Residual Drug Effects Research Articles

DOUBLE-BLIND RANDOMIZED MULTICENTRE TRIAL OF ACAMPROSATE IN MAINTAINING ABSTINENCE FROM ALCOHOL

A prospective placebo-controlled, randomized double-blind study of Acamprosate at two dose levels in alcohol-dependent patients followed up for 12 months was performed. After detoxification, each of the 538 patients included was randomly assigned to one of three groups: 177 patients received placebo, 188 received Acamprosate at 1.3 g/day (low dose group) and 173 received 2.0 g/day (high dose group) for 12 months. This was followed by a single blind 6 month period on placebo. The patients' mean age was 43.2 +/- 8.6 years. Their mean daily alcohol intake was high (nearly 200 g/day) and of long duration (9.5 +/- 7.1 years). Abstinence figures followed the order high dose > low dose > placebo. The difference was significant at 6 months (P < or = 0.02) but not at 12 months (P = 0.096). The number of days of continuous abstinence after detoxification was 153 +/- 197 for the high-dose group versus 102 +/- 165 for the placebo group (P = 0.005), with the lose-dose group reporting 135 +/- 189 days. Clinic attendance was significantly better in the Acamprosate groups than in the placebo group at 6 months (P = 0.002) and 12 months (P = 0.005). During the 6-month post-treatment period, no increased relapse rate or residual drug effect was observed. The side effect profile for Acamprosate was good compared with controls with only diarrhoea being reported more frequently (P < 0.01). This study confirms the pharmacological efficacy of Acamprosate and its good acceptability. As an adjunct to psychotherapy, this study supports the inclusion of Acamprosate in a strategy for treating alcoholism.

Postoperative Tracheal Extubation

Postoperative Tracheal Extubation

Postoperative Tracheal Extubation

Postoperative Tracheal Extubation

Hypnotic drugs, psychomotor performance and ageing.

This review examines studies, reported since 1976, in which the residual effects of hypnotic drugs on psychomotor performance have been evaluated in older people. The 33 studies involved a total of 934 subjects (aged 60-96 y), evaluated 21 different products, utilized 26 test procedures, and reported 169 drug versus placebo (or drug versus drug) comparisons, of which 42 were associated with significant residual impairment. While performance decrements were more associated with longer half-life drugs, repeated dosing, and frailty, these characteristics were often unreliable in predicting outcome. Significant improvements in performance were rare, and usually consistent with practice effects. While this literature provides a useful basis for clinical caution, it is not characterized by experimental rigour, and provides little or no empirical basis for predicting those real-life skills most likely to be affected. Issues of subject selection, experimental design, testing strategies, and data analysis need to be addressed if the risks and benefits of hypnotic drug use in later life are to be more clearly understood.

A double blind comparison of the effects of fluoxetine and amitriptyline on cognitive function in elderly depressed patients

AbstractSixty‐six elderly depressed patients received fluoxetine 20 mg (FLU) or amitriptyline 75 mg (AMI) for 42 days in a double blind parallel group study. Each week, subjects completed a test battery which is sensitive to the residual effects of psychoactive drugs. The results show that FLU and AMI were equally effective in relieving depression. However, the psychometric test battery showed that, compared to FLU, AMI, as expected, produced impairments in cognitive function and psychomotor performance. The relative impairment of cognitive and psychomotor skills following the tricyclic AMI and the lack of such activity after administration of the selective serotonin reuptake inhibition, FLU are important considerations when prescribing antidepressants, especially when the safety and well being of ambulant patients is essential.

A comparative study of on‐the‐road and simulated driving performance after nocturnal treatment with lormetazepam 1 mg and oxazepam 50 mg

AbstractThe main purpose of this study was to compare the sensitivity of a driving simulator test model (TS2) with a standard on‐the‐road driving test, after one night treatment with lormetazepam 1 mg, oxazepam 50 mg (as a verum) and placebo. The secondary purpose was to measure the effects of the intended drugs and placebo in the same subject sample, after two treatment nights in the morning and in the afternoon, on on‐the‐road driving performance. Eighteen healthy male volunteers received the three treatments (2 consecutive nights each) according to a double‐blind, three‐way crossover design. Time of administration was set at 22.00 hours each night. An on‐the‐road driving test and a simulator driving test were conducted in the morning following the first night. After the second treatment night, on‐the‐road driving tests were performed in the morning and in the afternoon. The on‐the‐road driving test consisted of operating an instrumental automobile over a 100 km highway circuit at a constant speed (90 km/h) and constant steady lateral position between the right lane boundaries. Primary performance measure was the SD of lateral position (SDLP). The simulator test consisted of repeatedly performing ‘curve‐following’ manoeuvres, which was the main tracking control task, while simultaneously reacting to secondary visual signs. Test parameters were the number of correctly executed manoeuvres (TC) and reaction time (RT). Oxazepam 50 mg seriously impaired, and lormetazepam 1 mg slightly impaired, on‐the‐road driving performance in the morning, both after the first and second treatment night. The drugs produced no significant effects in the afternoon test following the second night. In contrast with these results, neither oxazepam 50 mg nor lormetazepam 1 mg affected simulator tracking control after one night. No deterioration was found for reaction time. Correlational and multiple regression analyses were applied to determine relationships between SDLP, TC and RT. The major conclusion of this study was that the TS2 driving simulator test does not predict residual drug effects in the on‐the‐road driving test, and seems to be a less sensitive measure of sedative drug‐induced impairment in contrast to the on‐the‐road driving test.

Resedation after bolus administration of midazolam to an infant and its reversal by flumazenil

A 4-month-old infant was sedated with bolus doses of midazolam, and after initial apparent complete arousal, became unresponsive and hypotonic. Administration of flumazenil enabled differentiation of a residual drug effect from an intracerebral event.

Propofol in short gynaecological procedures

Recovery was assessed over 48 hours after anaesthesia with propofol or thiopentone as sole anaesthetic agent in 36 unpremedicated gynaecological patients. Immediate recovery, as measured by the Steward scale, was shown to be quicker for the patients given propofol. At one hour postoperatively the thiopentone group showed impaired visual-motor coordination on the aiming test (p less than 0.01) and dexterity task (p less than 0.05), and a slowing of reaction time (p less than 0.01). Patients given propofol showed only an increase in reaction time (p less than 0.05). By 2 hours the thiopentone group showed impairment only in the aiming task (p less than 0.05). No further significant impairment was detected at 4, 24 or 48 hours. However, patients reported symptoms throughout the 48 hours indicative of residual drug effects. There was a substantial practice effect with some tests which may have obscured impairment. It can be argued therefore that the better recovery profile after propofol is still evident at 24 hours.

Alcohol After Midazolam Sedation

Patients who arrive home several hours after ambulatory surgery may drink alcohol. The extent to which the residual effects of drugs used in ambulatory surgery interact with alcohol, perhaps potentiating alcohol effects, is not known. Accordingly, the purpose of this study was to determine whether intravenous midazolam had residual effects that would interact with alcohol consumed 4 h after the midazolam injection. Healthy male volunteers (n = 16) participated in a double-blind, randomized, placebo-controlled crossover trial. Subjects were studied four times successively with 1 wk between trials. On each test day the subjects randomly received by slow intravenous injection (30 s) either saline or 0.1 mg/kg of midazolam. Four hours after injection, the subjects consumed a beverage that either did or did not contain 0.7 g/kg of alcohol. Before and 1, 3, 5, and 7 h after injection (and before and 1 and 3 h after beverage consumption), psychomotor performance and mood were assessed. Whereas both midazolam and alcohol alone had effects on the dependent measures in this study, there were no significant interactions between the two drugs (i.e., potentiation of alcohol effects by midazolam or potentiation of midazolam by alcohol). We conclude that the effects of a short-acting benzodiazepine used in ambulatory surgery have probably dissipated by the time a patient arrives home, and that effects from alcohol ingested at home will probably not be influenced by the recent administration of a short-acting benzodiazepine such as midazolam.

Effects of 5-fluorouracil on B lymphocyte lineage cells.

Abstract The aim of these studies was to determine the sensitivity of B lymphocyte lineage precursor cells in mice to 5-fluorouracil (5-FU). Selective effects could be very helpful in dissecting precursor-product relationships between these and the rare multipotential stem cells from which they derive. Numbers and functions of particular types of cells were determined at intervals after a single treatment (3 mg) and, as expected, myeloid-committed stem cells were very severely affected. Day 8 spleen colony-forming cells (CFU-S) and colony-stimulating factor-responsive macrophage progenitors were reduced by 98% within 24 hr, whereas presumptive early stem cells (day 14 CFU-S) were much more resistant. B cells, which were probably recently formed in bone marrow and which are not thought to be actively dividing, were also 5-FU-sensitive, but perhaps less so than pre-B cells and immunoglobulin-negative lymphocytes bearing a B lineage marker. Approximately 5 wk were required for the normal cellular composition of marrow to return to normal. Transplantation of marrow from 5-FU-treated mice suggested that the slow regeneration of B lymphocytes might partially result from residual drug effects or damage to microenvironmental elements which are required for B lineage differentiation. Acute reductions of lymphocytes in the thymus were also documented, and the larger cells declined most rapidly and regenerated most slowly in that tissue. Of particular interest was the differential susceptibility of B cells in various lymphoid tissues to 5-FU. Whereas lymph node B cells were minimally affected, one-half of the splenic B cells disappeared within 48 hr of drug injection. Intrinsic differences in 5-FU sensitivity were confirmed by treatment of lymphocytes in vitro, and this suggests that particular B cell sets may be metabolically distinct. This drug should find additional experimental application in studies of B lymphocyte formation and functional heterogeneity.

11 - Immediate and Long-term Nervous System Effects of Anesthesia in Elderly Patients

The structural and functional changes which aging imposes upon the nervous system are extensive, reasonably well documented, and must be considered as significant factors which reduce the pharmacodynamic aspects of anesthetic requirement in elderly patients. However, changes in pharmacokinetics play the most important role in producing residual nervous system depression and prolonged unconsciousness in elderly patients in the immediate postoperative period. The high prevalence of cerebrovascular disease in the elderly surgical population makes it inevitable that catastrophic events such as cerebrovascular accident and embolization will contribute in a small but important manner to postoperative nervous system morbidity and mortality. The frequency with which elderly patients have multiple organ system disorders also makes them at high risk of metabolic and homeostatic disruption, frequently manifest as nervous system symptomatology. Sensitive tests of the more complex aspects of nervous system function of elderly patients such as affect, abstraction, memory and logic reveal a disturbing phenomenon: one-quarter to one-third of these individuals develop new and persistent dysfunction in the immediate or long-term periods of recovery from anesthesia. It is currently impossible to determine the relative magnitude of the contributions made by illness, the hospital environment, surgical stress or the residual effects of anesthetic drugs. Although increasingly favorable figures for gross mortality suggest that, in modern practice, age per se is no longer considered to be an absolute contraindication to general anesthesia as far as survival is concerned, there must be greater awareness that many subtle and intricate aspects of cognitive and affective mental function in these patients may be compromised even under the best of circumstances. Although permanent nervous system damage from routine general anesthesia is extremely rare, many elderly surgical patients require weeks or months to achieve full spontaneous recovery of their preoperative mental status, for reasons that are still unknown. At this stage in our understanding, one can expect a properly conducted general anesthetic to produce uneventful emergence from anesthesia and eventual full recovery of preoperative mental function if the surgical procedure contributes materially to the physical and psychological wellbeing or to the social integration of the elderly surgical patient.

New techniques for the analysis of the human sleep-wake cycle

Two new techniques for the analysis of the human sleep-wake cycle are presented and illustrated. The first is based on a wrist-worn solid-state activity monitor which can record movement activity for prolonged time periods. The method has been applied to document phase-shifts of the rest-activity cycle after crossing time-zones; to analyze the effect of hypnotic drugs on movements during sleep; and to record the severe disruption of sleep and waking in narcolepsy. The second technique consists of all-night spectral analysis of the sleep EEG. In addition to conventional sleep stage scoring by visual analysis, power density values of the sleep EEG are computed for 4-sec epochs in the range of 0.25-25.0 Hz. The spectra provide a more refined and quantitative description of the sleep process than analysis of the sleep stage distribution. The method revealed within individual sleep stages significant trends through the night as well as specific changes induced by sleep deprivation. Spectral analysis was also applied for determining the effect of benzodiazepine hypnotics on the sleep EEG, and for documenting subtle, residual drug effects in the following drug-free night.

