Abstract

The goal is to improve the effectiveness of the current therapy of inborn errors of urea synthesis. Of the two principal pharmaceutical agents currently in use one (sodium phenylacetate) has an offensive odor and the other (sodium benzoate) has half the effectiveness of the first. These studies are designed to test the acceptability of a second generation prodrug for phenylacetate, sodium phenylbutyrate which does not have the repugnant odor of phenylacetate. Because of its greater acceptability and greater effectiveness a study will be done of high dose phenylbutyrate which may obviate the need for sodium benzoate. Theoretical considerations suggest that sodium phenylbutyrate in high dosage will activate the biosynthesis of an amount of phenylacetylglutamine nitrogen that will completely substitute for urea nitrogen as a vehicle for waste nitrogen synthesis. The specific methods will include a study of the pharmacology of sodium phenylbutyrate and a study of long term outcome. In addition a study will be done to test a possible role of dietary citrate supplementation in the treatment of argininosuccinase deficiency.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD026358-04
Application #
3327793
Study Section
Special Emphasis Panel (SRC (NU))
Project Start
1989-12-01
Project End
1994-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Brusilow, Saul W; Cooper, Arthur J L (2011) Encephalopathy in acute liver failure resulting from acetaminophen intoxication: new observations with potential therapy. Crit Care Med 39:2550-3
Brusilow, S W; Maestri, N E (1996) Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 43:127-70
Brusilow, S W (1995) Urea cycle disorders: clinical paradigm of hyperammonemic encephalopathy. Prog Liver Dis 13:293-309
Maestri, N E; Clissold, D B; Brusilow, S W (1995) Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr 127:929-35
Collins, A F; Pearson, H A; Giardina, P et al. (1995) Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood 85:43-9
Pimentel Jr, J L; Brusilow, S W; Mitch, W E (1994) Unexpected encephalopathy in chronic renal failure: hyperammonemia complicating acute peritonitis. J Am Soc Nephrol 5:1066-73
Dover, G J; Brusilow, S; Charache, S (1994) Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate. Blood 84:339-43
Brusilow, S W; Finkelstien, J (1993) Restoration of nitrogen homeostasis in a man with ornithine transcarbamylase deficiency. Metabolism 42:1336-9
Maestri, N E; McGowan, K D; Brusilow, S W (1992) Plasma glutamine concentration: a guide in the management of urea cycle disorders. J Pediatr 121:259-61
Brusilow, S W (1991) Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion. Pediatr Res 29:147-50

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