Introduction
Angiotensin-Converting Enzyme inhibitors (ACE-i) were originally developed to target hypertension but now have additional clinical indications such as congestive heart failure, left ventricular dysfunction, atherosclerotic vascular disease and diabetic nephropathy [
1]. It is purported that they alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin (BK) and alter the metabolism of a number of other vasoactive substances [
1].
Zofenopril is indicated for the treatment of mild to moderate essential hypertension and of patients with acute myocardial infarction [
2]. After oral administration, zofenopril is completely absorbed and converted into its active metabolite, zofenoprilat, which reaches peak blood levels after 1.5 h [
3]. The plasma ACE activity is suppressed by 74.4% at 24 h after administration of single oral doses of 30 mg zofenopril calcium, the usual effective daily dose.
Ramipril is indicated for the treatment of hypertension, symptomatic heart failure, mild renal disease, for cardiovascular prevention and secondary prevention after acute myocardial infarction. Based on urinary recovery, the extent of absorption is at least 56%. Peak plasma concentrations of ramiprilat, the sole active metabolite of ramipril, are reached 2-4 h after intake. The peak antihypertensive effect of a single dose is usually reached 3-6 h after oral administration and usually lasts for 24 h [
4].
Dry, persistent cough is a well-recognized side effect of ACE-i, the mechanism of which is not completely understood [
5]. The incidence of ACE-i induced cough is variable, and ranges between 3-35% among various studies [
5],[
6]. Interestingly, some lines of evidence seem to suggest that coughing induced by the ACE-i zofenopril has a lower prevalence compared to other ACE-i [
5]. The inflammatory mediators BK and substance-P are known to be involved, since they accumulate in the upper respiratory tract or lung after the enzyme is inhibited and fails to degrade them [
6]. BK also stimulates the production of prostaglandins which, when accumulating, also seem to induce cough [
6].
A study performed on guinea pigs showed that zofenopril administration did not increase citric-acid induced cough, as opposed to ramipril, which augmented it by 40-60% [
7]. Similar results were obtained in rabbits, where ramipril, but not zofenopril, increased the cough response induced by both mechanical and chemical airway stimulation [
8].
The aim of this study was to assess changes in the sensitivity of the cough reflex, both spontaneous and induced by tussigens, in healthy volunteers administered with zofenopril and ramipril. This analysis was coupled with the analysis of the pharmacokinetics (PK) of the two administered drugs, the collection of airway inflammation data by means of a simple, non invasive method such as the measurement of the fractional exhaled nitric oxide (FeNO) and the assessment of serum BK.
Discussion
The main findings from this study suggest that short-term administration of therapeutic doses of zofenopril and ramipril have a different impact on the functionality of the cough reflex, with ramipril markedly affecting the cough sensitivity – as assessed in terms of C2 and C5 - to both capsaicin and citric acid, whereas zofenopril provoked only a minimal, albeit significant, decrease in citric acid C5. These results reinforce and extend similar observations previously obtained in animal models [
7],[
8] and in healthy volunteers [
14]. Although coughing is a well recognized, unwanted effect of ACE-i drugs [
6], the mechanism by which these agents cause cough remains unclear. The effect may be related to a cascade of effects beginning with the accumulation of kinins, followed by arachidonic acid metabolism and the production of nitric oxide [
15]. ACE inhibition can block BK dehydrogenase, the enzyme responsible for BK breakdown, and may lead to the accumulation of BK in the airways. BK has many local effects, including the release of histamine from mast cells, and also interferes with locally produced neurotransmitters, such as substance-P and neuropeptide-Y which are released by vagal C-fibres and are known to have irritant effects on the bronchial mucosa and increase cough responses [
8]. Another factor that has been reported to be involved in cough induction is prostaglandin synthesis in the airways, since prostaglandins act locally as inflammatory agents [
16]. Prostaglandin E2 stimulates airway sensory fibres possibly involved in cough mediation (as does BK), resulting in cough [
17]. On the other hand, treatment with a prostaglandin synthetase inhibitor may alleviate cough in affected patients [
18].
