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Biomedical subjects

D R Abernethy

Publications and source records attributed to D R Abernethy.

At least 73 records · Page 4Linked to original sources
PubMed1990

Forearm vascular alpha 1-adrenergic blockade by verapamil.

With use of direct brachial artery infusion and measurement of forearm blood flow and vascular resistance by strain gauge plethysmography, the effect of verapamil on phenylephrine-induced vasoconstriction was determined. Seven healthy men (age range, 19 to 47 years; weight range, 68 to 108 kg; mean blood pressure, 74 to 100 mm Hg; five nonsmokers) were systemically beta-blocked with intravenous administrations of 10 mg propranolol. Each subject then received ascending doses of phenylephrine (0.191 to 7.6 micrograms/min) alone and with concurrent verapamil (19.1 micrograms/min) by brachial arterial infusion. Dose-ratio during verapamil infusion compared with control was 8.1 (p less than 0.05). No change in slope of the phenylephrine dose-response curve was noted; however, consistent with the dose ratio, verapamil shifted the curve to the right with a decrease in the y intercept determined by linear regression (60.0 versus 40.3 mm Hg ml/100 ml forearm volume/min; p less than 0.05). Verapamil-induced attenuation of forearm vasoconstriction elicited by phenylephrine indicates that, in humans, in vivo verapamil forearm vasodilating effects are, in part, a result of alpha 1-adrenergic blockade.

Adult↗
PubMed1990

Effects of amlodipine, a long-acting dihydropyridine calcium antagonist in aging hypertension: pharmacodynamics in relation to disposition.

Pharmacodynamics and disposition of amlodipine, a dihydropyridine calcium antagonist, were compared between elderly and young patients with hypertension. Elderly (mean +/- SD; age, 68 +/- 3 years) and young (35 +/- 5 years) patients received single intravenous amlodipine doses followed by oral administration once daily for a total of 12 weeks. After intravenous administration, elderly patients had prolonged elimination half-life values (58 +/- 11 versus 42 +/- 8 hours; p less than 0.01) caused by decreased clearance (19 +/- 5 versus 25 +/- 7 L/hr; p less than 0.01). After a 3-months oral treatment washout period, half-life tended to be prolonged in the elderly patients (69 +/- 20 hours for the elderly patients versus 53 +/- 14 hours for the young patients; difference not significant) and was not markedly different from the short-term intravenous measurement. Both systolic and diastolic blood pressure were significantly decreased from baseline throughout the treatment period, with greater decreases in elderly patients for both systolic and diastolic pressure. When amlodipine plasma concentration was correlated to change in mean blood pressure after short-term intravenous doses, elderly patients had a greater decrease than young patients at a given drug concentration. However, after long-term oral administration, elderly and young patients had comparable decreases in mean blood pressure at a given drug concentration, and the increased antihypertensive effect in the elderly was associated with somewhat higher amlodipine plasma concentration. Amlodipine administered once daily is an effective antihypertensive agent in elderly patients and young patients with essential hypertension.

Administration, Oral↗
PubMed1990

Research challenges, new drug development, preclinical and clinical trials in the ageing population.

The aged are now viewed as a special population for the purposes of drug development. This has produced challenges for the investigator, in that separation of age- and disease-related changes in drug effect is only beginning to be defined. In addition, development of measurement tools for use in the elderly, particularly for central nervous system-active drugs, is an important ongoing process. As investigations proceed, we can look forward to an improved understanding of the physiology of normal ageing and the impact of disease processes and drugs on this physiological functioning. For the regulatory agency, evaluation of both efficacy and toxicity data in elderly patients for a drug-in-development is required; however, at present these data will be obtained in a 'young' elderly group, whereas much of the clinical use of the drug will be in the 'old' elderly. Extrapolation from one group to the other is required, although the relevance of this extrapolation is unknown. It is reassuring that, so far, few if any drug effects or toxicities have been identified which are truly unique to the elderly, though the magnitude of pharmacological or toxicological effects may differ.

