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Effects of Valproate and Citrulline on Ammonium‐Induced Encephalopathy
Author(s) -
Stephens Jeffrey R.,
Levy René H.
Publication year - 1994
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1994.tb02928.x
Subject(s) - hyperammonemia , citrulline , coma (optics) , encephalopathy , medicine , urea cycle , hepatic encephalopathy , ammonia , chemistry , ammonium , citrullinemia , endocrinology , urea , arginine , biochemistry , cirrhosis , physics , organic chemistry , amino acid , optics
Summary: Hyperammonemia is a recognized side effect of treatment with the antiepileptic drug (AED) valproate (VPA). Encephalopathic complications have also been observed in some patients receiving VPA therapy. The relation between VPA‐induced hyperammonemia and encephalopathy is not clear, however. A model of ammonium (NH 4 ,+)‐induced coma was used to investigate the contribution of VPA and to assess the efficacy of citrulline (a urea cycle intermediate) on hyperammonemia and encephalopathy. In groups of 6–12 rats, administration of VPA (2.5 mmol/kg) was associated with (a) a decrease in the dose of NH 4 + that produces coma in 50% of the animals (CD 50 ) from 6.1 to 3.6 mmol/kg, and (b) significant increases in blood ammonia concentrations in NH 4 ,+ treated animals. In addition, clear evidence also showed that in the presence of VPA, a lesser concentration of ammonia produced coma. Citrulline treatment (5. 0 mmol/ kg) was associated with (a) an increase in the CD 50 value of NH 4 ,+treated animals from 6.1 to 8.6 mmolikg, (b) a statistically significant decrease in ammonia concentration at all doses examined, (c) complete protection from encephalopathic effects of NH, + at citrulline concentrations threeto tenfold greater than basal levels; and (d) a 24% increase in the CD, value and a statistically significant decrease in ammonia concentration of VPA/NH 4 ,+ treated animals. These findings indicate that VPA has a dual effect on encephalopathy and that citrulline should benefit those patients treated with VPA who experience adverse encephalopathic effects.