TY - JOUR
T1 - A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria
AU - Nagamani, Sandesh C.S.
AU - Shchelochkov, Oleg A.
AU - Mullins, Mary A.
AU - Carter, Susan
AU - Lanpher, Brendan C.
AU - Sun, Qin
AU - Kleppe, Soledad
AU - Erez, Ayelet
AU - O'Brian Smith, E.
AU - Marini, Juan C.
AU - Lee, Brendan
N1 - Funding Information:
This work was supported by the NIH ( DK54450 , DK92921 , RR19453 , RR00188 , GM90310 , to B. Lee, GM07526 , DK081735 to A. Erez, RR024173 to J. Marini), Baylor College of Medicine General Clinical Research Center ( RR00188 ), Intellectual and Developmental Disabilities Research Center ( HD024064 ), The Texas Medical Center Digestive Disease Center , and the Urea Cycle Disorders Rare Disease Clinical Research Network, NIH ( HD061221 to BL). SCS Nagamani, OA Shchelochkov and A Erez are awardees of the National Urea Cycle Disorders Foundation Research Fellowship. OA Shchelochkov is an awardee of the O'Malley Fellowship of the UCDC RDCRN.
Funding Information:
We thank the subject families and the referring physicians for their kind participation. We are grateful A. Tran, J. Stuff, and the nursing staff of the General Clinical Research Center at Texas Children's Hospital. Ucyclyd Pharma provided sodium phenylbutyrate for the study. This work was made possible by the Urea Cycle Disorders Consortium (UCDC). This consortium is a part of the NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided by U54HD061221 from the National Institute of Child Health and Human Development (NICHD) and the NIH Office of Rare Diseases Research (ORDR) . The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
PY - 2012/11
Y1 - 2012/11
N2 - 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). Study design: 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. 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.
AB - 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). Study design: 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. 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.
KW - Arginine therapy
KW - Argininosuccinate lyase
KW - Argininosuccinic aciduria
KW - Hepatic disease
KW - Rare disease clinical research
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U2 - 10.1016/j.ymgme.2012.09.016
DO - 10.1016/j.ymgme.2012.09.016
M3 - Article
C2 - 23040521
AN - SCOPUS:84867897173
SN - 1096-7192
VL - 107
SP - 315
EP - 321
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 3
ER -