Efficacy of a fixed-dose combination of 40 mg penbutolol with 6 mg piretanide in the treatment of mild to moderate hypertension: a double-blind study against placebo.

The antihypertensive efficacy and tolerability of a fixed-dose combination containing 40 mg penbutolol (a beta-blocking agent) and 6 mg piretanide (a diuretic) in comparison to placebo was investigated in a double-blind, crossover study in 20 patients with mild to moderate essential hypertension. After a 1-week period on placebo, patients were allocated at random to receive 1 tablet daily for 4 weeks of either the combination preparation or placebo and were then crossed over to the alternative medication for a further 4 weeks. The reduction in systolic and diastolic blood pressure both at rest, during maximal ergometric exercise and isometric word load, and also in the diurnal blood pressure profile over 24 hours was significantly greater in the group treated with the fixed-dose combination than in the placebo group. Pulse rate was also decreased to a greater extent. Mean diastolic blood pressure before exercise was reduced to normal (85.5 mmHg) after 4-weeks' treatment with the fixed-dose combination. Biochemical, haematological and urinary parameters showed no clinically relevant changes after either treatment. One patient complained of transient dizziness during treatment with the fixed-dose combination. No patient withdrew prematurely from the study because of side-effects.

Ramipril and felodipine: a comparison of the efficacy and safety of monotherapy versus combination therapy.

A multinational, double-blind, randomised study was conducted to investigate the efficacy and safety of a low-dose combination of the angiotensin converting enzyme inhibitor, ramipril, and the calcium antagonist, felodipine ER, in 642 patients with mild to moderate hypertension [supine diastolic blood pressure (DBP) = 95-115 mm Hg]. After a 4-week single-blind placebo run-in, patients were randomly allocated to once-daily felodipine extended release (ER; 2.5 mg), ramipril (2.5 mg) or felodipine ER/ramipril (2.5/2.5 mg) for 12 weeks. In the intention-to-treat analysis, mean DBP decreased significantly (p < 0.0001) after felodipine ER, ramipril and the combination (-9.1, -9.8 and -11.4 mm Hg, respectively). The decrease was significantly greater with the combination than with felodipine ER monotherapy (p = 0.02). The number of responding patients (final DBP < or = 90 mm Hg or a decrease of > or = 10 mm Hg) was also higher with the combination than with felodipine ER or ramipril monotherapy (65.1%, 53.1%, 55.7%, respectively). There were no differences between the three groups with respect to the incidence of adverse events overall or those considered treatment-related. There were fewer cases of peripheral oedema with combination therapy than with felodipine ER monotherapy. Thirty-three patients (5.1%) withdrew from the study because of adverse events, but there was no clear pattern with regard to the specific events leading to withdrawal. There were no clinically relevant changes in laboratory or clinical safety variables. Ramipril/felodipine ER 2.5/2.5 mg is an appropriate starting dosage when initiating combination antihypertensive therapy.

A double-blind study of piretanide in the treatment of hypertension.

A double-blind trial was carried out in three parallel groups of patients with mild to moderate hypertension to assess the efficacy and tolerance of piretanide given as a single dose of 3 mg, 6 mg or 12 mg per day over a period of 12 weeks. Active drug treatment in the 90 patients studied was preceded and followed by 2-week periods on placebo. The results showed that although all three groups had significant reductions in systolic and diastolic blood pressures, both at rest and standing, compared with initial levels, the decrease was significantly greater in the two higher dosage groups. Pulse and respiratory rates also decreased and body weight was reduced slightly. The biochemical and haematological parameters in all three groups showed no clinically relevant changes during treatment with piretanide. Minor side-effects definitely or probably associated with piretanide treatment were observed in all three groups but were generally mild and did not interfere with treatment. Only 1 of the 9 patients who withdrew prematurely from the trial did so because of lack of effect, 1 patient withdrew because of side-effects and the other 6 patients who dropped out for drug-related reasons did so because the antihypertensive effects were too marked at the 6 mg (3 patients) or 12 mg (3 patients) per day dosage level.

A multi-centre comparative study between ramipril and enalapril in patients with mild to moderate essential hypertension.

