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Valproic acid efficacy, toxicity, and pharmacokinetics in neonates with intractable seizures

From the Moses H. Cone Memorial Hospital (Drs. Gal and Weaver), and the Greensboro Area Health Education Center (Dr. Gal), Greensboro, NC; the Bowman-Gray School of Medicine and the Northwest Area Health Education Center (Dr. Oles), Winston-Salem, NC; the Miami Children's Hospital (Dr. Gilman), Miami, FL; and the School of Pharmacy (Drs. Gal and Oles), University of North Carolina at Chapel Hill, Chapel Hill, NC.

Six neonates with prolonged, intractable seizures were treated with valproic acid (VPA). Each patient had received maximum doses of phenobarbital (>40 µg/ml), and five patients received at least two additional anticonvulsants, without success. Seizure activity was controlled in five of six (83%) cases. In four cases, all other anticonvulsants could be withdrawn, and seizures were controlled on VPA monotherapy. VPA was discontinued in three patients because of VPA-induced hyperammonemia. VPA pharmacokinetic measurements were as follows: for total VPA, volume of distribution (V) = 0.40 l/kg (range, 0.36 to 0.47 l/kg), serum clearance (Cl) = 14.4 ml/h/kg (5.5 to 18.2 ml/h/kg), half-life (T) = 26.4 hours (8.6 to 48.5); for unbound VPA, V = 2.02 l/kg (1.14 to 2.44 l/kg), Cl = 108.9 ml/h/kg (42.0 to 252.0 ml/h/kg). T = 17.6 hours (6.7 to 34.2). VPA free fraction ranged from 11.3 to 31.6% (mean, 19.2%).

Address correspondence and reprint requests to Dr. Gal, Pharmacy Research and Education, Greensboro AHEC, Moses H. Cone Memorial Hospital, 1200 North Elm Street, Greensboro, NC 27401.

Received March 5, 1987. Accepted for publication in final form June 3, 1987.

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