Valproic acid carnitine

Although carnitine administration may partially ameliorate hyperammonemia, it is expensive, and there are only limited data to support routine supplemental use in patients taking valproic acid. 

The incidence of the severe form is between 1 in 20,000 and 1 in 40,000 in adults, although the incidence is much higher in children (1 in 5000). The fatty liver is a "visible" symptom of dysfunction, not necessarily a cause of liver failure, although it can be. Valproic acid is similar to a fatty acid and therefore can become incorporated into fatty acid metabolism. This involves formation of an acyl CoA derivative and also a carnitine derivative. However, this depletes both CoA from the intramitochondrial pool and carnitine and so compromises the mitochondria and reduces the ability of the cell to metabolize short-, medium-, and long-chain fatty acids via p-oxidation (Fig. 7.15). 

As it is similar to a fatty acid, it forms an acyl CoA and a carnitine derivative. This depletes CoA from the intramitochondrial pool and carnitine. Also, valproic acid is metabolized to an unsaturated fatty acid analogue, which is incorporated into p-oxidation in mitochondria. The reactive analogue depletes GSH and damages mitochondria. Function is compromised and ATP depleted. 

Status epilepticus can occasionally be fatal therefore, seizures should be treated aggressively. Seizures can be managed with antiepileptic medications such as carbamazepine. The common antiepileptic drug valproic acid is contraindicated because it depletes the body of carnitine, which may in fact exacerbate symptoms. The potential risk of stroke may be reduced using appropriate medication. The complications... 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

Raskind JY and El-Chaar GM (2000) The role of carnitine supplementation during valproic acid therapy. Annals of Pharmacotherapy 34, 630-8. 

Thurston JH and Hauhart RE (1992) Amelioration of adverse effects of valproic acid on ketogenesis and liver coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice possible clinical significance. Pediatric Research 31, 419-23. 

A. Valproic acid is a low-molecular-weight (144.21), branched-chain carboxylic acid (pKg = 4.8) that increases levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and prolongs the recovery of inactivated sodium channels. These properties may be responsible tor its action as a general central nervous system depressant. Valproic acid also alters amino acid and fatty acid metabolism with dismption of the urea cycle, and can cause hepatotoxicity, metabolic perturbations, cerebral edema, and bone marrow depression. Some of these effects may be associated with carnitine deficiency. 

B. Low plasma free carnitine concentrations (reference range 19-60 mcmol/L) or total carnitine (reference range 30-73 mcmol/L) in patients taking valproic acid. 

The authors of the report advise caution if pivmecillinam is added to treatment with valproate. Although this appears to be the only report of an adverse effect due to the combined effects of pivmecillinam and valproate on carnitine levels, the manufacturers advise the avoidance of both pivampicillin or pivmecillinam with valproic acid or valproate or other medication liberating pivalic acid. " ... 

Valproic acid (2-propyl-n-pentanoic acid, VP A) is an anticonvulsant widely used in the treatment of various epileptic disorders. It has been known that VPA administration caused severe hepatic dysfunction similar to Reye s syndrome in a small number of patients. Deaths from hepatotoxicity were also reported. VPA affects carnitine and ammonia levels and other metabolic parameters related to fatty acid oxidation. The potential hepatotoxicity by VPA is caused by its unsaturated metabolites, such as 4-en-... 

We conclude that C8-camitine levels measured by MS-MS, are very useful to monitor the metabolic status in patients with MCAD deficiency. This marker will allow determining the best dietary treatment and fasting tolerance for these patients. This will probably be true as long as normal levels of free carnitine are maintained and valproic acid, which can increase C8-camitine levels and is contraindicated in patients with MCAD deficiency, is not given. Our results also highlight the importance of carefully recording the hours of fasting when values of AC are measured in patients with fatty acid oxidation disorders. 

Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic acid overdose a systematic review of published cases. Ann Phar-macother 2010 44(7-8) 1287-93. 

Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009 47(2) 101-11. 

Effect of Valproic Acid on the Expression of Acyl-CoA Dehydro nases in Various Tissues Table 2. Carnitine concentrations in liver, heart,... 

Valproic add (2-propyl-n-pentanoic acid, VPA) is an anticonvulsant widely used in the treatment of various epileptic disorders. It has been known that VPA administration caused severe hepatic dysfunction similar to Reye s syndrome in a small number of patients. Deaths from hepatotoxicity were also reptorted. VPA affects carnitine and ammonia levels and other metabolic parameters related to fatty acid oxidation. The potential hepatotoxidty by VPA is caused by its unsaturated metabolites, such as 4-en-VPA. Histologically, miaovesicular steatosis induced by 4-en-VPA is accon )anied by ultrastructural changes characterized by myeloid bodies, lipid vacuoles and mitochondrial abnormaUties. An enhanced excretion of Cg to Cio dicarboxylic acids by patients and rats indicates an interference with mitochondrial 3-oxidation as an important pathogenesis. If the normal pathway of fatty add oxidation is disrupted by VPA, it results in reduced ketone body formation and decrease of free coenzyme-A (CoA) in the liver. Especially, deaeased CoA would limit the activities of one or more enzymes in the pathway of fatty add oxidation. 

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