Survival after Treatment with Phenylacetate and Benzoate for Urea-Cycle Disorders

Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, United States
New England Journal of Medicine (Impact Factor: 55.87). 05/2007; 356(22):2282-92. DOI: 10.1056/NEJMoa066596
Source: PubMed


The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects.
We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia.
Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age (93 patients), who had 437 episodes, were more likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level above 1000 micromol per liter (1804 microg per deciliter) were least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or older during 7% of episodes.
Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, effectively lower plasma ammonium levels and result in survival in the majority of patients. Hemodialysis may also be needed to control hyperammonemia, especially in neonates and older patients who do not have a response to intravenous sodium phenylacetate and sodium benzoate.

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    • "This concentration is considerably higher than those seen in hepatic encephalopathy of <300 lM (Lockwood et al., 1979), with brain concentrations of ammonia ranging between 1.0 and 2.0 mM (Schenker et al., 1967; Hindfelt, 1975; Ehrlich et al., 1980). However, plasma ammonia concentrations well above 300 lM are seen in valproate poisoning (Commandeur et al., 2010), and in urea cycle disorders plasma ammonia concentrations of 600 lM are far from the maximum concentrations encountered (Enns et al., 2007). Although cerebral ammonia toxicity is undoubtedly multifactorial , the restricted brain extracellular space and the encagement of the brain within the skull may be the main reason for rapid ammonia-induced death due to cerebral swelling. "
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    ABSTRACT: Ammonia toxicity is clinically important and biologically poorly understood. We reported previously that 3 mM ammonia chloride (ammonia), a relevant concentration for hepatic encephalopathy studies, increases production of endogenous ouabain and activity of Na,K-ATPase in astrocytes. In addition, ammonia-induced upregulation of gene expression of α2 isoform of Na,K-ATPase in astrocytes could be inhibited by AG1478, an inhibitor of the EGF receptor (EGFR), and by PP1, an inhibitor of Src, but not by GM6001, an inhibitor of metalloproteinase and shedding of growth factor, suggesting the involvement of endogenous ouabain-induced EGF receptor transactivation. In the present study, we investigated ammonia effects on phosphorylation of EGF receptor and its intracellular signal pathway towards MAPK/ERK1/2 and PI3K/AKT; interaction between EGF receptor, α1, and α2 isoforms of Na,K-ATPase, Src, ERK1/2, AKT and caveolin-1; and relevance of these signal pathways for ammonia-induced cell swelling, leading to brain edema, an often fatal complication of ammonia toxicity. We found that i) ammonia increases EGF receptor phosphorylation at EGFR(845) and EGFR(1068); ii) ammonia-induced ERK1/2 and AKT phosphorylation depends on the activity of EGF receptor and Src, but not on metalloproteinase; iii) AKT phosphorylation occurs upstream of ERK1/2 phosphorylation; iv) ammonia stimulates association between the α1 Na,K-ATPase isoform, Src, EGF receptor, ERK1/2, AKT and caveolin-1; v) ammonia-induced ROS production might occur later than EGFR transactivation; vii) both ammonia induced ERK phosphorylation and ROS production can be abolished by canrenone, an inhibitor of ouabain, and vi) ammonia-induced cell swelling depends on signaling via the Na,K-ATPase/ouabain/Src/EGF receptor/PI3K-AKT/ERK1/2, but in response to 3 mM ammonia it does not appear until after 12 hr. Based on literature data it is suggested that the delayed appearance of the ammonia-induced swelling at this concentration reflects required ouabain-induced oxidative damage of the ion and water cotransporter NKCC1. This information may provide new therapeutic targets for treatment of hyperammonic brain disorders.
    Neurochemistry International 09/2013; 63(6). DOI:10.1016/j.neuint.2013.09.005 · 3.09 Impact Factor
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    • "BCAA levels in patients with acute injury are normal or even increased , and their enhanced intake should be avoided. Favorable effects of ammonia-lowering strategies have been reported in urea cycle disorders (Brusilow 1991; Enns et al. 2007) and in liver cirrhosis (Walshe 1953; McGuire et al. 2010). However, the use of ammonia-lowering strategies has not been found to be effective enough in patients with acute liver failure (Acharya et al. 2009; Bémeur and Butterworth 2013). "
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    ABSTRACT: There is substantial clinical and experimental evidence that ammonia is a major factor in the pathogenesis of hepatic encephalopathy. In the article is demonstrated that in hepatocellular dysfunction, ammonia detoxification to glutamine (GLN) in skeletal muscle, brain, and likely the lungs, is activated. In addition to ammonia detoxification, enhanced GLN production may exert beneficial effects on the immune system and gut barrier function. However, enhanced GLN synthesis may exert adverse effects in the brain (swelling of astrocytes or altered neurotransmission) and stimulate catabolism of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in skeletal muscle. Furthermore, the majority of GLN produced is released to the blood and catabolized in enterocytes and the kidneys to ammonia, which due to liver injury escapes detoxification to urea and appears in peripheral blood. As only one molecule of ammonia is detoxified in GLN synthesis whereas two molecules may appear in GLN breakdown, these events can be seen as a vicious cycle in which enhanced ammonia concentration activates synthesis of GLN leading to its subsequent catabolism and increase in ammonia levels in the blood. These alterations may explain why therapies targeted to intestinal bacteria have only a limited effect on ammonia levels in patients with liver failure and indicate the needs of new therapeutic strategies focused on GLN metabolism. It is demonstrated that each of the various treatment options targeting only one the of the ammonia-lowering mechanisms that affect GLN metabolism, such as enhancing GLN synthesis (BCAA), suppressing ammonia production from GLN breakdown (glutaminase inhibitors and alpha-ketoglutarate), and promoting GLN elimination (phenylbutyrate) exerts substantial adverse effects that can be avoided if their combination is tailored to the specific needs of each patient.
    Metabolic Brain Disease 08/2013; 29(1). DOI:10.1007/s11011-013-9428-9 · 2.64 Impact Factor
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    • "While these immediate interventions are underway, intravenous sodium benzoate and sodium phenylacetate are given to shunt nitrogen-containing compounds away from the urea cycle [10]. Sodium benzoate conjugates with glycine to form hippuric acid, and sodium phenylacetate conjugates with glutamine to form phenylacetylglutamine. "
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    ABSTRACT: Objective. To report an unusual cause of coma in an adult. Design. Case report. Setting. University teaching hospital. Patient. A previously healthy 53-year-old man initially presented with altered mental status and progressed to coma. He was found to be substantially hyperammonemic and did not improve with lactulose therapy and continuous venovenous hemodialysis. Results. Biochemical testing revealed previously undiagnosed ornithine transcarbamylase deficiency, and the patient responded to arginine, sodium phenylacetate, and sodium benzoate. Conclusion. Even in adult patients with no known history, inborn errors of metabolism must be considered in the differential diagnosis of unexplained coma. Defects of the urea cycle can present with an unprovoked hyperammonemic coma.
    02/2013; 2013. DOI:10.1155/2013/493216
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