs like phenobarbital or carbamazepine.     

Adiponectin and visfatin concentrations in children treated with valproic acid

Chronic antiepileptic therapy with valproic acid (VPA) is associated with increased body weight and insulin resistance in adults and children. Attempts to determine the underlying pathophysiologic mechanisms have failed. Adipocytokines have recently been defined as a link between glucose and fat metabolism. We herein demonstrate that VPA-associated overweight is accompanied by lower adiponectin and higher leptin concentrations in children. The absence of any relationship with visfatin concentration does not suggest a role of this novel insulin-mimetic hormone in VPA-associated metabolic alterations. Therefore, adiponectin and leptin but not visfatin may be considered as potential regulators of glucose and fat metabolism during VPA-therapy.     

Effect of phenytoin on plasma clozapine concentrations in two patients

Little is known about interactions of other drugs with the recently marketed antipsychotic clozapine. Two cases in which the addition of phenytoin caused a decrease in plasma clozapine concentrations and worsening of psychoses are described, and possible explanations are discussed.     

Simultaneous determination of valproic acid and 2-propyl-4-pentenoic acid for the prediction of clinical adverse effects in Chinese patients with epilepsy

Valproic acid (VPA) is a well-established anticonvulsant drug that has been increasingly used in the treatment of many forms of generalized epilepsy. Although there are many reports of adverse effects of VPA, studies focusing on the concentration-response relationships of VPA and its metabolites in patients with epilepsy are extremely limited. In this study, a rapid and specific high performance liquid chromatography-ultraviolet (HPLC-UV) method to simultaneously detect the concentrations of VPA and its major hepatotoxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in human plasma has been established, using 2,4'-dibromoacetophenone and octanoic acid as the derivatization reagent and internal standard, respectively. This method was used to analyze plasma samples (n=64) of Chinese patients with epilepsy. The results revealed that 4-ene VPA concentrations in Chinese patients were much higher than those in patients in other countries such as United States and Iran. Significant correlations between aspartate aminotransferase (AST), alanine aminotransferase (ALT) and 4-ene VPA concentration suggest that the simultaneous determination of VPA and 4-ene VPA is an effective tool for the prediction of clinical hepatotoxicity in epileptic patients. Furthermore, the present study describes a less costly and complex technique for the clinical monitoring of VPA plasma levels and the risk of hepatotoxicity which may be of particular interest in developing countries like China.     

Thrombocytopenia in pediatric patients on concurrent cannabidiol and valproic acid

In January 2019, a new plant-derived purified cannabidiol preparation, approved by the US Food and Drug Administration, became commercially available for patients ≥2 years old with Lennox-Gastaut syndrome or Dravet syndrome. Among our patients who were prescribed the new cannabidiol formulation, we observed several cases of thrombocytopenia and therefore embarked on this study. We conducted a single-center systematic chart review of all pediatric patients (<21 years old) who were prescribed cannabidiol from January to August 2019. We evaluated salient features of the patients’ epilepsy syndrome, age, concurrent medications, and surveillance laboratory results before and after cannabidiol initiation. Among 87 patients, nine (10%) developed thrombocytopenia (platelet nadir range = 17 000-108 000) following initiation of cannabidiol. Each of these nine children was on combination therapy of cannabidiol with valproic acid. Whereas no children on cannabidiol without valproic acid (0/57) developed thrombocytopenia, nine of 23 treated with combination valproic acid and cannabidiol developed platelets < 110 000/µL (P < .0001). We report a novel and clinically important side effect of thrombocytopenia in one-third of patients treated concurrently with cannabidiol and valproic acid. If this finding is confirmed, clinicians should perform close monitoring for thrombocytopenia when adding cannabidiol to a regimen that includes valproic acid.     

