Search PubMed⌕ Search

Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 253 records · Page 14Linked to original sources
PubMed1986

Influence of age, gender, and obesity on salicylate kinetics following single doses of aspirin.

Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (25-40 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (Vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.

Administration, Oral↗
PubMed1986

Enhanced bioavailability of triazolam following sublingual versus oral administration.

The rate and extent of the absorption of triazolam following sublingual and oral administration were evaluated in this study. Eight healthy volunteers received triazolam 0.5 mg in a commercially available tablet, by sublingual and oral routes on two occasions in random sequence. Plasma triazolam concentrations during 24 hours after each dose were measured by electron-capture gas-liquid chromatography. The mean total area under the curve for sublingual administration was significantly larger than that following oral dosage (28.9 vs 22.6 ng-hr/mL, P less than .025). The peak plasma concentration after sublingual dosage was also higher than after oral administration (4.7 vs 3.9 ng/mL, P less than .1). No significant differences between sublingual and oral administration were found for the elimination half-life of triazolam (4.1 vs 3.7 hr) and the time of peak concentration (1.22 vs 1.25 hr) after dose. Thus, the bioavailability of triazolam after sublingual administration is increased by an average of 28% compared with oral administration of the same dose, possibly because first-pass extraction is bypassed. Clinical effects of triazolam may likewise be enhanced by sublingual dosage.

Administration, Oral↗
PubMed1986

Interaction of diazepam with famotidine and cimetidine, two H2-receptor antagonists.

Famotidine is currently under investigation as an H2-receptor antagonist. Eleven healthy male volunteers received a single 10 mg intravenous dose of diazepam on three occasions: once during coadministration of famotidine 40 mg bid, once during coadministration of cimetidine 300 mg qid, and once without other drug treatment (control). Multiple blood samples were drawn during the seven days after each diazepam dose. Diazepam and desmethyldiazepam plasma concentrations were measured by electron capture gas chromatography. There were no significant differences among the three treatment conditions in diazepam central compartment volume or total volume of distribution. During the cimetidine as compared with the control treatment, diazepam elimination half-life was significantly increased (72 vs 55 hr, P less than .05), total area under the curve (AUC) increased (11.8 vs 9.8 hr-micrograms/mL, P less than .05), and total clearance reduced (0.20 vs 0.28 mL/min/kg, P less than .05). Seven-day AUC for desmethyldiazepam also increased (4.6 vs 3.8 hr-micrograms/mL, P less than .05). However, there were no significant differences between famotidine and control treatment conditions in diazepam elimination half-life (53 vs 55 hr), total AUC (9.5 vs 9.8 hr-micrograms/mL), or total clearance (0.28 vs 0.28 mL/min/kg) or in seven-day AUC for desmethyldiazepam (3.9 vs 3.8 hr-micrograms/mL). Thus, therapeutic doses of cimetidine significantly impair the clearance of diazepam and desmethyldiazepam. Therapeutic doses of famotidine do not impair diazepam and desmethyldiazepam kinetics, suggesting that there is no significant kinetic interaction when diazepam and famotidine are administered concurrently in clinical practice.

Adult↗
PubMed1986

The pharmacokinetics of diazepam and desmethyldiazepam in rat brain and plasma.

The pharmacokinetics of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) in both plasma and brain after a single 5 mg/kg IP dose of diazepam were studied in rats. Four rats were sacrificed at 5 min, 15 min, 30 min, 1 h, 1.5, 2, 3, 4, 5 and 6 h after the dose. DZ rapidly disappeared from plasma and brain in parallel, with nearly identical overall half-lives of 0.88 and 0.89 h, respectively. Apparent volume of distribution was 19.3 1/kg and the apparent total clearance was 255 ml/kg/min. Free fractions were 19.6% and 15.8% for DZ and DMDZ, respectively. DMDZ rapidly appeared in both plasma and brain. Thereafter, DMDZ was likewise eliminated in parallel from both compartments, with nearly identical half-lives of disappearance from plasma (1.11 h) and brain (1.09 h). The rapid elimination of DZ was due to its very high clearance. Brain to plasma concentration ratios did not differ significantly over time either for DZ or for DMDZ. The overall ratios (mean +/- SE) were 4.5 +/- 0.1 for DZ and 3.5 +/- 0.2 for DMDZ. Equilibrium was attained at no more than 5 min after dose for both DZ and DMDZ. No evidence was found for persistence or sequestration of DZ or DMDZ in brain longer than could be predicted on the basis of first-order exponential disappearance.

Animals↗
PubMed1986

Sedative effects and impaired learning and recall after single oral doses of lorazepam.

