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PubMed1990

Influence of food on the pharmacokinetics of perindopril and the time course of angiotensin-converting enzyme inhibition in serum.

Food has been shown to reduce the bioavailability of the angiotensin-converting enzyme inhibitor captopril, but not the bioavailability of inhibitors administered as ester prodrugs. Perindopril is the ester pro-drug of the angiotensin-converting enzyme inhibitor perindoprilat. The influence of food on the pharmacokinetics of perindopril (4 mg administered orally) and the time course of angiotensin-converting enzyme inhibition in serum was studied in a randomized crossover short-term study of 12 healthy subjects. Food significantly decreased the relative availability of perindoprilat by 35% +/- 42%, the fractional urinary excretion of perindoprilat from 19% +/- 7% to 13% +/- 4% (p less than 0.05), and the partial metabolic clearance of perindopril to perindoprilat from 102 +/- 57 ml.min-1 to 72 +/- 32 ml.min-1 (p less than 0.05). These changes were associated with a significant decrease in the area under the percent angiotensin-converting enzyme inhibition-versus-time curve by 15% (p less than 0.05). Food did not alter the total amount of drug recovered in urine as perindopril and its metabolites, and it did not alter perindoprilat renal clearance. We concluded that food alters the conversion of perindopril to its active metabolite perindoprilat after single-dose administration of perindopril.

Administration, Oral↗
PubMed1998

Renoprotective differences between perindopril and enalapril in the diabetic hypertensive rat do not reflect glomerular angiotensin-converting enzyme activity.

1. The various angiotensin-converting enzyme inhibitors have structural differences which affect their affinities for the catalytic sites on converting enzyme. We postulated that such differences might result in differences in renoprotective efficacy. We investigated this in the diabetic spontaneous hypertensive rat. We also investigated whether these differences might reflect variations in glomerular or plasma angiotensin-converting enzyme activity. 2. One week after induction of diabetes, rats were started on antihypertensive therapy: enalapril, 10 mg.day-1.kg-1, or perindopril, 4 mg.day-1.kg-1, in the drinking water. After 3 months, the rats were killed, blood samples were taken and tissues were harvested. Angiotensin-converting enzyme activity in isolated glomeruli and plasma was measured by fluorimetric assay. Glomerular protein content was also determined. 3. Urinary protein excretion was significantly lower in perindopril-treated rats than in either controls (P < 0.0005) or enalapril-treated rats (P < 0.05). Glomerular protein content was also lower in perindopril-treated rats (P < 0.05 versus enalapril; P < 0.005 versus control). There was no difference in glomerular angiotensin-converting enzyme activity between the two inhibitors although both were lower than control values (enalapril P < 0.025; perindopril P < 0.025). Plasma angiotensin-converting enzyme activity was significantly lower in the perindopril group than in either control (P < 0.005) or the enalapril group (P < 0.01). 4. We conclude that in the spontaneous hypertensive rat with streptozotocin-induced diabetes, perindopril is more effective than enalapril in reducing proteinuria and glomerular protein accumulation. This difference does not result from differences in glomerular-converting enzyme activity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

The perindopril in elderly people with chronic heart failure (PEP-CHF) study.

AIMS: Many patients who receive a diagnosis of heart failure have neither a low left ventricular (LV) ejection fraction nor valve disease. Few substantial randomized controlled trials have been conducted in this population, none has focussed on patients with evidence of diastolic dysfunction and none has shown clear benefit on symptoms, morbidity, or mortality. METHODS AND RESULTS: This was a randomized double-blind trial, comparing placebo with perindopril, 4 mg/day in patients aged > or =70 years with a diagnosis of heart failure, treated with diuretics and an echocardiogram suggesting diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease. The primary endpoint was a composite of all-cause mortality and unplanned heart failure related hospitalization with a minimum follow-up of 1 year. A total of 850 patients were randomized. Their mean age was 76 (SD 5) years and 55% were women. Median follow-up was 2.1 (IQR 1.5-2.8) years. Enrollment and event rates were lower than anticipated, reducing the power of the study to show a difference in the primary endpoint to 35%. Many patients withdrew from perindopril (28%) and placebo (26%) after 1 year and started taking open-label ACE-inhibitors. Overall, 107 patients assigned to placebo and 100 assigned to perindopril reached the primary endpoint (HR 0.919: 95% CI 0.700-1.208; P = 0.545). By 1 year, reductions in the primary outcome (HR 0.692: 95% CI 0.474-1.010; P = 0.055) and hospitalization for heart failure (HR 0.628: 95% CI 0.408-0.966; P = 0.033) were observed and functional class (P < 0.030) and 6-min corridor walk distance (P = 0.011) had improved in those assigned to perindopril. CONCLUSION: Uncertainty remains about the effects of perindopril on long-term morbidity and mortality in this clinical setting since this study had insufficient power for its primary endpoint. However, improved symptoms and exercise capacity and fewer hospitalizations for heart failure in the first year were observed on perindopril, during which most patients were on assigned therapy, suggesting that it may be of benefit in this patient population.

