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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

Pooled plasma-concentration/time profiles of zofenopril/ramipril (A) and zofenoprilat/ramiprilat (B) obtained in 40 volunteers. Data presented as mean ± SD.
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Fig2: Pooled plasma-concentration/time profiles of zofenopril/ramipril (A) and zofenoprilat/ramiprilat (B) obtained in 40 volunteers. Data presented as mean ± SD.

Mentions: At baseline, plasma zofenopril or ramipril and their respective active forms (zofenoprilat/ramiprilat) were not detected (Figure 2); the time course of plasma concentration after administration of either zofenopril or ramipril was qualitatively similar for both drugs and their respective active forms (Figure 2). Mean (±SD) AUCss,τ values (ng/ml x h) were 84.25 ± 34.47 for zofenopril, 653.67 ± 174.91 for zofenoprilat, 47.40 ± 21.30 for ramipril, and 182.26 ± 61.28 for ramiprilat. Both test and reference drugs Cmin was 0, whereas traces of the active compounds were found, with Cmin values for zofenoprilat and ramiprilat being 1 ± 1.29 and 1.25 ± 0.39 respectively.Figure 2


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)

Pooled plasma-concentration/time profiles of zofenopril/ramipril (A) and zofenoprilat/ramiprilat (B) obtained in 40 volunteers. Data presented as mean ± SD.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Pooled plasma-concentration/time profiles of zofenopril/ramipril (A) and zofenoprilat/ramiprilat (B) obtained in 40 volunteers. Data presented as mean ± SD.
Mentions: At baseline, plasma zofenopril or ramipril and their respective active forms (zofenoprilat/ramiprilat) were not detected (Figure 2); the time course of plasma concentration after administration of either zofenopril or ramipril was qualitatively similar for both drugs and their respective active forms (Figure 2). Mean (±SD) AUCss,τ values (ng/ml x h) were 84.25 ± 34.47 for zofenopril, 653.67 ± 174.91 for zofenoprilat, 47.40 ± 21.30 for ramipril, and 182.26 ± 61.28 for ramiprilat. Both test and reference drugs Cmin was 0, whereas traces of the active compounds were found, with Cmin values for zofenoprilat and ramiprilat being 1 ± 1.29 and 1.25 ± 0.39 respectively.Figure 2

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