Responses of diatoms and aquatic macroinvertebrates to deposited fine sediment in mesocosm channels as a basis for a new water quality guideline.

Water quality guidelines are an important tool for managing environmental pressures on freshwater streams. Currently, there is a lack of guideline values for fine sediment deposition in South Australian and, more broadly, Australian and overseas streams despite the potentially profound impacts of sediment deposition on aquatic communities. We used an outdoor recirculating stream mesocosm to assess the responses of freshwater diatoms and macroinvertebrates to fine sediment burial after six weeks following a pulsed event.

Normothermic Regional Perfusion in Controlled Donation After Circulatory Death Liver Transplantation: A Systematic Review and Meta-Analysis.

Liver grafts from controlled donation after circulatory death (cDCD) donors have lower utilization rates due to inferior graft and patient survival rates, largely attributable to the increased incidence of ischemic cholangiopathy, when compared with grafts from brain dead donors (DBD). Normothermic regional perfusion (NRP) may improve the quality of cDCD livers to allow for expansion of the donor pool, helping to alleviate the shortage of transplantable grafts. A systematic review and metanalysis was conducted comparing NRP cDCD livers with both non-NRP cDCD livers and DBD livers.

The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development.

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states.

First-in-human study to assess the safety, pharmacokinetics, and pharmacodynamics of BMS-986141, a novel, reversible, small-molecule, PAR4 agonist in non-Japanese and Japanese healthy participants.

BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD;  = 60) study; a multiple-ascending-dose (MAD;  = 32) study; and a Japanese MAD (JMAD;  = 32) study. Exposure was dose-proportional for BMS-986141 2.

New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans.

BMS-986120 is a novel first-in-class oral protease-activated receptor 4 (PAR4) antagonist exhibiting robust antithrombotic activity that has shown low bleeding risk in monkeys. We sought to assess pharmacokinetics, pharmacodynamics, and tolerability of BMS-986120 in healthy participants and platelet responses to BMS-986120 in participants carrying PAR4 A120T variants. Phase I, randomized, double-blind, placebo-controlled single-ascending-dose (SAD; N = 56) and multiple-ascending-dose (MAD; N = 32) studies were conducted.

Apixaban Pharmacokinetics and Pharmacodynamics in Subjects with Mild or Moderate Hepatic Impairment.

Background: Hepatic impairment can impact apixaban pharmacokinetics and pharmacodynamics by decreasing cytochrome P450-mediated metabolism and factor X production.

Objective: This study evaluated the effect of mild or moderate (Child-Pugh A and B) hepatic impairment on apixaban pharmacokinetics, pharmacodynamics, and safety.

Methods: This open-label, parallel-group, single-dose study included eight mildly and eight moderately hepatically impaired subjects, and 16 healthy subjects.

Apixaban Single-Dose Pharmacokinetics, Bioavailability, Renal Clearance, and Pharmacodynamics Following Intravenous and Oral Administration.

This randomized, double-blind, placebo-controlled, ascending single intravenous (IV) bolus-dose study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of apixaban, a direct factor Xa (FXa) inhibitor approved for multiple indications. Eight healthy subjects were randomized 3:1 (apixaban:placebo) within each IV dose cohort (0.5, 1.

Warming Arctic summers unlikely to increase productivity of shorebirds through renesting.

Climate change in the Arctic is leading to earlier summers, creating a phenological mismatch between the hatching of insectivorous birds and the availability of their invertebrate prey. While phenological mismatch would presumably lower the survival of chicks, climate change is also leading to longer, warmer summers that may increase the annual productivity of birds by allowing adults to lay nests over a longer period of time, replace more nests that fail, and provide physiological relief to chicks (i.e.

Assessing recovery of spectacled eiders using a Bayesian decision analysis.

Assessing species status and making classification decisions under the Endangered Species Act is a critical step towards effective species conservation. However, classification decisions are liable to two errors: i) failing to classify a species as threatened or endangered that should be classified (underprotection), or ii) classifying a species as threatened or endangered when it is not warranted (overprotection). Recent surveys indicate threatened spectacled eider populations are increasing in western Alaska, prompting the U.

Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review.

Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic disorders, including reduction of stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, the treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism. The absolute oral bioavailability of apixaban is ~ 50%. Food does not have a clinically meaningful impact on the bioavailability.

Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

Purpose: This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

Subjects And Methods: Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo.

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation.

This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination.

Regional Gastrointestinal Absorption of Apixaban in Healthy Subjects.

