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Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 181 records · Page 10Linked to original sources
PubMed1990

The relationship of alprazolam dose to steady-state plasma concentrations.

Alprazolam is a widely used antianxiety agent, yet relatively little is known about the relationship between chronic oral doses and steady-state plasma levels. This study examines the relationship over a wide range of therapeutic doses. We conducted a parallel, double-blind, placebo-controlled study in 36 patients with agoraphobia with panic attacks, or panic disorder with limited phobic avoidance based on DSM-III criteria. Patients received alprazolam (N = 25) or placebo (N = 11) beginning at 1 mg/day and increased weekly until either a maximum tolerated dose or 10 mg/day was achieved. Dosages were then gradually tapered according to a predetermined schedule. The entire study period lasted 14 weeks. Laboratory and clinical assessments were conducted weekly. Doses up to 6 mg/day were tolerated by 80% of patients on alprazolam and doses of 10 mg/day were tolerated by 40% of patients. Twenty-seven percent of the placebo patients reached 10 tablets/day. In the alprazolam group, the principal cause of intolerance was sedation. Throughout the study no significant changes in vital signs or laboratory parameters were observed. Steady state alprazolam, 4-hydroxy alprazolam, and alpha-hydroxy alprazolam plasma levels were linearly related to dose. A 1 mg dosage increment produced, on the average, a corresponding 10 ng/ml increase in steady state level of the parent drug. Significant response was observed in subjects who achieved concentrations greater than 20 ng/ml, with a maximum of 81% of the samples classified as responders within the 60 ng/ml and above group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics.

As clinical experience with fluoxetine grows, so do reports of drug interactions. The most common adverse interaction appears to be inhibition of drug metabolism. Other antidepressants are so affected, and toxicity may result if proper dosage adjustments are not made. Pharmacodynamic interactions may also occur, as evidenced by a serotonergic syndrome with concomitant administration of MAOIs and fluoxetine. Some have speculated that worsening of EPS in some fluoxetine-treated patients may be explained by alterations in serotonergic/dopaminergic balance, although a pharmacokinetic explanation may also fit some cases. Fluoxetine has been greeted with an enthusiasm that claims some advantages over other antidepressants. We should be mindful that any unique therapeutic benefits may be accompanied by a unique adverse effects profile and a special propensity for drug-drug interactions.

Animals↗
PubMed1990

Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABAA-receptor function.

1. Chronic benzodiazepine administration has been associated with tolerance and with downregulation of gamma-aminobutyric acidA (GABAA)-receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied. 2. To compare the effects of chronic lorazepam and alprazolam, we have administered these drugs to mice for 1 and 7 days (2 mg kg-1 day-1) and determined benzodiazepine receptor binding in vivo with and without administration of CL 218,872, 25 mg kg-1 i.p., and GABA-dependent chloride uptake in 3 brain regions at these time points. 3. Benzodiazepine binding was decreased in the cortex and hippocampus at day 7 compared to day 1 of lorazepam, with an increase in CL 218,872-resistant (Type 2) sites in both regions. Maximal GABA-dependent chloride uptake was also decreased in the cortex and hippocampus at day 7. 4. Binding was decreased only in the cortex after 7 days of alprazolam, with no significant change in Type 2 binding. Maximal GABA-dependent chloride uptake was also decreased only in the cortex. 5. These data suggest that the effects of chronic benzodiazepine administration on the GABAA-receptor may be both region-specific and receptor subtype-specific.

Alprazolam↗
PubMed1990

Caffeine-induced behavioural stimulation is dose- and concentration-dependent.

1. The relationship between plasma and brain caffeine and metabolite concentrations and behavioural stimulation was investigated over a 4 h time course. 2. CD-1 mice receiving single intraperitoneal doses of caffeine-sodium benzoate solution (caffeine doses: 0, 20, and 40 mg kg-1) were evaluated in an activity monitor, and their plasma and brain caffeine and metabolite concentrations were determined by high performance liquid chromatography (h.p.l.c.). 3. Kinetic variables for caffeine at low and high caffeine doses were: volume of distribution (Vd), 1.16 and 0.88 l kg-1; plasma elimination half-life (t1/2), 1.25 and 1.62 h; brain t1/2, 0.93 and 1.30 h; clearance, 0.64 and 0.38 l h-1 kg-1, respectively, with Vd and brain t1/2 differing significantly between the two caffeine doses. 4. Low-dose caffeine stimulated vertical behaviours significantly more than high-dose, during the first 150 min post-dosage; both doses stimulated vertical behaviours significantly more than vehicle treatment. 5. Low-dose and high-dose caffeine stimulated horizontal and stereotypic behaviours equivalently, during the first 150 min post-dosage; both doses stimulated these behaviours significantly more than vehicle. 6. Only later, 150 min post-dosage, did high-dose caffeine stimulate all behaviours significantly more than both low-dose and vehicle treatment; this occurred when caffeine concentrations had fallen to approximately 10 micrograms g-1 in the high-dose group. 7. The maximal stimulant effects of caffeine occurred in an intermediate concentration range, between 10-20 micrograms g-1, while lower and higher concentrations produced either no additional stimulation or decrements in activity.

