Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial.

Background: Tadalafil is being investigated for the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH-LUTS).

Objective: To assess efficacy, including onset, and safety of tadalafil on BPH-LUTS and the subject's and clinician's perception of changes in urinary symptoms.

Design, Setting, And Participants: This randomized, double-blind, placebo-controlled, 12-week trial enrolled men ≥45 yr of age with BPH-LUTS for >6 mo, International Prostate Symptom Score (IPSS) ≥13, and maximum urine flow rate (Q(max)) ≥4 to ≤15 ml/s.

Safety and clinical efficacy of platelet components prepared with pathogen inactivation in routine use for thrombocytopenic patients.

This study was conducted to evaluate the safety and efficacy of platelet concentrates (PC) after photochemical treatment (PCT) with the INTERCEPT Blood System™ and transfused in routine use in a population of patients suffering from a variety of hematological diseases. This was an observational, single-arm, open-label study of pooled buffy-coat PC (n=298) or apheresis PC (n=262) treated with INTERCEPT™ and transfused to 51 thrombocytopenic hematology patients. PCT replaced CMV screening and gamma irradiation, and made optional bacterial testing obsolete.

Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension.

Background: Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to bosentan were pre-specified.

An active hemovigilance program characterizing the safety profile of 7483 transfusions with plasma components prepared with amotosalen and UVA photochemical treatment.

Background: Photochemical pathogen inactivation treatment (PCT) of plasma components with amotosalen and UVA has been implemented in Europe. To establish a postapproval safety database, an active hemovigilance (HV) program utilizing an electronic data capture system (EDCS) was initiated.

Study Design And Methods: The response to transfusion was documented after each PCT-plasma transfusion.

The international PROGRESS registry of patients with severe sepsis: drotrecogin alfa (activated) use and patient outcomes.

Introduction: Since the launch of drotrecogin alfa activated (DrotAA), institutions and individual countries have published data on its use in clinical practice, based on audit or registry data. These studies were limited in size and geographic locale and included patients with greater disease severity and higher mortality than those in clinical trials. The purpose of this study was to compare baseline characteristics and clinical outcomes (using appropriate statistical adjustments) of patients treated or not treated with DrotAA from the international PROGRESS (Promoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis.

Transfusion of platelet components prepared with photochemical pathogen inactivation treatment during a Chikungunya virus epidemic in Ile de La Réunion.

Background: During the Chikungunya virus (CHIKV) epidemic on Ile de La Réunion, France, more than 30% of 750,000 inhabitants were infected. Local blood donation was suspended to prevent transfusion-transmitted infection (TT-CHIKV). To sustain the availability of platelet (PLT) components, the Etablissement Français du Sang implemented universal pathogen inactivation (INTERCEPT, Cerus Europe BV) of PLT components (CPAs).

Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated).

Rationale: Patients with severe sepsis frequently receive prophylactic heparin during drotrecogin alfa (activated) (DrotAA) treatment due to risk of venous thromboembolic events (VTEs). Biological plausibility exists for heparin to reduce DrotAA efficacy and/or increase bleeding.

Objectives: Primary: demonstrate in adult patients with severe sepsis receiving DrotAA treatment that 28-day mortality was equivalent for patients treated with concomitant prophylactic heparin compared with placebo; secondary: safety and VTE incidence.

Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial.

Background: Drotrecogin alfa (activated) (DrotAA) is used for the treatment of adults with severe sepsis who have a high risk of dying. A phase 1b open-label study has indicated that the pharmacokinetics and pharmacodynamics of DrotAA are similar in children and adults. We initiated the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE) trial to investigate the efficacy and safety of the drug in children.

An inhaled matrix metalloprotease inhibitor prevents cigarette smoke-induced emphysema in the mouse.

Inadequately regulated proteolytic activity is responsible for the chronic lung tissue degeneration and irreversible loss of pulmonary function that define emphysema. In this study, we show that an inhaled broad-spectrum matrix metalloprotease inhibitor, ilomastat, can provide protection against the development of emphysema in cigarette smoke-treated mice. Control animals were exposed to daily cigarette smoke for 6 months.

Alpha1-antitrypsin single dose adjuvant therapy for acute otitis media.

Objectives: Proteases have been shown to play a role in the pathogenesis of otitis media. Inhibition of these proteases can improve treatment outcomes in certain conditions. The goal of this study was to determine if intratympanic administration of a single dose of the protease inhibitor, recombinant alpha 1-antitrypsin (rAAT), can facilitate resolution of acute otitis media (AOM) in the chinchilla.

Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome.

