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Biomedical subjects

D R Abernethy

Publications and source records attributed to D R Abernethy.

At least 127 records · Page 7Linked to original sources
PubMed1985

Pharmacologic properties of acebutolol: relationship of hydrophilicity to central nervous system penetration.

Studies in various animal models have shown acebutolol to be a relatively cardioselective beta-adrenoceptor-blocking agent possessing both partial agonist and membrane-stabilizing activities. The latter property may not be significant at clinically used doses. Acebutolol has both antihypertensive and antiarrhythmic effects. As with beta blockers in general, the antihypertensive mechanism of acebutolol is not known. The antiarrhythmic activity of acebutolol may be related to beta blockade. Acebutolol is relatively hydrophilic and does not readily cross the blood-brain barrier, a fact that may be clinically significant in reducing the frequency and severity of central nervous system adverse effects. The pharmacologic profile of diacetolol, acebutolol's major metabolite, is similar to that of the parent compound in beta-blocking potency, cardioselectivity, and partial agonist activity. Diacetolol, however, does not possess membrane-stabilizing activity.

Acebutolol↗
PubMed1985

Lack of interaction between verapamil and cimetidine.

Nine healthy normal subjects received verapamil, 10 mg iv, before (control) and during cimetidine dosing (300 mg every 6 hours), and verapamil, 120 mg po, twice in the same manner. After intravenous doses, the t1/2 (means +/- SE: control, 3.60 +/- 0.40 hours; cimetidine trial, 4.30 +/- 0.60 hours), volume of distribution (5.8 +/- 0.6 vs. 6.6 +/- 0.9 L/kg), and total clearance (19.2 +/- 1.5 vs. 18.4 +/- 1.6 ml/min/kg) did not change during cimetidine dosing. After oral doses, the t1/2 (4.25 +/- 0.57 vs. 4.60 +/- 0.70 hours), plasma AUC (585 +/- 113 vs. 506 +/- 82 ng/ml X hr) and absolute bioavailability (35% +/- 7% vs. 30% +/- 5%) did not differ between control and cimetidine trials, respectively. Five of the subjects also received lidocaine, 25 mg iv, once in the control state and once during the cimetidine regimen described above. Lidocaine clearance fell (665 +/- 216 vs. 527 +/- 134 ml/min; P less than 0.05) during cimetidine therapy, resulting in a trend toward a longer t1/2 (1.81 +/- 0.41 vs. 2.44 +/- 0.42 hours; 0.1 greater than P greater than 0.05) with no change in volume of distribution (1.77 +/- 0.66 vs. 1.99 +/- 0.81 L/kg). Verapamil pharmacodynamics (ECG PR interval, blood pressure, and heart rate) were evaluated after intravenous doses. A decrease in mean arterial pressure (8 +/- 1 vs. 9 +/- 2 mm Hg) and a reflex increase in heart rate (14 +/- 3 vs. 17 +/- 2 bpm) were no different in the control and cimetidine trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Age, sex, and nitrazepam kinetics: relation to antipyrine disposition.

Forty healthy men and women 19 to 80 years old received a single 10 mg oral dose of the 7-nitro benzodiazepine nitrazepam. Nitrazepam plasma concentrations were measured during the next 72 hours. Among men, the elderly had a larger volume of distribution (Varea) than did younger subjects (1.96 vs. 1.63 L/kg; P less than 0.05); because clearance did not change with age (0.84 vs. 0.95 ml/min/kg), the prolonged t1/2 in elderly men (28 vs. 20 hours; P less than 0.01) was a result of the larger Varea. Elderly and young women did not differ in nitrazepam Varea (2.58 vs. 2.55 L/kg), t1/2 (26 vs. 27 hours), or total clearance (1.19 vs. 1.09 ml/min/kg). The nitrazepam free fraction in plasma (18% to 19% unbound) was not related to age or sex. Among 18 subjects who also received antipyrine, the clearance of nitrazepam and antipyrine were not correlated (r = 0.23). Thus age minimally influences nitrazepam clearance (accomplished mainly by nitroreduction), which in turn is not significantly related to antipyrine oxidizing capacity.

Administration, Oral↗
PubMed1985

Interaction of propoxyphene with diazepam, alprazolam and lorazepam.

Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half-life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min-1 kg-1). Propoxyphene significantly prolonged alprazolam half-life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min-1 kg-1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half-life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min-1 kg-1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N-demethylation, and has no apparent influence on lorazepam conjugation.

