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[Reflexion of French experts on the key points of the symposium].

The French experts present at the Eutherapy Symposium held in Prague confirmed the importance of left ventricular hypertrophy (LVH) and microalbuminuria as major independent risk factors for cardiovascular disease. Factors that must be considered for the treatment of hypertension in patients, particularly with type 2 diabetes. Professor J.M. Mallion stressed the contribution of thiazide and thiazide-like diruetics as indapamid, especially the 1.5 mg SR formulation. Professor F. Forette and Doctor O. Hanon recalled that the HYVET study is expected to confirm the beneficial effect of this same treatment on morbidity and mortality in very elderly patients. Professor O. Dubourg recalled the beneficial effect of indapamid SR on LVH demonstrated in the LIVE study. Likewise, Professor M. Marre emphasized its important impact on microalbuminuria as shown in the NESTOR study.

Adult↗

[CEA comprehensive evaluation for Western and traditional Chinese hypotensive drugs].

OBJECTIVE: To make a cost-effectiveness analysis (CEA) comprehensive evaluation for 4 hypotensive drugs, by observing the effects of drugs on blood pressure lowering, symptom improving, and adverse effect and quality of life (QOL) influencing. METHODS: Two hundred and ninety-two patients with mild to moderate hypertension were divided into 4 groups at random and treated with compound Lingjiao Jiangya Pill, benazepril, amlodipine and indapamide respectively with a therapeutic course of 6 weeks. QOL was measured with FS-36 questionnaire and efficacy policy model was applied for comprehensive evaluation of CEA. RESULTS: Through CEA a comprehensive evaluation was made in order as follows: indapamide 3.65 which was the best, and then Lingjiao Jiangya Pill 3.55, amlodipine 2.90 and benazepril 2.35. CONCLUSION: The 4 drugs can not only lower blood pressure but also improve clinical symptoms with less adverse effect. It is of great practical significance to evaluate hypotensive drugs by combining QOL appraisal. The position of Lingjiao Jiangya Pill in CEA order suggests that more attention should be paid to herbal hypotensive drugs.

Adult↗

Comparison of cicletanine with other antihypertensive drugs in SHR-SP models.

The effects of cicletanine were compared with those of four other antihypertensive drugs (prazosin, a highly selective alpha 1 antagonist; captopril, an angiotensin-converting enzyme inhibitor; indapamide, an antihypertensive diuretic; and hydrochlorothiazide, a purely diuretic agent) on young stroke-prone SHR rats with high-salt diet. All the drugs except hydrochlorothiazide prevented the onset of hypertension. The minimal effective dose on blood pressure was 1 mg/kg for both cicletanine and captopril, and 3 mg/kg for indapamide. The action on cardiac hypertrophy and diuresis occurs at a dose of cicletanine 10 to 30 times higher than that required to produce the antihypertensive effect. Renal hypertrophy was also decreased significantly by cicletanine at a dose of 100 mg/kg.

Animals↗

[Mechanism of action of benzothiadiazides in arterial hypertension: the energetic theory].

Hydrochlorothiazide, tienilic acid, chlorthalidone and indapamide inhibit membrane adenylate cyclase of pigeon erythrocytes in vitro. This effect is related to the action of these substances on the interface between the membranous phospholipids and adenylate cyclase. Indapamide with its strong lipophic properties, has a more specific action on the intracellular regulation of adenylate cyclase. The relationship between the inhibition of adenylate cyclase and the antihypertensive effects of these drugs is discussed.

Adenylyl Cyclase Inhibitors↗

Biochemical changes in black and Indian hypertensive patients on diuretic therapy.

Thirty-seven patients (19 Blacks and 18 Indians) suffering from mild hypertension were given each of five diuretics separately for 4 weeks after a 'washout' period on placebo of the same duration. The diuretics used were hydrochlorothiazide 25 mg/d (Dichlotride; Frosst MSD), hydrochlorothiazide 25 mg plus triamterene 50 mg (Dyazide; SKF) 1 tablet per day, amiloride hydrochloride 5 mg plus hydrochlorothiazide 50 mg (Moduretic; MSD) 1 tablet per day, chlorthalidone (Hygroton; Geigy) 50 mg/d and indapamide (Natrilix; Servier) 2.5 mg/d. The study showed that during the acute phase of diuretic therapy for the treatment of hypertension plasma potassium levels were decreased by thiazide and thiazide-like diuretics and increased by potassium-sparing diuretics. However, despite the decrease in plasma potassium levels produced by thiazide diuretics and indapamide these levels did not fall to 3.0 mmol/l or less. All the diuretics were effective in lowering the standing mean arterial pressure when compared with placebo values. In the absence of significant hypokalaemia, the choice of a diuretic for the Black hypertensive patient should therefore be determined by its cost.

Adult↗

Acute and chronic diuretic-induced alterations in urinary sodium and calcium excretion in the conscious rat.

The acute and chronic (5-day) effects of three low-ceiling diuretics (hydrochlorothiazide, indapamide or xipamide) and two high-ceiling diuretics (furosemide or muzolimine) on urinary volume and electrolyte excretion were examined in the saline-loaded conscious rat. The three low-ceiling agents produced qualitatively similar alterations in both acute and chronic volume and electrolyte excretion patterns. Each of these agents produced an acute disassociation between urinary sodium and calcium excretion and hypocalciuria after chronic administration. It is suggested that indapamide and xipamide, like hydrochlorothiazide, inhibit sodium but not calcium reabsorption in the distal nephron. Acute as well as chronic treatment with either furosemide or muzolimine produced dose-dependent increases in urinary volume and electrolyte excretion. A generally parallel response was observed on sodium and calcium excretion with these agents. It is suggested that muzolimine, like furosemide, inhibits both sodium and calcium reabsorption in the ascending limb of Henle's loop.

Animals↗

[Regression of hypertrophy of the left ventricle in patients with hypertension after 6-month treatment with Fludex].

Indapamide (Fludex) administered in daily doses of 2.5 mg resulted in optimal improvement of the blood pressure in patients with mild or moderate hypertension. During the period of 6 months treatment that was tolerated well by the patients, no influence of indapamide on the levels of glucose, cholesterol, triglycerides, and creatinine in blood was observed. A mild decrease of serum potassium in blood was clinically not relevant. Using echocardiography and electrocardiography a regression of the hypertrophy of the left ventricle of the heart was observed.

Blood Pressure↗

Pharmacoepidemiology of antihypertensive drugs in primary care setting of Bahrain between 1998 and 2000.

PURPOSE: To compare pattern of antihypertensive drug utilization in 1998 with 2000 following the: (a) publication of 1999 World Health Organization/International Society of Hypertension (WHO/ISH) guidelines for drug management of hypertension; and (b) introducing new antihypertensives to the essential drug list, in primary care, Bahrain. METHODS: Retrospective prescription-based survey carried out in seven out of 20 primary care health centers in Bahrain. A total of 9272 patients comprising 6543 with uncomplicated hypertension and 2729 with diabetic hypertension were studied. RESULTS: Between 1998 and 2000, the prescription rate of beta-blockers and methyldopa significantly declined (p < 0.0001) while the rate of angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) increased (p < 0.0001) in uncomplicated hypertension. However, in diabetic hypertension there was a non-significant decline in utilization of beta-blockers, CCBs, methyldopa, and diuretics whereas a significant increase in prescribing of ACE inhibitors (p < 0.0001). Inclusion of Perindopril into the essential drug list resulted in an overall increase in utilization of ACE inhibitors: use of captopril and enalapril declined while lisinopril and perindopril increased. Substitution of immediate-release (IR) indapamide by sustained-release (SR) formulation did not change the overall utilization of diuretics; however, intra-class changes were evident with a significant decline in use of thiazide diuretics and concomitant increase in use of SR indapamide by 2000. CONCLUSIONS: The antihypertensive prescribing pattern is influenced by WHO/ISH guidelines as well as by introduction of new antihypertensives to primary care essential drug list in primary care. The choice of a drug is also influenced by presence of co-morbidity with diabetes mellitus.

Adrenergic beta-Antagonists↗

Cell cultures in the investigation of thiazide phototoxicity.

The NHIK 3025 cell line (Norsk Hydro Institutt for Kreftforskning), a human in situ carcinoma of the cervix cell line, was used to investigate the thiazides bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlortalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide and xipamide for their potential phototoxic properties. Cell death following UVA irradiation and dependent on test substance concentration was observed in the presence of all the tested substances except chlortalidone, furosemide, indapamide and xipamide. Bendroflumethiazide was phototoxic at concentrations of 0.05 mM and higher; bemetizide, benzylhydrochlorothiazide, bumetanide and hydroflumethiazide were phototoxic at 0.25 mM and higher and butizide, hydrochlorothiazide, piretanide, polythiazide and trichlormethiazide were phototoxic at 0.5 mM and higher.