Aged↗
PubMed2003

Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS): interpretation and implementation.

OBJECTIVES: To determine the effects of a perindopril-based blood pressure lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack (TIA). DESIGN AND METHODS: 6105 subjects from 172 centres in Asia, Australasia, and Europe were randomised to receive active treatment (n = 3051) or placebo (n = 3054). Active treatment consisted of a flexible regimen based on the angiotensin-converting enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide, at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal). Analysis was by intention to treat. RESULTS: Active treatment reduced blood pressure by 9/4 mmHg over 4 years of follow-up. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo [relative risk reduction 28% (95% confidence interval 17-38), P < 0.0001]. Active treatment also reduced the risks of total major vascular events [26% (16-34)] including non-fatal myocardial infarction [38% (14-55)], severe cognitive decline [19% (4-32)], stroke-related dementia [34% (3-55)] and disability [18% (8-28)]. There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (P < 0.01). Combination therapy with perindopril plus indapamide lowered blood pressure by 12/5 mmHg and stroke risk by 43%. Single-drug therapy lowered blood pressure by 5/3 mmHg and produced no significant fall in the risk of stroke. CONCLUSIONS: The blood-pressure lowering regimen used in Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) reduced the risks of stroke and other serious events in hypertensive and non-hypertensive subjects with a history of stroke (whatever the subtype) or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger stroke reductions than monotherapy with perindopril alone. Treatment with these two agents should be considered routinely for all patients with a history of previous stroke or TIA, whether hypertensive or normotensive.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Effects of perindopril on tissue angiotensin-converting enzyme activity demonstrated by quantitative in vitro autoradiography.

Inhibition of plasma angiotensin II generation does not fully explain the chronic hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors. Therefore, the pattern of tissue ACE inhibition in rats was studied after oral administration of perindopril, a new ACE inhibitor. Tissue ACE was measured by quantitative in vitro autoradiography using [125I]-351A as a radioligand and compared with plasma ACE and the pressor response to intravenous (i.v.) angiotensin I. Following oral perindopril (1 mg/kg), plasma ACE activity was acutely reduced, but recovered over 24 h. The peak concentration of plasma perindoprilic acid, the active diacid of perindopril, occurred at 1 h, and the drug was undetectable by 24 h. The pressor response to i.v. angiotensin I was inhibited by 95% at 4 h and had not fully recovered by 24 h. Four hours after oral administration of perindopril, ACE was markedly inhibited in the proximal tubules of the kidney (24% control), lung parenchyma (10%), and aortic wall (18%) (p less than 0.01). At 24 h, ACE in these tissues had only partially recovered (32-63%). ACE was also identified in vascular endothelium of organs, including the lung, kidney, and testis; in these sites, vascular ACE showed a pattern of inhibition similar to that of aortic ACE. In contrast, ACE in testicular seminiferous tubules was unaffected by perindopril. These results demonstrate a prolonged effect of ACE inhibitors on tissue ACE that may better explain the time course of these drugs than the changes in plasma ACE or plasma levels of the drug.

Angiotensin I↗
PubMed1994

Beta-adrenoceptor subtypes in the atrioventricular conducting system and myocardium of spontaneously hypertensive rats: effects of angiotensin-converting enzyme inhibition by perindopril.

