Incidence of CXCR4 tropism and CCR5-tropic resistance in treatment-experienced participants receiving maraviroc in the 48-week MOTIVATE 1 and 2 trials.

Unlabelled: Maraviroc blocks HIV-1 entry into CD4+ cells by interrupting the interaction between viral gp120 and cell-surface CCR5. Resistance to CCR5 antagonist–mediated inhibition can develop by unmasking pre-existing CXCR4-using virus or through selection of CCR5-tropic resistant virus, characterized by plateaus in maximum percent inhibition <95%. Here, we examine viral escape in maraviroc-treated participants during virologic failure through Week 48 in the MOTIVATE 1 and 2 trials.

Population Pharmacokinetics of Fosdagrocorat (PF-04171327), a Dissociated Glucocorticoid Receptor Agonist, in Patients With Rheumatoid Arthritis.

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF-04171327), with active DAGR metabolite PF-00251802 (Metabolite-1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite-1 and its active metabolite PF-04015475 (Metabolite-2) in patients with moderate to severe RA enrolled in a 12-week, phase II, randomized, double-blind study (NCT01393639).

Assessment of Maraviroc Exposure-Response Relationship at 48 Weeks in Treatment-Experienced HIV-1-Infected Patients in the MOTIVATE Studies.

Efficacy exposure-response relationships of the CCR5 antagonist maraviroc were evaluated across two phase III clinical trials. This post-hoc analysis used 48-week efficacy data from 841 treatment-experienced patients infected with CCR5-tropic human immunodeficiency virus type 1 (HIV-1), identified by the enhanced sensitivity Trofile assay. Probability of treatment success (viral RNA <50 copies/ml) was modeled using generalized additive logistic regression, testing exposure, clinical, and virologic variables.

Baseline CD4+ T-cell counts predict HBV viral kinetics to adefovir treatment in lamivudine-resistant HBV-infected patients with or without HIV infection.

Background: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection.

Pharmacokinetics, safety, and tolerability of maraviroc in HIV-negative subjects with impaired renal function.

Purpose: This open-label, nonrandomized, parallel-group study was conducted to explore the pharmacokinetics, safety, and tolerability of maraviroc in renally impaired subjects.

Methods: Subjects with normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease (ESRD) (n = 6 per group) were enrolled. Subjects with normal function (period 1), severe impairment, and ESRD received a single 300 mg dose of maraviroc.

Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function).

Objectives: This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function).

Background: Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF.

Methods: A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days.

The use of the SAEM algorithm in MONOLIX software for estimation of population pharmacokinetic-pharmacodynamic-viral dynamics parameters of maraviroc in asymptomatic HIV subjects.

Using simulated viral load data for a given maraviroc monotherapy study design, the feasibility of different algorithms to perform parameter estimation for a pharmacokinetic-pharmacodynamic-viral dynamics (PKPD-VD) model was assessed. The assessed algorithms are the first-order conditional estimation method with interaction (FOCEI) implemented in NONMEM VI and the SAEM algorithm implemented in MONOLIX version 2.4.

Low lymphocyte ratio as a novel prognostic factor in acute heart failure: results from the Pre-RELAX-AHF study.

Background: Previous studies have suggested that a lower lymphocyte ratio (Ly%) in the white blood cell (WBC) differential count is related to worse outcomes in patients with acute heart failure (AHF) and other cardiovascular disorders.

Methods: In the Pre-RELAX-AHF study, 234 patients with AHF, systolic blood pressure >125 mm Hg and brain natriuretic peptide ≥350 pg/ml or equivalent were randomized to 1 of 4 intravenous doses of relaxin or placebo and followed up for 6 months following randomization. Complete blood count and differential were performed by a central laboratory at baseline and then daily to day 5 and on day 14.

Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure.

Background: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure.

Acute heart failure clinical drug development: from planning to proof of activity to phase III.

Over the last decades, attempts to develop new therapies for acute heart failure (AHF) have largely failed. Limitations in understanding the pathophysiology of AHF, its natural history, the effects of current therapies, the properties of new agents, and, importantly, study designs and execution have contributed to these disappointing results. We propose a novel approach for the development of new agents for AHF.

Haemodynamic effects of rolofylline in the treatment of patients with heart failure and impaired renal function.

Aims: The direct effects of adenosine A1 receptor antagonists on haemodynamic parameters in patients with acute heart failure (HF) remain largely unknown.

Methods And Results: We evaluated the haemodynamic effects of the AA(1)RA rolofylline in 59 HF patients with concomitant renal impairment (estimated creatinine clearance 20-80 mL/min). Placebo or rolofylline 30 mg was administered as a 4 h infusion followed by intravenous (i.

The effects of adenosine A(1) receptor antagonism in patients with acute decompensated heart failure and worsening renal function: the REACH UP study.

Background: Worsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A(1) antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A(1) antagonist (A(1)RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF.

Methods And Results: Seventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days.

Dyspnoea and worsening heart failure in patients with acute heart failure: results from the Pre-RELAX-AHF study.

Aims: Although dyspnoea is the most common cause of admission for acute heart failure (AHF), more needs to be known about its clinical course and prognostic significance.

Methods And Results: The Pre-RELAX-AHF study randomized 232 subjects with AHF to placebo or four doses of relaxin and evaluated early (6-24 h Likert scale) and persistent [change in visual analogue scale area under the curve (VAS AUC) through Day 5] dyspnoea relief. Worsening heart failure (WHF) was defined as worsening AHF signs and symptoms requiring additional therapy.

A randomized controlled trial of the safety and promise of cognitive-behavioral therapy using imaginal exposure in patients with posttraumatic stress disorder resulting from cardiovascular illness.

Objective: We investigated the physical safety of cognitive-behavioral therapy (CBT) utilizing imaginal exposure in patients who suffered from posttraumatic stress disorder (PTSD) following a life-threatening cardiovascular event.

Method: In this phase I, prospective, single-blind trial conducted from April 2006 through April 2008, we randomly assigned 60 patients to receive either 3 to 5 sessions of imaginal exposure therapy (experimental group) or 1 to 3 educational sessions only (control group). Criteria for PTSD and other mental health disorders were evaluated according to DSM-IV using the full Structured Clinical Interview for DSM-IV (SCID).

The management of acute heart failure.

Hospitalization for acute heart failure (AHF) is one of the burdensome aspects of 21st century medicine, leading to significant debilitating symptoms, high morbidity and mortality and consuming significant portion of the health care budget. Management of AHF is thought-provoking given the heterogeneity of the patient population, absence of a universally accepted definition, incomplete understanding of the pathophysiology and the beneficial and adverse effects of currently used therapies and lack of robust evidence-based guidelines. The article will discuss the clinical approach to the patients admitted with AHF, reviewing types of intervention (both approved and investigational) and will delineate their role and timing in specific AHF presentations.

Dyspnoea in patients with acute heart failure: an analysis of its clinical course, determinants, and relationship to 60-day outcomes in the PROTECT pilot study.

Aims: Dyspnoea is the most common symptom leading to hospitalization for acute heart failure (AHF). Its early and persistent relief is an important goal of therapy, but little is known about its course, determinants, and prognostic significance.

Methods And Results: In a post hoc analysis, we studied changes in dyspnoea and in-hospital course in 303 subjects with AHF enrolled in the PROTECT pilot trial.

Design and rationale of the PROTECT study: a placebo-controlled randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function.

Background: Current treatment for acute decompensated heart failure (ADHF) is associated with incomplete resolution of symptoms and signs, recurrent symptoms of heart failure in-hospital and after discharge and high mortality. Studies have consistently demonstrated an association between worsening renal function in ADHF and adverse outcomes. Adenosine A(1) receptor antagonists, such as rolofylline, appear in preliminary studies to produce potentially beneficial effects on natriuresis, diuresis, renal blood flow, and glomerular filtration rate.

Patterns of leukocyte counts on admissions for acute heart failure--presentation and outcome--results from a community based registry.

Objective: To determine the correlation between differential white blood cell (WBC) count and characteristics and outcome of acute heart failure (AHF) syndromes.

Background: Previous studies suggested that different white blood cell count patterns are related to outcome in patients with heart failure (HF) and other cardiovascular disorders.

Methods: Data from all qualifying AHF admissions to a city hospital (n=340) was prospectively collected.

Physician-determined worsening heart failure: a novel definition for early worsening heart failure in patients hospitalized for acute heart failure--association with signs and symptoms, hospitalization duration, and 60-day outcomes.

Objectives: To evaluate physician-determined worsening heart failure (PD-WHF) in patients admitted with acute heart failure (AHF).

Methods: The PROTECT pilot study evaluated rolofylline, an adenosine A(1) receptor antagonist, versus placebo in patients with AHF and renal impairment. Signs and symptoms of heart failure (HF) and diuretic administration were prospectively recorded daily for 7 days and patients were followed for 60 days.

Early worsening heart failure in patients admitted for acute heart failure: time course, hemodynamic predictors, and outcome.

Background: The most common outcome currently assessed in acute heart failure trials (AHF) is dyspnea improvement. Worsening hear failure (WHF) is a new outcome measure that incorporates failure to improve or recurrent symptoms of AHF requiring rescue intravenous therapy, mechanical circulatory or ventilatory support, or readmission because of AHF, occurring within 30 days of AHF admission.

Methods And Results: Retrospective data analysis of 120 patients with AHF requiring hemodynamic monitoring who enrolled in the placebo arm of 2 prospective randomized studies.

Maraviroc modelling strategy: use of early phase 1 data to support a semi-mechanistic population pharmacokinetic model.

Aims: To model the basic pharmacokinetic (PK) characteristics of maraviroc to construct an integrated semi-mechanistic PK model for use in later population PK analyses.

Methods: Three analyses were performed utilizing intravenous, oral and radiolabel data. Firstly, a PK disposition model was developed from data from 20 healthy males who received 3, 10 or 30 mg of intravenous maraviroc.

Early worsening heart failure in patients admitted with acute heart failure--a new outcome measure associated with long-term prognosis?

A major limitation in acute heart failure (AHF) research has been the lack of an outcome measure paralleling re-infarction in acute coronary syndromes. The aim of the present study was to assess the time course, prognostic factors and outcome of early worsening heart failure (WHF) in patients admitted for AHF to a community hospital. All AHF admissions between December 2003 and March 2004 in a regional medical center were recorded.

Rapid clinical assessment of patients with acute heart failure: first blood pressure and oxygen saturation--is that all we need?

Unlabelled: The risk stratification of patients with acute heart failure (AHF) has been addressed repeatedly in recent years. Low oxygen saturation (SaO2) and systolic blood pressure (SBP) are signs of impending respiratory and circulatory failure that can be obtained quickly in patients with AHF.

Methods: Admissions for AHF (340 patients) in a city hospital were recorded and patients were followed for symptoms of heart failure, re-admission and mortality for 6 months.