Every-12-hour administration of extended-release divalproex in patients with epilepsy: impact on plasma valproic acid concentrations

Extended-release divalproex sodium (divalproex-ER) biopharmaceutics after every-12-hour (q12h) administration was compared with that of once-daily divalproex-ER and conventional divalproex given every 6 hours (q6h) in a multiple-dose (14-day), randomized, three-period crossover design study in 24 patients with epilepsy concomitantly receiving enzyme-inducing antiepileptic medication(s). Plasma valproic acid (VPA) minimum concentration (Cmin) for divalproex-ER q12h was higher than the once-daily divalproex-ER Cmin (P=0.043). Once-daily divalproex-ER Cmin values were not different from those for divalproex q6h, suggesting that adequate trough steady-state concentrations are maintained with once daily dosing, despite enzyme-inducing comedication. The degree of peak-trough fluctuation (DFL, calculated as (Cmax-Cmin)/Cavg) in VPA concentration was less with both q12h (35.2% less) and once-daily (16.9% less) divalproex-ER regimens compared with q6h divalproex (P0.024). The DFL for divalproex-ER dosed as a q12h regimen was 22% less than that for once-daily divalproex-ER (P=0.02). The DFL in VPA concentration with divalproex-ER can be minimized with once-daily administration and more so with q12h administration, compared with conventional enteric-coated divalproex taken q6h.     

Quality of life and treatment satisfaction in Spanish epilepsy patients on monotherapy with lamotrigine or valproic acid

BackgroundPatients suffering from epilepsy have an impaired health related quality of life (HRQoL) because of seizures and treatment adverse events. Epilepsy affects differently both genders, due to hormonal influence in women. The aim of this study is to assess the impact on HRQoL and treatment satisfaction in epilepsy patients treated with stable doses of lamotrigine and valproic acid.MethodsObservational cohort prospective study was conducted in 18 Spanish neurology sites. Patients with clinically stable partial or generalized epilepsy, already receiving lamotrigine or valproic acid on monotherapy, were assessed in two visits: baseline and at 6 months. Socio-demographic and clinical variables were recorded at baseline; HRQoL (QOLIE-10) treatment satisfaction and women image self-perception were assessed at both visits. Impact on HRQoL was assessed in both treatment arms overall and in the women subgroup.ResultsA total of 107 patients were evaluated; 53 (14 men, 39 women) on lamotrigine and 54 (27 men, 27 women) on valproic acid. Mean (SD) age was 30.4 (9.1) years and mean (SD) time since epilepsy diagnosis was 8 (8.1) years. Mean (SD) QOLIE-10 score at baseline was 73.9 (15.7) points (76.6 and 71.4 for lamotrigine and valproic, respectively). At follow up, patients reported better HRQoL on both lamotrigine (78.8 points) (p < 0.05) and on valproic (72.4 points) in comparison with baseline. Women's HRQoL at follow up was better on the lamotrigine arm compared with valproic acid: 78.8 (12.8) vs. 70.3 (15.9) (p < 0.05). Women on the lamotrigine arm declared higher satisfaction with treatment and higher disagreement with the different statements referred to a negative image self-perception.ConclusionsChronic patients with epilepsy already treated with lamotrigine slightly improved HRQoL at 6 month follow up, whereas no significant changes were observed in the valproic acid group. Lamotrigine impact on patients’ HRQoL seems to be even more positive in the subgroup of women.     

Correlations between UGT2B712 gene polymorphisms and plasma concentrations of carbamazepine and valproic acid in epilepsy patients

Purpose

The study aims to detect the polymorphisms in uridine diphosphate glucuronyl transferase (UGT) 2B712 and investigate the corresponding effects on the blood concentrations of valproic acid (VPA) and carbamazepine (CBZ).

Use of valproic acid in treatment of infantile spasms

Nineteen babies with infantile spasms were treated with valproic acid over a two-year period. Eleven of the patients were also treated with purified corticotropin, but in no cases were the two drugs used simultaneously. Approximately 40% of the patients had good control of their infantile spasms with valproic acid. Side effects from valproic acid in these babies were not frequent and were, for the most part, minor. Though the percentage of infants with infantile spasms responding to valproic acid may be less than the percentage responding to corticotropin, the incidence and severity of side effects are less with valproic acid.     

Verapamil and valproic acid treatment of prolonged mania.

The case of an adolescent with severe mental retardation, blindness, and a complex of behavioral symptoms consistent with mania is reported. Symptoms include an increased activity level, mood liability, irritability, hyposomia, and severe self-injurious behavior. The successful use of verapamil and valproic acid in the treatment of prolonged mania in this child is described.