This study was conducted to investigate the extent of absorption in different regions of the gastrointestinal (GI) tract. The relative bioavailability of an apixaban crushed tablet was also assessed to investigate the effect of dissolution on absorption. This was an open-label, randomized, 4-period, 4-treatment crossover study with a 7-day washout period balanced for first-order residual effects in 12 healthy subjects.

First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects.

Aims: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects.

Methods: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.

Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma.

The objective was to characterise apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth-≤1 month], infants [>1-≤6 months], toddlers [>6 months-≤2 years], young children [>2-≤6 years], children [>6-≤12 years], adolescents [>12-≤18 years]), and six adult (19-45 years) subjects. Plasma spiked with apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT).

The effect of apixaban on the pharmacokinetics of digoxin and atenolol in healthy subjects.

Purpose: Apixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug-drug interactions (DDIs). The effects of apixaban on pharmacokinetics (PK) of multidose Lanoxin (digoxin) and single-dose Tenormin (atenolol) and the effects of single-dose atenolol on apixaban PK in healthy subjects were investigated in two Phase 1 studies.

Patients And Methods: The digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.

Apixaban Versus Warfarin for Mechanical Heart Valve Thromboprophylaxis in a Swine Aortic Heterotopic Valve Model.

Objective: Warfarin is the current standard for oral anticoagulation therapy in patients with mechanical heart valves, yet optimal therapy to maximize anticoagulation and minimize bleeding complications requires routine coagulation monitoring, possible dietary restrictions, and drug interaction monitoring. As alternatives to warfarin, oral direct acting factor Xa inhibitors are currently approved for the prophylaxis and treatment of venous thromboembolism and reduction of stroke and systemic embolization. However, no in vivo preclinical or clinical studies have been performed directly comparing oral factor Xa inhibitors such as apixaban to warfarin, the current standard of therapy.

Evaluation of Crushed Tablet for Oral Administration and the Effect of Food on Apixaban Pharmacokinetics in Healthy Adults.

Purpose: These studies evaluate the relative bioavailability of crushed apixaban tablets and the effect of food on apixaban pharmacokinetic properties.

Methods: An open-label, randomized, crossover study in 33 healthy adults compared the bioavailability of 2 × 5-mg apixaban tablets administered whole (reference), crushed and suspended in 30 mL of water, and crushed and mixed with 30 g of applesauce. A second open-label, randomized, crossover study in 22 healthy adults compared apixaban 1 × 5-mg tablet administered when fasted (reference) or immediately after consumption of a high-fat, high-calorie meal.

Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa.

Objective: Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous apixaban were evaluated in an open-label, randomized, sequential crossover study.

Methods: Twenty healthy participants received single doses of apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15.

Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.

This open-label study evaluated apixaban pharmacokinetics, pharmacodynamics, and safety in subjects with mild, moderate, or severe renal impairment and in healthy subjects following a single 10-mg oral dose. The primary analysis determined the relationship between apixaban AUC∞ and 24-hour creatinine clearance (CLcr ) as a measure of renal function. The relationships between 24-hour CLcr and iohexol clearance, estimated CLcr (Cockcroft-Gault equation), and estimated glomerular filtration rate (modification of diet in renal disease [MDRD] equation) were also assessed.

Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.

An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity.

Relative Bioavailability of Apixaban Solution or Crushed Tablet Formulations Administered by Mouth or Nasogastric Tube in Healthy Subjects.

Purpose: Crushed tablet and solution formulations of apixaban administered orally or via a nasogastric tube (NGT) may be useful in patients unable to swallow solid dose formulations. It is important to understand whether new formulations and/or methods of administration impact apixaban bioavailability and pharmacokinetic properties. These studies evaluated the relative bioavailability (Frel) of apixaban solution administered orally; oral solution administered via NGT flushed with either 5% dextrose in water (D5W) or with infant formula; oral solution via NGT with a nutritional supplement; and crushed tablet suspended in D5W and administered via NGT.

"Center punch" and "whole spot" bioanalysis of apixaban in human dried blood spot samples by UHPLC-MS/MS.

Apixaban (Eliquis™) was developed by Bristol-Myers Squibb (BMS) and Pfizer to use as an antithrombotic/anticoagulant agent and has been recently approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. A clinical study of apixaban, sponsored by BMS and Pfizer, included a pilot exploratory portion to evaluate the potential for future drug concentration monitoring using dried blood spot (DBS) sample collection. For DBS sample collection, a fixed blood volume was dispensed onto a DBS card by either regular volumetric pipette (venous blood collection) or capillary dispenser (finger prick blood collection).