A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria

• Published in: Molecular genetics and metabolism Vol. 107; no. 3; pp. 315 - 321
• Main Authors: Nagamani, Sandesh C.S., Shchelochkov, Oleg A., Mullins, Mary A., Carter, Susan, Lanpher, Brendan C., Sun, Qin, Kleppe, Soledad, Erez, Ayelet, O'Brian Smith, E., Marini, Juan C., Lee, Brendan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2012
• Subjects: Adolescent; Alanine transaminase; Alanine Transaminase - blood; Arginine; Arginine - blood; Arginine - therapeutic use; Arginine therapy; Argininosuccinate lyase; Argininosuccinic Acid - blood; Argininosuccinic aciduria; Argininosuccinic Aciduria - blood; Argininosuccinic Aciduria - drug therapy; Aspartate aminotransferase; Aspartate Aminotransferases - blood; Child; Child, Preschool; citrulline; Clinical trials; Coagulation factors; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glutamine; Hepatic disease; Humans; Isotopes; Liver; Liver Function Tests; Male; Metabolites; Nitrogen; Phenylbutyrates - blood; Phenylbutyrates - therapeutic use; Phenylbutyric acid; Placebos; Plasma levels; prothrombin; Rare disease clinical research; Sodium; Young Adult; Rare disease clinical research; Argininosuccinate lyase; Arginine therapy; Hepatic disease; Argininosuccinic aciduria
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2012.09.016

To compare the effects of combinatorial therapy with low-dose arginine and a nitrogen scavenging agent (sodium phenylbutyrate) vs. monotherapy with high-dose arginine on liver function tests in patients with argininosuccinic aciduria (ASA). Twelve patients with ASA were enrolled in a double-blind, placebo-controlled, cross-over study design. Subjects were randomized to receive either a low-dose of arginine therapy (100mg·kg−1·d−1) combined with sodium phenylbutyrate (500mg·kg−1·d−1) (LDA arm) or a high-dose of arginine alone (500mg·kg−1·d−1) (HDA arm) for one week. At the end of one week of therapy, liver function tests were assessed and metabolite fluxes were measured using a multi-tracer stable isotope protocol. Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and measures of synthetic functions of the liver were the primary outcomes. Subjects had significantly increased levels of argininosuccinate (P<0.03) and AST levels (P<0.01) after treatment with high-dose arginine. In the subset of subjects with elevated AST or ALT, treatment with high-dose of arginine was associated with further increases in plasma levels of both aminotransferases. Whereas subjects had increased arginine and citrulline flux with high-dose arginine therapy, the glutamine flux was not different between the two treatment arms. The synthetic liver functions as assessed by prothrombin time, INR, and coagulation factor levels were not different between the HDA and LDA arms. Administering higher doses of arginine in subjects with ASA results in increases in AST and ALT levels, especially in the subset of patients with elevated baseline aminotransferases. Hence, low-dose arginine sufficient to normalize arginine levels in plasma combined with nitrogen scavenging therapy should be considered as a therapeutic option for treatment of ASA in patients with elevations of hepatic aminotransferases. ► First investigator initiated randomized double-blind study in ASA. ► Effects of therapy with LDA plus NaPBA vs. HDA on hepatic function tests compared. ► Treatment with HDA leads to increase in plasma ASA, AST, and ALT.