Other factors that may explain the observed differences between zofenopril and ramipril in inducing cough reflex may be attributed to differences in the pharmacokinetic profiles and differences in the ability of tissue and blood esterases to hydrolyse their active metabolites, zofenoprilat and ramiprilat respectively [
19],[
20]. In this regards, a previous study has shown that the ramiprilat-ACE complex is very stable and dissociates more slowly compared with complexes formed by the enzyme and other ACE inhibitors [
21].
Spontaneous cough after either ACE-i drugs was infrequently reported by subjects, likely because it may take weeks or even months to develop ACE-i-associated cough [
5].
In the present study, BK levels did not differ after administration of zofenopril or ramipril; thus the less tussigenic property of zofenopril compared to ramipril cannot be explained by the elevated BK levels following ACE-i administration. However, as shown in a previous in-vivo study [
22], the capability of zofenopril to stimulate the production of prostaglandins, either directly or by inhibiting BK metabolism, is less than that of other ACE-i.
It has also been previously shown that in normotensive volunteers enalapril is capable of increasing FeNO within a few hours [
23]. Furthermore, it is unclear whether ‘ACEi-induced cough’ as a clinical problem is directly related to changes in FeNO, as the effects were not directly evaluated in hypertensive patients, but only in healthy volunteers. Evidence suggests that hypertensive patients have reduced baseline FeNO levels [
23],[
24] and did not show FeNO increase in response to enalapril administration, unlike normotensive subjects [
23]. Additional studies in hypertensive subjects are still needed to clarify this.
It is likely that the activation of sensory airway terminal by ACE-i agents may result in an enhancement of the cough reflex and, eventually, in a decrease of the stimulus intensity required to evoke cough, thus explaining the present findings of an increased cough sensitivity in normal subjects under treatment with therapeutic doses of ramipril. The fact that zofenopril affected cough sensitivity to a much lesser extent compared to ramipril is in keeping with the notion of a less pronounced stimulatory effect on prostaglandin production and/or inhibitory activity on BK breakdown by zofenopril [
7]. Further studies on the co-administration of an ACE-i and a COX inhibitor could help clarify the tussigenic role of prostaglandins with and without ACE-i.
To our knowledge, this is the first study to evaluate airway inflammation, as detected by a non invasive method such as the assessment of FeNO, in normal subjects undergoing short-term treatment with ACE-i. Results show that ramipril, but not zofenopril, causes airway inflammation. The same mechanisms as for cough induction may also be invoked to account for a lack of any significant change in FeNO observed following zofenopril, but not ramipril administration in our subjects. Again, this finding points to the possibility that these agents must have a different impact on arachidonic acid metabolism and BK breakdown.
In the present study we examined AUCss,τ values and these were quantitatively higher with zofenopril/zofenoprilat compared to ramipril/ramiprilat. These data suggest that a longer lasting activity is to be expected with zofenopril.
This study performed in normal subjects was planned and carried out following the crossover two-treatment, two-sequence, two-product design. This meant that all subjects experienced both treatments, and the crossover guaranteed a good degree of comparison of the two ACE-i, namely zofenopril, test drug, and ramipril, reference drug in this study.
A limitation of the present study is the absence of a placebo arm, and the question arises as to whether the observed differences in cough sensitivity and airway inflammation after ACE-i treatments are a true treatment effect. A placebo effect has been observed in several cough clinical trials, and up to 85% of the efficacy of some cough medicines can be attributed to a placebo effect [
25]. However, the presence of significant plasma concentration levels of both ACE-i drugs points at the possibility that the results obtained in the present study are related to treatment, rather than to a placebo effect.
In conclusion, findings of the present study suggest that zofenopril possesses a more favourable therapeutic profile when compared to ramipril, mainly consisting of a lower impact on the sensitivity of the cough reflex, as detected by widely used laboratory methods, and lack of a significant pro-inflammatory action at the level of the airways. The more tolerable profile of zofenopril is coupled with an equivalent or even better efficacy than ramipril in the prevention and treatment of cardiovascular diseases, as evidenced by several head-to-head trials [
26]-[
28].
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
FL and GAF designed the study, participated in the experiments and wrote the manuscript. EC, MI and GC enrolled subjects and patients and assisted in data analysis and interpretation. SM and CGE participated in the presentation of data and writing of the manuscript. All authors read and approved the final manuscript.