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Valproic Acid

Trade Names :

  • Depakene
  • Carnitine —Supplementation Possibly Helpful
  • Vitamin D —Supplementation Possibly Helpful
  • Folate –Supplementation Possibly Helpful
  • Melatonin —Supplementation Possibly Helpful
  • Biotin —Supplementation Possibly Helpful, but Take at a Different Time of Day
  • Vitamin A —Possible Increased Risk of Birth Defects
  • Glutamine —Theoretical Harmful Interaction
  • White Willow —Possible Negative Interaction
  • Ginkgo —Possible Harmful Interaction
  • St. John's Wort, Dong Quai —Possible Harmful Interaction
Valproic acid is a commonly used anticonvulsant treatment.
Drugs in this family include:
  • Divalproex Sodium
  • Depakote
  • Depakote Sprinkle
  • Sodium Valproate
  • Depakene Syrup
Carnitine
Carnitine is an amino acid that has been used for heart conditions, Alzheimer's disease, and intermittent claudication. Intermittent claudication is a possible complication of atherosclerosis in which impaired blood circulation causes severe pain in calf muscles during walking or exercising.
Long-term therapy with anticonvulsant agents, particularly valproic acid, is associated with low levels of carnitine. 1 However, it isn't clear whether the anticonvulsants cause the carnitine deficiency or whether it occurs for other reasons. It has been hypothesized that low carnitine levels may contribute to valproic acid's damaging effects on the liver. 2,3 The risk of this liver damage increases in children younger than 24 months, 4 and carnitine supplementation does seem to be protective. 5 However, in one double-blind crossover study, carnitine supplementation produced no real improvement in "well-being" as assessed by parents of children receiving either valproic acid or carbamazepine. 6
L-carnitine supplementation may be advisable in certain cases, such as in infants and young children (especially those younger than 2 years) who have neurologic disorders and are receiving valproic acid and multiple anticonvulsants. 7
Vitamin D
Valproic acid slows down the liver's conversion of vitamin D into the active form of the vitamin that can be used by the body. 8 This effect might lead to reduced calcium absorption, since the body needs active vitamin D to absorb calcium properly. Therefore, it might be advisable to take vitamin D supplements at the US Adequate Intake (AI) dosage.
Folate
Folate (also known as folic acid) is a B vitamin that plays an important role in many vital aspects of health, including preventing neural tube birth defects and possibly reducing the risk of heart disease. Because inadequate intake of folate is widespread, if you are taking any medication that depletes or impairs folate even slightly, you may need supplementation.
Valproic acid appears to decrease the body's absorption of folate, 9 and other antiseizure drugs can also reduce levels of folate in the body. 10-14
The low serum folate caused by anticonvulsants can raise homocysteine levels, a condition believed to increase the risk of heart disease. 15
Adequate folate intake is also necessary to prevent neural tube birth defects, such as spina bifida and anencephaly. Because anticonvulsant drugs deplete folate, babies born to women taking anticonvulsants are at increased risk for such birth defects. Anticonvulsants may also play a more direct role in the development of birth defects. 16
However, the case for taking extra folate during anticonvulsant therapy is not as simple as it might seem. It is possible that folate supplementation might itself impair the effectiveness of anticonvulsant drugs, and physician supervision is necessary.
Melatonin
One double-blind study in children found that use of melatonin improved general quality of life in children on valproic acid. 25 The most obvious way melatonin might help would involve improvements in sleep, as melatonin is a widely used treatment for insomnia . Another rather theoretical study by the same author suggests it might help in other more subtle ways that involve the body's biochemistry. 26
Biotin
Many antiseizure medications, including valproic acid, are believed to interfere with the absorption of biotin. 17,18 For this reason, individuals taking valproic acid may benefit from extra biotin. Biotin should be taken 2 to 3 hours apart from your antiseizure medication. Do not exceed the recommended daily intake, because it is possible that too much biotin might interfere with the effectiveness of the medication.
Vitamin A
Both valproic acid and vitamin A can increase the risk of birth defects. The effect might be additive, indicating that pregnant women should avoid such combination treatment. 19
Glutamine
Because valproic acid works (at least in part) by blocking glutamate pathways in the brain, high dosages of glutamine might possibly overwhelm the drug and increase the risk of seizures.
White Willow
The herb white willow contains substances very similar to aspirin. On this basis, it might not be advisable to combine white willow with valproic acid.
Ginkgo
The herb ginkgo is widely used for improving memory and mental function. Seizures have also been reported with the use of ginkgo leaf extract in people with previously well-controlled epilepsy; in one case, the seizures were fatal. 27 One possible explanation is contamination of ginkgo leaf products with ginkgo seeds. 20-24 It has also been suggested that ginkgo might interfere with the effectiveness of some anti-seizure medications, including phenytoin. 28 Finally, it has been noted that the drug tacrine (also used to improve memory) has been associated with seizures, and ginkgo may affect the brain in ways similar to tacrine. 29
Dong QuaiSt. John's Wort
Valproic acid has been reported to cause increased sensitivity to the sun, amplifying the risk of sunburn or skin rash. Because St. John's wort and dong quai may also cause this problem, taking them during treatment with this drug might add to this risk.

