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Biomedical subjects

W H Barr

Publications and source records attributed to W H Barr.

At least 37 records · Page 2Linked to original sources
PubMed1994

A pharmacokinetic evaluation of 14C-labeled afovirsen sodium in patients with genital warts.

Afovirsen sodium is a 20-mer phosphorothioate oligonucleotide designed to be complementary to the messenger ribonucleic acid sequence for the translation initiation codon of the E2 protein vital to replication of human papillomaviruses types 6 and 11. 14C-Labeled afovirsen was given as a single-dose intradermal injection in each of four warts of five patients to determine the time-dependent changes in concentration of intact afovirsen in genital warts and to determine the systemic absorption and elimination of radiolabeled compound. Intact afovirsen in genital warts was determined by high pressure liquid chromatography analysis of protease K digested extracts. Intact afovirsen was present in wart tissue for at least 72 hours at concentrations several times in excess of the estimated minimal inhibitory concentration of 1 mumol/L. Absorption of radiolabeled afovirsen from the injection site was rapid, with a peak plasma concentration achieved within 1 hour. Clearance of afovirsen was primarily attributable to slow metabolism, with about 30% of the radiolabel eliminated as 14C-CO2 in expired air over a 6-day period after dosing. Radioactivity eliminated in urine represented metabolites of afovirsen. From the clinical pharmacokinetic data presented here and from previously published pharmacokinetic data in rats, the disposition of afovirsen in humans appears to be relatively similar to that in rats. These data suggest that once or twice weekly dosing regimen in the clinic may be appropriate.

Adult↗
PubMed1994

Analysis of multiple-dose bioequivalence studies.

In multiple-dose bioequivalence studies, it is possible at steady state to take repeated measurements of pharmacokinetic variables, such as area under the curve (AUC) and the maximum concentration (CMAX) of the blood concentration-time profile, within each period of a crossover design. We develop a bivariate random effects model for such a situation in a 2 x 2 crossover design using the natural log scale for AUC and CMAX that assumes no differential carryover effects and includes components for inter- and intrasubject variability with respect to both formulations. We derive the uniformly minimum variance unbiased estimators, which also happen to be restricted maximum likelihood estimators, and we provide a sample size formula.

Cross-Over Studies↗
PubMed1993

Absorption of danazol after administration to different sites of the gastrointestinal tract and the relationship to single- and double-peak phenomena in the plasma profiles.

The absorption of danazol (100 mg) after oral or intraintestinal administration to the proximal jejunum or proximal ileum has been studied in healthy female subjects. The extent of danazol absorption after administration as a solubilized glycerol mono-oleate emulsion formulation was approximately twofold and fourfold greater after oral dosing when compared with jejunal or ileal administration, respectively. Although not statistically significant in this study, the extent of absorption after jejunal administration was generally greater than after ileal administration. After oral dosing, qualitative assessment identified the presence of double peaks or major shouldering characteristics in 14 of the 16 individual danazol plasma concentration-time profiles, whereas only single peaks were present after intraintestinal administration. These data are consistent with the double peaking phenomena after oral administration of the emulsion formulation being stomach-related. The double peaking effect may be explained in terms of a probable combination of gastric emptying regulated absorption (due to the presence of the lipid in the emulsion formulation) and the dependence of danazol solubility on bile salt solubilization within the upper small intestine.

Administration, Oral↗
PubMed1992

The site of gastrointestinal absorption of gepirone in humans.

This study was conducted in seven healthy male subjects and was performed over four sessions with a 1-week washout between sessions. It was designed to compare the bioavailability of an oral 20-mg gepirone dose (treatment 1) with that obtained after application of the same dose by gastric intubation to the distal (treatment 2) and proximal (treatment 3) regions of the small intestine, and after 4 consecutive 5-mg gepirone doses given orally at hourly intervals (treatment 4). Serial blood samples were taken over 24 hours after dose after each treatment. Plasma concentrations of gepirone and 1-(2-pyrimidinyl)-piperazine (1-PP), a metabolite of gepirone, were quantitated by gas chromatography-mass spectrometry. Mean gepirone time to reach peak concentration (tmax) after treatments 1, 2, and 3 ranged between 0.57 and 1.07 hours. There were no significant differences between sites and treatments for gepirone t1/2, which ranged between 2.8 and 3.3 hours. The mean gepirone maximum peak plasma concentration (Cmax) was significantly higher (P less than .05) after treatment 2 (12.92 +/- 7.24 ng/mL) compared with treatment 1 (6.79 +/- 3.54 ng/mL) or treatment 3 (6.33 +/- 2.26 ng/mL). Gepirone area under the curve (AUCinf) was also significantly higher (P less than .05) after treatment 2 (29.83 +/- 17.42 ng.h/mL) compared with treatment 1 (18.07 +/- 6.10 ng.h/mL) or treatment 3 (17.74 +/- 7.69 ng.h/mL). There were no significant differences in gepirone AUCinf between treatments 1 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

A correlation between digoxin plasma concentrations and systolic time intervals in hospitalized congestive heart failure patients.

Plasma digoxin level is at best an indirect measure of pharmacological response to digoxin in patients being treated for congestive heart failure. Systolic time interval (STI) measurement reflecting left ventricular function at the physiological site of action of digoxin, is both more direct and non-invasive. With a portable instrument to measure systolic time intervals, the measurement can also be convenient for hospital staff. A portable electrocardiogram (ECG) machine was modified to mimic the capabilities of a large, multichannel model. Upon satisfactory evaluation, it was employed in the collection of systolic time interval data from five hospitalized patients undergoing digoxin treatment. An attempt was made to show a relationship between STI indices and digoxin plasma concentrations. Additionally, a statistical comparison was made of change in STI (delta STI) and plasma digoxin concentration both before and after drug administrations. The change in pre-ejection period (delta PEP) values show a significant difference over the changes in total electromechanical systole (delta QS2) and the changes in left ventricular ejection time (delta LVET). In three congestive heart failure patients, the time course of the change in plasma concentration showed good correspondence with delta PEP.

Adolescent↗
PubMed1991

Cocaine inhalation in the rat: pharmacokinetics and cardiovascular response.

Despite the great attention given to the pharmacological actions of cocaine in recent years, the mechanisms leading to acute intoxication and related deaths after cocaine smoking have not been fully elucidated. The present study was therefore undertaken to examine the pharmacokinetics and pharmacological effects of cocaine by the inhalation route. Cannulated, male Sprague-Dawley rats were exposed to a constant concentration of cocaine vapor (13.6 +/- 0.4 micrograms cocaine per ml mainstream air), during which time their biodispositional profile and cardiovascular responses were evaluated. The bioavailable doses of cocaine were 0.26 +/- 0.05 and 1.54 +/- 0.46 mg/kg, after 1.5- and 5.0-min exposures, respectively. Peak cocaine plasma concentrations of 95 +/- 26 and 205 +/- 58 ng/ml, for the 1.5- and 5.0-min exposures, respectively, occurred 1 min after the start of exposure. Increasing the duration of exposure significantly increased the bioavailability from 0.29 to 1.03 (P less than .05). Transient changes in heart rate and arterial blood pressure were generally dose-dependent and correlated temporally with peak cocaine plasma concentrations. During exposure, 70% of the animals demonstrated electrophysiological aberrations consistent with atrial arrhythmia and incomplete heart block. These findings suggest that a direct cardiotoxic effect resulted from inhalation of cocaine.

Absorption↗
PubMed1989

Pharmacodynamic modeling of digoxin-induced bradycardia.

Digoxin-induced bradycardia in dogs was used to evaluate several pharmacodynamic models. Digoxin plasma concentrations and response were monitored in beagle dogs administered either 0.05 or 0.025 mg/kg of digoxin iv as an infusion over 5 min. The models investigated were the linking model, the linear model, the effect compartment model, and the inhibitory model. Regression procedures for investigating the effect compartment model were conducted with Emax (the maximal response, where response was the percentage decrease in heart rate) as a variable with an upper bound of 100%, with a constant value of 100%, or alternately with a constant value equal to the maximal observed response. Based on statistical criteria the effect model using Emax as a variable was found to be the best model for describing digoxin-induced bradycardia. For the effect compartment model, CPss(50) (concentration at steady state that will produce 50% of the maximal response) ranged from 3.8-9.8 ng/ml; delta (exponent describing the steepness of the concentration-response relationship) ranged from 0.6-7.1. The implication of these models in understanding concentration-effect relationships are discussed.

Animals↗
PubMed1986

Effect of ibuprofen on lithium plasma and red blood cell concentrations.

The effect of ibuprofen on steady-state lithium plasma and red blood cell concentrations was studied in 11 normal volunteers. During the seven-day control phase, sustained-release lithium carbonate 450 mg was administered every 12 hours. Lithium plasma and red blood cell concentrations were determined on days 5, 6, and 7. During the treatment phase (days 7-15), ibuprofen 400 mg was administered four times a day concurrently with lithium. Lithium plasma and red blood cell concentrations were obtained on days 14, 15, and 16. Multiple blood samples were obtained over a 12-hour period on days 6 and 15. Urine samples were collected from six subjects. The mean minimum lithium concentration increased 15% when ibuprofen was added. Mean maximum lithium concentration, area under the curve, red blood cell concentrations, and the lithium red blood cell to plasma ratio were significantly higher during the treatment phase. Mean lithium total body and renal clearance values were significantly lower during the treatment with ibuprofen. The administration of ibuprofen can increase steady-state plasma lithium concentrations and decrease lithium clearance.

Adult↗