Quantitative autoradiography was used to determine the density and distribution of beta 1- and beta 2-adrenoceptors in the atrioventricular (AV) conducting system and surrounding myocardium of spontaneously hypertensive rats (SHR) after chronic infusion of perindopril (1 mg/kg/day) for 14 days by osmotic mini-pumps. Systolic blood pressure (SBP) was measured for a period of 4 weeks (2 weeks before and 2 weeks during perindopril infusion) in control and treated animals. Animals infused with vehicle (water) had a mean SBP of 248 mm Hg (measured on day 29); animals treated with perindopril had lower SBP (121 mm Hg, day 29). Perindopril treatment also prevented development of cardiac hypertrophy in SHR. beta-Adrenoceptor densities were measured in the AV node, His bundle, left and right bundle branches (LB, BB), interventricular and interatrial septa (IVS, IAS), mitral valve (MV), right papillary muscle, left and right ventricles (LV, RV), left and right atria (LA, RA), and apex. Perindopril produced no significant change in beta-adrenoceptors in any cardiac region examined. The results suggest that under experimental conditions in which perindopril treatment prevented cardiac hypertrophy and decreased SBP, there was no significant interaction between the renin-angiotensin system (RAS) and beta-adrenoceptor system in rat heart.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Perindopril and physiologic responses to exercise.

Cardiovascular drugs have varying effects on hemodynamic, metabolic, and hormonal responses to exercise. To evaluate the effects of the novel angiotensin-converting enzyme (ACE) inhibitor, perindopril on these exercise-related responses, we studied 9 healthy volunteers in a double-blind, randomized, placebo-controlled trial. After a week of perindopril 4 mg orally daily or placebo therapy, volunteers performed a treadmill effort test; the sequence was repeated after a 1-week washout period. Perindopril caused a significant reduction in mean resting systolic and diastolic blood pressure (SBP, DBP) without increasing resting heart rate (HR); 15-min post-exercise SBP was also significantly reduced. There were no significant differences between the perindopril and placebo effort tests with respect to metabolic indexes studied (serum K+, plasma glucose, plasma free fatty acids) or plasma hormonal concentrations measured (ACTH and cortisol, norepinephrine (NE) and epinephrine (EPI), glucagon and insulin, growth hormone and prolactin, renin activity). In the perindopril arm of the study, however, there were modest but significant increases in mean serum K+ before exercise to immediately after exercise (0.4 +/- 0.1 mM, p < 0.01) and mean plasma glucose from before exercise to 5 min (0.6 +/- 0.2 mM, p < 0.01) and 15 min (0.5 +/- 0.2 mM, p < 0.05) after exercise. These data show that perindopril does not impair the hormonal changes associated with exercise in healthy subjects but induces a more consistent increase in blood K+ and glucose concentrations.

Adrenocorticotropic Hormone↗
PubMed1997

Acute and chronic in vivo inhibition of angiotensin-converting enzyme by perindopril in the endothelium and adventitia of large arteries and organs of the rabbit.

Angiotensin-converting enzyme (ACE) inhibitors are widely used in treating hypertension and chronic heart failure, but their precise sites and mechanisms of the actions are not completely understood. In this study, we evaluated the acute and chronic in vivo inhibition of ACE by perindopril in both the endothelium and adventitia of large blood vessels including the aorta, carotid, and femoral arteries, heart, lung, and kidney by using in vitro autoradiography with [(125)I]351A as a ligand. After short-term (0.1, 0.3, and 1 mg/kg) or long-term oral administration (0.3 mg/kg), perindopril significantly inhibited plasma ACE (p < 0.001), the plasma angiotensin II (Ang II)/Ang I ratio (p < 0.01), and decreased mean arterial pressure (p < 0.001) in a dose-related manner. In the aorta, carotid, and femoral arteries, free ACE was inhibited to a similar extent in both the endothelium and adventitia by perindopril, in a dose-dependent manner, whereas total ACE in both layers of these vessels was unaltered. Similar short- and long-term ACE inhibition by perindopril was observed in the lung and heart, with somewhat greater inhibition of kidney and plasma ACE. Vascular and tissue ACE inhibition correlated highly with both plasma ACE and the plasma Ang II/Ang I ratio (r = 0.63-0.89; p < 0.001). Whereas the effects of perindopril on blood pressure, plasma Ang II/Ang I ratio, plasma and vascular ACE were all highly dose dependent, there were no significant differences on the degree of ACE inhibition observed between the three large blood vessels or between their adventitial and endothelial layers. These results demonstrate that perindopril readily penetrates the vascular wall after short- or long-term oral administration, and in a dose-dependent manner, potently inhibits both endothelial and advential vascular ACE to a comparable degree. Therefore ACE inhibitors may be beneficial in inhibiting both circulating Ang II and its local formation in the vascular wall.

