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Nutrition Therapy of Inborn Errors of Metabolism
Published in Fima Lifshitz, Childhood Nutrition, 2020
Kimberlee Michals-Matalon, Reuben Matalon
Urea cycle defects are inborn errors of metabolism that produce a problem with the synthesis or excretion of nitrogen. Dietary treatment involves using an alternate pathway for the synthesis and excretion of waste nitrogen.28 Nitrogen may accumulate as glutamate, alanine, or ammonia, but ammonia is the most toxic. The signs and symptoms of the disease usually depend on ammonia intox-ification. As ammonia starts to increase, there is lethargy, vomiting, and refusal to eat. As ammonia rises more, the lethargy increases, and there is hyperventilation and grunting respirations. This is followed by coma, respiratory arrest, dilated pupils, and increased intracranial pressure. In severe forms, newborns can be comatose by 2–4 days. In the acute phase, treatment includes peritoneal or hemodialysis. Urea cannot be formed; therefore, precursors are given so the nitrogen can be excreted by an alternate pathway. For example, sodium benzoate is given to bind with glycine which is then excreted as hippuric acid and sodium phenyl-acetate which binds with glutamate and is then excreted as sodium phenylacetyl-glutamate. Long-term management includes oral intake of sodium phenylbutyrate to bind and excrete nitrogen. The urea cycle defects also require substrate restriction; therefore, dietary nitrogen is limited. The best outcome is for siblings when they are treated prospectively.29 All siblings are placed on treatment, and specimens are obtained to determine whether they are affected with the disease. If they are normal, the treatment is discontinued; however, if affected, the treatment continues.
Introduction to hyperammonemia and disorders of the urea cycle
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The infant or child usually requires a combination of pharmacologic therapy and restriction of the intake of protein. Arginine is employed in doses of 0.1–0.2 g/kg, 0.2–0.3 g/kg or even higher in citrullinemia type 1 or argininosuccinic aciduria. In OTCD and CPSD, sodium benzoate is given in doses of 0.25(–0.5) g/kg/day, and citrulline, which is more palatable than arginine, is employed as a source of ornithine in a dose of 0.17–0.25 g/kg. Oral sodium phenylbutyrate has been employed as a source of phenylacetate in doses of 0.25 g/kg. It may be used as a substitute for benzoate, but many of our patients have found it unpalatable. A gastrostomy may be required. Glycerol phenylbutyrate (RAVICTI) has the same mechanism of action as sodium phenylbutyrate, but is a sodium- and sugar-free prepro-drug of phenylacetic acid that has little odor or taste. Also, phenylbutyrate may deplete branched chain amino acids levels and cause menstrual dysfunction/amenorrhea in up to 25% of post-pubertal females [9]. To avoid complications, e.g. mucositis or gastritis, sodium benzoate and sodium phenylbutyrate should be administered several times daily during meals with abundant fluids [9]. Acute toxicity of benzoate and phenylbutyrate has been rare, but severe overdoses (2 to 10 times recommended) have led to symptoms that may be clinically mistaken for hyperammonemic episodes, including lethargy, hyperventilation, metabolic acidosis, cardiopulmonary collapse, and death [18].
Differentiation Induction in Acute Promyelocytic Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
The PML-RARα fusion protein leads to abnormal recruitment of histone deacetylase, which in turn leads to a transcription block (5). Therefore, treatment with an inhibitor of histone deacetylase may help reverse this transcription block. One patient with refractory APL resistant to ATRA alone was treated with sodium phenylbutyrate in addition to ATRA. Twenty-three days after initiation of therapy, the patient achieved clinical and cytogenetic CR. A second course of phenylbutyrate resulted in a molecular CR (81). This experience shows that histone deacetylase inhibitors may prove beneficial in ATRA-refractory APL.
Health care resource utilization in the management of patients with Arginase 1 Deficiency in the US: a retrospective, observational, claims database study
Published in Journal of Medical Economics, 2022
Aseel Bin Sawad, John Jackimiec, Mark Bechter, Michael Hull, Jason Yeaw, Yi Wang, George A. Diaz
Inpatient and outpatient visits are frequently needed to manage serious medical conditions. In the post-index period, around 20% of the patients had the linkage to hospital data (i.e. three patients in the disease cohort and one in the comparator cohort with an inpatient stay). Patients with ARG1-D were hospitalized nearly 3 times more often and the mean length of stay was longer compared with patients without ARG1-D, although this trend was not statistically significant. The proportion of patients with emergency room visits in the ARG1-D cohort was nearly double that for patients without ARG1-D (p < .05). Laboratory/pathology claims were 1.5 times more frequent with ARG1-D cohort (p < .01) (Table 3). Utilization of ammonia scavengers, including glycerol phenylbutyrate, sodium phenylbutyrate, or sodium benzoate/sodium phenylacetate were reported in a small percentage of ARG1-D patients post-index (Table 3). There was no trend suggesting use of any one medication class in the comparator group.
Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
Published in Gut Microbes, 2021
Yongguo Zhang, Destiny Ogbu, Shari Garrett, Yinglin Xia, Jun Sun
Currently, treatment with the FDA-approved drug, Riluzole merely extends the patient’s life span for a few months. The second new drug Radicava gained approval in 2017. However, there is still a need to develop new treatments for alleviating disease progression and improving the life quality of ALS patients. A phase 2 randomized, placebo-controlled trial treated patients for 24 weeks, which involved 137 ALS patients, 89 of whom received treatment with the combination of sodium phenylbutyrate and taurursodiol.74 It found a modest reduction in functional decline in patients receiving the combination therapy,74 suggesting the promising role of sodium phenylbutyrate. However, this study has no data on the changes in the human microbiome. A recent study reported the microbiota changes as a potential human ALS biomarker and suggested that targeting the microbiome could be considered to restore the status of the intestine.14 A larger trial testing more patients over a more extended period is also needed.
An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis
Published in Expert Review of Neurotherapeutics, 2023
Yuyao Sun, Xiaoyan Li, Richard Bedlack
Despite the overwhelming need for effective therapeutics for ALS, riluzole and edaravone were the only two FDA-approved medications as disease-modifying therapies for ALS prior to 2022 (initial approval in 1995 and 2017, respectively). The randomized, double-blind, multicenter, placebo-controlled CENTAUR trial demonstrated the safety and efficacy of sodium phenylbutyrate-taurursodiol (PB-TURSO) in PALS [5], leading to its conditional approval in Canada in June 2022 and full approval in the USA in September 2022. In this article, we reviewed the pharmacology and clinical trials evaluating sodium phenylbutyrate and/or taurursodiol in PALS.