Aged↗
PubMed1990

Pharmacokinetic investigations in elderly patients. Clinical and ethical considerations.

Over the past decade, clinical pharmacokinetic studies in the elderly, both healthy subjects and patients, have burgeoned. This data base has provided a useful first approximation to the understanding of age-related changes in drug disposition. It is now appropriate to reflect on the approach for future studies. The most accessible population, healthy elderly who are otherwise drug-free, may not provide completely relevant data for extrapolation to the very elderly, concurrently medicated patient population. Similarly, the most straightforward study, single dose drug exposure, may provide an incomplete understanding of pharmacokinetics during multiple dose drug administration in the very elderly patient. With careful attention to details of the study and informed consent procedures, it is appropriate to obtain the needed data.

Aged↗
PubMed1990

Altered pharmacodynamics of cardiovascular drugs and their relation to altered pharmacokinetics in elderly patients.

To properly predict drug effects in elderly patients for cardiovascular drugs requires understanding of age-related and disease-related changes in tissues and organs which mediate the observed pharmacodynamic response. Linking this understanding with the known changes in drug pharmacokinetics permits more effective cardiovascular pharmacotherapy in the geriatric patient. At the present time only a limited number of drug classes have been studied in this manner. Although it may be intuitively obvious that human pathophysiology may impact on drug response, until recently we have relied solely on description of drug concentration or pharmacokinetics to predict expected responses. We can look forward to improved geriatric therapeutics when the patient as well as the drug is considered as a variable in clinical therapeutic responses.

Aged↗
PubMed1989

The pharmacokinetic profile of amlodipine.

Amlodipine, a dihydropyridine calcium antagonist, was synthesized in an attempt to develop a compound with a pharmacokinetic profile characteristic of this class, which would also have an increased oral bioavailability and extended clearance time. A single intravenous dose of 10 mg resulted in an absolute bioavailability of 64% and a calculated elimination half-life of 34 hours. The pharmacokinetic profile of oral doses showed similar changes. These results were significantly different from those seen with most other dihydropyridines (elimination half-life of 3 to 10 hours and absolute bioavailability of 10% to 30%) and nondihydropyridine calcium antagonists (elimination half-life 3 to 6 hours and low absolute bioavailability). With chronic oral dosing of amlodipine once daily for 14 days, support was provided for the linearity of amlodipine's pharmacokinetics and absence of such with chronic oral dosing with verapamil, diltiazem, and nifedipine. In the elderly population, elimination half-life of 5 mg oral doses is significantly prolonged (48 vs 35 hours; p less than 0.025) suggesting decreased oral clearance or increased bioavailability. Comparison of the pharmacokinetics of amlodipine in patients with chronic stable angina pectoris with the profile in healthy volunteers suggested that clearance is not altered in patients with chronic stable angina, steady state being reached 6 to 12 hours after administration of the drug. In patients with cirrhosis, elimination half-life is significantly prolonged (60 vs 34 hours; p less than 0.01) suggesting that there is a greater accumulation of amlodipine in patients with severe liver disease than in individuals with normal hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1989

Calcium antagonists in geriatric patients: diltiazem in elderly persons with hypertension.

Pharmacodynamics and disposition of diltiazem were determined in twelve young (30 to 39 years of age) and twelve elderly (65 to 83 years of age) persons with hypertension after they had received diltiazem by rapid intravenous and long-term oral administration. Plasma disappearance half-life of diltiazem increased similarly and significantly in both groups with long-term dosing (young: rapid intravenous, 3.7 +/- 0.8 hour; long-term oral, 6.3 +/- 1 hour [mean +/- SE]; elderly: rapid intravenous, 3.8 +/- 0.7 hour; long-term oral, 7.2 +/- 2.1 hour; p less than 0.01). During long-term therapy both systolic and diastolic blood pressure was significantly lowered from baseline beyond a 12-hour dose interval, with greater decreases in systolic blood pressure in the elderly. Heart rate was decreased with long-term therapy in both groups. Maximal prolongation of PR interval was greater in the young after the intravenous dose (young: 46 +/- 28 msec; elderly: 24 +/- 11 msec; p less than .01), but this effect was not seen with long-term therapy. These data demonstrate that diltiazem administered every 12 hours is an effective antihypertensive agent in both young and elderly patients.

