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Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 307 records · Page 17Linked to original sources
PubMed1983

Alprazolam kinetics in the elderly. Relation to antipyrine disposition.

The pharmacokinetics of alprazolam, a triazolobenzodiazepine anxiolytic-antidepressant, were assessed in 32 healthy men and women aged 21 to 78 years after a single 1.0-mg oral dose. Peak alprazolam levels averaged 20.4 ng/mL and were reached a mean of 1.25 hours after dosage. Mean elimination half-life did not differ significantly between elderly and young women, nor did total metabolic clearance. However, half-life was significantly prolonged, and total clearance significantly reduced, in elderly v young men. Antipyrine oxidizing capacity was also evaluated, and half-life for the two drugs was highly correlated, as were their metabolic clearances. Thus, old age is associated with impaired capacity to oxidize alprazolam, but this effect is far more apparent in men than in women. A test of antipyrine half-life and clearance may help identify slow or rapid metabolizers of alprazolam.

Adult↗
PubMed1983

Long v short half-life benzodiazepines in the elderly. Kinetics and clinical effects of diazepam and oxazepam.

Oxazepam and diazepam were compared in healthy elderly volunteers. Absorption of diazepam was faster than oxazepam and onset of clinical effects were more profound. Diazepam accumulation was extensive, washout was slow and active compounds were present two weeks after the last dose. Oxazepam accumulation was significantly less and elimination significantly faster than diazepam. There was no difference between oxazepam and diazepam in sedation or fatigue during the drug treatment, but sedative effects persisted for two weeks after diazepam therapy was discontinued. Sedation rapidly returned to baseline in the oxazepam group. Thus, the differing pharmacokinetic profiles of diazepam and oxazepam have clinical consequences during multiple dosage in the elderly.

Age Factors↗
PubMed1983

Halazepam as a precursor of desmethyldiazepam: quantitation by electron-capture gas-liquid chromatography.

Halazepam and its major metabolite desmethyldiazepam (DMDZ) can be reliably quantitated in human plasma following single doses of halazepam. After addition of appropriate internal standards, halazepam and DMDZ are extracted directly into an organic solvent at physiological pH. The organic extract is separated, evaporated to dryness, reconstituted, and directly chromatographed using a 50:50 methyl:phenyl silicone column (SP-2250) and an electron-capture detector. After a single 40 mg oral dose of halazepam, the parent compound appears in plasma only transiently and at low levels. DMDZ appears in higher concentrations and is slowly eliminated. During multiple-dose therapy with halazepam, DMDZ will be the major active substance in blood.

Anti-Anxiety Agents↗
PubMed1983

Interaction of cimetidine with the triazolobenzodiazepines alprazolam and triazolam.

The influence of cimetidine on the pharmacokinetics of alprazolam and triazolam, two triazolobenzodiazepines metabolized by hepatic microsomal oxidation, was evaluated in a series of healthy volunteers. Subjects ingested single 1.0 mg dose of alprazolam or 0.5 mg doses of triazolam on two occasions, with and without concurrent administration of cimetidine (300 mg) every 6 h. For alprazolam, which has a low hepatic clearance and low extraction ratio, cimetidine significantly impaired total metabolic clearance (1.05 versus 1.66 ml/min/kg, P less than 0.005), resulting in significantly prolonged elimination half-life (16.6 versus 12.4 h, P less than 0.005). For triazolam, which has higher hepatic clearance and an intermediate extraction ratio, total clearance was reduced by cimetidine (3.9 versus 5.9 ml/min/kg), causing a significant increase in total area under the plasma concentration curve (25 versus 38 ng/ml X h, P less than 0.02). However, elimination half-life of triazolam was not influenced by cimetidine (3.3 versus 3.2 h), indicating that the reduction in clearance was manifested as increased systemic availability. Thus, cimetidine impairs the clearance of both alprazolam and triazolam, but the consequences of the kinetic change are different because of the differing hepatic extraction profiles of the two drugs.

Adult↗
PubMed1983

Close correlation of acetaminophen clearance with that of conjugated benzodiazepines but not oxidized benzodiazepines.

The clearance of the antipyretic-analgesic drug acetaminophen, biotransformed in humans by glucuronide and sulfate conjugation, was evaluated in 32 healthy young and elderly volunteers. Subjects received a single 650-mg dose of acetaminophen, and multiple plasma concentrations measured over the next 12 h. Random subgroups of subjects also participated in studies of the oxidized benzodiazepines diazepam, desmethyldiazepam and alprazolam, and of the conjugated benzodiazepines lorazepam, oxazepam and temazepam. Acetaminophen clearance was not related to that of the oxidized benzodiazepines, but was highly correlated with clearance of lorazepam (r = 0.70, n = 11, p less than 0.02), oxazepam (r = 0.76, n = 14, p less than 0.005) and temazepam (r = 0.63, n = 16, p less than 0.01). Thus acetaminophen may serve as a probe or marker compound to evaluate drug conjugating capacity in humans.

Acetaminophen↗
PubMed1983

Repeated diazepam dosing in cirrhotic patients: cumulation and sedation.

Five medically stable male patients with cirrhosis and four healthy age- and sex-matched controls received single 5-mg oral doses of diazepam (DZ) daily for 22 consecutive days. Plasma concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were measured daily during the period of dosing and in the 7-day washout period that followed. Clinical self-ratings of sedation, fatigue, mood state, and sleep patterns were obtained daily during the period of dosage with the use of visual analogue scales. Steady-state plasma DZ concentrations were higher (165 and 98 ng/ml), and DMDZ concentrations tended to be higher (399 and 206 ng/ml), in cirrhotics than in controls. Increases in self-rated daytime sedation also were greater in cirrhotics than in controls and correlated strongly with total DZ and DMDZ plasma concentration during the first 2 wk of diazepam dosing. Thus, reduced clearance of DZ in cirrhotics leads to increased cumulation during long-term dosing. This in turn is associated with increased clinical sedation. Sedative effects are partly offset as treatment proceeds because of adaptation or tolerance. Based on kinetic findings, diazepam can be given safely to cirrhotic patients provided daily dosage is reduced by approximately 50%.

Adult↗
PubMed1983

Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives.

Women on low-dose estrogen oral contraceptives (OC) and drug-free control women matched for age, weight, and cigarette smoking habits, received single 2-mg IV doses of lorazepam or single 30-mg oral doses of oxazepam, two benzodiazepines metabolized by glucuronide conjugation. Kinetics were determined from multiple plasma concentrations measured during 48 hr after dosing. Mean kinetic variables for lorazepam in control and OC groups (n = 15 in each group) were: volume of distribution (Vd), 1.33 and 1.45 l/kg; elimination t1/2, 13.1 and 12.2 hr; total clearance, 1.25 and 1.50 ml/min/kg; free fraction in plasma, 10.3% and 10.3% unbound. For oxazepam, kinetic variables in the two groups (n = 14 and 17) were: Vd, 1.05 and 1.19 l/kg; t1/2, 7.6 and 7.2 hr; total clearance, 1.60 and 2.03 ml/min/kg; free fraction, 4.6% and 4.9% unbound. None of these differences were significant. Thus, metabolic clearance by glucuronidation of lorazepam and oxazepam is not significantly affected by OC, in contrast with the highly significant reduction in clearance of the oxidized benzodiazepine diazepam.

Adult↗
PubMed1983

In vitro quantitation of benzodiazepine lipophilicity: relation to in vivo distribution.

In vitro lipophilicity of a series of benzodiazepines was evaluated by octanol: buffer partition ratio at physiological pH, and by retention time on a reverse-phase high-pressure liquid chromatographic (HPLC) system with a neutral-pH mobile phase. Both approaches ranked diazepam as highly lipophilic, but overall the two indices were poorly correlated (r = 0.23). For seven of the benzodiazepines, the in vivo volume of distribution (Vd) was determined in pharmacokinetic studies. After correlation for individual values of protein binding, Vd for unbound drug was significantly correlated with octanol: buffer partition ratio (r = 0.74), and to a greater extent with HPLC retention (r = 0.81). Thus, lipid solubility at least partly determines the extent of benzodiazepine distribution in vivo, which in turn is a major determinant of the duration of clinical action after single doses.

Adult↗
PubMed1983

Pilot pharmacokinetic study of brotizolam, a thienodiazepine hypnotic, using electron-capture gas-liquid chromatography.

Brotizolam, a thienodiazepine hypnotic, can be reliably and sensitively quantitated in human plasma using gas chromatography with electron-capture detection. After addition of an internal standard, samples are directly extracted into an organic solvent, evaporated, reconstituted, and chromatographed at 290 degrees C on a 1% OV-17 column. Sensitivity limits are 0.25 ng of brotizolam/ml of plasma. Six volunteers ingested single 0.25- and 0.5-mg doses of brotizolam on two occasions, and brotizolam concentrations were measured in plasma samples drawn during 24 h after each dose. Peak concentrations averaged 5.5 and 9.2 ng/ml at the two dose levels, and were always attained within 1.5 h after dosage. Elimination half-life averaged 4.4 h (range 2.6-6.9 h) and was independent of dose. Thus brotizolam is a rapidly absorbed hypnotic drug with a short elimination half-life.

Adult↗
PubMed1983

Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity.

Thirty-three healthy male and female volunteers aged 21 to 87 years received a single 0.5 mg oral dose of triazolam. Plasma triazolam concentrations were measured in multiple samples drawn during 24 h after the dose. Mean triazolam elimination half-life was not significantly different between young and elderly men (3.0 vs 4.6 h), nor between young and elderly women (2.7 vs 3.2 h). However, apparent oral clearance of triazolam was significantly reduced in elderly as compared to young groups of both sexes, leading to higher peak plasma concentrations and increased total area under the curve. Values of half-life and clearance of antipyrine, a low-extraction hepatically oxidized compound, were poorly correlated with those of triazolam (r = 0.34 and 0.44, respectively), suggesting different mechanisms controlling age-related changes in clearance of these two hepatically oxidized drugs.

Adult↗
PubMed1983

Pharmacokinetics of benzodiazepine hypnotics.

Three benzodiazepine derivatives are currently indicated specifically for the treatment of insomnia in the United States. Flurazepam is biotransformed to at least two rapidly appearing and rapidly eliminated intermediate metabolites which probably contribute to sleep induction. The final metabolite, desalkylflurazepam, appears slowly, but has a long half-life ranging from 40 to 150 h. This metabolite accumulates extensively during multiple dosage. Temazepam is a slowly absorbed drug and has an intermediate half-life in the range of 10-20 h. Triazolam has an intermediate absorption rate, but is rapidly eliminated (half-life 1.5-5 h) making it essentially non-accumulating. Understanding of the pharmacokinetics of benzodiazepine hypnotics can contribute to understanding of their clinical properties.

Anti-Anxiety Agents↗
PubMed1983

Psychiatrists' responses to violence: pharmacologic management of psychiatric inpatients.

Court decisions setting limits on the use of medication in psychiatric hospitals often assume that psychiatrists use medications inappropriately in response to patients' violent acts. No empirical data have existed to support or refute this assumption. The authors examined the types and doses of antipsychotic medications received by 45 violent patients and 48 control subjects. They found no significant differences in type and dose of medication before the violent act and no significant changes afterward. Violent patients tended to be on somewhat higher doses at discharge than control patients. The judicial concern that psychotropic medications will automatically be abused or overused is not supported by these results.

Antipsychotic Agents↗