Short-term and long-term cardiovascular actions of different doses of perindopril in the rabbit

Short-term (one week) and chronic (six week) cardiovascular effects of orally administered perindopril were examined in the rabbit to demonstrate if short-term results can predict chronic outcomes. In short-term treatment, five doses of perindopril were examined in random order separated by a one week recovery period in each of six rabbits. Two doses of perindopril which resulted in a moderate hypotensive effect (-14 mmHg) and no hypotensive effect, respectively, were then selected for long-term treatment. Each rabbit in the short-term study received perindopril in doses of 0.01, 0.06, 0.32, 1.8 and 10 mg kg(-1) day(-1) for a week at a time. Rabbits on long-term treatment received either 0.3 or 0.01 mg kg(-1) day(-1) perindopril for six weeks. All rabbits had their mean arterial blood pressure (MAP) and heart rate recorded throughout treatment. Plasma angiotensin I (AngI), perindoprilat, angiotensin converting enzyme (ACE) inhibition were also assayed. Perindopril treatment for one week produced a dose-dependent hypotensive effect with the threshold dose, 0.06 mg kg(-1) day(-1), producing a 6.5+/-1.8 mmHg fall in MAP. The highest dose (10.0 mg kg(-1) day(-1)) produced a large fall in blood pressure of -29.6+/-4.2 mmHg. The 0.01 and 0.06 mg kg(-1) day(-1) doses of perindopril produced an average 2.65 fold increase in plasma AngI levels compared to the initial control. The three higher doses (0.32-10.0 mg kg(-1) day(-1)) of perindopril produced an equivalent 5.7 fold increase in plasma AngI levels compared to the initial controls. However, over six weeks 0.01 mg kg(-1) day(-1) perindopril induced a similar decrease in MAP as the 30 fold higher dose (-9.3 mmHg compared to -11.7 mmHg,). This was in spite of a 3 fold difference in plasma perindoprilat concentrations between the high and low dose perindopril groups. Plasma ACE inhibition was >80% with both doses of perindopril. The results indicate that while perindopril decreases MAP in a dose-dependent manner in short-term (one week) periods, over longer treatment times (six weeks) low concentrations of perindopril, non-hypotensive with shortterm treatment, may be as anti-hypertensive as considerably higher doses. (C) 1996 The Italian Pharmacological Society.

Pulmonary Vascular remodelling in hypoxic rats: effects of amlodipine, alone and with perindopril

This study investigated whether pulmonary Vascular remodelling in hypoxic pulmonary hypertensive rats (10% oxygen; 4 weeks) could be prevented by treatment, during hypoxia, with amlodipine (IO mg/kg/day, p.o.), either alone or in combination with the angiotensin converting enzyme inhibitor, perindopril (30 mg/kg/day, p.o.). Medial thickening of pulmonary arteries (30-500 mum o.d.) was attenuated by amlodipine whereas it was totally prevented by the combination treatment (amlodipine plus perindopril); neomuscularisation of small alveolar arteries (assessed from critical closing pressure in isolated perfused lungs) was not affected. Pulmonary vascular resistance (isolated perfused lungs) was reduced by both treatment regimes but only combination treatment reduced right ventricular hypertrophy. Taus, amlodipine has anti-remodelling properties in pulmonary hypertensive rats. The finding that combining amlodipine with another anti-remodelling drug produced effects on vascular structure that were additive raises the question of whether combination therapy with two different anti-remodelling drugs may be of value in the treatment of patients with hypoxic (and possibly other forms of) pulmonary hypertension. (C) 2001 Elsevier Science B.V. All rights reserved.

Blood pressure normalization in a large population of hypertensive patients treated with perindopril/indapamide combination: results of the OPTIMAX trial.

OBJECTIVE: To determine if the fixed-dose perindopril/indapamide combination (Per/Ind) normalizes blood pressure (BP) in the same fraction of hypertensive patients when treated in everyday practice or in controlled trials. METHODS: In this prospective trial, 17 938 hypertensive patients were treated with Per 2 mg/Ind 0.625 mg for 3-6 months. In Group 1 Per/Ind was initiated in newly diagnosed patients (n = 7032); in Group 2 Per/Ind replaced previous therapy in patients already treated but having either their BP still uncontrolled or experiencing side-effects (n = 7423); in Group 3 Per/Ind was added to previous treatment in patients with persistently high BP (n = 3483). BP was considered normalized when < or = 140/90 mm Hg. A multivariate analysis for predictors of BP normalization was performed. RESULTS: Subjects were on average 62 years old and had a baseline BP of 162.3/93.6 mm Hg. After treatment with Per/Ind, BP normalization was reached in 69.6% of patients in the Initiation group, 67.5% in the Replacement Group, and 67.4% in the Add-on Group (where patients were more frequently at risk, diabetic, or with target organ damage). Mean decreases in systolic BP of 22.8 mm Hg and in diastolic BP of 12.4 mm Hg were recorded. CONCLUSIONS: This trial was established to reflect everyday clinical practice, and a treatment strategy based on the Per/Ind combination, administered as initial, replacement, or add-on therapy, led to normalization rates that were superior to those observed in Europe in routine practice. These results support recent hypertension guidelines which encourage the use of combination therapy in the management of arterial hypertension.

The ADVANCE trial: clarifying the role of perindopril/indapamide fixed-dose combination in the reduction of cardiovascular and renal events in patients with diabetes mellitus.

Patients with type 2 diabetes mellitus exhibit a marked increase in cardiovascular and renal risk. A number of interventional trials have shown that these patients benefit greatly from aggressive BP lowering, especially when the drug regimen comprises an inhibitor of the renin-angiotensin system. The results of the placebo-controlled ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial, conducted in patients with type 2 diabetes, are exemplary in this respect. The systematic use of a fixed-dose combination containing the ACE inhibitor perindopril and the diuretic indapamide afforded substantial protection against cardiovascular mortality and myocardial infarction, while providing important renoprotection, reducing the development of micro- and macroalbuminuria, and allowing regression of nephropathy. The beneficial effects were obtained regardless of baseline BP and whether or not the patients were receiving antihypertensive therapy.

Combined application of continuous wavelet transform-zero crossing technique in the simultaneous spectrophotometric determination of perindopril and indapamid in tablets

Signal processing methods based on the combined use of the continuous wavelet transform (CWT) and zero-crossing technique were applied to the simultaneous spectrophotometric determination of perindopril (PER) and indapamide (IND) in tablets. These signal processing methods do not require any priory separation step. Initially, various wavelet families were tested to identify the optimum signal processing giving the best recovery results. From this procedure, the Haar and Biorthogonal1.5 continuous wavelet transform (HAAR-CWT and BIOR1.5-CWT, respectively) were found suitable for the analysis of the related compounds. After transformation of the absorbance vectors by using HAAR-CWT and BIOR1.5-CWT, the CWT-coefficients were drawn as a graph versus wavelength and then the HAAR-CWT and BIOR1.5-CWT spectra were obtained. Calibration graphs for PER and IND were obtained by measuring the CWT amplitudes at 231.1 and 291.0 nm in the HAAR-CWT spectra and at 228.5 and 246.8 nm in BIOR1.5-CWT spectra, respectively. In order to compare the performance of HAAR-CWT and BIOR1.5-CWT approaches, derivative spectrophotometric (DS) method and HPLC as comparison methods, were applied to the PER-IND samples. In this DS method, first derivative absorbance values at 221.6 for PER and 282.7 nm for IND were used to obtain the calibration graphs. The validation of the CWT and DS signal processing methods was carried out by using the recovery study and standard addition technique. In the following step, these methods were successfully applied to the commercial tablets containing PER and IND compounds and good accuracy and precision were reported for the experimental results obtained by all proposed signal processing methods.

Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary hypertensive rats: comparative effects on pulmonary vascular structure and function

1 Hypoxic pulmonary hypertension in rats (10% O-2, 4 weeks) is characterized by changes in pulmonary vascular structure and function. The effects of the angiotensin converting enzyme inhibitor perindopril (oral gavage, once daily for the 4 weeks of hypoxia) on these changes were examined. 2 Perindopril (30 mg kg(-1) d(-1)) caused an 18% reduction in pulmonary artery pressure in hypoxic rats. 3 Structural changes (remodelling) in hypoxic rats included increases in (i) critical closing pressure in isolated perfused lungs (remodelling of arteries (50 mu m 0.d.) and (ii) medial wall thickness of intralobar pulmonary arteries, assessed histologically (vessels 30-100 and 101-500 mu m o.d.). Perindopril 10 and 30 mg kg(-1) d(-1) attenuated remodelling in vessels less than or equal to 100 mu m (lungs and histology), 30 mg kg(-1) d(-1) was effective in vessels 101-500 mu m but neither dose prevented hypertrophy of main pulmonary artery. 3 mg kg(-1) d(-1) was without effect. 4 Perindopril (30 mg kg(-1) d(-1)) prevented the exaggerated hypoxic pulmonary vasoconstrictor response seen in perfused lungs from hypoxic rats but did not prevent any of the functional changes (i.e. the increased contractions to 5-HT, U46619 (thromboxane-mimetic) and K+ and diminished contractions to angiotensins I and II) seen in isolated intralobar or main pulmonary arteries. Acetylcholine responses were unaltered in hypoxic rats. 5 We conclude that, in hypoxic rats, altered pulmonary vascular function is largely independent of remodelling. Hence any drug that affects only remodelling is unlikely to restore pulmonary vascular function to normal and, like perindopril, may have only a modest effect on pulmonary artery pressure.

The use of ACE-inhibitors after myocardial infarction

Background: There is good evidence that angiotensin-converting enzyme (ACE) inhibitors are beneficial after myocardial infarction (MI). However, it is not known how widely this evidence is used in practice and whether all eligible patients receive this therapy. Aim: To assess the usage of ACE inhibitors in patients after MI in a large teaching hospital. Method: A one month prospective analysis, combined with a three month retrospective analysis, was conducted at the Royal Brisbane Hospital (RBH) in February-March 2000. Patients admitted with an MI or who had been diagnosed with an MI during admission from November 1999 to March 2000 were identified from the coronary care unit (CCU) records. Inpatient medication charts and outpatient records were then reviewed. Information collected included: ACE inhibitor use, doses, reasons for prescribing/not prescribing ACE inhibitors, and ACE inhibitor prescribers (cardiologists or general physicians). Results: Forty four patients with an MI were included in the study, 28 of whom were prescribed ACE-inhibitors (64%). Twenty four of the 28 patients on ACE inhibitors were prescribed perindopril. The major reason given for prescribing ACE inhibitors was signs of congestive cardiac failure. All ACE inhibitors initiated in patients after MI at RBH were ordered by cardiologists. Conclusion: ACE inhibitors were prescribed appropriately in 88% of patients who met criteria for their use. This high percentage of appropriate prescribing was encouraging. Reevaluation as part of an ongoing quality assurance activity could be used to ensure this is maintained.

Hypertension: which aspects of hypertension should we impact on and how?

Cardiovascular complications may, to a large extent, be prevented by lowering blood pressure in hypertensive patients. International recommendations currently stress the importance of reaching values of below 140/90 mmHg in each patient or even lower in the case of concomitant diabetes or renal impairment. It is currently considered crucial to control the systolic pressure as well as the diastolic pressure, in particular because the relationship between cardiovascular risk and blood pressure is closer for the systolic than the diastolic value. An increase in systolic pressure is in itself a sign of the stiffening of the arterial tree. In most patients, the target pressure may only be reached by combining several different antihypertensive agents. In the STRATHE Study, a greater antihypertensive efficacy, in particular on systolic pressure, was obtained by instituting treatment with a fixed low-dose combination of an angiotensin-converting enzyme inhibitor (perindopril) and a diuretic (indapamide), in comparison with other therapeutic strategies based on single-agent therapy. Fixed-dose antihypertensive combinations have now become a validated option for initiating antihypertensive treatment.

Position of indapamide , a diuretic with vasorelaxant activities, in antihypertensive therapy.

Introduction: Diuretics play a pivotal role in the management of hypertension. A large experience has been accumulated with indapamide , a long-acting thiazide-like diuretic that lowers blood pressure (BP) primarily through its natriuretic diuretic effect. Some of its long-term antihypertensive efficacy may be due to calcium antagonist-like vasorelaxant activities. Indapamide has protecting effects in a variety of conditions associated with high cardiovascular risk, such as diabetes, left ventricular hypertrophy, nephropathy and stroke. It is highly effective in lowering BP, whether given alone or in combination. Indapamide is well tolerated and has the advantage of having no adverse impact on glucose and lipid metabolism. Today, thiazide-like diuretics are regarded more and more as preferred drugs, when diuretic therapy is required to lower BP. Areas covered: The aim of this paper is to review the experience accumulated with indapamide. It is limited to clinical studies that are relevant for the everyday management of hypertensive patients, whether or not they exhibit cardiovascular or renal disease. Expert opinion: Indapamide, because of its well-documented beneficial effects on cardiovascular and renal outcomes, represents a safe and valuable option for treating patients with high BP. There is, however, still room for new trials evaluating the combination of this diuretic with other types of antihypertensive drugs, in particular a calcium antagonist such as amlodipine. There is also the need to compare the indapamide-perindopril and indapamide-amlodipine combinations, in terms of antihypertensive efficacy, tolerability and effects on target organ damage and, ideally, on cardiovascular mortality.

Hypertension et diabète ADVANCE : une étude de morbidité-mortalité : nouveautés en médecine 2007 [ADVANCE: a morbidity mortality study of diabetes and hypertension]

The ADVANCE study is a morbidity-mortality double-blind trial carried out in normotensive or hypertensive patients with type 2 diabetes. The patients were randomly assigned to receive containing a fixed-combination tablet of an ACE inhibitor (perindopril) with a diuretic (indapamide) (4 mg/l,250 mg, n=5569), or placebo (n=5571), administered if needed on top of other blood pressure lowering agents. Significant reductions in the relative risk of death from cardiovascular disease (18%), total coronary events (14%), and total renal events (21%) were observed. Thus, in patients with type 2 diabetes, a drug regimen based on a fixed-dose combination of perindopril/ indapamide affords major protection against both the macro and microvascular complications. L'étude ADVANCE est un essai clinique de morbidité-mortalité réalisé en double insu chez des malades avec diabète de type 2 normo ou hypertendus. Les malades ont été alloués au hasard pour un suivi moyen de 4,3 ans à un traitement comportant soit une association fixe de l'inhibiteur de l'ECA périndopril et du diurétique indapamide (4 mg/1,250 mg, n = 5569), soit un placebo (n = 5571), ceci en plus si nécessaire d'autres médicaments antihypertenseurs. Des réductions significatives du risque relatif ont été observées sous périndopril/indapamide, en particulier de la mortalité cardiovasculaire (18%), de l'ensemble des événements coronaires (14%) et rénaux (21%). Ainsi chez le malade avec diabète de type 2, un traitement basé sur une association de périndopril et d'indapamide à doses fixes a un effet protecteur majeur contre les complications macro et microvasculaires.

Managing hypertension in high-risk patients: lessons and promises from the STRATHE and ADVANCE trials.

Pharmacological treatment of hypertension represents a cost-effective way of preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment, blood pressure should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Such targets cannot usually be reached using monotherapies. This is especially true in patients who present with a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases the blood pressure control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has been shown in controlled trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving the stiffness of large arteries. Using this combination to initiate antihypertensive therapy has been shown in a double-blind trial (Strategies of Treatment in Hypertension: Evaluation; STRATHE) to normalize blood pressure (< 140/90 mmHg) in significantly more patients (62%) than a sequential monotherapy approach based on atenolol, losartan and amlodipine (49%) and a stepped-care strategy based on valsartan and hydrochlorothiazide (47%), with no difference between the three arm groups in terms of tolerability. An ongoing randomized trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ADVANCE) is a study with a 2 x 2 factorial design assessing the effects of the fixed-dose perindopril-indapamide combination and of the intensive gliclazide modified release-based glucose control regimen in type 2 diabetic patients, with or without hypertension. A total of 11 140 patients were randomly selected. Within the first 6 weeks of treatment (run-in phase), the perindopril-indapamide combination lowered blood pressure from 145/81 +/- 22/11 mmHg (mean +/- SD) to 137/78 +/- 20/10 mmHg. Fixed-dose combinations are becoming more and more popular for the management of hypertension, and are even proposed by hypertension guidelines as a first-line option to treat hypertensive patients.

