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Abstract

431 AED = antiepileptic drug; CNS = central nervous system; CoA = coenzyme A; CPS = carbamyl phosphate synthase; GABA = γ-aminobutyric acid; NAGA = N-acetyl glutamic acid; NMDA = N-methyl-D-aspartate; PCT = palmityl carnitine transferase; VHE = VPA-induced hyperammonaemic encephalopathy; VHT = VPA-induced hepatotoxicity; VPA = valproic acid.Available online http://ccforum.com/content/9/5/431 AbstractValproic 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. Lcarnitine 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. IntroductionValproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that has been used for more than 30 years and is effective in the treatment of many different types of partial and generalized epileptic seizure. It is also prescribed to treat bipolar and schizoaffective disorders, social phobias and neuropathic pain, as well as for prophylaxis or treatment of migraine headache. VPA is a branched chain carboxylic acid (2-propylpentanoic acid or di-n-propylacetic acid), with a chemical structure very similar to that of short chain fatty acids (Fig. 1) [1].It is usually well tolerated. Indeed, VPA has fewer common side effects than do other AEDs, especially on behaviour and cognitive functions. Moreover, its adverse effects can often be minimized by initiating the drug slowly. However, rare serious complications may occur in some patients receiving VPA chronically, including fatal 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 either by a pre-existing carnitine deficiency or...

Characteristics of Idiosyncratic Drug‐induced Liver Injury in Children

“…The accurate characterization of potential DILI cases is crucial to improving our understanding of its pathogenesis and treatment. Further study into the role of autoimmunity in pediatric DILI and the potential role of corticosteroids and other targeted therapies (eg, carnitine for valproate hepatotoxicity) is needed (39). Future studies including larger numbers of children and a wider spectrum of DILI will enable us to better identify and manage children at risk for this potentially life-threatening cause of liver disease.…”

Histone Deacetylase Inhibitor Treatment Attenuates MAP Kinase Pathway Activation and Pulmonary Inflammation Following Hemorrhagic Shock in a Rodent Model

“…We specifically chose HDACI valproic acid (VPA) for several reasons: VPA has well-established HDACI activity (17), it is an FDA-approved drug with a known safety and side effect profiles, it is readily available, and has been successfully used in our previous survival studies of hemorrhagic shock in rodents and swine. We elected to study the lung because pulmonary inflammation and acute lung injury are early and deleterious consequence of hemorrhage (18, 19).…”

L-Carnitine Treatment In Acute Valproic Acid Intoxication: Case Report

“…Published evidence of the efficacy and safety of L-carnitine as an antidote for acute VPA intoxication is limited. L-carnitine has been shown to be generally safe and effective in retrospective trials and case reports (5,12,(17)(18)(19). The safety of L-carnitine administration in VPA overdoses, was evaluated in a retrospective study.…”

“…L-carnitine treatment has an important role in protection from hepatotoxicity and the reversal of coma due to VPA intoxication (11). As a result, L-carnitine has been considered as a potential antidote to restore mitochondrial function, reduce the production of toxic metabolites, and counter or reverse the toxic effects of VPA (12).…”