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Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 19 recordsLinked to original sources
PubMed1992

The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state.

We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study. The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes. Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography. Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P less than 0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng.ml-1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h.ng.ml-1. Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h. In general the two routes were significantly different from placebo but not from each other.

Administration, Oral↗
PubMed1992

Chronic benzodiazepine administration. X. Concurrent administration of the peripheral-type benzodiazepine ligand PK11195 attenuates chronic effects of lorazepam.

Chronic administration of benzodiazepine active at the tau-aminobutyric acidA receptor ("central" benzodiazepine sites) is associated with behavioral tolerance and receptor downregulation. Recent reports indicate possible interactions between central sites and benzodiazepines active at "peripheral-type" sites located primarily on non-neuronal cells. To evaluate these interactions during chronic administration, we treated mice with lorazepam for 1 to 14 days alone or in combination with the peripheral-type site ligand PK11195 [N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3-carboxamid e]. Lorazepam was associated with tolerance at 7 days, but tolerance was not observed during concurrent administration of PK11195. Lorazepam was also associated with benzodiazepine receptor down-regulation in cortex and hippocampus at 7 days. With concurrent administration of PK11195, this effect remained in cortex but was absent in hippocampus. tau-Aminobutyric acid-dependent chloride uptake was reduced in both cortex and hippocampus with lorazepam, but not with concurrent lorazepam and PK11195. PK11195 administration alone did not affect behavior or neurochemical parameters, or did it alter brain lorazepam concentrations. These data indicate that concurrent PK11195 administration attenuates behavioral and neurochemical effects of chronic lorazepam administration.

Animals↗
PubMed1992

Chronic low-dose alprazolam augments gamma-aminobutyric acid(A) receptor function.

After acute administration of low doses, alprazolam displays unusual behavioral and neurochemical characteristics. To determine whether chronic low-dose alprazolam has unique effects, we treated mice for 1-14 days with alprazolam 0.2 mg/kg per day and evaluated open-field activity, benzodiazepine receptor binding, t-butylbicyclophosphorothionate binding, and muscimol-stimulated chloride uptake. Open-field activity in treated mice was similar to that of control mice at each timepoint during alprazolam administration. Similarly, benzodiazepine receptor binding in vivo was unchanged in five brain regions. Benzodiazepine receptor binding in vivo was unchanged in five brain regions. Benzodiazepine binding in vitro in the cortex was unaffected by alprazolam treatment, as was t-butylbicyclophosphorothionate binding in the cortex. However, muscimol-stimulated chloride uptake was increased after 2 and 4 days of alprazolam compared with results after 1, 7, and 14 days. These results are consistent with prior reports of unusual effects of low-dose alprazolam and extend these findings to chronic administration.

Alprazolam↗
PubMed1992

Caffeine-induced behavioral stimulation is dose-dependent and associated with A1 adenosine receptor occupancy.

Caffeine's psychomotor stimulant effects may relate to its blockade of central adenosine receptors. We examined acute caffeine effects on motor activity, adenosine receptor occupancy in vivo, and receptor affinity and density ex vivo. Acute doses of caffeine-sodium benzoate (0, 20, 40, and 60 mg/kg, intraperitoneally [0, 0.10, 0.21, 0.31 mu mol/kg]) were given to CD-1 mice and their activity was measured in an animal activity monitor over a 1-hour period. Adenosine receptor occupancy in vivo was quantified in mice 1 hour postdosage, using the high-affinity, A1 receptor selective adenosine antagonist [3H]-8-cyclopentyl-1,3-dipropylxanthine. Adenosine receptor binding affinities and densities were determined from analyses of binding studies in cortical, hippocampal, and brainstem membranes from treated mice (0 and 40 mg/kg caffeine). Caffeine doses of 20 and 40 mg/kg, corresponding to mean brain concentrations of 5 and 17 micrograms/g, increased all horizontal and vertical motor activity measures and stereotypy counts, as compared to doses of 0 and 60 mg/kg. Additionally, all acute caffeine doses significantly altered specific A1 binding in vivo (decreasing binding between 55% and 73% versus vehicle), presumably as it occupied A1 receptors. Therefore, at doses of 20 and 40 mg/kg, caffeine stimulated motor activity as it occupied A1 receptors; at a dose of 60 mg/kg (mean brain concentration of 26 micrograms/g) caffeine had no stimulant effect even though it appeared to occupy A1 receptors. Acute caffeine dosage did not alter ex vivo adenosine receptor binding affinity or density in any brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Chronic benzodiazepine administration. IX. Attenuation of alprazolam discontinuation effects by carbamazepine.

