oxadiazoles and Pneumonia

Topics: Adult; Aged; Antitussive Agents; Asthma; Bronchitis; Child; Clinical Trials as Topic; Cough; Evaluation Studies as Topic; Humans; Infant; Infant, Newborn; Neoplasms; Oxadiazoles; Pneumonia; Tuberculosis, Pulmonary

We herein report the case of a 78-year-old woman who was diagnosed as having disseminated herpes zoster (DHZ) complicated with probable varicella-zoster pneumonia during maintenance therapy for microscopic polyangiitis. Because the patient had severe renal dysfunction, amenamevir administration was started to avoid any neurotoxicity of acyclovir, which is suggested to be optimal for treatment. It ameliorated her symptoms without any adverse events. This is the first report suggesting the efficacy of amenamevir in the treatment of severe herpes zoster infection with coexisting DHZ and probable varicella-zoster pneumonia. Amenamevir could thus be a treatment option for severe varicella zoster virus infections.

Topics: Acyclovir; Aged; Antiviral Agents; Chickenpox; Female; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunocompromised Host; Oxadiazoles; Pneumonia; Varicella Zoster Virus Infection

Rapid in situ detection of pathogens coupled with high resolution imaging in the distal human lung has the potential to provide new insights and diagnostic utility in patients in whom pneumonia is suspected. We have previously described an antimicrobial peptide (AMP) Ubiquicidin (fragment UBI

Topics: Animals; Antimicrobial Cationic Peptides; Bacteria; Cells, Cultured; Cystic Fibrosis; Disease Models, Animal; Fluorescent Dyes; Fungi; Humans; Hydrophobic and Hydrophilic Interactions; Inflammation; Lung; Models, Biological; Oxadiazoles; Pneumonia; Sheep; Signal-To-Noise Ratio

N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1β. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Dogs; Dose-Response Relationship, Drug; Emphysema; Female; Glycine; Guinea Pigs; Humans; Kinetics; Leukocyte Elastase; Mice; Mice, Inbred BALB C; Oxadiazoles; Pneumonia; Protein Binding; Pyridones; Pyrimidinones; Rats; Serine Proteinase Inhibitors; Species Specificity; Substrate Specificity; Sulfonamides; Sulfones; Swine; Tobacco Smoke Pollution

Sphingosine 1-phosphate (S1P) is a key endogenous regulator of the response to lung injury, maintaining endothelial barrier integrity through interaction with one of its receptors, S1P(1). The short-term administration of S1P or S1P(1) receptor agonists enhances endothelial monolayer barrier function in vitro, and attenuates injury-induced vascular leak in the lung and other organ systems in vivo. Although S1P(1) agonists bind to and activate S1P(1), several of these agents also induce receptor internalization and degradation, and may therefore act as functional antagonists of S1P(1) after extended exposure. Here we report on the effects of prolonged exposure to these agents in bleomycin-induced lung injury. We demonstrate that repeated administration of S1P(1) agonists dramatically worsened lung injury after bleomycin challenge, as manifested by increased vascular leak and mortality. Consistent with these results, prolonged exposure to S1P(1) agonists in vitro eliminated the ability of endothelial cell monolayers to respond appropriately to the barrier-protective effects of S1P, indicating a loss of normal S1P-S1P(1) signaling. As bleomycin-induced lung injury progressed, continued exposure to S1P(1) agonists also resulted in increased pulmonary fibrosis. These data indicate that S1P(1) agonists can act as functional antagonists of S1P(1) on endothelial cells in vivo, which should be considered in developing these agents as therapies for vascular leak syndromes. Our findings also support the hypothesis that vascular leak is an important component of the fibrogenic response to lung injury, and suggest that targeting the S1P-S1P(1) pathway may also be an effective therapeutic strategy for fibrotic lung diseases.

