Experience with once-daily and twice-daily slow-release frusemide in hypertension. [Efficacy and tolerability of cycletanine in aged patients with hypertension]. Antihypertensive and biochemical effects of indacrinone enantiomers.
Out of thirty-six patients with mild to moderate hypertension twenty-six patients completed a double-blind comparison of slow-release frusemide at two dose levels, and placebo. The two groups differed in their age pattern, baseline level of blood pressure and response to a low-salt diet during the wash-out/run-in period. Despite the lack of comparability of the two groups, firm clinical inferences could be drawn from the study. Seven of the eighteen placebo patients had to be withdrawn from further participation because of deterioration in their hypertension: in contrast, fifteen of the eighteen frusemide patients showed an anti-hypertensive response and none was withdrawn because of lack of effect. Twice-daily administration of the slow-release formulation, however, produced an unacceptable level of such side-effects as nocturia, nausea and vomiting. Once-daily administration of the preparation is therefore preferred. Moderate arterial hypertension of the elderly has to be treated but the efficacy has to be progressive. Cicletanine has a pharmacokinetic profile well fitted to the therapy of this age group. The mechanism of action is characterized by synthesis of prostacyclin. A double blind prospective randomized study was conducted at two institutions on 132 patients aged more than 60, with diastolic arterial pressure over 95 mmHg and systolic over 160 mmHg. 62.9% of them were aged more than 75. The analysis of those two studies shows that the three groups with cicletanine (respectively 50, 100 and 150 mg per day) had a significant decrease of both pressures versus placebo. In the 50 mg group, 40% of arterial pressures were normalized after 3 months of treatment. There were no difference between 50 and 100 mg. There were no adverse drug reaction like falling down, day or night, or orthostatic hypotension. The biological tolerance, more particularly renal, was excellent with this dose of 50 mg a day. Cicletanine at the dose of 50 mg/day is a recommended treatment in arterial hypertension of the elderly. The enantiomers of indacrinone (I), an investigational loop diuretic, have different pharmacologic activity. The (-) enantiomer is natriuretic, and the (+) enantiomer is uricosuric. To determine the antihypertensive effects and an isouricemic ratio of indacrinone enantiomers, 37 patients with sitting diastolic blood pressure (BP) between 90 and 104 mm Hg, after a 4-week placebo washout, randomly received one of the ratios of I enantiomers, namely -2.5/+80 mg (A), -5/+80 mg (B), -10/+80 mg (C) or placebo (P), once daily for 12 weeks in a double-blind, parallel study. The mean reductions (baseline-end of treatment) in BP of 23/8, 20/10 and 25/10 mm Hg with treatments A, B and C respectively were greater (p less than 0.01) than that on P (0/3). Initially, serum uric acid decreased with treatments A and B but not with C. Mean changes in serum uric acid were -0.3, -0.4, 0.2 and 0.3 mg/dl respectively with treatments A, B, C and P. The ratio of -10/+80 mg produced least variation in serum uric acid. Reduction in serum K+ and Cl- appeared to be dose related to (-) enantiomer. No serious adverse effects were reported. A 1:9 ratio of I enantiomers intended for wide-scale use as a diuretic also showed good antihypertensive activity, a favorable uric acid profile and absence of hepatic toxicity in 14 patients.
Based on the limited number of published RCTs, the systolic/diastolic blood pressure lowering effect of loop diuretics is modest (-8/-4 mmHg) and is likely an overestimate due to the high risk of bias in the included studies. There are no clinically meaningful BP lowering differences between different drugs within the loop diuretic class. The dose ranging effects of loop diuretics could not be evaluated. The review did not provide a good estimate of the incidence of harms associated with loop diuretics because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.