Effect of EP395, a novel anti-inflammatory macrolide, in an inhaled lipopolysaccharide challenge model in healthy volunteers: a randomised controlled trial
Jens M. Hohlfeld , Philipp Badorrek , Olof Breuer , Kate Hanrott , Jennifer Kricker , Michael J. Parnham , Virginia Norris
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引用次数: 0
Abstract
EP395, a macrolide with negligible antimicrobial activity but with anti-inflammatory effects in murine lipopolysaccharide (LPS) challenge model, is being developed as a potential treatment to reduce COPD exacerbations. This double-blind, placebo-controlled clinical study evaluated the pharmacodynamics of EP395 in response to inhaled LPS, an established clinical model for assessing anti-inflammatory effects of potential new treatments.
Forty-nine healthy, non-smoking participants were randomised to oral 375 mg EP395 or placebo, daily for 3 weeks. An inhaled LPS challenge (2 μg) was then given, followed 6 h later by bronchoscopy for bronchoalveolar lavage fluid (BALF) collection. Blood samples were collected pre, 6 and 24 h after LPS challenge.
BALF concentrations of IL-6, TNF-α, MIP-1α, MIP-1β and MCP-1 were lower with EP395 than placebo, while IL-33, IL-8, and IL-1β were higher with EP395 than placebo (not statistically significant). Neutrophil counts were unaffected, but neutrophil elastase and myeloperoxidase were higher with EP395 than placebo (not statistically significant). Serum concentrations of surfactant protein-D significantly increased in the EP395 group in response to LPS at both 6 and 24 h compared with pre-LPS (mean pre-LPS 148.8 ng/mL; mean 24 h post-LPS 183.0 ng/mL) but not in the placebo group (mean pre-LPS 142.4 ng/mL; mean 24 h post-LPS 142.4 ng/mL). The log2 transformed fold difference in the EP395 group, before and 24 h after LPS challenge was 0.33 (95 % CI 0.52, 0.14; p = 0.0007).
EP395 treatment increased the host defence response to inhaled LPS, including the epithelial response, whilst reducing inflammatory site pro-inflammatory mediators.
期刊介绍:
Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews.
Research Areas Include:
• All major diseases of the lung
• Physiology
• Pathology
• Drug delivery
• Metabolism
• Pulmonary Toxicology.