Limits...
A crossover randomized comparative study of zofenopril and ramipril on cough reflex and airway inflammation in healthy volunteers.

Lavorini F, Chellini E, Innocenti M, Campi G, Egan CG, Mogavero S, Fontana GA - Cough (2014)

Bottom Line: Animal studies have shown that the ACE-i zofenopril has a less tussigenic effect compared to the widely used ACE-i ramipril.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Mean (±SD) Log values of the capsaicin (A, B) and the citric acid (C, D) concentration causing at least two (C2) and five (C5) coughs recorded in control conditions (pre-treatment, cross hatched bars) and after a 7-day treatment (filled bars) with zofenopril (blue bars) or ramipril (red bars) in 40 normal volunteers. *, p < 0.05; **, p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4308941&req=5

Fig1: Mean (±SD) Log values of the capsaicin (A, B) and the citric acid (C, D) concentration causing at least two (C2) and five (C5) coughs recorded in control conditions (pre-treatment, cross hatched bars) and after a 7-day treatment (filled bars) with zofenopril (blue bars) or ramipril (red bars) in 40 normal volunteers. *, p < 0.05; **, p < 0.01.

Mentions: With capsaicin, mean (±SD) control LogC2 values observed prior to zofenopril (0.81 ± 0.42 μM) and ramipril (0.78 ± 0.41 μM) administration did not significantly differ (Figure 1A). However, ramipril administration consistently lead to an increase in cough sensitivity following inhaled capsaicin, as shown by the significant reduction in LogC2 (0.33 ± 0.28 μM, p < 0.01) compared to control values. In contrast, zofenopril administration resulted in only a slight and non-significant decrease in capsaicin LogC2 (0.75 ± 0.40 μM).Overlapping results were observed with capsaicin LogC5 values (Figure 1B). Prior to drug administration, LogC5 values for zofenopril and ramipril controls were similar (1.4 ± 0.72 μM and 1.3 ± 0.63 μM, respectively); they were reduced to 1.3 ± 0.68 (non significant, [ns]) after zofenopril and to 0.45 ± 0.38 μM (p < 0.01) after ramipril treatment.Figure 1


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

Lavorini F, Chellini E, Innocenti M, Campi G, Egan CG, Mogavero S, Fontana GA - Cough (2014)

Mean (±SD) Log values of the capsaicin (A, B) and the citric acid (C, D) concentration causing at least two (C2) and five (C5) coughs recorded in control conditions (pre-treatment, cross hatched bars) and after a 7-day treatment (filled bars) with zofenopril (blue bars) or ramipril (red bars) in 40 normal volunteers. *, p < 0.05; **, p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308941&req=5

Fig1: Mean (±SD) Log values of the capsaicin (A, B) and the citric acid (C, D) concentration causing at least two (C2) and five (C5) coughs recorded in control conditions (pre-treatment, cross hatched bars) and after a 7-day treatment (filled bars) with zofenopril (blue bars) or ramipril (red bars) in 40 normal volunteers. *, p < 0.05; **, p < 0.01.
Mentions: With capsaicin, mean (±SD) control LogC2 values observed prior to zofenopril (0.81 ± 0.42 μM) and ramipril (0.78 ± 0.41 μM) administration did not significantly differ (Figure 1A). However, ramipril administration consistently lead to an increase in cough sensitivity following inhaled capsaicin, as shown by the significant reduction in LogC2 (0.33 ± 0.28 μM, p < 0.01) compared to control values. In contrast, zofenopril administration resulted in only a slight and non-significant decrease in capsaicin LogC2 (0.75 ± 0.40 μM).Overlapping results were observed with capsaicin LogC5 values (Figure 1B). Prior to drug administration, LogC5 values for zofenopril and ramipril controls were similar (1.4 ± 0.72 μM and 1.3 ± 0.63 μM, respectively); they were reduced to 1.3 ± 0.68 (non significant, [ns]) after zofenopril and to 0.45 ± 0.38 μM (p < 0.01) after ramipril treatment.Figure 1

Bottom Line: Animal studies have shown that the ACE-i zofenopril has a less tussigenic effect compared to the widely used ACE-i ramipril.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.

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.

No MeSH data available.


Related in: MedlinePlus