Effect of simple short term dietary control on urine electrolyte excretion in normal men.

Normal diet and a simple short term prescribed diet were compared with respect to mean excretion of urine electrolytes and the variability in these responses in 12 healthy male subjects. Urine was collected from 7 to 15 h (overnight) and 15 to 25 h (daytime) after the start of dietary control. Differences in mean responses were slight. For sodium and potassium excretion, however, there were tendencies for responses in subjects with high excretion on normal diet to decrease and for responses in those with low excretion on normal diet to increase towards the overall mean during the prescribed diet. The prescribed diet reduced markedly the variability in electrolyte responses and for log transformed data reductions in variability were statistically significant in the daytime urine collections. The results of this study have confirmed quantitatively the benefit of a short period of simple dietary control. The marked reduction in the variability of sodium and potassium excretion improves considerably the precision and sensitivity of studies of urine electrolyte composition.

Relative potency of prorenoate potassium and spironolactone in attenuating diuretic induced hypokalaemia.

The plasma potassium responses to the aldosterone antagonists prorenoate K (10 mg/day and 40 mg/day) and spironolactone (25 mg/day and 100 mg/day) were compared following treatment for 11 days in combination with the diuretic metolazone (2.5 mg/day) in a double-blind crossover study in twelve healthy men. The best estimate of the potency of prorenoate K relative to spironolactone in attenuating metolazone induced hypokalaemia was 5.6 with 95% confidence limits 2.4-35.2. The method employed allowed a statistically valid quantitative comparison of the potassium sparing properties of the mineralocorticoid antagonists after repeated doses and may be useful in the preclinical evaluation of these drugs.

Propantheline bromide plasma level, urinary excretion and pharmacological data in a comparison of the bioavailability of three oral formulations of Pro-Banthine.

To determine the comparative bioavailability of three oral formulations of propantheline bromide (PB) by both pharmacokinetic and pharmacodynamic parameters, six normal men received three standard Pro-Banthine 15 mg tablets, two prolonged acting (PA) Pro-Banthine 30 mg tablets or one developmental PA Pro-Banthine 45 mg capsule, in a study of balanced random crossover design. Plasma concentrations and urinary excretion of the unchanged drug were measured after each treatment using a stable isotope dilution assay. Salivary secretion rate and heart rate measurements were also made at intervals after each medication. The standard Pro-Banthine formulation was significantly more bioavailable, weight for weight, than either the developmental PA capsule (45 mg), p less than 0.05, or the two 30 mg PA tablets (60 mg), p less than 0.01, based on urinary excretion and plasma levels of PB and on salivary secretion and heart rate data. There was no evidence of significant prolonged action for the PA formulations.

Use of a bioassay in healthy men to evaluate diuretic-spironolactone combinations.

The plasma potassium responses to 1 week's treatment with metolazone 0.625 mg, 1.25 mg and 2.5 mg in combination with spironolactone 50 mg, and metolazone 2.5 alone were examined in a double-blind, crossover study in twelve healthy subjects. Spironolactone attenuated the hypokalaemia induced by metolazone--addition of spironolactone 50 mg to metolazone 2.5 mg raised plasma potassium by 0.18 mmol/l (P less than 0.025). In the presence of spironolactone, a linear log metolazone dose-plasma potassium response relationship (P less than 0.01) was demonstrated. Spironolactone was unable to compensate fully for metolazone's hypokalaemic effect although in combination with metolazone 0.625 mg and 1.25 mg, plasma potassium concentration was maintained close to pretreatment levels. The human bioassay employed provided conveniently quantitative information which allows the rational development of a fixed dose diuretic-spironolactone combination tablet.

Diuretic induced hypokalaemia: relationship to dosage interval and plasma aldosterone.

Plasma potassium and aldosterone responses to 9 days treatment with hydrochlorothiazide (100 mg/day) alone or in combination with spironolactone (100 mg/day), prescribed once daily or in doses 12 h apart, were examined in a double-blind, crossover study in twelve healthy subjects. Plasma potassium concentrations were lower when the drugs were administered 12 h apart (P less than 0.01). Spironolactone attenuated significantly hydrochlorothiazide induced hypokalaemia--mean rise in plasma potassium, 0.36 mmol/l (P less than 0.001). The increase in plasma aldosterone was greater following combination therapies (P less than 0.001), but there were no significant differences between once daily and twice daily regimens. We conclude that plasma potassium concentration is better maintained when diuretics are given once daily and that this is not related closely to differences in plasma aldosterone responses.

Effect of micronization on the bioavailability and pharmacologic activity of spironolactone.

The bioavailability and pharmacologic activity of tablets containing micronized spironolactone chemical (median particle size 2.21 micrometers) were compared to those of tablets made from standard spironolactone chemical (median particle size 78.8 micrometers) in healthy men. Apart from particle size, all features of these tablets were identical. After 200-mg single doses, the bioavailability of micronized tablets was significantly higher than that of standard tablets. Furthermore, as assessed by 24-hour urine log10 10 Na/K ratio, the pharmacologic activity of micronized spironolactone was significantly greater than that of the standard formulation. The significant influence on renal antimineralocorticoid activity of raised plasma and urinary levels of canrenone, quantitatively the major active metabolite of spironolactone in man, emphasizes the clinical importance of the bioavailability of spironolactone preparations. Since this study, the process used in the manufacture of spironolactone (Aldactone) tablets has been under review.

Spironolactone dose-response relationships in healthy subjects.

1 The effect of single oral doses of spironolactone 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, and placebo in reversing the urinary electrolyte changes induced by fludrocortisone between 2-10 h and 12-16 h after treatment was examined in healthy subjects. 2 In the two collection periods, there were statistically significant log linear dose-response relationships for sodium excretion (P less than 0.001), potassium excretion (P less than 0.001 and P less than 0.025 respectively) and log10 10 Na/K (P less than 0.001). 3 However, there was evidence that the log spironolactone dose-urinary sodium responses did not increase monotonically, while the relationship for urinary potassium appeared to enter the lower 'plateau' at doses between 100 mg and 200 mg, and when compared to placebo values, potassium excretion was not significantly depressed 12-16 h after treatment (P greater than 0.1). Thus, sodium and potassium responses were dissociated in dose producing maximal effect and in duration of activity, reinforcing the view that functions or the urinary sodium/potassium ratio alone cannot be considered an adequate description of renal antimineralocorticoid activity. 4 Dose-response relationships for all urinary electrolyte variables seem consistently steep and linear between 25 mg and 100 mg of spironolactone, suggesting that, in studies employing this model, the doses of spironolactone should be restricted to this range.

Relative potency and structure activity relationships of aldosterone antagonists in healthy man: correlation with animal experience.

1 The renal antimineralocorticoid potency of single doses of thirteen compounds with properties in animals compatible with competitive aldosterone antagonism was compared to that of spironolactone in healthy men. 2 Twelve compounds showed significant activity when compared to placebo but only one, prorenoate potassium, was significantly more potent than spironolactone on a weight basis. 3 The results allowed ranking of the compounds in order of potency relative to spironolactone and general observations on structure activity relationships in man. 4 Animal bioassays and in vitro aldosterone binding studies are unreliable predictors of the human activity of competitive mineralocorticoid antagonists.

Dose-response relationships for spironolactone at steady state.

The overnight urine electrolyte and plasma potassium responses to spironolactone (25, 50, 100, and 200 mg daily) at steady state were investigated in 11 healthy subjects after fludrocortisone challenge. For sodium excretion and urine log10 10 Na/K, log dose-response relationships were defined (P less than 0.001 in each case), but there was little evidence of dose-related influences on potassium excretion or plasma potassium. The findings confirm the limitations of the fludrocortisone model in evaluating the potassium-sparing properties of aldosterone antagonists at steady state and of the urine sodium; potassium ratio as an overall index of renal antimineralocorticoid activity.

Comparison of prorenoate potassium and spironolactone after repeated doses and steady state plasma levels of active metabolites.

1 After repeated single daily doses, the aldosterone antagonists prorenoate potassium and spironolactone were compared with regard to renal antimineralocorticoid activity, plasma potassium concentration and steady state plasma levels of their active metabolites, prorenone and canrenone respectively, in a balanced crossover study of twelve healthy subjects. 2 Following challenge with the mineralocorticoid, fludrocortisone, best estimates of the potency of prorenoate potassium relative to spironolactone were 3.6 (95% confidence limits 1.6-10.4) for urinary sodium excretion and 3.4 (95% confidence limits 2.0-6.5) for urinary log10 10Na/K. Estimates with respect to urinary potassium excretion and plasma potassium concentration were imprecise, confirming the limitations of the fludrocortisone model in the evaluation of aldosterone antagonists at steady state. 3 Both compounds exhibited directly proportional relationships between daily dose and steady state plasma levels of active metabolites. The approximate mean terminal elimination half-life of prorenone at steady state was 32.6 h (range 18-80 h).

Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

1 The potency of single doses of the aldosterone antagonist SC8109 relative to spironolactone in reversing the urinary electrolyte effects of fludrocortisone was examined in a double-blind, balanced, crossover study in six healthy volunteers. 2 For the urinary ratio log10 10Na/K, the relative potency of SC8109; spironolactone on a weight basis was 0.08:1 (95% confidence limits 0.04--0.13:1). 3 The potency of SC8109 relative to spironolactone for natriuresis and antikaliuresis was 0.10:1 and 0.05:1, respectively. 4 The results show excellent agreement with clinical experience where SC8109 was considered to have one tenth the potency of spironolactone. We suggest that the human bioassay employed in this study provides quantitative information which should be predictive of the therapeutic potency of aldosterone antagonists.

Bioassay of a new aldosterone antagonist and evaluation of a simple method of quantitative comparison.

