Angiotensin-converting Enzyme Inhibitor Zofenopril Research Articles

Extemporaneous combination therapy with amlodipine/zofenopril in hypertensive patients: a real-world data analysis in Italy

Objectives To provide clinical characteristics and to quantify the number of patients receiving the extemporaneous combination of the calcium channel blocker amlodipine and the angiotensin converting enzyme inhibitor zofenopril in a real-world setting. This evidence can provide a snapshot of the potential users of the two molecules in a single pill combination (SPC). Methods Retrospective observational study using data from the IQVIA Italian Longitudinal Patient Database. Adult patients firstly prescribed with amlodipine and zofenopril between 1 July 2011 and 30 June 2020 were identified and demographic and clinical characteristics were extracted. Treatment adherence was evaluated as proportion of days covered (PDC). The potential number of patients eligible for a SPC was calculated. Results A population of 2394 hypertensive patients, mean age of 68.6 years ±12.7, 52.6% male were treated with amlodipine and zofenopril. The majority of patients (54.5%) were low adherent (PDC <40%), 25.9% were intermediate adherent and only 19.6% were high adherent (>80%) to therapy. Around 42,500 adult hypertensive patients were estimated to be prescribed the extemporaneous combination in 2019 in Italy, being potentially eligible for treatment with amlodipine and zofenopril SPC. Conclusions The administration of the extemporaneous combination of zofenopril and amlodipine in hypertensive patients is a common practice in Italy. The development of a SPC can be a viable treatment option to simplify therapy and to increase adherence in hypertensive patients who are already on the two monotherapies in combination.

Hydrogen Sulphide Release via the Angiotensin Converting Enzyme Inhibitor Zofenopril Prevents Intimal Hyperplasia in Human Vein Segments and in a Mouse Model of Carotid Artery Stenosis

Hypertension is a major risk factor for intimal hyperplasia (IH) and re-stenosis following vascular and endovascular interventions. Preclinical studies suggest that hydrogen sulphide (H2S), an endogenous gasotransmitter, limits re-stenosis. While there is no clinically available pure H2S releasing compound, the sulfhydryl containing angiotensin converting enzyme inhibitor zofenopril is a source of H2S. Here, it was hypothesised that zofenopril, due to H2S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitors (ACEi) in reducing intimal hyperplasia. Spontaneously hypertensive male Cx40 deleted mice (Cx40-/-) or wild type (WT) littermates were randomly treated with enalapril 20 mg or zofenopril 30 mg. Discarded human vein segments and primary human smooth muscle cells (SMCs) were treated with the active compound enalaprilat or zofenoprilat. IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for seven days exvivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied invitro. Compared with control animals (intima/media thickness 2.3 ± 0.33 μm), enalapril reduced IH in Cx40-/- hypertensive mice by 30% (1.7 ± 0.35 μm; p= .037), while zofenopril abrogated IH (0.4 ± 0.16 μm; p < .002 vs. control and p > .99 vs. sham operated Cx40-/- mice). In WT normotensive mice, enalapril had no effect (0.9665 ± 0.2 μm in control vs. 1.140 ± 0.27 μm; p > .99), while zofenopril also abrogated IH (0.1623 ± 0.07 μm; p < .008 vs. control and p > .99 vs. sham operated WT mice). Zofenoprilat, but not enalaprilat, also prevented IH in human vein segments exvivo. The effect of zofenopril on carotid and SMCs correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the mitogen activated protein kinase and mammalian target of rapamycin pathways in SMCs and human vein segments. Zofenopril provides extra beneficial effects compared with non-sulfhydryl ACEi in reducing SMC proliferation and re-stenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension.

Efficacy of Zofenopril Alone or in Combination with Hydrochlorothiazide in Patients with Kidney Dysfunction.

Hypertension and kidney disease often coexist, further increasing the risk of future cardiovascular events. Treatment of hypertensive adults with an angiotensin converting enzyme inhibitor in case of concomitant kidney disease may slow disease progression. The third-generation liphophilic angiotensin converting enzyme inhibitor zofenopril, administered alone or combined with a thiazide diuretic, has proved to be effective in lowering blood pressure in hypertensive patients and to reduce the risk of fatal and non-fatal events in post-acute myocardial infarction and heart failure. In almost three-hundred hypertensive patients with kidney impairment zofenopril administered for 12 weeks showed a similar blood pressure-lowering effect irrespective of the stage of the disease, with larger effects in combination with a thiazide diuretic, particularly in patients with slightly or moderately impaired kidney function. In animal models, zofenopril produced a significant and long-lasting inhibition of kidney angiotensin converting enzyme inhibitor and prevented kidney morphological and functional alterations following kidney ischemia-reperfusion injury. Treatment of hypertensive patients for 18 weeks with a combination of zofenopril 30 mg and hydrochlorothiazide 12.5 mg resulted in a reduction in albumin creatinine ratio of 8.4 mg/g (49.6% reduction from baseline values) and no changes in glomerular filtration rate, variations in line with those obtained in the control group treated with a combination of irbesartan 150 mg and hydrochlorothiazide 12.5 mg. Thus, some preliminary evidence exists to support that relatively long-term treatment with the angiotensin converting enzyme inhibitor zofenopril alone or combined with hydrochlorothiazide is effective in controlling blood pressure and may confer some kidney protection due to ACE inhibition properties.

Effect of ACE inhibitors and AT1 receptor antagonists on pentylenetetrazole-induced convulsions in mice.

Experimental data show that some angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT(1) receptor antagonists that are normally used as antihypertensive drugs can exert anticonvulsant-like activity against audiogenic seizures. In the current study, a number of ACE inhibitors (captopril, enalapril, cilazapril, perindopril and zofenopril) and AT(1) antagonists (losartan, telmisartan and candesartan) were examined against pentylenetetrazole (PTZ)-induced seizures in mice. Captopril (50 mg/kg) administered intraperitoneally significantly raised the PTZ threshold (p < 0.05). The remaining drugs were not protective against PTZ-induced convulsions. The current study indicates that captopril decreases PTZ-evoked seizures in mice, which is an animal model of myoclonic convulsions.

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

BackgroundPersistent 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.MethodsForty 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.ResultsRamipril, 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).ConclusionsZofenopril has a more favourable profile when compared to ramipril as shown by a reduced pro-inflammatory activity and less impact on the cough reflex.

Capacities of the current angiotensin-converting enzyme inhibitor zofenopril in clinical practice: cardioprotective, anti-ischemic, and antiatherogenic effects

The given review discusses the use of angiotensin-converting enzyme (ACE) inhibitors in patients with cardiovascular diseases, including those with prior acute myocardial infarction. The paper places particular emphasis on the currently available ACE inhibitor zofenopril. It discusses its special pharmacological properties and considers its additional effects associated with cardioprotective, anti-ischemic, antiatherogenic effects. The review provides a rationale for the clinical efficacy of zofenopril and a possibility for its wider clinical application.

POTENTIAL OF THE MODERN ACE INHIBITOR ZOFENOPRIL IN CLINICAL PRACTICE: CARDIOPROTECTIVE, ANTI-ISCHEMIC, AND ANTIATHEROGENIC EFFECTS

The review discusses various aspects of angiotensin-converting enzyme (ACE) inhibitor therapy in patients with cardiovascular disease (CVD), including acute myocardial infarction (AMI). The focus is on the modern ACE inhibitor zofenopril, its specific pharmacological characteristics, and additional cardioprotective, anti-ischemic, and antiatherogenic effects. The existing evidence of clinical effectiveness of zofenopril and its potential for a wider use in clinical practice are also addressed.

Combination antihypertensive therapy in patients with arterial hypertension and coronary heart disease

The leading positions in the treatment of patients with arterial hypertension (AH) and coronary heart disease (CHD) are held by angiotensin-converting enzyme (ACE) inhibitors and beta-adrenoblockers (BAB), which have demonstrated their effectiveness in terms of improved patients’ survival. In patients with AH and CHD, the rational, pathogenetic pharmacotherapy using a combination of an ACE inhibitor zofenopril and a highly cardio-selective and vasodilating BAB nebivolol demonstrates antihypertensive and antiischemic action, decreases the risk of potential adverse cardio-metabolic effects, reduces the severity of endothelial dysfunction, and, consequently, improves quality of life.

Long-term treatment with sulfhydryl angiotensin-converting enzyme inhibition reduces carotid intima-media thickening and improves the nitric oxide/oxidative stress pathways in newly diagnosed patients with mild to moderate primary hypertension

Aim. Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated. Objectives. In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-L-arginine, and isoprostanes). Material and methods. In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosisrelated diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-L-arginine, and isoprostane levels were measured. Results. In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P b .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group. Conclusion. Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure–lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients. (Am Heart J 2008;156:1154.e1-1154.e8.)

