title: A crossover randomized comparative study of zofenopril and ramipril on cough reflex and airway inflammation in healthy volunteers.
abstract: 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 randomized 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 < 0.01) cough sensitivity to both tussigenic agents as assessed by C2. With citric acid, C5 values calculated after both ramipril and zofenopril administration were significantly (p < 0.05 and p < 0.01, respectively) lower than corresponding control values. With both ACE-i drugs, spontaneous cough was infrequently reported by subjects. Zofenopril/zofenoprilat PK analysis showed higher area under the curve of plasma concentration, τ values (ng/ml x h) than ramipril/ramiprilat (zofenopril vs. ramipril, 84.25 ± 34.47 vs. 47.40 ± 21.30; and zofenoprilat vs. ramiprilat, 653.67 ± 174.91 vs. 182.26 ± 61.28). Both ACE-i drugs did not affect BK plasma levels; in contrast, ramipril, but not zofenopril, significantly increased control FeNO values (from 24 ± 9.6 parts per billion [PPB] to 33 ± 16 PPB; p < 0.01).
  
  
  CONCLUSIONS
  Zofenopril has a more favourable profile when compared to ramipril as shown by a reduced pro-inflammatory activity and less impact on the cough reflex.
authors: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.
authors: Federico
authors: F
authors: Lavorini
authors: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.
authors: Elisa
authors: E
authors: Chellini
authors: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.
authors: Margherita
authors: M
authors: Innocenti
authors: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.
authors: Giacomo
authors: G
authors: Campi
authors: Primula Multimedia S.r.L., Via Giuseppe Ravizza 22/B, 56121 Pisa, Italy.
authors: Colin Gerard
authors: CG
authors: Egan
authors: Primula Multimedia S.r.L., Via Giuseppe Ravizza 22/B, 56121 Pisa, Italy.
authors: Selene
authors: S
authors: Mogavero
authors: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.
authors: Giovanni A
authors: GA
authors: Fontana
keywords: ACE-inhibitors; Airway inflammation; Cough; Ramipril; Zofenopril
references: Clin Pharmacokinet. 1996 Jul;31(1):47-64
references: 8827399
references: Curr Opin Allergy Clin Immunol. 2004 Aug;4(4):267-70
references: 15238791
references: Am J Respir Crit Care Med. 2009 Nov 15;180(10):923-8
references: 19729667
references: Ther Clin Risk Manag. 2011;7:459-71
references: 22162922
references: Expert Opin Pharmacother. 2004 Sep;5(9):1965-77
references: 15330734
references: Clin Cardiol. 2012;35(7):416-23
references: 22707187
references: Am Heart J. 1991 May;121(5):1319-30
references: 1850188
references: Am J Med. 1999 Dec 13;107(6A):11S-16S; discussion 16S-17S
references: 10628589
references: Eur Respir J. 2007 Jun;29(6):1256-76
references: 17540788
references: Lancet. 1987 Nov 14;2(8568):1116-8
references: 2890021
references: Naunyn Schmiedebergs Arch Pharmacol. 2010 Dec;382(5-6):455-61
references: 20848272
references: Arzneimittelforschung. 1999 Dec;49(12):992-6
references: 10635443
references: Clin Pharmacokinet. 1994 Jan;26(1):7-15
references: 8137599
references: Lung. 2010 Jan;188 Suppl 1:S53-61
references: 19760296
references: Cough. 2009 Mar 17;5:4
references: 19292930
references: Int J Clin Pract. 2000 May;54(4):255-60
references: 10912316
references: Expert Rev Cardiovasc Ther. 2012 Aug;10(8):973-82
references: 23030285
references: J Cardiovasc Pharmacol. 1989;14 Suppl 4:S46-52
references: 2483429
references: Circulation. 1998 Apr 14;97(14):1411-20
references: 9577953
references: Eur Respir J. 1994 Mar;7(3):467-71
references: 8013603
references: Chest. 2006 Jan;129(1 Suppl):169S-173S
references: 16428706
references: Hypertension. 2000 Dec;36(6):934-40
references: 11116103
references: Am J Respir Crit Care Med. 2005 Apr 15;171(8):912-30
references: 15817806
references: Cochrane Database Syst Rev. 2009 Jul 08;(3):CD006362
references: 19588387
references: Am J Cardiol. 2013 Jul 1;112(1):90-3
references: 23582628
references: Lancet. 2012 Nov 3;380(9853):1583-9
references: 22951084
references: J Cardiovasc Pharmacol Ther. 2010 Dec;15(4):384-92
references: 20924096