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The New England Journal of Medicine Sep 2020Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.
METHODS
In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.
RESULTS
A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.
CONCLUSIONS
Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
Topics: Aged; Amyotrophic Lateral Sclerosis; Disease Progression; Double-Blind Method; Drug Combinations; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Phenylbutyrates; Severity of Illness Index; Taurochenodeoxycholic Acid; Treatment Outcome
PubMed: 32877582
DOI: 10.1056/NEJMoa1916945 -
Nature Reviews. Nephrology Aug 2020Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common... (Review)
Review
Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.
Topics: Arginine; Carnitine; Child; Child, Preschool; Continuous Renal Replacement Therapy; Delphi Technique; Diet, Protein-Restricted; Humans; Hybrid Renal Replacement Therapy; Hyperammonemia; Infant; Infant, Newborn; Parenteral Nutrition; Peritoneal Dialysis; Phenylacetates; Phenylbutyrates; Practice Guidelines as Topic; Renal Dialysis; Sodium Benzoate; Urea Cycle Disorders, Inborn; Vitamin B Complex
PubMed: 32269302
DOI: 10.1038/s41581-020-0267-8 -
Muscle & Nerve Jan 2021An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized,... (Randomized Controlled Trial)
Randomized Controlled Trial
An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Phenylbutyrates; Taurochenodeoxycholic Acid; Time; Young Adult
PubMed: 33063909
DOI: 10.1002/mus.27091 -
Annals of Clinical and Translational... Dec 2023Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo-controlled and open-label extension phases. On intent-to-treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6-month double-blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo-to-active crossover, we performed a post hoc survival analysis comparing PB and TURSO-randomized participants from CENTAUR and a propensity score-matched, PB and TURSO-naïve external control cohort from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.
METHODS
Clinical trial control participants from the PRO-ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO-randomized CENTAUR participants using prognostically significant covariates in ALS.
RESULTS
Baseline characteristics including propensity score-matched covariates were generally well balanced between CENTAUR PB and TURSO (n = 89) and PRO-ACT external control (n = 85) groups. Estimated median (IQR) OS was 23.54 (14.56-39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83-19.20) months in the PRO-ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31-0.72; p = 0.00048).
INTERPRETATION
This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo-to-active crossover than seen on ITT analysis in CENTAUR. Analyses using well-matched external controls may provide additional context for evaluating survival effects in future ALS trials.
Topics: Humans; Amyotrophic Lateral Sclerosis; Phenylbutyrates; Survival Analysis; Proportional Hazards Models
PubMed: 37807839
DOI: 10.1002/acn3.51915 -
CNS Neuroscience & Therapeutics Jan 2018Endoplasmic reticulum (ER) stress has been demonstrated to regulate neuronal death caused by ischemic insults via activation of apoptosis, but it still remains unclear...
AIMS
Endoplasmic reticulum (ER) stress has been demonstrated to regulate neuronal death caused by ischemic insults via activation of apoptosis, but it still remains unclear whether ER stress participates in regulation of parthanatos, a new type of programmed cell death characterized by PARP-1 overactivation and intracellular accumulation of PAR polymer.
METHODS
we used oxygen-glucose deprivation (OGD) and human SH-SY5Y cells to simulate neuronal damage caused by ischemia.
RESULTS
Oxygen-glucose deprivation induced time-dependent death in SH-SY5Y cells, which was accompanied with upregulation of PARP-1, accumulation of PAR polymer, decline of mitochondrial membrane potentials and nuclear translocation of AIF. Pharmacological inhibition of PARP-1 with its specific inhibitor 3AB rescued OGD-induced cell death, as well as prevented PAR polymer accumulation, mitochondrial depolarization, and AIF translocation into nucleus. Similar results could be found when PARP-1 was genetically knocked down with SiRNA. These indicated that OGD triggered parthanatos in SH-SY5Y cells. Then, we found inhibition of overproduction of ROS with antioxidant NAC attenuated obviously OGD-induced parthanatos in SH-SY5Y cells, suggesting ROS regulated OGD-induced parthanatos. Additionally, OGD also induced upregulation of ER stress-related proteins. Mitigation of ER stress with chemical chaperone 4-PBA or trehalose suppressed significantly OGD-induced overproduction of ROS, PARP-1 upregulation, PAR polymer accumulation, and nuclear accumulation of AIF, and cell death in SH-SY5Y cells.