Angiotensin I↗
PubMed1987

Haemodynamic and humoral effects of oral perindopril, an angiotensin converting enzyme inhibitor, in man.

The tolerance to and dynamic effects of 1 week's oral treatment with the angiotensin converting enzyme inhibitor, perindopril, were assessed in a placebo controlled, parallel group study in 36 normotensive males. The daily dose of perindopril was 1, 2, 4, 8 or 16 mg. The drug was well tolerated and produced no change in routine haematology or serum biochemistry tests. Dose related inhibition of plasma angiotensin converting enzyme was observed. Perindopril 16 mg produced 90% inhibition 4 h after dosing and 60% after 24 h. A dose related rise in plasma renin activity followed doses of 4 mg and over. The renin remained above the normal range for 24 h. Perindopril caused a modest lowering of plasma aldosterone levels but had no effect on plasma adrenaline or noradrenaline levels. Standing diastolic blood pressure was lowered, particularly with 16 mg daily of perindopril but only a slight rise in heart rate occurred. Perindopril appears to be a well tolerated inhibitor of plasma angiotensin converting enzyme, with predictable effects on the renin angiotensin system and blood pressure. An appropriate dose range for further study would appear to be 4 to 16 mg daily.

Adolescent↗
PubMed1989

The pharmacokinetics and pharmacodynamics of perindopril in patients with hepatic cirrhosis.

1. Perindopril, a new ACE inhibitor, is a prodrug requiring conversion into its active form perindoprilat by hydrolysis in the liver. 2. The pharmacodynamics and pharmacokinetics of perindopril (8 mg oral) and perindoprilat (2 mg intravenously) were studied in a double-blind randomised crossover study in a group of patients with compensated biopsy-proven hepatic cirrhosis. 3. Blood pressure and heart rate responses were similar after the two routes of administration as were plasma renin activity and aldosterone levels following dosing. 4. The AUC of perindoprilat after oral administration of perindopril represented 46 +/- 4% of the total AUC of perindopril and its metabolite when expressed in molar terms. Comparison with the AUC of perindoprilat after its intravenous administration suggested that 30 +/- 6% of the oral dose of perindopril was converted to its active metabolite. 5. The findings are comparable with those in healthy subjects. It appears that the presence of relatively mild hepatic cirrhosis does not significantly alter the pharmacokinetics of perindopril.

Administration, Oral↗
PubMed1995

Comparison of the pharmacokinetics and pharmacodynamics of oral doses of perindopril in normotensive Chinese and Caucasian volunteers.

1. The pharmacokinetics of perindopril and perindoprilat and the hormonal and haemodynamic responses following a single oral dose were studied in 12 Chinese and 10 Caucasian healthy, normotensive volunteers on two occasions. Perindopril was given on the first occasion as a 4 mg dose and then after at least 10 days as a weight-adjusted dose of 4 mg/70 kg. Plasma was sampled for assay of perindopril, perindoprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE activity. Urine was collected for perindopril and perindoprilat assay. A radioimmunoassay technique was used to measure the prodrug and its active metabolite. 2. The time to maximum concentration (tmax) for perindopril was shorter for the Chinese group after the 4 mg dose (median 0.5, range 0.5-1.5 h vs median 1.0, 0.5-1.5 h P < 0.05) and also tended to be shorter after the weight-adjusted dose (median 0.5, range 0.5-1.0 h vs median 1.0, range 0.5-3.0 h). Cmax and AUC tended to be higher after the 4 mg dose in the Chinese group who had a lower body weight than the Caucasians. 3. The tmax of perindoprilat tended to be shorter for both doses and there was a tendency towards a higher Cmax after the 4 mg dose in the Chinese group but there was no statistically significant difference between the two groups. 4. There were no differences in the levels of PRA, plasma AI, plasma aldosterone or the degree of ACE-inhibition for either dose in the two ethnic groups. 5. Blood pressure was measured at intervals up to 24 h post-dose in both the supine and standing positions. Perindopril reduced blood pressure acutely with respect to the pre-dose level with good tolerability in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

The angiotensin-converting enzyme inhibitor, perindopril, prevents cardiac hypertrophy in low-renin hypertensive rats.

