9^th Annual European Pharma Congress

Biography

Biography: Hussam AS Murad

Abstract

Statement of the Problem: Bronchial asthma affects about 150 million people all over the world. The inflammatory mediators released from eosinophils, T-helper 2 lymphocytes, airway epithelium, and airway smooth muscle contribute to chronic inflammation and remodeling. Airway remodeling leads to progressive decline of lung functions and it is steroid resistant, thus there is a need for new medications with better anti-remodeling effect. Phosphodiesterase (PDE)-4 inhibitors have anti-inflammatory and anti-remodeling properties. Roflumilast; a selective PDE-4 inhibitor; is approved as an add-on therapy for chronic obstructive pulmonary disease (COPD). The inflammation in COPD and severe asthma is neutrophilic while in asthma it is eosinophilic. Consequently, investigating effects of roflumilast in eosinophilic inflammation is beneficial. During exacerbation of murine acute asthma, roflumilast (oral and intratracheal) decreased airway macrophages, eosinophils, neutrophils, T-helper 2 cytokines, and hyperresponsiveness (AHR). In contrast, steroids failed to affect AHR or neutrophil numbers which are considered important parameters for exacerbations of human asthma. Addition of roflumilast to high-dose fluticasone in patients with uncontrolled asthma improved asthma possibly through affecting the neutrophilic component of the disease. Ability of roflumilast to reduce sputum eosinophils, neutrophils, and macrophages makes it of potential off-label use in asthma. In a lipopolysaccharide-induced inflammation model in Wistar rats, "inhaled" roflumilast N-oxide decreased neutrophils in the bronchoalveolar lavage fluid (BALF).  Thus "inhaled" roflumilast N-oxide could be as a useful alternative to oral roflumilast in airway disorders. Conclusion & Significance: Roflumilast (oral or inhalational) significantly decreases airway hyperresponsiveness, the elevated inflammatory mediators, the elevated BALF levels of matrix metalloproteinase-9 and its inhibitor (TIMP-1), and remodeling in both human asthma and animal asthma models. These benefits are due to its anti-inflammatory and anti-fibrotic effects.  Investigating the effects of a triple inhalation therapy consisting of roflumilast, corticosteroids, and long acting β₂ agonists in chronic asthma models is a point for research.