Biomedical subjects

R A Boyd

Publications and source records attributed to R A Boyd.

27 records · Page 2Linked to original sources

PubMed1996

Pharmacokinetics of a 7-day 17 beta-estradiol transdermal delivery system: effect of application site and repeated applications on serum concentrations of estradiol and estrone.

FemPatch (Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI), a new 7-day 17 beta-estradiol transdermal delivery system (TDS), has been developed for treatment of menopausal vasomotor symptoms. This two-period crossover study was conducted to determine the effects of TDS application site (buttocks versus abdomen) and early TDS replacement on estradiol and estrone concentrations, and to quantify intersubject and intrasubject pharmacokinetic variability. Eighteen healthy, postmenopausal female volunteers received a single 7-day TDS application to the abdomen and repeated TDS applications to the buttocks (regular replacement on days 7 and 14, intentional early replacement on day 17, and removal on day 21). Serial serum samples were assayed for estradiol and estrone by validated radioimmunoassay methods. The 7-day TDS delivers estradiol at a constant, near zero-order rate for the duration of application, independent of application site. Mean serum estradiol concentrations were higher after application to the buttocks than after application to the abdomen (19 and 15 pg/mL above baseline, respectively), making the buttocks the preferred site for TDS application. Mean serum concentration of estradiol was slightly higher (23 pg/mL above baseline) for the treatment week with early TDS replacement due to the transient increase in concentration over the first 24 hours after replacement. Parallel but smaller increases in concentrations of estrone were observed. Serum estradiol and estrone concentrations are reproducible within an individual from application to application (coefficient of variation, 25%). Variability between individuals was higher (coefficient of variation, 40-50%).

Abdomen↗

PubMed1992

Phase I and pharmacokinetic study of the novel platinum analogue CI-973 on a 5-daily dose schedule.

CI-973, a platinum(II) derivative with a 2-methyl-1,4-butanediamine carrier ligand, has activity in cisplatin-resistant tumor models in vitro and in vivo. In a Phase I pharmacokinetic study, 31 patients were treated with CI-973 (24 to 50 mg/m2/day for 5 days; 28-day cycles) given i.v. over 30 min without routine antiemetic prophylaxis or hydration. Of the 29 patients evaluable for maximum tolerated dose determination, most had a performance status of 0 or 1, and most had received prior chemotherapy. Neutropenia was dose limiting at 40 and 50 mg/m2/day. Recovery from neutropenia was generally rapid with nadir counts and recovery usually occurring by Days 15 and 22, respectively. Drug-associated thrombocytopenia was uncommon and never severe, even in patients with Grade 4 neutropenia. Anemia was common, but did not appear dose related. Drug-related nausea and vomiting and changes in renal function were relatively infrequent and mild. No clinically evident ototoxicity was reported, although changes in audiograms were noted in several patients. CI-973 concentrations were measured in plasma ultrafiltrate and urine by high-pressure liquid chromatography. The harmonic mean terminal half-life was 2.0 h. The mean CI-973 renal and nonrenal clearance values were 42.3 and 37.4 ml/min/m2, respectively. The mean recovery of CI-973 in urine was 53% of the administered dose. The mean ratio of CI-973 renal clearance to creatinine clearance was 0.92. Total clearance correlated with creatinine clearance (r2 = 0.63). A relationship between toxicity, expressed as the percentage of reduction in absolute granulocyte count, and area under the CI-973 plasma concentration-time curve was found in a subgroup of "good-risk" patients. This relationship, described well by a sigmoidal Emax pharmacodynamic model, did not hold for patients with extensive prior therapy or poor performance status. A model for toxicity prediction based on dose and creatinine clearance has been derived and will be validated in future studies. The recommended Phase II dose of CI-973 is 30 mg/m2/day for 5 days.

Adolescent↗

PubMed1991

Effect of probenecid on the pharmacokinetics and pharmacodynamics of procainamide.

Renal tubular transport of organic anions and cations is assumed to be mutually exclusive. However, results of a number of in vitro and in vivo studies suggest an interaction between the organic anion, probenecid, and various organic cations in the proximal renal tubule. To evaluate the clinical importance of such an interaction, the authors investigated the pharmacokinetics and pharmacodynamics of procainamide, an organic cation with a low therapeutic index that is excreted in part by active secretion in the proximal tubule, in the presence and absence of probenecid. In a randomized crossover study, six healthy subjects received a single 750-mg IV dose of procainamide, with and without prior probenecid administration (2 g orally). Blood and urine samples were obtained and pharmacokinetic parameters of procainamide were determined in each treatment period. QT intervals were measured from ECG recordings that were obtained at blood collection times for pharmacodynamic evaluation. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different (488 +/- 95 mL/min without probenecid vs. 478 +/- 69 mL/min in the presence of probenecid). Our data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exit. Reasons for this lack of interaction are discussed.

Adult↗

PubMed1989

The pharmacokinetics and pharmacodynamics of diltiazem and its metabolites in healthy adults after a single oral dose.

A potential complicating factor in the characterization of the pharmacokinetics and pharmacodynamics of diltiazem after an oral dose in the presence of two metabolites, N-demethyldiltiazem and desacetyldiltiazem, in plasma. Both N-demethyldiltiazem and desacetylditiazem have been shown to have pharmacologic activity in animal tissues. It is therefore possible that these metabolites contribute to the pharmacologic effect of diltiazem, but this possibility has not been explored. The purpose of this study was to investigate the pharmacokinetics and pharmacodynamics of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem. Particular attention was paid to the effect of diltiazem on atrioventricular conduction. Six healthy men received a 120 mg oral dose of diltiazem. Concentrations of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem in plasma and urine were measured by a sensitive HPLC method. Measures of pharmacologic response (heart rate, blood pressure, and PR interval) were obtained at each blood sampling time. Mean (+/- SD) peak plasma concentrations of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem were 174.3 +/- 72.7, 42.6 +/- 10.0, and 14.9 +/- 3.3 ng/ml, respectively. The apparent half-lives of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem were 6.5 +/- 1.4 hours, 9.4 +/- 2.2 hours, and 18 +/- 6.2 hours, respectively. Both N-demethyldiltiazem and diltiazem were eliminated by net secretion, whereas the renal clearance of desacetyldiltiazem did not exceed clearance by filtration. Both N-demethyldiltiazem and desacetyldiltiazem are bound to plasma proteins, with unbound fractions of 0.323 +/- 0.035 and 0.230 +/- 0.021. These values are similar to the unbound fraction of diltiazem (0.254 +/- 0.027). No significant effect of diltiazem on blood pressure or heart rate was noted. However, a prolongation of the PR interval was observed in all six subjects. Furthermore, an apparent clockwise hysteresis in the concentration-effect relationship was found in four of the six subjects. These findings suggest that some form of acute tolerance to the electrophysiologic effect of diltiazem develops, but the results of pharmacodynamic modeling suggest that this is not caused by the antagonistic effects the metabolites.

Administration, Oral↗

PubMed1989

The pharmacokinetics of the enantiomers of atenolol.

A number of studies have demonstrated that lipophilic beta-adrenoceptor blocking agents, eliminated almost exclusively by hepatic metabolism, are stereoselectively metabolized in human beings. Previous studies in our laboratory have demonstrated that pindolol, a beta-adrenoceptor blocking agent of intermediate lipophilicity that is eliminated by both hepatic metabolism and renal excretion, is eliminated stereoselectively in the kidney. In the present study we examined the pharmacokinetics of the enantiomers of atenolol, a hydrophilic cardioselective beta-adrenoceptor blocking agent that is eliminated almost exclusively by the kidney. A single 100 mg oral dose of racemic atenolol was administered to six healthy adult men. Concentrations of d- and l-atenolol in plasma and urine were measured by a stereospecific HPLC analytic procedure. In each subject the peak concentration of d-atenolol was greater than the peak concentration of l-atenolol (mean +/- SD of 420 +/- 81 ng/ml vs 366 +/- 61 ng/ml; p less than 0.05). The peak concentration of both enantiomers was reached at the same time in each subject (between 2 and 3 hours). The renal clearances of d- and l-atenolol were not significantly different (109.7 +/- 33.5 ml/min vs 112.5 +/- 36.7 ml/min), probably because the major route of renal elimination is glomerular filtration. The half-lives of d- and l-atenolol were not significantly different (mean +/- SD of 4.6 +/- 1.1 hours vs 5.2 +/- 0.9 hours). However, both the AUC and the amount excreted unchanged in the urine in 24 hours Ae [0-24]) were significantly greater for d-atenolol than for l-atenolol (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

The effect of probenecid on the renal elimination of cimetidine.

It is generally assumed that the systems involved in the transport of organic cations and organic anions in the renal proximal tubule are substrate selective (i.e., organic anions do not inhibit organic cation transport and vice versa). However, recent data obtained in vitro have suggested that the organic anion probenecid inhibits the renal transport of the organic cation cimetidine. We addressed the question of whether this interaction is biologically relevant in human beings. The study involved a two-treatment, randomized crossover design. Six healthy male subjects were given an intravenous infusion of 300 mg cimetidine alone as one treatment and, as the other treatment, received multiple oral doses of probenecid before receiving the cimetidine infusion. The renal clearance of cimetidine and inulin was determined in each period. There were no significant differences between treatments in cimetidine plasma concentrations, apparent volume of distribution, systemic clearance, half-life, amount of drug excreted unchanged in the urine, or nonrenal clearance. Probenecid significantly decreased the renal clearance of cimetidine by decreasing both the filtration clearance and the net secretory clearance. These effects were most evident in the first 1/2 to 1 hour after cimetidine administration, when probenecid levels in plasma and renal tissue would have been the highest. Because there was no effect of probenecid on cimetidine plasma concentrations, this interaction is not clinically relevant to the therapeutic use of these two compounds. However, the study demonstrates that renal interactions between organic cations and organic anions can occur in human beings. The mechanism of this interaction and the implications to other drug combinations are being explored.

Adult↗

PubMed1988

Species differences in the negative inotropic response of 1,4-dihydropyridine calcium channel blockers in myocardium.

To determine if species differences exist in myocardial response to 1,4-dihydropyridine (DHP) calcium channel blockers, the binding and pharmacologic responses of a series of DHP compounds were examined in both rat and rabbit myocardium. [3H]Nitrendipine was used to label specific binding sites in myocardial membrane particulates. The results of saturation binding experiments (n = 3) indicated no statistically significant difference in either Kd or Bmax between rat and rabbit myocardial membranes (0.19 +/- 0.02 nM and 157 +/- 29 fmol/mg protein in rat and 0.14 +/- 0.06 nM and 227 +/- 125 fmol/mg protein in rabbit). Furthermore, [3H]nitrendipine binding inhibition experiments using 12 unlabeled DHP analogues yielded Ki values for each compound that were almost identical in myocardium from rat and rabbit, resulting in an excellent 1:1 correlation when data for all of the compounds were compared (r = 0.997, p less than 0.001). The negative inotropic effect of five of these DHP compounds was studied in vitro in isolated right papillary muscles from rabbit and right ventricular strips from rat, and concentration required to displace 50% of ligand binding (IC50) values for inhibition of contraction were determined. The IC50 values were significantly greater in rat myocardium than in rabbit myocardium (p less than 0.003). Therefore, a significantly lower potency of DHP calcium channel blockers has been demonstrated in rat compared with rabbit myocardium, and this species difference cannot be explained by a difference in the DHP binding site. Rat myocardium differs from rabbit myocardium in a number of ways that may explain this lower potency.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Comparison of binding affinities and negative inotropic potencies of the 1,4-dihydropyridine calcium channel blockers in rabbit myocardium.

The binding and pharmacologic response of a series of 1,4-dihydropyridine analogs were examined in rabbit myocardium. [3H]Nitrendipine was used to label specific binding sites in myocardial membrane particulates and displacement experiments were carried out with the unlabeled analogs to determine their IC50 values. Binding of [3H]nitrendipine could be characterized by a Kd of 0.15 +/- 0.06 nM and a maximum number of binding sites of 247 +/- 150 fmol/mg of protein. Saturation binding experiments performed with higher concentrations of [3H]nitrendipine did not reveal the presence of a lower affinity site. Binding IC50 values of 12 unlabeled 1,4-dihydropyridine analogs ranged from 4.3 X 10(-10) M to 1.32 X 10(-6) M. The negative inotropic effect of the same compounds was studied in vitro in isolated papillary muscles and the IC50 values for inhibition of contraction determined. There was a statistically significant correlation between the IC50 values for binding and response (r = 0.79, P less than .005; rs = 0.78, P less than .005). Consistent with previous studies with several of these compounds, the response IC50 value for each compound was greater than the binding IC50 value. For most of the compounds, this difference was from one to two orders of magnitude. For three compounds, nitrendipine, nimodipine and nicardipine, this difference reached three orders of magnitude. These three dihydropyridine analogs share structural features that may determine their low myocardial potency and, at the same time, their high vascular smooth muscle potency. Elucidation of these structural features may be useful in determining which analogs will have the highest vascular smooth muscle selectivity.

Animals↗

PubMed1980

Neuropsychologic decrements as a function of alcohol intake in male students.

Drinking history and sober neuropsychologic performance were examined in 45 male university students between the ages of 21 and 30 yr. Sober performance on the Shipley-Hartford Institute of Living Scale was significantly and inversely related to the amount of alcohol consumed per drinking event. Neither frequency of drinking nor lifetime alcohol consumption were significantly related to cognitive performance in controlled multiple regression equations. These findings emphasize the need for more information about the effects of social drinking on health.

Adult↗