Nouveautés en médecine ambulatoire [Innovations in ambulatory care]

During 2008, we selected 8 studies of interest. It seems important to continue to treat high tension for old patients. To give a good medication against pain, to maintain activity and to reassure patient is the treatment for acute back pain; surgery for spinal stenosis has better results than other treatments at two years of evolution. Pregabalin seems to provide clinically benefit to patients with fibromyalgia. Helicobacter pylori test and treat has the same results than proton pomp inhibitor in initial management of dyspepsia; extending triple therapy beyond 7 days is unlikely to be a clinical useful strategy. Syphilis testing algorithms using treponemal tests for initial screening could be inversed. Finally, selective reporting of clinical trials results for antidepressant are relatively frequent.

A patient with Hypertension Uncontrolled by Previous treatment

Co-administration of antihypertensive agents with different modes of action is required in most hypertensive patients to control blood pressure. This led to the development of fixed-dose combinations of established efficacy and tolerability, with the convenience of a single tablet facilitating long-term adherence with therapy. Blockade of the renin-angiotensin system (RAS) is widely used in hypertensive patients, particularly in those at high risk of cardiovascular or renal diseases. There is therefore a strong rationale for including a blocker of the RAS in fixed combinations, together with either a diuretic or a calcium antagonist. Patient characteristics and cardiovascular risk profiles are useful in guiding the choice of combinations administered. Adding a diuretic or a calciumantagonist to aRAS blocker is a valuable option in practically all patients, whether or not they have comorbidities. Amajor task is to individualize the treatment, ie, to find a drug regimen that normalizes the patient's blood pressure while preserving his or her quality of life. This can be achieved in most patients using the fixeddose combination containing the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide. A number of trials have established the antihypertensive efficacy and the protective effects of this combination in hypertensive patients, which justifies its broad use in patients with blood pressure uncontrolled by other blood pressure-lowering agents.

Application in the STRATHE trial of a score system to compare the efficacy and the tolerability of different therapeutic strategies in the management of hypertension

A score system integrating the evolution of efficacy and tolerability over time was applied to a subpopulation of the STRATHE trial, a trial performed according to a parallel group design, with a double-blind, random allocation to either a fixed-dose combination strategy (perindopril/indapamide 2 mg/0.625 mg, with the possibility to increase the dose to 3 mg/0.935 mg, and 4 mg/1.250 mg if needed, n = 118), a sequential monotherapy approach (atenolol 50 mg, followed by losartan 50 mg and amlodipine 5 mg if needed, n = 108), or a stepped-care strategy (valsartan 40 mg, followed by valsartan 80 mg and valsartan 80 mg+ hydrochlorothiazide 12.5 mg if needed, n = 103). The aim was to lower blood pressure below 140/90 mmHg within a 9-month period. The treatment could be adjusted after 3 and 6 months. Only patients in whom the study protocol was strictly applied were included in this analysis. At completion of the trial the total score averaged 13.1 +/- 70.5 (mean +/- SD) using the fixed-dose combination strategy, compared with -7.2 +/- 81.0 using the sequential monotherapy approach and -17.5 +/- 76.4 using the stepped-care strategy. In conclusion, the use of a score system allows the comparison of antihypertensive therapeutic strategies, taking into account at the same time efficacy and tolerability. In the STRATHE trial the best results were observed with the fixed-dose combination containing low doses of an angiotensin enzyme converting inhibitor (perindopril) and a diuretic (indapamide).