PubMed Health⌕ Search

Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 199 records · Page 11Linked to original sources
PubMed1989

Pharmacokinetic determinants of dynamic differences among three benzodiazepine hypnotics. Flurazepam, temazepam, and triazolam.

Healthy adult volunteers (n = 52) received single oral doses of flurazepam hydrochloride (15 mg), temazepam (15 mg), triazolam (0.25 mg), or placebo in a parallel, double-blind study. Sedative effects were greatest with triazolam, followed next by temazepam; peak effects closely coincided with peak plasma concentrations. Differential recovery from sedation corresponded in part to differences in mean elimination halflife, although sedative effects returned to baseline before plasma drug concentrations became undetectable. Sedation following flurazepam administration was less intense than with triazolam and temazepam. When tested at three hours after dosing, none of the active treatments impaired learning of a 16-item word list. However, at 24 hours, triazolam recipients could not recall a significant fraction of what was learned. Thus, dynamic differences among three benzodiazepine hypnotics may be partly explained by kinetic differences, as well as, we should caution, by possible "clinical inequivalence" in dosage.

Administration, Oral↗
PubMed1989

Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo.

Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1-minute infusion in a double-blind, three-way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepam's half-life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50 value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emax values were similar for both drugs (+19.4% and +21.3%, respectively).

Adult↗
PubMed1989

A large-sample study of diazepam pharmacokinetics.

Healthy male volunteers (n = 48) aged 18-44 years received a single 10-mg oral dose of diazepam. Plasma diazepam and desmethyldiazepam concentrations were measured at multiple points during the next 11 days. The distribution of peak plasma concentration (mean, 406 ng/ml) was not skewed and did not differ significantly from normal (Guassian). However, the distributions of elimination half-life (44.2 h), elimination rate constant (0.0219/h), clearance (26.6 ml/min), and volume of distribution (83 L) all were significantly skewed and deviated significantly fron normal. After logarithmic transformation, the distributions of elimination rate constant, elimination half-life, and volume of distribution were consistent with normal; however, this was not the case for time of peak plasma concentration. Thus, the pharmacokinetic characteristics of oral diazepam are highly variable even in a relatively homogeneous population. Parametric statistical testing procedures and pharmacokinetic forecasting schemes may be improved by more precise delineation of the underlying distributions for pharmacokinetic variables.

Adolescent↗
PubMed1989

Lorazepam discontinuation promotes 'inverse agonist' effects of benzodiazepines.

1. The effects of lorazepam discontinuation on responses to benzodiazepine agonists and antagonists were studied in mice. 2. The convulsant dose of pentylenetetrazol was decreased after an acute dose of lorazepam (0.5 mg kg-1) at 4 days after drug discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. 3. The percentage of mice undergoing convulsions after an acute dose of FG 7142 (40 mg kg-1) was increased at 4 days after lorazepam discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. 4. After an acute dose (0.5 mg kg-1), lorazepam concentrations in cortex tended to be greater in lorazepam-treated compared to vehicle-treated mice at 4 days after discontinuation compared to 1 and 7 days. 5. These data indicate a shift toward reduced agonist sensitivity and increased inverse agonist sensitivity in mice 4 days after lorazepam discontinuation.

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

Clearance of the antihistamine doxylamine. Reduced in elderly men but not in elderly women.

A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine concentrations were determined during a 30-hour period after each dose. Elderly and young women did not differ significantly in peak plasma doxylamine concentration (Cmax) [116 vs 103 micrograms/L], time to Cmax (tmax) [2.4 vs 2.4 h], elimination half-life (12.2 vs 10.1 h), volume of distribution (179 vs 176 L) or clearance (191 vs 218 ml/min). Cmax (107 vs 108 micrograms/L) and tmax (2.1 vs 1.6 h) also did not differ between elderly and young men. However, elderly men had reduced doxylamine clearance (174 vs 240 ml/min, p less than 0.02; 2.5 vs 3.2 ml/min/kg, p less than 0.07) and prolonged half-life (15.5 vs 10.2 h, p less than 0.05). The reduced doxylamine clearance and prolonged half-life in elderly men, but not in elderly women, is similar to results for many other drugs which are transformed by oxidation.

Adult↗
PubMed1989

Relationship of plasma and brain concentrations of caffeine and metabolites to benzodiazepine receptor binding and locomotor activity.

CD-1 mice were treated with caffeine-sodium benzoate solution (caffeine doses: 0, 5, 15 or 30 mg/kg i.p.) to determine plasma and brain concentrations, effects on benzodiazepine receptor binding based on specific uptake of a high affinity ligand, and locomotor activity. There was a linear relationship between caffeine dose and mean brain or plasma concentrations, but concentrations varied considerably at any given dose. There were also linear relationships between plasma and brain concentrations of caffeine and each metabolite, with caffeine itself having the greatest brain:plasma uptake ratio. Benzodiazepine receptor binding was determined based on uptake of the benzodiazepine receptor ligand [3H]Ro15-1788, 3 microCi i.v. given 40 min after caffeine (30 mg/kg). Nonspecific binding was measured in animals pretreated with saturating doses of clonazepam. Specific uptake (measured by subtracting nonspecific from total [3H] Ro15-1788 uptake) increased significantly with caffeine as opposed to vehicle treatment in the cortex, hippocampus and hypothalamus. Brain caffeine concentrations associated with enhanced uptake were between 11 to 17 micrograms/g. Total locomotor activity and activity at 60 min, measured by an infrared sensor system, increased progressively with brain caffeine concentrations when comparing the following groups: 0, 2 to 9 micrograms/g of brain and 9 to 20 micrograms/g. Animals with brain concentrations exceeding 20 micrograms/g showed a decline in both measures but activity was significantly greater than placebo. In conclusion, brain caffeine concentrations between 9 to 20 micrograms/g are associated with increases in specific ligand uptake and motor activity.

Adenosine↗
PubMed1989

Chronic benzodiazepine administration. III. Upregulation of gamma-aminobutyric acidA receptor binding and function associated with chronic benzodiazepine antagonist administration.

Chronic administration of a benzodiazepine agonist appears to downregulate benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptor function. To examine the effects of chronic treatment with a benzodiazepine antagonist, we administered Ro15-1788, 1, 2 and 5 mg/kg/day to mice via implanted s.c. osmotic pumps for 1 to 14 days. Plasma and cortex (CX) concentrations of Ro15-1788 remained constant between days 1 and 7, indicating no change in pharmacokinetics. Open-field activity studies showed no change in distance traveled or ambulatory time at days 1, 2 and 4, but an increase in both parameters at days 7 and 14 in mice receiving Ro15-1788, 2 mg/kg/day. Benzodiazepine receptor binding was unchanged in CX, cerebellum (CB), hypothalamus, hippocampus and ponsmedulla at 1, 2 and 4 days at a dose of 2 mg/kg/day. Binding was increased in CX, CB and hippocampus at day 7 compared to days 1 and 2, and remained elevated at day 14. Similar results were observed at Ro15-1788 doses of 1 and 5 mg/kg/day. Benzodiazepine binding assessed in vitro in CX and CB also was increased at day 7 compared to day 1, due to an increase in receptor number rather than a change in apparent affinity. Binding of t-[35S]butylbicyclophosphorothionate to the chloride channel site in CX after Ro15-1788, 2 mg/kg/day, was increased at days 7 and 14 compared to days 1, 2 and 4 and controls due to an increase in number of binding sites. t-Butylbicyclophosphorothionate binding in CB was unchanged throughout.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

"Dingelling".

Explore the source record for details and available documents.

Humans↗
PubMed1989

Kinetic and dynamic study of intravenous lorazepam: comparison with intravenous diazepam.

Six healthy volunteers received a single i.v. dose of 'low dose' lorazepam (0.0225 mg/kg), 'high dose' lorazepam (0.045 mg/kg) and placebo by 1-min infusion in a double-blind three-way crossover study. Plasma concentrations were measured 24 hr after dosage, and the EEG power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13-30-Hz range. Low and high dose lorazepam did not differ significantly in distribution volume (1.89 versus 1.81 l/kg) or elimination half-life (11.5 versus 12.2 hr); clearance was slightly although significantly reduced at the higher dose (2.08 versus 1.88 ml/min/kg, P less than .005). EEG effects were of relatively slow onset, reaching their maximum change over baseline 30 min after infusion. The duration of action was prolonged, with the fraction of EEG activity in the 13-30-Hz range still significantly above baseline 8 hr after the 0.045 mg/kg dose. Five of these subjects received 0.15 mg/kg of i.v. diazepam in a companion study of identical design. EEG effects of diazepam were shorter than those of lorazepam, probably because of the more rapid and extensive decline in plasma diazepam concentrations in the postinfusion distribution phase. In addition, the onset of diazepam's effect was immediate. In male CD-1 mice that received i.v. diazepam (8.3 mg/kg) or lorazepam (3.3 mg/kg), the brain:plasma concentration ratio was maximal 2.5 min after dosage for diazepam, but equilibration was delayed at least 30 min after dosage for lorazepam. Thus the slow onset of action of lorazepam is probably attributable to slow entry into brain.

Adult↗