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Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 163 records · Page 9Linked to original sources
PubMed1991

Modification of gamma-aminobutyric acidA receptor binding and function by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in vitro and in vivo: effects of aging.

The irreversible protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to investigate binding site characteristics on the gamma-aminobutyric acidA (GABAA) receptor complex. In vitro, preincubation with EEDQ led to a concentration-dependent decrease in receptor number for benzodiazepine, t-butylbicyclophosphorothionate (TBPS), and GABA binding sites in cerebral cortex. The effect was maximal at the highest concentration of EEDQ used (10(-4) M) and was greatest for the benzodiazepine site. Pretreatment of membranes with the benzodiazepine antagonist Ro 15-1788, 1 or 10 microM, or the agonist lorazepam, 10 microM, largely prevented the effects of EEDQ. Scatchard analysis indicated no effect of EEDQ, 10(-4) M, on apparent affinity, but a decrease in receptor density for each site. Administration of EEDQ to mice, 12.5 mg/kg i.p., led to a substantial (55-65%) decrease in number of benzodiazepine binding sites in cortex after 4 h. Slightly smaller changes were observed for TBPS and GABA binding. No changes were observed in apparent affinity at any site. Prior administration of Ro 15-1788, 5 mg/kg, prevented the effect of EEDQ on benzodiazepine binding. Density of benzodiazepine binding sites gradually recovered over time, and receptor density returned to control values by 96 h after EEDQ injection. Number of binding sites in cortex for TBPS and GABA also increased over time after EEDQ. Benzodiazepine sites in cerebellum were decreased proportionally to cortex after EEDQ, and increased over a similar time course. Function of the GABAA receptor in chloride uptake in cortex was markedly reduced (65%) by EEDQ.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1991

Benzodiazepine receptor binding response to acute and chronic stress is increased in aging animals.

Benzodiazepine receptor binding in vivo, as determined by the uptake of the high-affinity specific benzodiazepine receptor ligand [3H]Ro15-1788, was examined following acute and chronic defeat stress in male mice aged 6 weeks, 7 months and 1 year. Specific uptake in 6-week-old mice was increased from control values only in the cerebellum following acute but not chronic stress. Specific uptake in the cortex and hypothalamus was unchanged from control values following both acute and chronic stress. Seven-month-old mice demonstrated an increased specific uptake in the cortex and cerebellum when measured immediately following both acute stress and the final session of chronic stress. This enhanced binding returned to baseline levels by 24 h after stress. One-year-old mice demonstrated no change in specific uptake when measured after acute stress, while binding was enhanced in all brain regions after the final session of chronic stress. This increased binding was still evident at 24 h after the cessation of chronic stress. Changes in benzodiazepine binding differ as a response to acute and chronic stress, and this response varies markedly with age.

Acute Disease↗
PubMed1991

Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part I).

Anxiolytic and hypnotic drugs are extensively prescribed for elderly individuals throughout Western society. Old age may be associated with an altered clinical response to this class of compounds, and there is a considerable ethical and economic stake in understanding these changes so that therapy may be approached with a maximum likelihood of therapeutic benefit and a minimum risk of side effects. Old age may lead to altered pharmacokinetics of sedative-anxiolytic drugs, causing higher plasma concentrations (relative to young individuals) after single or multiple doses. By far the majority of the available scientific data refer to the benzodiazepines, which have become the most widely prescribed class of sedative-anxiolytic drugs. Although there is not complete consistency in the available data, the weight of evidence indicates that old age is associated with impaired clearance of the benzodiazepines which are biotransformed by microsomal oxidation (such as diazepam, desmethyldiazepam, desalkylflurazepam, bromazepam, alprazolam, triazolam and others). For those benzodiazepines metabolised mainly by glucuronide conjugation (oxazepam, lorazepam, temazepam) or nitroreduction (nitrazepam), there are minimal, if any, age-related decrements in clearance. Only in the case of triazolam is there direct evidence linking impaired clearance to enhanced clinical effects in the elderly. The logical suggestion that benzodiazepines biotransformed by conjugation or by nitroreduction may be safer for the elderly than those biotransformed by oxidation has not yet been directly validated. Reasonable epidemiological evidence has linked the use of long (versus short) half-life benzodiazepines (regardless of the specific metabolic pathway) with an increased incidence of adverse reactions such as confusion, falls and hip fractures in elderly persons. However, the decreased clearance and increased accumulation of the benzodiazepines in question are not clearly validated as the cause of the increased frequency of adverse reactions. Old age may also be associated with an increased intrinsic sensitivity to benzodiazepines; that is, enhanced pharmacodynamic response, relative to young individuals, at any given plasma or target organ concentration. This change in sensitivity may coexist with, or be independent of, alterations in pharmacokinetics. Altered benzodiazepine sensitivity has been documented both in the course of clinical use of benzodiazepines prior to endoscopy or cardioversion, and in placebo-controlled laboratory trials. Animal models of aging have validated an enhanced response to benzodiazepines as a consequence of impaired clearance, increased intrinsic sensitivity or both. However, many studies directly assessing benzodiazepine receptor affinity, density and function in aging animals have failed to identify significant age-related changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1991

Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part II).

Part I of this article, which appeared in the previous issue of the Journal, discussed the scope of and scientific basis for special pharmacokinetic studies of anxiolytic and hypnotic drugs in the elderly, and examined the methodology and results of such studies and the prediction of pharmacokinetic changes. In Part II the authors continue their review, focusing on age-related pharmacodynamic changes in the effects of these drugs, the attempts to correlate pharmacokinetic with pharmacodynamic findings, and the clinical applications of these data.

Aged↗
PubMed1991

The effect of benztropine on haloperidol-induced dystonia, clinical efficacy and pharmacokinetics: a prospective, double-blind trial.

Twenty-nine inpatients with major psychotic disorders were treated for 14 days with a clinician-determined dose of haloperidol and with either benztropine or placebo given by double-blind random assignment on days 1 through 7. No differences were noted in haloperidol mean dose, haloperidol blood levels, or BPRS scores during the first seven days between benztropine (N = 14) and placebo (N = 15) groups. Benztropine-treated patients demonstrated increased dry mouth and diminished sweat and a non-significantly lower rate of dystonia compared to placebo (14% vs. 33%). Dystonic patients were significantly younger than nondystonic patients, but did not differ in haloperidol mean dose or plasma concentration. The effect of benztropine on the incidence of dystonia was consistent with other studies, which, when analyzed together, demonstrate the efficacy of anticholinergic prophylaxis. The relatively low incidence of anticholinergic side effects, coupled with the lack of effect on haloperidol blood levels or antipsychotic efficacy, suggest that moderate doses of benztropine in conjunction with haloperidol are a rational approach for the treatment of acute psychosis in young patients.

Adult↗
PubMed1990

Augmentation of GABAA receptor function by chronic exposure to GABA-neutral and GABA-negative benzodiazepine ligands in cultured cortical neurons.

Chronic benzodiazepine agonist administration may lead to decreases in gamma-aminobutyric acidA (GABAA) receptor binding and function, but little information is available concerning chronic GABA-neutral or GABA-negative benzodiazepine exposure. We evaluated effects of chronic exposure to flumazenil (Ro15-1788) and FG 7142 (N-methyl-beta-carboline-3-carboxamide) on GABA-dependent chloride uptake in chick cerebral cortical neurons in primary culture. Acute flumazenil treatment (1 microM) had no effect on chloride uptake, but uptake was increased after 2 days of exposure. Similar increases were observed after 4 and 10 days. Flumazenil, 0.1 microM, had no effect after 10 days, and a 10 microM concentration had a similar effect as the 1 microM concentration. Acute FG 7142 (1 microM) decreased chloride uptake, but uptake was increased markedly after 2, 4, and 10 days of treatment. No effect was observed after treatment for 10 days with 0.1 microM, but a 10 microM concentration showed similar enhancement to the 1 microM concentration. Concurrent treatment with 0.3 microM flumazenil which did not affect chloride uptake and 1 microM FG 7142 for 10 days substantially attenuated the effects of FG 7142, suggesting that FG 7142 effects are mediated at the benzodiazepine site. Benzodiazepine receptor binding was increased in cultures treated for 10 days with 1 microM flumazenil or FG 7142, with an increase in receptor number in both cases but no change in apparent affinity. Neither flumazenil nor FG 7142 (1 microM for 10 days) altered GABA-independent chloride uptake, total cellular protein, protein synthesis or degradation, or neuronal survival. These results indicate that both chronic GABA-neutral and GABA-negative benzodiazepine exposures in cultured cortical neurons lead to increases in GABA-dependent chloride uptake and benzodiazepine binding. Effects of GABA-negative benzodiazepine exposure appear to be greater than those observed with GABA-neutral benzodiazepine exposure.

Animals↗
PubMed1990

Neurochemical and pharmacokinetic correlates of the clinical action of benzodiazepine hypnotic drugs.

Benzodiazepine derivatives are presumed to exert their pharmacologic activity via interaction with specific molecular recognition sites, termed benzodiazepine receptors, within the brain. The various benzodiazepines used in clinical practice differ considerably in their intrinsic receptor affinity, but the qualitative character of the drug-receptor interaction is similar or identical among this class of drugs. All benzodiazepines are lipophilic (lipid-soluble) substances that relatively rapidly cross the blood-brain barrier and equilibrate with brain tissue. After equilibrium is attained, a constant brain:plasma ratio is maintained, such that plasma concentrations proportionately reflect concentrations of drug in brain. Brain concentrations are proportional to the extent of receptor occupancy, which in turn determines the acute behavioral effect. Clinical differences among benzodiazepines largely reflect differences in pharmacokinetic properties. The onset of action after single oral doses reflects the rate of absorption from the gastrointestinal tract, whereas the duration of action is determined by the rate and extent of drug distribution to peripheral tissues, as well as by the rate of elimination and clearance. During multiple dosage, long half-life drugs accumulate, with the concurrent possibility of daytime sedation. However, a benefit of long half-life drugs is that rebound insomnia on abrupt termination is unlikely. Short half-life drugs accumulate minimally and have a lower likelihood of producing daytime sedation. However, they may be more likely to produce rebound insomnia on abrupt discontinuation.

Anti-Anxiety Agents↗
PubMed1990

Reduced benzodiazepine sensitivity in panic disorder.

We evaluated the functional sensitivity of the gamma-aminobutyric acid-benzodiazepine supramolecular complex in 9 patients with panic disorder and 10 psychiatrically healthy control subjects by comparing the effects of four logarithmically increasing doses of intravenous diazepam on saccadic eye movement velocity, memory, and self-rated sedation. Patients with panic disorder were less sensitive than controls to diazepam using eye velocity as the dependent measure. Sedation and memory effects did not distinguish the two groups. These findings suggest that panic disorder is associated with functional subsensitivity of the gamma-aminobutyric acid-benzodiazepine supramolecular complex in brain-stem areas controlling saccadic eye movements.

Adult↗
PubMed1990

The neuropsychiatric effects of aspartame in normal volunteers.

Ten healthy volunteers with no history of aspartame intolerance (6 men and 4 women, aged 21-36 years) received a single dose of aspartame (15 mg/kg body weight in capsules) or matching placebo in a randomized, double-blind crossover study. Eleven blood samples collected over 24 hours were analyzed for plasma glucose and amino acid concentrations. The following variables were evaluated at 1, 2, 4, 8, and 24 hours post-dosage: changes in mood measured on visual analog scales, cognitive function determined by digit-symbol substitution test (DSST) and arithmetic test scores, and reaction time measured with a brake-pedal reaction timer. Memory was tested at 2 and 24 hours after dosage based on recall of standardized 16-item word lists. No significant differences between aspartame and placebo were found in measures of sedation, hunger, headache, reaction-time, cognition, or memory at any time during the study. Plasma phenylalanine levels were significantly higher following aspartame (P less than .01) than with placebo between 1 and 6 hours postdosage, reaching a maximum difference of +3.36 mumols/dl at 2 hours. Plasma glucose concentrations were not significantly different between aspartame and placebo. The results of this study suggest that following a single 15 mg/kg dose of aspartame, no detectable effects are observed in a group of healthy volunteers with no history of aspartame intolerance, despite significant increases in plasma phenylalanine concentrations.

