Delapril plus indapamide: a review of the combination in the treatment of hypertension

Although many data indicate that the management of hypertension has improved over the last two decades, there is still a large proportion of hypertensive individuals who do not receive adequate management of their blood pressure (BP). Combination therapy with two or more antihypertensive agents from different drug classes is increasingly being recognised as the most effective means of achieving target BP values by pharmacological means, particularly in the large number of patients in whom monotherapy proves to be ineffective. Use of an angiotensin-converting enzyme (ACE) inhibitor combined with a diuretic is a well established antihypertensive combination that is very effective because of the different, yet synergistic, mechanisms of actions of agents from these two drug classes. Delapril is a potent antihypertensive ACE inhibitor, and indapamide is a thiazide-like diuretic with additional antihypertensive properties. The combination of delapril and indapamide provides renoprotective effects, and indapamide is also cardioprotective. Use of these two drugs together is therefore a rational selection for combination therapy, and one that has consistently demonstrated lowering of BP to target values with a level of efficacy that is at least as good as other combinations of ACE inhibitors and diuretics. This combination has also been found to provide favourable effects on haemodynamic parameters, including left ventricular mass index and ejection fraction. Furthermore, combining an ACE inhibitor and a thiazide-type diuretic has been associated with a decreased risk of stroke and is recommended for patients with cerebrovascular disease, a setting in which the combination of delapril and indapamide has therapeutic potential. Because of the additive mechanisms of delapril and indapamide, the dose required for an effective antihypertensive effect is relatively low, and the combination is well tolerated at such doses. In particular, metabolic effects normally associated with diuretics are rare at the therapeutic dose of indapamide used in combination with delapril, making the combination suitable for patients with metabolic disorders in whom diuretic therapy would otherwise not be recommended. Delapril 30 mg and indapamide 2.5mg have been combined in a fixed combination, offering the convenience of a one-tablet-per-day antihypertensive drug regimen for most patients, which, along with good tolerability, helps to address the issue of noncompliance.     

Indapamide: Clinical Pharmacology,Therapeutic Efficacy in Hypertension,and Adverse Effects

Indapamide will soon be marketed in the United States as an oral antihypertensive agent and diuretic. Its molecular structure includes both a polar sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline molety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and it contains only one sulfonamide group. Indapamide is rapidly and well absorbed after oral Ingestion, and it has a long terminal half-life in whole blood which permits once daily administration. Indapamide is extensively metabolized by the liver with excretion of unchanged drug accounting for approximately 5% of the total dose. Although indapamide is thought to exert its antihypertensive effect by its diuretic action, several investigations employing laboratory animal preparations have documented a direct vascular action. It has been categorized as a calcium channel blocking agent and this may account for a portion of its antihypertensive effectiveness. In both the treatment of edema and as an antihypertensive agent, indapamide appears to be comparable to hydrochlorothiazide, chlorthalidone and furosemide and seems to have no clinically important advantage over these agents. Side effects associated with indapamide are minimal and appear to be comparable to those observed with other antihypertensive diuretics. Based on few published studies, indapamide appears to be a useful long acting antihypertensive and diuretic agent that is well tolerated and associated with minimal biochemical abnormalities or side effects.     

Treating hypertension by rational use of diuretics: results of the Russian ARGUS-2 study

ABSTRACT

Objective: Insufficient use of diuretics in combination antihypertensive therapy is a main cause of poor blood pressure (BP) control in Russia. The objective of the ARGUS-2 study was to demonstrate that a rational use of a thiazide-like diuretic, indapamide sustained release (SR), alone or in combination, improves BP control in patients with arterial hypertension difficult to control due to isolated systolic hypertension (ISH), diabetes mellitus (DM), chronic nephropathy, or metabolic syndrome.

Methods: The open-label, non-comparative, 3-month study without preliminary washout included 1438 hypertensive patients (mean age: 57.3?±?10.7 years, mean BP: 158.8?±?14.2/93.4?±?10.0?mmHg), with difficult-to-control arterial hypertension and who had never been treated with diuretics previously. Throughout the study, patients received indapamide SR 1.5?mg OD. BP control was defined as <140/90?mmHg for all patients and <130/80?mmHg for those with diabetes mellitus or chronic nephropathy.

Results: Indapamide SR was given as initiation monotherapy to 13.7% of the patients, as substitutive monotherapy to 6.8% of the patients uncontrolled by a previous monotherapy, as additive therapy to 31.9% of the patients uncontrolled by previous monotherapy, and as additive therapy to 47.6% uncontrolled by previous combination therapy without a diuretic. Among included patients 75.7% received also an ACE inhibitor or an angiotensin II receptors blocker, 43.9% a calcium channel blocker, and 32.8% a beta-blocker. In 3 months after indapamide SR administration, average BP level decreased to 131.8?±?9.7/80.5?±?6.9?mmHg and 84.5% of the study population achieved BP control. BP was controlled in 91.9% of patients with ISH (n?=?477), 74.8% of those with diabetes (n?=?214), 75.6% of those with chronic nephropathy (n?=?82), and 85.1% of patients with metabolic syndrome (n?=?745). No case of hypokalemia was reported.

Conclusion: The study demonstrates the value of including the thiazide-like diuretic indapamide SR in a combined antihypertensive regimen to control BP in hypertensive patients with added cardiovascular risk factors whose hypertension is difficult to treat. Methodological limitations of this study are its open-label design and the possibility of a change in concomitant antihypertensive treatment during the study.     

Acute effect of indapamide on urine calcium excretion in nephrolithiasis and human essential hypertension

The effects of indapamide (2.5 mg once a day) on urinary composition are reported in 20 patients (10 with recurrent calcium nephrolithiasis and 10 with essential hypertension) compared with 20 controls. Indapamide was well absorbed in every patient (mean plasma level at the steady state was 111 +/- 41 ng/ml) and its antihypertensive action was more pronounced in hypertensive than in normotensive patients. It lowered calcium excretion in 18/20 patients (mean fall on the 7th day of treatment: 53%) and raised the Mg/Ca ratio in 20/20 patients (mean increase on the 7th day: 167%). The effect on Ca2+ and Mg2+ excretion was not associated with a strong diuretic effect. During intravenous calcium loading (0.375 mmol/kg body weight) 6 normal subjects after a single oral dose of indapamide excreted less calcium, suggesting a direct renal hypocalciuric action by the drug. Indapamide could represent an alternative drug to thiazide diuretics in diseases with dangerous renal calcium losses, but long-term studies are needed.     

Indapamide sustained release: a review of its use in the treatment of hypertension

A low-dose sustained-release (SR) formulation of the thiazide-type diuretic indapamide, indapamide SR (Natrilix SR), retains the antihypertensive activity of the immediate-release (IR) formulation, with a smoother pharmacokinetic profile. In well controlled 12- to 52-week clinical trials, indapamide SR 1.5 mg/day was well tolerated and reduced blood pressure as effectively as therapeutic dosages of amlodipine, candesartan, enalapril, hydrochlorothiazide or indapamide IR. Indapamide SR was also more effective than enalapril in reducing left ventricular hypertrophy (LVH), and similar reductions in renal end-organ damage, assessed by microalbuminuria, were seen with indapamide SR- and enalapril-based antihypertensive strategies. Indapamide SR provides an effective option for initial antihypertensive monotherapy and a basis for multidrug antihypertensive strategies.     

Indapamide. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension

Indapamide is an orally active sulphonamide diuretic agent. Although some evidence appears to indicate that the antihypertensive action of indapamide is primarily a result of its diuretic activity, only a limited diuresis occurs with the usual antihypertensive doses of 2.5 mg daily, and in vitro and in vivo data suggest that it may also reduce blood pressure by decreasing vascular reactivity and peripheral vascular resistance. In mild to moderate hypertension it is as effective as thiazide diuretics and beta-adrenergic blocking agents in lowering blood pressure when used as the sole treatment. Indapamide has been successfully combined with beta-adrenergic blocking agents, methyldopa, and other anti-hypertensive agents. While such findings need confirmation, it appears that indapamide shares the potential with other diuretic agents to induce electrolyte and other metabolic abnormalities, although it may do so with less frequency or severity. Thus, indapamide appears to offer a suitable alternative to more established drugs as a 'first-line' treatment in patients with mild to moderate hypertension. Whether it differs significantly from other diuretics when used as antihypertensive therapy, either in its mode of action or its side effect profile, needs further clarification.     

Effects of a fixed-dose ACE inhibitor-diuretic combination on ambulatory blood pressure and arterial properties in isolated systolic hypertension

The ideal therapy for patients with isolated systolic hypertension remains unclear; diuretics, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors are all used in clinical practice. The aim of this study was to determine whether a fixed-dose ACE inhibitor/diuretic combination would reduce ambulatory blood pressures (BP) and arterial stiffness in isolated systolic hypertension more than antihypertensive monotherapy. In this randomized, double-blind study, 8 weeks of fosinopril/hydrochlorothiazide combination (10/12.5 mg titrated up to 20/12.5 mg) was compared with the calcium channel blocker (amlodipine, 5 mg titrated up to 10 mg) and diuretic (indapamide, 2.5 mg) monotherapy in 28 patients with isolated systolic hypertension. Each patient received all 3 therapies. Assessments included 24-hour ambulatory BP, clinic BP, and applanation tonometry-derived augmentation index. At 8 weeks, the fall in average 24-hour systolic BP and night time systolic BP were significantly greater in the fosinopril-hydrochlorothiazide group, compared to amlodipine and indapamide. The decrease in augmentation index and central aortic systolic BP was also greater in the fosinopril-hydrochlorothiazide group, compared to either amlodipine or indapamide. There was no difference between therapies in decrease in clinic systolic or diastolic BP, or diastolic ABP (average 24-h, diurnal, or nocturnal). Compared with either calcium channel blocker or diuretic therapy, a fixed-dose ACE inhibitor-diuretic combination induces greater reductions in systolic ABP, particularly at night, favorable effects that may be related to a decrease in the intensity of or delay in arterial wave reflections. ACE inhibitor-diuretic combination therapy is a useful approach to cardiovascular risk reduction in isolated systolic hypertension.     

Effect of indapamide on the proliferation of Balb/C 3T3 cells induced by platelet-derived growth factor.

The effects of indapamide (a nonthiazide antihypertensive diuretic) on the growth promoting activity of serum, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) or Ca3(PO4)2 on Balb/C 3T3 cells were studied. Indapamide inhibited the growth promoting activity of serum, but furosemide (a nonthiazide antihypertensive diuretic) had no such inhibitory effect. Indapamide inhibited the growth promoting activity of PDGF, but not that of FGF and Ca3(PO4)2. The present experiments demonstrate that indapamide selectively inhibits the growth promoting activity of PDGF.     

Fixed-Dose Combination Antihypertensives and Reduction in Target Organ Damage

Hypertension is a multifactorial disorder leading to pathophysiologic changes in target organs over time through diverse mechanisms. In addition, hypertension frequently resists control with monotherapy, necessitating combination therapy with two or more antihypertensive agents. Many currently available fixed-dose antihypertensive combinations combine drugs with different, but complementary, mechanisms of action to improve overall efficacy and tolerability. In addition, it is possible to select drug combinations whereby one drug offsets the negative effects of the other drug. Fixed-dose antihypertensive combinations may provide significant advantages over high-dose monotherapy, such as improved BP-lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs, and shorter time to BP control. Combination therapy has been recommended as potential first-line therapy in recent consensus guideline statements, especially for higher-risk patients, such as those with stage 2 hypertension. The combination of a renin-angiotensin-aldosterone system-targeting agent, such as an ACE inhibitor or angiotensin II receptor antagonist (ARB), and a diuretic or calcium channel antagonist appears to provide synergy with regard to BP lowering. In addition, ACE inhibitors and ARBs have demonstrated beneficial effects beyond BP reduction, reducing cardiovascular morbidity and mortality, inhibiting development and progression of type 2 diabetes mellitus and the progression of renal disease. Preliminary studies of fixed-dose combinations have shown reductions in left ventricular hypertrophy and improvements in markers of renal function. Additional studies currently underway will compare the effects of available fixed-dose combinations on cardiovascular morbidity and mortality, and markers of renal dysfunction.     

The ADVANCE Trial

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.     

Identification and pharmacological properties of binding sites for the atypical thiazide diuretic, indapamide

[3H]Indapamide bound to a single class of binding sites in pig renal cortex membranes with a dissociation constant Kd = 35 +/- 13 nM and a binding site density Bmax = 40 +/- 9 pmol/mg of protein. [3H]Indapamide binding was inhibited by the carbonic anhydrase inhibitor, acetazolamide, and by thiazide diuretics with the following rank order of potency: chlorothiazide greater than hydrochlorothiazide approximately metolazone greater than hydroflumethiazide. The effect of the latter drugs to inhibit [3H]indapamide binding was not related to their activity as thiazide diuretics, but was significantly correlated with their inhibitory effect on carbonic anhydrase II. These results suggest that the major renal binding site of [3H]indapamide is a membrane form of carbonic anhydrase. Inhibition of carbonic anhydrase may play a role in the antihypertensive effect of indapamide.     

Antihypertensive action of indapamide. Comparative studies in several experimental models.

1-(4-Chloro-3-sulfamylbenzamido)-2-methyl-indoline (indapamide), after single oral dose administration, showed antihypertensive activity in genetically hypertensive rats, DOCA/saline hypertensive rats, unilaterally-nephrectomised DOCA/saline hypertensive rats and dogs made hypertensive by renal encapsulation. The activity was observed at doses as low as 1-3 mg/kg and lasted at least 48 h. Increasing the dose level considerably prolonged the duration of action but did not substantially enhance the maximum antihypertensive effect. In genetically hypertensive rats indapamide was 30-300 times more potent than furosemide, spironolactone and chlorthalidone. Indapamide had no effect on blood pressure in normotensive rats. In concentrations of 1 X 10(-5) to 1 X 10(-3) g/ml, indapamide antagonised contractions of arterial and venous strips to angiotensin, epinephrine and norepinephrine revealing a direct vascular action. Indapamide has a prolonged saluretic action which in combination with the direct vascular effects may well account for its antihypertensive activity.     

Perindopril/indapamide 2/0.625 mg/day: a review of its place in the management of hypertension

The fixed low-dose combination of the ACE inhibitor perindopril and the non-thiazide diuretic indapamide has been evaluated in the management of patients with mild to moderate hypertension. Combination therapy aims to improve overall therapeutic efficacy while minimising adverse effects. In well-designed multicentre clinical trials, perindopril/indapamide at doses ranging from 2/0.625 to 8/2.5 mg/day was significantly more effective than placebo in achieving adequate blood pressure (BP) control. A similar reduction in supine BP was observed when combined perindopril/indapamide 2/0.625 mg/day was compared with losartan 50 mg/day or atenolol 50 mg/day. Similar reductions in 24-hour ambulatory BP were also seen with perindopril/indapamide 2/0.625 mg/day and irbesartan 150 mg/day. However, response and normalisation rates were significantly higher with combination therapy than with losartan or irbesartan monotherapy. Combined perindopril/indapamide 2/0.625 mg/day therapy effectively reduced BP in elderly patients aged 65 to 85 years to a significantly greater extent than either atenolol 50 mg/day or placebo. Supine BP was also normalised in approximately two-thirds of patients in a small noncomparative trial in patients with hypertension and renal impairment. Low-dose perindopril/indapamide 2/0.625 mg/day was well tolerated in clinical trials; the most common adverse events were headache and cough. Hypokalaemia, associated with the use of diuretics, occurred with a higher incidence with combined perindopril/indapamide 2/0.625 mg/day therapy than with either atenolol 50 mg/day or placebo. Perindopril/indapamide 2/0.625 mg/day has shown efficacy in well designed comparative trials with atenolol, losartan and irbesartan including elderly patients and patients with renal impairment. Studies comparing this dosage of perindopril/ indapamide with other combination therapies would be beneficial in allowing the place of perindopril/indapamide to be more accurately determined. The fixed-low dose combination of perindopril/indapamide provides a promising and well tolerated treatment option in the management of patients with mild to moderate hypertension.     

Metabolic profile of indapamide sustained-release in patients with hypertension: data from three randomised double-blind studies.

OBJECTIVE: To evaluate the influence of indapamide sustained-release (SR) 1.5 mg/day, a thiazide-related sulfonamide diuretic, on serum levels of lipids (total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and triglycerides), glucose and uric acid, and renal function (serum urea and creatinine levels). METHODS: Pooled data from three randomised, double-blind, controlled studies are analysed. Two of these studies were of short duration (2 and 3 months), one of which included a 9-month nonblind extension phase, and the third was a 12-month prospective study. Short- and long-term metabolic effects of the treatment could thus be analysed. All studies were conducted in patients with mild-to-moderate hypertension; the total population randomised in these studies comprised 1195 patients, of whom 505 had left ventricular hypertrophy (LVH). RESULTS: After 2 to 3 months' treatment with indapamide SR 1.5 mg/day, there was no significant change from baseline in serum lipid levels and glucose levels. This neutral effect was maintained after 9 and 12 months of treatment. Renal function was not affected by short- or long-term indapamide SR 1.5 mg/day therapy. Serum uric acid level was slightly increased after short-term therapy, but was restored to baseline values during long-term therapy with indapamide SR 1.5 mg/day. CONCLUSIONS: Indapamide SR 1.5 mg/day has no deleterious effect on glucose metabolism, serum levels of lipids and uric acid, or renal function. This antihypertensive agent can be considered to be an attractive therapeutic choice for all patients with mild-to-moderate hypertension, including the elderly and patients with increased cardiovascular risks, i.e. those with LVH.     

Indapamide and bendrofluazide: a comparison in the management of essential hypertension.

1 To compare the efficacy of indapamide with that of bendrofluazide a randomised trial was carried out in twenty patients with essential hypertension. 2 Indapamide (2.5 mg a day) and bendrofluazide (5 mg a day) produced a significant but equivalent fall in blood pressure. 3 Both drugs caused a reduction in body weight and serum potassium with a rise in plasma renin activity but there were no other major side effects. 4 In twelve patients treated with a combination of indapamide and bendrofluazide there was no additional fall in mean blood pressure or serum potassium compared to treatment with bendrofluazide or indapamide alone.     

A Meta-Analytical Approach to the Efficacy of Antihypertensive Drugs in Reducing Blood Pressure

INTRODUCTION: Hypertension constitutes a veritable public health issue. Several classes of drugs are available for the treatment of hypertension. The objective of this meta-analytical approach was to assess the efficacy of antihypertensive drugs most commonly used in France in reducing clinical SBP and DBP. METHODS: The antihypertensive drugs selected were hydrochlorothiazide, indapamide sustained release (SR), furosemide and spironolactone for diuretics; amlodipine and lercanidipine for calcium channel antagonists; atenolol for beta-adrenoceptor antagonists (beta-blockers); enalapril and ramipril for ACE inhibitors; and candesartan cilexetil, irbesartan, losartan, and valsartan for angiotensin II receptor antagonists. The trials selected were published between 1973 and 2004, evaluated monotherapy with trial drugs as fixed-dosage or with dosage increase, and assessed blood pressure reduction between 2 and 3 months. The analysis method used was based on the calculation of the sum weighted for the trial size. RESULTS: A total of 72 trials (comprising 9094 patients) were selected and analyzed. No trial evaluating furosemide or spironolactone satisfied the inclusion criteria for this analysis. For SBP, the reduction was more marked with diuretics, calcium channel antagonists, and ACE inhibitors. Of all the drugs studied, indapamide SR gave the greatest SBP reduction (-22.2 mm Hg). Evaluated therapeutic classes had a similar magnitude of effect on DBP, i.e. reduction between -11.4 mm Hg with beta-adrenoceptor antagonists and -10.3 mm Hg with angiotensin II type 1 receptor antagonists. CONCLUSION: Indapamide SR 1.5 mg appeared to be the most effective drug for a significant reduction in SBP within 2-3 months, which is an essential element in optimizing cardiovascular prevention among hypertensive patients. The clinical application of these results should take into consideration all the limitations discussed in this analysis.     

