Global Challenges After a Global Challenge: Lessons Learned from the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) has affected not only individual lives but also the world and global systems, both natural and human-made. Besides millions of deaths and environmental challenges, the rapid spread of the infection and its very high socioeconomic impact have affected healthcare, economic status and wealth, and mental health across the globe. To better appreciate the pandemic's influence, multidisciplinary and interdisciplinary approaches are needed.

Laser-assisted see-through technology for locating sound sources inside a structure.

A laser-assisted see-through technology is developed to locate sound sources inside a structure and to analyze the interior sound field. Six lasers were employed to measure simultaneously the normal velocities on the exterior surface. These input data were used to locate sound sources inside a solid structure using a passive sonic detection and ranging algorithm, and then to reconstruct the interior sound field using the Helmholtz equation least squares method, and finally to observe the changes of the interior sound field over time through computer tomography.

PK/PD modeling links accelerated resolution of COVID-19-related clinical symptoms to SARS-CoV-2 viral load reduction in patients following treatment with Bamlanivimab alone or Bamlanivimab and Etesevimab together.

The relationship between severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral load reduction and disease symptom resolution remains largely undefined for coronavirus disease 2019 (COVID-19). While the vaccine-derived immunity takes time to develop, neutralizing monoclonal antibodies offer immediate, passive immunity to patients with COVID-19. Bamlanivimab and etesevimab are two potent neutralizing monoclonal antibodies directed to the receptor binding domain of the spike protein of SARS-CoV-2.

Dose/Exposure-Response Modeling to Support Dosing Recommendation for Phase III Development of Baricitinib in Patients with Rheumatoid Arthritis.

Baricitinib is an oral inhibitor of Janus kinases (JAKs), selective for JAK1 and 2. It demonstrated dose-dependent efficacy in patients with moderate-to-severe rheumatoid arthritis (RA) in a phase IIb study up to 24 weeks. Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed to characterize concentration-time profiles and dose/exposure-response (D/E-R) relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the phase IIb study.

Effect of co-ligands on chemical and biological properties of (99m)Tc(III) complexes [(99m)Tc(L)(CDO)(CDOH)2BMe] (L=Cl, F, SCN and N3; CDOH2=cyclohexanedione dioxime).

Introduction: (99m)Tc-Teboroxime ([(99m)TcCl(CDO)(CDOH)2BMe]) is a member of the BATO (boronic acid adducts of technetium dioximes) class of (99m)Tc(III) complexes. This study sought to explore the impact of co-ligands on solution stability, heart uptake and myocardial retention of [(99m)Tc(L)(CDO)(CDOH)2BMe] ((99m)Tc-Teboroxime: L=Cl; (99m)Tc-Teboroxime(F): L=F; (99m)Tc-Teboroxime(SCN): L=SCN; and (99m)Tc-Teboroxime(N3): L=N3).

Methods: Radiotracers (99m)Tc-Teboroxime(L) (L=F, SCN and N3) were prepared by reacting (99m)Tc-Teboroxime with NaF, NaSCN and NaN3, respectively.

Simultaneous optimal experimental design for in vitro binding parameter estimation.

Simultaneous optimization of in vitro ligand binding studies using an optimal design software package that can incorporate multiple design variables through non-linear mixed effect models and provide a general optimized design regardless of the binding site capacity and relative binding rates for a two binding system. Experimental design optimization was employed with D- and ED-optimality using PopED 2.8 including commonly encountered factors during experimentation (residual error, between experiment variability and non-specific binding) for in vitro ligand binding experiments: association, dissociation, equilibrium and non-specific binding experiments.

Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy.

In TRITON-TIMI 38, levels of the prasugrel active metabolite (pras-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras-AM was observed in low-weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non-coronary artery bypass graft (CABG)-related TIMI-related bleeding observed in these 2 patient populations.

Integrated analysis of pharmacokinetic data across multiple clinical pharmacology studies of prasugrel, a new thienopyridine antiplatelet agent.

An integrated analysis of pharmacokinetic (PK) parameter estimates for prasugrel, from 16 phase I clinical pharmacology studies, consolidated exposure estimates from 506 healthy male and female participants and evaluated the effect of specific intrinsic and extrinsic factors on exposure to prasugrel's active metabolite (AM, R-138727). A linear mixed effect model was fitted with study and subject nested within study as random effects and subject factors as fixed effects. Prasugrel AM exposure was similar in males and females, in participants <65 years and ≥65 years, in smokers and nonsmokers, in drinkers and nondrinkers of alcohol, and in Asians, Caucasians, and participants of African and Hispanic descent.

Methodological comparison of in vitro binding parameter estimation: sequential vs. simultaneous non-linear regression.

Purpose: Analysis of simulated data was compared using sequential (NLR) and simultaneous non-linear regression (SNLR) to evaluate precision and accuracy of ligand binding parameter estimation.

Methods: Commonly encountered experimental error, specifically residual error of binding measurements (RE), experiment-to-experiment variability (BEV) and non-specific binding (B(NS)), were examined for impact of parameter estimation using both methods. Data from equilibrium, dissociation, association and non-specific binding experiments were fit simultaneously (SNLR) using NONMEM VI compared to the common practice of analyzing data from each experiment separately and assigning these as exact values (NLR) for estimation of the subsequent parameters.

Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease.

Objective: The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end-stage renal impairment.

Methods: Two of the three protocols were parallel-design, open-label, single dose (60-mg prasugrel) studies in subjects with end-stage renal disease (ESRD; n = 12) or moderate renal impairment (n = 10) and matched healthy subjects with normal renal function (n = 10).

Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver disease.

Background And Objective: Prasugrel is a thienopyridine antiplatelet agent under investigation for the prevention of atherothrombotic events in patients with acute coronary syndrome who undergo percutaneous coronary intervention. Patients with chronic liver disease are among those in the target population for prasugrel. As hepatic enzymes play a key role in formation of prasugrel's active metabolite, hepatic impairment could affect the safety and/or efficacy of prasugrel in such patients.

Effect of age on the pharmacokinetics and pharmacodynamics of prasugrel during multiple dosing: an open-label, single-sequence, clinical trial.

Background: A substantial portion of patients at risk for acute coronary syndrome (ACS) are >65 years old. Prasugrel is a novel antiplatelet agent approved for the treatment of ACS patients undergoing percutaneous coronary intervention, and will be used in this population.

Objective: This study assessed the effect of age >or=65 years on the pharmacokinetics (PK) and pharmacodynamics (PD) of the active metabolite (R-138727) of prasugrel in healthy subjects taking aspirin (acetylsalicylic acid).

Everyday cognitive functioning in cardiac patients: relationships between self-report, report of a significant other and cognitive test performance.

Candidates for cardiac bypass surgery often experience cognitive decline. Such decline is likely to affect their everyday cognitive functioning. The aim of the present study was to compare cardiac patients' ratings of their everyday cognitive functioning against significant others' ratings and selected neuropsychological tests.

Inhibition of platelet aggregation with prasugrel and clopidogrel: an integrated analysis in 846 subjects.

This integrated analysis compared speed of onset, level of platelet inhibition, and response variability to prasugrel and clopidogrel in healthy subjects and in patients with stable coronary artery disease with data pooled from 24 clinical pharmacology studies. Data from subjects (N = 846) were categorized into the following treatment groups: prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD), clopidogrel 300 mg LD/75 mg MD, or clopidogrel 600 mg LD/75 mg MDs. Maximum platelet aggregation (MPA) and inhibition of platelet aggregation (IPA) to 5 and 20 muM ADP were assessed by turbidimetric aggregometry.

Prediction of prasugrel active metabolite concentrations from 2 downstream inactive metabolite concentrations using multilinear regression analysis.

Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras-AM), which inhibits adenosine diphosphate (ADP)-induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was used to quantitatively predict concentrations of Pras-AM from downstream inactive metabolites, R-119251 and R-106583, for the purpose of estimating Pras-AM exposure in patients in the TRITON-TIMI 38 substudies. The model development included 1462 Pras-AM, 1345 R-119251, and 1456 R-106583 concentration data points from 103 healthy participants with a prasugrel dose range of 15 to 80 mg.

Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38.

Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON-TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrel's active metabolite (Pras-AM) concentrations from its 2 downstream inactive metabolites. Population-based methods were then applied to Pras-AM concentration data to characterize the PK.

Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects.

Study Objective: To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.

Design: Open-label, randomized, crossover, two-arm, parallel-group study.

Setting: Single clinical research center in the United Kingdom.

Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease.

The aim of the current analysis was to characterize the population PK of prasugrel and clopidogrel metabolites, the resulting PD response, and identification of covariates for key PK/PD parameters. Aspirin-treated subjects with coronary artery disease were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD) followed by daily 75 mg maintenance dose (MD) or prasugrel 60 mg LD and daily 10 mg MD for 28 days. Plasma concentrations of prasugrel active metabolite (Pras-AM) and prasugrel's inactive thiolactone metabolite (Pras-thiolactone) were simultaneously fit to a multicompartmental model; a similar model adequately described clopidogrel's active metabolite (Clop-AM) PK.

Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel.

Objective: Clopidogrel is an oral thienopyridine antiplatelet agent indicated for the treatment of atherothrombotic events in patients with acute coronary syndrome (ACS). Prasugrel, a novel oral thienopyridine, is under investigation for the reduction of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. Prasugrel's solubility decreases with increasing pH, suggesting that concomitantly-administered medications that increase gastric pH may lower the rate and/or extent of prasugrel absorption.

Living alone predicts 30-day hospital readmission after coronary artery bypass graft surgery.

Background: Earlier studies show that medical factors and disease severity predict early readmission to hospital after coronary artery bypass graft surgery (CABGS). Few studies have investigated psychosocial predictors. This study investigated medical, sociodemographic and psychosocial predictors of 30-day hospital readmission.

Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans.

Prasugrel, a thienopyridine prodrug, is hydrolyzed in vivo by esterases to a thiolactone followed by a single cytochrome P450 (CYP)-dependent step to an active metabolite that is a potent inhibitor of adenosine diphosphate-induced platelet aggregation. This open-label, multiple-dose, 2-period, fixed-sequence study assessed CYP2B6 inhibition by prasugrel using bupropion as a probe substrate, where its active metabolite, hydroxybupropion, is almost exclusively formed by CYP2B6. Thirty healthy subjects received a single 150-mg oral dose of sustained-release bupropion.

Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel.

Prasugrel pharmacodynamics and pharmacokinetics after a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MD) were compared in a 3-way crossover study to clopidogrel 600-mg/75-mg and 300-mg/75-mg LD/MD in 41 healthy, aspirin-free subjects. Each LD was followed by 7 days of daily MD and a 14-day washout period. Inhibition of platelet aggregation (IPA) was assessed by turbidometric aggregometry (20 and 5 microM ADP).

Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.

Background: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y(12) adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized.

Objective: To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel.