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Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 235 records · Page 13Linked to original sources
PubMed1988

Abuse liability and clinical pharmacokinetics of alprazolam in alcoholic men.

The abuse liability of alprazolam was studied in 17 abstinent alcoholic and 12 control subjects. A single 1-mg oral dose of alprazolam was administered, and subjective effects were measured by scales modified from the Addiction Research Center Inventory (ARCI). Multiple blood samples for alprazolam measurement were drawn over 48 hours. No statistically significant differences in pharmacokinetic parameters were found between groups. Alcoholics had lower baseline scores on the ARCI-Morphine/Benzedrine Group Scale (euphoria) and had greater drug-induced changes than nonalcoholics. The findings suggest that alcoholics may be at high risk to abuse alprazolam because it has a positive mood effect not seen in nonalcoholics.

Adult↗
PubMed1987

Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam.

Sixty volunteers with insomnia participated in a randomized, double-blind, controlled clinical trial. After an initial six nights of placebo, 30 subjects (the abrupt-withdrawal group) received 0.5 mg of triazolam nightly for 7 to 10 nights, after which they received placebo. The other 30 subjects (the tapered-dosage group) received the same initial placebo treatment, then triazolam at 0.5 mg for seven nights, at 0.25 mg for two nights, and at 0.125 mg for two nights, and then placebo. As compared with the initial placebo period, the triazolam period significantly reduced the interval before the onset of sleep (sleep latency), and it prolonged sleep duration, reduced the number of awakenings, and improved the self-rated soundness of sleep in all cohorts. In the abrupt-withdrawal group, plasma levels of triazolam were undetectable the morning after the first night of placebo substitution, and subjects reported prolongation of sleep latency (57 minutes longer than base line), reduction in sleep duration (1.4 hours less than base line), and increased awakenings (1.2 per night above base line). The symptoms of rebound sleep disorder lasted one or possibly two nights, and there was a reversion toward base line on subsequent placebo nights. In the tapered-dosage group, however, plasma triazolam levels fell gradually to zero, and rebound symptoms were decreased or eliminated. Thus, rebound sleep disorder following abrupt discontinuation of triazolam can be attenuated by a regimen of tapering.

Adult↗
PubMed1987

Rapid increase in brain benzodiazepine receptor binding following defeat stress in mice.

Defeat stress in mice, a model of social stress, increases benzodiazepine receptor binding as measured by specific [3H]Ro15-1788 binding in vivo, but not by [3H]flunitrazepam binding in vitro. This increase occurs rapidly, by 20 min following exposure to stress, and resolves by 60 min. Increased benzodiazepine receptor binding is observed in the cerebral cortex, cerebellum and hypothalamus, and appears to be due to an increase in receptor number rather than apparent affinity. The stress-induced increase in central benzodiazepine receptors is decreased in a dose-dependent fashion by lorazepam, a benzodiazepine agonist, but not by the receptor antagonist Ro15-1788. The stress-induced increase in benzodiazepine receptors is also blocked by adrenalectomy and is restored by corticosterone replacement.

Adrenalectomy↗
PubMed1987

Actual versus reported benzodiazepine usage by medical outpatients.

Benzodiazepines are widely prescribed, and in 1979 almost 10% of the adult population was taking them. Prior studies of outpatient usage of benzodiazepines have relied on survey or prescription data, which may be confounded by noncompliance. To determine the actual use of benzodiazepines, plasma benzodiazepine concentrations were measured in 225 consecutive outpatients from a university cardiology outpatient service. Self reports indicated that the great majority of the patients (191) were taking at least one medicine, and 70 reported being on a psychotropic drug. Seventy-seven patients reported taking benzodiazepines, the majority being on bromazepam (20), diazepam (26) or oxazepam (19). In 25 of those 77 patients, the reported drug could not be detected in plasma. Conversely, in 10 of the 225 patients, benzodiazepines which were not reported were detected (diazepam or flurazepam). Of those taking benzodiazepines, many had a low concentration, suggesting intermittent rather than regular use. Thus, many patients for whom benzodiazepines are prescribed take them irregularly, and a small group uses them without reporting their prescription. These findings have implications for the clinical presentation of illness and for the possibility of drug interactions.

Adolescent↗
PubMed1987

Trazodone kinetics: effect of age, gender, and obesity.

