Bayesian analysis of 1D H-NMR spectra.

Extracting spin system parameters from 1D high resolution H-NMR spectra can be an intricate task requiring sophisticate methods. With a few exceptions methods to perform such a total line shape analysis commonly rely on local optimization techniques which for increasing complexity of the underlying spin system tend to reveal local solutions. In this work we propose a full Bayesian modeling approach based on a quantum mechanical model of the spin system.

Automatic classification of signal regions in H Nuclear Magnetic Resonance spectra.

The identification and characterization of signal regions in Nuclear Magnetic Resonance (NMR) spectra is a challenging but crucial phase in the analysis and determination of complex chemical compounds. Here, we present a novel supervised deep learning approach to perform automatic detection and classification of multiplets in H NMR spectra. Our deep neural network was trained on a large number of synthetic spectra, with complete control over the features represented in the samples.

Deconvolution of 1D NMR spectra: A deep learning-based approach.

The analysis of nuclear magnetic resonance (NMR) spectra to detect peaks and characterize their parameters, often referred to as deconvolution, is a crucial step in the quantification, elucidation, and verification of the structure of molecular systems. However, deconvolution of 1D NMR spectra is a challenge for both experts and machines. We propose a robust, expert-level quality deep learning-based deconvolution algorithm for 1D experimental NMR spectra.

Clopidogrel, a CYP2C8 inhibitor, causes a clinically relevant increase in the systemic exposure to the active metabolite of selexipag in healthy subjects.

Aims: Selexipag is a prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension. Cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. This study evaluated the interaction of selexipag and clopidogrel, a CYP2C8 inhibitor.

Bioequivalence of macitentan and tadalafil given as fixed-dose combination or single-component tablets in healthy subjects.

Aims: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects.

Methods: Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103.

Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects.

Background: Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug-drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH.

Objective: Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects.

Population-Based Study on the Epidemiology of Ménière's Disease.

Background And Objective: Ménière's disease (MD) is a disorder of the inner ear typically showing recurrent acute episodes of vertigo, hearing loss, and tinnitus. Epidemiologic studies on MD are scarce. We assessed the incidence rates (IRs) of MD and describe the characteristics of MD cases, comparing them to control patients without recorded evidence of MD.

Effect of gemfibrozil and rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects.

Aims: Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8.

Methods: The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design.

Biocomparison Study of Adult and Paediatric Dose Strengths of the Prostacyclin Receptor Agonist Selexipag.

Background And Objectives: Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 µg selexipag (Treatment A) vs.

A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects.

Purpose: In vitro data showed that selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration (C ) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4.

Methods: This study was conducted according to an open-label, randomized, two-way crossover design.

Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension.

Selexipag (Uptravi) is an oral selective IP prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal GRIPHON study was the largest clinical study ever conducted in PAH patients, providing long-term data from 1,156 patients. PAH comedication did not affect exposure to selexipag, while exposure to its active metabolite ACT-333679 was reduced by 30% when taken in combination, clinically not relevant in the context of individual dose up-titration.

Clinical pharmacology, efficacy, and safety of selexipag for the treatment of pulmonary arterial hypertension.

Selexipag is the first oral, non-prostanoid, selective prostacyclin receptor (IP receptor) agonist, approved for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients. Areas covered: This article reviews the clinical pharmacology, efficacy, and safety of selexipag in the treatment of PAH. Expert opinion: Selexipag is the first oral drug that selectively targets the prostacyclin pathway, and has evidence of long-term efficacy and safety.

The association between thyroid disorders and incident gout: population-based case-control study.

Context: Thyroid hormones influence kidney function and thereby might alter serum urate levels, a major risk factor for gouty arthritis.

Objective: To assess the risk of developing incident gout in association with hypothyroidism or hyperthyroidism.

Design: Retrospective population-based case-control analysis.

Investigation of Potential Pharmacodynamic and Pharmacokinetic Interactions Between Selexipag and Warfarin in Healthy Male Subjects.

Purpose: Selexipag is a new orally available nonprostanoid prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Warfarin is commonly used in patients with pulmonary arterial hypertension. Possible pharmacodynamic and pharmacokinetic interactions between selexipag and warfarin in healthy individuals were investigated.

Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study.

