A crossover randomized comparative study of zofenopril and ramipril on cough reflex and airway inflammation in healthy volunteers (Cough)

Background: Persistent dry cough is a well known unwanted effect of Angiotensin-Converting Enzyme inhibitors (ACE-i). Animal studies have shown that the ACE-i zofenopril has a less tussigenic effect compared to the widely used ACE-i ramipril. The aim of this study was to compare cough sensitivity to inhaled tussigens, as well as spontaneous cough in response to the administration of zofenopril and ramipril in healthy volunteers; pharmacokinetic (PK) data of both zofenopril and ramipril, as well as their respective active forms, zofenoprilat and ramiprilat, was also collected. Methods: Forty healthy volunteers were enrolled in a randomised crossover study. Patients were administered zofenopril calcium salt (test drug) coated tablets, 30?mg daily dose or ramipril (reference drug) tablets, 10?mg daily dose, for 7 consecutive days in two periods separated by a 21-day wash-out period. Cough sensitivity to capsaicin and citric acid was assessed as the concentration of each tussigenic agent causing at least 2 (C2) or 5 coughs (C5); spontaneous cough was also monitored throughout the study. PK parameters of zofenopril, ramipril and their active forms, were collected for each of the two study periods. Airway inflammation, as assessed by fractional exhaled nitric oxide (FeNO) and bradykinin (BK) levels, were measured prior to and following each treatment period. Results: Ramipril, but not zofenopril, increased (p?