Zofenopril 30mg tablets

BACKGROUND: Oxidative stress is increased in hyperuricemic patients with acute myocardial infarction (AMI). Use of sulfhydryl ACE-inhibitors (ACEIs), such as zofenopril or captopril, plus xanthine oxidase inhibitors (XOIs), may potentially result in enhanced antioxidant effects and improved survival. OBJECTIVE: We verified the benefit of such combination in a randomly stratified sample of 525 of the 3630 post-AMI patients of the four randomized prospective SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies. METHODS: One hundred sixty-five (31.4%) patients were treated with XOIs (79 under zofenopril, 86 placebo, lisinopril or ramipril), whereas 360 were not (192 zofenopril, 168 placebo or other ACEIs). In these four groups, we separately estimated the 1-year combined risk of major cardiovascular events (MACE, death or hospitalization for cardiovascular causes). RESULTS: MACE occurred in 10.1% of patients receiving zofenopril + XOIs, in 18.6% receiving placebo or other ACEIs + XOIs, in 13.5% receiving zofenopril without XOIs and in 22.0% receiving placebo or other ACEIs, but no XOIs (p = 0.034 across groups). Rate of survival free from MACE was significantly larger under treatment with zofenopril + XOIs than with other ACEIs with no XOIs [hazard ratio: 2.29 (1.06-4.91), p = 0.034]. A non-significant trend for superiority of zofenopril + XOIs combination was observed vs. zofenopril alone [1.19 (0.54-2.64), p = 0.669] or vs. placebo or other ACEIs + XOIs [1.82 (0.78-4.26), p = 0.169]. CONCLUSIONS: Our retrospective analysis suggests an improved survival free from MACE in post-AMI patients treated with a combination of an urate lowering drug with antioxidant activity and an ACEI, with best effects observed with zofenopril.

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In the Survival of Myocardial Infarction Long-term Evaluation (SMILE) 1, 3, and 4 studies, early administration of zofenopril in acute myocardial infarction showed to be prognostically beneficial versus placebo or ramipril. The SMILE-2 showed that both zofenopril and lisinopril are safe and showed no significant differences in the incidence of major cardiovascular (CV) complications. In this pooled analysis of individual data of the SMILE studies, we evaluated whether the superior efficacy of zofenopril is maintained also in patients with ≥1 CV risk factor (CV+, n = 2962) as compared to CV- (n = 668). The primary study end point was set to 1-year combined occurrence of death or hospitalization for CV causes. The risk of CV events was significantly reduced with zofenopril versus placebo either in the CV+ (-37%; hazard ratio: 0.63; 95% confidence interval: 0.51-0.78; P = 0.0001) or in the CV- group (-55%; hazard ratio: 0.45; 0.26-0.78; P = 0.004). Also, the other angiotensin-converting enzyme inhibitors reduced the risk of major CV outcomes, though the reduction was not statistically significant versus placebo (CV+: 0.78; 0.58-1.05; P = 0.107; CV-: 0.71; 0.36-1.41; P = 0.334). The benefit was larger in patients treated with zofenopril than other angiotensin-converting enzyme inhibitors, with a statistically significant difference for CV+ (0.79; 0.63-0.99; P = 0.039) versus CV- (0.62; 0.37-1.06; P = 0.081). In conclusion, zofenopril administered to patients after acute myocardial infarction has a positive impact on prognosis, regardless of the patient's CV risk profile.

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Zofenopril is a lipophilic, sulfhydryl group-containing angiotensin-converting enzyme (ACE)-inhibitor, characterized by wide tissue distribution, long duration of action, and pleiotropic effects on endothelial dysfunction. Its clinical efficacy and safety have been described in the four randomized controlled trials of the SMILE program, which globally enrolled more than 3600 patients in post-acute myocardial infarction (AMI) setting. The SMILE-4 study specifically selected patients with left ventricular dysfunction at admission, and compared the effects of zofenopril or ramipril in combination with acetylsalicylic acid (ASA). Zofenopril demonstrated its superiority over ramipril in reducing the combined occurrence of death or hospitalization for cardiovascular causes both in the overall population included in the original study and in subgroups of patients at highest risk, namely hypertensive and diabetic subjects. The effects of the early treatment with zofenopril were sustained over time, and, after 5 years of follow-up, zofenopril increased the survival likelihood and reduced the hospitalization rate. Compared to ramipril, zofenopril was cost-effective with a number to treat of 13 and an incremental cost-effectiveness ratio (ICER) of 2125.45 euros for any additional event prevented. Furthermore, in real-world settings, zofenopril decreased the risk of death in patients with heart failure, particularly in men, and in subjects older than 76 years or with ejection fraction lower than 54%. These results support the early use of zofenopril immediately after AMI, even in the presence of comorbidities, and its maintenance over time to reduce the risk of heart failure. FUNDING: Menarini International Operations Luxembourg S.A.

