Extemporaneous combination therapy with nebivolol/zofenopril in hypertensive patients: usage in Italy.

OBJECTIVE: Clinically describing hypertensive patients initiating nebivolol/zofenopril extemporaneous combination (NZ-EXC) and estimating the number of patients currently receiving NZ-EXC and of those potentially eligible for the fixed-dose combination of the two molecules (NZ-FDC) in Italy. METHODS: This retrospective observational study used data from IQVIA Italian Longitudinal Patient Database (LPD). Adult hypertensive patients firstly prescribed NZ-EXC between 1 July 2011 and 30 June 2020 were identified and their demographic and clinical characteristics were extracted. Treatment adherence was evaluated as proportion of days covered (PDC) and classified as low (PDC <40%), intermediate (PDC ≥40% and <80%) or high (PDC ≥80%). Two additional cohorts were identified in 2019 to provide the national-level yearly estimates of patients prescribed NZ-EXC and of patients eligible for NZ-FDC. RESULTS: In total 1745 patients were prescribed NZ-EXC: 60% were women; mean age was 65 years. The most frequent comorbidities were dyslipidemia (19.0%), diabetes (15.5%) and thyroid diseases (13.1%); the most common co-prescribed treatments were antithrombotics (29.1%), lipid-lowering agents (28.8%), nonsteroidal anti-inflammatory drugs (26.1%) and antihyperglycemic agents (13.5%). Mean PDC was 39%, and 57% of the patients had a PDC < 40%. The yearly estimate of patients prescribed NZ-EXC in 2019 was 59,000, while potential users of NZ-FDC were estimated to be 29,000. CONCLUSIONS: NZ-EXC in hypertensive patients is a common practice in Italy and the development of a NZ-FDC can be a viable treatment option for hypertensive patients who are already receiving nebivolol and zofenopril through the concomitant assumption of two distinct pills. As supported by scientific literature, FDCs of antihypertensive drugs could simplify treatment, improve adherence and potentially reduce health-care costs as related to a better control of blood pressure.

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.

OBJECTIVE: 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. METHODS: 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 ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro. RESULTS: 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 ex vivo. 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. CONCLUSION: 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.

Zofenopril: Blood pressure control and cardio-protection.

Current hypertension guidelines suggest various strategies to reduce blood pressure levels, thereby reducing cardiovascular events: combinations of drugs with different mechanisms of action, such as an angiotensin converting enzyme inhibitors (ACEIs) and a diuretic, are the cornerstone of the modern treatment of hypertension, also as initial therapy. Among ACEIs, zofenopril has been shown to be effective in the management of hypertension both as monotherapy and in combination with a diuretic: zofenopril/hydrochlorothiazide fixed dose combination is particularly useful to improve treatment adherence through simplification of treatment regimen. Moreover, thanks to the sulfhydryl group, zofenopril has some peculiar properties (higher lipophilicity and tissue penetration, lower bradykinin-dependent effect, higher affinity for, and more persistent binding to, tissue ACE, significant antioxidant effect), which may account for the cardioprotective effects of the drug demonstrated in both pre-clinical studies and randomized clinical trials. The positive impact of zofenopril on clinical outcomes has been extensively documented by the SMILE program, including several clinical trials in patients with different conditions of myocardial ischemia treated with zofenopril: the results of the SMILE program, demonstrating the benefits of zofenopril vs. placebo and other ACEIs, emphasize the importance of a differentiated approach to patients with ischemic heart disease, based on a careful choice of the adopted agent, in order to improve the overall impact of pharmacological treatment on clinical outcomes.

Optimization of S-Nitrosocaptopril Monohydrate Storage Conditions Based on Response Surface Method.

From unstable crystals to relatively stable monohydrate crystals, many researchers have been working on S-nitrosocaptopril for more than two decades. S-nitrosocaptopril monohydrate (Cap-NO·H2O) is a novel crystal form of S-nitrosocaptopril (Cap-NO), and is not only a nitric oxide (NO) donor, but also an angiotensin-converting enzyme inhibitor (ACEI). Yet, a method for long-term storage has never been reported. In order to determine the optimal storage conditions, Plackett-Burman (PB) design was performed to confirm the critical factors. Response surface methodology (RSM) was employed to determine the optimal Cap-NO·H2O storage condition, based on the rough interval determined by the path of steepest ascent experiment. The optimized storage condition was denoted as nitrogen purity of 97%, temperature of -10 °C and 1.20 g deoxidizer. In this case, a final preservation rate of 97.91 ± 0.59% could be obtained. In specific storage conditions, Cap-NO·H2O was found to be stable for at least 6 months in individual PE package, procreating a potentially applicable avenue.

Why do we lack a specific magic anti-COVID-19 drug? Analyses and solutions.

The Coronavirus 2019 (COVID-19) pandemic represents the greatest worldwide public health crisis of recent times. The lack of proven effective therapies means that COVID-19 rages relatively unchecked. Current anti-COVID-19 pharmacotherapies are drugs originally designed for other diseases, and administered orally or intravascularly. Thus, they can have various adverse effects. A specific anti-Coronavirus drug should not only target the virus per se, but also treat the related respiratory and cardiovascular symptoms. Here, we examine the advantages and disadvantages of current anti-COVID-19 pharmacotherapies, and analyze the reasons why in the era of big data we have not yet established specific coronavirus therapies and related technical bottlenecks. Finally, we present our design of a novel nebulized S-nitrosocaptopril that is under development for targeting both coronaviruses and their related symptoms.

Zofenopril versus ramipril in the early phase of acute myocardial infarction with systolic dysfunction: A retrospective study.

INTRODUCTION: Prognostic benefits of zofenopril over ramipril in the early phase of acute myocardial infarction have been reported by the SMILE study, but these benefits have not been tested in clinical practice in the Chinese population. The objective of this study was to compare the effectiveness and safety of zofenopril plus aspirin against ramipril plus aspirin in patients with acute myocardial infarction. METHODS: Patients in the early phase of acute myocardial infarction received 30 mg zofenopril (ZF cohort, N=191) or 5 mg ramipril (RP cohort, N=256) b.i.d. plus 100 mg aspirin/day. Data regarding hospitalisation for cardiovascular disease, non-cardiovascular events and mortality were collected and analysed. RESULTS: During 1 year of treatment, 47 (25%) patients in the ZF cohort and 97 (40%) patients in the RP cohort were hospitalised due to cardiovascular disease (p=0.002), and three (2%) patients in the ZF cohort and 14 (6%) patients in the RP cohort died (p=0.043). Lower incidences of dry cough (p=0.001) and anaemia (p=0.049) were reported in the ZF cohort. CONCLUSIONS: The study recommends zofenopril with 100 mg aspirin for a longer period in patients with acute myocardial infarction with systolic dysfunction.

Angiotensin-Converting Enzyme Inhibition: Beyond Blood Pressure Control-The Role of Zofenopril.

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.

Effect of endostatin and insulin-like growth factor-1 on angiogenesis in patients with acute myocardial infarction with obesity under the influence of zofenopril.

OBJECTIVE: The aim: To study the dynamics of markers of angiogenesis based on insulin-like growth factor-1 (IGF-1) and endostatin, as well as to determine 6-month survival in patients taking zofenopril from the first day of AMI with and without obesity. PATIENTS AND METHODS: Materials and methods: using enzyme immunoassay, we determined the level of endostatin and IGF-1 in serum on days 1 and 12 in patients with AMI with the presence and absence of obesity, and a statistical processing of the data obtained. RESULTS: Results: The relationship between obesity and angiogenesis indicators, both activators and inhibitors, was determined, and a significant relationship was found between zofenopril therapy and angiogenesis activator IGF-1. Differences in the survival of patients with complicated AMI were determined depending on the choice of ACE inhibitor in favor of a higher survival rate of patients who took zofenopril. CONCLUSION: Conclusions: patients who underwent complicated AMI, taking zofenopril, have a higher survival rate during the 6-month follow-up period. Zofenopril stimulated angiogenesis in the examined patients, which was expressed in patients with and without obesity.