Comparison Between Zofenopril and Ramipril in Combination With Acetylsalicylic Acid in Patients With Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction: Results of a Randomized, Double‐Blind, Parallel‐Group, Multicenter, European Study (SMILE‐4)

Angiotensin-converting enzyme inhibitors (ACEIs) are largely employed for treating patients with left ventricular dysfunction (LVD), but their efficacy may be negatively affected by concomitant administration of acetylsalicylic acid (ASA), with some difference among the different compounds. The interaction between ASA and the two ACEIs zofenopril and ramipril may result in a different impact on survival of cardiac patients, due to differences in the pharmacological properties of the two ACEIs. This phase IIIb, randomized, double-blind, parallel-group, multicenter, European study compared the safety and efficacy of zofenopril (60 mg/day) and ramipril (10 mg/day) plus ASA (100 mg/day), in 771 patients with LVD (clinical signs of heart failure or a left ventricular ejection fraction <45%) following acute myocardial infarction (AMI). The primary study end point was 1-year combined occurrence of death or hospitalization for cardiovascular causes. In the intention-to-treat population, the primary outcome was significantly reduced by zofenopril (n = 365) vs ramipril (n = 351) (odds ratio [OR]: 0.70, and 95% confidence interval [CI]: 0.51-0.96; P = 0.028) as a result of a decrease in cardiovascular hospitalization (OR: 0.64,95% CI: 0.46-0.88; P = 0.006). Mortality rate was not significantly different between the 2 treatments (OR: 1.51, 95% CI: 0.70-3.27; P = 0.293). Blood pressure values did not significantly change during the 1-year follow-up. N-terminal pro-brain natriuretic peptide levels were progressively reduced during the study, with no statistically significant between-treatment differences. Proportion of patients with deterioration of renal function during the study was similar between the 2 groups. Drug safety profile was comparable between treatments. In patients with LVD following AMI, the efficacy of zofenopril associated with ASA was superior to that of ramipril plus ASA, indicating some important clinical implications for the future use of ACEIs in patients with LVD or overt heart failure.

Zofenopril and incidence of cough: a review of published and unpublished data

ObjectiveCough is a typical side effect of angiotensin-converting enzyme (ACE) inhibitors, though its frequency quantitatively varies among the different compounds. Data on the incidence of cough with the lipophilic third-generation ACE inhibitor zofenopril are scanty and never systematically analyzed. The purpose of this paper is to give an overview on the epidemiology, pathophysiology, and treatment of ACE inhibitor-induced cough and to assess the incidence of cough induced by zofenopril treatment.MethodsPublished and unpublished data from randomized and postmarketing zofenopril trials were merged together and analyzed.ResultsTwenty-three studies including 5794 hypertensive patients and three studies including 1455 postmyocardial infarction patients exposed for a median follow-up time of 3 months to zofenopril at doses of 7.5–60 mg once-daily were analyzed. The incidence of zofenopril-induced cough was 2.6% (range 0%–4.2%): 2.4% in the hypertension trials (2.4% in the double-blind randomized studies and 2.4% in the open-label postmarketing studies) and 3.6% in the doubleblind randomized postmyocardial infarction trials. Zofenopril-induced cough was generally of a mild to moderate intensity, occurred significantly (P < 0.001) more frequently in the first 3–6 months of treatment (3.0% vs 0.2% 9–12 months), and always resolved or improved upon therapy discontinuation. Zofenopril doses of 30 mg and 60 mg resulted in significantly (P = 0.042) greater rate of cough (2.1% and 2.6%, respectively) than doses of 7.5 mg and 15 mg (0.4% and 0.7%, respectively). In direct comparison trials (enalapril and lisinopril), incidence of cough was not significantly different between zofenopril and other ACE inhibitors (2.4% vs 2.7%).ConclusionEvidence from a limited number of studies indicates a relatively low incidence of zofenopril-induced cough. Large head-to-head comparison studies versus different ACE inhibitors are needed to highlight possible differences between zofenopril and other ACE inhibitors in the incidence of cough.