Prolonged inhibition of striatal dopamine receptor sites by isofloxythepin

Using the [ 3H]spiperone binding technique to measure the residual drug effect of subcutaneously injected isofloxythepin (1 mg/kg, single dose) in the rat, we observed a significant blockade of [ 3H]spiperone-labeled, high affinity dopamine receptors (D 2) in the striatum up to 4 days after drug administration. Higher doses of isofloxythepin (5 or 10 mg/kg) produced a receptor blockade and were associated with an inhibition of apomorphine-induced stereotypy which lasted more than a week. Neither dopaminergic behavior supersensitivity nor striatal D 2 receptor up-regulation was observed in isofloxythepin-treated rats, even after the animals were withdrawn from the drug for an extended period of time. Isofloxythepin was shown to decrease the B max without altering the K D of [ 3H]spiperone binding (a non-competitive inhibition), and in vitro its binding was not readily dissociated even when the drug-receptor complex was washed repeatedly with large volumes of drug-free buffer. The IC 50 of isofloxythepin for displacing [ 3H]spiperone binding was 0.8 nM. Isofloxythepin is therefore a potent dopamine receptor antagonist with prolonged pharmacological action and strong binding at D 2 receptors.

Prolonged accumulation of diazepam in obesity.

Six obese (mean weight 92 kg) and five normal (60 kg) subjects received 2 mg diazepam nightly for 30 nights. Determination of diazepam and desmethyldiazepam plasma concentrations during the dosing period and for a withdrawal period indicated that accumulation half-life for both diazepam (7.8 days in obese vs. 3.1 days in normal subjects, P less than 0.05) and desmethyldiazepam (30.3 vs. 7.2 days, P less than 0.05) was markedly prolonged in obese subjects. However, mean steady-state plasma concentrations of diazepam (68 vs. 67 ng/ml) and desmethyldiazepam (156 vs. 91 ng/ml) did not significantly differ between groups. To determine the basis for this delay in accumulation in obese subjects, single-dose pharmacokinetics of diazepam and desmethyldiazepam were determined. Diazepam elimination half-life was greatly prolonged in the obese subjects (82 vs. 32 hours, P less than 0.005), with no change in total metabolic clearance (32 vs. 26 ml/min). Instead, a large increase in volume of distribution (228 vs. 70 liters, P less than 0.01) was the reason for prolongation of the elimination half-life. Similarly for desmethyldiazepam, elimination half-life was prolonged in obese subjects (130 vs. 56 hours, P less than 0.01), without a change in total metabolic clearance (13.7 vs. 19.2 ml/min), due to increased volume of distribution (151 vs. 73 liters, P less than 0.01). During chronic dosing with diazepam, obese patients may experience a much slower onset of maximal drug effect compared to normal-weight patients because of the greatly delayed accumulation of diazepam and desmethyldiazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Catecholamine depletion in mice upon reexposure to stress: mediation of the escape deficits produced by inescapable shock.

Immediately following exposure to 60 inescapable shocks, Swiss-Webster mice had significantly reduced hypothalamic norepinephrine (NE). Within 24 hr NE levels returned to control values. Reexposure to as few as 10 shocks 24 hr after initial stress exposure resulted in a significant decline of hypothalamic NE. Moreover, at this interval after inescapable shock, escape performance was severely disrupted, with a large proportion of mice exhibiting numerous failures to escape shock. Increasing brain dopamine (DA) and NE by L-dopa treatment prior to inescapable shock prevented the escape deficits. Conversely, pairing five inescapable shocks with NE depletion by FLA-63, or both DA and NE depletion by alpha-methyl-p-tyrosine, disrupted escape performance 24 hr later. Residual drug effects, state dependence, or sustained amine turnover could not account for the behavioral changes observed. Data are discussed in terms of catecholamine mediation of escape performance through variations in response maintenance abilities. Furthermore, it is suggested that the long-term effects of inescapable shock may be due to sensitization effects or conditioned amine depletion.

Effects of nitrous oxide on decision-strategy and sustained attention.

Effects of 10,20, and 30% N2O on decision-making strategy, reaction-times, sustained attention, the Digit Symbol Subsititution Test (DSST), short-term memory and the Clyde Mood Scale were assessed in 12 test subjects. Decision-making strategy, as measured by 2-choice probability-learning, was unaffected by 30% N2O once a strategy had been formulated, but reaction-times were increased. Sustained attention was significantly affected in 33% of our subjects, whereas performance on the DSST and on the short-term memory task was impaired in virtually all subjects. Changes were noted in several mood-scale factors with 30% N2O. No residual drug effects were found.

Autonomie arousal and affiliation in rats

Pairs of rats were injected with adrenalin, placebo, or chlorpromazine and allowed to interact freely in an open field. Adrenalin-injected rats were significantly more sociable than placebo rats, who in turn were more sociable than chlorpromazine. On later test trials, all animals received placebo injections. There were no differences among conditions, suggesting no residual effects of drugs or of drug-induced experiences in the field.