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The extensive use of angiotensin-converting enzyme inhibitors (ACEIs) as antihypertensive agents and the huge amount of data collected in clinical trials and post-marketing studies has allowed the extending of the indication of ACEIs beyond blood pressure control. Current guidelines recommend ACEIs in symptomatic patients with heart failure with reduced ejection fraction to decrease the risk of heart failure hospitalization, and also in patients after acute myocardial infarction (AMI) with ST-elevation with or without post-AMI ventricular dysfunction. Analyzing the association between the choice of an ACEI after AMI with the risk of mortality and re-infarction, a class effect, rather than the superiority of some agents, has been described. The focus of this review is centered on the role of ACEIs in addition to and beyond blood pressure control. It summarizes clinical evidence on the use of these agents in cardiovascular diseases, with a specific interest in the experience with zofenopril, which presents a peculiar pharmacological profile that may contribute to additional clinical benefits in some identifiable populations of patients. Indeed, the presence of a sulfhydryl group in its structure confers on zofenopril high anti-oxidant and anti-ischemic properties involving the activation of the H2S system, resulting in a cardioprotective effect. The efficacy and safety of zofenopril have been extensively evaluated and proved in the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) program in numerous clinical settings. The pharmacological features and ancillary characteristics of zofenopril with potent cardioprotective effects seem to differentiate it from other ACEIs and to confer further benefits to patients.

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Combinations between an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ) are among the recommended treatments for hypertensive patients uncontrolled by monotherapy. Four randomized, double-blind, parallel group studies with a similar design, including 1469 hypertensive patients uncontrolled by a previous monotherapy and with ≥1 cardiovascular risk factor, compared the efficacy of a combination of a sulfhydryl ACE inhibitor (zofenopril at 30 or 60 mg) or an ARB (irbesartan at 150 or 300 mg) plus HCTZ 12.5 mg. The extent of blood pressure (BP)-lowering was assessed in the office and over 24 h. Pleiotropic features of the treatments were evaluated by studying their effect on systemic inflammation, organ damage, arterial stiffness, and metabolic biochemical parameters. Both treatments similarly reduced office and ambulatory BPs after 18-24 weeks. In the ZODIAC study a larger reduction in high sensitivity C reactive protein (hs-CRP) was observed under zofenopril (-0.52 vs. +0.97 mg/dL under irbesartan, p = 0.001), suggesting a potential protective effect against the development of atherosclerosis. In the ZENITH study the rate of carotid plaque regression was significantly larger under zofenopril (32% vs. 16%; p = 0.047). In the diabetic patients of the ZAMES study, no adverse effects of treatments on blood glucose and lipids as well as an improvement of renal function were observed. In patients with isolated systolic hypertension of the ZEUS study, a slight and similar improvement in renal function and small reductions in pulse wave velocity (PWV), augmentation index (AI), and central systolic BP were documented with both treatments. Thus, the fixed combination of zofenopril and HCTZ may have a relevant place in the treatment of high-risk or monotherapy-treated uncontrolled hypertensive patients requiring a more prompt, intensive, and sustained BP reduction, in line with the recommendations of current guidelines.

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Angiotensin-converting enzyme inhibitors (ACEIs) reduce arterial stiffness beyond their antihypertensive effect. Studies showed that sulfhydryl ACEIs have the antioxidative potential to improve endothelial function, which might have a clinical effect on arterial distensibility. However, there are no studies that directly compare the effects of sulfhydryl (zofenopril) and non-sulfhydryl ACEIs (enalapril) on arterial stiffness. Therefore, this prospective study aims to compare the effects of enalapril and zofenopril on arterial stiffness and oxidative stress in both short- and long-term treatment of arterial hypertension (AH). Baseline and post-treatment peripheral and central arterial pressure indices, augmentation index (Aix), aortic pulse wave velocity (ao-PWV), serum levels of oxidized low-density cholesterol lipoprotein, LDL and uric acid (UA) were measured. The results showed that acute treatment with zofenopril, in contrast to enalapril, significantly decreased peripheral and central Aix (p < 0.001). Chronic treatment with zofenopril showed a superior effect over enalapril on the reduction of the peripheral systolic arterial pressure with reduction of ao-PWV (p = 0.004), as well as a reduction in peripheral Aix (p = 0.021) and central Aix (p = 0.021). Therefore, this study indicates that zofenopril has beneficial effects on the reduction of arterial stiffness compared to enalapril. It has potent clinical efficacy in AH treatment and further studies should compare its safety and long-term efficacy to other AH drugs that would aid clinicians in treating AH and other various cardiovascular diseases that have arterial stiffness as a common denominator.

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Abstract Background Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H 2 S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN). Results Zofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H 2 S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H 2 S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect. Conclusions Zofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H 2 S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling.

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Ischemia–reperfusion (I/R) injury, a prevalent pathological condition in medical practice, presents significant treatment challenges. Hydrogen sulfide (H2S), acknowledged as the third gas signaling molecule, profoundly impacts various physiological and pathophysiological processes. Extensive research has demonstrated that H2S can mitigate I/R damage across multiple organs and tissues. This review investigates the protective effects of H2S in preventing I/R damage in the heart, brain, liver, kidney, intestines, lungs, stomach, spinal cord, testes, eyes, and other tissues. H2S provides protection against I/R damage by alleviating inflammation and endoplasmic reticulum stress; inhibiting apoptosis, oxidative stress, and mitochondrial autophagy and dysfunction; and regulating microRNAs. Significant advancements in understanding the mechanisms by which H2S reduces I/R damage have led to the development and synthesis of H2S-releasing agents such as diallyl trisulfide-loaded mesoporous silica nanoparticles (DATS-MSN), AP39, zofenopril, and ATB-344, offering a new therapeutic avenue for I/R injury.

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