Carnitine in the treatment of valproic acid-induced toxicity.

INTRODUCTION: Valproic acid (VPA) is a broad-spectrum antiepileptic drug that is now used commonly for several other neurological and psychiatric indications. VPA is usually well tolerated, but serious complications, including hepatotoxicity and hyperammonemic encephalopathy, may occur. These complications may also arise following acute VPA overdose, the incidence of which is increasing. Intoxication usually only results in mild central nervous system depression, but serious toxicity and death have been reported. VALPROIC ACID AND CARNITINE: As a branched chain carboxylic acid, VPA is extensively metabolized by the liver via glucuronic acid conjugation, mitochondrial beta- and cytosolic omega-oxidation to produce multiple metabolites, some of which may be involved in its toxicity. Carnitine is an amino acid derivative that is an essential cofactor in the beta-oxidation of fatty acids. It is synthesized endogenously from the essential amino acids, methionine and lysine. VPA inhibits the biosynthesis of carnitine by decreasing the concentration of alpha-ketoglutarate and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se. CARNITINE SUPPLEMENTATION: Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy although a correlation between ammonia concentrations and the clinical condition was not always observed. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children, although the clinical benefit in terms of liver protection or hastening of recovery from unconsciousness has not been established clearly. Prophylactic carnitine supplementation is also advocated during VPA therapy in high-risk pediatric patients. CONCLUSION: Further controlled, randomized, and probably multicenter trials are required to better delineate the therapeutic and prophylactic roles of l-carnitine and the optimal regimen of administration in the management of VPA toxicity.

Bench-to-bedside review: hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers.

Hyperinsulinaemia/euglycaemia therapy (HIET) consists of the infusion of high-dose regular insulin (usually 0.5 to 1 IU/kg per hour) combined with glucose to maintain euglycaemia. HIET has been proposed as an adjunctive approach in the management of overdose of calcium-channel blockers (CCBs). Indeed, experimental data and clinical experience, although limited, suggest that it could be superior to conventional pharmacological treatments including calcium salts, adrenaline (epinephrine) or glucagon. This paper reviews the patho-physiological principles underlying HIET. Insulin administration seems to allow the switch of the cell metabolism from fatty acids to carbohydrates that is required in stress conditions, especially in the myocardium and vascular smooth muscle, resulting in an improvement in cardiac contractility and restored peripheral resistances. Studies in experimental verapamil poisoning in dogs have shown that HIET significantly improves metabolism, haemodynamics and survival in comparison with conventional therapies. Clinical experience currently consists only of a few isolated cases or short series in which the administration of HIET substantially improved cardiovascular conditions in life-threatening CCB poisonings, allowing the progressive discontinuation of vasoactive agents. While we await further well-designed clinical trials, some rational recommendations are made about the use of HIET in severe CBB overdose. Although the mechanism of action is less well understood in this condition, some experimental data suggesting a potential benefit of HIET in beta-adrenergic blocker toxicity are discussed; clinical data are currently lacking.

Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well tolerated, but rare serious complications may occur in some patients receiving VPA chronically, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity (VHT) and VPA-induced hyperammonaemic encephalopathy (VHE). Some data suggest that VHT and VHE may be promoted by carnitine deficiency. Acute VPA intoxication also occurs as a consequence of intentional or accidental overdose and its incidence is increasing, because of use of VPA in psychiatric disorders. Although it usually results in mild central nervous system depression, serious toxicity and even fatal cases have been reported. Several studies or isolated clinical observations have suggested the potential value of oral L-carnitine in reversing carnitine deficiency or preventing its development as well as some adverse effects due to VPA. Carnitine supplementation during VPA therapy in high-risk patients is now recommended by some scientific committees and textbooks, especially paediatricians. L-carnitine therapy could also be valuable in those patients who develop VHT or VHE. A few isolated observations also suggest that L-carnitine may be useful in patients with coma or in preventing hepatic dysfunction after acute VPA overdose. However, these issues deserve further investigation in controlled, randomized and probably multicentre trials to evaluate the clinical value and the appropriate dosage of L-carnitine in each of these conditions.