References

1 De Vivo DC, Bohan TP, Coulter DL, et al. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 39: 1216-1225, 1998.

2 Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity [letter]. Lancet 1984;1:689.

3 Ater SB, et al. A developmental center population treated with VPA and L-carnitine. In: Update 1993: inborn errors of metabolism in the patient with epilepsy. Sigma-Tau Pharmaceuticals; 1993.

4 Dreifuss FE and Langer DH. Hepatic considerations in the use of antiepileptic drugs. Epilepsia 1987;28(suppl 2):S23-S29.

5 Ater SB, et al. A developmental center population treated with VPA and L-carnitine. In: Update 1993: inborn errors of metabolism in the patient with epilepsy. Sigma-Tau Pharmaceuticals; 1993.

6 Freeman JM, Vining EP, Cost S, et al. Does carnitine administration improve the symptoms attributed to anticonvulsant medications? A double-blinded, crossover study. Pediatrics . 1994;93:893-895.

7 De Vivo DC, Bohan TP, Coulter DL, et al. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia. 1998;39:1216-1225.

8 Tomita S, Ohnishi J, Nakano M, and Ichikawa Y. The effects of anticonvulsant drugs on vitamin D 3 -activating cytochrome P-450-linked monooxygenase systems. J Steroid Biochem Mol Biol . 1991;39:479-485.

9 Hendel J, Dam M, Gram L, et al. The effects of carbamazepine and valproate on folate metabolism in man. Acta Neurol Scand . 1984;69:226-231.

10 Kishi T, Fujita N, Eguchi T, et al. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci . 1997;145:109-112.

11 Reynolds EH. Mental effects of anticonvulsants, and folic acid metabolism. Brain . 1968;91:197-214.

12 Berg MJ, Stumbo PJ, Chenard CA, et al. Folic acid improves phenytoin pharmacokinetics. J Am Diet Assoc . 1995;95:352-356.

13 Lewis DP, Van Dyke DC, Willhite LA, et al. Phenytoin-folic acid interaction. Ann Pharmacother . 1995;29:726-735.

14 Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998;32:802-817.

15 Ono H, Sakamoto A, Eguchi T, et al. Plasma total homocysteine concentrations in epileptic patients taking anticonvulsants. Metabolism . 1997;46:959-962.

16 Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother . 1998;32:802-817.

17 Krause K-H, Bonjour J-P, Berlit P, et al. Biotin status of epileptics. Ann N Y Acad Sci . 1985;447:297-313.

18 Said HM, Redha R, and Nylander W. Biotin transport in the human intestine: inhibition by anticonvulsant drugs. Am J Clin Nutr . 1989:49:127-131.

19 Nau H, Tzimas G, Mondry M, et al. Antiepileptic drugs alter endogenous retinoid concentrations: a possible mechanism of teratogenesis of anticonvulsant therapy. Life Sci . 1995;57:53-60.

20 Arenz A, Klein M, Fiehe K, et al. Occurrence of neurotoxic 4'-O-methylpyridoxine in Ginkgo biloba leaves, ginkgo medications and Japanese ginkgo food. Planta Med . 1996;62:548-551.

21 Mizuno N, Kawakami K, and Morita E. Competitive inhibition between 4'-substituted pyridoxine analogues and pyridoxal for pyridoxal kinase from mouse brain. J Nutr Sci Vitaminol (Tokyo) . 1980;26:535-543.

22 Wada K, Ishigaki S, Ueda K, et al. An antivitamin B 6 , 4'-methoxypyridoxine, from the seed of Ginkgo biloba L. Chem Pharm Bull (Tokyo) . 1985;33:3555-3557.

23 Yagi M, Wada K, Sakata M, et al. Studies on the constituents of edible and medicinal plants. IV. Determination of 4-O-methylpyridoxine in serum of the patient with gin-nan food poisoning [in Japanese; English abstract]. Yakugaku Zasshi . 1993;113:596-599.

24 Arenz A, Klein M, Fiehe K, et al. Occurrence of neurotoxic 4'-O-methylpyridoxine in Ginkgo biloba leaves, ginkgo medications and Japanese ginkgo food. Planta Med. 1996;62:548-551.

25 Gupta M, Aneja S, Kohli K. Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial. Epilepsy Behav . 2004;5:316-21.

26 Gupta M, Gupta YK, Agarwal S, et al. A randomized, double-blind, placebo controlled trial of melatonin add-on therapy in epileptic children on valproate monotherapy: effect on glutathione peroxidase and glutathione reductase enzymes. Br J Clin Pharmacol. 2004;58:542-547.

27 Granger AS. Ginkgo biloba precipitating epileptic seizures Age Ageing 2001;30:523-525. Kupiec T, Raj V. Fatal seizures due to potential herb-drug interactions with Ginkgo biloba. J Anal Toxicol. 2006;29:755-758.

28 Kupiec T, Raj V. Fatal seizures due to potential herb-drug interactions with Ginkgo biloba. J Anal Toxicol . 2006;29:755-758.

29 Gregory PJ. Seizure associated with Ginkgo biloba? [letter]. Ann Intern Med. 2001;134:344.

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