Central effects of the diuretic, bendrofluazide.

1. Central effects of the diuretic, bendrofluazide (2.5, 5 and 10 mg) were studied in 12 healthy volunteers. Two placebos and an active control drug, oxazepam (15 mg), were included. Single doses were administered double-blind at 10.00 h. The effects of drugs on performance and subjective feelings were assessed before and from 1.5-2.5 and 3.5-4.5 h after ingestion, and recording of the electrical activity of the brain (EEG) and body sway carried out. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, together with critical flicker fusion and two flash fusion. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. The EEG was recorded with eyes open while the subjects carried out a mental arithmetic task, and with eyes closed, when they were required to relax. Body sway was recorded with eyes open and with eyes closed. 3. Bendrofluazide (10 mg) increased the number of errors at letter cancellation and reduced the rate of finger tapping (P < 0.05), while oxazepam increased the number of errors and reduced accuracy at continuous attention (P < 0.01), and increased the number of involuntary rest pauses during tapping (P < 0.05). 4. There were no effects of drugs on subjective assessment of mood. 5. No changes in the electrical activity of the brain were observed with bendrofluazide. In recordings with eyes open, oxazepam reduced delta (0.5-3 Hz), theta (3.5-7 Hz) and alpha 2 (10.5-13 Hz) while increasing beta 1 (13.5-21 Hz) activity.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetic studies and bioavailability of bendroflumethiazide in combination with spironolactone]. / Untersuchungen zur Pharmakokinetik und Bioverfügbarkeit von Bendroflumethiazid in Kombination mit Spironolacton.

An intraindividual comparative multiple-dose study (6 days) was carried out under controlled conditions on 10 healthy volunteers in order to establish the bioavailability of bendroflumethiazide (Bft; 3-benzyl-6-trifluoromethyl-7-sulfamyl-3,4-dihydro-1,2,4-benzoth iad iazine-1, 1-oxide), the sum of the fluorogenic metabolites of spironolactone (3-[3-oxo-7-alpha-acetylthio-17 beta-hydroxy-4-androstene-17-alpha-yl]-propionic acid-gamma-lactone) and canrenone, the main spironolactone metabolite from a fixed combination of Bft with spironolactone vs. the commercial preparations of the single drugs. Canrenone was assayed from plasma by high-performance liquid chromatography (HPLC) whereas Bft and the total aldosterone antagonistically acting spironolactone metabolites were determined fluorometrically. Both the fixed and the monosubstance formulation can be considered as bioequivalent for canrenone and the total fluorescence. Bft, in contrast, shows a reduced systemic availability of 61% when administered as the single drug formulation. A 2-compartment model was taken as the basis for the calculation of the steady-state plasma concentration curves and the pharmacokinetic parameters of Bft, canrenone and the sum of the fluorogenic spironolactone metabolites. Following oral multiple administration of 2.5 mg Bft (b.i.d.), the terminal elimination half-life, the steady-state volume of distribution and the total plasma clearance were determined to be 8.6-8.2 h, 0.88 l/kg and 269.4 ml/min, resp. In contrast to Bft, the AUC(120,tlast)-values for post-steady-state elimination, starting with the final spironolactone dose on day 6 were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

Skin blister fluid--an access to the peripheral compartment. Implications of a study on the behaviour of bendroflumethiazide in rats.

Pharmacokinetics of bendroflumethiazide (bft) were investigated in blood and skin suction blister fluid (SBF) in rats dosed 10 mg/kg intravenously. Additionally tissue levels were determined. Mean volume of skin blisters amounted to 10 or 20 microliters, respectively. While blood levels were best described according to a three-compartment model (terminal half-life 152 min) bft concentrations in SBF raised to a maximum 60 min post administration and thereafter declined (half-life 143 min). There was no significant effect of blister volume on SBF level-time course. A close relation between bft concentrations in SBF and the calculated amount of drug in the deep compartment was observed (r = 0.987). Plasma protein binding of bft was 84% while binding to SBF amounted to 76%. The drug is evenly distributed between plasma and erythrocytes. Therefore concentrations of unbound drug in SBF exceed those in plasma during the terminal phase. The determination of tissue levels showed bft concentrations in liver, kidney, lung and heart to follow blood levels whereas the pharmacokinetic behaviour of skin and muscle is rather close to that of the deep compartment. The results suggest the determination of skin blister fluid levels to be valuable if a drug acts from the tissue compartment then SBF being closer to the biophase than blood.

Comparative pharmacological and pharmacokinetic observations on propranolol (long acting formulation) and bendrofluazide administered separately and concurrently to volunteers.

1 The effect of long-acting (LA) propranolol, LA propranolol and bendrofluazide, and a new combined formulation of LA propranolol/bendrofluazide (Inderex) on exercise tachycardia was studied in ten normal volunteers. 2 The preparations were given in random order, double-blind, on three separate study weeks. Observations were made 0, 1, 3, 6, 8, 24, 33 and 48 h after drug administration. 3 The three preparations produced a significant reduction in exercise tachycardia up to 48 h after drug administration, and the effects of the three preparations were not significantly different from each other. 4 Following LA propranolol, LA propranolol and bendrofluazide, and the combined formulation the mean reductions in exercise heart rate 24 h after drug administration were 16.7 +/- 2.1%, 13.0 +/- 1.8% and 16.2 +/- 1.7% respectively. 5 Plasma levels of propranolol and bendrofluazide were measured at 0, 1, 2, 3, 6, 8, 10, 12, 24, 33 and 48 h after dose administration. 6 There was no significant difference in plasma propranolol levels, Cmax propranolol or AUCo-x following the three preparations. The mean apparent t1/2 beta of propranolol after LA propranolol alone was significantly shorter than following the other two preparations (P less than 0.05), but this was not associated with a different pharmacodynamic response. 7 There was no significant difference in the pharmacokinetic parameters of bendrofluazide following the two preparations containing bendrofluazide. No bendrofluazide was detected in plasma after LA propranolol alone. 8 The new combined formulation produces similar pharmacodynamic and pharmacokinetic responses to LA propranolol and bendrofluazide given separately, and to LA propranolol given alone, and so may be of value in the treatment of hypertension.

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.