Background: Drug discovery needs better animal models to mimic human features of idiopathic pulmonary fibrosis (IPF). As we previously reported1, double intratracheal (i.t.) instillation of bleomycin (BLM) produces a more severe and diffuse fibrosis compare to the single BLM instillation in mice. Aim of the study: Nintedanib, a drug approved for IPF treatment, and Macitentan, and Prednisolone, that failed in clinical trials, have been used for the pharmacological validation of the lung fibrosis model induced by double BLM treatment Methods: C57BL/6 mice were challenged i.t. at day 0 and day 4 with BLM (1 mg/kg). At day 14, once fibrosis was well established, oral therapeutic dosing with Nintedanib (30 mg/kg), Macitentan (100 mg/kg) and Prednisolone (100 mg/kg BID) was started for 2 weeks. Masson's trichrome staining was used to stage the severity of fibrosis by Ashcroft score and to quantify % collagen content and % air area. Bronchoalveolar lavage fluid (BALF) was also sampled for cell count. Results: As expected, mice treated twice with BLM had a robust increase in the severity of fibrosis scores and collagen deposition. The Aschroft score, % collagen content and % air area were significantly lower (27%, 40%, and 40%, respectively) in the group treated therapeutically with Nintedanib . This was accompanied by a reduction of BALF inflammatory cell number (36%). Macitentan and Prednisolone did not show any effect on fibrosis nor on inflammation. Conclusions: The double BLM mouse model seems to recapitulate some of the features of human IPF and is able to respond selectively to clinically-approved drugs for IPF treatment 1-ERS London (UK) 2016. Session 559
The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a
Nasal continuous positive airway pressure (nCPAP) is a widely accepted technique of non-invasive respiratory support in spontaneously-breathing premature infants with respiratory distress syndrome (RDS). Surfactant administration techniques compatible with nCPAP ventilation strategy are actively investigated. Our aim is to set up and validate a respiratory distress animal model that can be managed on nCPAP suitable for surfactant administration techniques studies. Surfactant depletion was induced by bronchoalveolar lavages (BALs) on 18 adult rabbits. Full depletion was assessed by surfactant component analysis on the BALs samples. Animals were randomized into two groups: Control group (nCPAP only) and InSurE group, consisting of a bolus of surfactant (Poractant alfa, 200 mg/kg) followed by nCPAP. Arterial blood gases were monitored until animal sacrifice, 3 hours post treatment. Lung mechanics were evaluated just before and after BALs, at the time of treatment, and at the end of the procedure. Surfactant phospholipids and protein analysis as well as surface tension measurements on sequential BALs confirmed the efficacy of the surfactant depletion procedure. The InSurE group showed a significant improvement of blood oxygenation and lung mechanics. On the contrary, no signs of recovery were appreciated in animals treated with just nCPAP. The surfactant-depleted adult rabbit RDS model proved to be a valuable and efficient preclinical tool for mimicking the clinical scenario of preterm infants affected by mild/moderate RDS who spontaneously breathe and do not require mechanical ventilation. This population is of particular interest as potential target for the non-invasive administration of surfactant.
Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.
Postoperative atrial fibrillation (AF) is a complication of thoracic surgery for lung cancer, with a reported incidence that can run as high as 42%. Recently, it has been observed retrospectively that B-type natriuretic peptide predicts AF after cardiac surgery. We performed a prospective study to evaluate the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a marker for risk stratification of postoperative AF in patients undergoing thoracic surgery for lung cancer.We measured NT-proBNP levels in 400 patients (mean age, 62+/-10 years; 271 men) 24 hours before and 1 hour after surgery. The primary end point of the study was the incidence of postoperative AF. Overall, postoperative AF occurred in 72 patients (18%). Eighty-eight patients (22%) showed an elevated perioperative NT-proBNP value. When patients with either preoperatively or postoperatively elevated NT-proBNP were pooled, a greater incidence of AF was observed compared with patients with normal values (64% versus 5%; P<0.001). At multivariable analysis, adjusted for age, gender, major comorbidities, echocardiography parameters, pneumonectomy, and medications, both preoperative and postoperative NT-proBNP values were independent predictors of AF (relative risk, 27.9; 95% CI, 13.2 to 58.9; P<0.001 for preoperative NT-proBNP elevation; relative risk, 20.1; 95% CI, 5.8 to 69.4; P<0.001 for postoperative NT-proBNP elevation).Elevation of perioperative NT-proBNP is a strong independent predictor of postoperative AF in patients undergoing thoracic surgery for lung cancer. This finding should facilitate studies of therapies to reduce AF in selected high-risk patients.