1. To examine whether an angiotensin-converting enzyme (ACE) inhibitor prevents left ventricular (LV) hypertrophy even in low-renin hypertension, we studied the effect of the administration of perindopril on cardiac hypertrophy induced by partial renal ablation in hypertensive rats. 2. Rats that had undergone partial nephrectomy were randomly divided into four groups that received the following as drinking water: Group A, tap water; Group B, 1% sodium chloride (NaCl); Group C, NaCl + perindopril 3 mg/kg per day; and Group D, NaCl + perindopril 1 mg/kg per day. Plasma renin activity (PRA), angiotensin-II (AII) concentration and cardiac tissue AII were measured. 3. Supplementation of NaCl following nephrectomy increased the blood pressure and cardiac weight compared with rats that had undergone nephrectomy alone (P < 0.05). Treatment with perindopril (3 mg/kg per day) did not affect the blood pressure and plasma AII but inhibited the increase of cardiac weight (P < 0.05). Left ventricular AII was decreased in cases of reduced renal mass hypertension, but was not changed by treatment with perindopril. 4. These results demonstrate that perindopril may be able to prevent LV hypertrophy even in low-renin hypertension, which was not mediated by a reduction of blood pressure or suppression of the circulating and cardiac renin-angiotensin systems. Other mechanisms of ACE inhibitors may contribute to the cardioprotective effects.

Angiotensin II↗
PubMed2000

Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats.

The combination therapy with ACE inhibitors, angiotensin II type 1 (AT(1)) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal alpha-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-beta receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-beta receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT(1) receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT(1) receptor antagonist or monotherapy with each agent.

Adrenergic beta-Antagonists↗
PubMed2002

Long-term treatment with perindopril ameliorates dobutamine-induced myocardial ischemia in patients with coronary artery disease.

The present study was designed to examine whether long-term blockade of angiotensin-converting enzyme (ACE) with perindopril ameliorates dobutamine-induced myocardial ischemia in patients with coronary artery disease (CAD). Twelve patients with proven CAD were randomly divided in two groups; one group received perindopril (8 mg/day, p.o.) for 3 months and another group served as a control. To evaluate anti-ischemic effects of perindopril, dobutamine stress echocardiography was performed before and 3 months after the treatment in a double-blind manner. Long-term treatment with perindopril significantly ameliorated the dobutamine-induced myocardial ischemia, as evaluated by time to the onset of symptoms, magnitude of electrocardiographic ST-segment changes, and left ventricular wall motion score (all P<0.05). The treatment significantly decreased serum ACE activities (P<0.01) and increased plasma bradykinin concentrations (P<0.05). The extent of reduction of left ventricular wall motion score by perindopril was closely correlated with that of inhibition of serum ACE activities (P<0.01) and with that of increase in plasma bradykinin concentrations (P<0.05). By contrast, no such beneficial changes were noted in the control group. These results provide the first evidence that long-term treatment with perindopril exerts anti-ischemic effects on the myocardial ischemia induced by increased myocardial oxygen demand in patients with CAD.

Aged↗
PubMed2006

Perindopril.

Perindopril is a third-generation ACE inhibitor that is characterised as a small, lipophilic molecule with a therapeutically active carboxyl side group. These and other features combine to make this a unique member of a very well-established class of drugs that have proven efficacy in a wide range of cardiovascular diseases. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) demonstrated benefit in the secondary prevention of patients with stroke, whereas the Perindopril and Remodelling in Elderly with Acute Myocardial Infarction (PREAMI) trial supports extended routine use after myocardial infarction. The most recent evidence from the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) show that perindopril is able to improve the prognosis of patients with a relatively low global cardiovascular risk, denoted either by the presence of stable coronary artery disease or of essential hypertension in conjunction with at least three other risk factors. The fact that major relative risk reductions have been reported for these two studies is matched by the significance of the findings to modern clinical practice. Both studies were conducted in the context of advance concomitant care that is typically better in clinical trials than in routine practice. In particular, the benefits observed were seen to be of a similar magnitude, and also independent of those resulting from statin therapy. Of particular interest is the likely complimentary action of these treatment strategies with regard to the stabilisation of atheromatous plaques. Perindopril is a well-established drug, the full value of which is only now becoming fully apparent.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril.