A new strategy for taste masking on bitter drug by other combined drug in fixed-dose combination: bitterness of Amlodipine besylate could be masked efficiently by Valsartan.

OBJECTIVES: The aim of this study was to evaluate the bitterness of amlodipine besylate (AML) combined with other five antihypertensive drugs: alacepril, benazepril, hydrochlorothiazide, telmisartan (TEL) and valsartan (VAL), which have possibility of usage as a fixed-dose combination (FDC) drugs. METHODS: The bitterness of individual six drugs and AML combined with each of the five drugs was evaluated using taste sensor SA402B (Intelligent Sensor Technology Inc.). AML combined with TEL or VAL was evaluated by taste sensor and human gustatory sensation tests. The interaction between AML with TEL or VAL was evaluated by 1 H-NMR. KEY FINDINGS: The bitterness of AML was significantly decreased by addition of VAL, whereas it remained unchanged by the addition of TEL in taste sensor and human gustatory sensation test. In the 1 H-NMR spectrum of AML with VAL, signal shifts of protons in AML were observed compared to that in AML alone. On the other hand, in the 1 H-NMR spectrum of AML with TEL, signal shifts of protons in AML were not observed. CONCLUSIONS: It was suggested that when VAL was mixed with AML, the electrostatic interactions between positive charged amino group of AML and negative charged tetrazole group of VAL were caused, and thereby led the suppression the bitterness of AML.

Effects of high-dose alacepril on left atrial pressure and central aortic pressure in awake dogs with mitral valve regurgitation.

The purpose of this study was to clarify how alacepril in amounts greater than those recommended on the product labeling approved by drug regulatory agencies affects left atrial pressure (LAP) and central aortic pressure in dogs with experimentally induced mitral valve regurgitation (MR). Six healthy Beagle dogs were surgically induced for MR and received alacepril at either 1.5mg/kg/12-h (3.0mg/kg/day) or 3.0mg/kg/12-h (6.0mg/kg/day) per one administration for seven days. After a four-week washout period, another dosage was administrated as a crossover study. Dogs were randomised to receive 3.0mg/kg/day or 6.0mg/kg/day first. LAP and central systolic (SAP), mean (MAP), and diastolic (DAP) aortic pressure were measured for 24-h before and during the administration of alacepril. The earliest decreases in SAP, MAP, and DAP with 6.0mg/kg/day were observed on days 4, 4, and 5, respectively. With 3.0mg/kg/day, the earliest decrease in DAP was observed on day 7. The maximum LAP was decreased on days 5 and 7 with 6.0mg/kg/day. The mean LAP was decreased on day 7 with 6.0mg/kg/day. In conclusion, the administration of alacepril at 6.0mg/kg/day reduced the LAP and central aortic pressure within several days.

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.

S-Nitrosocaptopril prevents cancer metastasis in vivo by creating the hostile bloodstream microenvironment against circulating tumor cells.

A perfect microenvironment facilitates the activated circulating tumor cells (CTCs) to spark the adhesion-invasion-extravasation metastatic cascade in their premetastatic niche. Platelet-CTC interaction contributes to the progression of tumor malignancy by protecting CTCs from shear stress and immunological assault, aiding CTCs entrapment in the capillary bed, enabling CTCs to successfully exit the bloodstream and enter the tissue, inducing epithelial-mesenchymal-like transition (EMT), and assisting in the establishment of metastatic foci. To prevent the cascade from sparking, we show that, the multifunctional S-nitrosocaptopril (CapNO) acts on both CTCs and platelets to interrupt platelet/CTCs interplay and adhesion to endothelium, thus inhibiting CTC-based pulmonary metastasis in vivo. The activated platelets cloak cancer HT29 cells, resulting in HT29-exhibiting platelet biomarkers CD61 and P-selectin positive. CapNO inhibits both sialyl Lewisx (Slex) expression on HT29 and ADP-induced activation of platelets through P-selectin- and GPIIb/IIIa-dependent mechanisms, confirmed by the corresponding antibody assay. CapNO inhibits platelet- or interleukin (IL)-1ß-mediated adhesion between HT29 and endothelial cells, and micrometastatic formation in the lungs of immunocompetent syngeneic mouse models. CapNO have also shown the effects of vasodilation, anticoagulation, inhibition of matrix metalloproteinase-2 (MMP2) expression on cancer cells, and inhibition of cell adhesion molecules (CAMs) expression on vascular endothelium. Due to a series of the beneficial effects of CapNO, CTCs remain exposed to the hostile bloodstream environment and are vulnerable to death induced by shear stress and immune elimination. This new discovery provides a basis for CapNO used for cancer metastatic chemoprevention, and might suggest regulation of the CTCs bloodstream microenvironment as a new avenue for cancer metastatic prevention.

A novel S-nitrosocaptopril monohydrate for pulmonary arterial hypertension: H2O and -SNO intermolecular stabilization chemistry.

S-nitrosocaptopril (CapNO) possesses dual capacities of both Captopril and an NO donor with enhanced efficacy and reduced side effects. CapNO crystals are difficult to make due to its unstable S-NO bond. Here, we report a novel stable S-nitrosocaptopril monohydrate (CapNO·H2O) that is stabilized by intermolecular five-membered structure, where one H of H2O forms a hydrogen bond with O- of the stable resonance zwitterion Cap-S+=N-O-, and the O in H2O forms the dipole-dipole interaction with S+ through two unpaired electrons. With the chelation and common ion effect, we synthesized and characterized CapNO·H2O that is stable at 4 °C for 180 days and thereafter without significant degradation. Compared to Captopril, CapNO showed direct vasorelaxation and beneficial effect on PAH rats, and could be self-assembled in rat stomach when Captopril and NaNO2 were given separately. This novel CapNO·H2O with low entropy paves an avenue for its clinical trials and commercialization.

Efficacy of zofenopril in combination with amlodipine in patients with acute myocardial infarction: a pooled individual patient data analysis of four randomized, double-blind, controlled, prospective studies.

OBJECTIVE: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients. METHODS: This was a post-hoc analysis of pooled individual patient data from the four large randomized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes. RESULTS: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR = 0.66; and 95% confidence interval, CI = 0.44-0.98; p = .039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR = 0.78; 95% CI = 0.63-0.97; p = .026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR = 0.76; 95% CI = 0.61-0.94); p = .013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering. CONCLUSIONS: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1 year.

Effects of the concomitant administration of xanthine oxidase inhibitors with zofenopril or other ACE-inhibitors in post-myocardial infarction patients: a meta-analysis of individual data of four randomized, double-blind, prospective studies.

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.

Effects of the angiotensin-converting enzyme inhibitor alacepril in dogs with mitral valve disease.

Alacepril is a relatively novel angiotensin-converting enzyme inhibitor; however, the safety, tolerance, and efficacy of alacepril in terms of cough suppression in dogs with mitral valve disease (MVD) remain unknown. The aim of this study was to investigate the safety, tolerance, and cough suppression efficacy of alacepril in dogs with MVD. This was a multi-center, prospective study. Forty-two dogs with echocardiographic or radiographic evidence of cardiac enlargement in addition to cough were enrolled. Dogs were treated with alacepril (1.0-3.0 mg/kg/day) for at least 4 weeks. One dog (2.4%) developed complications, including appetite loss, lethargy, and vomiting. Thirty-six dogs were re-evaluated after 4 weeks of treatment. Cough resolved or improved in 20 dogs (55.6%) after treatment. Based on the efficacy of alacepril, the dogs were divided into an effective group (n=20) and an ineffective group (n=16). After treatment, the left ventricular end-diastolic internal diameter corrected for body weight was significantly increased from baseline in the ineffective group but was significantly decreased in the effective group. Univariate binomial logistic regression analyses showed that high atrial natriuretic peptide level, N-terminal pro-B-type natriuretic peptide level, and E wave velocity at baseline were significantly correlated with alacepril inefficacy. Alacepril as treatment for MVD is well tolerated in most dogs, and different conditions of cardiac loading may influence the effect of the drug. Alacepril is expected to improve the quality of life of dogs with early stage MVD.

L-Captopril and its derivatives as potential inhibitors of microbial enzyme DapE: A combined approach of drug repurposing and similarity screening.

The perils of antimicrobial drug resistance can be overcome by finding novel antibiotic targets and corresponding small molecule inhibitors. Microbial enzyme DapE is a promising antibiotic target due to its importance to the bacterial survival. The potency of L-Captopril, a well known angiotensin-converting enzyme inhibitor, as an inhibitor of DapE enzyme has been evaluated by analyzing its binding modes and binding affinity towards DapE enzyme. L-Captopril is found to bind the metal centers of DapE enzyme either via its thiolate group or through its carboxylate group. While the latter binding mode is found to be thermodynamically favorable, the former binding mode, also seen in the crystal structure, is kinetically favored. To optimize the binding affinity of the inhibitor towards DapE enzyme, a series of L-Captopril-based inhibitors have been modelled by changing the side groups of L-Captopril. The introduction of a bipolar functional group at the C4 position of the pyrrolidine ring of L-Captopril and the substitution of the thiol group with a carboxylate group, have been shown to provide excellent enzyme affinity that supersedes the binding affinity of DapE enzyme towards its natural substrate, thus making this molecule a potential inhibitor with great promise.

Efficacy and Safety of Zofenopril Versus Ramipril in the Treatment of Myocardial Infarction and Heart Failure: A Review of the Published and Unpublished Data of the Randomized Double-Blind SMILE-4 Study.

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.

A Capillary Zone Electrophoresis Method with Multiresponse Chemometric Optimization for the Simultaneous Determination of Zofenopril Calcium and Hydrochlorothiazide in Presence of Hydrochlorothiazide Major Impurities.

In the present decade, great importance has been focused on the development of green analytical methods (GAM) as eco-friendly techniques. Minimizing the wastes, analysis time, hazardous reagents, sample size and energy are the main important principles for development of GAM. This manuscript describes a green, novel, rapid, accurate and reliable capillary zone electrophoresis method (CZE) for the simultaneous separation and determination of zofenopril calcium (ZOF) and hydrochlorothiazide (HCT) in presence of two major impurities of HCT, namely; chlorothiazide (CT) and salamide (DSA). Uncoated fused-silica capillary (50 µm i.d. × 48.5 cm and 40 cm effective length) was used. The main factors affecting the separation were the buffer concentration, pH of the buffer and applied voltage. Optimization of the experimental conditions was performed by applying response surface methodology (RSM). The experiments were designed using central composite face-centered design (CCD). The model obtained from the design described the linear, non-linear and interaction effects of factors on the responses. The optimum conditions given by the design were running buffer of sodium borate (pH 9.15; 10 mM) and 17 kV as positive mode applied voltage. Upon applying these conditions, baseline separation for the four compounds with short analysis time of 5.0 min was achieved. UV detection was performed at 225.0 nm and the capillary temperature was maintained at 25°C. The method was validated and applied for quantitative determination of the studied drugs according to the International Conference on Harmonization (ICH) guidelines. Good linearity was obtained in the range of 10.0-100.0 µg/mL for both ZOF and HCT. As for CT and DSA (HCT impurities), linearity range was 5.0-100.0 µg/mL. The proposed method was successfully applied for the analysis of these drugs in their synthetic mixtures and in their co-formulated pharmaceutical formulations.