Seven healthy subjects received oral placebo, 1.5 mg lorazepam, or 3.0 mg lorazepam in a single-dose, three-way crossover study. Plasma lorazepam concentrations and subjects' self-rated sedative effects were evaluated at multiple points during 24 hours after each dose. Information acquisition and recall was studied by use of a 16-item word list at 3 and 24 hours after dosing. Lorazepam plasma concentrations were proportional to dose. Self-rated sedation was maximal 2 to 3 hours after lorazepam dosing, persisted for 8 hours, and was dose dependent in intensity; no significant sedation occurred with placebo. At 3 hours after placebo dosing, subjects learned a mean 96% of words presented during six trials; this was reduced to 79% and 62% after lorazepam, 1.5 and 3.0 mg, respectively (F = 6.2; P less than 0.02). Twenty-four hours after placebo, subjects recalled 92% of words presented the previous day, then improved to 99% after six relearning trials. After 1.5 and 3.0 mg lorazepam, however, only 52% and 44% of words were initially recalled from the previous day. Thus single oral doses of lorazepam within the therapeutic range produce dose-dependent sedation and impairment of information acquisition and recall.

Administration, Oral↗
PubMed1986

Obesity effects on nitrazepam disposition.

Nitrazepam pharmacokinetics were studied in 14 obese (mean +/- s.e. mean body weight 107 +/- 9 kg; percent ideal body weight [IBW] 166 +/- 12%) and 14 normal body weight (63 +/- 3 kg; percent IBW 98 +/- 2%) subjects. After an overnight fast, each subject ingested 10 mg nitrazepam orally. Nitrazepam concentrations were determined in plasma samples obtained over the following 72 h. Comparison of peak nitrazepam plasma concentration (94.2 +/- 10.3-obese vs 119 +/- 14.6 ng ml-1; NS) and time required after drug administration to reach peak concentration (1.52 +/- 0.24-obese vs 1.59 +/- 0.36 h; NS) indicated no differences between obese and control subjects. Elimination half-life was markedly increased in obese subjects (33.5 +/- 2.2 vs 23.9 +/- 1.2 h; P less than 0.001) due to increased apparent volume of distribution (Vd) (290 +/- 45 vs 137 +/- 12 l; P less than 0.005). Oral clearance was also increased in the obese subjects (101 +/- 12.4 vs 66.8 +/- 12.4 ml min-1; P less than 0.02). Extent of nitrazepam binding to plasma proteins was slightly decreased in obese subjects (% unbound--19.7 +/- 0.4-obese vs 17.9 +/- 0.3%; P less than 0.005). Correction of both Vd (2.62 +/- 0.17-obese vs 2.22 +/- 0.19 l kg-1; NS) and clearance (0.93 +/- 0.06-obese +/- 1.07 +/- 0.07 ml min-1 kg-1; NS) for total body weight (TBW) suggested that increases in obese subjects of both of these parameters were a function of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Population study of triazolam pharmacokinetics.

The kinetics of a single 0.5 mg oral dose of the triazolobenzodiazepine hypnotic triazolam, were studied in 54 healthy young men aged 20-44 years, with a mean body weight of 77 kg. Triazolam kinetics were determined from multiple plasma concentrations measured during 14 h post-dose. The overall mean +/- s.e. mean (with range) kinetic variables were: peak plasma concentration, 4.4 +/- 0.3 (1.7-9.4) ng ml-1; time of peak, 1.3 +/- 0.1 (0.5-4.0) h after dose; elimination half-life, 2.6 +/- 0.1 (1.1-4.4) h; total AUC: 19.1 +/- 1.1 (4.4-47.7) ng ml-1 h; oral clearance, 526 +/- 38 (175-1892) ml min-1. All kinetic variables were consistent with Poisson distributions, based on the Kolmogorov-Smirnov Goodness of Fit test. None of the variables fit normal distributions. Four of five were consistent with a log normal distribution. Peak plasma level was highly correlated with clearance (r = -0.85, P less than 0.0001), and AUC (r = 0.85, P less than 0.0001) but not with body weight (r = 0.21, NS). Clearance and body weight were not correlated (r = -0.01). Triazolam clearance may vary widely even within a homogeneous group of healthy young men.

Adult↗
PubMed1986

Kinetic and dynamic interaction of brotizolam and ethanol.

Thirteen healthy male volunteers ingested a single 0.25 mg dose of the thienodiazepine hypnotic, brotizolam, on two occasions: once with a typical social cocktail (containing 60 ml of vodka), and in a second trial with an 'ethanol-placebo' cocktail. Brotizolam kinetics were determined from multiple plasma concentrations measured during the 24 h after dosage. Coadministration of brotizolam with ethanol, as opposed to the placebo cocktail, slightly imparied brotizolam clearance (1.85 vs 2.19 ml min-1 kg-1 P less than 0.005), increased peak plasma concentrations (5.3 vs 4.3 ng ml-1, P less than 0.05), and prolonged elimination half-life (5.2 vs 4.4 h, P less than 0.05). There was evidence of impairment of performance, although not statistically significant, for the first 4-6 h after brotizolam dosage in the reaction time test, the digit-symbol substitution test, and a tracking task. None of these was enhanced by ethanol. In both trials, brotizolam produced significant increases in self-rated perceptions of sedation, fatigue, feeling 'spaced-out', and thinking slowed down. These effects were more intense during the brotizolam-ethanol as compared to brotizolam-placebo. In both trials, recovery was essentially complete by 6-8 h after dosage. Coadministration of brotizolam with ethanol produces a small but significant impairment of brotizolam clearance. Brotizolam produced self-rated perceptions of sedation and fatigue during 4-6 h after dosage, but objective impairment of psychomotor performance was minimal. Subjective perceptions of sedation were enhanced by ethanol coadministration, but the effects on psychomotor performance were not.

Adult↗
PubMed1986

Benzodiazepine hypnotic metabolism: drug interactions and clinical implications.

Benzodiazepines are the drugs of choice when initiating hypnotic therapy. Though the mechanism of benzodiazepine action in the central nervous system is similar for all drugs in this class, differences in absorption and pathway of elimination are associated with differences in observed clinical effect. After single-dose administration, onset of hypnotic effect is most closely related to rate of drug absorption and duration of effect is more closely associated with extent of drug distribution. Relative affinity of the individual benzodiazepine for the specific central nervous system binding site may also determine duration of action. During multiple-dose chronic therapy, route of metabolic biotransformation and elimination half-life assume more importance. An increased incidence of adverse drug effects due to high doses of accumulating benzodiazepines may be seen in the elderly and patients with central nervous system deficits or chronic liver disease. Benzodiazepine metabolic biotransformation and clearance is broken into three groups. Group 1--oxidative biotransformation; Group 2--high clearance drugs; Group 3--drug conjugation. Groups 1 and 2 are implicated in a number of drug-disease and drug-drug interactions. Group 3 drugs have little change in patients with liver disease or when administered with inhibitors of drug biotransformation. Clinical implications of these metabolic interactions are variable, but inhibition of Group 1 and 2 benzodiazepine clearance has been associated with increased sedation and psychomotor impairment.

Anti-Anxiety Agents↗
PubMed1986

Absence of interaction of cimetidine and ranitidine with intravenous and oral midazolam.

Eight healthy volunteers received a single 5-mg intravenous dose of the imidazobenzodiazepine derivative midazolam on three occasions in random sequence: a, control, with no other treatment; b, during coadministration of cimetidine, 300 mg every 6 hr; c, during coadministration of ranitidine, 150 mg every 12 hr. Midazolam kinetics in each trial were determined from multiple plasma midazolam levels measured by gas chromatography for 24 hr after each dose. High pressure liquid chromatography analysis of plasma also verified compliance with cimetidine (mean level, 0.61 microgram/ml) and ranitidine (mean level, 0.36 microgram/ml) regimens. Analysis of variance indicated no significant differences in mean values for trials a, b, and c in midazolam elimination half-life (2.25 vs 2.02 vs 2.05 hr), volume of distribution (2.13 vs 2.14 vs 2.16 L/kg) or total clearance (10.8 vs 12.2 vs 12.3 ml . min-1 . kg-1). In a second study, six subjects received a 15-mg oral dose of midazolam on three occasions identical to those described above. Again, there were no significant differences among trials a, b, and c in midazolam peak plasma level (90 vs 95 vs 117 ng/ml), time of peak level (0.65 vs 1.45 vs 0.90 hr after dose), elimination half-life (3.04 vs 3.38 vs 3.30 hr), or apparent oral clearance (16.2 vs 14.3 vs 13.8 ml . min-1 . kg-1). Thus the usual therapeutic doses of cimetidine or ranitidine do not significantly alter the kinetics of intravenous or oral midazolam in healthy individuals.

Administration, Oral↗
PubMed1986

Kinetics and dynamics of single doses of oxazepam in the elderly: implications of absorption rate.

Five healthy elderly volunteers aged 64 to 67 years and 12 healthy young subjects aged 23 to 44 years received single 30 mg oral doses of oxazepam in two different dosage forms (two 15 mg tablets or one 30 mg capsule) on two occasions in a random crossover sequence, with at least 1 week elapsing between trials. In both age groups, rate of oxazepam absorption of the capsule form of the drug was significantly slower than that of the tablets. Peak plasma concentrations were lower and were delayed longer with the capsule form; however, the relative extent of oxazepam absorption did not differ between preparations in either age group. Clinical self-ratings in the elderly group, based on visual analog scales, were consistent with the delayed onset of sedative effects that is associated with the capsule form of administration. Kinetic comparisons in the two groups indicated a significantly prolonged oxazepam elimination half-life with the tablet (p less than .001) and with the capsule (p less than .06) and a trend (p less than .08) toward reduced oxazepam clearance in the elderly. The delayed absorption of oxazepam from the capsule was found in both the young and elderly groups.

Administration, Oral↗