Serum Carnitine During Valproic Acid Therapy

This study was initiated to examine the influence of valproic acid (VPA) on serum carnitine, as well as the possible etiological role of carnitine in VPA-induced fatal hepatotoxicity. Free, total, and short-chain acylcarnitine were measured in the serum of 21 pediatric patients receiving VPA therapy, 21 healthy matched controls, and 21 patients receiving various antiepileptic drugs other than VPA. The free carnitine level was lowest in the VPA group (p less than 0.05), and the short-chain acylcarnitine/free carnitine ratio was highest in the VPA group (p less than 0.01). Patients receiving VPA polytherapy had lower total carnitine values than patients receiving VPA monotherapy (p less than 0.05). No correlation was found between serum ammonia and VPA drug levels. A 3 1/2-year-old girl developed hepatic failure under VPA therapy. Her serum carnitine values were normal. Despite the oral intake of L-carnitine this patient died. In this case, apparently VPA-induced hepatotoxicity was not associated with carnitine deficiency. The reduction of carnitine in the serum of VPA-treated patients is most probably due to alterations of fatty acid metabolism. However, neither primary carnitine deficiency nor VPA-induced secondary carnitine deficiency can be the only reason for the VPA-induced fatal hepatotoxicity.     

Valproic Acid: Reversibly Acting Drug?

Valproic acid [dipropylacetic acid (DPA)] was evaluated in an alumina-gel monkey model (N= 12) by constant-rate intravenous infusion. The data indicated: (a) a statistically significant decrease in seizure frequency the first 2 days of drug Step I (45–55 μg/ml) and drug Step II (90–110 μg/ml) which was temporary, lasting 2 days only; (b) a later, more permanent decrease in seizure frequency which was not apparent until drug Step III (130–170 μg/ml); and a delayed return of the seizure frequency to predrug levels for 2 weeks after drug administration was discontinued, with no DPA detectable in plasma after the initial postdrug day. Whether DPA will behave as a reversibly acting drug was discussed.     

Blood Ammonia Level during Valproic Acid Therapy

Abstract: We determined the blood ammonia level of epileptic patients in relation to valproic acid (VPA) therapy. A total determination of 256 specimens obtained from 174 cases were analyzed. The materials were assigned to the following three treatment groups: (a) VPA-monotherapy, (b) VPA-polytherapy and (c) non-administration of VPA. The distribution ranges of the blood ammonia level (μg/dl) were 40.5, 56.6 and 40.7 in mean, respectively. The VPA-polytherapy group showed a significantly higher level compared with the other two groups. On the other hand, the latter two groups showed no difference. There was a positive relationship between the blood ammonia and VPA serum levels with statistical significance. In conclusion, a critical factor causing hyperammonemia seemed to be the multiple use of antiepileptic drugs including VPA.     

Dose-Dependent Valproic Acid Thrombocytopenia in Bipolar Disorder

The increased use of anticonvulsants in the treatment of bipolar disorders necessitates a greater appreciation of potential complications from these agents. The authors present a bipolar disorder patient with dose-dependent valproic acid thrombocytopenia and suggest treatment strategies.     

β-Oxidation of Valproic Acid.

The effect of fasting and glucose-infusion on valproate (VPA) disposition was investigated to determine the involvement of endogenous fatty acid (FA) beta-oxidation in the metabolism of VPA. Fifteen healthy volunteers received multiple oral doses of VPA to achieve steady state under both conditions. Depressed plasma FA concentrations in the glucose-infused state (median 51%, p less than 0.0001) were associated with lower unbound plasma VPA fractions (median 17%, p less than 0.0001). Unbound plasma VPA concentrations were notably lower in the glucose-infused state due to significantly higher (median 41%, p less than 0.0001) metabolic clearance, beta-oxidative metabolite formation clearance, representing the largest urinary dose fraction recovered, was significantly higher (median 60%, p less than 0.004) in the glucose-infused state. This finding is consistent with competition between endogenous FA and VPA for the enzymes of beta-oxidation modulated by conditions which affect FA mobilization to the site of catabolism.     

Hepatotoxicity in Rat Following Administration of Valproic Acid

Chronic injections of valproic acid (VPA), VPA with phenobarbital (PB), and PB were studied for their effects on liver mitochondrial morphology and carnitine metabolism in rats. Mitochondrial enlargement was induced by the administration of VPA (500 mg/kg/day) for a period of 7 consecutive days. The administration of VPA (500 mg/kg/day)-plus-PB (20 mg/kg/day) for 7 days, however, did not induce megamitochondrial formation, but in these livers an unusual increase was observed in the number of liver mitochondria, microvesicular steatoses, and myeloid bodies. VPA-treated rats had significantly lower levels of serum-free and total carnitine and higher levels of acylcarnitine and acyl to free ratio than those of the controls. The free carnitine concentrations in serum and liver of the rats treated with VPA-plus-PB were much lower as compared with those treated with either VPA or PB. These morphological and biochemical results, especially of carnitine metabolism, suggest that inhibition of beta-oxidation in liver mitochondria occurred in rats treated with VPA and PB and that, in particular, polytherapy with VPA-plus-PB could be clinically hazardous in causing hepatic injury.     