Clinical studies suggest that carbamazepine may attenuate effects of alprazolam discontinuation. Since discontinuation of chronic alprazolam in a mouse model is associated with behavioral alterations and upregulation at the gamma-aminobutyric acidA (GABAA) receptor, we studied the effects of carbamazepine administration after alprazolam (2 mg/kg/day) discontinuation. Open-field activity was increased in mice 4 days after alprazolam discontinuation, but this effect was reduced significantly by continuous infusion of carbamazepine, 25 or 100 mg/kg/day. Benzodiazepine receptor binding in vivo was increased in cortex at 2 and 4 days after alprazolam discontinuation, and in hypothalamus at 4 days; with carbamazepine, 100 mg/kg/day, binding in both regions at these time points was similar to control values. Similar results were observed in cortex with benzodiazepine receptor binding in vitro. GABA-dependent chloride uptake was also increased at 4 days alprazolam administration. Treatment with carbamazepine attenuated (P less than 0.10) this increase. Carbamazepine alone after vehicle did not alter benzodiazepine binding or GABA-dependent chloride uptake. These results indicate that carbamazepine administration after alprazolam discontinuation attenuates behavioral and neurochemical alterations associated with discontinuation.

Alprazolam↗
PubMed1991

Sensitivity to triazolam in the elderly.

BACKGROUND: Elderly persons frequently appear to be sensitive to the effects of many drugs that depress the central nervous system. We studied the effect of age on the pharmacokinetics and pharmacodynamics of the benzodiazepine hypnotic agent triazolam, now the most frequently prescribed hypnotic drug in the United States. METHODS: Twenty-six healthy young subjects (mean age, 30 years) and 21 healthy elderly subjects (mean age, 69 years) participated in a four-way crossover study. After a single-blind adaptation trial with placebo, each subject received, in random order and in double-blind fashion, single doses of placebo, 0.125 mg of triazolam, and 0.25 mg of triazolam. For 24 hours after the administration of each of the three study medications, plasma triazolam levels were determined and psychomotor performance, memory, and degree of sedation were assessed. RESULTS: Plasma triazolam concentrations increased in proportion to the dose, but the elderly subjects had higher plasma concentrations due to reduced clearance of the drug. The degree of sedation as rated by an observer and the reduction in the subjects' performance on the digit-symbol substitution test were both greater in the elderly than in the young subjects after they were given the same doses. The relation of the plasma triazolam concentration to the degree of impairment was similar for the two groups. As part of the study, information was presented 1 1/2 hours after the administration of the drugs; the subjects' ability to recall the information 24 hours later was impaired by both doses of triazolam, and the percent decrease was similar in the young and elderly groups. CONCLUSIONS: Triazolam caused a greater degree of sedation and greater impairment of psychomotor performance in healthy elderly persons than in young persons who received the same dose. These effects resulted from reduced clearance and higher plasma concentrations of triazolam rather than from an increased intrinsic sensitivity to the drug. On the basis of these results, the dosage of triazolam for elderly persons should be reduced on average by 50 percent.

Adult↗
PubMed1991

Chronic benzodiazepine administration. VII. Behavioral tolerance and withdrawal and receptor alterations associated with clonazepam administration.

Clonazepam administration may lead to tolerance and "withdrawal" syndromes in clinical use. To assess the effects of this drug in a mouse model, we administered clonazepam (1.5 mg/kg/day) for 1-14 days and evaluated open-field activity, cortical clonazepam concentrations, and binding and function at the GABAA receptor. We also evaluated the same parameters at 1, 2, 4 and 7 days after discontinuation of 7 days of clonazepam administration. During chronic treatment, tolerance developed to the effects of clonazepam on motor activity at 7 days and persisted to 14 days. Cortical clonazepam concentrations did not change significantly during this period. Benzodiazepine receptor binding in vivo was decreased in cortex at days 7 and 14 of clonazepam, but was unchanged in other regions. Binding determined in vitro was also decreased at these points. TBPS (t-butylbicyclophosphorothionate) binding in cortex was slightly, but not significantly, decreased. Muscimol-stimulated chloride uptake was also decreased at days 7 and 14. After clonazepam discontinuation, open-field activity returned to control values at 1 day but was increased above baseline at 4 days. Benzodiazepine binding in vivo and in vitro, as well as TBPS binding, were increased at 4 days. Muscimol-stimulated chloride uptake was also increased at this point. These results indicate that chronic clonazepam administration is associated with tolerance to motoric effects, with discontinuation effects, and with receptor alterations in a mouse model. Clonazepam is similar to other benzodiazepines in this regard.

