Introduction/Aims: Trials incorporating placebo-to-active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank-preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo-controlled and open-label extension (OLE) phases.Methods: Intent-to-treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed.Results: Hazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35-0.92) on ITT analysis and 0.39 (0.17-0.88) in the primary on-treatment RPSFTM analysis (p = .023). Median ITT survival duration for PB and TURSO (25.8 mo) was 6.9 mo longer than placebo (18.9 mo) on ITT analysis and 10.6 mo longer than the median RPSFTM-adjusted survival duration for placebo (15.2 mo). Median survival duration was 18.8 mo longer in the PB and TURSOrandomized subgroup who continued into the OLE phase versus the placebo-randomized subgroup who did not continue into the OLE phase (p < .0001), although OLE phase selection bias may have potentially confounded these results.Discussion: Similar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.

Peritoneal dialysis has become an accepted treatment modality for end-stage renal disease. The introduction of continuous ambulatory peritoneal dialysis (CAPD) has further popularised this technique. The need for adjustment of drug dosage in patients with endstage renal disease and the need for supplemental dosages following haemodialysis are well recognised. Little documentation exists concerning the need for supplemental drug dosage in patients on peritoneal dialysis. Knowledge of the influence of peritoneal dialysis on the elimination of specific drugs is essential to the rational design of dosage regimens in patients undergoing this dialysis technique. This review addresses the clinical pharmacokinetic aspects of drug therapy in patients undergoing peritoneal dialysis and considers: the efficiency of the peritoneal membrane as a dialysing membrane; the effects of peritoneal dialysis on the pharmacokinetics of drugs; the pharmacokinetic models and estimation methods for peritoneal dialysis clearance and the effects of peritoneal dialysis on drug elimination; the influence of the pharmacokinetic parameters of drugs on drug dialysability; and the application of pharmacokinetic principles to the adjustment of drug dosage regimens in peritoneal dialysis patients. Data on drugs which have been studied in peritoneal dialysis are tabulated with inclusion of pharmacokinetic and dialysability information.

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Recently, a second pathway for the generation of potential oxidants with the reactivity of the hydroxyl radical without the need for metal catalysis has been described. In response to various inflammatory stimuli, lung endothelial, alveolar, and airway epithelial cells, as well as activated alveolar macrophages, produce both nitric oxide ('NO) and superoxide anion radicals (02). 'NO regulates pulmonary vascular and airway tone and plays an important role in lung host defense against various bacteria. However, 'NO may be cytotoxic by inhibiting critical enzymes such as mitochondrial aconitase and ribonucleotide reductase, by S-nitrosolation of thiol groups, or by binding to their iron-sulfur centers. In addition, 'NO reacts with O2-at a near diffusion-limited rate to form the strong oxidant peroxynitrite (ONOO-, which can nitrate and oxidize key amino acids in various lung proteins such as surfactant protein A, and inhibit their functions. The presence of ONOO-in the lungs of patients with acute respiratory distress syndrome has been demonstrated by measuring levels of nitrotyrosine, the stable product of tyrosine nitration. Various studies have shown that inhalation or intratracheal instillation of various respirable mineral dusts or asbestos fibers increased levels of inducible nitric oxide synthase mRNA. In this presentation, we review the evidence for the upregulation of 'NO in the lungs of animals exposed to mineral particulates and assess the contribution of reactive nitrogen species in the pathogenesis of the resultant lung injury. Environ Health Perspect 106(Suppl 5):1 157-1163 (1998). http.//ehpnetl.niehs.nih.gov/ docs/1998/Suppl-5/1 157-1 163zhu/abstracthtml