Chronic Valproic Acid Therapy and Incidence of Increases in Venous Plasma Ammonia

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Abstract
Results are described on the association of elevated ammonia (NH3) with valproic acid (VPA) therapy in a large group (n = 157) of randomly selected, chronically medicated (> 2 yr) outpatients. The highest incidence (45.5%) of elevations occurred in patients comedicated with VPA-phenobarbital (PB)-phenytoin (PHT) combinations, followed by VPA-PB (33.3%) and VPA-PHT (15.4%). No NH3 elevations were detected in all patients (n = 38) on chronic VPA monotherapy. Considering the total sample (n = 157), NH3 concentrations were found to linearly and directly correlated with VPA plasma concentration (n = 125, r = 0.249, P < 0.001). PB concentration (n = 86, r = 0.411, P < 0.001), sum of VPA-PB concentration (n = 60, r = 0.721, P < 0.001), and sum of VPA-PB-PHT concentration (n = 33, r = 0.802, P < 0.001). When patients in the subgroups (n = 73) that included all the patients with elevated NH3 were separated into 1 group (n = 47) with normal NH3 (.ltoreq. 0.70 .mu.g/ml) and 1 group (n = 26) with elevated NH3 (.gtoreq. 0.71 .mu.g/ml). Student''s t test for equality of means showed that the group with elevated NH3 had a significantly higher mean plasma concentration for VPA, PB, sum of VPA-PB, and sum of VPA-PB-PHT (all at P < 0.001) when compared with the normal group. Futhermore, there was a linear and direct correlation with elevated NH3 and VPA concentrations (n = 26, r = 0.606, P < 0.001), sum of VPA-PB (n = 24, r = 0.486, P < 0.001), and sum of VPA-PB-PHT (n = 15, r = 0.525, P < 0.001). None of the patients had NH3 elevations higher than thrice the upper limit of normal. Medication with VPA is a necessary but not sufficient condition for increased incidence of venous plasma NH3 elvations in chronically medicated patients. Patients on VPA and coanticonvsulant therapy (especiallly PB) are the most likely group to show NH3 elevations. At highest risk are those patients with relatively high VPA and PB plasma concentrations who are also medicated with PHT.