Benzothiadiazines↗

The influence of non-beta-blocking drugs on the lipid profile: are diuretics outclassed as initial therapy for hypertension?

Diuretic drugs, when used in the treatment of hypertension, raise the blood concentrations of total cholesterol and low-density or very low-density lipoprotein cholesterol. Triglycerides often increase as well. Thiazide, phthalimidine, loop, potassium-sparing, and methylindoline drugs produce a similar effect. Only indapamide, a methylindoline agent with vasodilator activity, has been free of adverse lipid effects. It remains unclear whether it is the low dose of indapamide or some other quality that frees it of this effect. In long-term diuretic therapy, total cholesterol returns to, or below, baseline values, suggesting that the lipid elevations are transitory. However, in studies with adequate control groups, total cholesterol declines below baseline valves in control subjects such that an adverse differential in lipid values persists in long-term treatment. Selective alpha-1-adrenoceptor-blocking drugs cause no change or favorable alterations in lipid concentrations in short-term and long-term (1 year) treatment. Among all antihypertensive drugs, this class of agents, and especially prazosin, has produced the most consistently salutary lipid and metabolic effects. Although less well examined, guanabenz, clonidine, guanfacine, and diltiazem have been associated with favorable lipid changes. Captopril and nifedipine have caused no change in lipid-lipoprotein values in limited investigations. These agents are preferable to diuretics and certain beta blockers with respect to short-term effects on lipids and lipoproteins. Their ultimate superiority as monotherapy depends on whether they lower blood pressure equally well. Lowering of the probability of coronary heart disease in hypertensive patients depends as much on blood pressure control as on lipid effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

FI-chemiluminometric study of thiazides by on-line photochemical reaction.

The present manuscript deals with a simple and sensitive flow-injection method for the chemiluminescent determination of thiazides. The method is based on the on-line photodegradation and chemiluminescent determination of the resulting photo-fragments. The on-line photodegradation is performed in basic medium by using a photoreactor consisting of a 550cm long x 0.8mm ID piece of PTFE tubing helically coiled around an 8W low-pressure mercury lamp. The determination of the photo-irradiated thiazides is performed by a chemiluminescent oxidative reaction with Ce(IV) in sulphuric acid medium. A heterogeneous group of thiazides (indapamide, metolazone, hydroflumethiazide, chlorthalidone and bendroflumethiazide) has been studied. Hydrochlorothiazide was selected as a test substance. The "on-line" photochemical reaction approach allows the sensitive chemiluminescent determination of thiazides which do not present native chemiluminescence in the absence of sensitizers such as Rhodamine 6G. Linear calibration graphs were typically over the range 0.5-12 microgml(-1) (indapamide, metolazone, hydroflumethiazide and chlorthalidone); and over the range 0.5-5 microgml(-1) (hydrochlorothiazide). Limits of detection ranged between 0.005 microgml(-1) (hydrochlorothiazide) and 0.06 microgml(-1) (bendroflumethiazide). The relative standard deviation for the test substance was 2.0% for 2 microgl(-1) of the drug (n = 11) and the throughput was 65 h(-1) in all cases. The assessment of the photodegradation step on the molecular structure of thiazides was established by recording UV and fluorimetric spectra. The viability of the on-line photoinduced fluorescent determination of hydroflumethiazide and bendroflumethiazide was confirmed. The method was also applied to the determination of hydrochlorothiazide in commercially available formulation.

Flow Injection Analysis↗

Direct determination by capillary electrophoresis of cardiovascular drugs, previously included in liposomes.

The lipophilicity of some cardiovascular drugs was determined by capillary electrophoresis (CE). Mexiletine, amlodipine and indapamide, the drugs considered, were in contact with liposomial vescicles for 2, 4 or 6 h. After the contact time the drugs, penetrated into liposomial vesicles, were determined by CE using phosphate buffer (pH 6.3 or 7.4) or borate buffer (pH 9). The lipophilicity of three drugs was determined considering the drug percentage penetrated into liposomial vesicles. The found lipohilicity order was amlodipine > mexiletine > indapamide.

Cardiovascular Agents↗

Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease.