Rationale for the use of a fixed-dose combination in the management of hypertension: efficacy and tolerability of lercanidipine/enalapril

Hypertension, a significant factor in the development of cerebrovascular disorders, heart disease and renal failure, is a common disorder worldwide. Despite the availability of a wide range of antihypertensive agents, almost two-thirds of hypertensive patients have poorly controlled blood pressure (BP). Numerous clinical trials have shown that most patients require at least two antihypertensive agents to achieve adequate BP control and associated significant reductions in cardiovascular morbidity and mortality. Combination therapy using two drugs with different, complementary mechanisms of action achieves better efficacy and tolerability outcomes than treatment with either component drug alone. When such a combination is administered as a fixed-dose formulation, other benefits, such as improved compliance and potentially lower costs, are also likely. The good efficacy and tolerability of the combination of a calcium channel antagonist and an angiotensin-converting enzyme inhibitor is well established, and this combination is recommended by European Society of Hypertension/European Society of Cardiology guidelines as a first choice in high-risk hypertensive patients, including those with type 2 diabetes mellitus. Lercanidipine/enalapril is a promising example of a fixed-dose combination of these drug classes. In clinical trials in hypertensive patients, including those with type 2 diabetes, lercanidipine/enalapril improved BP to a greater extent than either drug as monotherapy (in patients who were previous non-responders to lercanidipine or enalapril) or the combination of lercanidipine/hydrochlorothiazide, and was equally well tolerated. Further studies are required to evaluate the cardiovascular protective effects of lercanidipine/enalapril.     

Modification of the antihypertensive effect of indapamide by indomethacin

Oral treatment with indapamide was found to reduce blood pressure of hypertensive rats but not of normotensive rats. Chronic indomethacin treatment had no effect on blood pressure of untreated normotensive and hypertensive rats. Also indomethacin did not modify the antihypertensive effect of indapamide excluding the direct involvement of PGs in the antihypertensive effect of indapamide. Vascular reactivity to pressor agents NA, ADR and ANG was significantly increased after indomethacin treatment. This may be due to the blockade of the actions of PG in modifying vascular reactivity to vasoconstrictor agents or may be a direct effect of indomethacin on calcium fluxes. Indapamide reduced the reactivity to NA and ANG in the presence of indomethacin suggesting that the antihypertensive effect of indapamide may be through a decrease in reactivity to pressor agents which is independent of increase in the synthesis of vasodilator PGs.     

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.     

Antihypertensive effect of indapamide given in conjunction with captopril in severe hypertension

Summary

The efficacy of captopril alone or in combination with indapamide was evaluated in 17 patients with severe hypertension (diastolic > 120 mmHg) previously treated with triple antihypertensive therapy, i.e. diuretic, beta-blocker and a vasodilator. After a wash-out period of 1 week, captopril was given initially as 75?mg/day for 2 weeks; at the end of this period, the dosage was doubled to 150?mg/day and continued at this level for a further 2 weeks. Indapamide (2.5?mg/day) was then added to the regimen and administered for 1 month. The results showed that captopril alone lowered, but did not normalize the blood pressure. The mean diastolic pressure was reduced to 117 and 103.8 mmHg after dosages of captopril of 75?mg and 150?mg, respectively. On the addition of indapamide, the blood pressure was normalized to 93.82 mmHg mean diastolic pressure. Systolic readings were similarly reduced. Two patients developed skin rashes while on captopril alone: no other treatment-related side-effects were reported once indapamide therapy had commenced.