The overall objective of this proposal is to develop better diagnostic and therapeutic measures for the management of patients with inborn errors of urea synthesis. These objectives will be met by a long term clinical evaluation of the outcome of such patients treated by dietary modification supplemented with the investigative new drugs, sodium benzoate and sodium phenylacetate which activate endogenous latent pathways of waste nitrogen synthesis and excretion. Modifications of the current protocol includes a study of phenylbutyrate as a substitute for phenylacetate as well as a study of different dosage schedules of these drugs. The role of the intravenous dosage form of these drugs on the hyperammonemia of Reye's syndrome will also be evaluated. The hypothesis that the increased intracranial pressure accompanying hyperammonemia is caused by osmotic shifts of water induced by intracellular free glutamine will be studied in animal models of hyperammonemia. The reliability of the protein tolerance test in identifying women heterozygous for a mutant ornithine transcarbamylase gene will be evaluated comparing the results of this test done on obligate heterozygotes with normal women. The role of arginine deficiency in the pathogenesis of the skin lesion in kwashiorkor will be examined by studying the effect of dietary arginine. The effect of an arginine free diet in normal man and animals will be studied as well as arginine metabolism in an animal model of ornithine transcarbamylase deficiency-the sparse fur mouse. A study in rats of the dietary determinants of citrullinogenesis in isolated mitochondria and ureagenesis in hepatocytes will be done using a meal feeding technique. The relationship between meal feeding and citrullinogenic and ureagenic capacity will be evaluated as will the time course of urea cycle enzyme adaptive changes. A new analytic method for N-acetylglutamate will be employed to re-evaluate its role in ureagenesis under meal feeding conditions. The role of glucagon in citrullinogenesis and ureagenesis in the meal fed rat will be evaluated. The role of glutamine as the nitrogen donor for citrullinogenesis and ureagenesis will be studied in isolated mitochondria and hepatocytes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Biochemistry Study Section (BIO)
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Johns Hopkins University
Schools of Medicine
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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
Maestri, N E; Brusilow, S W; Clissold, D B et al. (1996) Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 335:855-9
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
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
Beliveau Carey, G; Cheung, C W; Cohen, N S et al. (1993) Regulation of urea and citrulline synthesis under physiological conditions. Biochem J 292 ( Pt 1):241-7
Takahashi, H; Koehler, R C; Hirata, T et al. (1992) Restoration of cerebrovascular CO2 responsivity by glutamine synthesis inhibition in hyperammonemic rats. Circ Res 71:1220-30
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

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