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P less than 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P less than 0.05), thereby increasing elimination half-life (t1/2) in elderly men (8.2 vs. 4.7 hours; P less than 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P less than 0.02), causing increased t1/2 (7.6 vs. 5.9 hours; P less than 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P less than 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t1/2 in obese subjects (13.3 vs. 5.9 hours; P less than 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.

Adult↗
PubMed1987

Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol.

Pharmacokinetics of the benzodiazepine bromazepam were evaluated in volunteer subjects who received single 6 mg oral doses followed by blood sampling during the next 48 hours. Age and gender effects were studied in 32 subjects, divided into young (aged 21 to 29 years) and elderly (aged 60 to 81 years) groups. Compared with young subjects, the elderly had significantly higher peak serum bromazepam concentrations (132 vs. 82 ng/ml), smaller volume of distribution (0.88 vs. 1.44 L/kg), lower oral clearance (0.41 vs. 0.76 ml/min/kg), and increased serum free fraction (34.8% vs. 28.8% unbound). However, gender had no significant influence on bromazepam kinetics. In 11 young female users of oral contraceptive steroids, compared with seven age- and weight-matched control women not using oral contraceptives, no differences in bromazepam kinetics were observed. Coadministration of cimetidine (1.2 gm daily) significantly reduced bromazepam clearance (0.41 vs. 0.82 ml/min/kg) and prolonged elimination half-life (29 vs. 23 hours). Propranolol (160 mg daily) significantly prolonged bromazepam half-life (28 vs. 23 hours), but the reduction in clearance associated with propranolol (0.65 vs. 0.82 ml/min/kg) did not reach significance. Bromazepam has the pharmacokinetic characteristics of benzodiazepines with half-life values between 20 and 30 hours. Consistent with its biotransformation pathway by hepatic microsomal oxidation, bromazepam clearance is significantly impaired in elderly individuals, by coadministration of cimetidine and possibly propranolol.

Administration, Oral↗
PubMed1987

Benzodiazepine receptor binding of triazolobenzodiazepines in vivo: increased receptor number with low-dose alprazolam.

Triazolobenzodiazepines are in clinical use as hypnotics and anxiolytics. We analyzed in vivo receptor binding and brain concentrations of alprazolam, triazolam, and estazolam. Drug concentrations measured in the cerebral cortex 1 h after administration were directly proportional to dose for all three compounds. In vivo receptor binding, as defined by the specific uptake of [3H]Ro15-1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds. Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam. At higher doses of alprazolam (greater than 0.2 mg/kg), receptor binding by [3H]Ro15-1788, likewise decreased with increasing dose of the former drug. However, at lower doses of alprazolam (0.02-0.05 mg/kg), which resulted in cortex concentrations of 2-7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions. Binding returned to control values at doses of greater than or equal to 0.01 mg/kg. Similar results were obtained in time course studies. At 8 and 10 h after a dose of 1 mg/kg i.p., corresponding to cortex concentrations of 2.7-7 ng/g, receptor binding was increased compared with controls. Similarly, at 1, 2, and 3 h after a single dose of 0.05 mg/kg, corresponding to cortex concentrations of 3.7-5.8 ng/g, receptor binding was also increased. The apparent affinity of benzodiazepine receptors for clonazepam in mice receiving alprazolam (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of alprazolam increased receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprazolam↗
PubMed1987

Clonazepam pharmacokinetics, brain uptake, and receptor interactions.

The 7-nitrobenzodiazepine derivative clonazepam is initially biotransformed by nitroreduction, followed by acetylation. Neither the amino- nor the acetamido- metabolites appear to have important pharmacologic activity. Clonazepam elimination half-life falls in the range of 20 to 80 hours, but means within the population and variance are not well defined. Absorption of orally administered clonazepam is 80% or more. In experimental studies, clonazepam appears to diffuse passively from plasma into brain, with a constant brain-plasma concentration ratio. The drug disappears in a parallel fashion from both brain and plasma, with no evidence of sequestration in brain tissue. Clonazepam has a relatively high molar affinity for the benzodiazepine receptor in vitro, and the fractional extent of benzodiazepine receptor occupation by clonazepam in vivo is directly and predictably related to the drug's concentration in brain tissue. Acute behavioral effects are in turn directly related to the extent of receptor occupancy. Compared to other benzodiazepines, the reportedly unique clinical properties of clonazepam are neither associated with unusual/unexpected pharmacokinetic properties or with a qualitatively different in vivo interaction with the presumed benzodiazepine binding site.

Acetylation↗
PubMed1987

Effect of age, body composition, and lipid solubility on benzodiazepine tissue distribution in rats.

Changes in body composition with age may alter tissue drug uptake and result in altered pharmacokinetics and pharmacodynamics. Four young, 4 middle-aged and 4 old Fischer-344 male rats were given a single intraperitoneal dose of alprazolam (2.5 mg/kg), diazepam (5 mg/kg) and triazolam (1.25 mg/kg) and sacrificed after 1 h. Diazepam, desmethyldiazepam, oxazepam, temazepam, alprazolam, and triazolam concentrations were determined in brain, kidney, liver, spleen, lung, heart, adrenal, muscle, fat and plasma by gas chromatography. Free fraction in plasma was determined by equilibrium dialysis. Drug uptake varied widely among tissues. Highest uptake ratios relative to free (unbound) drug in plasma were in adrenal (56-135), liver (35-116) and kidney (19-50). Free fraction in plasma varied from 0.13 for desmethyldiazepam to 0.30 for triazolam, and was unrelated to age. Tissue drug uptake relative to muscle, total plasma or free plasma concentration showed no significant variation with age or body habitus. In vivo fat uptake was highly correlated (R = 0.95) with in vitro octanol/buffer partition ratio. Muscle and fat were the largest quantitative drug storage sites, with total uptake explained by lipophilicity. Thus, age-related changes in body habitus and clearance do not alter tissue binding of benzodiazepines at distribution equilibrium.

Aging↗
PubMed1987

Benzodiazepine receptor occupancy in vivo: correlation with brain concentrations and pharmacodynamic actions.

A tracer radioligand technique employing [3H]Ro 15-1788 was used to measure in vivo benzodiazepine receptor occupancy in mice. Animals were administered clonazepam (CNZ) or lorazepam (LRZ) i.p. or i.v., followed by [3H]Ro 15-1788. Plasma and cerebral cortical concentrations of the drug and cortical benzodiazepine receptor occupancy were determined at varying doses and times after administration. For both drugs, plasma and brain concentrations decreased in parallel with decreasing doses and with time, and the brain/plasma ratios remained constant. Receptor occupancy was maximal for CNZ and LRZ at doses above 1 and 4 mg/kg, respectively, and decreased with decreasing doses. Comparison of receptor occupancy with brain concentration yielded IC50 values of 21 ng/g for CNZ and 133 ng/g for LRZ. The apparent dissociation constant (Kd) for CNZ was 56 pmol/g and, for LRZ, 372 pmol/g. Hill plots yielded slopes of 1.30 for CNZ and 1.71 for LRZ. Alterations in the nonspecific uptake or elimination of Ro 15-1788 did not explain occupancy changes, inasmuch as brain concentrations of unlabeled Ro 15-1788 (6 mg/kg) were not changed by LRZ administration. The correlation between receptor occupancy and the pharmacodynamic actions of these drugs in blocking pentylenetetrazol seizures and inducing rotarod ataxia indicated that ED50 for these effects occurred at receptor occupancy of 30 to 60% for both drugs.

Animals↗
PubMed1987

Alprazolam kinetics following sublingual and oral administration.

Thirteen healthy volunteers received 1 mg of alprazolam, as the commercially available oral tablet, by sublingual and oral routes on two occasions in random sequence. Plasma alprazolam concentrations during 48 hours after each dose were measured by electron-capture gas-liquid chromatography. The peak plasma concentration after sublingual dosage was higher than after oral administration (17.3 vs. 14.9 ng/ml), and the time of peak concentration following sublingual administration was reached (1.17 vs. 1.73 hours after dose). However, these differences did not reach statistical significance. The mean total area under the plasma concentration curve for sublingual administration was slightly but not significantly larger than that following oral dosage (203.7 vs. 194.4 hr.ng/ml) and no significant differences between sublingual and oral dosage were found for elimination half-life (11.7 vs. 11.8 hours) or for clearance (86.4 vs. 92.4 ml/min). Thus, alprazolam absorption following sublingual administration is as rapid as after oral dosage on an empty stomach, and completeness of absorption is comparable. In clinical terms, sublingual and oral dosages of alprazolam are likely to be therapeutically equivalent. The sublingual route may be a useful alternative for panic disorder patients who cannot swallow pills or for those who do not have access to a liquid at the time of dosing.

Administration, Oral↗