Administration, Oral↗
PubMed1989

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs: VII. Verapamil and thiopental.

To assess the role of basal anesthesia in the negative inotropic properties of verapamil, the effect of thiopental (30 mg/kg followed by 3.5 mg.kg-1.min-1) on verapamil pharmacokinetics (200 micrograms/kg iv; n = 6) and its pharmacodynamics (3 and 6 micrograms.kg-1.min-1; n = 11) in chronically instrumented dogs was studied. In the presence of thiopental, verapamil pharmacokinetics remained essentially unchanged. In contrast, anesthesia altered verapamil hemodynamic properties. In the conscious animal verapamil infusions increased heart rate (14 +/- 3 and 27 +/- 4 beats/min, respectively), cardiac output (0.22 +/- 0.07 and 0.24 +/- 0.08, l/min, respectively) and PR interval (14 +/- 2 and 25 +/- 6 ms, respectively) and slightly decreased dP/dt (-315 +/- 114 and -419 +/- 106 mmHg/s, respectively). Systemic vascular resistance (SVR) decreased at the low dose (-2.7 +/- 0.7 mmHg.1.min-1), and stroke volume decreased at the high dose (-4.4 +/- 0.6 ml). Yet the presence of thiopental resulted in an accentuation of verapamil-induced tachycardia (27 +/- 7 and 31 +/- 6 beats/min, respectively), and a decrease in stroke volume (-5.3 +/- 2.0 and -6.3 +/- 2.1 ml, respectively). At 3 micrograms.kg-1.min-1 verapamil did not increase PR interval, cardiac output, or vasodilation. Finally, at 6 micrograms.kg-1.min-1 verapamil did not decrease dP/dt and increased renal blood flow (21.8 +/- 6.4 ml/min). These data provide evidence that the negative inotropic properties of verapamil are more pronounced in the presence of thiopental. However, the role of basal anesthesia appears to be limited.

Animals↗
PubMed1989

Age and gender effects on chlordiazepoxide kinetics: relation to antipyrine disposition.

Twelve normal subjects aged 24-41 years, and 12 subjects aged 62-79 years, received single 50-mg doses of chlordiazepoxide hydrochloride by mouth and by intravenous injection on two occasions. Chlordiazepoxide volume of distribution was significantly correlated with body weight (r = 0.63, p less than 0.001), but was not related to age or sex. Among male subjects, elimination half-life was prolonged (20 vs. 8 h, p less than 0.025) and clearance reduced (20 vs. 43 ml/min, p less than 0.05) in elderly as opposed to young volunteers. Among women, there was no significant difference between elderly and young subjects in elimination half-life (12 vs. 13 h) or clearance (29 vs. 22 ml/min). Absolute bioavailability of oral chlordiazepoxide was not less than 100%, and was unrelated to age or sex. Among 20 subjects who received a single 1.0- to 1.2-gram intravenous dose of antipyrine on another occasion, clearance of chlordiazepoxide and of antipyrine were significantly correlated (r = 0.62, p less than 0.01). Like many other low-clearance oxidatively metabolized compounds, chlordiazepoxide clearance is reduced and half-life prolonged in elderly men, but not elderly women. Individual variations in chlordiazepoxide clearance are significantly correlated with those of antipyrine, a drug commonly used as an index of hepatic oxidizing capacity.

Adult↗
PubMed1989

Oral 5-fluorouracil in psoriasis: pharmacokinetic-pharmacodynamic relationships.

