Inhaled pan-selectin antagonist Bimosiamose attenuates airway inflammation in COPD.

Selectins, a family of cell adhesion molecules, are involved in leukocyte extravasation to sites of inflammation. We investigated the safety and efficacy of the inhaled pan-selectin antagonist Bimosiamose in patients with chronic obstructive pulmonary disease (COPD). 77 COPD patients (mean forced expiratory volume in 1 s, 57% pred.) were enrolled in a cross-over, double-blind, randomized, Placebo-controlled, multi-center trial. Bimosiamose (10 mg) or Placebo was inhaled twice daily via the breath actuated nebulizer Akita2 Apixneb™ for 28 days on top of standard bronchodilator therapy. Efficacy was assessed by measurement of inflammatory parameters in induced sputum (differential cell count, interleukin-8, matrix-metalloproteinase-9, myeloperoxidase) and lung function at day 28 of both treatment periods. The total adverse event ratio of Bimosiamose compared to Placebo treatment was balanced. Compared to Placebo, treatment with Bimosiamose led to a decrease of the interleukin-8 concentration (-9.49 ng/mL, 95%CI -18.8 to -2.7 ng/mL, p = 0.008), for the neutrophil count a difference of -0.368 × 10(6) cells/mL (95%CI -1.256 to 0.407 × 10(6)/mL, p = 0.313) was found. The macrophage count decreased by -0.200 × 10(6) cells/mL (95%CI -0.365 to -0.044 × 10(6) cells/mL, p = 0.012). Most lung function parameters showed a small numeric increase. Inhalation of Bimosiamose for 28 days was safe and well tolerated in patients with COPD. It led to an attenuation of airway inflammation (EudraCT 2009-017257-35; NCT ID: NCT01108913).

Rational design of novel, potent small molecule pan-selectin antagonists.

This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity. Biological evaluation involves two kinds of in vitro assays, a static molecular binding assay, and a dynamic HL-60 cell attachment assay. As compared to controls, the novel compounds showed improved biological in vitro activity both under static and dynamic conditions.

Ozone-induced release of neuropeptides from human nasal mucosa cells.

Studies examining the effect of pharmacological agents on respiratory responses to ozone support the concept that the effects are mediated, at least in part, by neural mechanisms, including neuropeptide release. Using a special tissue culture system the influence of ozone (0.1 ppm/24 h) on nasal mucosa from allergic and nonallergic patients undergoing surgery for chronic nasal obstruction was examined. Substance P (SP)-immunoreactive nerves were found in air-exposed as well as in ozone-exposed tissue samples. The content of neurokinin A (NKA) and SP in the culture supernatants was significantly increased following ozone exposure compared to controls. Tissue of allergic patients showed an ozone-induced increase in the release of NKA and SP compared to tissue of nonallergic patients. These results suggest that the mode of action of ozone results in an increased activity of sensory nerves in the upper airways with a subsequent increased release of neuropeptides. In addition to the known ozone-induced release of proinflammatory mediators, these mechanisms may explain the increased responsiveness of patients with hypersensitive airways.