ARE THERE DIFFERENCES BETWEEN ZOFENOPRIL AND NEBIVOLOL EFFECT ON BLOOD PRESSURE, SERUM LEPTIN, ADIPONECTIN AND ENDOTHELIN-1 IN OBESE HYPERTENSIVE PATIENTS?: PP.33.330

Purpose: To compare the effect of zofenopril (Z) and nebivolol (N) on blood pressure (BP), serum leptin, adiponectin and endothelin-1 in obese hypertensive patients. Methods: 61 pts (f – 27, m – 34, mean age 51,6 ± 9,7 years) with essential hypertension (EH) and obesity (body mass index 34,3 ± 4,8 kg/m2) were enrolled in randomized, open-labeled study. We performed the oral glucose tolerance test, the office measurement and 24-hours ambulatory blood pressure monitoring (ABPM), test of serum leptin, adiponectin, endothelin-1 before and after 12 weeks therapy by Z (30 mg/day, 31 pts) and N (5 mg/day, 29 pts). Results: In obese hypertensives mean office BP was 150,2 ± 14,6/92,1 ± 10,8 ììHg before treatment. According ABPM there was abnormal circadian profile of BP in 63,9% of pts. The impaired glucose tolerance was revealed in 47,5% of pts. The endothelin-1 hyperactivity was defined in obese hypertensives in comparison with control group (normal weight hypertensives, n = 20) - 0,38 (0,25; 0,89) and 0,30 (0,25; 0,59) fmol/ml accordingly (p < 0,05). Office BP was decreased on 16,3/5,8 mmHg (p < 0,05) and 16,4/11,4 ììHg (p < 0,05) after 12 weeks of Z (37,5 mg/d) and N (7,5 mg/d) treatment. ABPM parameters have significantly improved: mean daytime SBP on 8,0 and 5,0 ììHg, mean daytime DBP on 4,3 and 6,2 ììHg, mean nighttime SBP on 12,3 and 6,0 ììHg, mean nighttime DBP on 7,2 and 5,0 ììHg, mean daily SBP on 9,0 and 5,1 ììHg, mean daily DBP on 4,5 and 5,4 ììHg (p<0,05 in al cases) with improvement of circadian BP profile. The serum leptin was decreased from 18,7 to 17,5 ng/ml (p < 0,05) in Z group, the serum adiponectin was increased from 10,4 to 13,6 mcg/ml (p < 0,05). The serum endothelin-1 was decreased significantly in N on 0,10 fmol/ml (p<0,05) and non significantly in Z group. Conclusions: In obese hypertensives both the angiotensin-converting enzyme inhibitor zofenopril and β1-adrenoblocker nebivolol demonstrates similar antihypertensive activity but different beneficial effects on adipokynes profile.

ACE inhibition and protection from doxorubicin-induced cardiotoxicity in the rat

The angiotensin converting enzyme inhibitor zofenopril has been shown to possess cardioprotective effects toward myocardial damage induced by chronic doxorubicin treatment in the rat. In the present study we have investigated the relationship between cardioprotection exerted by 2 angiotensin converting enzyme inhibitors (zofenopril and lisinopril) and degree of inhibition of cardiac versus serum angiotensin converting enzyme. Both zofenopril and lisinopril produced a dose-dependent inhibition of serum and cardiac angiotensin converting enzyme in rats (0.1, 1 or 10 mg/kg/day in the diet for 1 week). However, zofenopril at 0.1 mg/kg/day showed a significantly ( P < 0.05) greater inhibition of angiotensin converting enzyme in the myocardium than in the serum ( Δ about 20%). Using dose levels (0.1 mg/kg/day and 10 mg/kg/day) which inhibits partially (about 50%) or almost totally (about 80%) serum angiotensin converting enzyme, we evaluated the effects of zofenopril and lisinopril in preventing cardiac alterations (QαT prolongation) induced by chronic treatment with doxorubicin (1.5 mg/kg q7dx5 i.v.). Zofenopril, at a dose level (0.1 mg/kg/day) that did not affect haemodynamics and only partially inhibits serum angiotensin converting enzyme activity, almost totally prevent the QαT lengthening induced by doxorubicin, whereas lisinopril was ineffective at this dose level. At the higher dose level (10 mg/kg/day), both angiotensin converting enzyme inhibitors totally prevented the electrocardiographic alteration induced by chronic doxorubicin administration. Cardioprotection exerted by zofenopril at a dose level that partially inhibits serum angiotensin converting enzyme without affecting haemodynamics, suggests that inhibition of cardiac angiotensin converting enzyme and additional cardioprotective mechanism(s) may have a role in its ability to prevent myocardial damages in the rat subjected to chronic anthracycline treatment.