AIM: To determine the effects of a perindopril-based blood pressure lowering regimen on major cardiac events among hypertensive and non-hypertensive patients with a history of cerebrovascular disease. METHODS AND RESULTS: A total of 6105 individuals with a history of stroke or transient ischaemic attack were randomly assigned active treatment (n=3051) or placebo (n=3054). Active treatment comprised the angiotensin-converting-enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide at the discretion of treating physicians. Over a mean of 3.9 years of follow-up, active treatment reduced blood pressure by 9/4 mm Hg compared with placebo and reduced the primary outcome, stroke, by 28%. Major coronary events occurred in 269 participants (active 3.8%, placebo 5.0%) and heart failure was diagnosed in 264 participants (active 3.7%, placebo 4.9%). Active treatment reduced the risk of major coronary events by 26% (95% CI: 6-42%; p=0.02) and the risk of congestive heart failure by 26% (5-42%; p=0.02). For each of these outcomes, there was no clear evidence of differences between the treatment effects in participants classified as hypertensive or non-hypertensive, and those with or without a history of coronary heart disease. CONCLUSIONS: Among individuals with cerebrovascular disease, blood pressure lowering with a regimen involving perindopril and indapamide not only reduced the risk of stroke, but also substantially reduced the risks of cardiac outcomes.

Angiotensin-Converting Enzyme Inhibitors↗

Antihypertensive drugs and endothelial cell function.

Arterial hypertension is associated with increased capillary permeability, a possible contributor to the vascular remodeling process which could be involved in certain pathological conditions arising from elevated blood pressure. This study evaluated the effects of various antihypertensive drugs on capillary permeability in the normal rat, using Evan's blue dye (EB) as a marker of albumin extravasation. The results reveal that acute injection of certain diuretics (furosemide, indapamide, hydrochlorothiazide) increase while others (amiloride, cicletanine) decrease capillary permeability via stimulation of the cyclooxygenase pathway. 10 day gavage with indapamide, amiloride and cicletanine, as well as angiotensin-converting enzyme (ACE) inhibitor perindopril and calcium channel blockers nifedipine and verapamil decreases capillary permeability, whereas furosemide, hydrochlorothiazide, ACE inhibitor captopril and calcium channel blocker clentiazem do not modify or increase EB extravasation. Hence, selected antihypertensive agents reduce capillary permeability and could therefore have a supplemental protective vascular effect, in addition to their lowering arterial pressure.

Angiotensin-Converting Enzyme Inhibitors↗

[Antihypertensive therapy in diabetes mellitus].

Approximately 150 million people worldwide have diabetes mellitus, of whom 90% are type II diabetics. It is therefore of no surprise that diabetic nephropathy has become the leading cause of end-stage renal disease. Opposite to what has been known previously, kidney disease is at least as common in type II as in type I diabetes. However, because the majority of type II diabetics has hypertension for many years before diabetes mellitus becomes clinically relevant, renal lesions are often heterogeneous with frequent exclusive presence of ischemic changes. For the treatment of hypertension in diabetics without nephropathy (no microalbuminuria), drugs that exert beneficial effects or are at least neutral with respect to lipid and glucose metabolism, such as ACE inhibitors, angiotensin II-receptor antagonists, non-dihydropyridine-calcium channel blockers and the thiazide-like indapamide, are to be preferred. Although metabolically neutral, dihydropyridine calcium channel blockers should be used with caution, since an increase in cardiovascular morbidity and mortality in type II diabetics treated with these compounds has most recently been described. Once that diabetic nephropathy is established, blood pressure should be lowered to 120/80 mmHg (measured in seated position). Antihypertensive treatment should primarily be based on ACE inhibitors; angiotensin II-receptor antagonists are a valuable alternative if ACE inhibitors are not tolerated. Both ACE inhibitors and angiotensin II-receptor antagonists should be used with high caution in elderly patients with severe atherosclerosis in whom acute renal failure could occur due to the presence of bilateral renal artery stenosis. Newer studies indicate that non-dihydropyridine calcium channel blockers such as verapamil and diltiazem may be as effective as ACE inhibitors in preserving renal function in diabetic nephropathy. A fix-dose combination of the ACE inhibitor trandolapril with verapamil is now available; it should be reserved for patients whose blood pressure and/or proteinuria can not be adequately controlled with ACE inhibitors. Finally, indapamide is the only antihypertensive diuretic with nephroprotective properties.

Antihypertensive Agents↗

Antihypertensive drug treatment: a comparison of usual care with self blood pressure measurement.

