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Biomedical subjects

S G Carruthers

Publications and source records attributed to S G Carruthers.

At least 37 records · Page 2Linked to original sources
PubMed1993

Cardiovascular risk factors in perspective.

Coronary heart disease and other manifestations of atherosclerosis are leading causes of morbidity and mortality in Canada. Despite favourable trends in recent years, we should try to reduce cardiovascular events further. Physicians must translate current knowledge into public health policies and management strategems for individual patients. Patients are best served by a comprehensive risk management approach, involving nonpharmacological (mainly lifestyle) changes and drug therapy.

Age Factors↗
PubMed1991

Genetic aspects of variability in superficial vein responsiveness to norepinephrine.

Venoconstriction of the dorsal hand vein by local norepinephrine infusion was measured by the linear variable differential transformer method in 15 healthy unrelated subjects and eight pairs of monozygotic and six pairs of dizygotic twins. Incremental norepinephrine infusion produced dose-related venoconstriction. In unrelated subjects the doses of norepinephrine constricting basal vein diameter by 50% (ED50) ranged from 3.9 to 120.5 ng/min. There was a positive linear relationship between doses of norepinephrine infused and local steady-state plasma concentrations of norepinephrine achieved in each subject. The reciprocals of the slopes of these dose-concentration relationships, which reflect local norepinephrine clearance (disposition) in the vein, ranged from 0.47 to 1.86 ml/min. Plasma concentrations of norepinephrine associated with reduction of basal vein diameter by 50% (EC50) ranged from 1.4 to 110.2 ng/ml, with variability similar to that of ED50. There was a very high level of concordance in ED50, EC50, and clearance of norepinephrine within pairs of monozygotic twins but not within dizygotic twins. Differences in pharmacokinetics of infused norepinephrine exert a minor impact on overall intersubject variability. Genetic aspects of "tissue responsiveness" (i.e., vascular alpha-adrenoceptor response, smooth muscle contractility, and endothelial function) appear to be largely responsible for the wide intersubject variability in venoconstrictor responsiveness to norepinephrine.

Adult↗
PubMed1991

Interaction between oral verapamil and beta-blockers during submaximal exercise: relevance of ancillary properties.

The interaction between verapamil and beta-blockers may involve negative chronotropic, inotropic, and dromotropic effects. Three randomized, double-blind, crossover trials evaluated standardized submaximal exercise hemodynamics after oral verapamil (120 mg) and beta-blocker, alone and in combination, in groups of eight healthy men. The beta-blockers were propranolol (80 mg), metoprolol (100 mg), and pindolol (5 mg). During submaximal exercise, each beta-blocker produced similar reductions in heart rate. Likewise, each verapamil and beta-blocker combination caused greater decreases in heart rate and prolongation of PR interval than did either drug alone. Only the verapamil and propranolol combination produced greater reduction of systolic blood pressure and prolongation of rate-adjusted PR interval. All verapamil and beta-blocker combinations caused frequent adverse events, predominantly exercise fatigue and resting first-degree heart block. Although the verapamil and metoprolol or pindolol combinations produced lesser negative dromotropic or inotropic effects compared with verapamil and propranolol, coadministration of verapamil and any beta-blocker should be performed cautiously.

Administration, Oral↗
PubMed1991

The cyclosporin-erythromycin interaction: impaired first pass metabolism in the pig.

1. The pharmacokinetic interaction between cyclosporin (CsA) and erythromycin has been studied in the weanling pig model. 2. Blood CsA and metabolite-1 (M1) concentrations were monitored by high performance liquid chromatography in portal, hepatic and jugular venus blood before and after treatment with erythromycin stearate for 7 days. 3. Erythromycin significantly increased maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC) of CsA in the peripheral circulation. This was accompanied by a significant reduction in the hepatic extraction ratio calculated from portal and hepatic Cmax and AUC data. 4. The extraction ratio appears to be concentration-dependent in that values derived from Cmax (high concentrations) were greater than those from AUC (average concentrations). 5. Time to Cmax (tmax) and t1/2 of CsA were essentially unchanged and no significant changes were observed in peripheral M1 kinetics apart from a small increase in tmax. 6. The pharmacokinetic changes observed in the pig suggest that the CsA-erythromycin interaction is caused by inhibition of hepatic metabolism and the impact of inhibition is greatest during first-pass when CsA concentrations are at their highest.

Animals↗
PubMed1990

Relation of amiodarone hepatic and pulmonary toxicity to serum drug concentrations and superoxide dismutase activity.