Animals↗
PubMed1990

The diagnosis and treatment of panic disorder in alcoholics: three cases.

It has been postulated that many alcoholics use alcohol to "self-mediate" symptoms of anxiety or panic. Early diagnosis and treatment in this population are both complicated by symptoms of alcohol withdrawal and controversial because of the belief that alcoholics will abuse anxiolytics. The authors present three patients with alcoholism in whom diagnosis of panic was facilitated by intravenous lactate infusion, and whose symptoms were alleviated by clonazepam. All three patients were able to maintain sobriety during treatment. The authors conclude that in a subpopulation of alcoholics, pharmacotherapy for panic may be indicated and not lead to anxiolytic abuse.

Adult↗
PubMed1990

Chronic benzodiazepine administration: effects in vivo and in vitro.

Chronic benzodiazepine administration is associated with neurochemical alterations in the GABAergic system, as determined in a variety of animal models and tissue culture systems. In animals, effects of chronic benzodiazepine agonists on receptor binding are uncertain, but several studies indicate a decrease in GABA-dependent chloride uptake. In contrast, limited data indicate that chloride uptake is increased after chronic antagonist administration, and results of inverse agonist administration are uncertain. Most animal studies are limited by lack of attention to drug choice and to pharmacokinetic variables, and by failure to determined delivered drug concentrations. More limited data in tissue culture systems are conflicting with regard to effects on benzodiazepine binding, but recent studies indicate that GABA-dependent chloride uptake may be decreased after chronic agonist exposure, and increased after chronic antagonist and inverse agonist administration. Data from these systems may complement results obtained in intact animals, and cultures may allow more detailed examination of the kinetics and specificity of drug effects.

Animals↗
PubMed1990

Kinetic and dynamic components of increased benzodiazepine sensitivity in aging animals.

Male CD-1 mice (age 6 weeks, 6 months, 1 and 2 years) received single 2-mg/kg i.p. doses of clonazepam. Plasma and cortex clonazepam concentrations, rotarod ataxia and in vivo benzodiazepine receptor occupancy were measured at multiple times up to 14 hr after dosage. Elimination of clonazepam from plasma and cortex became slower with age, but cortex concentrations always exceeded those in plasma. The mean ratio was 1.82, and was not influenced by age. Rotarod ataxia was quantitatively greater and of longer duration in aging animals. This was not explained entirely by kinetic changes, as ataxia at any given cortex clonazepam concentration or degree of receptor occupancy was greater in 1-year-old animals than in those age 6 weeks or 6 months. In a second study, 6-week and 1-year-old animals were tested at a fixed time (1 hr) after variable doses of clonazepam (0.01-2.0 mg/kg); findings were consistent with results from the fixed-dose study. In vitro studies evaluated benzodiazepine receptor binding, chloride channel binding and muscimol-stimulated chloride uptake in cortical membrane preparations from animals of the four age groups. Binding affinity and number of binding sites were not influenced by age, or was gamma-aminobutyric acid-dependent muscimol-stimulated chloride uptake (either with or without addition of lorazepam) significantly related to age. Thus, increased overall sensitivity of aging animals to the central depressant effects of clonazepam is evident in the described model.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1990

Chronic benzodiazepine administration. VI. A partial agonist produces behavioral effects without tolerance or receptor alterations.

Chronic benzodiazepine administration has been reported to lead to behavioral tolerance and, in some cases, downregulation of gamma-aminobutyric acid A (GABAA)-receptor binding and function. So-called "partial agonist" benzodiazepines appear to cause limited benzodiazepine effects and little or no behavioral tolerance. To evaluate behavioral and neurochemical effects of a partial agonist during chronic administration, we treated mice with Ro16-6028, 0.25, 1 and 4 mg/kg/day by implanted osmotic pumps, evaluating open-field activity and binding and function at the GABAA receptor. All three doses of Ro16-6028 caused dose-dependent decreases in vertical movements (rearing), and no tolerance was observed up to 14 days at any dose. In contrast, tolerance occurred to the effects of clonazepam at 7 days. Benzodiazepine receptor occupancy was essentially complete in all brain regions evaluated at doses of 1 and 4 mg/kg/day. Benzodiazepine binding in vivo at 0.25 mg/kg/day was transiently decreased in cortex at 7 days but was unchanged in any other brain region. Benzodiazepine binding in cortex in vitro was unchanged over time at any of the three doses, as were t-butylbicyclophosphorothionate binding and binding at the low- and high-affinity GABA sites measured by [3H]SR-95531. GABAA receptor function as determined by muscimol-stimulated chloride uptake was unchanged over 14 days of administration at Ro16-6028 doses of 0.25 and 4 mg/kg/day. Concentrations of Ro16-6028 were constant during administration at 1 and 4 mg/kg/day. These data indicate that chronic Ro16-6028 causes dose-dependent behavioral effects without the development of tolerance and that, despite substantial or complete benzodiazepine receptor occupancy, few effects occur at the GABAA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cocaine augments peripheral benzodiazepine binding in humans.

Acute cocaine administration has been reported to alter central benzodiazepine binding in animals. The authors examined the effects of chronic cocaine use on binding at the peripheral benzodiazepine site on platelets in cocaine users (N = 8), heavy ethanol users (N = 4), and controls (N = 7). The groups were matched for age and sex. None of the subjects reported recent benzodiazepine use, but neither serum nor urine testing was performed. Apparent affinity at the peripheral benzodiazepine site was similar in the three groups. However, the number of binding sites was significantly greater in cocaine users. These results indicate that cocaine use affects peripheral benzodiazepine binding in humans and might also alter central benzodiazepine effects.

Adult↗
PubMed1989

Interaction of caffeine with the GABAA receptor complex: alterations in receptor function but not ligand binding.

Behavioral and neurochemical evidence indicates interactions between caffeine and other adenosine receptor ligands and the gamma-aminobutyric acid (GABA)-benzodiazepine system. To assess the effects of caffeine on binding and function at the GABAA receptor, we studied the effects of behaviorally-active doses of caffeine on benzodiazepine and Cl- channel binding and on overall function of the GABAA receptor as measured by Cl- uptake. There was no effect of caffeine on benzodiazepine receptor binding in cortical synaptosomal membranes at concentrations of 1-100 microM. No effects on benzodiazepine binding were found ex vivo in mice treated with caffeine, 20 and 40 mg/kg. At the putative Cl- channel site labeled by t-butylbicyclophosphorothionate (TBPS), binding was unchanged in vitro after caffeine treatment (1 and 10 microM) in washed and unwashed membranes. However, in ex vivo studies caffeine (20 and 40 mg/kg) increased numbers of TBPS sites in unwashed but not washed membranes. Muscimol-stimulated Cl- uptake into cortical synaptoneurosomes was decreased in mice treated with caffeine, 20 and 40 mg/kg. Similar results were observed in in vitro preparations treated with 50 microM but not 100 microM caffeine. These results indicate that caffeine administration significantly alters the Cl- transport function of the GABAA receptor complex.

Animals↗
PubMed1989

Chronic benzodiazepine administration. IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration.

The triazolobenzodiazepine compound alprazolam may have unique clinical effects compared to other benzodiazepines, and both behavioral and neurochemical studies have indicated unusual results after acute doses of alprazolam. To determine the effects of chronic dosage in mice, alprazolam (2 mg/kg/day) was administered via osmotic pumps for 1-14 days, and open-field activity, plasma and brain concentrations, benzodiazepine receptor binding in vivo and in vitro, [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding, and muscimol-stimulated chloride uptake were determined. Alprazolam decreased motor activity after 1 and 2 days, but tolerance developed by day 4 and persisted to day 14. Plasma and brain concentrations remained constant during the 2-week period. Benzodiazepine receptor binding in vivo was decreased at day 4 compared to day 1 in cortex (CX) and hypothalamus (HYPO), and remained depressed to day 14 in CX but not HYPO. Benzodiazepine binding in vitro and [35S]TBPS binding were decreased in CX at day 7. Muscimol-stimulated [36Cl-] uptake was decreased at days 4 and 7 compared to day 1, but at day 14 uptake was similar to day 1. These results indicate that behavioral tolerance and receptor downregulation develop rapidly during chronic alprazolam administration. Behavioral and neurochemical changes were similar to those associated with lorazepam administration, but occurred more rapidly and with different regional specificity.

Alprazolam↗