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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.

Adult

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.

Bendroflumethiazide

Comparative natriuretic and diuretic efficacy of theophylline ethylenediamine and of bendroflumethiazide during long-term treatment with the potent diuretic bumetanide. Permutation trial tests in patients with congestive heart failure.

The additive natriuretic and diuretic effects of theophylline ethylenediamine and of bendroflumethiazide have been compared in permutation trial tests in patients with advanced congestive heart failure receiving long-term treatment with the highly potent diuretic, bumetanide. Statistical analysis of renal water and electrolyte excretion revealed that theophylline ethylenediamine, 400 mg orally, and bendroflumethiazide, 5 mg orally, had very similar effects, both quantitatively and qualitatively. The mechanism of action of the supplementary diuretics is discussed. It is concluded that theophylline ethylenediamine represents a useful alternative to thiazide diuretics when supplementary natriuretic treatment is considered in patients with congestive heart failure during long-term treatment with potent diuretics. The significance of maintaining the potassium balance during such a combined regimen is stressed.

Bendroflumethiazide

Investigations on the antihypertensive activity of timolol and bendroflumethiazide and the combination in dogs and rats.

The effects of timolol and bendroflumethiazide, either alone or combined in a fixed ratio of 4:1, on blood pressure, plasma renin activity, and plasma potassium concentration, have been investigated in normotensive and renal hypertensive dogs, and in normotensive and spontaneously hypertensive rats. In addition, the urinary kallikrein excretion has been measured in normotensive and hypertensive rats. When administered to hypertensive dogs and rats, the drug combination significantly reduced the blood pressure. Marginal reductions were observed in normotensive animals or after the administration of the single drugs. The thiazide-induced hypokalaemia and hyperreninaemia were almost completely antagonised by the concomitant administration of timolol in both animal species. A highly significant elevation of urinary kallikrein excretion was also observed in rats treated with the drug combination. A less marked increase of kallikrein excretion was noted in the bendroflumethiazide treated rats. The possibility that renal haemodynamic changes, in addition to the inhibition of the increase in plasma renin, play a role in the observed antihypertensive effects is discussed.

Animals

Pharmacokinetics of bendroflumethiazide.

Bendroflumethiazide (bft), 10 mg, was administered orally to 9 healthy volunteers. The concentrations of the diuretic in plasma and urine were determined by gas-liquid chromatography (GLC). Peak plasma levels (86 +/- 18 ng/ml) of bft were reached at 2 +/- 0.4 hr. The concentration declined with a mean t1/2 of 3.0 hr. The apparent volume of distribution averaged 1.48 L/kg. The major part of the drug was eliminated via nonrenal mechanisms, the nonrenal clearance being estimated to 269 +/- 77 ml/min and renal clearance to 105 +/- 24 ml/min. Urinary recovery of the thiazide averaged 30%.

Adolescent

Effect of food on the bioavailability of bendroflumethiazide.

Bendroflumethiazide (BFT), 10 mg, was given orally to eight subjects after fasting overnight and together with a meal. Concentrations of the diuretic in plasma and urine were determined by GLC. As judged by AUC and urinary recovery of BFT, the bioavailability of the diuretic was not influenced by concomitant intake of a meal.

Administration, Oral

Effects of therapy with bendroflumethiazide in patients with recurrent renal calcium stones.

Forty-four patients with recurrent formation of calcium-containing renal stones were treated with bendroflumethiazide for at least 2 years. Prior to treatment each patient had formed, on average, one stone per year for 8 years; during treatment only 4 patients formed new stones. A reduction in urinary calcium excretion was seen in almost all patients irrespective of their initial urinary calcium level. The apparent clinical benefit was not related to pre-treatment urinary electrolyte levels. Side effects were slight: one patient developed symptomatic hyperuricaemia and in one case sustained hypercalcaemia was found. Long-term treatment with thiazides appears to be a safe and effective method for the prevention of recurrent calcium stones.

Bendroflumethiazide

Effects on rat urinary kallikrein excretion of bumetanide, bendroflumethiazide and hydralazine.

Single and/or repeated administrations of bumetanide, bendroflumethiazide and hydralazine to normotensive and spontaneously hypertensive rats resulted in an increase of urinary kallikrein excretion. No correlation was found with sodium output. The role of the increased plasma renin activity is discussed and it is suggested that the activation of the renal kallikrein-kinin system is related to the increase in renal blood flow.

Administration, Oral

Pharmacokinetics of bendroflumenthiazide in hypertensive patients.

After four weeks on placebo treatment, 8 hypertensive patients (WHO stage I) were treated for 2 weeks with bendroflumethiazide (bft) 2.5 mg and KCl 1.5 g daily. Subsequently they received bft 5 mg and KCl 1.5 g daily for a further fortnight. At the end of each period of treatment blood pressure was recorded and blood samples and urine were collected for analysis of bft by GLC. Before taking the daily dose of bft, no trace of the drug was found in plasma. Peak levels of bft were seen after 2.3 h and averaged 23 and 50 ng . ml-1 after 2.5 and 5 mg, respectively. After bft 2.5 mg the plasma level was too low for kinetic analysis. The plasma half-life after 5 mg averaged 4.1 h. The mean apparent volume of distribution was 1.18 1 . kg-1. Non-renal clearance averaged 200 ml . min-1. The renal clearance of bft was significantly lower (p less than 0.05) after 5 mg (48 ml . min-1) than after 2.5 mg bft (93 ml . min-1), although the creatinine clearance remained unchanged. No correlation was found between the plasma level of bft and its effect on blood pressure.

Adult

Hydrochlorothiazide-induced pulmonary edema. Report of a case and review of the literature.

Immediately following the initial ingestion of hydrochlorothiazide, acute pulmonary edema developed in a patient who previously used bendroflumethiazide. Unlike previously published reports, we studied the patient from immunologic and pulmonary function aspects. Using standard techniques, no significant immunological mechanisms could be demonstrated. The pulmonary function testing disclosed a widened alveolar-arterial oxygen gradient and mildly decreased diffusing capacity that cleared on serial testing. We believe that this demonstrates a rare idiosyncratic reaction that apparently is seen specifically with hydrochlorothiazide and not with other thiazide medications.

Female

[Renal kallikrein-kinin system and control of blood pressure (author's transl)].

Kallikrein excreted with the urine appears to be formed in the kidney. The kallikrein-kinin system in the kidney is localized in the distal nephron from the juxtaglomerular apparatus to the collecting duct. It has been shown that intrarenal infusion of kinins produces an increase in renal blood flow as well as diuresis and natriuresis. Part of the effect of kinins appears to be mediated by the release of prostaglandins. However, the precise role of the renal kallikrein-kinin system in sodium and volume homeostasis and in blood pressure regulation still remains to be determined. Mineralocorticoids as well as the diuretics furosemide, bumetanide and bendroflumethiazide increase, spironolactone decreases kallikrein excretion. Urinary kallikrein has been shown to increase acid-as well as cryoactivation of prorenin in vitro. It is unclear as yet, however, whether the renal kallikrein-kinin system takes part in converting inactive prorenin into active renin in vivo. There are reports on subnormal, normal as well as increased kallikrein excretion in spontaneously hypertensive rats. In rats susceptible to the hypertensive effect of salt a substantially decreased excretion of kallikrein has been observed. Kallikrein excretion has been described to be increased in primary aldosteronism and to be reduced in a proportion of patients with established essential hypertension. In patients with labile hypertension, however, kallikrein excretion appears to be normal suggesting that decreased urinary kallikrein in essential hypertension is a consequence rather than a cause of hypertension. The renal kallikrein-kinin system does not appear to play a primary role in the pathogenesis of hypertension.

Angiotensin II

Amelioration of bendrofluazide-induced hypokalemia by timolol.

The beta adrenergic blocking drug, timolol, tended to correct the hypokalemia of short-term bendrofluazide treatment in 6 healthy male subjects and although the effect was small it was significant. Timolol also reduced the rise in plasma aldosterone and urine potassium excretion following bendrofluazide and increased the urine sodium/potassium ratio. There was no evidence of a shift of potassium from the intracellular to the extracellular space.

Bendroflumethiazide

Timolol and bendrofluazide in the management of hypertension in general practice.

The beta-adrenergic blocking drug, timolol, was combined with bendrofluazide in a comparative trial between once and twice daily dosage, conducted on 51 patients suffering from hypertension seen in general practice. During the initial control period seven of these patients became normotensive, leaving 44 who entered the trial. Using a crossover design, treatment was continued for a total period of up to 16 weeks. With both dose regimes, systolic and diastolic pressures were rendered normotensive in over three-quarters of the patients, significant reductions occurring within the first two to four weeks of treatment.

Bendroflumethiazide

Total body and serum potassium during prolonged thiazide therapy for essential hypertension.

Serum-potassium and total body potassium (T.B.K.) were measured serially for 1 year in a group of eighteen patients with mild essential hypertension. The patients were receiving a single daily dose of 10 mg. bendrofluazide without potassium supplements. At 12 months the mean value for serum-potassium (3-86 mmol per litre) was significantly lower than the mean pre-treatment value (4-26 mmol per litre). There was no significant decrease in T.B.K. in the same period. Diastolic blood-pressure fell significantly, and there were no apparent side-effects from the medication. In the group as a whole, a reduction of about 1 mmol per litre in serum-potassium was associated with an average reduction of 10% in T.B.K., but there was a large individual variation. The amount of potassium loss during the period of study did not seem to be clinically significant. It is suggested that routine potassium supplements are not essential in the treatment of uncomplicated essential hypertension with thiazide diuretics.

Bendroflumethiazide