Relationship between drug plasma concentrations and psychomotor performance after single doses of ethanol and benzodiazepines

In a placebo controlled, crossover study psychomotor effects of single doses of diazepam, 10 and 20 mg, flunitrazepam, 1 and 2 mg, as well as 0.9 g ethanol/kg body weight were investigated over a time period of 6 h in 12 healthy men. Blood samples were collected simultaneously with the test sessions to determine drug concentrations in plasma or blood. The ethanol dose caused the least performance impairment, followed by 10 mg diazepam. The most pronounced impairment was caused by 2 mg flunitrazepam, whereas 20 mg diazepam and 1 mg flunitrazepam caused intermediate impairment and were approximately equipotent on group level. Considerable interindividual differences with respect to maximal impairment following a particular drug treatment were observed, with poor correlation between individual maximal impairments and individual peak plasma concentrations of the drug. The maximal impairment in simple reaction time following the flunitrazepam treatments occurred earlier relative to the peak plasma concentration of the drug as compared to the diazepam treatments. This may indicate that acute tolerance develops differently for the two drugs.     

Acute effects on psychomotor performance of binedaline alone and with alcohol

The effects of single oral doses of binedaline (100 mg), imipramine (50 mg) and placebo administered without and with alcohol (0.8 g/kg) were compared on performance tasks (posturographic recordings, i.e., body sway to study alertness, squares test to explore attention and concentration) and subjective assessments in 12 healthy volunteers. The tasks were completed 1.4 and 8 h after drug administration. Blood samples were collected at the same times. Binedaline had no significant effects on any of the task parameters and did not interact with alcohol. Imipramine alone impaired performance at 4 h as shown on posturographic parameters. These disturbances were potentiated by the intake of alcohol. No pharmacokinetic interaction was noted.     

Relationship between plasma concentrations and pharmacological effects of labetalol

Summary In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the administered dose of labetalol. Labetalol was rapidly absorbed from the gastrointestinal tract and peak plasma concentrations occurred two hours after oral administration. There was a linear correlation (r=0.84) between the logarithm of the plasma concentration and the maximum inhibition of exercise tachycardia at two hours. After intravenous administration there was an immediate reduction in systolic and diastolic blood pressure with a concomitant small increase in heart rate. There was a rapid decline in the associated plasma concentration but the pharmacological effects were maintained in excess of two hours. Our findings are consistent with those of others who have studied the relationship between pharmacological events and plasma concentrations after single doses of other adrenoceptor blocking drugs.     

Acute and subacute effects on psychomotor performance of femoxetine alone and with alcohol

Summary The effects on human psychomotor performance of femoxetine (FEMO), a 5-hydroxytryptamine-selective antidepressant, alone and in combination with alcohol (EtOH) were compared with those of amitriptyline (AMI) and placebo in a controlled double-blind crossover trial in 11 student volunteers. Objective measurements (body sway, choice reaction, flicker fusion, tracking, nystagmus, digit symbol substitution, backwards recall) and subjective self-assessment (visual analogue scales, reporting of side-effects) were done after single doses of FEMO, AMI and placebo, and subacute administration of FEMO and placebo. Single doses of 200 mg FEMO did not impair psychomotor performance, but 50 mg AMI did so in several respects. AMI but not FEMO increased the objective and subjective effects of EtOH. After FEMO 600 mg/d for 10 days almost no objective difference from placebo was noted, although mild sedation at home was reported as a side-effect. FEMO either did not increase or slightly decreased the effect of EtOH on reactive and co-ordination skills. The plasma concentrations of FEMO varied widely from 0 to 156 ng/ml, as in previous clinical trials but reduced a blood 5-hydroxytryptamine concentration in each subject indicating an effect of FEMO on serotoninergic mechanisms.     

Relationship between blood alcohol concentration and carbohydrate-deficient transferrin among drivers

Carbohydrate-deficient transferrin (CDT) was quantified in 408 blood specimens, randomly selected from 1260 drivers apprehended and submitted to blood alcohol concentration (BAC) determination. The first step of the study was to observe whether a BAC based pre-evaluation was relevant for deciding to test drivers for chronic alcohol abuse. For this purpose, the diagnosis of chronic alcohol abuse was verified by CDT quantification, with a voluntary high positive cut-off fixed at 3% for high specificity. The results display a significant increase in the part of chronic alcohol abusers with respect to increasing BAC: a few alcohol abusers were present in the BAC category below 0.5 g/L, and their frequency increased to 47 and 67% when BAC was between 3 and 3.5 g/L and above 3.5 g/L, respectively. Secondly, the usefulness of the biomarker CDT in the traffic safety context was investigated by observing whether drivers with abnormally increased CDT value had also higher BAC. The average BAC was 1.32 g/L in drivers with CDT below 1%, and increased to 2.28 g/L in drivers with CDT above 3%. Statistical analysis showed evidence of a monotone increasing link between BAC and CDT (P<0.0001). We confirmed here the relevance of BAC-based pre-evaluation before testing chronic alcohol abuse among drivers, and demonstrated that CDT is a biomarker suitable for traffic safety context, as drivers with increased CDT had significantly higher BAC.     