Objective: Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. Film-coated tablets with strength between 200 and 1,600 μg were used. Bioequivalence between 8 x 200 μg and a new 1,600 μg tablet was evaluated at steady state in healthy male subjects.

Association of hormone therapy and incident gout: population-based case-control study.

Objective: This study aims to assess the odds of developing incident gout in association with the use of postmenopausal estrogen-progestogen therapy, according to type, timing, duration, and route of administration of estrogen-progestogen therapy.

Methods: We conducted a retrospective population-based case-control analysis using the United Kingdom-based Clinical Practice Research Datalink. We identified women (aged 45 y or older) who had a first-time diagnosis of gout recorded between 1990 and 2010.

Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects.

Aims: This study investigated the effect of a fixed dose combination of lopinavir/ritonavir on the pharmacokinetics (PK) of selexipag and its active metabolite ACT-333679.

Methods: This was an open label, randomized, single centre, two way, crossover study. Twenty healthy male subjects were treated with a single dose of 400 µg selexipag alone and in combination with multiple doses of lopinavir/ritonavir (400/100 mg) twice daily.

Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag.

Purpose: Targeting the prostacyclin pathway is an effective treatment option for pulmonary arterial hypertension (PAH). Patients with PAH have a deficiency of prostacyclin and prostacyclin synthase. Selexipag is an orally available and selective prostacyclin receptor (IP receptor) agonist.

A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist.

The effects of selexipag and its active metabolite ACT-333679 on cardiac repolarization were assessed in a thorough QT study as per International Conference on Harmonisation E14 guidance. In this randomized, double-blind, placebo/positive-controlled, parallel-group study, healthy male and female subjects were randomized to receive escalating doses of selexipag (n=91) or placebo/moxifloxacin (n=68). Ascending multiple doses of selexipag in the range of 400-1,600 μg or placebo were administered twice daily for 21 days.

First-in-humans study of the safety, tolerability, and pharmacokinetics of ACT-451840, a new chemical entity with antimalarial activity.

Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant Plasmodium falciparum strains. This was a first-in-humans single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of ACT-451840 across doses of 10, 50, 200, and 500 mg in healthy male subjects.

A new reversible and potent P2Y12 receptor antagonist (ACT-246475): tolerability, pharmacokinetics, and pharmacodynamics in a first-in-man trial.

Background And Objectives: ACT-246475 is a new reversible, selective, and potent antagonist of the platelet P2Y12 receptor. This study was a first-in-man trial investigating the tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of ACT-246475 and its di-ester prodrug (ACT-281959) in healthy males.

Methods: The study had a double-blind, randomized, ascending single-dose design with an oral formulation F1 (i.

Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects.

Objective: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects.

Methods: This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level.

Poorly controlled type 2 diabetes mellitus is associated with a decreased risk of incident gout: a population-based case-control study.

Objective: The aim of this study was to explore the risk of incident gout in patients with type 2 diabetes mellitus (T2DM) in association with diabetes duration, diabetes severity and antidiabetic drug treatment.

Methods: We conducted a case-control study in patients with T2DM using the UK-based Clinical Practice Research Datalink (CPRD). We identified case patients aged ≥18 years with an incident diagnosis of gout between 1990 and 2012.

Incidence of and risk factors for severe hypoglycaemia in treated type 2 diabetes mellitus patients in the UK--a nested case-control analysis.

Aims: To assess incidence rates (IRs) of and identify risk factors for incident severe hypoglycaemia in patients with type 2 diabetes newly treated with antidiabetic drugs.

Methods: Using the UK-based General Practice Research Database, we performed a retrospective cohort study between 1994 and 2011 and a nested case-control analysis. Ten controls from the population at risk were matched to each case with a recorded severe hypoglycaemia during follow-up on general practice, years of history in the database and calendar time.

Challenges in collecting pharmacokinetic and pharmacodynamic information in an intensive care setting: PK/PD modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage.

Purpose: This paper describes the pharmacokinetic/pharmacodynamic modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage (aSAH), and the impact of collecting data in an intensive care unit (ICU) setting. Factors influencing data quality, analysis, and interpretation are provided with recommendations for future clinical studies in ICU settings.

Methods: CONSCIOUS-2 was a phase III study involving 1,157 patients with aSAH.