• Divalproex Sodium
• Valproic Acid and Derivatives
  

Valproic acid (VPA) causes carnitine deficiency in infants and children with epilepsy (Castro-Gago, et al. 1998; Chung et al. 1997; Coulter 1991; Van Wouwe 1995). VPA impairs carnitine hepatic biosynthesis, inhibits fatty acid oxidation, increases esterification of carnitine, and enhances urinary carnitine excretion by VPA metabolites (Van Wouwe 1995).

Although carnitine is synthesized by the body, clinical deficiency can occur. Carnitine deficiency is characterized by inadequate tissue levels, resulting in impaired tissue fatty acid oxidation (Van Wouwe 1995). VPA-treated patients may experience anemia, fatigue, hyperammonemia, hypotonia, lethargy, unexplained stupor, and carnitine-responsive cardiomyopathy; recurrent episodes of a Reye's-like syndrome with low concentrations of carnitine in liver and muscle, reduced plasma glucose levels, and ketone bodies may be the most serious consequence of carnitine depletion (Chung et al. 1997; Van Wouwe 1995).

Carnitine: Patients experiencing fatigue during VPA treatment should receive carnitine supplements (15 mg/kg); daily administration at this dosage level reverses clinical symptoms of carnitine deficiency (Van Wouwe 1995). However, daily doses of 100 mg/kg of carnitine have been recommended; up to 2 g/day may be required for patients experiencing carnitine deficiency secondary to drug therapy (De Vivo et al. 1998). L-carnitine supplementation (50 mg/kg/day for 7 days) significantly reduces elevated serum ammonia levels commonly associated with VPA treatment in children; intravenous administration may be warranted for VPA-induced hepatoxicity (De Vivo et al. 1998; Gidal et al. 1997). Serum carnitine levels should be monitored in patients taking both divalproex sodium and VPA (Castro-Gago, et al. 1998; Chung et al. 1997).

VPA treatment alters copper and zinc homeostasis in epileptic children. In one study, serum zinc levels were significantly lower than controls, while serum copper levels were normal (Sozuer et al. 1995). In a second study, serum zinc and copper levels were normal, but erythrocyte zinc content was significantly lower than controls (Lerman-Sagie et al. 1987). In another study serum copper, but not zinc, levels were significantly lower than controls (Kaji et al. 1992). None of the children in this study exhibited symptoms of copper deficiency.

Copper: A clinical copper deficiency is rare (National Research Council 1989). Signs and symptoms of a deficiency include anemia, neutropenia, changes in structure and appearance of hair, cardiac damage, growth retardation, impaired collagen formation, bone demineralization, osteoporosis, and emphysema (Falchuk 1998; National Research Council 1989).

Zinc: Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000).

Copper: The reference daily intake value for copper is 2 mg (Covington 1999). Depending on the patient's clinical presentation, doses may need to be adjusted accordingly to replenish the body's stores of this trace element.

Zinc: Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.

The zinc and copper status of epileptic children taking valproate derivatives should be monitored.

Valproate reduces plasma selenium levels in patients chronically treated with this drug (Hurd et al. 1984). VPA also decreases levels of glutathione peroxidase (GSH-Px), a selenium-dependent enzyme, in children experiencing serious adverse reactions to drug therapy (Graf et al. 1998; Hurd et al. 1984). Hepatotoxicity and other adverse effects may be related to diminished antioxidant capacity due to depleted selenium and glutathione levels.

Selenium deficiency may lead to oxidative DNA damage (Ames 2000). Chronically low levels of this trace element are associated with pathologies such as cardiovascular disease, rheumatic disorders, muscle, and digestive problems (Navarro-Alarcon and Lopez-Martinez 2000). In addition, there may be a connection between depleted selenium levels and cancer, cirrhosis, and diabetes.

The recommended dietary allowance (RDA) for selenium ranges from 0.70 to 3.50 mg/day (Ames 2000). Doses of 0.02 to 0.05 mg/day have been suggested to prevent selenium deficiency and its associated disorders (Navarro-Alarcon and Lopez-Martinez 2000). Optimal and toxic levels of this nutrient have not been established (Ames 2000). Selenium supplementation may play a role in cancer prevention, including prostate, breast, colon, and cervical carcinoma.

All anticonvulsant drugs interfere with folate metabolism to different degrees (Goggin et al. 1987).

Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.

Although VPA appears to have a minor impact on folate levels, supplementation may still be warranted, especially for epileptic women who are planning to become pregnant (Goggin et al. 1987). Daily doses of 5 mg have been recommended for these women (Robertson 1986). While the recommended dietary allowance (RDA) of folic acid for adults is 300 to 600 mcg/day (Covington 1999), recommendations of doses as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1995). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, age, gender, dietary habits, and medication regimen.

This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.

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Goggin T, Gough H, Bissessar A, et al. A comparative study of the relative effects of anticonvulsant drugs and dietary folate on the red cell folate status of patients with epilepsy. Q J Med. 1987;65(247):911-919.

Graf WD, Oleinik OE, Glauser TA, et al. Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy. Neuropediatr. 1998;29(4):195-201.

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Sozuer DT, Baruteu UB, Karakoe Y, et al. The effects of antiepileptic drugs on serum zinc and copper levels in children. J Basic Clin Physiol Pharmacol. 1995;6(3-4):265-269.

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