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Biomedical subjects

D R Abernethy

Publications and source records attributed to D R Abernethy.

At least 91 records · Page 5Linked to original sources
PubMed1988

Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans.

Antipyrine and theophylline disposition was studied in healthy volunteer subjects in the control state while the subjects were taking verapamil (120 mg) orally four times daily or diltiazem (120 mg) orally three times daily. Both verapamil and diltiazem treatment decreased antipyrine clearance (verapamil, 42.5 to 30.1 ml/min, P less than .01; diltiazem, 41.7 to 29.9 ml/min, P less than .01), resulting in prolonged antipyrine half-life with no change in distribution volume. Fractional clearances of urinary antipyrine metabolites 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, norantipyrine and unchanged antipyrine were differentially changed by verapamil and diltiazem treatment. With verapamil treatment, 4-hydroxyantipyrine and norantipyrine fractional clearances were markedly decreased, with 3-hydroxymethylantipyrine slightly decreased and antipyrine unchanged. With diltiazem treatment, 3-hydroxymethylantipyrine was decreased, with no significant change in 4-hydroxyantipyrine, norantipyrine or antipyrine. Effect on theophylline clearance differed between verapamil treatment (57.7 to 44.7 ml/min; P less than .01) and diltiazem treatment (50.2 to 49.4 ml/min; N.S.), with prolonged theophylline half-life during verapamil treatment, no change in half-life during diltiazem treatment and distribution volume unchanged by either treatment. Fractional clearances of urinary theophylline metabolites 3-methylxanthine, 1-methyluricacid, 1,3-dimethyluricacid and unchanged theophylline reflected the differential plasma theophylline clearance. During verapamil treatment, 3-methylxanthine and 1,3-dimethyluricacid fractional clearances were decreased, with no change in 1-methyluricacid or theophylline. During diltiazem treatment, 1,3-dimethyluricacid fractional clearance was slightly decreased, and 3-methylxanthine, 1-methyluricacid and theophylline were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Acute and chronic studies of diltiazem in elderly versus young hypertensive patients.

The pharmacodynamics, disposition and hormonal responses to acute intravenous and chronic oral diltiazem treatment were compared in young and elderly hypertensive patients. In elderly patients, supine diastolic blood pressure decreased significantly during the first week of treatment (baseline mean +/- standard error of the mean, 100 +/- 1 to 93 +/- 2 mm Hg) and decreased further during the study to 86 +/- 2 mm Hg at the end of the study. Diastolic blood pressure of the young patients decreased significantly by the third week of treatment (from 104 +/- 2 to 97 +/- 3 mm Hg) and decreased further during the study to 94 +/- 2 mm Hg at the end of the study. Baseline supine systolic blood pressure was greater in elderly than in young patients (167 +/- 5 vs 144 +/- 3 mm Hg; p less than 0.01) and was significantly reduced in the elderly by the fourth week (167 +/- 5 to 154 +/- 3 mm Hg; p less than 0.003), with a significantly reduction sustained throughout the 14-week period. Young patients had little change in systolic blood pressure. Supine heart rate tended to decrease in both groups during the 14-week period. Acute intravenous diltiazem pharmacokinetics determined at the beginning of the study showed that total diltiazem clearance was similar in elderly (13.3 +/- 1.0 ml/min/kg) and young (13.7 +/- 1.9 ml/min/kg) patients as was volume of distribution (4.2 +/- 0.3 vs 4.3 +/- 0.6 liters/kg) and elimination half-life (3.78 +/- 0.19 vs 3.69 +/- 0.23 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension.

Pharmacodynamics and pharmacokinetics of labetalol, a combined alpha- and beta-adrenoceptor antagonist drug, were studied in elderly and young hypertensive patients. After receiving intravenous labetalol, elderly patients had a greater maximal mean decrease in systolic blood pressure (BP) (39 +/- 8 vs 25 +/- 13 mm Hg, p less than 0.02); however, maximal decrease in diastolic BP was similar in elderly (18 +/- 10 mm Hg) and young (17 +/- 6 mm Hg) patients. After receiving oral labetalol, elderly patients had a greater maximal decrease in standing systolic BP (41 +/- 16 vs 16 +/- 14 mm Hg, p less than 0.001) and similar decreases in standing diastolic BP (21 +/- 7 vs 17 +/- 9 mm Hg). Sitting maximal BP decreases after oral labetalol treatment were similar in elderly and young patients (12 +/- 16 vs 17 +/- 7 mm Hg systolic and 24 +/- 6 vs 12 +/- 7 diastolic). The decrease in heart rate was greater in young patients after intravenous labetalol administration. To evaluate labetalol pharmacodynamics, a linear model was used. Slope of labetalol concentration vs systolic BP for elderly vs young patients was 0.928 +/- 1.05 vs 0.326 +/- 0.490 ng/ml X mm Hg-1 (difference not significant). The slope of labetalol concentration vs heart rate for elderly vs young patients was 0.176 +/- 0.063 vs 0.406 +/- 0.303 ng/ml X beats/min-1 (p less than 0.05), with 2 elderly patients showing no decrease in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Responses to intravenous and oral diltiazem in elderly and younger patients with systemic hypertension.

Diltiazem concentrations and blood pressure, heart rate, PR interval and forearm vascular resistance responses to intravenous (25 and 50 mg) and oral (120 mg) diltiazem were compared in 13 elderly persons (mean age 68 +/- 4 years) and 10 young persons (mean 30 +/- 5 years) with essential hypertension. Diltiazem elimination was slower in the elderly. After a dose of 25 mg, clearance was 13 +/- 4 ml/min/kg in the elderly and 23 +/- 7 in the young (p less than 0.05); after 50 mg, 16 +/- 6 and 21 +/- 12 ml/min/kg (p less than 0.05); and after oral administration, 22 +/- 9 and 35 +/- 14 ml/kg/min (p less than 0.02). No age-related differences in volume of distribution (by model or area methods) were seen. Elimination half-lives were 4.5 +/- 2.2 hours in the elderly and 3.8 +/- 0.7 hour in the young persons (p less than 0.01); 4.5 +/- 1.6 and 3.3 +/- 0.7 hours (p = 0.10); and 4.7 +/- 1.5 and 3.3 +/- 1.8 hours (p = 0.08) after 50, 25 and 120 mg. Maximal decreases in mean blood pressure were from 113 +/- 14 to 91 +/- 12 mm Hg (19%) in the elderly patients and from 108 +/- 8 to 99 +/- 9 mm Hg in the younger patients (8%) after 50 mg; from 106 +/- 13 to 93 +/- 14 mm Hg and from 109 +/- 11 to 99 +/- 13 mm Hg, respectively, after 25 mg; and from 113 +/- 10 to 97 +/- 10 mm Hg and from 109 +/- 11 to 97 +/- 8 after 120 mg orally.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Labetalol in the treatment of hypertension in elderly and younger patients.

The efficacy and safety of labetalol therapy were evaluated in 20 patients 60 years and older with isolated systolic or diastolic hypertension and 19 patients aged younger than 60 years with diastolic hypertension. After a two-week placebo washout period, labetalol was titrated for up to four weeks (100-400 mg bid) until blood pressure control was achieved (standing systolic less than 160 mm Hg or greater than or equal to 10% reduction from baseline, and standing diastolic less than 90 mm Hg or a decrease of 10 mm Hg from baseline). Mean decreases in standing systolic and diastolic blood pressure from baseline were statistically significant for both age groups (greater than or equal to 60 years, -23/-13; less than 60 years, -18/-12, P less than .01). Control criteria were met in 18 (90%) older and 15 (79%) younger patients who then entered a four-week maintenance period. Sixteen (80%) of the older patients and six (32%) of the younger patients maintained blood pressure control on 200 mg or less of labetalol bid (P less than .05). Three patients, two of whom withdrew from the study, were judged to have experienced adverse events that were drug related. It was concluded that labetalol was effective and well-tolerated antihypertensive therapy in both elderly and younger patients. In addition, significantly less medication was required to achieve blood pressure control in the elderly.

Adrenergic alpha-Antagonists↗
PubMed1987

The effect of propylene glycol on antipyrine clearance in humans.

To evaluate the potential interaction of propylene glycol on hepatic drug oxidation, antipyrine disposition was measured in 10 healthy subjects who received 1.2 gm antipyrine alone on one occasion and 1.2 gm antipyrine with propylene glycol on a second occasion. Propylene glycol was given as a 5 ml dose every 4 hours during the 48 hours of the study. Propylene glycol had no effect on antipyrine half life (11.7 hours control vs. 12.1 hours treatment), clearance (42.6 vs. 39.2 ml/min), or volume of distribution (42.1 vs 41.9 L). At a dose similar to that used as a vehicle for administration of other drugs, propylene glycol had no significant effect on antipyrine clearance in humans.

Adult↗
PubMed1987

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. IV. Chronically administered oral verapamil and halothane, enflurane, and isoflurane.

Dogs were chronically instrumented to measure aortic and left atrial blood pressures, left ventricular maximal rate of tension development (dP/dt), cardiac output, and carotid, coronary and renal blood flows. Measurements were taken with the animals awake and during steady-state low and high concentrations of halothane (1.2%, 2.4%), enflurane (2.4%, 4.0%), and isoflurane (1.6%, 3.0%) with and without at least 2 weeks of oral verapamil, 120 mg, three times per day. Plasma verapamil levels varied widely, with means of 500-700 ng X ml-1 in awake animals and lower (300-400 ng X ml-1) at the time of hemodynamic measurements during anesthesia. Chronic oral verapamil in awake dogs produced predominantly tachycardia. The hemodynamic effects of low-dose halothane and isoflurane before and after oral verapamil were unchanged except for decreased renal blood flow after oral verapamil and no coronary vasodilation nor tachycardia. However, left atrial pressure was increased and cardiac output and coronary blood flow were decreased by low concentrations of enflurane with oral verapamil compared to without. The combination of oral verapamil with low (clinical) doses of enflurane was more depressant to the cardiovascular system of healthy dogs than was the combination of verapamil and halothane or isoflurane.

Administration, Oral↗
PubMed1987

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. V. Role of pharmacokinetics and the autonomic nervous system in the interactions between verapamil and inhalational anesthetics.

To assess the role of both pharmacokinetics and the autonomic nervous system in the interaction between inhalational anesthetics and verapamil, dogs were chronically instrumented to measure heart rate, PR interval, dP/dt, cardiac output, and aortic blood pressure. In a first group of seven dogs, studied awake and during halothane (1.2%), enflurane (2.5%), and isoflurane anesthesia (1.6%), verapamil was infused for 30 min in doses calculated to obtain similar plasma concentrations (83 +/- 10, 82 +/- 6, 81 +/- 10, and 77 +/- 9 ng.ml-1, respectively). For the latter purpose, the infusion dose was 3 and 2 micrograms.kg-1.min-1 awake and during anesthesia, respectively, preceded by a loading dose of 200, 150, and 100 micrograms.kg-1, awake, during isoflurane, and halothane and enflurane, respectively. In awake dogs, verapamil induced an increase in heart rate (24 +/- 5 bpm) and PR interval (35 +/- 9 msec) and a decrease in mean arterial pressure (-5 +/- 2 mmHg) and dP/dt (-494 +/- 116 mmHg/s). Although plasma concentrations were similar in awake and in anesthetized dogs, the only statistically significant changes induced by verapamil were an increase in heart rate and a decrease in dP/dt during halothane and enflurane, while left atrial pressure increased only with enflurane. In a second group of six dogs, verapamil pharmacokinetics were determined in the presence and absence of a ganglionic blocking drug (chlorisondamine, 2 mg.kg-1 iv). Blockade of ganglionic transmission resulted in a decrease in both initial volume of distribution and total clearance of verapamil--changes similar to those previously reported with inhalational anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗
PubMed1987

N-monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives.

1 Twelve young (ages 30-39 years) and twelve elderly (ages 65-83 years) hypertensives were administered diltiazem twice daily for 2 weeks at doses up to 240 mg day-1. 2 Plasma was analysed for diltiazem, N-monodesmethyldiltiazem, and desacetyldiltiazem concentrations after a single 10 min intravenous infusion of 21.8 mg diltiazem HCl on day 1 and after the morning oral dose of 120 mg diltiazem base on day 14. 3 N-monodesmethyldiltiazem accumulated to higher plasma concentrations than desacetyldiltiazem at steady state on day 14 in both age groups. 4 Prolongation of plasma diltiazem half-life occurred after 2 weeks of oral diltiazem therapy in both age groups. 5 There were no significant differences between the young and elderly with regard to half-life, area under the curve, and the peak and trough plasma concentrations of diltiazem, N-monodesmethyldiltiazem, and desacetyldiltiazem; systemic clearance and volume of distribution of diltiazem were also similar in both groups.

Adult↗
PubMed1987

Evidence for a pathogenetic role of xanthine oxidase in the "stunned" myocardium.

Recent evidence suggests that postischemic myocardial dysfunction (or myocardial "stunning") may be mediated by oxygen free radicals, but the mechanism for their production remains unknown. To explore the role of xanthine oxidase as a potential source of free radicals, open-chest dogs undergoing a 15-min occlusion of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion (REP) received intravenously either allopurinol (50 mg/kg 48 h, 20 h, and 30 min before occlusion, 10 mg/kg 1 min before REP, and 6.25 mg X kg-1 X h-1 throughout REP, n = 13) or saline (n = 14). The two groups were similar with respect to occluded bed size (postmortem perfusion) and collateral flow (radioactive microspheres). In controls, the transcardiac difference in plasma uric acid (great cardiac vein - arterial concentration) increased 199 +/- 70% (means +/- SE) during ischemia (P less than 0.02) and remained elevated for 5 min after REP; no increase was observed in treated dogs. Regional myocardial function was assessed by measuring systolic wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under base-line conditions and similar degrees of dyskinesis during ischemia. Following REP, however, recovery of contractile function (expressed as percent of preocclusion values) was considerably greater in allopurinol-treated as compared with control dogs: 57 +/- 14 vs. -22 +/- 16 (P less than 0.01) at 1 h, 70 +/- 13 vs. -15 +/- 15 (P less than 0.001) at 2 h, 65 +/- 14 vs. -28 +/- 13 (P less than 0.001) at 3 h, and 68 +/- 13 vs. -17 +/- 14 (P less than 0.001) at 4 h. These differences could not be ascribed to hemodynamic factors. The results suggest that xanthine oxidase is a source of the oxygen free radicals responsible for myocardial stunning following a brief episode of reversible regional ischemia.

Allopurinol↗
PubMed1987

Cardiac drugs: adjusting their use in aging patients.

Reduced drug metabolism, both renal and hepatic, occurs with aging. Algorithms for dose adjustments of renally excreted drugs are available, but dose adjustments must be empiric for drugs which undergo hepatic metabolism. Decreased drug clearance in combination with potentially increased sensitivity to drugs in the elderly means that, as a general rule, drug dosages should be reduced as the age of the patient increases. The frequent need for multi-drug therapy may also lead to adverse effects in the elderly compared with younger cardiac patients. Managing the geriatric patient requires careful drug monitoring and a heightened awareness of the potential for adverse drug effects.

Aged↗
PubMed1987

Role of isoflurane on hemodynamic properties and disposition of nicardipine.

Nicardipine properties (30 micrograms/kg i.v.) were studied in a group of eight dogs awake and anesthetized with isoflurane 1.6% end-tidal. Awake, nicardipine produced a decrease in mean arterial pressure (-12 +/- 2 mm Hg) associated with an increase in cardiac output (1.63 +/- 0.2 liters/min), heart rate (75 +/- 9 beats/min), dP/dt (741 +/- 202 mm Hg/sec) and carotid (41 +/- 11 ml/min) and coronary blood flows (39 +/- 6 ml/min). During isoflurane, responses to nicardipine injections were less pronounced except for mean arterial pressure (-19 +/- 2 mm Hg) and reversed for dP/dt (-290 +/- 63 mm Hg/sec). In a second group of six conscious dogs, nicardipine (30 micrograms/kg i.v.) injected after ganglionic blockade (chlorisondamine, 2 mg/kg i.v.) elicited changes similar to those recorded during isoflurane anesthesia, data that demonstrated the importance of isoflurane-induced baroreflex blockade as a mechanism of the pharmacodynamic interactions between nicardipine and isoflurane. Isoflurane reduced nicardipine initial volume of distribution (11.6 +/- 1.2 vs. 8.9 +/- 0.8 liters), total clearance (28.5 +/- 2.9 vs. 19.2 +/- 2.1 liters/hr) and volume of distribution at steady state (50.0 +/- 11.3 vs. 29.2 +/- 3.7 liters, P less than .05). Nicardipine-induced hemodynamic changes were linearly correlated with the drug concentrations in plasma. In the presence of isoflurane, the slopes of these relationships were reduced for all hemodynamic variables except for mean arterial pressure, for which the slope was more pronounced, and dP/dt, for which the slope was reversed. In conclusion, isoflurane alters the drug plasma concentration-effect relationship of nicardipine as a result of both pharmacokinetic and pharmacodynamic interactions.

Animals↗
PubMed1987

Pharmacodynamic and pharmacokinetic interactions between lidocaine and verapamil.

Lidocaine (3 mg/kg i.v.) injected during steady-state verapamil infusions (3 micrograms/kg i.v.) induced slight and transient hemodynamic changes in nine conscious dogs. Systemic vascular resistance and left ventricular dP/dt decreased by 16% from 41 +/- 4 mm Hg/liter/min and by 20% from 2876 +/- 137 mm Hg/sec, respectively, whereas heart rate and cardiac output increased by 18% from 100 +/- 5 beats/min and by 17% from 2.5 +/- 0.2 liters/min, respectively. Simultaneously, lidocaine induced a transient but more pronounced decrease in verapamil plasma concentration of 48% from 60 +/- 3 ng/ml. This pharmacokinetic interaction was not the result of a lidocaine-induced decrease in the fraction of verapamil bound to plasma protein because in vitro lidocaine failed to displace verapamil from its protein binding site. Moreover, an increase in verapamil total clearance was not the only mechanism because steady-state lidocaine (6 mg/kg over 5 min followed by 60 micrograms/kg/min) in the presence of steady-state verapamil (200 micrograms/kg over 3 min followed by 3 micrograms/kg/min) also resulted in a transient decrease in verapamil plasma concentration from 59 +/- 9 to 23 +/- 2 ng/ml in six conscious dogs. Although verapamil did not affect lidocaine pharmacokinetics, in the presence of the steady-state lidocaine we recorded an increase in verapamil initial volume of distribution of 44% from 40 +/- 4 liters, and intercompartmental clearance increased by 88% from 101 +/- 20 liters/hr, combined with an increase in verapamil total clearance of 47% from 54 +/- 6 liters/hr (n = 6).

Animals↗
PubMed1986

Minoxidil analysis in human plasma using high-performance liquid chromatography with electrochemical detection. Application to pharmacokinetic studies.

A method is described for determination of minoxidil in human plasma using high-performance liquid chromatography with electrochemical detection. The method is specific and sensitive (500 pg/ml), however, minoxidil and minoxidil sulfate cannot be differentiated due to rapid autohydrolysis of minoxidil sulfate to minoxidil. The extraction procedure employs a C18 preparatory column to remove endogenous plasma constituents which would interfere with the assays. The calibration curves are linear for concentrations from 500 pg to 10 ng/ml. Within-day and between-day reproducibility are satisfactory with coefficient of variation less than 5.7% for all concentrations. Sample recovery from extraction is consistent at 45 to 55% at low and high concentrations, respectively. A pharmacokinetic study in a hypertensive volunteer receiving two different oral doses of minoxidil (1.25 and 2.5 mg) on different occasions demonstrates the utility of the method.

Chemical Phenomena↗