Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model.

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1h; >200 fold at 6h) than with tiotropium (1.5 and 4.2 fold at 1h; 4.6 and 5.5 fold at 6h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium.

Therapeutic approaches towards the treatment of gastroinstestinal disorders.

The Society for Medicines Research gathered an international panel of speakers and about 60 delegates for their symposium September 21, 2006, on Therapeutic Approaches Towards the Treatment of Gastroinstestinal Disorders, at the National Heart and Lung Institute, in London, U.K. The focus of the conference was to discuss therapeutic strategies taken towards the treatment of inflammatory bowel disease, acid related disorders and irritable bowel syndrome. Key note lectures addressed the development of tegaserod, a 5-HT(4) receptor agonist, for the treatment of constipation dominant irritable bowel syndrome (cIBS), the use of tumor necrosis factor alpha (TNFalpha) inhibitors in the treatment of chronic inflammatory diseases, including Crohn's disease, the development of effective inhibitors of gastric acid secretion, the role of alpha(4)beta(7) integrin in the development of Crohn's disease and ulcerative colitis, the parts played by the neuropeptides ghrelin and motilin in the control of gastrointestinal motility, and the role of bacteria in functional gastrointestinal disease.

Emerging therapies for respiratory diseases.

This Society for Medicines Research symposium, sponsored by UCB, was held on September 11, 2007, at the Wellcome Trust Conference Centre, Hinxton, Cambridge, United Kingdom. The meeting, organized by Ruth Lock, Steve Collingwood and Andrew Ratcliffe, reviewed current thinking in the area of airway drug delivery and the challenges and progress made in the discovery and development of novel medicines to treat respiratory diseases, such as chronic obstructive pulmonary disease, asthma, allergic rhinitis and cystic fibrosis.