A multi-centre, randomized, double-blind, parallel group study was undertaken in order to assess efficacy and tolerability of ramipril as compared to enalapril in mild to moderate hypertension. A 4-week placebo run-in period was followed by 4 weeks of treatment with active medication (5 mg ramipril or 10 mg enalapril in a single morning dose). In patients not responding to this dosage regimen at the end of a 4-week treatment period, the dose was doubled. After 8 weeks of active medication, 3 mg daily of the diuretic piretanide was added to the treatment of patients not responding to the doubled dose. A total of 202 patients was admitted in the placebo phase from which 174 patients who had evaluable data at the end of the study were included in the efficacy analysis. Based on the definition of a 'responder' as a patient who achieved a supine diastolic blood pressure of 90 mmHg or less, 40% of those on 5 mg ramipril achieved this level within 4 weeks; in the enalapril group, the corresponding figure was 36.6%. By the end of 12 weeks of active treatment, a total of 55% of the ramipril group had responded to a daily dose of 5 to 10 mg ramipril. An additional 18% responded when 3 mg piretanide was added to the regimen. In the enalapril group, 59% responded to 10 to 20 mg enalapril. A further 17% responded to addition of piretanide to 20 mg enalapril. A total of 19 patients developed 29 adverse drug events while receiving ramipril, alone and in combination with piretanide. In the enalapril group, 24 patients developed 36 adverse events during enalapril monotherapy and combination treatment. It is concluded that ramipril and enalapril in a ratio of 1:2 have comparable antihypertensive efficacy in mild to moderate hypertension but the number of adverse reactions was slightly higher with enalapril in this study.

Pharmacokinetics, metabolism and biliary and urinary excretion of oral ramipril in man.

In order to evaluate the pharmacokinetics and excretion of ramipril in man, 8 cholecystectomy patients aged between 53 and 68 years received 5 mg ramipril orally as a single dose. All patients had a T-drain inserted to permit bile collection; all gave their informed consent to participate in the trial. Serum samples were collected half-hourly until 2 hours, then hourly until 6 hours, then at 8, 10, 24 and 25 hours after intake. Urine was collected in 2-hour fractions until 8 hours, followed by a 4- and a 12-hour fraction. Bile was collected hourly until 6 hours, followed by a 6- and a 12-hour collecting fraction. Concentrations of ramipril and ramiprilat in serum, and determinations in urine and bile of ramipril, ramiprilat, ramipril glucuronide, ramiprilat glucuronide, diketopiperazine and diketopiperazine acid were made; total amounts excreted were calculated. Peak concentrations of ramiprilat in plasma (8.7 +/- 1.6 ng/ml) were reached after about 8 hours. AUC0-8 and AUC0-24-values were 36.5 and 111.9 ng.h/ml, respectively. Ramiprilat Cmax-concentrations were about 300-fold higher in bile than in plasma, the corresponding difference for ramipril between bile and plasma was about 4-fold. The main fractions excreted in the urine were diketopiperazine acid and ramiprilat amounting to 13.2 +/- 5.6 and 4.4 +/- 2.4%, respectively, of the dose administered. Only a very small fraction of the dose was excreted with urine as unchanged ramipril, on average 0.9 +/- 1.0%. The main fractions excreted in the bile were diketopiperazine acid, ramiprilat glucuronide and diketopiperazine, 9.0 +/- 5.3, 3.4 +/- 4.2 and 2.0 +/- 1.2% in 24 hours, respectively, of the dose administered. Only a negligible fraction of the dose (average 0.1 +/- 0.1%) was excreted with bile as unchanged ramipril. In conclusion, there is strong evidence that circulating ramipril and ramiprilat are eliminated by both the liver and the kidneys. For the patients studied it can be estimated from late collection periods that some 2/3 of circulating ramipril and ramiprilat are eliminated by the kidneys and 1/3 eliminated by the liver.

Cost effectiveness of ramipril in patients with non-diabetic nephropathy and hypertension: economic evaluation of Ramipril Efficacy in Nephropathy (REIN) Study for Germany from the perspective of statutory health insurance.

BACKGROUND: In the Ramipril Efficacy In Nephropathy (REIN) trial, ramipril significantly lowered the rate of reaching the combined end-point of doubling of baseline serum creatinine levels or end-stage renal failure (ESRF). OBJECTIVE: To determine the additional cost per patient-year of chronic (long term) dialysis avoided (PYCDA) when the ACE inhibitor, ramipril, was added to conventional treatment of patients with non-diabetic nephropathy and hypertension. STUDY PERSPECTIVE: Statutory Health Insurance (SHI) provider in Germany. DESIGN AND SETTING: Data from the REIN Study were used in a cost-effectiveness analysis (CEA). A modelling approach was used, which was based on secondary analysis of published data, and costs were those incurred by the SHI provider (i.e. SHI expenses). In the base-case analysis, average case-related SHI expenses were applied and PYCDA were quantified using the cumulative incidence of ESRF as observed in the REIN trial. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost-effectiveness ratios (ICERs) of ramipril varied between about -76,700 deutschmarks (DM) and -DM81,900 per PYCDA (DM 1 approximately equals 0.55 US dollars; 1999 values), according to the treatment periods of 1 year and 3 years, respectively. In the sensitivity,analysis, the robustness of the model and its results were shown when the extent of influence of different model variables on the base-case results was investigated. First, probabilities of ESRF and PYCDA were estimated according to the Weibull method. Second, the influence of the model variables on the target variable was quantified using a deterministic model. Third, the dependency of the target variable (ICER) on random variables was described in a simulation. The cost for chronic dialysis had by far the greatest impact on the target variable, which was 28 times greater than the impact of clinical effectiveness of ramipril, i.e. the number of PYCDA. There were net savings per PYCDA with ramipril treatment after 1, 2 and 3 years: 95% of the 10,000 simulation steps resulted in savings of between DM69 500 and D94,600 per PYCDA after 3 years. CONCLUSIONS: Results from this evaluation show that ramipril offers enormous savings from the perspective of the SHI provider (third-party payer) in Germany when added to the conventional treatment of patients with non-diabetic nephropathy and hypertension.

Efficacy of penbutolol + piretanide combinations in the treatment of arterial hypertension.

The efficacy and tolerability of penbutolol alone and in combination with piretanide at two dose levels were investigated in a double-blind parallel group study in patients with mild to moderate essential hypertension. All three treatments were given as a single daily dose. One hundred and eight patients entered the study; 82 completed a 7-day placebo run-in period followed by 3 weeks of active therapy. Penbutolol 20 mg plus piretanide 3 mg and penbutolol 40 mg plus piretanide 6 mg both produced a significantly greater reduction in supine diastolic blood pressure (16% and 19% respectively) than penbutolol 20 mg (9%). The reduction in supine diastolic blood pressure was significant for all three treatments with respects to the baseline reading. Side-effects were generally mild and transient and were similar in type and incidence in the three groups. Six patients did not complete the trial period because of an excessive response to the hypotensive medication: five in the high dose combination group, and one in the low dose combination group. Low doses of penbutolol (20 mg) and piretanide (3 mg) used in combination and in a once-daily administration provide a simple, effective and well tolerated regimen for patients with mild to moderate hypertension.

Piretanide in the treatment of essential hypertension. A double-blind comparison versus placebo.

In a randomized, double-blind parallel group study the 24-hour hypotensive effect of piretanide and its influence on biochemical variables were compared with those of placebo in patients with mild to moderate essential hypertension. Sixty patients entered the study, all of whom met the inclusion criteria (RRdiast between 95 and 120 mmHg). There was no drop-out during the study, so that the results of all 60 patients were statistically analysed. Piretanide produced a significant reduction of both systolic and diastolic blood pressure over 24 hours which was evident at four weeks and was maintained and further enhanced over the ensuing trial period. A mean maximal fall (at 12 weeks) of 10.7% (BPdiast supine) was observed. Placebo tablets did not produce any clinically relevant changes in systolic blood pressure, whereas a slight decrease was seen in diastolic blood pressure. This blood pressure reduction was significantly less in the placebo group than in the piretanide group at the end of the study (weeks 10 and 12). Dose doubling was needed in 13 of the 30 patients in the piretanide group, whereas as many as 20 out of 30 patients needed dose doubling in the placebo group. Pulse rate did not change relevantly during the trial in either group. A slight reduction in body weight was observed in the piretanide group. The mean values of serum potassium and sodium showed a slight decrease but remained within the normal range during the study period. A small increase in serum phosphorus was noted. None of these changes required any specific measures.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect of piretanide (a potassium-stable diuretic) on serum magnesium.

Serum magnesium and potassium concentrations were determined in 188 patients undergoing diuretic treatment for mild to moderate hypertension in four controlled clinical trials (eleven treatment groups). Measurements were made before and after 12 weeks of treatment with piretanide monosubstance (including the retarded form) in the range 3 to 12 mg daily, with triamterene as monosubstance and in fixed dose combination with piretanide, and with amiloride in combination with hydrochlorothiazide. Eumagnesaemia and eupotassaemia were preserved at all dosage of the piretanide monosubstance. Mean serum potassium concentrations were significantly increased following treatment with the potassium-sparing agents triamterene (with and without piretanide) and amiloride in combination with hydrochlorothiazide. These changes were not accompanied by changes in mean serum magnesium levels, that is, a magnesium-sparing effect was not demonstrated. Individual values of changes in serum magnesium levels before and after diuretic therapy did not correlate with the corresponding changes in serum potassium levels in any of the eleven groups of patients. This result is in contrast to the findings of other authors, which suggested that serum magnesium and potassium levels were correlated. Long-term treatment with diuretics can lead to hypomagnesaemia and hypokalaemia, and, if in combination with a potassium-sparer, to hyperkalaemia. The results of this analysis show that piretanide, in addition to its smooth and effective antihypertensive action, is also able to preserve serum magnesium and potassium homeostasis when administered in the range of 3 to 12 mg for 12 weeks.

Piretanide, a potassium stable diuretic, in the treatment of essential hypertension: a double-blind comparison of two formulations.

In a randomized double-blind parallel group study the effects of two formulations of piretanide (standard tablet and slow-release capsule) were compared in patients with mild to moderate essential hypertension. Forty patients entered the study and thirty-seven completed it. Both formulations of piretanide produced a significant reduction in erect and supine blood pressure which was evident at 2 weeks and was maintained and further enhanced over the ensuing trial period. A mean maximal fall in supine diastolic pressure of 22% was observed in the piretanide tablet group, and of 20% in the slow-release piretanide group. Blood pressure fell more quickly at the beginning of treatment with the tablet preparation, such that there was a significant difference between the groups up to the fourth week. After this point the blood pressure lowering effect was very similar in both groups and there was a progressive reduction in supine blood pressures over the 12-week active-treatment period. Slow-release piretanide produced a smoother effect than the tablet formulation. There were no significant changes in serum potassium and serum magnesium in either treatment group. Minor changes were seen in some other biochemical and haematological variables but these were of no clinical significance. Three patients were withdrawn from the study because of side-effects: one because of an excessive antihypertensive response to the tablet formulation; and two because of allergic reactions to the slow-release preparation. Side-effects were otherwise mild and infrequent.

[ACE inhibitor or AT1 antagonist. Is there a differential therapy?]. / ACE-Hemmer oder AT1-Antagonist. Gibt es eine Differenzialtherapie?

ACE-inhibitors and AT, receptor antagonists play an important role in the treatment of cardiovascular and renal diseases. The criteria of evidence-based medicine indicate that ACE-inhibitors (in appropriate combinations with other cardiovascular agents) continue to represent the treatment of first choice in chronic heart failure, post-myocardial infarction with compromised ventricular function, high cardiovascular risk, and diabetic (type 1) nephropathy. It is here that the AT1 antagonists should be used--in particular when ACE-inhibitors are not tolerated. The AT1 antagonists, Irbesartan and Losartan, are applied, at appropriately high doses, primarily in hypertensives with diabetic (type 2) nephropathy. With the current exception of chronic heart failure, no confirmed data are yet available on the value of combination treatment. The LIFE study has shown that an AT1 antagonist is superior to an established beta blocker in hypertensives with an increased risk (left-ventricular hypertrophy), in particular when diabetes mellitus is impending or already present.

Initiation of hypertension treatment with a fixed-dose combination or its monocomponents -- does it really matter?

Despite efforts to diagnose and treat hypertension effectively, the goal of lowering blood pressure (BP) levels is rarely achieved, as treatment is often initiated with a single antihypertensive agent. The aim of this study was to assess the safety and efficacy of a first-line fixed-dose combination treatment compared with treatment with its monocomponents over a period of 4 weeks. Patients (n = 149) with essential hypertension were randomised to receive 2.5 mg of either ramipril or felodipine ER or the fixed-dose combination of ramipril 2.5 mg/felodipine ER 2.5 mg over a 4-week treatment period. BP and heart rate were measured by conventional methodology and 24-hour ambulatory blood pressure measurements. Treatment with the fixed-dose combination was significantly more effective in reducing systolic and diastolic BP (-15.8/-9.2 mmHg) compared with its monocomponents, ramipril (-7.6/-3.8 mmHg) and felodipine ER (-8.0/-5.0 mmHg). No significant difference could be observed in the occurrence of a greater fall in systolic and diastolic BP 6 h after the first dose of the three study medications. The adverse effects reported were mild, and less number of patients in the fixed-dose combination complained of adverse events. It can be concluded that initiating antihypertensive treatment with a low fixed-dose combination of ramipril/felodipine ER is more effective and safe when compared with treatment with its monocomponents.

Therapeutic effects of angiotensin II inhibition or blockade on the progression of chronic renal disease.

Experimental and clinical research has supported the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in diabetic, hypertensive and proteinuric nephropathies. This review will evaluate the role of angiotensin II in the progression of renal damage in kidney diseases; the diagnostic value of microalbuminuria as an early clinical sign of renal damage and the possibility of preventing its further progression; the clinical results obtained with ACE inhibitors and/or ARBs in diabetic and non-diabetic nephropathies; and the therapeutic possibilities of ACE inhibitors and ARBs in renal transplantation. Based on available clinical data, ACE inhibitors can be considered to be the gold standard in reducing and/or preventing albuminuria, and thereby decreasing the percentage of patients who will progress to end-stage renal disease and death. Renal transplantation and chronic allograft nephropathy appear to be a promising field for the use of ACE inhibitors and ARBs.

Management of hypertension and its sequelae with ACE inhibitors: biochemical, pharmacological and clinical aspects.

ACE inhibitors are a widely prescribed class of drug for the management of hypertension. Their therapeutic role in the treatment of heart failure, diabetic nephropathy and post myocardial infarction with left ventricular dysfunction is steadily increasing. Although ACE inhibitors have a similar mechanism of action--namely, inhibition of circulatory ACE, thereby decreasing the formation of angiotensin II--individual members differ in their physicochemical properties, enzyme-binding kinetics, pharmacokinetic profile, organ-specific affinity and selectivity, as well as in their bradykinin potentiating effect. These factors play an important part in influencing the pharmacological profile of an agent and its clinical efficacy, especially in the treatment of hypertension. It is therefore prudent to take into account the existing pharmacological and clinically relevant differences between the individual members of this drug class before making the decision to select a particular ACE inhibitor for the long-term management of arterial hypertension.

Single and divided daily dose piretanide in the treatment of uncomplicated essential hypertension: a double-blind comparison with a combination of hydrochlorothiazide and amiloride.

In a randomised double blind study in patients with mild to moderate hypertension, piretanide 6 mg once and twice daily significantly reduced both supine and erect blood pressure. This was seen after only 2 weeks and a further progressive reduction was evident over the ensuing 12-week trial period. The higher dose produced a mean maximal fall of 29% in supine diastolic pressure, compared with 23% after the lower dose; the difference is not significant. Hydrochlorothiazide 50 mg/amiloride 5 mg twice daily (HCT/A) also reduced supine blood pressure significantly after 2 weeks, but the reduction in erect diastolic blood pressure did not achieve statistical significance until 8 weeks. The maximal effect (a 13% fall in supine diastolic blood pressure) was significantly less than that of either piretanide regimen. Blood pressures in this group also returned more rapidly to pretreatment levels during the placebo washout phase at the end of the study. HCT/A produced a significant sustained rise in serum potassium and a reduction in serum sodium and chloride. Piretanide had minimal effects on serum electrolytes.

[Comparative study of 2 diuretic-containing combination preparations in patients with edematous heart failure]. / Vergleichende Untersuchung zweier diuretikahaltiger Kombinationspräparate bei Patienten mit hydropischer Herzinsuffizienz.

The efficacy and tolerability of two combinations, namely 50 mg spironolactone + 20 mg furosemide (SF) or 50 mg spironolactone + 5 mg butizide (SB), were compared in a randomised intraindividual trial in 22 patients with congestive heart failure. The parameters used were: weight, ankle- and calf-circumference, blood pressure, resting pulse, resting ECG, spirometry and blood chemistry. The physicians' judgement of the success of treatment was also recorded. Clinical symptoms improved clearly in both groups and in most cases there was significant improvement of the various parameters. The trend towards improvement was more apparent with SF. The physicians considered SF to be more effective in 12 cases compared to one case with SB. In all other cases both treatments were considered equally effective. The blood chemistry data showed relevant differences: serum-potassium levels were less scattered with SF and showed a - desirable - shift into the upper normal range. The number of patients with elevated serum-creatinin-levels increased during SB-treatment whereas the opposite was noted with SF. This could be due to furosemide's positive effects on renal functions.

Efficacy of a low fixed-dose combination of penbutolol with piretanide in the treatment of mild to moderate hypertension: a double-blind study against placebo.

A double-blind crossover study was carried out in 20 patients with mild to moderate essential hypertension to assess the efficacy and tolerability of a low fixed-dose combination containing 20 mg penbutolol (a beta-blocking agent) and 3 mg piretanide (a diuretic) in comparison to placebo over a period of 4 weeks. Active drug treatment in the 20 patients studied was preceded by a 1-week period of placebo. The results showed that there was an effective significant reduction in systolic and diastolic blood pressure compared with initial levels in the fixed-dose combination group, when compared to the placebo group, both at rest, during maximal ergometric and isometric work load, and also in the diurnal blood pressure profile over 24 hours. Pulse rate also decreased in the combination group. The biochemical, haematological and urinary parameters showed no clinically relevant changes in either group during the entire study period. Minor side-effects definitely or probably associated with the treatment were observed in both groups but were generally mild and did not interfere with treatment. No patient withdrew prematurely from the trial.

Fixed dose combinations of ACE inhibitors.

First-line antihypertensive monotherapy is effective in reducing blood pressure to within the normal range in approximately 50% of patients. Normalisation in the remaining patients may require a combination of two or more drugs. This review considers the clinical efficacy and tolerability of combinations involving angiotensin-converting enzyme (ACE) inhibitors. The efficacy of combinations with diuretics or calcium antagonists, as initial therapy or in patients with inadequate responses to monotherapy, has been demonstrated in many trials. With combination therapy, normalisation rates approaching 80% can be achieved using submaximal doses of both components. Therapy with both combinations is well tolerated; with ACE inhibitors reducing the diuretic metabolic effects or counteracting some calcium antagonist-associated vasodilatory effects. Data on ACE inhibitors with beta-blockers are limited. When patients respond inadequately to first-line monotherapy, the increasing availability of drug combinations will allow individual selection of the most appropriate combination, taking account of additional risk factors and concomitant disease.

Physicochemical and enzyme binding kinetic properties of a new angiotensin-converting enzyme inhibitor ramipril and their clinical implications.

After oral administration, ramipril, a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, is transformed in the liver into its active metabolite ramiprilat. Because of its pentane ring it is at least 23 times more lipophilic than enalaprilat. The in vitro affinity for ACE is 7 times higher than for enalaprilat and 47 times higher than for captopril. The ramiprilat-ACE complex is therefore very stable and dissociates 6 times more slowly than the enalaprilat ACE complex and 72 times more slowly than the captopril ACE complex. Consequently, ramipril is pharmacologically more potent and has a longer duration of action than enalapril and captopril. The blood pressure lowering effect of ACE inhibitors is attributed to the decrease in angiotensin II in serum and locally in target organs of hypertension: heart, vessel wall, kidney and brain. Inhibition of tissue renin-angiotensin system by ramipril has been described in target organs of hypertension in animal models and in clinical studies. Possibly due to its high lipophilicity, and strong affinity to the converting enzyme a better tissue penetration and a more pronounced local ACE inhibition in the target organs has been observed, as compared to other ACE inhibitors. In a preliminary investigation a direct action of ramipril on the tissue RAS in hypertensive patients could also be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of piretanide capsules on blood pressure during ergometric and isometric work loads in patients with mild to moderate essential hypertension.

A single-blind study was carried out in 22 out-patients with mild to moderate hypertension to investigate the effects of piretanide capsules on systolic and diastolic blood pressure during standardized ergometric and isometric exercise. After a 4-week run-in period on placebo, patients received 1 capsule (6 mg) once daily for 6 weeks. If diastolic pressure was normalized (less than 95 mmHg), this dosage was continued for a further 6 weeks; patients whose blood pressure remained high after the initial 6 weeks received 1 capsule twice daily for a further 6 weeks. Significant reductions in blood pressure (9.2% for systolic, 14.6% for diastolic) were measured after 12-weeks' treatment during maximum ergometric work load exercise; during isometric exercise the reductions were 8.1% and 12.4%, respectively. The pulse-pressure product (a parameter indicating myocardial oxygen consumption), calculated for maximum ergometric exercise, was also significantly reduced by 8.8% after 12-weeks' active drug treatment. Serum levels of potassium, creatinine, urea, uric acid and cholesterol showed no clinically relevant changes during treatment. Side-effects definitely or probably associated with piretanide were observed in 13 patients. These, however, were generally mild and did not lead to interruption of piretanide treatment. Transient polyuria was reported by 5 patients during the first 2 weeks of active drug treatment; only 3 patients reported mild polyuria after 12 weeks of active drug treatment. The beneficial effect of piretanide especially on systolic blood pressure during exercise was in marked contrast effect of piretanide especially on systolic blood pressure during exercise was in marked contrast to the lack of such an effect reported during treatment with thiazide and other thiazide-like diuretics.