Sodium phenylbutyrate 483mg/g granules

Objective: To evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol (PB–TURSO) and its components in slowing disease progression and improving survival in patients with amyotrophic lateral sclerosis (ALS). Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing PB–TURSO or its components to placebo or standard of care in adults with ALS were included. The primary outcomes were functional decline (Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised [ALSFRS-R]) and survival. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. A random-effects model was used for the meta-analysis, and a narrative synthesis was conducted for Tauroursodeoxycholic Acid (TUDCA) monotherapy and secondary analyses from the CENTAUR trial. Results: Two RCTs (n = 801) were included in the meta-analysis. The pooled analysis demonstrated no statistically significant difference in either ALSFRS-R decline (mean difference [MD] 1.51, 95% confidence interval [CI] −1.01 to 4.02; P = 0.24; I² =71%) or survival (hazard ratio [HR] 0.90, 95% CI 0.73–1.11; P = 0.31; I² = 61%). A separate trial of TUDCA monotherapy (n = 34) demonstrated significant functional benefits. Post hoc analyses of the CENTAUR trial reported a survival benefit of 6.5–10.6 months and delayed progression to major disease milestones. Biomarker analyses suggested anti-inflammatory effects. The risk of bias was moderate to high, and the certainty of evidence was rated very low by GRADE. Conclusions: Based on very low certainty evidence, the available RCT data do not support a definitive conclusion regarding the efficacy of PB–TURSO in ALS. Post hoc exploratory analyses suggest a potential survival benefit, which requires confirmation in adequately powered, prospectively designed trials; current results are hypothesis-generating rather than practice-defining.

Abstract licence: CC BY-NC-ND 4.0

Background: To determine the efficacy of 4-phenylbutyrate (4-PB) or sodium 4-phenylbutyrate (SPB) in treating diseases caused by genetic mutations. Methods: We searched PubMed, Web of Science, Cochrane Library, and EMBASE for studies of patients with genetic mutations treated with 4-PB or SPB. All data were tested using RStudio software. Results: 4-PB or SPB corrected the “functional” production of mutant genes (0.88 [95% confidence interval {CI}: 0.73–1.00], P = .45, I 2 = 0%), restored mRNA transcription of mutant genes (0.50 [95% CI: 0.18–0.82], P = .13, I² = 47%), and improved symptoms (0.89 [95% CI: 0.78–1.00], P = .99, I² = 0%) and biochemical laboratory values (1.00 [95% CI: 0.89–1.00], P = .11, I² = 33%) in patients with inherited genetic diseases. Conclusion: 4-PB or SPB can be used to treat genetic diseases. However, they must be validated in high-quality randomized controlled trials before clinical use.

Abstract licence: CC BY-NC 4.0

Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease) is a progressive neurodegenerative disease affecting hundreds of thousands of people worldwide. It is characterized by the degeneration of the neurons in the brain and spinal cord of the patients, leading to a loss of control of muscles. Over time, without nerves to stimulate them muscles tend to atrophy. ALS may occur sporadically or run in families; many mutations have been identified for the latter. Treatment of ALS is mostly limited to three approved therapeutic agents: riluzole, edaravone, and tauroursidiol/ sodium phenylbutyrate. Among these, riluzole remains the most effective despite its early discovery. There are no conclusive meta-analysis comparing riluzole monotherapy to all possible co-therapies present. In this work we have attempted to address such a concern and observed that no adjunct therapy significantly improved the performance of riluzole. However, mitochondrial/ oxidative stress modulator and neuroimmune/ neuroexcitability modulator co-therapy exhibited positive trends. Surprisingly, trials were mainly confined to the USA and European countries, indicating unequal demographic representation in ASL research. We have concluded that large double blinded inter-continental RCTs to be carried out for better understanding of the scenario.

Abstract licence: CC BY

OBJECTIVE Chronically elevated free fatty acids contribute to insulin resistance and pancreatic β-cell failure. Among numerous potential factors, the involvement of endoplasmic reticulum (ER) stress has been postulated to play a mechanistic role. Here we examined the efficacy of the chemical chaperone, sodium phenylbutyrate (PBA), a drug with known capacity to reduce ER stress in animal models and in vitro, on lipid-induced insulin resistance and β-cell dysfunction in humans. RESEARCH DESIGN AND METHODS Eight overweight or obese nondiabetic men underwent four studies each, in random order, 4 to 6 weeks apart. Two studies were preceded by 2 weeks of oral PBA (7.5 g/day), followed by a 48-h i.v. infusion of intralipid/heparin or saline, and two studies were preceded by placebo treatment, followed by similar infusions. Insulin secretion rates (ISRs) and sensitivity (SI) were assessed after the 48-h infusions by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively. RESULTS Lipid infusion reduced SI, which was significantly ameliorated by pretreatment with PBA. Absolute ISR was not affected by any treatment; however, PBA partially ameliorated the lipid-induced reduction in the disposition index (DI = ISR × SI), indicating that PBA prevented lipid-induced β-cell dysfunction. CONCLUSIONS These results suggest that PBA may provide benefits in humans by ameliorating the insulin resistance and β-cell dysfunction induced by prolonged elevation of free fatty acids.

Abstract licence: CC BY-NC-ND 3.0