Long-term treatment with sulfhydryl angiotensin-converting enzyme inhibition reduces carotid intima-media thickening and improves the nitric oxide/oxidative stress pathways in newly diagnosed patients with mild to moderate primary hypertension

Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated. In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostanes). In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosis-related diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostane levels were measured. In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P < .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group. Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure-lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients.

Application of an angiotensin)converting enzyme inhibitor zofenopril in patients with paroxismal form of atrial fibrillation

In article the received data of pilot research of application of an angiotensin-converting enzyme inhibitor zofenopril in patients with paroxismal form of atrial fibrillation without structural diseases of heart are submitted. It is shown, that prescription of zofenopril in this category of patients is an effective and safe method of treatment. Probable mechanisms of positive influence of a preparation on current of an arrhythmia are discussed.

Effects of zofenopril on myocardial ischemia in post–myocardial infarction patients with preserved left ventricular function: The Survival of Myocardial Infarction Long-term Evaluation (SMILE)–ISCHEMIA study

The aim of the study was to investigate the cardioprotective effects of the angiotensin-converting enzyme inhibitor zofenopril in post-myocardial infarction (MI) patients with preserved left ventricular function (LVF). Three hundred forty-nine post-MI patients with preserved LVF (LV ejection fraction >40%) were treated for 6 months with zofenopril 30 to 60 mg (n = 177) or placebo (n = 172) according to a double-blind, randomized study design. The primary end point of the study was the combined occurrence of significant ST-T abnormalities on ambulatory electrocardiography (ECG), ECG abnormalities or symptoms of angina during standard exercise test, recurrence of MI, and need for revascularization procedures for angina. The primary end point occurred in 20.3% of zofenopril-treated and 35.9% of placebo-treated patients (P = .001), despite no differences in blood pressure control, LVF, and concomitant therapy. ST-T depression during ambulatory ECG occurred in 22.7% of patients treated with placebo and 10.7% of those undergoing ACE-inhibition treatment (P = .027). ST-T depression in response to exercise test occurred in 14.2% and 26.7% of patients treated with zofenopril or placebo, respectively, (P = .024), with a lower proportion of zofenopril-treated patients who complained of anginal pain (4.7 vs 14.3%; P = .017), significant ST depression (14.2 vs 26.7%; P = .024), and major ventricular arrhythmias (3.8 vs 10.5%; P = .048). The rate of major cardiovascular events was reduced in patients treated with ACE inhibitor, with a lower rate of development and progression of congestive heart failure. The results of the SMILE-ISCHEMIA study support the cardioprotective role of zofenopril when given to patients with normal LVF after acute MI.

Use of the ACE inhibitor zofenopril in the treatment of ischemic heart disease

Zofenopril, an inhibitor of the angiotensin-converting enzyme (ACE), has recently been widely introduced into the pharmaceutical market. Its clinical safety and efficacy has been demonstrated in patients with hypertension and in patients with acute myocardial infarction (AMI). The Survival of Myocardial Infarction Long-term Evaluation (SMILE) project provided valuable information regarding the safety of early onset ACE inhibition with zofenopril after AMI and a greater perception of the early and late benefits. The SMILE-I study demonstrated that most benefits of ACE inhibition may be obtained early after AMI and persist after discontinuation of treatment. The SMILE-II study demonstrated that early zofenopril treatment (initiated <12 h) is safe and associated with a low rate of severe hypotension in thrombolyzed patients with acute myocardial infarction when administered in accordance with an adequate dose-titration scheme. Many other studies of clinical ACE-inhibitors (ACEIs) over the last 30 years have provided us with information in order to understand the effects of ACEIs and have demonstrated that patients benefit from ACEI treatment at different stages of the pathophysiological continuum of cardiovascular diseases. The current guidelines recommend that ACEIs should be used for routine secondary prevention in all patients with coronary artery disease and should be considered for all other patients with coronary or other vascular disease unless contraindicated.