CONCLUSION
Endoplasmic reticulum stress regulates OGD-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS.
Topics: Acetylcysteine; Apoptosis; Cell Line, Tumor; Endoplasmic Reticulum Stress; Free Radical Scavengers; Glucose; Glutathione; Humans; Hypoxia; L-Lactate Dehydrogenase; Lipid Peroxidation; Membrane Potential, Mitochondrial; Neuroblastoma; Phenylbutyrates; RNA, Small Interfering; Reactive Oxygen Species; Time Factors; Transfection
PubMed: 29045036
DOI: 10.1111/cns.12771 -
British Journal of Biomedical Science 2022Pyruvate dehydrogenase (PDH) deficiency is caused by a number of pathogenic variants and the most common are found in the gene. The gene encodes one of the subunits of... (Review)
Review
Pyruvate dehydrogenase (PDH) deficiency is caused by a number of pathogenic variants and the most common are found in the gene. The gene encodes one of the subunits of the PDH enzyme found in a carbohydrate metabolism pathway involved in energy production. Pathogenic variants of gene usually impact the α-subunit of PDH causing energy reduction. It potentially leads to increased mortality in sufferers. Potential treatments for this disease include dichloroacetate and phenylbutyrate, previously used for other diseases such as cancer and maple syrup urine disease. However, not much is known about their efficacy in treating PDH deficiency. Effective treatment for PDH deficiency is crucial as carbohydrate is needed in a healthy diet and rice is the staple food for a large portion of the Asian population. This review analysed the efficacy of dichloroacetate and phenylbutyrate as potential treatments for PDH deficiency caused by pathogenic variants. Based on the findings of this review, dichloroacetate will have an effect on most PDHA1 pathogenic variant and can act as a temporary treatment to reduce the lactic acidosis, a common symptom of PDH deficiency. Phenylbutyrate can only be used on patients with certain pathogenic variants (p.P221L, p.R234G, p.G249R, p.R349C, p.R349H) on the PDH protein. It is hoped that the review would provide an insight into these treatments and improve the quality of lives for patients with PDH deficiency.
Topics: Humans; Phenylbutyrates; Pyruvate Dehydrogenase (Lipoamide); Pyruvate Dehydrogenase Complex Deficiency Disease
PubMed: 35996497
DOI: 10.3389/bjbs.2022.10382 -
JCI Insight Jul 2022Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic...
Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic disorder of the polyamine pathway, caused by X-linked recessive loss-of-function mutations in spermine synthase. In the Drosophila SRS model, altered spermidine/spermine balance has been associated with increased generation of ROS and aldehydes, consistent with elevated spermidine catabolism. These toxic byproducts cause mitochondrial and lysosomal dysfunction, which are also observed in cells from SRS patients. No efficient therapy is available. We explored the biochemical mechanism and discovered acetyl-CoA reduction and altered protein acetylation as potentially novel pathomechanisms of SRS. We repurposed the FDA-approved drug phenylbutyrate (PBA) to treat SRS using an in vivo Drosophila model and patient fibroblast cell models. PBA treatment significantly restored the function of mitochondria and autolysosomes and extended life span in vivo in the Drosophila SRS model. Treating fibroblasts of patients with SRS with PBA ameliorated autolysosome dysfunction. We further explored the mechanism of drug action and found that PBA downregulates the first and rate-limiting spermidine catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), reduces the production of toxic metabolites, and inhibits the reduction of the substrate acetyl-CoA. Taken together, we revealed PBA as a potential modulator of SAT1 and acetyl-CoA levels and propose PBA as a therapy for SRS and potentially other polyamine dysregulation-related diseases.
