Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study.

Objective: Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects.

Methods: This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supra-therapeutic dose (8-fold clinical dose in COPD patients) of 400 µg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazettcorrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability.

Development of comprehensive functional genomic screens to identify novel mediators of osteoarthritis.

Objective: The aim of this study was to develop high-throughput assays for the analysis of major chondrocyte functions that are important in osteoarthritis (OA) pathogenesis and methods for high-level gene expression and analysis in primary human chondrocytes.

Methods: In the first approach, complementary DNA (cDNA) libraries were constructed from OA cartilage RNA and full-length clones were selected. These cDNAs were transferred into a retroviral vector using Gateway Technology.

Chondrocyte cluster formation in agarose cultures as a functional assay to identify genes expressed in osteoarthritis.

Understanding altered gene expression in osteoarthritic cartilage can lead to new targets for drug intervention. We established a functional assay based on chondrocyte cluster formation, a phenotype associated with osteoarthritis (OA), to screen an OA cartilage gene library. Previous reports have demonstrated that normal chondrocytes grown in suspension culture maintain their chondrocytic phenotype, however, certain growth factors such as basic fibroblast growth factor (bFGF) will induce the cells to proliferate in tight clusters similar to those seen in osteoarthritic cartilage.

Fluorescently labeled mesenchymal stem cells (MSCs) maintain multilineage potential and can be detected following implantation into articular cartilage defects.

Several studies have reported enhanced repair of damaged cartilage following implantation of mesenchymal stem cells (MSCs) into full-thickness cartilage defects suggesting that the cells in the repair tissue were derived from the implant. However, it cannot be excluded that the enhanced tissue repair is derived from host cells recruited to the defect in response to the implant, rather than the re-population of the tissue by the implanted MSCs. Our objective was to study the short-term fate of fluorescently labeled MSCs after implantation into full-thickness cartilage defects in vivo.

Carboxy-substituted cinnamides: a novel series of potent, orally active LTB4 receptor antagonists.

A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B4 (LTB4) receptor. Binding was determined through measurement of [3H]LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils.