Serotonin antagonism reduces the adverse symptoms of beta blockade

Summary Beta-adrenoceptor antagonists (beta blockers) are a well-established first-line treatment for hypertension, but they have been associated with unwanted symptoms including cold extremities, lethargy, and nightmares. Ketanserin is a serotonin S₂-receptor antagonist that has previously been shown to reduce blood pressure in hypertensive patients by reducing systemic vascular resistance. Hypertensive patients whose sitting diastolic blood pressure was 95 mmHg, despite at least 4 weeks therapy with an optimal dose of beta blocker, were selected for the study. The beta-blocker dose remained constant throughout the study, but patients were randomly allocated to receive ketanserin 20 mg twice daily, ketanserin 40 mg twice daily, or bendrofluazide 5 mg each morning plus placebo at night in addition to the beta-blocker therapy. One hundred and forty two patients completed the symptom questionnaire at randomization and after 12 weeks treatment. The treatment groups were well matched for age, sex, weight, and blood pressure. Blood pressure was reduced significantly by all treatments, and there were no between-group differences. Bendrofluazide adversely affected alertness (p<0.05) and concentration (p<0.01) whereas ketanserin had no significant effect and the ketanserin 20 mg twice daily group had better concentration than the bendrofluazide group (p<0.05). Ketanserin treatment reduced the incidence of nightmares (p<0.05 for 20 mg twice daily and 40 mg twice daily) and was an improvement over bendrofluazide treatment in this respect (p<0.05).Leg pain on walking (p<0.01) and at rest (p<0.05) was worse on bendrofluazide, whereas ketanserin treatment 20 mg twice daily improved incidence of leg pain on walking (p<0.05) and was an improvement over bendrofluazide treatment in this respect (p<0.05). Incidence of flushing was reduced by ketanserin 40 mg twice daily (p<0.01) more effectively than by bendrofluazide treatment (p<0.05).The present study indicated that serotonin antagonism by ketanserin can reduce the nightmares and sleep disturbance and reverse the deterioration in peripheral circulation that may accompany treatment with beta blockers.representing the KTN 165 study group     

Effects on body elemental composition of prophylactic diuretic treatment of urinary lithiasis

Summary Whole body elemental compostion was measured by in vivo neutron activation analysis before and after treatment of urinary stoneformers with bendrofluazide for 6 months. There was no significant change in whole body calcium, sodium, nitrogen or body weight. There were significant reductions in whole body potassium (6%), chlorine (7.3%) and phosphorus (1.5%).     

The effect of diuretic therapy on adrenaline-induced hypokalaemia and hypomagnesaemia

Summary We have examined the interaction between the administration of bendrofluazide, frusemide, spironolactone, and placebo and increased plasma adrenaline concentrations in a double-blind, placebo-controlled, cross over study.We studied healthy subjects on the fourteenth day of each treatment period and after a two hour infusion of adrenaline (0.06 µg·kg^–1·min^–1 {0.33 nmol·kg^–1·min^–1}) we measured their heart rates, blood pressures, and plasma potassium and magnesium concentrations.There were no differences in heart rates or blood pressures for all four treatments. Baseline potassium concentrations were not significantly different compared to placebo, and plasma potassium fell during the period of the infusion on all study days. this fall was significantly greater on frusemide (0.5 mmol·l^–1) and bendrofluazide (0.4 mmol·l^–1) compared with both placebo and spironolactone.Baseline plasma magnesium concentration were not different and similar falls in plasma magnesium were seen on all four treatments during and after the adrenaline infusion.We conclude that chronic diuretic therapy with a thiazide diuretic or frusemide may increase the severity of hypokalaemia during short-term rises in plasma adrenaline. Pretreatment with spironolactone had no effect on adrenaline-induced hypokalaemia. None of the diuretics studied altered adrenaline-induced hypomagnesaemia.     

A comparison of the acute effects of cicletanine and bendrofluazide on urinary electrolytes and plasma potassium in essential hypertension

The acute effects on urinary electrolyte excretion and plasma potassium were compared of the anti-hypertensive dihydrofuropyridine cicletanine with the thiazide bendrofluazide in 6 patients with uncomplicated essential hypertension. Cicletanine 50 mg or 100 mg and bendrofluazide 5 mg caused no acute decrease in blood pressure compared to placebo for 24 h after treatment. In the 24 h after a single dose of cicletanine 50 mg there was no increase in urinary sodium, potassium or volume compared to placebo. After a single dose of cicletanine 100 mg there was a significant increase in 2 h urinary sodium excretion compared to cicletanine 50 mg and in the first 6 h a significant increase in urinary potassium compared to placebo. Urine volume did not change significantly. After bendrofluazide 5 mg urinary sodium excretion increased significantly in the first 6 h as well as in the subsequent 18 h compared to placebo and both cicletanine 50 mg and 100 mg. Urinary potassium excretion was also significantly increased in the first 6 h after bendrofluazide compared to placebo, and urine volume significantly increased from 6 to 24 h after bendrofluazide 5 mg compared to placebo and cicletanine 100 mg. Plasma potassium was significantly reduced and plasma renin activity significantly increased 24 h after bendrofluazide 5 mg but these measurements were not significantly different from placebo after cicletanine 50 or 100 mg. These results suggest that cicletanine 100 mg has milder acute natriuretic effects than the thiazide bendrofluazide 5 mg. In contrast cicletanine 50 mg is associated with no major acute renal effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Timolol and bendrofluazide in the management of hypertension in general practice

Summary 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 cross-over 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.     

A multi-centre general practice study on the use of a timolol/bendrofluazide combination (‘Prestim’) in the management of hypertension: preliminary report

Summary

A preliminary report is given on the first 500 patients entered in an on-going open study in general practice of a combination of 10?mg timolol maleate and 2.5?mg bendro-fluazide used to treat mild to moderate essential hypertension. After a 2-week placebo period, dose titration was conducted at weekly intervals, with a final assessment 8 weeks after the diastolic blood pressure was controlled. Data for 472 patients out of 492 commencing active therapy were evaluated. Four-hundred and thirty-seven (93%) became normotensive (≤95 mmHg diastolic) on a mean dose of 1.9 tablets taken as a single daily dose. Control was maintained over the follow-up period in all but 13 (2.6%) patients who required a dosage reduction and 2 (0.4%) who required a dosage increase. The incidence of side-effects was low, 22 (4.4%) patients stopping treatment due to adverse events. Biochemical parameters all stayed within normal values. The rapidity of dosage titration, patient acceptability, compliance with regard to the once daily dosage and the low incidence of side-effects suggest that the timolol/bendrofluazide combination approaches optimum therapy for mild to moderate hypertension.     

The influence of antihistamines on human performance

Summary The effects of verapamil and bendrofluazide used singly and in combination were examined in patients with primary hypertension in a patient blind, partly observer blind placebo controlled study of parallel group design; there were ten subjects in each arm of the trial.Verapamil 160 mg twice daily caused supine mean arterial pressure to fall by 21 mm Hg; this reduction was significantly greater (p<0.05) than that induced by bendrofluazide 5 mg daily which caused a fall of only 10 mm Hg.The addition of verapamil 160 mg twice daily to bendrofluazide 5 mg daily caused a further fall in pressure of 18 mm Hg (p<0.005), but the reduction in pressure when bendrofluazide was added to verapamil was only 1 mm Hg and not significant.Bendrofluazide therapy caused a fall in plasma potassium concentration and an increase in plasma urate concentration; urinary calcium excretion was reduced. Verapamil caused no detectable biochemical alterations in plasma or urine.     

Effect of bendrofluazide on calcium reabsorption in hypoparathyroidism

Summary In hypoparathyroidism the absence of parathyroid hormone leads to a reduction in the absorption of calcium by renal tubular cells. In spite of treatment with vitamin D, hypercalciuria persists and normocalcaemia can only be maintained by providing the kidney with a large load of calcium. Thiazide diuretics enhance tubular calcium reabsorption and it has been suggested that they can be used as an alternative to vitamin D. Bendrofluazide in a dose of 10 mg daily was given to 9 patients with severe hypoparathyroidism in addition to their usual treatment with calcium and vitamin D. Following the introduction of Bendrofluazide the calculated renal threshold for calcium reabsorption (TmCa/GFR) increased by a mean value of 0.14 mmol/l, and the mean rise in serum calcium was 0.13 mmol/l. This increase was due to a direct effect of the drug and was not caused by salt restriction or changes in glomerular filtration rate. The rise in serum calcium is modest compared to the rise following the introduction of vitamin D and except for patients with mild hypoparathyroidism, thiazides are not an alternative to vitamin D. They may however reduce the oral calcium load required to maintain normocalcaemia.     

Comparison of labetalol and clonidine in hypertension

Summary The antihypertensive effect of labetalol (L) was compared with that of clonidine (C) in a randomized cross-over study in 17 hypertensive outpatients on bendrofluazide (B). After treatment for two weeks with B (5 mg qd), either L (100 mg tid) or C (0.1 mg tid) was given and their doses were titrated at 2-weekly visits until normotension was achieved, or intolerable side-effects occurred. The treatment with B and L or C was then continued in a cross-over fashion for two 6-week periods, with 3 week diuretic washouts and subsequent dose-titration periods between the treatment periods. At the end of B, the supine blood pressure (BP) was 156/101, and at the end of B + L and B + C it was 136/91 (p<0.001) and 137/91 (p<0.001), respectively, pooling the data from both periods. At the end of B, the standing BP was 155/115, and at the end of B + L and B + C 134/100 (p<0.001) and 139/106 (p<0.001), respectively. The mean daily doses required were L 476mg and C 0.335 mg. On a weight basis, labetalol had about 1/1400 of the potency of clonidine. 12 patients complained of tiredness and dry mouth on clonidine and 2 patients of unsteadiness on labetalol. Labetalol caused a psoriasiform rash on the hands in one patient and limb weakness in one patient.