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Background: Epoprostenol sodium for injection is approved for the treatment of severe cases of primary pulmonary arterial hypertension. Currently, there are 3 approved formulations of this drug containing the same active ingredient (epoprostenol sodium) but differing with regard to excipients. When compared with epoprostenol sodium formulated with glycine-mannitol (epoprostenol GM), 2 new formulations of epoprostenol sodium, one formulated with arginine-mannitol (epoprostenol AM) and one formulated with arginine-sucrose (epoprostenol AS), have improved stability after reconstitution and dilution. The biocomparability of epoprostenol AM and epoprostenol GM, with regard to pharmacokinetic (PK), pharmacodynamic (PD), safety, and tolerability profiles, has been shown previously. Objective: This study compared PK, PD, safety, and tolerability profiles of the 3 different formulations of epoprostenol sodium for injection. Methods: This was a prospective, single-center, open-label, 2-period, 2- treatment, randomized, crossover, ascending dose study in 2 parts. Twenty healthy men in part 1 and 20 different individuals in part 2 received epoprostenol AM and epoprostenol AS and epoprostenol GM and epoprostenol AS, respectively, in a crossover fashion, as sequential IV infusions of 2, 4, 6, and 8 ng/kg/min for 2 hours each. In each part, the PK profile of epoprostenol was characterized via analysis of the concentration-time profiles of its 2 primary metabolites: 6- keto-prostacyclin Fla and 6,15-diketo-13,14-dihydro-prostacyclin Fla. The effect of the formulations was assessed using the 90% CI of the geometric mean ratio calculated for the exposure PK parameters. The PD variables cardiac output, cardiac index, and heart rate were assessed using echocardiography. Adverse events were recorded through the study. Results: The plasma concentration versus time curves of epoprostenol AM and epoprostenol AS in part 1 and epoprostenol GM and epoprostenol AS in part 2 were similar in shape and almost superimposable. For each study part, the 90% CIs of ratios of geometric means for AUC0_∞ of the assessed epoprostenol formulations were within the range for bioequivalence (0.8-1.25). The increases in cardiac output, cardiac index, and heart rate resulting from infusion with epoprostenol sodium were comparable between all formulations, with maximum values attained after 8 hours. Almost all study participants reported at least one treatment-emergent adverse event, the most common being headache, which was reported in 80% to 85% of study participants. Conclusions: Overall, the PK, PD, safety, and tolerability profiles of the 3 formulations of epoprostenol sodium for injection are comparable and meet the criteria of bioequivalence. Australian New Zealand Clinical Trials Registry identifier: ACTRN12612001086853. [ABSTRACT FROM AUTHOR]

Chronic pain (CP) and cognitive impairment are common in older adults. CP was found to be associated with cognitive impairment in many cross-sectional studies. However, their cross-sectional design precluded inference on temporality. Accordingly, we aimed to prospectively assess the association between cognitive functioning and the occurrence of CP in older community dwellers. Analyses were based on data of the first (FU1) and the second follow-up (FU2) of CoLaus|PsyCoLaus, a prospective cohort study conducted in the general population of Lausanne (Switzerland) including the participants aged 65 and over. Neuropsychological functioning including memory, language, attention and executive function was measured at FU1. CP was assessed at FU1 and FU2 by self-rating questionnaire. The association between cognitive scores and subsequent CP was determined using multiple logistic regressions. Among the 337 participants without CP at FU1, 107 (31.8%) developed CP at FU2. A significant association was observed between higher Stroop color-time and interference index at FU1 and a higher risk of CP at FU2 (OR = 1.02; P = .03 and OR = 1.49; P = .03, respectively). Our results suggest that patients with inhibitory deficit may be at higher risk of developing CP in the presence of painful events. A cognitive assessment could be recommended to identify frail patients in these situations. PERSPECTIVE: This study suggests that presence of inhibitory deficits is associated with a higher risk of developing subsequent CP in older adults. In the presence of painful events, a cognitive assessment should be recommended to identify frail patients and to manage them carefully., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.

Purpose: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of escalating single oral doses of ACT-077825, a novel orally active renin inhibitor, in healthy male subjects., Methods: In this single-center, double-blind, placebo- and active-controlled (with enalapril) randomized study, 70 subjects received a single dose of ACT-077825 (1-1,000 mg), placebo, or enalapril 20 mg under fasted conditions. The main pharmacokinetic endpoints were area under the plasma ACT-077825 concentration-time curve from time zero to infinity and the terminal half-life (t(1/2)). The pharmacodynamic endpoints included immunoactive active renin (iAR) plasma concentrations and plasma renin activity (PRA). Standard laboratory and safety data were collected., Results: Of the few adverse events reported, diarrhea and headache were the most frequent. The pharmacokinetics of ACT-077825 were dose-proportional in the dose range 100 to 1,000 mg. Terminal t(1/2), best characterized following a dose of 1,000 mg, was 41.6 h and t(max) 4-5 h post-dose. ACT-077825 dose-dependently increased iAR and decreased PRA, effects that were associated with a decrease in blood pressure at 1,000 mg, similar to following treatment with enalapril., Conclusion: The results provide evidence that ACT-077825, with a pharmacokinetic profile consistent with a once-a-day dosing regimen, may represent an effective antihypertensive agent and pave the way toward a multiple-ascending dose study.