The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting β 2-adrenoceptor agonist in preclinical animal species.

Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled β 2-adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)-6-[[3-[[4-[5-[[2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long-acting β 2-adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS-5759 dose-dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ≤ 10 μg/kg.

The in vitro pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long acting β2-adrenoceptor agonist.

Inhaled long-acting β(2)-adrenoceptor agonists (LABA) that act as bronchodilators and the oral anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor roflumilast are both approved therapies for chronic obstructive pulmonary disease (COPD). Here we describe the activity of a novel, inhaled, bifunctional, small molecule (R)-6-[(3-{[4-(5-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}pent-1-yn-1-yl)phenyl]carbamoyl}phenyl)sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), which has specific β(2) agonist and PDE4 inhibitory activity. GS-5759 demonstrated potent and full agonist activity at β(2) adrenoceptors (EC(50) = 8 ± 4 nM) and is a potent inhibitor of the PDE4 enzyme (IC(50) = 5 ± 3 nM).

Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion.

Mucus clearance is an important component of the lung's innate defense system. A failure of this system brought on by mucus dehydration is common to both cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Mucus clearance rates are regulated by the volume of airway surface liquid (ASL) and by ciliary beat frequency (CBF).

Treating laminitis: beyond the mechanics of trimming and shoeing.

Laminitis is typically classified into developmental or prodromal, acute, subacute, and chronic phases. Scientific evidence regarding the pathophysiology of laminitis does exist, but it is often conflicting and dependent on the clinician's interpretation/understanding of the study or the model used for inducing laminitis. The diagnosis of laminitis consists of obtaining an accurate history, performing a thorough physical examination, and taking good-quality radiographs.

Fosfomycin enhances the active transport of tobramycin in Pseudomonas aeruginosa.

Elevated levels of mucins present in bronchiectatic airways predispose patients to bacterial infections and reduce the effectiveness of antibiotic therapies by directly inactivating antibiotics. Consequently, new antibiotics that are not inhibited by mucins are needed to treat chronic respiratory infections caused by Pseudomonas aeruginosa and Staphylococcus aureus. In these studies, we demonstrate that fosfomycin synergistically enhances the activity of tobramycin in the presence of mucin.

Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis.

Objectives: To compare the in vitro and in vivo activities of a 4:1 (w/w) fosfomycin/tobramycin combination (FTI) with those of fosfomycin and tobramycin alone against cystic fibrosis (CF) and non-CF bronchiectasis pathogens.

Methods: Clinical isolates of CF Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Stenotrophomonas maltophilia, Burkholderia cepacia complex, Escherichia coli and Klebsiellia spp. were evaluated by MIC, MBC, post-antibiotic effect (PAE), synergy, time-kill, a rat pneumonia model and spontaneous mutation frequency (SMF).

A prodrug approach toward the development of water soluble fluoroquinolones and structure--activity relationships of quinoline-3-carboxylic acids.

A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery.