Biomedical subjects

G S Stokes

Publications and source records attributed to G S Stokes.

At least 19 recordsLinked to original sources

PubMed1995

Diet modification in lowering plasma cholesterol levels. A randomised trial of three types of intervention.

OBJECTIVE: To compare the efficacy of three types of diet and lifestyle interventions for lowering plasma lipid levels. DESIGN: Randomised parallel-group trial. SUBJECTS AND SETTING: Adults with plasma cholesterol levels of 5.5-8.0 mmol/L attending two Sydney community health screening clinics were asked to participate: 179 agreed and 131 completed the study. INTERVENTIONS: A pamphlet with brief advice; group dietary counselling; or individual counselling. Counselling included three sessions with a dietitian/nutritionist over six months. MAIN OUTCOME MEASURES: Plasma total cholesterol levels measured by Reflotron analyser; fasting serum lipid levels measured by standard laboratory methods; and calculated low-density lipoprotein cholesterol levels. RESULTS: Significantly lower plasma total cholesterol levels (Reflotron) were observed at two months and at six months with each of the three interventions. Additionally, both types of dietitian-based counselling resulted in small but significant decreases in plasma low-density lipoprotein cholesterol levels at six months in a subset of subjects. CONCLUSION: Although there were no statistically significant differences in efficacy between the three types of intervention, dietitians have a role to play in setting up such counselling programs.

Adult↗

PubMed1995

Interaction between Ca2+, verapamil, and ketanserin in rat tail artery and aorta.

To elucidate the complex pharmacological actions of the 5-hydroxytryptamine2A (5-HT2A)-receptor antagonist ketanserin, we investigated certain similarities between these properties and those of the Ca antagonist verapamil. We investigated the interactions of Ca2+, ketanserin, and verapamil on the contractile responses to 5-HT in rat isolated perfused tail artery and aortic strip preparations. In both tissues, variations in perfusate [Ca2+] had similar effects: threshold contractile concentrations of 5-HT were unaffected, and the upper ends of the 5-HT dose-response curves were augmented or decreased by increased or decreased [Ca2+], respectively. Ketanserin competitively antagonised contractile responses to 5-HT in both tissues, with mean pA2 values of 9.17 and 7.46 in tail artery and aorta, respectively. However, increase in [Ca2+], with addition of ketanserin, caused a parallel leftward shift of the 5-HT dose-response curve in tail arteries with a nonparallel leftward shift in aorta. Verapamil nonsurmountably antagonised contractile responses to 5-HT in aorta and competitively antagonised 5-HT in tail arteries. Subsequent addition of ketanserin to the verapamil-containing perfusate caused a further shift to the right of the 5-HT dose-response curve in aorta, but had no additional antagonist effect above that of verapamil alone on tail artery responses to 5-HT. The results show that although the pharmacological properties of ketanserin and verapamil overlapped, there were marked differences between the pharmacologies of the 5-HT2A-receptors in the two tissues studied, suggesting either that the mechanism of the 5-HT-induced influx of Ca2+ is different in the two tissues or that the 5-HT2A receptors differ structurally between tissues.

Animals↗

PubMed1994

Comparative and combined efficacy of doxazosin and enalapril in hypertensive patients.

Twenty patients with essential hypertension were randomised to a 7-week period of dose titration with doxazosin, 1-8mg/day or enalapril, 5-20mg/day. In a further 7-week period the dosage level reached with the initial drug was halved, and titration with the second agent was carried out. Blood pressure responses at the end of each treatment period were assessed by clinic measurements made 24 hours post-dose. In the first treatment period, enalapril (mean dose 19mg/day) reduced serum free ACE activity by 40% and had a greater effect than doxazosin (mean dose 5.2mg/day) on clinic supine blood pressure (systolic and diastolic). In the second period, the addition of enalapril to doxazosin was associated with a significant fall in clinic standing blood pressure (systolic and diastolic), despite the doxazosin dose reduction and consequent decrease in median plasma doxazosin concentration (from 10.6 to 5.2ng/ml). Alternatively, when doxazosin was added to enalapril, free ACE activity remained 40% decreased despite enalapril dose reduction, and blood pressure was not further affected. Plasma renin activity was increased by enalapril. No changes were observed in plasma aldosterone or lipid concentrations with either drug. The combination of doxazosin and enalapril was well tolerated and lowered blood pressure overall. Judged by clinic measurements 24 hours post-dose, most of the antihypertensive effect was attributable to the enalapril component. However, ambulatory blood pressure monitoring 0-12 hours post-dose in a subset of patients suggested a contribution of doxazosin earlier in the dose interval.

Acetylcholinesterase↗

PubMed1992

Effects of oral contraceptives containing oestrogen combined with norethisterone or levonorgestrel on erythrocyte cation transport in normal women.

1. Studies were undertaken in pre-menopausal women to examine the effects of treatment with standard oestrogen-progestogen and progestogen-ony oral contraceptives on erythrocyte Na+,K+ co-transport and Na(+)-Na+ countertransport over 3- and 6-month periods. Concurrent observations were made on other erythrocyte cation transport components, plasma lipid concentrations, plasma renin activity, plasma aldosterone concentration and blood pressure. 2. Na+,K+ co-transport, measured as the ouabain-resistant, frusemide-sensitive component of 86Rb+ influx, and Na(+)-Na+ countertransport, measured as the ouabain-resistant, phloretin-sensitive component of 22Na+ influx, were both increased in women taking, on days 1-21 of their cycle, ethinyloestradiol (30-50 micrograms) combined with norethisterone (1000 micrograms or 500-1000 micrograms) for 3 or 6 months. Neither of these fluxes was increased in a control group of women, or in women treated for the same time periods with ethinyloestradiol combined with levonorgestrel. 3. In a separate study of erythrocyte cation transport (excluding Na(+)-Na+ countertransport), in which women undertook treatment with norethisterone only (350 micrograms/day) for 6 months starting 6 weeks post partum, no changes in Na+,K+ co-transport were observed at 3 or 6 months; there were no changes in cation transport in a corresponding control group. 4. The results of these studies confirm that certain oral contraceptive compounds can alter erythrocyte cation transport, and indicate that norethisterone in higher dose preparations is the component predominantly responsible. The alterations observed could not be explained by a direct link with concurrent changes in plasma triacylglycerol concentrations or in the renin-aldosterone axis and were not closely associated with elevation of blood pressure.

Adolescent↗

PubMed1992

A study of the interaction between the hypotensive actions of doxazosin and enalaprilat in anaesthetized rats.

OBJECTIVE AND DESIGN: This study was designed to test whether previous work, which showed that the angiotensin converting enzyme (ACE) inhibitor enalaprilat potentiated the alpha 1-adrenoceptor antagonist activity of doxazosin in isolated rat tail arteries, could be extended to demonstrate a synergistic hypotensive effect of these two drugs. METHODS: Groups of untreated or chronically deoxycorticosterone acetate (DOCA)-salt-treated female Sprague-Dawley rats were used. Rats were anaesthetized with Inactin (barbiturate); drugs were administered via a jugular venous catheter; blood pressure was monitored via a carotid arterial catheter. RESULTS: In previously untreated rats, pretreatment with enalaprilat shifted the dose-response curve for the hypotensive effect of doxazosin to the left, indicating synergism. In rats dosed with DOCA-salt (which suppresses renin and angiotensin II production): (1) there was no synergism between the hypotensive actions of enalaprilat and doxazosin; (2) doxazosin was more potent than in untreated rats; and (3) enalaprilat lowered blood pressure, suggesting a hypotensive mechanism separate from ACE inhibition. CONCLUSION: In the absence of angiotensin II (resulting from enalaprilat administration or from chronic DOCA-salt), doxazosin had a greater hypotensive action than in the presence of angiotensin II. This is consistent with the concept that angiotensin II modulates alpha 1-adrenoceptor activity.

Anesthesia↗

PubMed1992

Increase in serum total angiotensin-converting enzyme activity with enalapril therapy in humans: a controlled trial.

1. In a controlled, randomized double-blind trial, 15 patients with essential hypertension were treated with enalapril 5-20 mg/day, or doxazosin 1-8 mg/day, during a 7 week dose titration phase. This was followed by 7 weeks of combined treatment with doxazosin and enalapril. 2. Blood was taken after a 2 week placebo run-in phase, and at 3 and 7 weeks in the single-agent and combined treatment phases, for measurement of plasma renin activity (PRA), plasma angiotensin II (AII), plasma aldosterone and serum free and total angiotensin-converting enzyme (ACE) activities. 3. Doxazosin had no effect on serum free or total ACE activities. 4. Enalapril reduced serum free ACE activity and increased serum total ACE activity, which at 7 weeks was significantly greater than in patients receiving doxazosin. 5. In those patients who received enalapril, 10 mg/day for 3 weeks and then 20 mg/day for 4 weeks (n = 12), with or without doxazosin, mean serum total ACE activity increased by 51%. PRA was also increased in this group, but there were no changes in plasma AII or aldosterone concentrations.

Double-Blind Method↗

PubMed1992

Concurrence of primary aldosteronism and renal artery stenosis.

1. An unusual clinical case is described in which renal artery stenosis (RAS) was found to coexist with adrenocortical hyperplasia, resulting in hypertension. 2. Partial relief of the hypertension was achieved by correction of RAS, and then further relief by extirpation of one adrenal gland affected by unilateral hyperplasia, in interventions 8 months apart. 3. Biochemical features typical of primary hyperaldosteronism were observed both before and after RAS repair but were not present after unilateral adrenalectomy. 4. The association of these two lesions could have occurred by chance, through genetic linkage, or by progression from RAS to tertiary aldosteronism.

Adrenal Cortex↗

PubMed1992

An Na, K ATPase inhibitor from ultrafiltrate obtained by hemodialysis of patients with uremia.

Ultrafiltrate obtained by hemodialysis of patients with uremia who were not taking cardiac glycosides was used as a source of Na, K adenosine triphosphatase inhibitor for purification and further study. Inhibitory activity was measured by a linked-enzyme assay and by effect on rubidium 86 uptake in guinea pig aortic strips. Two approaches were used in purification: dialysis with a 500 dalton membrane followed by gel filtration with Sephadex G-25, and removal of protein by acidification and boiling followed by Sephadex G-10. The first procedure failed to separate the inhibitor from the salt fraction, whereas the second separated the inhibitor from the salt peak but resulted in partial coelution of the inhibitor with endogenous pyruvate, which interferes with the linked-enzyme assay. Pooled, concentrated G-10 elution fractions from the early part of the inhibitor peak, which were free of pyruvate, produced a dose-response relationship by enzymatic assay that was close to parallel with that for ouabain. Like ouabain, these fractions also inhibited 86Rb uptake in guinea pig aorta. Despite these properties, our previous work has demonstrated that the inhibitor, unlike some other ouabain-like or digitalis-like substances obtained from blood or urine, has no apparent role in body fluid homeostasis.

Animals↗

PubMed1991

The effects of sulindac and diclofenac in essential hypertension controlled by treatment with a beta blocker and/or diuretic.

A placebo-controlled, double blind crossover study of the non-steroidal anti-inflammatory drugs (NSAIDs) sulindac and diclofenac was conducted in 16 patients with essential hypertension that was controlled by treatment with a beta blocker, a diuretic or co-administration of both. In 4 cases, another antihypertensive agent (prazosin or verapamil) was also co-administered. In every patient, plasma creatinine concentration was less than 0.14 mmol/l (normal range 0.07-0.12 mmol/l). Sulindac and diclofenac were each given for 7 weeks. Diclofenac caused a decrease of borderline significance in plasma aldosterone concentration. Neither NSAID altered the mean values for systolic or diastolic blood pressure, body weight, plasma electrolyte concentrations, urate clearance, creatinine clearance or plasma renin activity. However, rises in plasma creatinine concentration and falls in creatinine clearance occurred during NSAID therapy in three individual subjects. No significant differences were observed in this study between the effects on renal function or blood pressure of sulindac and diclofenac, both of which appear not to interfere with the antihypertensive actions of beta blockers and diuretics.

Adrenergic beta-Antagonists↗

PubMed1991

Effects of 17 alpha-ethinyl oestradiol in vitro on erythrocyte cation transport in men and women.

The effects of 17 alpha-ethinyl oestradiol in vitro upon erythrocyte Na(+)-K+ cotransport were investigated in nine normal males and in eight normal females during the mid-follicular phase of the menstrual cycle. At a concentration of 10(-1) mmol/l, Na(+)-K+ cotransport was almost completely inhibited. At concentrations of 10(-12) to 10(-2) mmol/l, a minor concentration-related effect was observed in males but not females. In the same concentration range, there was a significant difference in Na(+)-K+ cotransport between sexes. Thus, erythrocyte Na+K+ cotransport is lower in females than males, probably due to chronic exposure of their erythrocytes to endogenous oestrogen.

Adult↗

PubMed1990

The pharmokinetics of isradipine in hypertensive subjects.

In conjunction with a multicentre clinical trial of the calcium antagonist isradipine in hypertension, pharmacokinetic and pharmacodynamic studies were conducted in 9 subjects. An initial dose of 5 mg (capsule formulation) of isradipine was given orally. The mean Cmax, tmax and AUC(0-8) were 6.0 ng.ml-1, 1.5 h and 15.1 h.ng.ml-1 respectively. Seven subjects repeated the study at steady state after 10 week's dose titration with isradipine. Cmax, tmax and AUC(0-8) were 3.7 ng.ml-1, 1.2 h and 12.2 h.ng.ml-1 respectively indicating that the drug does not accumulate over time. Control of blood pressure paralleled plasma isradipine concentrations which suggested that the drug should be given at least twice daily. Pharmacokinetic studies performed in conjunction with clinical trials can provide valuable information about the patterns of drug response.

Adult↗

PubMed1990

Effect of dialysis on circulating Na,K ATPase inhibitor in uremic patients.

Deproteinized plasma from patients with renal failure had an inhibitory effect on Na,K ATPase activity measured in vitro by a linked-enzyme assay. No inhibitory effect was observed with plasma from normal subjects or from patients undergoing chronic ambulatory peritoneal dialysis. The inhibition of Na,K ATPase whether measured by the linked-enzyme assay or by 86Rb uptake in guinea pig aortic strips was decreased acutely by a single hemodialysis treatment, but was unaffected during a time-control study or ultrafiltration. Changes in Na,K ATPase activity and in Rb uptake were correlated, indicating that the presence of the enzyme inhibitor in uremic plasma was associated with depressed Na pump activity. Change in inhibition of Na,K ATPase activity did not correlate with change in body weight. Dialysis in vitro against a membrane of molecular weight 3,500 cut-off decreased the inhibitory effect of uremic plasma on Na,K ATPase. It was concluded that a dialyzable, low-molecular-weight Na,K ATPase inhibitor circulates in uremia but has no demonstrable role in volume homeostasis.

Adult↗

PubMed1990

Timing of blood pressure measurements in determining anomalies in duration of effect of an antihypertensive drug: assessment of isradipine.

Analysis of an antihypertensive drug trial, which involved measurements of blood pressure (BP) during visits to the clinic at a set time of day, showed that the initial dosage titration procedure had been inadequate in some patients. Plasma drug concentration-time curves and corresponding BP values suggested that control of BP was closely related to plasma drug concentration and that the duration of drug effect was shorter than the dosage interval of 12 h. This interpretation was supported by measurements of BP and drug concentrations taken at steady state, before and 2 h after taking the drug. Measurements of ambulatory BP revealed that some patients whose doses had been titrated at peak plasma drug concentrations had high BP at the time of trough plasma drug concentrations, whereas some of those titrated at trough times were hypotensive at peak times. Adjustment of antihypertensive therapy should entail observations of BP at times coincident with both peak and trough concentrations of the drug concerned, and can be facilitated by ambulatory BP monitoring.

Adult↗

PubMed1990

Optimum drug treatment in hypertension.

The ultimate objective in treating hypertension is to select an agent directed at the specific mechanism causing blood pressure elevation in the individual case. Such a choice is not possible in most cases at present; it is usually more important to match the profile of drug activity to the characteristics of the patient. In combination therapy, it is important also to match drug with drug, so as to obtain synergistic actions and to avoid adverse interactions. Finally, drugs that allow once-daily dosing are advantageous. These principles are used in deriving an optimum approach for practical application of the antihypertensive drug armamentarium available in 1990.

Antihypertensive Agents↗

PubMed1989

Comparison of the immediate and long-term effects of captopril and isosorbide dinitrate as adjunctive treatment in mild heart failure.

1. The efficacy of captopril and isosorbide dinitrate (ISDN) as adjunctive therapy to digoxin and diuretics in mild heart failure was compared in a double-blind study. 2. Twenty-one patients were randomly allocated to captopril (twice or three times daily) or ISDN. Eighteen patients completed a protocol of placebo run-in, dose titration and maintenance treatment for 3 months. 3. Symptom-limited exercise tolerance, ejection fraction and radionuclide indices of diastolic function estimated by gated blood pool scan did not change with either treatment. 4. Captopril improved functional class (Canadian Cardiovascular Society) and reduced requirements for increased diuretic dosage at both 1 and 3 months of maintenance treatment. Patients treated with ISDN required increased diuretic and did not improve their functional class. Differences between the treatments were significant only for diuretic dosage requirements. 5. We conclude that adjunctive therapy of mild heart failure with captopril administered twice daily provides a diuretic-sparing effect and may improve functional class during 3 months of maintenance treatment.

Blood Pressure↗

PubMed1989

Life history prototypes in the study of human individuality.

Using biographical data collected in late adolescence and young adulthood, prototypes or subgroups of individuals with similar patterns of prior behaviors and experiences were empirically identified. The prototypes are described, and the pathways taken by the prototypes from adolescence to adulthood are examined. Focusing on the various pathways or trajectories followed by different prototypes, we discuss implications of prototype membership for continuity and change in personality.

Achievement↗

PubMed1989

The effects of oestradiol administration on blood pressure and erythrocyte Na+ influx in oophorectomized rats.

The effects of oestrogen on blood pressure and erythrocyte Na+ influx were measured in oophorectomized rats treated with oestradiol benzoate (100ug/kg/week i.m.) or vehicle for eight weeks. A significant increase in mean blood pressure was observed in the oestradiol-treated compared to the vehicle-treated group, together with a significant increase in red cell [Na+]. Oestradiol administration produced no significant changes in total Na+ influx, cotransport, countertransport or Na+ diffusion and did not alter plasma [Na+], red cell [K+], mean corpuscular haemoglobin concentration (MCHC) or blood volume per 100g body weight. However, significant decreases in body weight, haematocrit and plasma [K+] were observed in the oestradiol-treated group. These results support previous observations that oestradiol increases blood pressure and suggest that chronic administration of oestrogen increases red cell [Na+], probably by a mechanism other than alteration in erythrocyte passive Na+ transport.

Animals↗

PubMed1988

Age-related effects of antihypertensive therapy with alpha-blockers.

Currently, the most important alpha-blockers used in treating hypertension are prazosin and its long-acting congeners, doxazosin and terazosin. Although there are minor age-related changes in the pharmacokinetics of these compounds, they result in no appreciable alteration in dose requirements. Overall, published evidence does not indicate any loss of responsiveness to alpha-blockade in the elderly. Despite the potential risks of first-dose hypotension and of postural hypotension, long-acting alpha-blockers may warrant further consideration as possible first-line therapy in elderly hypertensive patients. These agents allow the simplicity of once-daily dosing, and their cardiac and metabolic effects offer potential advantages.

Adrenergic alpha-Antagonists↗