Administration, Oral↗
PubMed1990

Separate and combined effects of caffeine and alprazolam on motor activity and benzodiazepine receptor binding in vivo.

CD-1 mice received single intraperitoneal (IP) doses of caffeine-sodium benzoate (caffeine doses: 0, 20 and 40 mg/kg) followed by injections of alprazolampropylene glycol (0, 0.05, and 2 mg/kg, IP) to determine brain concentrations, effects on in vivo receptor binding of a specific high-affinity benzodiazepine receptor ligand [3H]Ro15-1788, and effects on motor activity over a 1-h period. A behavioral monitoring device, using infrared sensors, measured horizontal and ambulatory activity. Caffeine produced significant increases in all motor activity measures as compared to vehicle treatment, with low dose caffeine (with brain concentrations of 13 micrograms/g) stimulating activity to a greater degree than the high dose (with brain concentrations of 30 micrograms/g). The overall effect of caffeine on benzodiazepine receptor binding was not significant. Alprazolam significantly diminished motor activity and altered benzodiazepine receptor binding. Low dose alprazolam increased binding, while the high dose diminished it. Caffeine and alprazolam antagonized each other's behavioral effects in this study, but did not alter each other's uptake into brain. Alprazolam's antagonism of caffeine-induced motor stimulation was associated with decreases in receptor binding, whereas caffeine's reversal of alprazolam-induced motor depression was not associated with any changes in binding. The lack of a clear association between drug effects on benzodiazepine binding and on motor activity suggests that behavioral effects of caffeine and alprazolam may be mediated by other sites in addition to the benzodiazepine receptor.

Alprazolam↗
PubMed1990

Chronic morphine administration augments benzodiazepine binding and GABAA receptor function.

Behavioral and neurochemical evidence indicates links between the opioid and GABA neurotransmitter systems. To assess effects of chronic opiates on the major site of postsynaptic GABAergic activity, the GABAA receptor, we administered chronic morphine and naltrexone to mice and evaluated binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites and GABA-dependent chloride uptake. After morphine (3 days), benzodiazepine receptor binding in vivo but not in vitro was increased in cortex compared to placebo-treated mice. TBPS binding was unchanged in cortex, but muscimol-stimulated chloride uptake was increased at low doses of muscimol. Benzodiazepine and TBPS binding and muscimol-stimulated chloride uptake were unchanged in naltrexone-(8 days) compared to placebo-treated mice. When naltrexone was administered previously to block opiate sites, the increases in benzodiazepine binding and chloride uptake observed with chronic morphine were reversed. These results indicate that chronic morphine but not naltrexone enhances benzodiazepine binding and GABAA receptor function, perhaps by an action at opioid receptors.

Animals↗
PubMed1990

Chronic administration of benzodiazepines--V. Rapid onset of behavioral and neurochemical alterations after discontinuation of alprazolam.

Discontinuation of chronic treatment with alprazolam may cause a characteristic clinical syndrome. To assess the basis of this syndrome, mice were treated with alprazolam, 2 mg/kg, for 7 days, a regimen associated with the development of tolerance and downregulation of receptors. Effects on motor activity and the binding and function of GABA receptors were evaluated 1, 2, 4 and 7 days after discontinuation. Motor activity was similar to controls 1 day after cessation of alprazolam, increased from days 2 to 4 after-alprazolam, and returned to control values by 7 days. The binding of benzodiazepines in vivo and in vitro was increased in the cortex 2 and 4 days after alprazolam and in the hypothalamus at 4 days after alprazolam. Binding returned to control values in all areas by 7 days. Binding at the chloride channel, using [35S]t-butylbicyclophosphorothionate, was not significantly altered after discontinuation. Muscimol-stimulated uptake of [36Cl-] in cortical synaptoneurosomes was increased at 4 days after alprazolam, compared to days 1, 2 and 7. Thus, behavioral and neurochemical alterations was associated with the discontinuation of alprazolam. These alterations were qualitatively similar to those observed following discontinuation of lorazepam but occurred more rapidly and with differing regional specificity.

Alprazolam↗