Topics: Animals; beta-Alanine; Bleomycin; Blood Coagulation; Endothelial Cells; Fibrosis; Fingolimod Hydrochloride; Humans; Lung Injury; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Oxadiazoles; Pneumonia; Propylene Glycols; Pulmonary Alveoli; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Survival Analysis; Thiophenes; Vascular Diseases

Glucocorticoids (GC) remain the first choice of treatment in asthma, but GC therapy is not always effective and is associated with side effects. In a porcine study in our laboratory, simultaneous administration of GC and nitric oxide (NO) attenuated the endotoxin-induced inflammatory response and made GC treatment more effective than inhaled NO or steroids alone. In the present study, we aimed to further investigate the interactions between NO and GC treatment in two murine models of asthma. Inflammation was induced by endotoxin, ovalbumin, or a combination of both. With an animal ventilator and a forced oscillation method (FlexiVent), lung mechanics and airway reactivity to methacholine in response to various treatments were assessed. We also describe histology and glucocorticoid receptor (GR) protein expression in response to inhaled NO treatment [40 ppm NO gas or NO donors sodium nitroprusside (SNP) or diethylamine NONOate (DEA/NO)]. SNP and GC provided protection against bronchoconstriction to a similar degree in the model of severe asthma. When GC-treated mice were given SNP, maximum airway reactivity was further reduced. Similar effects were seen after DEA/NO delivery to GC-treated animals. Using 1-H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor, we found this effect of NO donors to be mediated through a cGMP-independent mechanism. In the severe model, prolonged NO treatment restored or even increased the nuclear levels of GR. In conclusion, in our murine model of severe asthma GC treatment provided protection to only a limited degree against bronchoconstriction, while concomitant treatment with a NO donor was markedly more potent than the use of either NO or GC alone.

Topics: Administration, Inhalation; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Cyclic GMP; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucocorticoids; Guanylate Cyclase; Hydrazines; Hydrocortisone; Injections, Intraperitoneal; Lipopolysaccharides; Methacholine Chloride; Mice; Mice, Inbred BALB C; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Ovalbumin; Oxadiazoles; Pneumonia; Quinoxalines; Receptors, Cytoplasmic and Nuclear; Receptors, Glucocorticoid; Respiration, Artificial; Respiratory Mechanics; Soluble Guanylyl Cyclase

We investigated the pharmacology of a new class of phosphodiesterase 4 (PDE4) inhibitor, 6,8-disubstituted 1,7-naphthyridines, by using 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171) as a representative compound and compared its potency with the most advanced PDE4 inhibitor, undergoing clinical trials, Ariflo [cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexanecarboxylic acid)]. NVP-ABE171 inhibited the activity of phosphodiesterase 4A, 4B, 4C, and 4D with respective IC(50) values of 602, 34, 1230, and 1.5 nM. Ariflo was about 40 times less potent. In human cells, NVP-ABE171 inhibited the eosinophil and neutrophil oxidative burst, the release of cytokines by T cells, and the tumor necrosis factor-alpha release from monocytes, in the nanomolar range. Ariflo presented a similar inhibition profile but was 7 to 50 times less potent. In BALB/c mice challenged with lipopolysaccharide, NVP-ABE171 inhibited the airway neutrophil influx and activation with an ED(50) in the range of 3 mg/kg. Ariflo was inactive up to a dose of 10 mg/kg. In ovalbumin sensitized Brown Norway rats, NVP-ABE171 inhibited the lipopolysaccharide-induced airway neutrophil influx and activation (ED(50) of 0.2 mg/kg) and the ovalbumin-induced airway eosinophil influx and activation (ED(50) of 0.1 mg/kg). Ariflo was about 100 times less potent in both models. In the ovalbumin model, NVP-ABE171 had a duration of action of more than 24 h. NVP-ABE171 is a novel PDE4 inhibitor that shows activity both in vitro on human inflammatory cells and in vivo in animal models of lung inflammation. This compound class may have potential for the treatment of airway inflammatory conditions such as asthma and chronic obstructive pulmonary diseases.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; Caco-2 Cells; Cell Division; Cell Membrane Permeability; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Humans; Isoenzymes; Mice; Mice, Inbred BALB C; Naphthyridines; Neutrophils; Nitriles; Oxadiazoles; Phosphodiesterase Inhibitors; Pneumonia; Rats; Rats, Inbred BN; Respiratory Burst; Tumor Necrosis Factor-alpha

Topics: Antitussive Agents; Bronchial Diseases; Bronchitis; Bronchopneumonia; Hemopneumothorax; Humans; Influenza, Human; Lung Diseases; Oxadiazoles; Pleurisy; Pneumonia; Pneumonia, Viral; Respiratory Tract Infections; Tetracycline