Topics: Acetyl Coenzyme A; Acetylesterase; Acetyltransferases; Animals; Drosophila; Mental Retardation, X-Linked; Phenylbutyrates; Polyamines; Spermidine; Spermine
PubMed: 35801587
DOI: 10.1172/jci.insight.158457 -
International Journal of Molecular... Dec 2023Artificial insemination (AI) with liquid-stored semen is the most prevalent and efficient assisted reproduction technique in the modern pork industry. Pyruvate...
Artificial insemination (AI) with liquid-stored semen is the most prevalent and efficient assisted reproduction technique in the modern pork industry. Pyruvate dehydrogenase complex component X (PDHX) was demonstrated to be associated with sperm metabolism and affected the boar sperm viability, motility, and fertility. Pyruvate Dehydrogenase Kinases (PDKs) are the key metabolic enzymes that regulate pyruvate dehydrogenase complex (PDHC) activity and also the conversion from glycolysis to oxidative phosphorylation. In the present study, two PDK inhibitors, Dichloroacetate (DCA) and Phenylbutyrate (4-PBA), were added to an extender and investigated to determine their regulatory roles in liquid-stored boar sperm at 17 °C. The results indicated that PDK1 and PDK3 were predominantly located at the head and flagella of the boar sperm. The addition of 2 mM DCA and 0.5 mM 4-PBA significantly enhanced the sperm motility, plasma membrane integrity (PMI), mitochondrial membrane potential (MMP), and ATP content. In addition, DCA and 4-PBA exerted their effects by inhibiting PDK1 and PDK3, respectively. In conclusion, DCA and 4-PBA were found to regulate the boar sperm metabolic activities via PDK1 and PDK3. These both can improve the quality parameters of liquid-stored boar sperm, which will help to improve and optimize liquid-stored boar semen after their addition in the extender.
Topics: Swine; Male; Animals; Semen; Phenylbutyrates; Semen Preservation; Sperm Motility; Spermatozoa; Semen Analysis; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Pyruvate Dehydrogenase Complex
PubMed: 38069413
DOI: 10.3390/ijms242317091 -
Journal of Internal Medicine Sep 2018
Topics: Cholecalciferol; Ethiopia; Humans; Phenylbutyrates; Tuberculosis; Tuberculosis, Pulmonary; Vitamin D
PubMed: 29888817
DOI: 10.1111/joim.12784 -
Selective inhibition of protein secretion by abrogating receptor-coat interactions during ER export.Proceedings of the National Academy of... Aug 2022Protein secretion is an essential process that drives cell growth, movement, and communication. Protein traffic within the secretory pathway occurs via transport...
Protein secretion is an essential process that drives cell growth, movement, and communication. Protein traffic within the secretory pathway occurs via transport intermediates that bud from one compartment and fuse with a downstream compartment to deliver their contents. Here, we explore the possibility that protein secretion can be selectively inhibited by perturbing protein-protein interactions that drive capture into transport vesicles. Human proprotein convertase subtilisin/kexin type 9 (PCSK9) is a determinant of cholesterol metabolism whose secretion is mediated by a specific cargo adaptor protein, SEC24A. We map a series of protein-protein interactions between PCSK9, its endoplasmic reticulum (ER) export receptor SURF4, and SEC24A that mediate secretion of PCSK9. We show that the interaction between SURF4 and SEC24A can be inhibited by 4-phenylbutyrate (4-PBA), a small molecule that occludes a cargo-binding domain of SEC24. This inhibition reduces secretion of PCSK9 and additional SURF4 clients that we identify by mass spectrometry, leaving other secreted cargoes unaffected. We propose that selective small-molecule inhibition of cargo recognition by SEC24 is a potential therapeutic intervention for atherosclerosis and other diseases that are modulated by secreted proteins.
Topics: COP-Coated Vesicles; Endoplasmic Reticulum; Humans; Membrane Proteins; Phenylbutyrates; Proprotein Convertase 9; Protein Interaction Mapping; Protein Transport; Secretory Pathway; Vesicular Transport Proteins
PubMed: 35901214
DOI: 10.1073/pnas.2202080119