[MK 870. A comparison of the saluretic action of MK 870, bendroflumethiazide and bendroflumethiazide + MK 870].
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Metolazone and bendroflumethiazide in hypertension: physiologic and metabolic observations.
A double-blind crossover comparison was made in 18 nonedematous hypertensive subjects with glomerular filtration rates exceeding 70 ml/min/1.73 m2 of the effects of 5 mg metolazone and 5 mg bendroflumethiazide on blood pressure and metabolic parameters. After a 4-wk run-in placebo period, patients received either metolazone or bendroflumethiazide for 6 wk in a crossover fashion with an intervening washout period of 4 wk. Metolazone induced a more sustained and greater blood pressure response than bendroflumethiazide. Changes in plasma potassium, urate, bicarbonate, renin, and angiotensin II occurred during treatment with both metolazone and bendroflumethiazide; the only significant difference, however, was in changes in plasma bicarbonate. Total body potassium (TBK), measured by whole-body monitor, did not fall outside the normal range with either metolazone or bendroflumethiazide, although metolazone induced a greater reduction in TBK (6.2 gm, 5.5% of TBK) than bendroflumethiazide (1.2 gm, 1.1% of TBK, p < 0.05). Our results suggest that metolazone is a more effective antihypertensive and induces similar but greater metabolic changes than bendroflumethiazide. The results of our comparison suggest that although changes in plasma potassium and TBK are minor, they are greater with metolazone, and potassium supplements may not be necessary in nonedematous hypertensive patients with normal renal function.
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The supra-additive natriuretic effect addition of bendroflumethiazide and bumetanide in congestive heart failure. Permutation trial tests in patients in long-term treatment with bumetanide.
The additive natriuretic effect of a single dose of bendroflumethiazide, 5 mg., has been studied in patients with advanced congestive heart failure in long-term treatment with bumetanide, 4 mg., daily. Three permutation trial tests were performed including six patients each. In the first trial, the response to supplementary bendroflumethiazide, 5 mg., was definitely superior to that of additional bumetanide, 4 mg., in terms of renal output of sodium, chloride, potassium, water, and osmolar clearance. In the second trial, a similar pattern was found in patients receiving a combination of bumetanide, 4 mg., and spironolactone, 100 mg., daily. The third trial compared the effects of bendroflumethiazide, 5 mg., plus bumetanide, 4 mg.; of bendroflumethiazide, 5 mg.; and of bumetanide, 4 mg. In terms of natriuresis and chloruresis, the response to the combination of two drugs was significantly larger than the sum of the effects of other treatments. It is concluded that the combined effects of the drugs represent a supra-additive effect addition for sodium and chloride. A tentative explanation of the mechanism of interaction in terms of inhibition of renal tubular supplementary spironolactone, involve a tendency to development of hypokalemia, hypochloremia, and alkalosis, it is recommended that supplementary use of bendroflumethiazide in this setting is combined with the administration of potassium chloride or potassium-saving diuretics.
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Antihypertensive effect and side-effects of bendroflumethiazide and propranolol.
The antihypertensive effect and side-effects during 12 months' treatment with bendroflumethiazide and propranolol have been compared in two randomly selected, equally large groups (n= 53) of previously untreated male hypertensives. Systolic BP above 170 or diastolic BP above 105 mmHg on two occasions were defined as hypertension. The same BP reduction was achieved in both groups. During the 12 months' treatment one subject on bendroflumethiazide developed diabetes mellitus and one on propranolol developed cardiac decompensation. None developed gout. Contrary to what had been presumed, glucose tolerance improved during 12 months' treatment with both agents, while there were no changes in fasting blood sugar, insulin or triglyceride concentrations. No changes were found in serum potassium or total body potassium during 12 months' bendroflumethiazide treatment, while serum potassium increased during treatment with propranolol. Uric acid increased slightly during treatment with both agents. Prolongation of the follow-up to 24 months did not change any of the findings regarding metabolic changes during treatment. The frequency of subjective side-effects decreased to the same extent during treatment with both drugs. It is concluded that bendroflumethiazide and propranolol are equally useful as antihypertensive agents and that the risk of impariment of glucose metabolism and potassium balance seems to be very slight during treatment with bendroflumethiazide in mild hypertension.
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Comparison of slow-release piretanide and bendroflumethiazide in the treatment of mild to moderate hypertension.
After 4 weeks of placebo treatment, 76 hypertensive patients were randomly allocated to 6 or 12 mg/day piretanide, or 2.5 mg/day bendroflumethiazide for 12 weeks in a double-blind study. Piretanide was given in a slow-release formulation and bendroflumethiazide as a tablet. All three treatments produced a significant reduction in supine and erect systolic and diastolic blood pressures after 2 weeks, and this effect was maintained throughout the study. Normotension (i.e. supine diastolic pressure less than or equal to 95 mmHg) was achieved in 73% of the patients receiving 12 mg/day piretanide and in 57% receiving 6 mg/day piretanide compared with 72% receiving bendroflumethiazide (not significant). Overall, five patients were withdrawn due to increased diuresis: two patients on each dosage of piretanide and one receiving bendroflumethiazide. Three patients receiving 6 mg/day piretanide were withdrawn due to diastolic blood pressure rising above 120 mmHg. Other side-effects reported were mild and transient. There were no significant changes in serum creatinine, glucose or high-density lipoprotein cholesterol. A small, but non-significant rise in uric acid level was seen in all three groups. Clinically relevant hypokalaemia requiring potassium supplementation occurred in three patients receiving bendroflumethiazide.
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Multicentre comparison between slow-release furosemide and bendroflumethiazide in congestive heart failure.
The effects of slow-release furosemide and bendroflumethiazide in the ambulatory treatment of mild to moderate congestive heart failure were compared in a controlled multicentre study using a randomized, double-blind procedure. In the first trial, slow-release furosemide 60 mg daily was compared with 2.5 mg bendroflumethiazide; in the second trial the daily doses were 30 mg and 2.5 mg, respectively. There were 47 patients in Trial I and 39 in Trial II. The randomised allocation to the treatment regimen was made after a four-week period on bendroflumethiazide 2.5 mg daily, and treatment was continued for 12 weeks. Clinical and laboratory data were recorded before, during and at the end of the trial. Adverse effects were few and minor in both medication groups, and there were no significant intergroup differences. It was concluded slow-release furosemide 30 mg or 60 mg daily was as effective as bendroflumethiazide 2.5 mg daily for maintenance treatment in mild to moderate congestive heart failure.
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Pharmacokinetics of bendroflumethiazide after low oral doses.
The pharmacokinetics of bendroflumethiazide after oral administration of 1.25, 2.5, and 5.0 mg were studied in nine healthy male volunteers. Bendroflumethiazide was analyzed by GLC after extractive alkylation. After the lowest dose, the plasma concentration, could be followed to 14 hr, and the data were adequately fitted by a one-compartment model; the half-life was 3.1 hr. After the 2.5 and 5.0 mg doses, the plasma concentration was followed for 24 hr, and the data were fitted by a two-compartment model with half-lives of 8.9 hr. The urinary sodium concentration was doubled after bendroflumethiazide intake, but the urinary potassium concentration remained almost constant. The renal clearance of bendroflumethiazide was around 30 ml . min-1.
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Double-blind comparison between propranolol and bendroflumethiazide in captopril-treated resistant hypertensive patients.
In a double-blind crossover trial, 15 captopril (daily dose 600 mg) treated patients received in addition to the converting enzyme inhibitor, placebo, propranolol (240 mg), or bendroflumethiazide (7.5 mg). Propranolol produced an additional hypotensive effect, while pulse rate slowed, indicating effective beta-adrenoceptor blockade. Plasma renin activity decreased, but the hypotensive effect of propranolol was not accompanied by changes in the plasma angiotensin II and aldosterone levels or in the urinary aldosterone excretion. Also bendroflumethiazide lowered blood pressure, while body weight decreased slightly. During captopril-bendroflumethiazide treatment, serum sodium and potassium decreased while the plasma renin-angiotensin-aldosterone system was stimulated. In these captopril-treated patients, the hypotensive response to bendroflumethiazide tended to be somewhat larger than the response to propranolol, but the difference was small and statistically not significant.
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Enalapril versus bendroflumethiazide in type 2 diabetes complicated by hypertension.
In a double-blind, double-dummy, randomized, multi-centre study, the effects of bendroflumethiazide vs. enalapril on blood pressure, glycaemic control, lipoprotein concentrations and albuminuria were compared in non-proteinuric, hypertensive type 2 diabetic patients; they were treated for 20 weeks with either bendroflumethiazide 2.5-5.0 mg (n = 59) or enalapril 10-20 mg (n = 55). Age, fasting plasma glucose, HbA1c and BMI were similar in the groups. Systolic and diastolic blood pressure were reduced in both groups. Bendroflumethiazide was accompanied by minor but significant elevations in fasting plasma glucose and serum C-peptide. HbA1c was increased during both treatments. Lipoproteins and urinary albumin/creatinine ratio were stable. Bendroflumethiazide caused a decrease in serum potassium and an increase in serum urate. No significant correlations were observed between the decline in blood pressure and changes in the metabolic risk factors. Baseline levels of age, sex, BMI, blood pressure or urinary albumin/creatinine ratio were not related to changes in blood pressure, metabolic parameters or urinary albumin/creatinine ratio.
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Atenolol versus bendroflumethiazide in middle-aged and elderly hypertensives.
The antihypertensive effect and patient tolerability during 12 weeks' treatment with atenolol and bendroflumethiazide were evaluated in an open, randomized, between-patient trial. Out of a total of 162 patients, aged 50-75 years, with previously untreated hypertension, 151 completed the trial. They were randomly allocated to two groups. Forty-nine patients, aged 50-64 years (middle-aged), and 23, aged 65-75 years (elderly), were treated with atenolol. Forty middle-aged and 39 elderly were treated with bendroflumethiazide. Significant reductions in blood pressure (BP) were observed during treatment with each drug (p less than 0.001). The change in diastolic BP in middle-aged patients was significant in favour of atenolol (p less than 0.01), but otherwise no difference was found between the two drugs. Uric acid increased during treatment with both drugs (p less than 0.001). Serum potassium decreased during bendroflumethiazide treatment (p less than 0.001). Subjective side-effects of both drugs were few and expected. The results of this study indicate that atenolol and bendroflumethiazide are equally effective in reducing BP in patients aged 50-75 years.
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The effects of bendroflumethiazide added to nifedipine in patients with hypertension.
It has been suggested that a diuretic added to a calcium antagonist may not reduce blood pressure further in patients with hypertension. Bendroflumethiazide 5 mg was given to 17 patients with essential hypertension who had persistent mild to moderate hypertension despite treatment with nifedipine slow-release tablets 20 mg bid. One group received bendroflumethiazide before (N = 8) and the other after placebo (N = 9) in a double-blind, randomized cross-over trial. Supine blood pressure following active bendroflumethiazide administration was significantly reduced in both groups compared with trial entry (166/105 to 150/96 mm Hg, P less than .01; 170/108 to 156/98 mm Hg, P less than .01). A reduction in serum potassium level and a rise in serum uric acid concentration were seen with combined treatment. We cannot substantiate theoretic arguments for the ineffectiveness of a bendroflumethiazide-nifedipine combination on blood pressure.
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The effect of bendroflumethiazide and hydrochlorothiazide on the rate of dissolution of calcium hydroxyapatite.
Inhibition of dissolution of calcium hydroxyapatite in the presence of bendroflumethiazide, Centyl, and of hydrochlorothiazide has been investigated. The former compound has a pronounced larger inhibitory effect than the latter. The trifluormethyl group in bendroflumethiazide has been shown to hydrolyze, with the release of fluoride and hydrogen ions, presumably forming a carboxylic acid. The inhibitory effect of hydrolyzed bendroflumethiazide is found to be similar to the effect of a potassium fluoride solution with the same fluoride ion concentration, as measured by a fluoride selective ion electrode.
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Antihypertensive action of bendroflumethiazide: increased prostacyclin production?
A within-patient randomized, double-blind, crossover study was performed to investigate mechanisms of action of bendroflumethiazide in mild essential hypertension. Significant reductions in lying, standing, and postexercise blood pressure were seen after both 3 days and 10 wk treatment with bendroflumethiazide 10 mg daily. Plasma levels of 6-oxo-PGF1 alpha, the chemical hydrolysis product of prostacyclin, were increased by both 3 days and 10 wk therapy with bendroflumethiazide. This raises the possibility that thiazides may reduce peripheral resistance by increasing prostacyclin biosynthesis.
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Controlled trial of nifedipine and bendroflumethiazide in hypertension.
In a double-blind study 30 patients with mild or moderate (World Health Organization classification I or II) hypertension were treated with either nifedipine, 20 mg twice a day, or bendroflumethiazide, 2.5 mg (+0.57 g KCl) twice a day for 24 weeks. All patients were then given a combination of half the initial dosage of both drugs for an additional period of 6 weeks. Nifedipine caused a significant reduction of both supine and standing blood pressures (16/10 and 11/5 mm Hg, respectively). Bendroflumethiazide also reduced both recumbent and standing blood pressures significantly (15/10 and 11/10 mm Hg, respectively). Combined treatment with nifedipine and bendroflumethiazide caused a further reduction of both supine and standing blood pressures. The total reduction compared with placebo was 23/12 mm Hg (p less than 0.001) and 17/11 mm Hg (p less than 0.001), respectively. There was no significant correlation between antihypertensive effect and age of patient.
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Clinical experience with long-term bendroflumethiazide treatment in calcium oxalate stone formers.
Bendroflumethiazide was administered to 85 patients (62 men, 23 women) with recurrent calcium oxalate stone disease. Side effects leading to interrupted treatment were observed in 26 (31%) of the patients. Fifty-nine (40 men, 19 women) remained on treatment for a mean (+/- SD) period of 3.7 +/- 1.0 years, and 21 reported late side effects. Twenty patients were given 2.5 mg bendroflumethiazide daily (Group A), 27 were given 2.5 mg twice daily (Group B), and 12 were given 5 mg once daily (Group C). Eight patients (14%) formed new stones and another two demonstrated stone growth during treatment. A beneficial effect on stone formation was observed in Groups B and C but not in Group A. Patients who failed to respond to treatment had a pre-treatment stone formation rate of 0.74 stones per year compared with 0.22 in those who did not form new stones. Those with recurrence during treatment had a lower citrate excretion than other patients. No effect on urinary citrate was recorded during treatment, and long-term treatment with bendroflumethiazide did not affect oxalate excretion.
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Effects of the thiazide diuretic bendroflumethiazide on salivary flow rate and composition.
Thiazide diuretics are among the first-line alternatives in the treatment of primary hypertension. The effects of thiazide treatment on salivary production are, however, little studied and the results so far available are not decisive. The aim of the present study was to evaluate and compare salivary flow rate and composition during treatment with the thiazide diuretic bendroflumethiazide in a low dose (2.5 mg o.d.) and placebo. The study was performed with a randomized, double-blind, cross-over design (2 x 2 wk) in 34 healthy volunteers. The treatment periods were separated by a wash-out period of 2 wk. Resting and stimulated whole saliva was sampled three times daily on scheduled days during the treatment periods. Flow rate was assessed for resting saliva, whereas flow rate, pH, buffer capacity, amount of total proteins and concentrations of sodium, potassium, calcium, phosphate and magnesium were measured for stimulated whole saliva. No effect of bendroflumethiazide on the resting salivary flow rate could be detected, while the stimulated flow rate was significantly reduced by about 10% during the thiazide treatment. The total sodium output was significantly decreased by approximately 30%, without any detectable change in total potassium output. All other variables of stimulated whole saliva studied were not different from placebo. It is concluded that treatment with bendroflumethiazide in a low dose significantly reduces the stimulated whole salivary flow rate and total sodium output in healthy volunteers.
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Diurnal variation of urine composition in calcium oxalate stone disease during treatment with bendroflumethiazide.
Urine samples, collected hourly between 6.00 and 23.00 h and in one single night fraction, were analyzed for calcium (Ca) and magnesium (Mg) before and during daily administration of 5 mg bendroflumethiazide to 13 Ca-oxalate (CaOx) stone formers. In some of them urinary oxalate (Ox), citrate and sodium were analyzed as well. Bendroflumethiazide was administered in divided doses to 7 and in a single dose to 6 patients. After 4-8 weeks of treatment urinary Ca decreased by approximately 25% in both groups and the reduction was evenly distributed over the day. The reduction of the Ca/Mg quotient and the CaOx risk index was most pronounced following meals. The AP(CaOx) index, an estimate of the CaOx ion activity product, was favorably reduced. No important differences were recorded for the different types of bendroflumethiazide administration and thus one single dose might be equally as efficient as two divided doses.
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Hydrochlorothiazide and bendroflumethiazide in low doses--a comparative trial.
The effect and tolerability of hydrochlorothiazide 12.5 mg and bendroflumethiazide 2.5 mg were compared in 36 previously untreated hypertensives in a double-blind randomized multicenter trial. The results show a significant blood pressure reduction with both hydrochlorothiazide 12.5 mg and bendroflumethiazide 2.5 mg both at month 6 and 12 compared with month 0. Serum potassium was not significantly changed after twelve months of therapy with either of the thiazide compared with month 0. There was no significant difference between hydrochlorothiazide and bendroflumethiazide with respect to the hypotensive effect, the effect on potassium and uric acid in serum, fasting blood glucose, or any other variable studied. Few subjective side effects were reported.
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