Blood pressure self-measurement is increasing in most communities and yet its role in the management of hypertension is poorly understood. This study was devised to evaluate the behaviour of doctors in general practice when treating patients with poorly controlled essential hypertension who use self-measurement. Patients, most of whom were already taking antihypertensive medications were commenced on perindopril or indapamide at their doctor's discretion and were randomly allocated to self-measurement (SM) using an OMRON HEM706 oscillometric device or a continuation of their usual care (UC) over an 8-week period. This was an observational study without any specific or set treatment goals for the doctor to follow. Sixty of 62 subjects completed the study and the two groups were equally matched for age, body mass index, gender, and blood pressure (BP). While additional perindopril or indapamide produced a significant fall in BP in both groups over the study period, the systolic pressure remained significantly higher in the SM group (sitting 148 +/- 3 compared with 142 +/- 3; 145 +/- 3 compared with 138 +/- 3 mm Hg respectively; P < 0.05). Twenty-four hour and daytime ambulatory monitor systolic pressures were also significantly higher in the SM group. Differences in diastolic BP were not statistically significant. Furthermore, SM patients were less likely to have their medications increased and more likely to have them reduced or ceased. Doctors and patients found self-measurement convenient and useful. This study suggests that doctors prescribing decisions are influenced by evidence from self-measurement of BP with consequential increases in office BP related to reduced drug use. While self-BP measurement can offer reassurance about adequacy of control when away from a physicians office, our best evidence of understanding target blood pressures comes from large randomised studies using office blood pressures as an end-point. There is an urgent need for further study to provide arbitration between self-measurement and office blood pressures although each measurement must contribute to the management of hypertension.

Antihypertensive Agents↗

Progress in reducing the burden of stroke.

1. The burden of stroke worldwide is growing rapidly, driven by an ageing population and by the rapid rate of urbanization and industrialization in the developing world. There are approximately 5 million fatal and 15 million non-fatal strokes each year and over 50 million survivors of stroke alive, worldwide, today. 2. The most important determinant of stroke risk is blood pressure, with a strong, continuous relationship between the level of the systolic and diastolic pressures and the risk of initial and recurrent stroke, in both Western and Asian populations. 3. Randomized clinical trials have clearly demonstrated that blood pressure lowering reduces the risk of initial stroke by 35-40% in hypertensive patients; but, until recently, there was no conclusive evidence that blood pressure lowering was effective in the secondary prevention of stroke. 4. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) has provided definitive evidence that blood pressure lowering in patients with previous stroke or transient ischaemic attack (TIA) reduces the incidence of secondary stroke by 28%, of major vascular events by 26% and of major coronary events by 26%. These reductions were all magnified by approximately 50% in a subgroup of patients in whom the angiotensin-converting enzyme inhibitor perindopril was routinely combined with the diuretic indapamide. 5. Successful global implementation of a treatment with perindopril and indapamide in patients with a history of stroke or TIA would markedly reduce the burden of stroke and could avert between 0.5 and one million strokes each year, worldwide.

Angiotensin-Converting Enzyme Inhibitors↗

Demonstration of an in vitro direct vascular relaxant effect of diuretics in the presence of plasma.

OBJECTIVE: To determine whether diuretics have direct vascular actions and to compare the in vitro effects of a loop diuretic with thiazide and thiazide-like diuretics. DESIGN: A randomized, double-blind, vehicle-controlled design was used to avoid experimenter bias. METHODS: Concentration-response curves to hydrochlorothiazide, chlorthalidone, indapamide, and furosemide were tested on the following male Wistar rat vascular smooth muscle preparations: rat aortic rings, rat pulmonary artery rings, and rat mesenteric portal vein. RESULTS: All four diuretics demonstrated no vasorelaxant action in Krebs solution. They all exhibited vasorelaxant actions in aortic and pulmonary artery rings when plasma was mixed with Krebs solution in a 50:50 ratio. The magnitude of the relaxation was greater in the aortic ring preparation. This direct vascular action was found to be concentration dependent and endothelium independent. The order of potency of the vasorelaxant action of the diuretics was (from most to least) indapamide, hydrochlorothiazide, chlorthalidone, and furosemide on both aortic and pulmonary artery rings. CONCLUSION: Diuretics possess direct vasorelaxant effects that are dependent upon the presence of plasma; this action may contribute to their antihypertensive properties.

Animals↗