Introduction: Protein C, because of its central role in hemostasis, plays an integral role in the host response to infection. Protein C depletion, resulting from increased consumption, degradation, and/or decreased synthesis, is characteristic of sepsis and has been shown to predict morbidity and mortality. The objective of this study was to determine whether early directional changes in protein C levels correlate with outcome.

Use of an integrated clinical trial database to evaluate the effect of timing of drotrecogin alfa (activated) treatment in severe sepsis.

Introduction: Several studies have indicated that early identification and treatment of patients with severe sepsis using standard supportive care improves outcomes. Earlier treatment with drotrecogin alfa (activated) (DrotAA) may also improve outcomes in severe sepsis. Using a recently constructed integrated severe sepsis database, our objectives in this study were to describe the influence of baseline clinical characteristics on timing of DrotAA treatment in patients with severe sepsis, to evaluate the efficacy of DrotAA with respect to timing of administration, and to examine the association between early intervention with DrotAA and patient outcomes, using adjustments for imbalances.

Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment.

Objective: To provide further evidence for the efficacy and safety of drotrecogin alfa (activated) treatment in severe sepsis.

Design: Single-arm, open-label, trial of drotrecogin alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in January 2003.

Inflammatory proteases in chronic otitis externa.

Objectives: Proteases are known to contribute to the pathogenesis of chronic inflammatory skin conditions such as atopic dermatitis and psoriasis. Inhibition of these proteases has shown promise in the treatment of these skin conditions. The purpose of this study was to measure the matrix metalloproteinases (MMP) and human neutrophil elastase (HNE) activities in chronic otitis externa (COE) and to determine whether administration of protease inhibitors recombinant alpha 1-antitrypsin (rAAT) and ilomastat might reduce these protease activities.

Effects of drotrecogin alfa (activated) in human endotoxemia.

In a phase III clinical trial, drotrecogin alfa (activated) was shown to improve survival and promote faster improvement of cardiovascular and respiratory dysfunction in patients with severe sepsis. To further examine mechanisms involved in the action of this drug, a healthy human endotoxin model was used. Healthy volunteers (eight per group) received drotrecogin alfa (activated) or placebo intravenously for 8 h in a randomized, double-blind, controlled manner.

Protease inhibitors alpha1-antitrypsin and ilomastat are not ototoxic in the chinchilla.

Objectives: Proteases of both the serine and the metalloprotease families have been shown to play a role in the pathogenesis of otitis media. Inhibitors of proteases from each of these families have been shown to beneficially impact disease progression in a number of related chronic inflammatory conditions. The purpose of this study was to assess the safety of protease inhibitors when instilled into the middle ear, with a view to their potential use in the treatment of human otitis media.

Alpha 1-antitrypsin and ilomastat inhibit inflammatory proteases present in human middle ear effusions.

Objectives: Proteases of both the serine and metalloproteinase families have been shown to play a role in the pathogenesis of otitis media (OM). Inhibitors of proteases from each of these families have been shown to beneficially impact disease progression in a number of related chronic inflammatory conditions, but their use has not been studied in OM. The purpose of this study was to assess the activity of the protease inhibitors recombinant alpha 1-antitrypsin (rAAT) and ilomastat on inflammatory proteases present in human middle ear effusions (MEEs), with a view to their potential utility in the treatment of OM.

Clusterin protects renal tubular epithelial cells from gentamicin-mediated cytotoxicity.

Clusterin is a heterodimeric secreted glycoprotein that is upregulated after acute renal injury. In aminoglycoside nephrotoxicity, clusterin is induced in the tubular epithelium and increased levels are found in the urine. In this study, we developed an in vitro model of gentamicin-induced cytotoxicity in renal proximal tubule cells and tested whether clusterin protected these cells from injury.

Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome.

Normal reabsorption of glomerular filtrate proteins probably requires recycling of the endocytic receptors megalin (gp330) and cubilin. Both receptors are located on the luminal surface of the renal proximal tubule epithelium. Whether abnormal amounts of receptor are present in the urine of patients with Dent's disease, Lowe's syndrome, or autosomal dominant idiopathic Fanconi syndrome was explored.

Gentamicin inhibits renal protein and phospholipid metabolism in rats: implications involving intracellular trafficking.

Studies were undertaken to characterize the mechanism of aminoglycoside-induced nephrotoxicity. Early time points in gentamicin treatment (1 to 3 d) were used to investigate the development of toxic events without the complication of gross morphologic cellular alterations. Enzyme activities of cortical homogenates and brush border membrane (BBM) preparations documented little effect on specific activities or the ability to isolate representative membrane fractions.