Antiischemic and antiarrhytmic effects of angiotensin-converting enzyme inhibitor zofenopril in the rat model of acute myocardial ischemia

Angiotensin-converting enzyme (ACE) inhibitors are widely used in heart failure therapy, but little is known about their antiischemic effccts. The primary aim of this study was to investigate antiischemic effectiveness of SH-containing ACE inhibitor zofenopril in rats in comparison to captopril. The results provide an evidence that zofenopril, in contrast to captopril, reduces infarct size when administered intravenously at a dose of 2,5 mg/kg 30 minutes before ischemia. Antiischemic effect of zofenopril may be due to its high affinity to myocardial tissue. Unlike captopril, zofenopril exerted significant antiarrhythmic effect against ischemic ventricular tachyarrhytmias. Antiischemic effect of zofenopril was evident at a relatively high dose only and, therefore, was associated with considerable hypotensive effect.

Sulfhydryl angiotensin-converting enzyme inhibition induces sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential hypertension

Background Essential hypertension is associated with enhanced LDL oxidation and impaired endothelium-dependent vasodilation. The antioxidant status is linked to the nitric oxide (NO) pathway. Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors inhibit oxidative stress and atherogenesis in experimental models; therefore we tested whether this beneficial antioxidant activity could be also clinically relevant in patients with essential hypertension. Methods Plasma LDL oxidizability was investigated initially in untreated normocholesterolemic patients with moderate essential hypertension without clinically evident target organ damage (n = 96) and in control normotensive subjects (n = 46). Patients were then randomly assigned into two age- and sex-matched groups to receive the new sulfhydryl ACE inhibitor zofenopril (15 to 30 mg/d; n = 48) or enalapril (20 mg/d, n = 48). LDL oxidizability was evaluated (generation of malondialdehyde, MDA) and systemic oxidative stress was evaluated by isoprostanes (8-isoPGF 2α). Asymmetrical dimethyl- l-arginine (ADMA), a competitive inhibitor of endothelial NO synthase, and plasma nitrite and nitrates (NOx) were also measured. Results LDL from hypertensive subjects had enhanced susceptibility to oxidation in vitro compared with that in control subjects ( P < .05). Similarly, isoprostanes were significantly increased ( P < .01) in hypertensive subjects versus control subjects. After 12-week treatment, MDA levels were significantly reduced by zofenopril ( P < .05) but not enalapril treatment ( P = not significant). Isoprostanes were normalized after zofenopril treatment ( P < .03), whereas enalapril was ineffective. After treatment with both ACE inhibitors, plasma NOx concentrations were significantly reduced ( P < .05). Similarly, hypertension increased ADMA concentration compared with the normotensive state, whereas ACE inihibition elicited a significant decrease. However, the reduction of ADMA concentration was significantly higher in patients receiving sulfhydryl ACE inhibition ( P < .05 vs enalapril). Conclusions The sulfhydryl ACE inhibitor zofenopril reduces oxidative stress and improves the NO pathway in patients with essential hypertension. If confirmed in a large multicenter clinical trial, our data suggest a possible vasculoprotective effect of the compound in retarding vascular dysfunction and atherogenesis that often develops rapidly in hypertensive patients.

The effect of angiotensin-converting enzyme inhibition on endothelial function and oxidant stress

Angiotensin-converting enzyme (ACE) inhibitors effectively interfere with the renin–angiotensin system and exert various beneficial actions on vascular structure and function beyond their blood pressure-lowering effects. Data from experimental studies showed that angiotensin-converting enzyme inhibitors can attenuate the development of atherosclerosis in a wide range of species. The postulated mechanisms of this atheroprotective effect are the antioxidant actions of angiotensin-converting enzyme inhibitors and their enhancement of the endothelial elaboration of bioactive nitric oxide. The aim of this study was to assess the comparative effects of three angiotensin-converting enzyme inhibitors on endothelial nitric oxide production and action, and on endothelial oxidative stress. Using bovine aortic endothelial cells in culture grown to confluence, we examined the effects of 1, 10, 30 and 60 μM of each of captopril, zofenopril and enalapril on nitrite/nitrate accumulation in the media, cyclic GMP accumulation in the cell lysate, and F 2-isoprostanes in lipid extracts from the cells. Results showed that the sulfhydryl angiotensin-converting enzyme inhibitor zofenopril has unique properties compared with captopril and enalapril. This compound improves nitric oxide production and bioactivity, and does so in conjunction with decreased endothelial cell oxidant stress. The biochemical basis for this protective mechanism is not entirely clear; however, these actions suggest that zofenopril may reduce endothelial effects of risk factors for atherothrombotic disease.