Previous studies have suggested oral 5-fluorouracil (5-FU) is unpredictably and erratically absorbed. We studied oral pharmacokinetics of 5-FU in 16 patients (aged 34-71 years) with severe recalcitrant psoriasis. Each patient received repeated single oral doses of 5-FU, each separated by 1 week. Doses were ascending (300, 600, 900, 1,200 mg/m2), and after the first 3 patients, doses were started at 600 mg/m2 and increased. Multiple blood samples were obtained after each 5-FU dose and plasma 5-FU concentration determined by HPLC. Response was determined by clinical assessment of skin thickening, redness, and scaling on upper and lower body and quantified as percent improvement. Among all patients total dose and total area under the plasma 5-FU concentration-time curve (AUC) was significantly related (r = 0.65; p less than 0.01). In contrast no relationship between either total 5-FU dose and response (r = -0.07) or AUC and response (r = -0.08) was identified. With each individual patient, total 5-FU dose and response were well correlated in 11 of 14 patients (r = 0.96, 0.92, 0.92, 0.97, 0.78, 0.85, 0.71, 0.89, 0.96, 0.76, 0.94) and less well related in 3 of 14 (r = 0.57, 0.51, 0.15). Similarly, cumulative 5-FU AUC and response were well correlated in 11 of 14 patients (r = 0.91, 0.84, 0.83, 0.91, 0.77, 0.86, 0.75, 0.93, 0.99, 0.74, 0.89) and less well related in the same 3 patients (r = 0.61, 0.40, 0.03). The relationship of the 5-FU dose and AUC was nonlinear with normalized dose: AUC 1.0 at the lowest dose for each patient, at 1.5 dose AUC was 3.4 times baseline, at 2.0 dose AUC was 5.3 times baseline, and at 3.0 dose AUC was 36 times baseline. In patients with recalcitrant psoriasis 5-FU is consistently absorbed into the systemic circulation with extent of absorption increased with increasing dose in a nonlinear manner. Evaluation of both total 5-FU dose and total 5-FU AUC indicates a clear within-patient dose and AUC:response relationship.

Administration, Oral↗
PubMed1988

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites.

The benzodiazepine derivative flurazepam (FLZ) is widely used as a hypnotic, but the relative contributions of FLZ and its metabolites desalkylflurazepam (DA-FLZ), hydroxyethylflurazepam (ETOH-FLZ), and flurazepam aldehyde (CHO-FLZ) to overall clinical activity remain uncertain. A single 20 mg/kg dose of FLZ.HCl was administered to mice, with plasma and brain concentrations of FLZ and metabolites determined during 5 h after dosage. Brain and plasma concentrations of FLZ were maximal at 0.5 h after dosage, then declined rapidly in parallel, whereas those of DAFLZ were maximal at 2 h, then declined slowly. Concentrations of ETOH-FLZ, the most polar metabolite, were maximal at 0.5 h, and were undetectable after 3 h. Little CHO-FLZ was detected in either brain or plasma. A single 30-mg oral dose of FLZ.HCl was given to 18 human volunteers, with plasma levels determined over 9 days. FLZ was detected in plasma at low concentrations for no more than 3 h after dosage. ETOH-FLZ concentrations were higher and persisted for 8 h after dosage. CHO-FLZ reached intermediate peak levels and was present longer than FLZ or ETOH-FLZ. In contrast, DA-FLZ achieved the greatest peak concentrations, occurring at 10 h after dosage. Levels declined very slowly, with a mean half-life of 71.4 h, and were still detectable 9 days after FLZ dosage. Plasma free fractions (percent unbound) in mice were 40.3, 51.4, and 25.0% for FLZ, ETOH-FLZ and DA-FLZ, respectively; in humans, values were 17.2, 35.2, and 3.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. VI. Verapamil and fentanyl-pancuronium.

To assess the interaction between verapamil and fentanyl-pancuronium, dogs were chronically instrumented to measure heart rate; PR interval; aortic, left ventricular, and left atrial pressures; and coronary, carotid, and renal blood flows. The effect of fentanyl citrate infusion on single-dose verapamil pharmacokinetics was examined in six animals. The effects of verapamil infusion (3 micrograms.kg-1.min-1 and 6 micrograms.kg-1.min-1) were examined in the conscious state and during fentanyl infusion plus pancuronium on two separate occasions in nine dogs. In addition, the effects of fentanyl citrate (500 micrograms.kg-1 followed by 1.5 micrograms.kg-1.min-1) were examined over 1 h of infusion. Fentanyl infusion did not affect single-dose verapamil pharmacokinetics. In the conscious animals, verapamil increased heart rate and PR interval, and slightly decreased LV dP/dt. Fentanyl combined with pancuronium increased mean arterial pressure and LV dP/dt. During fentanyl infusion, verapamil decreased mean arterial pressure and LV dP/dt, increased PR interval, and did not change heart rate. The hemodynamic effects of fentanyl infusion were steady over 1 h. In contrast to the inhalational anesthetics, which alter verapamil pharmacokinetics and have mainly additive effects with verapamil on left ventricular contractility, cardiac conduction, and regional blood flows, fentanyl-pancuronium had no effect on verapamil pharmacokinetics and minimal effect on verapamil pharmacodynamics in healthy dogs.

Animals↗
PubMed1988

Amlodipine in elderly hypertensive patients: pharmacokinetics and pharmacodynamics.

Elderly (65-73 years) and young (28-34) hypertensive patients received amlodipine by i.v. infusion (2.5, 5.0, or 10.0 mg). Patients were then started on oral amlodipine 2.5 mg daily for 2 weeks, at the end of which amlodipine disposition and effect were evaluated over one 24-h dose interval. Patients were treated subsequently with amlodipine in an escalating dose protocol (maximum 10.0 mg once daily) for 12 weeks to control blood pressure. After i.v. amlodipine, clearance tended to be decreased in elderly as compared with young patients with resulting prolongation in elimination half-life (64 +/- 20 vs. 48 +/- 8 h; mean +/- SD). Maximum decrease in systolic blood pressure (SBP) after i.v. doses tended to be greater in the elderly (-34 +/- 15 vs. -23 +/- 15 mm Hg) and maximum decrease in diastolic blood pressure (DBP) was similar in the two groups (-21 +/- 10 vs. -18 +/- 7 mm Hg). SBP was significantly decreased after 14 weeks' therapy in the elderly at doses ranging from 2.5 to 10.0 mg per day (171 +/- 17 to 149 +/- 22 mm Hg; p less than 0.01). DPB was decreased both at 2 and 14 weeks' therapy in the elderly (baseline 100 +/- 7, 2 weeks 93 +/- 5, 14 weeks 90 +/- 5 mm Hg; p less than 0.01 vs. baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Effects of nifedipine on hepatic drug oxidation.

To determine whether inhibition of drug oxidation is a general property of all calcium antagonist drugs or just of a few, we measured effects of therapeutic doses of nifedipine on antipyrine biotransformation. Antipyrine was administered in random order to 10 subjects while drug-free and while taking nifedipine 30 mg 3 times daily. Total antipyrine clearance (means +/- SE, 43.1 +/- 4.8 control vs. 50.4 +/- 6.5 ml/min; NS) tended to increase but not significantly. Elimination half-life decreased slightly (13.7 +/- 1.0 control vs. 11.7 +/- 0.9; p less than 0.05). Antipyrine metabolite excretion, measured to evaluate selective oxidative pathways, was unaffected by concurrent nifedipine administration. Nifedipine in therapeutic doses had no effect on antipyrine oxidation, unlike verapamil and diltiazem, both of which inhibit hepatic drug oxidation. Inhibition of drug oxidation appears not to be a general property of calcium antagonist drugs.

Adult↗
PubMed1988

Pharmacokinetics of calcium antagonists under development.

Calcium antagonist drugs under clinical development are of the Type I (verapamil, diltiazem-like) and Type II (nifedipine-like) classes. Tiapamil, the only Type I drug currently available, is a high clearance, widely distributed drug which undergoes extensive presystemic elimination. Pharmacokinetically it is quite similar to verapamil; however, it does have increased biliary excretion and decreased binding to plasma proteins. Eight Type II (dihydropyridine) drugs are reviewed. Seven of these drugs (felodipine, isradipine, nicardipine, nilvadipine, nimodipine, nisoldipine and nitrendipine) are pharmacokinetically similar to nifedipine, with high clearance, extensive distribution, and significant presystemic elimination. Amlodipine has lower clearance, even greater peripheral distribution, and greatly decreased presystemic elimination. Three of the 8 dihydropyridines have been reported to have plasma protein binding greater than 90%. Unlike nifedipine, each dihydropyridine drug under development has an asymmetric centre; therefore each in fact is a racemic mixture. Human pharmacokinetic and pharmacodynamic data have not been reported for any of the racemates. Each of the drugs has been studied in patients with hepatic and renal disease. Predictably, patients with severe hepatic disease have decreased presystemic clearance and, in some cases decreased clearance after intravenous administration of the dihydropyridines, although renal failure has little influence on their pharmacokinetics. Unfortunately, disease-drug interaction studies of this class of drugs do not generally report plasma protein binding. The effect of age on the disposition of 2 of the dihydropyridines has been reported; however, only for nicardipine can a conclusion be drawn, namely that volume of distribution may increase with age and clearance may remain unchanged. A variety of potential drug-drug interactions have been evaluated, most commonly the effect of these drugs on cardiac glycoside disposition and effect, and the effect of cimetidine on the disposition of dihydropyridines. Tiapamil, like verapamil, impairs digoxin clearance significantly. Among the dihydropyridines, although minor pharmacokinetic effects have in some cases been reported, the magnitude of the interactions suggest they have limited clinical importance. From drugs currently under development, it is clear that a large number of calcium antagonists will soon be introduced into clinical use. Only 1 of the newer drugs, amlodipine, has significant pharmacokinetic differences from the agents currently in use, although possible pharmacodynamic differences among the drugs have been suggested.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Verapamil pharmacodynamics and disposition in obese hypertensive patients.

Verapamil (0.15 mg/kg) was administered by 10-min intravenous infusion to 12 obese (127 +/- 8 kg) and 11 normal weight (74 +/- 4 kg) hypertensive patients. All subjects were of similar age and without clinical or laboratory evidence of cardiac or renal dysfunction. Verapamil plasma concentrations were determined and pharmacokinetic parameters derived. Electrocardiographic P-R interval, used as a measure of A-V nodal conduction, mean blood pressure, and heart rate were determined simultaneously with blood sampling for 24 h following the dose. Elimination half-life was prolonged in obese patients (10.1 +/- 1.8 vs. 3.6 +/- 0.4 h; p less than 0.005) due to a marked increase in volume of distribution at steady-state (713 +/- 99 vs. 301 +/- 33 L; p less than 0.005) with no change in total verapamil clearance [1,339 +/- 180 obese vs. 1,250 +/- 147 ml/min; not significant (NS)]. Verapamil plasma protein binding was similar between groups (percent unbound, 4.8 +/- 0.5 obese vs. 5.1 +/- 0.5%; NS). Using a sigmoid Emax pharmacodynamic model, Emax (maximal prolongation in P-R interval) was unchanged in obesity (53.7 +/- 12.5 obese vs. 45.9 +/- 12.0 ms; NS). However, EC50 (verapamil concentration required to achieve 50% of Emax prolongation in P-R interval) was greater in obese patients (45.9 +/- 6.7 vs. 22.6 +/- 2.0 ng/ml; p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Liver injury due to verapamil.

A 56-year-old female patient on verapamil for hypertension experienced two episodes of jaundice, pruritus and upper abdominal pain with transaminase elevated up to six-fold and alkaline phosphatase up to four-fold when inadvertently re-challenged with the drug. Liver biopsy showed marked cholestasis. Verapamil can occasionally cause mixed cytotoxic-cholestatic liver injury.

Chemical and Drug Induced Liver Injury↗