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PubMed1983

Extrarenal contributions to indapamide's antihypertensive mechanism of action.

Autonomic responses in heart rate and blood pressure to Valsalva maneuvers and changes in vascular reactivity to pressor doses of phenylephrine and angiotensin II were studied before and after treatment with indapamide, a new antihypertensive diuretic. Six healthy male volunteers, placed on a daily diet consisting of 100 mEq of sodium, 80 mEq of potassium, and a fluid intake of 2500 ml, participated in this single-blind, placebo-controlled study. During active treatment, 5 mg of indapamide was administered once daily for 14 days. On the mornings of hemodynamic testing, samples of blood, 24-hour urine, and plasma were obtained and analyzed for hematocrit, catecholamines and their metabolites, plasma renin activity, and aldosterone levels. Since each subject served as his own control, the results were analyzed by the paired t-test method. Plasma renin activity and 24-hour urinary aldosterone levels increased (p less than 0.05), and serum potassium and chloride levels decreased (p less than 0.05). No other significant laboratory changes were noted after treatment, including changes in the plasma and urinary catecholamine levels. Following treatment, responses in heart rate and blood pressure to Valsalva maneuvers were unaltered. During the control period the doses of phenylephrine and angiotensin II required to raise the systolic pressure 25 to 35 mm Hg and the diastolic pressure 20 to 30 mm Hg were 5.03 +/- 0.72 micrograms/kg and 16.7 +/- 2.1 ng/kg, respectively. After treatment, the doses of phenylephrine and angiotensin II were significantly (p less than 0.05) greater: 10.72 +/- 1.02 micrograms/kg and 31.7 +/- 4.8 ng/kg, respectively. Dose-response relationships to these pressor agents were shifted in parallel to the right after treatment. A small but significant decrease in body weight, which may have reflected a decrease in plasma volume, was observed. However, no orthostatic changes between the supine and erect mean arterial blood pressures or incremental increases in heart rates were noted between the two periods. An increase in hematocrit and blunting of the diastolic overshoot during the Valsalva maneuvers that were used as indexes of plasma volume contraction were also not observed. In summary, our results indicate that changes in vascular responsiveness occurred by mechanisms independent of changes in the autonomic nervous system, since plasma norepinephrine levels did not change and responsiveness to Valsalva maneuvers was unaltered. Furthermore, it appears that this effect on the vasculature was probably not related to changes in plasma volume.

Adult↗
PubMed1983

Some wrong-way chemical changes during antihypertensive treatment: comparison of indapamide and related agents.

Despite the beneficial therapeutic effects of antihypertensive drugs, some agents--particularly diuretics--seem to go in the "wrong direction" chemically. In fact, these changes could counteract some of the benefits resulting from lowering a patient's blood pressure. In the absence of hard evidence of the efficacy of long-term diuretic treatment of mild hypertension, we must be maximally sure that such therapy causes no harm. Thiazide and related diuretics have been associated with four distinct wrong-way chemical changes: increases in plasma concentrations of cholesterol, glucose, and uric acid, and a decrease in plasma potassium levels. The potential ramifications of such changes are well understood. The increase in circulating cholesterol, an established risk factor of myocardial infarction and stroke, is of particular concern--each year approximately one million hypertensive patients have myocardial infarctions. As a result, the search for safer and more effective diuretics must continue. Indapamide, a new antihypertensive drug, appears to meet these criteria. It is an effective diuretic with a considerable peripheral vasodilatory effect. Additionally, it does not appear to induce any significant change in circulating cholesterol, whereas chlorthalidone has been found to increase total cholesterol by 5%. Hydralazine is the only antihypertensive agent that seems to lower total cholesterol levels significantly. Neither indapamide nor hydralazine appears to affect plasma glucose levels; benzothiadiazines, however, have been found to induce an increase in circulating glucose.

Adult↗
PubMed1991

Regression of microalbuminuria in type II diabetic, hypertensive patients after long-term indapamide treatment.

The influence of hypertension on the progression of persistent microalbuminuria in type II diabetes has not yet been clarified. We have studied the effects of 36 months of indapamide treatment (2.5 mg once daily) on blood pressure (BP), albumin excretion rate (AER), urinary immunoglobulin G4 (IgG4), and glomerular filtration rate (GFR) in 10 patients who were mildly hypertensive and had type II microalbuminuric diabetes (AER greater than 30 mg/24 hours and less than 300 mg/24 hours). BP, AER, and IgG4 significantly decreased after 6 months until the end of the study. Mean GFR was 94.4 +/- 7.5 ml/min/1.73 m2 in the baseline and did not change significantly throughout the course of the antihypertensive therapy. AER and IgG4 were directly related (r = 0.57; p less than 0.004), whereas BP did not relate to GFR, AER, or IgG4. The nephropathy index (45.5 +/- 4 in the baseline) significantly decreased at 12 months (38.7 +/- 2.1), 24 months (35.4 +/- 1.6), and 36 months (36.5 +/- 1.5) (at least p less than 0.01). Long-term indapamide treatment reduced BP and urinary protein loss without affecting GFR. These results indicate a potential role of this drug in the long-term renal protection of patients with type II diabetes, mild hypertension, and microalbuminuria.

Adult↗
PubMed2005

QT interval prolongation and torsade de pointes associated with indapamide.

Direct blockade of the delayed rectifier repolarising potassium current is the major underlying mechanism of drug-induced QT interval prolongation. Indapamide is a well known blocker of the slow component of the delayed rectifier current leading to prolongation of cardiac repolarization. The case of an acquired long QT and torsade de pointes ventricular tachycardia in a woman with systemic lupus erythematosus and hypertension receiving prednisolone and indapamide, respectively, is described in the present report.

Adult↗
PubMed2005

Determination of lauroyl-indapamide in rat whole blood by high-performance liquid chromatography.

A method based on a liquid-liquid extraction procedure followed by high-performance liquid chromatography (HPLC) coupled with UV-visible detection is described and validated for the determination of lauroyl-indapamide in rat whole blood. The blood sample was extracted with diethyl ether after the addition of 10% trifluoroacetic acid (aq.). The chromatographic separation was performed on a Chromasil ODS column, using methanol-acetonitrile-tetrahydrofuran-0.2% trifluoroacetic acid (170:20:15:38, v/v/v/v) as the mobile phase. The UV detection wavelength was set at 240 nm. The extraction recovery of lauroyl-indapamide was ranged from 76.5 to 82.6%, and the calibration curve had a good linearity in the range of 0.048-200 microg/ml (r = 0.9976). The method presents appropriate intra-day and inter-days repeatabilities, showing values below 7.4% in terms of the percentage of relative standard deviation (R.S.D.). The method proposed is simple, rapid and sensitive, being useful for pharmacokinetic studies in rats.

Animals↗
PubMed2006

Simple, sensitive and rapid LC-MS method for the quantitation of indapamide in human plasma--application to pharmacokinetic studies.

A sensitive and specific method using liquid chromatography with electrospray ionization mass spectrometry (LC-ESI-MS) has been developed and validated for the identification and quantification of indapamide in human plasma. A simple liquid-liquid extraction procedure was followed by injection of the extracts on to a C18 column with gradient elution and detection using a single quadrupole mass spectrometer in selected ion monitoring (SIM) mode. The method was tested using six different plasma batches. Linearity was established for the concentration range 0.5-100.0 ng/ml, with a coefficient of determination (r) of 0.9998 and good back-calculated accuracy and precision. The intra- and inter-day precision (RSD%) was lower than 10%, and accuracy ranged from 85 to 115%. The lower limit of quantification was reproducible at 0.2 ng/ml with 0.2 ml plasma. The proposed method enables the unambiguous identification and quantification of indapamide for pre-clinical and clinical studies.

Antihypertensive Agents↗
PubMed1988

Antihypertensive profile of cicletanine, a furopyridine derivative: comparison with captopril, indapamide and prazosin.

The effects of cicletanine were compared with those of three other antihypertensive drugs: prazosin, a highly selective alpha 1 antagonist, captopril an angiotensin converting enzyme inhibitor and indapamide a diuretic antihypertensive agent, on young stroke-prone SHR rats with high salt diet; furthermore, vascular reactivity to cicletanine was studied on isolated rat aorta. At an equal dose (30 mg/kg per os) all the drugs prevent the onset of hypertension with the same intensity. 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 diuresis and electrolyte excretion occurs at a dose of cicletanine 10 to 30 times higher than that required to produce the anti-hypertensive effect. One of the possible mechanisms of the antihypertensive effects of cicletanine could be due to a direct action of the drug on the vascular wall. This vascular impact could be an interaction with the alpha-adrenoceptor system (apparent pA2 cicletanine = 5.12) or a decrease in the vascular spasmogenic response whatever agonist was studied.

Animals↗
PubMed2002

Two derivative spectrophotometric determinations of indapamide in pharmaceutical dosage forms.

Simple, fast and reliable derivative spectrophotometric methods were developed for determination of indapamide in bulk and pharmaceutical dosage forms. The solutions of standard and the sample were prepared in methanol. The quantitative determination of the drug was carried out using the first-derivative values measured at 252.8 nm (N=6) and the second-derivative values measured at 260.4 nm (N=9). Calibration graphs constructed at their wavelengths of determination were linear in the concentration range of indapamide using peak to zero 1.00-30.00 microg ml(-1) for first-derivative and 1.00-35.00 microg ml(-1) for second-derivative spectrophotometric method. The developed methods were successfully applied for the assay of pharmaceutical dosage forms which do not require any preliminary separation or treatment of the samples. The details of the statistical treatment of analytical data are also presented. The results obtained from two derivative spectrophotometry were compared with a spectrophotometric method reported in literature and no significant difference was found statistically.

Dosage Forms↗
PubMed2003

Optimization of a solid-phase extraction method for determination of indapamide in biological fluids using high-performance liquid chromatography.

A new simple and rapid high-performance liquid chromatographic (HPLC) method with UV detection for the determination of indapamide in biological fluids has been developed. Indapamide and internal standard were isolated from serum and whole blood samples by solid-phase extraction with RP select B cartridges. The chromatographic separation was accomplished on a reversed-phase C(8) column with a mobile phase composed of 0.1% (v/v) triethylamine in water (pH 3.5) and acetonitrile (63:37, v/v). UV detection was set at 240 nm. The calibration curves were linear in the concentration range of 10.0-100.0 ng/ml for serum, and 50.0-500.0 ng/ml for whole blood, and the limits of quantification were 10.0 and 50.0 ng/ml, respectively.

Antihypertensive Agents↗
PubMed1999

Low dose indapamide plus perindopril combination effects on cardiovascular structure and function in genetic hypertension.

1. Although the fixed combination preparations of thiazide and angiotensin-converting enzyme inhibitor are gaining wide acceptance in clinical practice, data on the basic pharmacology of the combinations are relatively limited. The long-term structural and functional effects of a fixed low dose (0.24 + 0.76 mg/kg per day) combination of indapamide + perindopril (I + P,S5590) is spontaneously hypertensive rats (SHR) were examined in the present study. 2. Male SHR (10-12 weeks) were treated with I + P or vehicle for 8 weeks. The blood pressure and heart rate were monitored by weekly measurements. At the end of the treatment period, left ventricular, aortic and intramyocardial coronary arteriole structures were assessed. Contractile and relaxant properties of mesenteric arteries were determined by wire-myography. 3. Indapamide + perindopril combination caused a significant lowering of both systolic (P < 0.001) and diastolic (P < 0.001) blood pressures. Left ventricle plus septum:bodyweight ratio (P < 0.001), aortic medial cross-sectional area (P < 0.05) and media:lumen ratios (P < 0.005) were all significantly reduced by I + P treatment. In contrast, the effect of I + P on intramyocardial coronary vascular structure did not reach statistical significance. There was some improvement in endothelium-independent vasorelaxation of mesenteric vessels but contractile responses to noradrenaline and calcium were unaffected by treatment. 4. In summary, a low dose I + P combination treatment of SHR partly normalizes both systolic and diastolic blood pressures. Cardiac and larger vessel hypertrophy was reversed but intramyocardial coronary arteriole structure was not as readily regressed by the end of the study.

Animals↗
PubMed2001

Indapamide-induced pemphigus foliaceus.

A variety of drugs have been implicated to induce or trigger pemphigus. A case of pemphigus foliaceus that was probably caused by indapamide, in whom the diagnosis was based on clinical, histologic and direct immunofluorescence testing, is reported here. To the best of the authors' knowledge, this is the first reported patient with indapamide-induced pemphigus.

Aged↗
PubMedDate not supplied

Efficacious response with low-dose indapamide therapy in the treatment of type II diabetic patients with normal renal function or moderate renal insufficiency and moderate hypertension.

We examined the efficacy of low daily dose (1.25 mg/day) of indapamide in the treatment of high blood pressure in patients with diabetes mellitus with normal renal function and those with moderate renal insufficiency (serum creatinine <1.5 mg/dl). The study was an open label one of four months duration. Twenty-eight patients were enrolled in the study and only 15 completed it. Within 2 weeks of therapy, systolic blood pressure fell from 173 +/- 4.5 to 144 +/- 2.0 mm Hg and diastolic blood pressure from 96 +/- 2.1 to 80 +/- 1.8 mm Hg (p < 0.01) and blood pressure remained at these levels throughout the study. The results show that low dose indapamide is effective in the treatment of moderate hypertension in patients with diabetes mellitus who have normal renal function or moderate renal insufficiency. Therefore, this dose of 1.25 mg/day is recommended for the treatment of such patients.

Adult↗
PubMedDate not supplied

Effect of indapamide on blood pressure and glucose tolerance in non-insulin-dependent diabetes.

Ten hypertensive non-insulin-dependent diabetic patients were treated with the antihypertensive drug indapamide to assess its effect on glucose tolerance over 1 year. Both systolic and diastolic blood pressures fell significantly (p less than 0.001) over the first month of treatment, and no change in plasma glucose or plasma insulin levels during an oral glucose tolerance test occurred at any time. Indapamide is an effective antihypertensive drug and, in contrast to thiazide diuretics, has no adverse effect on glucose tolerance in non-insulin-dependent diabetic patients.

Adult↗
PubMedDate not supplied

Serum lipoprotein levels during long-term treatment of hypertension with indapamide.

The beneficial effect of antihypertensive pharmacotherapy in decreasing morbidity and mortality in hypertensive patients may be counteracted by metabolic and biochemical disturbances, such as hypokalemia, hyperglycemia, hyperuricemia, and hyperlipoproteinemia, that occur with the administration of thiazides and related diuretics. Antiatherogenic high-density lipoprotein cholesterol may be unchanged, whereas the potentially atherogenic low-density lipoprotein cholesterol may be increased by long-term therapy with thiazide diuretics. Indapamide is a methylindoline antihypertensive diuretic with a considerable peripheral vasodilatory effect. At a low dose of 2.5 mg daily, it did not alter total circulating cholesterol, in contrast to chlorthalidone. High-density lipoprotein cholesterol levels increased significantly in 20 hypertensive men after 6 months of therapy with indapamide, resulting in a significant fall of the low-density lipoprotein/high-density lipoprotein ratio, an atherogenic risk factor, regardless of preexisting lipid disorders.

Adult↗
PubMed1983

Diuretic and cardiovascular effects of indapamide in hypertensive subjects: a dose-response curve.

In a single-blind, placebo-controlled study, the effects were evaluated of increasing doses of indapamide (1.0, 2.5 and 5.0 mg/day, each dose for 4 weeks) on volume and haemodynamic status of 10 hypertensive subjects. Body weight showed a decrease of 0.5 kg at the 1 mg dose, of 1.0 kg at the 2.5 mg dose and no further decrease at 5 mg. Plasma volume did not change. Mean arterial pressure decrease in 8 subjects by about 20 mmHg; 2 patients were classified as 'non-responders'. The decrease in blood pressure was accompanied by a reduction in total peripheral resistance and no change in cardiac output. LV end-diastolic volume decreased by about 20 ml. These results suggest that indapamide not only has a diuretic effect, but also acts as a veno-arterial vasodilator.

Adult↗
PubMed1983

Indapamide in hypertension: results of a French multi-centre study in ambulant subjects.

The antihypertensive effect of indapamide (2.5 mg/day) was evaluated in 2184 patients with essential hypertension by 300 French general practitioners over a period of treatment of 3 months. Indapamide produced a significant reduction in blood pressure, the amplitude of which was directly related to pre-treatment blood pressure levels; normalization of blood pressure was achieved in approximately 66% of patients. Addition of a beta-blocker to the treatment regimen on the second month was required in only 10% of patients. No severe side-effect was reported, although a significant reduction in kalaemia was noted in less than 5% of patients.

Aged↗
PubMed1983

Effects of indapamide and various diuretics alone or combined with beta-blockers on serum lipoproteins.

A prospective evaluation was started in 1976 to study the influence of diuretics alone or combined with beta-blockers on serum lipoproteins in normal or hypertensive subjects. Compared to placebo conditions, 4 or 6-weeks' monotherapy with various diuretics significantly (p less than 0.05) increased the beta-lipoprotein fraction (furosemide, 80 mg/day or chlorthalidone, 100 mg/day; n = 16) or low-density lipoprotein-cholesterol (LDL-C) (chlorthalidone, 100 mg/day, n = 27 men; tienilic acid, 250 mg/day, n = 16 men, clopamide, 5 mg/day, n = 17 men; or muzolimine, 20 to 40 mg/day, n = 13 men or post-menopausal women). No increase in LDL-C was noted in 43 men (32 normal, 11 with mild hypertension) treated with indapamide, 2.5 mg/day. Serum high-density lipoprotein-cholesterol and apoproteins A1, A2 and B were not consistently changed by any of these agents. In women, chlorthalidone (100 mg/day) significantly increased LDL-C in the (100 mg/day) significantly increased LDL-C in the post-menopausal (n = 18) but not in the pre-menopausal (n = 22) state. Increases in LDL-C caused by chlorthalidone monotherapy were prevented or reversed by the addition of a beta-blocker, usually propranolol or atenolol (n = 18); increases in LDL-C during clopamide monotherapy were reversed after the addition of the beta-blocker pindolol (10 mg/day, n = 17). In all studies, variations in beta-lipoprotein or LDL-C levels could not be explained by changes in blood volume, serum glucose or insulin and did not correlate with alterations in blood pressure, plasma potassium, renin, aldosterone, adrenaline or noradrenaline. These observations indicate that various diuretics may increase serum LDL-C in men or post-menopausal women. Pre-menopausal women may often be protected from this side-effect. Long-term studies are now needed to clarify the pathogenic and prognostic relevance of lipoprotein changes induced by diuretics. In the meantime, it is of clinical interest that indapamide had no significant effect on serum lipoproteins and that certain beta-blockers appear to prevent or reverse increases in LDL-C during diuretic treatment in men and post-menopausal women.

Adrenergic beta-Antagonists↗
PubMed1983

Effects of the acute and chronic administration of indapamide on systemic and renal haemodynamics in essential hypertension.

The effects of acute and chronic administration of indapamide on systemic and renal haemodynamics were studied in 10 patients with arterial essential hypertension. No important changes were observed on mean arterial blood pressure, cardiac index and total peripheral resistance during acute administration of the drug. Chronic administration produced a significant reduction in both mean arterial blood pressure and total peripheral resistance whereas the cardiac index did not change. Glomerular filtration rate diminished significantly during the acute administration of the drug, while renal plasma flow remained unchanged. Urinary volume did not change whereas osmotic clearance increased and free water clearance decreased evidently. Both urinary sodium and potassium increased significantly during acute administration of indapamide. Long-term administration of this substance had no effect on renal haemodynamics.

Adult↗