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Biomedical subjects

M J Tidd

Publications and source records attributed to M J Tidd.

18 recordsLinked to original sources
PubMed1978

Endocrine effects of spironolactone in man.

A double blind, controlled study was carried out in order to investigate the effects of administering spironolactone, 200 mg daily, to five healthy male volunteers. The patterns of change in plasma testosterone (T) and luteinizing hormone (LH) after spironolactone were significantly different from placebo and there were significant increases in the urinary excretion of androsterone (A), aetiocholanolone (EC) and total oestrogen. Urinary dehydroepiandrosterone (DHA) excretion, after an initial rise, declined progressively during the treatment period relative to controls. The results are discussed in the light of previous observations. It is concluded that treatment with spironolactone for 2--4 days will lead to a transient rise in plasma T and urinary DHA. Continued treatment (4--10 days) is thought to cause increased LH secretion, with normalization of plasma T and DHA excretion. These changes are accompanied by increased androgen catabolism and a slightly increased conversion of androgens to oestrogens. Healthy men may therefore show alterations in sex steroid metabolism if treated for several days with high doses of spironolactone.

17-Ketosteroids↗
PubMed1978

Identification of some urinary metabolites of propantheline bromide in man.

The peak plasma concn. of total radioactivity occurred 6 h after a single oral dose of [carboxyl-14C; methyl-2H3] propantheline bromide was administered to a healthy man. At this time 10% of the dose was present in the total plasma volume. 2. A total of 71% dose of radioactivity was excreted in urine in 96 h after dosage, 59% dose being excreted in the first 24 h. About 5.3% of the orally administered propantheline bromide was excreted unchanged. 3. T.l.c. analysis and g.l.c.-mass spectrometry showed xanthanoic acid, hydroxyxanthanoic acid(s), and propantheline as urinary metabolites of the drug. 4. A glucuronide of xanthanoic acid, a hydroxylated propantheline and the (2-hydroxyethyl)diisopropylammonium ion were tentatively identified as urinary metabolites. Hydrolysis of propantheline and conjugation of the resulting xanthanoic acid appear to be the major routes of metabolism of this compound. 5. A mean elimination half-life of 9.2 h was obtained for the total radioactivity by pharmacokinetic analysis of plasma and urine levels of 14C.

Adult↗
PubMed1977

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.

Adult↗
PubMed1977

Factors influencing comparative bioavailability of spironolactone tablets.

The bioavailability of spironolactone from 10 tablet formulations, selected to provide a wide range of specifications and in vitro dissolution rates, was assessed from the plasma and urinary levels of its major unconjugated metabolite, canrenone, in a study of balanced incomplete block design using 11 healthy subjects. Significant but weak correlations existed between the amount of spironolactone in solution at 40 min in vitro and the area under the plasma concentration-time curve for canrenone and urinary canrenone excretion. The correlations between in vitro dissolution and bioavailability parameters appeared to be weakened by two tablet formulations, one with dibasic calcium phosphate as the principal excipient and the other formulated from micronized spironolactone bulk drug. Measurement of in vitro dissolution of spironolactone tablets is of value for quality control purposes, provided no major alteration is made in the formulation.

Adult↗
PubMed1977

Ethical review in the pharmaceutical industry.

1. There seems no reason why clinical pharmacology studies conducted within the pharmaceutical industry should be exempt from the requirement of ethical review, and independent review in this situation reduces the vulnerability of the company and its employees, in addition to serving its primary function of protecting the volunteer subjects. 2. Experience within one company has shown that independent ethical review need not seriously influence the pace of research. 3. It is important that such committees should be seen to be independent and competent.

Drug Evaluation↗
PubMed1977

Validation of plasma and urinary canrenone for determination of bioavailability of spironolactone--comparison of tablets with solution/suspension.

Data showing a linear relationship between spironolactone dose and the levels of canrenone in plasma and urine are presented to support the use of canrenone levels as a measure of the bioavailability of spironolactone. The bioavailability of a selected batch of spironolactone 25 mg tablets was compared to that of an oral aqueous suspension of spironolactone in a separate balanced cross-over study involving 10 healthy subjects. The tablets were equivalent to suspension as regards area under the plasma concentration-time curve and total urinary excretion of canrenone, the prinicipal unconjugated metabolite of spironolactone. Peak plasma concentrations of canrenone were higher, and were attained significantly earlier, after treatment with spironolactone in suspension. The results indicate that spironolactone was absorbed more rapidly from the suspension, but that the total absorption did not differ between the two formulations.

Administration, Oral↗
PubMed1976

Hazards to bladder and intestinal tissues from intravesical underwater electrical discharges from a surgical electronic lithoclast.

Previous studies have shown that electronic lithoclast discharges produce effects resembling an underwater explosion. It was predicted that the shock wave produced by each discharge could damage nearby gas-containing gut through a mechanism known to be associated with underwater detonations. Effects associated with rapid oscillation of the vapour bubble produced could cause damage to the wall of the bladder. Investigation of lithoclast discharges in vivo on goat, and in vitro on sheep bladders demonstrated perforation of both. In vitro studies in the rabbit demonstrated the predicted greater susceptibility of air-filled gut over that filled with fluid. These hazards would be even greater in the ureter and caution in the use of electronic fragmentation of vesical and ureteric calculi is urged in the light of these findings.

Animals↗
PubMed1976

The pharmacodynamics of single doses of prorenoate potasssium and spironolactone in fludrocortisone treated normal subjects.

1 The pharmacodynamic profile of single oral doses of prorenoate potassium (40 mg) and spironolactone (100 mg), as judged by reversal of the effects of fludrocostisone on the urinary electrolyte composition, was compared to that of placebo in a double-blind crossover study in six healthy subjects. 2 Both drugs showed evidence of significant activity in all periods between 2-16 h after treatment, and the time course of their activity was very similar. 3 In the total 24 h period after treatment both drugs significantly increased sodium excretion, the Na/K ratio and the log 10 Na/K ratio over placebo values, and urine potassium concentration was significantly reduced. Changes in urine volume and in potassium excretion were not significant. 4 The responses to prorenoate potassium (40 mg) were not significantly different from those to spironolactone 100 mg), and were very similar as judged by the urine log 10 Na/K ratio, indicating that the two drugs were approximately equiactive at these doses. 5 Reductions in urinary potassium excretion, when expressed in relation to the amount of sodium excreted, were significantly larger after prorenoate potassium than after spironolactone, confirming a qualitative difference in the pharmacological activity of the two drugs which has been reported previously.

Administration, Oral↗
PubMed1976

Comparison of hydrophilic polymer-coated latex, uncoated latex and PVC indwelling balloon catheters in the prevention of urinary infection.

Latex, hydrophilic polymer-coated latex and PVC balloon indwelling urethral catheters were compared in respect of the urinary tract infections arising in association with their use in male patients. The polymer (Hydron) coating conferred no benefit over uncoated latex which in turn was indistinguishable from PVC. No significant differences in the spectra of infecting organismns were observed between the 3 catheter types.

Adult↗
PubMed1976

A comparison of the dissolution and bioavailability characteristics of three spironolactone tablet formulations, including preliminary data on two spironolactone metabolites.

The bioavailabilities of three spironolactone tablet formulations specially selected for major differences in in vitro dissolution tests were compared in normal male volunteers by measuring plasma and urinary levels of the pharmacologically active spironolactone metabolite canrenone. It was possible to demonstrate small but statistically significant differences in plasma canrenone concentration-time curves derived from the three formulations together with significant differences in the time course of urinary canrenone excretion. The bioavailabilities of the three formulations did not differ significantly although the tablet with the poorest in vitro dissolution produced a significant delayed peak canrenone concentration. The dissolution rate methodology and results are described and an approach to the development of improved in vitro dissolution tests for spironolactone is suggested. The use of a new method for canrenone estimation resulted in the incidental detection of two other quantitatively significant spironolactone metabolites and preliminary information is given on these.

Adolescent↗
PubMed1976

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.

Calculi↗
PubMed1975

Bioassay of aldosterone antagonists in normal human subjects: a relationship between the level of plasma uric acid before treatment and apparent drug responses.

The activity of single doses of SC-23992, a new aldosterone antagonist, and spironolactone in reversing the effects of fludrocortisone on urinary electrolyte composition in normal subjects was compared with that of placebo in a double-blind crossover study. 2 SC-23992 (50 mg) and spironolactone (125 mg) each significantly increased sodium excretion and the sodium : potassium (Na/K) ratio, and decreased potassium excretion, when compared with placebo. The response to the two active drugs did not differ significantly. 3 The urine Na/K ratio, and log10 Na/K, in response to spironolactone correlated negatively with the level of plasma uric acid measured 12 h before treatment. Similar trends were present after SC-23992 and placebo treatments. 4 It is suggested that the correlations between plasma uric acid and apparent drug response reflect a correlation between plasma uric acid and the aldosterone secretion rate in normal subjects. The sensitivity of this method of bioassay may be improved by suppressing endogenous aldosterone prior to medication.

Adult↗