Perindopril is a long-acting, once-daily lipophilic angiotensin-converting enzyme inhibitor with high tissue angiotensin-converting enzyme affinity, lowering angiotensin II and potentiating bradykinin. Its efficacy, safety and tolerability are well established in the treatment of hypertension and heart failure. Moreover, large morbidity-mortality trials, such as the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) and Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS), have shown that antihypertensive treatment with perindopril reduces and prevents cardiovascular disease in a large range of patients with vascular diseases, whether hypertensive or not. Thus, the outcome of these and other trials support the concept of cardiovascular protective properties of angiotensin-converting enzyme inhibition with perindopril in addition to the obvious blood-pressure-lowering effect. Considering its properties and the gathered clinical evidence on efficacy and tolerability, perindopril fulfils the criteria of the latest guidelines for hypertension and cardiovascular disease management and should therefore be considered as a first-line antihypertensive agent, forming a consistent part of the comprehensive strategy against hypertension and related cardiovascular complications.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Perindopril. A review of its pharmacokinetics and clinical pharmacology.

Perindopril is an orally active, non-thiol angiotensin-converting enzyme (ACE) inhibitor, which in doses of 4 to 8mg is effective in the control of essential hypertension. As monotherapy it is as effective as once-daily atenolol and possibly more effective than twice-daily captopril. A synergistic response has been noted when perindopril is combined with a thiazide diuretic. Maximal pharmacodynamic effects (ACE inhibition, increase in plasma renin activity and angiotensin I, reduction in aldosterone and angiotensin II and blood pressure) are seen 4 to 6 hours after dosing, with substantial effects still present at 24 hours. Perindopril is a prodrug which requires de-esterification to perindoprilat for useful ACE inhibition. Maximal plasma perindoprilat concentrations are reached 2 to 6 hours after oral administration of perindopril, and 70% of the active metabolite is cleared by the kidneys. The other major metabolite of perindopril is an inactive glucuronide. Ageing is associated with increased serum perindoprilat concentrations, which are probably caused by a combination of enhanced conversion to the active metabolite and diminished renal clearance. Compensated cirrhosis does not appear to have an independent effect. There is little published experience of the use of perindopril in patients with cardiac failure or other cardiac disease, but preliminary evidence would support the general value of this class of agent as adjunctive therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Effects of perindopril and carvedilol on endothelium-dependent vascular functions in patients with diabetes and hypertension.

OBJECTIVE: To compare the effects of the ACE inhibitor perindopril and the beta-blocker carvedilol on blood pressure and endothelial functions in NIDDM patients with hypertension. RESEARCH DESIGN AND METHODS: We conducted a double-blind randomized trial in 26 patients with NIDDM and mild hypertension. A 4-week run-in placebo period preceded the active 12-week treatment with perindopril (4-8 mg daily) or carvedilol (25-50 mg daily). Endothelial functions were assessed by evaluating the hemodynamic (mean blood pressure, leg blood flow) and rheological (platelet aggregation, blood viscosity, and blood filterability) responses to an intravenous bolus of 3 g L-arginine, the natural precursor of nitric oxide. RESULTS: Both perindopril and carvedilol significantly reduced mean blood pressure (P < 0.001) and increased leg blood flow (P < 0.05) to the same extent; blood filterability remained unchanged in both perindopril- and carvedilol-treated groups. Carvedilol reduced platelet aggregation and blood viscosity significantly (P < 0.05) but perindopril did not. Before treatment, the hemodynamic and rheologic responses to L-arginine were significantly lower in patients (P < 0.05-0.01) than in 20 nondiabetic nonhypertensive control subjects. After 12 weeks of treatment, both drugs normalized the hemodynamic responses to L-arginine. Platelet aggregation response to L-arginine was ameliorated by carvedilol and remained unchanged in the perindopril group. CONCLUSIONS: At the doses used, both drugs effectively reduce blood pressure and normalize the hemodynamic responses to L-arginine. The implications of the ameliorated endothelial function for the poor cardiovascular outlook of the NIDDM hypertensive patient need further assessment.

Adrenergic beta-Antagonists↗