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Biomedical subjects

G T McInnes

Publications and source records attributed to G T McInnes.

At least 91 records · Page 5Linked to original sources
PubMed1985

Pharmacokinetics and pharmacodynamics following single and repeated nightly administrations of loprazolam, a new benzodiazepine hypnotic.

The pharmacokinetics of oral loprazolam and pharmacodynamic responses on the morning following nightly drug administration were examined after single and after seven consecutive 1 mg doses in six non-fasting healthy subjects. The serum concentration-time profiles for unchanged loprazolam measured by a specific high pressure liquid chromatography/gas chromatography (h.p.l.c./g.c.) method and for benzodiazepine material measured by radioimmunoassay (RIA) were qualitatively similar although RIA levels were consistently higher. Approximate elimination half-life of unchanged loprazolam after single doses was 8.0 h. For RIA measured material, approximate half-life was 11.7 h following acute administration and 12.8 h after seven consecutive doses. Compared to results after single doses, maximum serum concentration and AUC were greater following 1 week's treatment. Using RIA results, the increases were 27.2% (95% CL 6.9 to 47.4%) and 35.1% (95% CL 15.8 to 54.3%) respectively and using h.p.l.c./g.c. data, 11% (95% CL - 22.6% to 44.5%) and 41% (95% CL - 50.9 to 133.0%). After repeated doses of loprazolam, there were no significant changes with respect to results after single doses in psychomotor function assessed objectively by critical flicker fusion threshold or choice reaction time, or in sleep quality or behaviour on awakening assessed subjectively by 10 cm analogue scales. Mean time to maximum serum concentration was 4.95 h with considerable inter-individual variability (range 1-12 h) and there was a lag time of 1-1.5 h before drug was detectable in blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Cardiovascular responses to verapamil and propranolol in hypertensive patients.

Since there is concern that the potentially useful antihypertensive combination of verapamil and propranolol might lead to adverse cardiovascular responses, we have investigated its effects, not only on blood pressure, but also on electrocardiographic and echocardiographic variables. Fourteen hypertensive patients participated in a double-blind, randomized, crossover comparison of verapamil 360 mg, propranolol 240 mg, verapamil 360 mg + propranolol 240 mg, and placebo, each given for 4 weeks. The antihypertensive effect of verapamil + propranolol was greater than that of either drug alone. Pulse rate was reduced by propranolol but not verapamil. However, addition of verapamil to propranolol led to further reduction in pulse rate. The PR interval was prolonged by verapamil + propranolol when compared with all other treatments. The active drugs increased ventricular dimensions and the effect of the combination was statistically significant. Thus, verapamil + propranolol is an effective antihypertensive combination, but heart rate, atrio-ventricular conduction and left ventricular function may be affected adversely, necessitating careful monitoring of therapy.

Adult↗
PubMed1984

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.

Adult↗
PubMed1983

Dose-response relationships for spironolactone in combination with a potassium-wasting diuretic.

The plasma and urine electrolyte responses to repeated doses of spironolactone, 25, 50, and 100 mg, in combination with metolazone, 2.5, 5.0, and 10 mg, were examined in 18 healthy subjects (six at each dose of metolazone). During the period of pharmacologic steady state, there were log linear spironolactone dose-response relationships for plasma potassium, sodium, and bicarbonate (P less than 0.001 in each case) with no contraindication to parallelism between the metolazone groups. In the absence of mineralocorticoid challenge, spironolactone dose-urine electrolyte responses could not be demonstrated. However, after fludrocortisone, spironolactone log dose-response trends were linear with respect to natriuresis (P = 0.027), antikaliuresis (P = 0.020), and log 10 Na/K (P = 0.001), which is usually considered the best single index of renal antimineralocorticoid activity, and exhibited parallelism between the metolazone doses. These observations suggest that a convenient bioassay for aldosterone antagonists in normal men may be provided by the electrolyte responses to repeated doses of such drugs in combination with potassium-wasting diuretics. In view of the limitations of other methods, this approach may have particular relevance to the evaluation of potassium-sparing properties.

Adult↗
PubMed1983

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.

Adult↗
PubMed1983

Hepatic enzyme induction and leucocyte delta-aminolaevulinic acid synthase activity: studies with carbamazepine.

Antipyrine metabolism, daily urinary 6-beta-hydroxycortisol excretion, carbamazepine (CBZ) half-lives and leucocyte delta-aminolaevulinic acid synthase (ALA.S) activities were measured following 2 weeks' treatment with CBZ 400 mg and 600 mg once daily in eight healthy male volunteers. Dose-dependent induction of antipyrine metabolism was demonstrated but cortisol hydroxylation appeared maximally induced by the 400 mg dose. CBZ half-lives fell significantly in both studies (P less than 0.01 in each case) but a greater fall was seen with the higher dose (P less than 0.01). Plasma CBZ concentrations were higher following the eighth doses (P less than 0.01) in both studies. Leucocyte ALA.S activity increased by a mean of 657% following 1 week's treatment with 400 mg CBZ and 1145% on the 600 mg dose. In both studies ALA.S activities fell towards baseline during the second week of treatment. CBZ possesses potent dose-dependent hetero- and auto-inducing properties. Leucocyte ALA.S activity may represent a novel in vivo index of extrahepatic enzyme induction in man.

5-Aminolevulinate Synthetase↗
PubMed1982

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.

Adult↗
PubMed1982

Relative potency of amiloride and spironolactone in healthy man.

The renal antimineralocorticoid activity of single oral doses of amiloride, a physiologic aldosterone antagonist, was compared to that of spironolactone, a competitive aldosterone antagonist, in 12 healthy men pretreated with fludrocortisone. For up to 20 hr amiloride induced linear log dose-urinary electrolyte response relationships but spironolactone dose-response trends were demonstrated only in the period from 10 to 20 hr after treatment. In this period, the best estimate of the potency of amiloride relative to spironolactone for urine log10 10 Na/K was 36 (95% confidence limits 23 to 69). The fludrocortisone model seems appropriate for quantitative comparisons of physiologic and competitive aldosterone antagonists, but does not indicate therapeutic relative potency.

Adult↗
PubMed1982

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).

Adolescent↗
PubMed1982

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.

Animals↗
PubMed1982

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.

Adult↗
PubMed1982

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.

Adult↗
PubMed1982

Evaluation of aldosterone antagonists in healthy man.

The development of methods to allow the quantitative comparison of aldosterone antagonists in healthy men is reviewed. Pharmacological action is measured against a background of mineralocorticoid excess, induced either by administration of exogenous mineralocorticoid (usually aldosterone or fludrocortisone), or by stimulation of endogenous mineralocorticoid using salt restriction, diuretic administration, or a combination of the two. Use of fludrocortisone as the exogenous mineralocorticoid has proved convenient and useful, but the influence of aldosterone antagonists on potassium metabolism has proved somewhat inconstant in this experimental model. Repeated administration of a medium-potency diuretic appears to provide a clinically relevant situation in which the effect of aldosterone antagonists on potassium metabolism can be assessed. We describe these experimental methods in detail, discuss their applications, and make some suggestions for further research.

Aldosterone↗
PubMed1981

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.

Double-Blind Method↗