Animals↗
PubMed1991

Prenatal exposure to benzodiazepine--I. Prenatal exposure to lorazepam in mice alters open-field activity and GABAA receptor function.

Prenatal exposure to benzodiazepines may lead to developmental abnormalities in humans and animals. To assess the behavioral and neurochemical effects of such exposure, pregnant mice were treated with lorazepam, 2 mg/kg/day, from days 13-20 of gestation, and open-field activity was assessed in offspring at 3 and 6 weeks of age and the function of GABAA receptors at 6 weeks of age. Activity was increased in mice exposed to lorazepam, compared to untreated or vehicle-treated controls at 3 weeks, but was unchanged at 6 weeks. Muscimol-stimulated uptake of chloride was decreased in lorazepam-treated mice, compared to controls, with a decrease in maximum uptake but no change in the EC50 for muscimol. Concentrations of lorazepam in maternal plasma and brain showed a similar brain:plasma ratio as previously reported and concentrations in fetal brain were about 50% of maternal levels. Lorazepam persisted for 48 hours after birth in dams but not in the offspring. These results indicate persistent behavioral and neurochemical alterations after prenatal exposure to lorazepam. This model may be useful in assessing other effects of prenatal exposure to benzodiazepine.

Animals↗
PubMed1991

Prenatal benzodiazepine administration. II. Lorazepam exposure is associated with decreases in [35S]TBPS binding but not benzodiazepine binding.

Prenatal benzodiazepine exposure has been associated with neurobehavioral alterations in humans and animals. To determine effects of prenatal benzodiazepine exposure on binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites on the GABAA receptor in mature offspring, we treated mice with lorazepam, 2 mg/kg/day, during days 13-20 of gestation. Binding was assessed at 6 weeks of age. There were no differences among controls, vehicle- or lorazepam-exposed mice in benzodiazepine receptor binding determined in vivo or in vitro. However, receptor density for [35S]TBPS binding sites was decreased in lorazepam-exposed offspring compared to the other groups. These data are consistent with prior neurochemical results indicating decreased TBPS binding and GABAA receptor function in several systems.

Animals↗
PubMed1991

Accelerated benzodiazepine receptor recovery after lorazepam discontinuation.

Benzodiazepine discontinuation can lead to a behavioral syndrome in animals and humans. In a mouse model, this syndrome is associated with benzodiazepine receptor up-regulation. The protein-modifying reagent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), has been used to irreversibly inactivate a number of neurotransmitter receptors including benzodiazepine receptors, and thus allows estimation of receptor recovery in vivo. To assess benzodiazepine receptor recovery after benzodiazepine discontinuation, we treated mice with lorazepam (LRZ), 2 mg.kg-1.day-1 for 1 wk. After 24 h, EEDQ (12.5 mg/kg) was administered, and benzodiazepine binding in the cortex and cerebellum was determined after 4-144 h. EEDQ treatment decreased receptor density in the cortex in both LRZ- and vehicle-treated groups by approximately 50%, with no change in apparent affinity as previously reported. Binding in both groups returned to control values after 96 h. Kinetic analysis indicated a more rapid increase in binding in LRZ-compared with vehicle-treated animals, with t1/2 for LRZ 19.1 h, and for vehicle, 30.8 h (P less than 0.05). Receptor density was decreased in the cerebellum after EEDQ by approximately 40% in both treatment groups, with no change in apparent affinity. Receptor density returned to control values at 96 h, with no difference in kinetics in LRZ- compared with vehicle-treated mice. The decrease in receptor t1/2 associated with lorazepam discontinuation is consistent with the observed increase in benzodiazepine receptors in this setting.

Animals↗