The renal antimineralocorticoid activity of single oral doses of a new aldosterone antagonist OH OPC(ME)-K was compared to that of spironolactone in two studies in healthy men. OH OPC(ME)-K reversed the urinary electrolyte response to fludrocortisone in the period up to 16 hr after treatment, but it was less potent than spironolactone on a weight basis. The best estimate of the relative potency of OH OPC(ME)-K: spironolactone (derived from a simple protocol using equal single doses of the two drugs) was 0.60:1 (95% confidence limits 0.24:1 to 1.42:1), in good agreement with the estimate from a more complex three-dose parallel-line bioassay (0.61:1, 95% confidence limits 0.48:1 to 0.79:1). The results of simple single-dose studies can be used, with certain assumptions, to provide a useful estimate of the relative potency of new aldosterone antagonists at an early stage of development.

Steady-state relative potency of aldosterone antagonists: spironolactone and prorenoate.

The dose ratio approach was used to define the steady-state relative potency of the competitive mineralocorticoid antagonists prorenoate potassium and spironolactone in six healthy male subjects using fludrocortisone as mineralocorticoid agonist. Log fludrocortisone dose-response relationships in the presence or absence of antagonists did not differ from linearity and parallelism, supporting the theoretical basis of the method. Urinary sodium and plasma potassium responses appeared to behave according to the law of mass action, which made possible estimation of the potency of prorenoate relative to spironolactone on a weight basis-4.2:1 (95% C.L. 2.7-6.9:1) and 2.68:1 (95% C.L. 0.71-6.57:1, respectively. The steady-state relative potency for sodium excretion was greater than previously estimated after single doses. Mass action theory could not explain the urinary potassium and log 10 Na/K responses to repeated doses of spironolactone, precluding valid estimation of relative potency for these variables and suggesting that the latter response alone is an unreliable index of overall renal antimineralocorticoid activity.

Activity of sulfur-containing intermediate metabolites of spironolactone.

The renal antimineralocorticoid activity of single administration of 2 sulfur-containing compounds, which are thought to be intermediate metabolites of spironolactone, was assessed in healthy subjects. They were each active in reversing the urinary electrolyte changes indiced by fludrocortisone for 2 to 10 hr after dosing, but only the 7 alpha-thiomethyl derivative exhibited activity in the period 12 to 16 hr after treatment. The activity of both drugs was less than of spironolactone. Taking urinary log 10 Na/K as the best index of antimineralocorticoid activity, the potencies of the intermediates relative to spironolactone were 0.26 (95% confidence limits, 0.12 to 0.49) for 7 alpha-thio-spirolactone and 0.33 (95% confidence limits, 0.15 to 0.62) for 7 alpha-thiomethyl-spirolactone in the period 2 to 10 hr after medication. We conclude that these minor sulfur-containing intermediate metabolites of spironolactone are unlikely to contribute significantly to the renal antimineralocorticoid activity of spironolactone.

Computer-aided holographic vibration analysis for vectorial displacements of bladed disks.

Photographs of hologram reconstructions which display vibration modes of bladed disks are digitized and numerically processed to determine translations and rotations of blade segments at radial locations. Because the blades are assumed not to move in the radial direction, only two holograms, each with a different sensitivity vector, are required of each vibration mode. In addition, a photograph of fringes projected onto the bladed disk is used to determine blade surface contours and compensate for their effect on the holographic fringes.

Paradoxical potassium excretion in response to aldosterone antagonists.

The activity of two aldosterone antagonists in reversing the urinary electrolyte changes induced by the mineralocorticoid fludrocortisone was examined in healthy subjects. Between 2-10 h after treatment there were dose-related increases in sodium excretion and the urine log 10 Na/K ratio, but no significant changes in urine volume, potassium concentration, or potassium excretion. Between 12-16 h after treatment there were dose-related increases in urine sodium excretion and the log 10 Na/K ratio. Unexpectedly, there were significant dose-related increases in potassium excretion despite significant dose-related reductions in urinary potassium concentration. The paradoxical increases in potassium excretion were attributed to dose-related increases in urine volume in the same period. These observations may explain the increased potassium excretion occasionally observed during clinical use of aldosterone antagonists and suggest that potassium excretion in man is influenced by the urine flow rate.

Mode of action of a surgical electronic lithoclast--high speed pressure, cinematographic and schlieren recordings following an ultrashort underwater electronic discharge.

In order to investigate the mode of action of the electrical discharges from a surgical electronic lithoclast in shattering bladder stones high speed pressure-time recordings were made. The results indicated effects similar to those following an underwater detonation of high explosive. Subsequent high speed photographic analysis confirmed this. Calculations based on the results suggested that the shock waves and pressure pulses generated were of a potentially hazardous magnitude and that gas-containing bowel close to the bladder might be at particular risk as well as solid tissue as the bladder wall. Photographic data also suggested that danger might be incurred by the use of similar devices in a small enclosed space such as the ureter or renal pelvis.