title: A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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 (100 mg · kg(-1) · d(-1)) combined with sodium phenylbutyrate (500 mg · kg(-1) · d(-1)) (LDA arm) or a high-dose of arginine alone (500 mg · 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. nagamani@bcm.edu
authors.forename: Sandesh C S
authors.initials: SC
authors.lastname: Nagamani
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Shchelochkov
authors.forename: Mary A
authors.initials: MA
authors.lastname: Mullins
authors.forename: Susan
authors.initials: S
authors.lastname: Carter
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Lanpher
authors.forename: Qin
authors.initials: Q
authors.lastname: Sun
authors.forename: Soledad
authors.initials: S
authors.lastname: Kleppe
authors.forename: Ayelet
authors.initials: A
authors.lastname: Erez
authors.forename: E
authors.initials: E
authors.lastname: O'Brian Smith
authors.forename: Juan C
authors.initials: JC
authors.lastname: Marini
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D001120:Arginine / Q000097:blood / Q000627:therapeutic use*; D001125:Argininosuccinic Acid / Q000097:blood; D056807:Argininosuccinic Aciduria / Q000097:blood / Q000188:drug therapy*; D001219:Aspartate Aminotransferases / Q000097:blood; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D010654:Phenylbutyrates / Q000097:blood / Q000627:therapeutic use*; D010919:Placebos; D055815:Young Adult
chemical_list: D010654:Phenylbutyrates; D010919:Placebos; D001125:Argininosuccinic Acid; D001120:Arginine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase