CARDIOVASCULAR DISEASE MANAGEMENT | REVIEW

Safety and Efficacy of the bi-Sulfydryl ACE-Inhibitor in the Management of Cardiovascular Disease

Claudio Napoli, Department of General Pathology, Division of Clinical Pathology & Excellence Research Centre on Cardiovascular Disease Recieved 15/08/2009, Reviewed 21/08/2009, Accepted 27/08/2009 Keywords: ACE, zofenopril, atherosclerosis, acute myocardial infarction DOI:10.5083/ apjcm.20424906.05

ABSTRACT CORRESPONDENCE

In the 1970s, pharmacological therapy interrupting the - system was considered Claudio Napoli beneficial for patients with high-renin hypertension. Angiotensin-converting enzyme (ACE) Department of inhibitors proved to be effective not only in patients with high renin and elevated blood pressure, General Pathology, but also in many hypertensive patients with normal levels of plasma renin activity. ACE inhibitors are Division of Clinical Pathology used in a wide range of chronic illnesses such as atherosclerosis, hypertension, myocardial infarction, and Excellence Research Centre on Cardiovascular heart failure, diabetic complications, and stroke. To date, more than ninety controlled clinical trials Disease, evaluating the beneficial effects of 14 different ACE inhibitors were conducted. Moreover, data from 1st School of Medicine, experimental studies showed that ACE inhibitors can attenuate the development of atherosclerosis, II University of Naples, oxidative stress, and vascular inflammation in a wide range of species indicating that ACE inhibition Complesso S. Andrea also favourably affects the vasculature. More than fifteen years ago, the bi-sulfydryl ACE-inhibitor delle Dame, zofenopril has shown an excellent clinical safety and efficacy in patients with hypertension and in 80138 Naples, those with myocardial infarction. More recently, this compound exhibited a potent antioxidant and Italy. antiatherosclerotic effect indicating a clinical useful vasoprotective action. Email: [email protected] or claudio. [email protected]

Rationale of the use of ACE Inhibitors NO induces vasodilation, inhibits expression of Acknowledgments as Vasculoprotective Agents adhesion molecules, and decreases platelet ag- gregation and VSMC proliferation.4 ANG II coun- This work was made possible through a grant from Angiotensin-converting enzyme (ACE), which teracts NO by its vasoconstricting properties “Regione Campania 2008” is responsible for conversion of angiotensin I to and, more important, by altering NO bioactiv- 1,4 and an unrestricted educational angiotensin II (ANG II) and degradation of ity. Although ANG II infusion increases plasma grant from Menarini Foundation, bradykinin, is a component of the renin-angio- NO, it can interfere with tissue NO bioactivity, Milan, Italy. tensinaldosterone axis. ANG II is a potent probably via increased production of superox- vasoconstrictor and the principal active peptide ide radicals (and other ROS) by VSMCs.1,4 In turn, of the reninangiotensin system. ANG II also reduced NO synthesis increases levels of super- Disclosure regulates cellular proliferation, inflammation, oxide and nuclear factor-kB, thereby increasing The authors report no conflicts oxidation-sensitive mechanisms, and endothe- ACE expression and ANG II–receptor type 1. ac- of interest. lial function.1 tivation.1,4

The ACE inhibitor has a sulfydryl group Accordingly, chronic antagonism of nitric oxide to coordinate to the active site zinc ion, enala- synthase (NOS) can lead to increased ANG II- prilat has a carboxylate group, and has receptor type 1 gene transcription, which also a phosphate group; zofenopril has 2 sulfydryl suggests that endothelial dysfunction can di- groups.2,3 , and are rectly increase the ANG IIinduced adverse vascu- ethyl-ester derivatized prodrugs that are well lar effects.1–6 By contrast, bradykinin stimulates absorbed from the gut and, although inactive in NO synthesis by the endothelium. ANG II and vitro, are hydrolysed to the active diacid forms bradykinin have opposite effects on fibrinolysis: (, ramiprilat and cilazaprilat) in vivo angiotensin metabolites increase plasminogen by esterases in the liver, blood and other tissues. activator inhibitor-1 activity, whereas bradyki- In plaques from human coronary arteries, ACE nin increases levels of tissue plasminogen acti- and ANG II were found to be overexpressed in vator.1–6 Because ANG II and bradykinin affect unstable atherosclerotic lesions,1–3 primarily at endothelial function, oxidation-sensitive mech- the site of plaque rupture where macrophages anisms, and arterial inflammation, and because and interleukin-6 colocalize. Interleukin-6 ex- ACE activity is mainly (90%) localized in the pression in VSMCs and macrophages is stimu- endothelium, using ACE inhibitors to treat ath- lated by ANG II.1 erosclerosis and its clinical sequalae is consistent with the hypothesis.1–5

ISSN 20424906

20 THE ASIA-PACIFIC JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I SAFETY AND EFFICACY OF THE BI-SULFYDRYL ACE-INHIBITOR ZOFENOPRIL IN THE MANAGEMENT OF CARDIOVASCULAR DISEASE

Since then, an expanded view of RAS has gradually emerged.6 Specifically, some trials of patients with heart failure (HF) following Local tissue RAS systems have been identified in most organs. acute myocardial infarction (AMI) support the benefit of ACE inhi- Recently, evidence for an intracellular RAS has been reported. bition in this large patient population. In the SOLVD study, at 40 The new expanded view of RAS therefore covers both endocrine, months, enalapril lowered significantly the risk of AMI by 23% and paracrine and intracrine functions. Other peptides of RAS have unstable angina by 20%,20 and continued to lower the rates of cor- been shown to have biological actions; angiotensin 2–8 hepta- onary events throughout follow-up. In the SAVE trial, AMI survivors peptide (Ang III) has actions similar to those of Ang II.6 Further, the with reduced left ventricular function were randomly assigned to angiotensin 3–8 hexapeptide (Ang IV) exerts its actions via insulin- receive captopril or placebo.21 After 42 months of followup, capto- regulated amino peptidase receptors while angiotensin 1–7 (Ang pril not only reduced all-cause mortality by 19%, but also lowered 1–7) acts via mas receptors.6 The discovery of another ACE2 and of significantly the risk of recurrent infarction by 25%.21 In the Acute renin receptors has made our view of RAS unexpectedly complex.6 Infarction Ramipril Efficacy (AIRE)22 and Cardiac Evalu- Great expectations are now generated by the introduction of renin ation (TRACE)23 clinical trials, patients with HF were randomly as- inhibitors. signed to receive an ACE inhibitor or placebo within days after AMI.

Experimental Studies in which the The rate of recurrent infarction did not differ between groups; how- Sulfydryl ACE-Inhibitor Zofenopril Exerted ever, a systematic overview of these trials reported a significant 24 Potent Vasoprotective Effects reduction in recurrent infarction with ACE inhibition. Another detailed meta-analysis of trials of ACE inhibitors after AMI found Different ACE inhibitors have quite different chemical functional that ACE inhibitor therapy lowered the risk of sudden cardiac death 25 groups and these structural variations may account for different significantly (odds RATIO = 0.80; [CI]: 0.70 to 0.92). Taken togeth- in vivo and in vitro effects. The ACE inhibitor captopril has a sulfy- er, these clinical data can be interpreted that ACE inhibitors lower dryl group to coordinate the zinc ion of the active site, enalaprilat the risk of coronary events attributed to plaque instability and/or 2,17–19 has a carboxylate group, and zofenopril has 2 sulfydryl groups.1–3,7 rupture. In the Prevention of Atherosclerosis with Ramipril-2 26 Sulfhydryl ACE-inhibition, in particular zofenopril, stimulates the (PART-2) study, patients with carotid atherosclerosis were as- NO activity and decreases oxidative stress in human endothelial signed to receive ramipril or placebo. Throughout the 4-year follow- cells.4,8,9 Zofenopril decreases atherosclerotic development also up, carotid artery wall thickness and plaques differed between the reducing reactive oxygen species in rabbits and mice.10,11 This two groups favoring placebo. effect was more potent than that achieved by the sulfhydryl ACE inhibitor captopril. Nevertheless, ramipril reduced significantly cardiovascular mortali- ty or nonfatal AMI by 34%.26 Similar findings were reported in a trial Consistently, zofenopril induced cardioprotective effect in -per of simvastatin and enalapril administered randomly to normocho- 27 fused rat heart subjected to ischemia and reperfusion12 as well as lesterolemic patients. Angiographic measures of coronary ath- attenuated hypertrophic response in rats with myocardial infarc- erosclerosis did not differ between enalapril- and placebo-treated tion.13 Moreover, the impact of zofenopril in comparison to the patients, although fewer patients receiving enalapril experienced 27 non-sulfhydryl ACE-inhibitor enalapril was studied in in non non- clinical events at 4-year follow-up. In the Study to Evaluate Ca- obese diabetic mice (NOD).14 Insulin-dependent diabetes mellitus rotid Ultrasound Changes in Patients Treated with Ramipril and Vi- 28 (IDDM) development was monitored weekly through glycosuria tamin E (SECURE), a substudy of the Heart Outcomes Prevention 29 measurement. Evaluation (HOPE) trial, patients at high risk of coronary events were assigned to receive ramipril, vitamin E, or both. Interestingly, Zofenopril delays the onset of diabetic conditions of about 50%, at 4.5 years, ramipril reduced significantly progression of carotid and ameliorates polyuria. These data suggest that ACE-inhibitor intima-media thickness by 0.008 mm per year. therapy may be useful in IDDM, in particular sulfhydryl inhibition would display a better efficacy than enalapril. Finally, zofenopril, Zofenopril has shown clinical safety and efficacy in hyperten- 30 also prevente renal ischemia/reperfusion injury in rats.15 The in- sive patients and in those with AMI. Preliminary in vivo human teraction between antioxidant action of sulfhydryl ACE-inhibitors, evaluation showed that zofenopril accumulates in organs which nitric oxide and vascular function may explain the vascular protec- express high levels of ACE, like lungs and kidneys, and in organs 31 tion afforded by these drugs. involved in drug metabolism such as the liver and gall bladder. A measurable concentration of zofenopril was also found in the target Vasoprotective Effects in Humans tissues such as the kidney and to a minor extent, the heart, where it can afford organ protection.31 When clinical trials conducted with zofenopril began with a vast study program called SMILE, certain Carotid intima-media thickness (CIMT) measured by ultrasound questions remained unanswered, notably the long-term benefit of has been shown to correlate with the presence of cardiovascular the ACE inhibitors beyond a short administration period. disease and is now widely accepted as a subclinical marker for atherosclerotic disease16 Studies have shown that ACE-inhibitors SMILE (Survival of Myocardial Infarction Long-Term Evaluation), exert anti-atherosclerotic effects, which depend to some extent begun in 1995, is studying zofenopril to determine the effects of on the degree of blood pressure lowering provided by these using this ACE inhibitor in the follow-up of AMI.32–34 Indeed, drugs.1,2,5–7,17–19 Many randomized clinical trials of antihyperten- zofenopril is effective in reducing cardiac events after AMI and sive drugs compared with placebo or no-treatment have demon- as an antihypertensive drug in the SMILE study. Zofenopril has strated both a reduction of CIMT, a validated measure of subclinical successively demonstrated benefits on the reduction of morbidity atherosclerosis and predictor risk for clinical cardiovascular events, and mortality after anterior AMI in STEMI patients, benefits that than a protection against clinical stroke events. are maintained over the long term, since at 1 year, the mortality rate is significantly lower in the zofenopril group compared to the placebo group.

THE ASIA-PACIFIC JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I 21 HEALTHCARE BULLETIN | CARDIOVASCULAR DISEASE MANAGEMENT

SMILE’s analyses have shown the value of zofenopril in subpopula- Interestingly, we established also that zofenopril reduced potently tions, particularly at-risk patients, hypertensive patients, and dia- oxidative stress in comparison to enalpril in patients with essential betics, whose prognosis after AMI is more severe than in patients hypertension.43 Moreover, sulfhydryl ACE-inhibition normalizes without hypertension or diabetes. Zofenopril can be administered nitrate production and potently reduces the asymmetrical early, even in a more favorable situation, to AMI patients with no ST- dimethyl-l-Arginine (ADMA) increase observed in hypertensive segment elevation (NSTEMI).30,32–34 The SMILE program is continu- patients.43 Specifically, NOx levels were found to be significantly ing, notably with SMILE IV, where it is being compared to ramipril, higher in zofenopril-treated compared to enalapril-treated patients. and in the ZAAMIS trial, designed to confirm its vasoprotective ef- fects. The results of the SMILE-ISCHEMIA study support the cardio- More relevantly, and consistently with preclinical studies,9–11 we protective role of zofenopril when given to patients with normal also show that the carotid antiatherosclerotic effect (CIMT) of the left ventricular function after AMI.35 sulfhydryl ACE inhibitor zofenopril in comparison to enalapril in hy- pertensive patients.44 The observation of higher plasma levels of Finally, it was evaluate the clinical efficacy of the early administra- ADMA in the zofenopril group might seem at odds with the reduced tion of zofenopril in a group of patients with and without metabolic CIMT. In our conditions, CIMT of the right and left common carotid syndrome and anterior AMI enrolled in the Survival of Myocardial arteries was similar at baseline in both groups (P = NS). However, Infarction Long-Term Evaluation (SMILE) Study.36 Results demon- CIMT for 5 years revealed a significant reduction in the zofenopril strated the striking benefit of early administration of zofenopril group but not in the enalapril group (P < 0.05 vs. enalapril-treat- in metabolic syndrome.patients with AMI.36 The antihypertensive ed group).44 The anti-atherosclerotic effect seen in our long-term effect of zofenopril + hydrochlorothiazide or zofenopril was simi- study was coupled with beneficial effects on endothelial function lar in patients with (77%) and without metabolic syndrome. In pa- measured by ultrasound detection of brachial artery reactivity and tients with and without metabolic syndrome, however, diastolic endothelium-dependent dilation (flow-mediated dilation, FMD).45 and systolic blood pressure reductions were significantly greater with zofenopril + hydrochlorothiazide (with metabolic syndrome: FMD was significantly increased in the zofenopriltreated group 14+/-8/21+/-14 mmHg; without metabolic syndrome: 15+/-7/23+/- (P < 0.01).45 14 mmHg) than with zofenopril alone (with metabolic syndrome: 10+/-9/11+/-15; without metabolic syndrome: 12+/-10/14+/-18 mmHg).37 CONCLUSIONS

The safety of the two treatments was similar in patients with and We still do not know whether some parameters, such as genetic without metabolic syndrome. This effect was particularly evident in determinants, for example such of endothelial nitric oxide synthase patients with metabolic syndrome, in whom blood pressure control in affording atheroprotective effect,46 or markers of inflammation is more difficult to achieve and who are at greater risk for cardiovas- not investigated in the HOPE study, can help to identify patients in cular events. whom ACE inhibitors would produce a more marked benefit than that found in the total trial population. Besides, improvement in en- Overall, in patients with mild to moderate hypertension, the effica- dothelial function with was limited to coronary patients cy and safety of zofenopril 30 mg od was compared with enalapril with the insertion allele (DI or II) of the ACE gene;47 and, conversely, 20 mg od during 12 weeks of treatment.38 Both treatments signifi- enalapril improved endothelial function primarily in patients with cantly reduced systolic and diastolic blood pressure. However, BP the deletion allele (DI or DD genotypes).48 A great bulk of evidence reduction was significantly greater with zofenopril during the initial indicates that the additional antioxidant properties of the ACE in- 4 weeks of treatment compared with enalapril.38 A similar number hibitors are particularly evident in those containing a sulfhydryl of patients reported adverse events in the two study groups. How- group. These protective effects might include a reduction of growth ever, the severity of adverse events were significantly milder with factor gene expression, and reduction of polymorphonuclear cell zofenopril compared with enalapril. Similarly, in a multi-centre and chemoattractant release. Zofenopril which possesses 2 sulfhydryl double-blind study including 304 middle-aged to elderly patients groups is one of the most effective and vasoprotective ACE drugs. with mild to moderate hypertension who were randomized to re- ceive either zofenopril or atenolol for 4 weeks, BPs were substantial- In the absence of major contraindications (angioedema, intolerable ly reduced by either treatment, but after 4 weeks, the systolic and cough or hypotension, or decline in renal function), patients with diastolic BP reductions were significantly greater with zofenopril established atherosclerosis should be treated with ACE inhibitor (P < 0.05) compared with atenolol.39 The number of subjects with therapy. In this regard, zofenopril showed an excellent safety and adverse drug reactions possibly or probably related to the study efficacy both in adult and elderly patients. Diabetic patients with an medication was 14 (9.1%) in the zofenopril group and 30 (20.8%) in additional cardiovascular risk factor should also be on ACE inhibitor the atenolol group (P = 0.008). Moreover, zofenopril was compared therapy. also with the calcium antagonist amlodipine among 303 hyperten- sive patients, aged 18–75 years.40 One major problem of establishing an “antiatherosclerotic drug” is the difficulty in assessing “true” antiatherosclerotic activity over Both drugs were well tolerated and lowered blood pressure.40 many years in human arteries. The majority of preclinical studies Zofenopril also induces a more rapid initial lowering of BP over the are based on the drug effects on atherosclerotic lesion progression. first month of therapy in comparison to the angiotensin II type 1 Obvious concerns related to the differences in atherosclerotic dis- receptor (AT1) antagonist .41 Patients aged >/= 65 years ease between humans and animal models are important to empha- with mild to moderate essential hypertension were randomised to size. As it is well establised that atherosclerosis begins in the very receive either zofenopril 30 mg or 10 mg.42 At the end of early phase of human life, more questions are arising regarding the the treatment diastolic BP was not significantly different between “ideal” age for starting preventive therapy for the disease.49,50 This the two treatment groups (P = NS). Thus, in elderly hypertensive issue is particular relevant when considering primary prevention of patients, treatment with zofenopril or lisinopril were effective and atheroscleroticrelated diseases.49,50 well tolerated.

22 THE ASIA-PACIFIC JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I SAFETY AND EFFICACY OF THE BI-SULFYDRYL ACE-INHIBITOR ZOFENOPRIL IN THE MANAGEMENT OF CARDIOVASCULAR DISEASE

If the “ideal” treatment were to begin in early life, we must 16 Riccioni G. The Effect of Antihypertensive Drugs on Carotid Intima consider the issue of safety.7,8 Indeed, since the follow-up of the Media Thickness: An Up-to-Date Review. Curr Med Chem. 2009; clinical studies is usually 1–7 years, we do not know very much 16:988–96. about the effects of long-term exposure for the majority of 17 O’Keefe JH, Wetzel M, Moe RR, Bronsnahan K, Lavie CJ. Should an available drugs. angiotensin-converting enzyme inhibitor be standard therapy for patients with atherosclerotic disease? J Am Coll Cardiol. 2001;37:1–8.

REFERENCES 18 Re RN. Mechanisms of disease: local renin-angiotensin-aldosterone systems and the pathogenesis and treatment of cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2004;1:42–7. 1 Heeneman S, Sluimer JC, Daemen MJ. Angiotensin-converting enzyme and vascular remodeling. Circ Res. 2007;101:441–54. 19 Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet. 2007;369:1208–19. 2 Napoli C, Loscalzo J. New challenges for ACE-inhibitors in vascular diseases. Drug Design Rev. 2005;2:485–93. 20 Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. 3 Napoli C, Sica V, Pignalosa O, de Nigris F. New trends in anti- Lancet. 1992;340:1173–8. atherosclerotic agents. Curr Med Chem. 2005;12:1755–72. 21 Pfeffer MA, Braunwald E, Moye LA, et al.Effect of captopril on 4 Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Ignarro LJ. mortality and morbidity in patients with left ventricular dysfunction Nitric oxide and atherosclerosis: An update. Nitric Oxide. 2006; after myocardial infarction: Results of the survival and ventricular 15:265–79. enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327: 669–77. 5 Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: from genes to treatment. Arch Intern Med. 2003;26; 22 Cleland JG, Erhardt L, Murray G, et al. Effect of ramipril on morbidity 163:1155–64. and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure: A report from the AIRE Study 6 Fyhrquist F, Saijonmaa O. Renin-angiotensin system revisited. Investigators. Eur Heart J. 1997;18:14–5. J Intern Med. 2008;264:224–36. 23 Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the 7 Unger T. The role of the renin-angiotensin system in the development angiotensin-converting-enzyme inhibitor trandolapril in patients with of cardiovascular disease. Am J Cardiol. 2002;89:3A–10A. left ventricular dysfunction after myocardial infarction: Trandolapril Cardiac Evaluation (TRACE) study group. N Engl J Med. 1995;333: 8 Scribner AW, Loscalzo J, Napoli C.The effect of angiotensin-converting 1670–6. enzyme inhibition on endothelial function and oxidant stress. Eur J Pharmacol. 2003;482(1–3):95–9. 24 Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a system- 9 Cominacini L, Pasini A, Garbin U, et al. Zofenopril inhibits the atic overview of data from individual patients. ACEInhibitor Myocardial expression of adhesion molecules on endothelial cells by reducing Infarction Collaborative Group. Lancet. 2000;355:1575–81. reactive oxygen species. Am J Hypertens. 2002;15(10 Pt 1):891–5. 25 Domanski MJ, Exner DV, Borkowf CB, et al. Effect of angiotensin 10 Napoli C, Cicala C, D’Armiento FP, et al. Beneficial effects of converting enzyme inhibition on sudden cardiac death in patients ACEinhibition with zofenopril on plaque formation and lowdensity following acute myocardial infarction: A meta-analysis of randomized lipoprotein oxidation in watanabe heritable hyperlipidemic rabbits. clinical trials. J Am Coll Cardiol. 1999;33:598–604. Gen Pharmacol. 1999;33:467–77. 26 MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebo- 11 de Nigris F, D’Armiento FP, Somma P, et al. Chronic treatment controlled trial of the angiotensin-converting enzyme inhibitor, with sulfhydryl angiotensin-converting enzyme inhibitors reduce ramipril, in patients with coronary or other occlusive arterial disease: susceptibility of plasma LDL to in vitro oxidation, formation of PART-2 Collaborative Research Group. Prevention of Atherosclerosis oxidation-specific epitopes in the arterial wall, and atherogenesis in with Ramipril. J Am Coll Cardiol. 2000;36:438–43. apolipoprotein E knockout mice. Int J Cardiol. 2001;81:107–15. 27 Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol 12 Frascarelli S, Ghelardoni S, Ronca-Testoni S, Zucchi R. Cardioprotective lowering, and angiotensin-converting enzyme inhibition on coronary effect of zofenopril in perfused rat heart subjected to ischemia and atherosclerosis: the Simvastatin/Enalapril coronary atherosclerosis trial. reperfusion. J Cardiovasc Pharmacol. 2004;43:294–9. Circulation. 2000;102:1748–54.

13 Westendorp B, Schoemaker RG, Buikema H, de Zeeuw D, van 28 Lonn EM, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on Veldhuisen DJ, van Gilst WH. Dietary sodium restriction specifically atherosclerosis: the Study to Evaluate Carotid Ultrasound Changes in potentiates left ventricular ACE inhibition by zofenopril, and is Patients Treated with Ramipril and Vitamin E (SECURE). Circulation. associated with attenuated hypertrophic response in rats with 2001;103:919–25. myocardial infarction. J Renin Angiotensin Aldosterone Syst. 2004;5:27–32. 29 The Heart Outcomes Prevention Evaluation Study Investigators, Effects of an angiotensin-converting-enzyme inhibitor ramipril, on 14 Bucci M, Roviezzo F, Brancaleone V, et al. ACE-inhibition ameliorates cardiovascular events in high-risk patients. N Engl J Med. 2000;342: vascular reactivity and delays diabetes outcome in NOD mice. Vascul 145–53. Pharmacol. 2008;49:84–90. 30 Ambrosioni E. Defining the role of zofenopril in the management of 15 Altunoluk B, Soylemez H, Oguz F, Turkmen E, Fadillioglu E. An hypertension and ischemic heart disorders. Am J Cardiovasc Drugs. Angiotensin-converting enzyme inhibitor, zofenopril, prevents renal 2007;7:17–24. ischemia/reperfusion injury in rats. Ann Clin Lab Sci. 2006;36:326–32.

THE ASIA-PACIFIC JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I 23 HEALTHCARE BULLETIN | CARDIOVASCULAR DISEASE MANAGEMENT

31 Matarrese M, Salimbeni A, Turolla EA, et al. 11C-Radiosynthesis and 42 Malacco E, Piazza S, Omboni S; on behalf of the Zofenopril Study preliminary human evaluation of the disposition of the ACE inhibitor Group. Zofenopril versus Lisinopril in the Treatment of Essential [11C] zofenoprilat. Bioorg Med Chem. 2004;12:603–11. Hypertension in Elderly Patients: A Randomised, Double-Blind, Multicentre Study. Clin Drug Investig. 2005;25(3):175–82. 32 Ambrosioni E, Borghi C, Magnani B. The effect of angiotensin- convertingenzyme inhibitor zofenopril on mortality and morbidity 43 Napoli C, Sica V, de Nigris F, et al. Sulfhydryl angiotensin-converting after anterior myocardial infarction. N Engl J Med. 1995;332:80–5. enzyme inhibition induces sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential 33 Borghi C, Bacchelli S, Esposti DD, Bignamini A, Magnani B, hypertension. Am Heart J. 2004;148:e5–12. Ambrosioni E. Effects of the administration of an angiotensin converting enzyme inhibitor during the acute phase of myocardial 44 Napoli C, Bruzzese G, Ignarro LJ, et al. Long-term treatment with infarction in patients with arterial hypertension. SMILE Study sulfhydryl angiotensin-converting enzyme inhibition reduces carotid Investigators. Survival of Myocardial Infarction Long-term Evaluation. intima-media thickening and improves the nitric oxide/oxidative stress Am J Hypertens. 1999;12:665–72. pathways in newly diagnosed patients with mild to moderate primary hypertension. Am Heart J. 2008;156:e1154–8. 34 Borghi C, Ambrosioni E. Double-blind comparison between zofenopril and lisinopril in patients with acute myocardial infarction: Results of 45 Pasini AF, Garbin U, Nava MC, et al. Effect of sulfhydryl and the Survival of Myocardial Infarction Long-Term Evaluation-2 (SMILE-2) non-sulfhydryl angiotensin-converting enzyme inhibitors on study. Am Heart J. 2003;145:80–7. endothelial function in essential hypertensive patients. Am J Hypertens. 2007;20:443–50. 35 Borghi C, Ambrosioni E; Survival of Myocardial Infarction Long-term Evaluation Study Group. Effects of zofenopril on myocardial ischemia in 46 Napoli C, Ignarro LJ. Polymorphisms in endothelial nitric oxide post-myocardial infarction patients with preserved left ventricular synthase and carotid artery atherosclerosis. J Clin Pathol. 2007;60: function: the Survival of Myocardial Infarction Long-term Evaluation 341–4. (SMILE)-ISCHEMIA study. Am Heart J. 2007;153(3):445:e7–e14. 47 Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study 36 Borghi C, Cicero AF. Ambrosioni E. Effects of early treatment with of ACE-inhibition, angiotensin II antagonism, and calcium channel zofenopril in patients with myocardial infarction and metabolic blockade on flow-mediated vasodilation in patients with coronary syndrome: the SMILE Study. Vasc Health Risk Manag. 2008;4:665–71. disease. J Am Coll Cardiol. 2000;35:60–6.

37 Malacco E, Omboni S. Antihypertensive efficacy of zofenopril plus 48 Prasad A, Narayanan S, Husain S, et al. Insertion-deletion hydrochlorothiazide fixed combination for treatment in metabolic polymorphism of the ACE gene modulates reversibility of endothelial syndrome. Adv Ther. 2007;24:1006–15. dysfunction with ACE inhibition. Circulation. 2000;102:35–41.

38 Mallion JM. An evaluation of the initial and long-term antihypertensive 49 Napoli C, Lerman LO, de Nigris F, Goessl M, Balestrieri ML, Lerman A. efficacy of zofenopril compared with enalapril in mild to moderate Rethinking primary prevention of atherosclerosis-related diseases. hypertension. Blood Press Suppl. 2007;2:13–8. Circulation. 2006;114:2517–2527.

39 Nilsson P. Antihypertensive efficacy of zofenopril compared with 50 Napoli C, Cacciatore F. Novel pathogenic insights in the atenolol in patients with mild to moderate hypertension. Blood Press primary prevention of cardiovascular disease. Prog Cardiovasc Dis. Suppl. 2007;2:25–30. 2009;51:503–23.

40 Farsang C. Blood pressure control and response rates with zofenopril 51 Originally published in Clinical Medicine: Therapeutics 2009:1 847-853 compared with amlodipine in hypertensive patients. Blood Press Suppl. 2007;2:19–24.

41 Narkiewicz K. Comparison of home and office blood pressure in hypertensive patients treated with zofenopril or losartan. Blood Press Suppl. 2007;2:7–12.

24 THE ASIA-PACIFIC JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I