Hepatic enzymes, pulmonary function, serum amiodarone and desethylamiodarone (DEA) concentrations and erythrocyte superoxide dismutase (SOD) activity were monitored at regular intervals for 1 year in 30 patients receiving amiodarone. Subclinical hepatotoxicity developed in 5 patients. These patients had higher baseline alanine transaminase values (42.6 +/- 6.8 vs 22.9 +/- 1.8 U/liter) and had an increase in serum aspartate transaminase from 27 +/- 4.1 at baseline to 147 +/- 77.3 U/liter at 12 months. The other patients had little variation in aspartate transaminase. Six patients with normal baseline carbon monoxide diffusing capacity had subclinical pulmonary toxicity develop with a mean decrease in diffusing capacity to 0.7 +/- 0.05 of the baseline value, which correlated with decreasing erythrocyte SOD activity. Mean carbon monoxide diffusing capacity and SOD activity remained unchanged in the other patients. The mechanisms of hepatic and pulmonary injury remain unknown, but appear to be associated with exposure to higher total serum concentrations of amiodarone plus DEA. Patients who had hepatic and/or pulmonary abnormalities develop received higher doses of amiodarone (440 +/- 27 vs 340 +/- 18 mg/day), but also had a higher amiodarone:DEA ratio suggesting that dose-dependent kinetics contributed to the higher concentrations. Elevated baseline alanine transaminase may indicate increased risk for hepatotoxicity while a progressive decrease in erythrocyte SOD may be an early indication of pulmonary toxicity. The latter finding indicates a need to investigate the role of free radicals in the pathogenesis of amiodarone pulmonary toxicity.

Alanine Transaminase↗
PubMed1990

The heart rate-PR interval relationship: a model for evaluating drug actions on SA and AV nodal function.

The relationship between heart rate (HR) and PR interval (PR) has been investigated to determine inter-subject variability, within-subject variability and potential reference standards. Eight healthy male volunteers underwent upright graded submaximal treadmill exercise during eight separate study sessions. All subjects exhibited statistically significant negative linear relationships between PR and HR. Although there was considerable inter-subject variability, there was little within-subject variability in the interpolated PR at HR between 80 and 120 beats min-1. The HR-PR regression model has greatest validity within this HR range and for individual subjects rather than pooled or group data.

Adult↗
PubMed1989

Correlation of amiodarone dosage, heart rate, QT interval and corneal microdeposits with serum amiodarone and desethylamiodarone concentrations.

Pharmacokinetic-dynamic relations for amiodarone have been difficult to define. Few studies have successfully correlated serum amiodarone concentration with either dose or pharmacodynamic effects. Reduction in heart rate, prolongation of corrected QT interval and accumulation of corneal microdeposits are 3 clinical effects well suited for making kinetic-dynamic comparisons because they occur in virtually all patients receiving amiodarone. Data on heart rate, corrected QT interval, corneal microdeposits, cumulative dose and serum concentrations of amiodarone and desethylamiodarone (DEA) were collected over the course of 1 year after initiation of therapy in 27 patients (mean age 55.4 +/- 2.35 years). Mean elimination half-lives in this study population were 56 days for amiodarone and 129 days for DEA, as estimated from cumulation kinetics without drug withdrawal. The extremely long half-lives of amiodarone and DEA make demonstration of steady-state concentration-response relations difficult. A new approach using analysis of sequential data before steady-state reveals general relations between dose, DEA concentration and 3 clinically observable effects of amiodarone. A linear relation was evident between DEA concentration and log mean cumulative amiodarone dose (mg/kg) for the population. The steep segments of the concentration-response curves for heart rate, microdeposits and corrected QT interval occurred at low, medium and high serum amiodarone and DEA concentrations, respectively. Patients not developing a decrease in heart rate or corneal microdeposits likely have very low serum drug concentrations and may not be adequately treated. The monitoring of heart rate, corrected QT interval and corneal microdeposits as an aid to assessing adequacy of amiodarone therapy requires further study.

Amiodarone↗
PubMed1989

Synergistic adverse hemodynamic interaction between oral verapamil and propranolol.

The interaction between oral verapamil and propranolol may involve negative chronotropic, inotropic or dromotropic effects. The immediate effects of orally administered verapamil (120 mg) and propranolol (80 mg), alone and combined, on submaximal exercise hemodynamics and on pharmacokinetics were studied in eight healthy male volunteers in a randomized, double-blind, crossover manner. Maximum effects on heart rate, systolic blood pressure, PR interval and rate-adjusted PR prolongation were greatest with the combined administration of verapamil and propranolol. The combination caused a high frequency of adverse drug events, predominantly exercise fatigue. Verapamil increased the AUC and Cmax and shortened the tmax of propranolol. Propranolol decreased the AUC and Cmax of verapamil. The greater reduction of heart rate with the combination of verapamil and propranolol was only partially explained by higher plasma concentrations of propranolol. The combination of propranolol and verapamil produced clinically important synergistic adverse effects during exercise. Negative dromotropic effects occurred primarily by direct AV node inhibition and were more important than previously recognized.

Administration, Oral↗
PubMed1989

A double-blind, randomized trial of PY108-068 in acute ischemic cerebral infarction.

A double-blind, randomized, pilot trial of the calcium channel antagonist PY108-068 was completed in patients with acute ischemic cerebral infarction. Nine treated patients received PY108-068 orally (150 mg/day in divided doses) and 10 control patients received placebo within 48 hours of stroke onset for 21 days. The mean age of the treated patients (four men, five women) was 63.7 years and of the control patients (seven men, three women) 64.4 years. Most infarctions were in the territory of the middle cerebral artery. One treated patient died of sudden cardiac death on Day 12; one control patient died of cerebral herniation. Two treated patients had episodes of clinically insignificant hypotension during Day 1 of treatment. Two control patients had myocardial infarctions during the trial. The mean Toronto Stroke Scale scores at stroke onset were 67 and 90 and at Week 12 were 22.5 and 34.7 in the treated and control groups, respectively. There was parallel improvement in the two groups, with no significant difference between groups (p = 0.12). The mean Barthel Index functional scores at stroke onset were 32.8 and 33 and at Week 12 were 90 and 78.8 in the treated and control groups, respectively. There was a trend in favor of the treated group, but differences between groups did not reach significance. In this pilot trial, PY108-068 was found to be safe but not effective in patients with acute ischemic cerebral infarction.

Acute Disease↗
PubMed1988

Elevation of serum total cholesterol and triglyceride levels during amiodarone therapy.

Over the last decade there has been increasing awareness that some cardiovascular medications may adversely affect serum cholesterol concentrations. It has been suggested previously that amiodarone may alter serum cholesterol, triglyceride and glucose concentrations, but no substantive data support this observation. During the course of a 1-year study of adverse effects in patients taking amiodarone, 21 patients with normal total serum cholesterol before entry in the study were prospectively investigated for changes in lipid metabolism. A statistically significant sustained rise of 17% in total serum cholesterol occurred from a baseline of 178 +/- 7 mg/dl (4.6 +/- 0.2 mmol/liter) to 208 +/- 9 mg/dl (5.4 +/- 0.2 mmol/liter). Ten of the patients developed elevations of cholesterol above the 75th percentile for their age and sex. This group experienced a sustained rise of 20% in mean cholesterol concentration from baseline, had statistically significant elevations of triglyceride concentrations and had higher glucose and desethylamiodarone concentrations than patients who did not develop elevations in cholesterol greater than the 75th percentile. It may be possible to predict these differences in response as early as 4 to 8 weeks after starting therapy. Because amiodarone is increasingly used in patients without ischemic heart disease or life-threatening arrhythmias, the potential atherogenic risk of these metabolic abnormalities merits further investigation.

Amiodarone↗
PubMed1988

Mean apical concentration and duration in the comparative bioavailability of slowly absorbed and eliminated drug preparations.

Present criteria for comparing bioavailability are inadequate when the Cmax and tmax cannot be reliably identified in individual subjects. Drug formulations which are slowly absorbed and eliminated have concentration-time profiles with a broad apex, increasing the likelihood that samples taken at the apical region of the curve will have statistically indistinguishable concentrations. Using data from a study of three dosage forms of piroxicam, we propose an alternative approach which decreases the influence of sampling bias and analytical error on the identification of the apex of the concentration-time curve and provides a simple tool for describing the shape of the curve around the apex. An adequate frequency of sampling around the expected apex of the concentration-time curve and consideration of the coefficient of variation (CV) of the analytical assay when assessing the observed Cmax are used in defining new parameters. This approach may be useful for studying the relationship of onset and duration of maximal plasma concentration to the efficacy and toxicity of drugs and in developing standards for comparing the bioavailability of slow-release preparations, which is of increasing interest to pharmaceutical companies and regulatory agencies.

Absorption↗
PubMed1988

Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial.

The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.

Antipyrine↗
PubMed1988

The centrally acting drugs.

Concern has been expressed about the adverse effects of the centrally acting antihypertensive drugs. The use of this class of medication has declined in recent years. However, evidence from carefully controlled trials indicates that the centrally acting antihypertensive medications can be effective and well tolerated in elderly hypertensive patients when low starting doses are used and when the doses are increased carefully. Centrally acting antihypertensive medications appear to have a useful role in the management of hypertension in the elderly.

Aged↗
PubMed1987

Tolerance and cardiovascular effects of single dose felodipine/beta-blocker combinations in healthy subjects.

The effects of single oral doses of 10 mg felodipine and four beta-blockers (100 mg metoprolol, 5 mg pindolol, 80 mg propranolol, and 10 mg timolol) were evaluated alone and in combination in a 10-way crossover, double-blind, placebo-controlled trial in 10 healthy male volunteers randomized to the medication sequence according to a latin square design. Adverse effects were recorded from spontaneous complaints and investigator observations. Heart rate (HR), PR interval, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured supine, standing, and after treadmill exercise, before and 2 h after drug administration. The adverse effects experienced with felodipine were as expected for a vasodilator. Seven subjects mentioned complaints voluntarily on the combinations while three experienced side effects receiving felodipine or beta-blocker alone. Felodipine increased resting HR significantly. Timolol produced a greater depression of exercise heart rate than the other beta-blockers, indicating that the dose given was not equivalent to that of the other beta-blockers. Pindolol was ineffective in preventing the increase in supine HR produced by felodipine. Felodipine did not alter PR interval at any level of activity, but rate-corrected supine PR interval was prolonged slightly by felodipine. Metoprolol and timolol significantly prolonged standing PR interval. All beta-blockers prolonged exercise PR interval. Felodipine/beta-blocker combinations did not prolong PR interval more than beta-blockers alone. Prolonged PR interval was the result of reduced HR and direct inhibition of atrioventricular (AV) conduction. Only timolol and the timolol/felodipine combination lowered supine systolic blood pressure significantly. Timolol and all beta-blocker/felodipine combinations reduced exercise SBP significantly.

Adrenergic beta-Antagonists↗
PubMed1987

Relationships between heart rate and PR interval during physiological and pharmacological interventions.

The relationships between heart rates (HR) and corresponding PR intervals (PR) were studied in 12 healthy young subjects during rest, standing and graduated treadmill exercise to heart rates of 160 to 170 beats min-1 and during the infusion of isoprenaline to heart rates of 100 to 110 beats min-1. During exercise, PR diminished with increasing HR. Over the range of HR from 60 to 160 beats min-1 all 12 individual subjects exhibited negative linear correlations between HR and PR described by the equation: PR (ms) = -0.351 HR (beats min-1) + 176.7 for composite data. During isoprenaline infusion the PR interval also diminished with increasing heart rate. Over the range of HR from 60 to 110 beats min-1, 11 of the 12 subjects exhibited negative linear correlations between HR and PR described by the equation: PR (ms) = -0.582 HR (beats min-1) + 186.5 for composite data. The exercise model was used to study the indirect (or rate-dependent) effects and the direct actions on atrioventricular conduction of beta-adrenoceptor blocking drugs and calcium channel antagonists, alone and in combination, in three groups of healthy subjects. Control and placebo observations on HR and PR at rest, standing and during exercise in these additional subjects also exhibited individual inverse linear relationships between HR and PR. Following the administration of beta-adrenoceptor blockers, PR were prolonged more than expected at the HR observed. Rate-adjusted PR prolongation during exercise exceeded standing which exceeded resting, indicating greater beta-adrenoceptor blockade in atrioventricular nodal tissue than in sinoatrial nodal tissue at each level of activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1987

Cyclosporin-erythromycin interaction in normal subjects.

We studied the pharmacokinetic interaction between cyclosporin (CYA) and erythromycin in normal subjects. Plasma CYA concentrations were measured by high performance liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA) and estimates of metabolite formation were obtained from inter-assay differences between these measurements. Erythromycin significantly increased the maximum concentration and the area under concentration-time curve. Time to maximum concentration and apparent oral clearance of CYA were significantly decreased. The half-life, however, was not altered. Significant reductions in the proportion of apparent metabolite were observed at times of maximum CYA concentrations but not at later time periods (12 and 24 h). The mechanism of the drug interaction appears to be decreased hepatic first-pass metabolism but an effect on CYA absorption cannot be excluded. These results on normal subjects confirm that patients administered CYA and erythromycin risk CYA toxicity. However, the risk can be reduced by dose reduction based on more frequent CYA monitoring or by using a different antibiotic.

Adult↗