We report in the present study the critical role of uridine phosphorylase (UPase) in uridine homeostatic regulation and pyrimidine nucleotide metabolism, employing newly developed UPase؊/؊ mice. Our data demonstrate that the abrogation of UPase activity led to greater than a 6-fold increase in uridine concentrations in plasma, a 5-6-fold increase in lung and gut, and a 2-3-fold increase in liver and kidney, as compared with wild type mice. Urine uridine levels increased 24-fold normal in UPase؊/؊ mice. Uridine half-life and the plasma retention of pharmacological doses of uridine were significantly prolonged. Further, in these UPase؊/؊ mice, abnormal uridine metabolism led to disorders of various nucleotide metabolisms. In the liver, gut, kidney, and lung of UPase؊/؊ mice, total uridine ribonucleotide concentrations increased 2-3 times as compared with control mice. Cytidine ribonucleotides and adenosine and guanosine ribonucleotides also increased, although to a lesser extent, in these organs. Most significant deoxyribonucleotide changes were present in the gut and lung of UPase؊/؊ mice. In these tissues, dTTP concentration increased more than 4-fold normal, and dCTP, dGTP, and dATP concentrations rose 1-2 times normal. In kidney, dTTP concentration increased 2-fold normal, and dCTP and dGTP concentrations rose less than 1-fold normal. In addition, the accumulated uridine in plasma and tissues efficiently reduced 5-fluorouracil host toxicity and altered the anesthetic effect of pentobarbital. These data indicate that UPase is a critical enzyme in the regulation of uridine homeostasis and pyrimidine nucleotide metabolism, and 5-fluorouracil activity.

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Adenosine appears to be effective and safe for the pre-hospital treatment of PSVT.

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Abrogation of uridine phosphorylase (UPase) leads to abnormalities in pyrimidine metabolism and host protection against 5-fluorouracil (5-FU) toxicity. We elucidated the effects on the metabolism and antitumor efficacy of 5-FU and Capecitabine in our UPase knockout (UPase −/−) model. Treatment with 5-FU (85 mg/kg) or Capecitabine (1000 mg/kg) 5 days a week for 4 weeks caused severe toxicity and structural damage to the intestines of wild-type (WT) mice, but not in UPase −/− animals. Capecitabine treatment resulted in a 70% decrease in blood cell counts of WT animals, with only a marginal effect in UPase −/− mice. UPase expressing colon 38 tumors implanted in UPase −/− mice revealed an improved therapeutic efficacy when treated with 5-FU and Capecitabine due to the higher maximum tolerated dose for fluoropyrimidines achievable in UPase −/− mice. 19F-MRS evaluation of Capecitabine metabolism in tumors revealed similar activation of the pro-drug in UPase −/− mice compared to WT. In WT mice, approximately 60% of Capecitabine was transformed over 3 hours into its active metabolites, while 80% was transformed in tumors implanted in UPase −/− mice. In UPase −/− mice, prolonged retention of 5′dFUR allowed a proportional increase in tumor tissue. The similar presence of fluorinated catabolic species confirms that dihydropyrimidine dehydrogenase activity was not altered in UPase −/− mice. Overall, these results indicate the importance of UPase in the activation of fluoropyrimidines, the effect of uridine in protecting normal tissues, and the role for tumor-specific modulation of the phosphorolytic activity in 5-FU or Capecitabine-based chemotherapy.

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Hyperammonemic crises in ornithine transcarbamylase deficiency (OTC) can be associated with devastating cerebral edema resulting in severe long-term neurologic impairment and death. We present an 8-year-old boy who had late-onset OTC deficiency in which early and aggressive management of hyperammonemia and associated cerebral edema, including therapeutic hypothermia and barbiturateinduced coma, resulted in favorable neurologic outcome. Our patient presented with vomiting and altered mental status, and was found to have a significantly elevated serum ammonia level of 1561 mmol/L. Hyperammonemia was managed with hemodialysis, 10% sodium phenylacetate, 10% sodium benzoate, L-arginine, intravenous 10% dextrose, intralipids, and protein restriction. He developed significant cerebral edema with intracranial pressures .20 mm Hg, requiring treatment with 3% saline and mannitol. Despite this treatment our patient continued to have elevated intracranial pressures, which were treated aggressively with non-conventional modalities including therapeutic hypothermia, barbiturate-induced coma, and external ventricular drainage. This therapy resulted in stabilization of hyperammonemia and resolution of cerebral edema. Molecular testing later revealed a hemizygous mutation within the OTC gene. Neuropsychological testing 1 year after discharge showed normal intelligence with no visualmotor deficits, minor deficits in working memory and processing speed, and slightly below average processing speed and executive functioning. Pediatrics 2014;133:e1072-e1076 Dr Bergmann conceptualized the case report, drafted the initial manuscript, and critically reviewed and revised the manuscript; Dr McCabe coordinated data collection and critically reviewed and revised the manuscript; Dr Smith critically reviewed and revised the manuscript; Dr Guillaume provided expertise in neurosurgical management and critically reviewed and revised aspects of the manuscript pertaining to neurosurgical intervention; Dr Sarafoglou provided expertise in endocrine and metabolic management and critically reviewed and revised aspects of the manuscript pertaining to endocrine and metabolic intervention; Dr Gupta conceptualized the case report and critically reviewed and revised the manuscript with emphasis on aspects pertaining to critical care medicine; and all authors approved the final manuscript as submitted.www.pediatrics.org/cgi