Adult↗
PubMed1985

An investigation of the cause of accumulation of verapamil during regular dosing in patients.

The accumulation of verapamil during regular dosing conditions was studied. Plasma concentrations of verapamil (V) and norverapamil (NV) were measured as were urinary concentrations of verapamil, norverapamil, and four other N- and O-dealkylated metabolites in nine patients after an initial single dose and after chronic oral verapamil administration to steady-state plasma concentrations. Indocyanine green (ICG) clearance was determined immediately prior to the initial verapamil dose and prior to the verapamil washout from regular dosing. An approximately two-fold accumulation of V had occurred during regular dosing. The area under the plasma concentration-time curve (AUC1) after the first dose was 417.4 +/- 276.7 ng ml-1 h (mean +/- s.d.) and increased to 786.5 +/- 54 ng ml-1 h (P less than 0.01) during one dosage interval at steady-state (AUCss). NV also tended to accumulate from an AUC1 of 552.6 +/- 411 to an AUCss 668.7 +/- 332 ng ml-1 h (P less than 0.09). The ratio of AUC-V to AUC-NV was unchanged. The verapamil elimination half-life (t 1/2) increased from 8.4 +/- 4.2 to 12.0 +/- 3.6 h (P less than 0.01) whereas the norverapamil t 1/2 was unchanged. ICG clearance was unchanged. Urinary excretion of NV increased slightly but the ratio of urinary V/NV concentrations was not significantly altered nor was the ratio of four other metabolites to verapamil or the ratio of the combined o-demethylated to the N-dealkylated metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Caffeine disposition in obesity.

Caffeine pharmacokinetics were studied in 16 obese (mean +/- s.e. mean body weight; 110 +/- 8 kg; % ideal body weight (IBW); 186 +/- 14%) and 23 normal body weight (64 +/- 3 kg; 103 +/- 3% IBW) subjects. Eight obese and four control subjects were cigarette smokers. After abstaining from caffeine for 48 h and an overnight fast, each subject ingested 162 mg caffeine orally. Concentrations of caffeine were measured in plasma samples obtained during the 24 h following the dose and pharmacokinetic variables were determined. The apparent volume of distribution was increased markedly in obese subjects (69.9 +/- 5.9 vs 43.6 +/- 2.8 l; P less than 0.001) in the absence of any change in oral clearance (135 +/- 14-obese vs 112 +/- 12 ml/min; NS), resulting in a trend toward increased elimination half-life (7.05 +/- 1.08-obese vs 5.40 +/- 0.40 h; NS). Apparent volume of distribution correlated well with percent IBW (r = 0.65; P less than 0.001). Caffeine clearance, suggested as a measure of in vivo cytochrome P-448 activity in humans, was not altered in obesity. In contrast, the extent of caffeine distribution increased in direct relation to body weight. If caffeine is used therapeutically, the loading dose should be calculated as a function of total body weight. Since clearance of caffeine is not related to body weight, these data indicate that a chronic dosing regimen to maintain a given plasma caffeine concentration should not be altered due to obesity.

Adult↗
PubMed1985

Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: relation to lipid solubility.

In an anaesthetized dog model, serum kinetics and CSF entry were determined after i.v. administration of the following 8 drugs: salicylic acid (as acetylsalicylic acid), antipyrine, acetaminophen (paracetamol), lidocaine (lignocaine), trimipramine, amitriptyline, haloperidol, and imipramine. Kinetic variables were evaluated in relation to in-vitro lipophilicity, measured by the reverse-phase high-pressure liquid chromatographic (HPLC) retention index. After correction for individual values of serum binding (determined as the CSF: serum ratio at equilibrium), in-vivo volume of distribution was highly correlated with HPLC retention (r = 0.92). Conversely, the time of peak CSF concentration and the CSF entry half-life were negatively correlated with HPLC retention (r = -0.83 and -0.63, respectively). Thus lipophilicity is a physiochemical property which has an influence on the peripheral distribution of drugs as well as their rate of entry into CSF.

Animals↗
PubMed1985

Methodologic factors influencing plasma binding of alpha-1-acid glycoprotein-bound and albumin-bound drugs.

Plasma binding of imipramine and lidocaine, two drugs that bind predominantly to alpha-1 acid glycoprotein (AAG), and of diazepam and phenytoin, albumin-bound drugs, were studied in fresh human plasma. Binding was determined by equilibrium dialysis with 0.1 M pH 7.4 phosphate buffer at 37 degrees C. AAG was determined by immunodiffusion. Lidocaine free fraction (FF) (30-35%) was time-dependent, reaching equilibrium by five hours. However, dialysis time exceeding 8 hours greatly increased lidocaine FF (60%) accompanied by a decrease in AAG concentration. Lidocaine binding and AAG-concentration were not affected by plasma freezing, and were independent of lidocaine concentrations from 0.5-10 micrograms/ml. Imipramine behaved comparably, with FF increasing from 15% at 5 hours of dialysis to 30% at 24 h, concurrent with a drop in AAG concentration. Imipramine binding and AAG concentration were also independent of plasma freezing and drug concentration from 0.25 to 10.0 micrograms/ml. Binding of diazepam (FF = 1.2%) and phenytoin (FF = 17%) were stable at 24 hours, not affected by sample freezing or drug concentration, and were independent of AAG concentration. Therefore, changes in AAG concentration alter plasma protein binding of AAG-bound drugs lidocaine and imipramine. Extended dialysis results in decreased concentrations of immunoreactive AAG and increased FF. In contrast, the binding of albumin-bound drugs diazepam and phenytoin are not affected by these variables.

Dialysis↗
PubMed1985

Imipramine and desipramine disposition in the elderly.

Forty-six healthy male and female volunteers aged 21 to 88 received single 12.5-mg i.v. doses of imipramine, and 35 of these people received single 50-mg p.o. imipramine doses on a different occasion. Thirty-five similar volunteers received single 50-mg p.o. desipramine doses. Among these subjects 25 participated in studies of both imipramine and desipramine. Kinetic variables for the respective drugs were determined from multiple plasma drug concentrations from samples obtained during 96 hr after the dosage. Imipramine half-life was markedly prolonged in elderly vs. young males (28.6 vs. 16.5 hr; P less than .001) and females (30.2 vs. 17.8 hr; P less than .01) due to decreased clearance (males: 567 vs. 945 ml/min, P less than .01; females: 599 vs. 975 ml/min, P less than .005) with no change in volume of distribution. After p.o. imipramine doses time to peak imipramine concentration was shorter in elderly females (2.1 vs. 4.8 hr; P less than .005) but no different in males. Peak concentration achieved was greater in the elderly of both sexes (males: 40.2 vs. 19.5 ng/ml, P less than .005; females: 44.7 vs. 10.4 ng/ml, P less than .01). Comparison of p.o. and i.v. imipramine doses indicated no difference in absolute bioavailability between the elderly and young of either sex. In contrast, after p.o. desipramine more limited age-related changes were noted. Desipramine half-life was slightly prolonged in elderly males (30.8 vs. 21.2 hr; P less than .05) apparently related to a nonsignificant decrease in p.o. clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Probenecid impairment of acetaminophen and lorazepam clearance: direct inhibition of ether glucuronide formation.

Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1984

Clinical importance of the interaction of diazepam and cimetidine.

Cimetidine is known to impair the hepatic microsomal oxidation of diazepam, reducing its clearance and prolonging its half-life. We studied the clinical importance of this effect in 10 patients, who were receiving long-term treatment with diazepam for anxiety, tension, or difficulty in sleeping, in an eight-week double-blind controlled study during which the diazepam dosage remained constant. The study was in four two-week phases: base-line or adaptation, coadministration of cimetidine (300 mg) or matching placebo four times daily, crossover to the opposite treatment (placebo or cimetidine), and recovery treatment with diazepam alone. During the cimetidine phase, plasma concentrations of diazepam plus desmethyldiazepam rose an average of 57 per cent (P less than 0.005), then fell when cimetidine was withdrawn. However, there were no significant changes in scores on the digit-symbol-substitution test, a tracking task, or a reaction-time test. Clinical self-ratings indicated no increases in sedation, fatigue, or drowsiness. Patients experienced shortening of sleep latency (P less than 0.05) and an increase in self-rated depth or soundness of sleep (P less than 0.001) during the cimetidine period, but there were no changes in sleep duration or in the number of nocturnal awakenings. Although coadministration of cimetidine to diazepam-treated patients causes a large increase in plasma diazepam and desmethyldiazepam concentrations, the increase is of minimal clinical importance.

Adult↗
PubMed1984

Lidocaine disposition in obesity.

Fourteen obese men (mean weight 124 +/- 8 kg (+/- standard error of the mean), percent ideal body weight (IBW) 169 +/- 10%), 11 obese women (96 +/- 6 kg; 174 +/- 11% IBW), 19 control men (69 +/- 1 kg; 93 +/- 2% IBW), and 12 control women (59 +/- 2 kg; 102 +/- 3% IBW), all of similar age and without clinical or laboratory evidence of cardiac or renal dysfunction, received a single 25-mg intravenous dose of lidocaine. Elimination half-life was markedly prolonged in obese compared with control men (2.69 +/- 0.2 vs 1.62 +/- 0.06 hour, p less than 0.001) and in obese compared with control women (2.95 +/- 0.1 vs 2.08 +/- 0.06 hour, p less than 0.01). This was not the result of a change in clearance (men, obese vs control: 1,427 +/- 117 vs 1,346 +/- 86 ml/min, difference not significant, [NS]; women: 1,089 +/- 83 vs 1,162 +/- 84 ml/min, NS), but rather of an increased absolute volume of distribution (Vd) in obese men (325 +/- 29 vs 186 +/- 12 liters, p less than 0.001) and obese women (264 +/- 20 vs 209 +/- 15 liters, p less than 0.025). Vd corrected for total body weight was unchanged in obesity for both men (2.67 +/- 0.22 vs 2.71 +/- 0.18 1/kg, NS) and women (2.88 +/- 0.31 vs 3.57 +/- 0.25, NS), suggesting that lidocaine Vd increases in parallel with body weight in both sexes. Because lidocaine clearance is determined mainly by hepatic blood flow, these findings suggest that extremes of body weight do not change hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Pharmacokinetic studies on Ro 15-1788, a benzodiazepine receptor ligand, in the brain of the rat.

Methods for determining Ro 15-1788 in brain tissue were developed using gas chromatography with nitrogen-phosphorus detection, and using reverse-phase high performance liquid chromatography. Application of the methods to pharmacokinetic studies in the rat found the elimination half-life of Ro 15-1788 from rat brain to be 16 min. Ro 15-1788 was undetectable in rat plasma at the time points studied. Concentrations of Ro 15-1788 in the brain were reduced if chlordiazepoxide was coadministered.

Animals↗
PubMed1984

Interaction of cimetidine with oxazepam, lorazepam, and flurazepam.

The influence of cimetidine coadministration, 300 mg every 6 hours, on the kinetics of single oral doses of oxazepam (30 mg), lorazepam (2 mg), and flurazepam (30 mg) was evaluated in healthy volunteers. Cimetidine had no significant effect on the peak plasma concentration or the time of peak concentration for either oxazepam, lorazepam, or desalkylflurazepam (formed from flurazepam). Cimetidine likewise did not alter the elimination half-life of oxazepam (9.4 hours) or lorazepam (11.6 hours), and did not change total AUC for lorazepam. Oxazepam AUC was increased an average of 10 per cent by cimetidine (P less than 0.02). In contrast, cimetidine prolonged desalkylflurazepam elimination half-life (141 vs. 94 hours, P less than 0.1) and increased AUC an average of 65 per cent (P less than 0.05). Thus, cimetidine has little or no influence on the absorption or disposition of oxazepam and lorazepam, two benzodiazepines biotransformed by glucuronide conjugation. However, cimetidine slows the elimination of flurazepam's metabolite, desalkylflurazepam, which is biotransformed by oxidation.

Adult↗
PubMed1984

Noninteraction of temazepam and cimetidine.

The possible kinetic interaction of the hypnotic temazepam and the H2-receptor antagonist cimetidine was evaluated. Nine healthy male and female volunteers received a 30-mg oral dose of temazepam on two occasions in random sequence, separated by at least 1 week. On one occasion, temazepam was given in the otherwise drug-free state; on the other, temazepam was given with concurrent administration of cimetidine, 300 mg every 6 h. Mean pharmacokinetic parameters for temazepam in control versus cimetidine trials were: peak plasma concentration, 560 versus 498 ng/mL; time of peak concentration, 2.0 versus 2.1 h after the dose; volume of distribution, 1.30 versus 1.39 L/kg; elimination half-life, 9.9 versus 11.4 h; total clearance, 1.59 versus 1.60 mL/min/kg; free fraction of temazepam in plasma, 4.1 versus 3.8% unbound. Cimetidine has been shown to reduce the metabolic clearance of the benzodiazepines that are biotransformed by oxidative mechanisms. Temazepam, transformed by conjugation, appears unaffected by the coadministration of cimetidine.

Adult↗