Valproic Acid: Update on Its Mechanisms of Action

Valproic acid (VPA; 2-propylpentanoic acid or dipropylacetic acid) was synthesized by Burton in 1882 and shown to have anticonvulsant properties by Meunier et al. in 1963. VPA was licensed for use as an anticonvulsant in the United States in 1978. It is used primarily for the treatment of generalized seizures.     

Valproic Acid and Warfarin: An Underrecognized Drug Interaction

Background  

Drug interactions in the neurosciences intensive care unit (NICU) may involve antiepileptic drugs and warfarin. Most commonly used antiepileptic drugs are either potent hepatic enzyme inducers or inhibitors and they affect the metabolism of warfarin. Valproic acid also displaces warfarin from the protein binding sites resulting in significant INR changes but this type of drug interaction is less well known.     

Valproic Acid in Women and Girls of Childbearing Age

Purpose of Review

The aim of this paper is to evaluate recent literature on valproic acid (VPA) in women and girls of childbearing age and to emphasize new findings.

Recent Findings

Recent research confirms VPAs teratogenicity and risk of hormone disruption. VPA exposure in utero increases the risk for a variety of major congenital malformations (MCMs), reduced IQ and behavioral problems. In girls and women, VPA increases the risk of hormone abnormalities, obesity, and polycystic ovarian syndrome (PCOS). Despite guidelines recommending caution, VPA use continues to be prescribed to reproductive-aged women and girls.

Summary

Despite significant and well-documented risk, adherence to guidelines in VPA use in reproductive-aged girls and women remains low.

     

Valproic Acid and Metabolites: Pharmacological and Toxicological Studies

Valproic acid (VPA) is a widely used anticonvulsant drug with a wide spectrum of activity, which is particularly well suited for the treatment of primary generalized seizures of the absence type.     

Excretion of Valproic Acid into Semen of Rabbits and Man

Dipropylacetic acid (VPA, valproic acid) has been quantified in plasma and semen from rabbits and man using a new gas-liquid chromatographic assay. The drug assay is rapid, sensitive and free from interference by VPA metabolites. The beta phase half-life of VPA in rabbits after an i.v. dose (50 mg/kg) was 56 +/- 6 min. The concentration of VPA in rabbit plasma was 17 to 30 times the concentration in rabbit semen. In man, 500 mg doses of the free acid, p.o., resulted in VPA concentrations in plasma that were 11 to 17 times the concurrent levels in semen. VPA, in concentrations up to 10(-3) M, did not influence the motility of rabbit spermatozoa in vitro.     

Low Serum Biotinidase Activity in Children with Valproic Acid Monotherapy

PURPOSE: Valproic acid (VPA) is an effective antiepileptic drug (AED), which is associated with dose-related adverse reactions such as skin rash, hair loss (alopecia), etc. Profound as well as partial biotinidase deficiency causes dermatologic manifestations similar these. Therefore, it was of interest to evaluate serum biotinidase activity in patients receiving VPA monotherapy. METHODS: Seventy-five patients with seizures, mean age, 8.6 years (+/-1.9 years) were divided into three groups. Group A (n = 25) was treated with VPA 28.7 +/- 8.5 mg/kg/24 h, group B (n = 25) with 41.6 +/- 4.9 mg/kg/24 h, and group C with 54.5 +/- 5.8 mg/kg/24 h. Their "trough" VPA serum levels were 40.9 +/- 13.2, 86.25 +/- 11.5, and 137 +/- 14.5 microg/ml, respectively. Fifty healthy children were the controls. Patients and controls underwent clinical and laboratory evaluations including liver function data, complete blood counts, NH3, and so on, after 45 days of VPA treatment. Biotinidase serum levels were evaluated fluorometrically. RESULTS: Liver function data were found elevated in the groups B and C. On the contrary, biotinidase activity was significantly statistically lowered (p < 0.001) in groups B and C (1.22 +/- 1.11, 0.97 +/- 0.07 mmol/min/L respectively), as compared with controls (5.20 +/- 0.90 mmol/min/L). Strong inverse correlations were observed between liver enzymes and VPA blood levels with the activity of the enzyme. Additionally, no inhibitory effect on biotinidase activity was found, when the enzyme was incubated in vitro with high (1.2 mM) concentrations of the drug. Skin lesions (seborrheic rash, alopecia) were improved in our patients after biotin (10 mg/day) supplementation. CONCLUSIONS: It is suggested that VPA impairs the liver mitochondrial function, resulting in a low biotinidase activity and or biotin deficiency. Biotin supplementation could restore some of the side effects of the drug.