Correlations between serum ami- and nortriptyline concentrations and psychomotor performance

Correlations of serum nortriptyline (NT) and amitriptyline (AT) levels with psychomotor performance choice reaction performance, eye-hand coordination, and divided attention was studied in two experiments each with 20 healthy subjects. In the first experiment serum NT level was measured with an isotope derivative method after treatment for 14 days with NT. In the second trial plasma AT and NT concentrations were measured with gas-chromatography after treatment for 14 days with AT. No linear correlations between the levels of the antidepressants and performance variables were found. Low levels of NT (less than 50 ng/ml) tended to shorten reaction time, and intermediate levels (50--80 ng/ml) to prolong it, when compared with the reaction times during placebo. The correlation between serum NT levels and the increase of the tyramine dose in the tyramine pressor test was not significant. A new assay method for AT and NT is presented.     

Ethanol effects on brain concentrations of amitriptyline and the relationship to psychomotor function

The effect of amitriptyline (AMI), ethanol (ETOH), and ETOH followed by AMI on both general activity (open field) and motor performance (two rotorod tasks) was tested in reference to a saline-injected control. The combination (ETOH plus AMI) produced greater impairment on all three taks than did either drug alone. ETOH pretreatment also produced a 223% increase in the total tricyclic antidepressant (TCA) brain concentration. The decrement in motor performance was logarithmically related to total TCA brain concentrations in both animals treated with AMI alone and those pretreated with ETOH prior to AMI. The concentration which consistently produced behavioral impairment was similar to those previously reported to cause cognitive and electroencephalographic dysfunction in humans.     

Relationship between lung tissue and blood plasma concentrations of inhaled budesonide

In 11 patients, in whom a lung lobe or whole lung was to be resected, a single dose of 1.6 mg inhaled budesonide was given pre-operatively. In 9 of them, concentrations of the drug in both lung tissue and blood plasma were measured. Budesonide concentrations in lung tissue, at least 90 min after dosage, were 2.1–8.9 nmol kg^?1. Concentrations in blood plasma (0.27–1.1 nmol kg^?1) were 1/8th of those in lung tissue.     

Relationship between blood alcohol concentration on admission and outcome in dimethoate organophosphorus self-poisoning

AIMS

Many patients acutely poisoned with organophosphorus insecticides have co-ingested alcohol. Although clinical experience suggests that this makes management more difficult, the relationship between plasma concentration of alcohol and insecticide is unknown. We aimed to determine whether acute intoxication results in ingestion of larger quantities of insecticide in dimethoate self-poisoning and a worse clinical outcome.

METHODS

We set up a prospective study of acute dimethoate self-poisoning in Sri Lankan district hospitals. An admission plasma sample was analysed to identify the ingested insecticide; in patients with detectable dimethoate, plasma alcohol was measured.

RESULTS

Plasma from 37 of 72 (51.4%) dimethoate-poisoned patients had detectable alcohol {median concentration 1.10 g l⁻¹[110 mg dl⁻¹][interquartile range (IQR) 0.78–1.65]} a median of 3 h post ingestion. The median plasma dimethoate concentration was higher in patients who had ingested alcohol [479 µmol l⁻¹ (IQR 268–701) vs. 145 µmol l⁻¹ (IQR 25–337); P < 0.001]. Plasma dimethoate concentration was positively correlated with plasma alcohol (Spearman''s ρ= 0.34; P= 0.0032). The median alcohol concentration was higher in the 21 patients who died compared with survivors (0.94 vs. 0.0 g l⁻¹, P= 0.018). Risk of death was greater amongst individuals who consumed alcohol [odds ratio (OR) 4.3, 95% confidence interval (CI) 1.2, 16.4]; this risk was abolished by controlling for dimethoate concentration (OR 0.3, 95% CI 0.0, 8.8), indicating that deaths were not due to the direct toxic effects of alcohol.

CONCLUSIONS

Alcohol co-ingestion is associated with higher plasma concentrations of dimethoate and increased risk of death. Larger studies are required to assess this finding''s generalizability, since efforts to reduce deaths from self-poisoning may benefit from concurrent efforts to reduce alcohol consumption.     

Acute and subacute effects of diazepam on psychomotor skills: interaction with alcohol.

Effects of diazepam and alcohol on psychomotor skills were measured in two trials. In the first one, 200 healthy students volunteered for a double-blind single-dose study. Three doses of diazepam (5, 10 and 20 mg) and alcohol (0.5, 0.8 and 1.2 g/kg) were used alone and combined to construct dose-response graphs. All doses of alcohol impaired divided attention while co-ordinative skills were impaired by the 1.2 g/kg dose. Diazepam alone did not impair reactive or co-ordinative skills whereas the combinations of diazepam and alcohol did so. To further elucidate the subactue effects, a double-blind randomized study was conducted administering 2 and 10 mg of diazepam t.i.d. for two weeks to 18 healthy volunteers. The psychomotor tests were performed on the 7th and 14th days of drug administration, and 0.5 g/kg of alcohol was given on either day. Diazepam 2 mg, alone or with alcohol, did not differ from placebo. 10 mg of diazepam slightly increased reaction times but not reaction mistakes, and impaired both co-ordination and attention. Alcohol did not enhance diazepam effects. We suggest that a development of tolerance to diazepam may compensate the deleterious interaction of the agents found in acute studies.     

Relationship between the cardiac response to acute intoxication and alcohol-induced subjective effects throughout the blood alcohol concentration curve

RATIONALE: There is evidence to suggest that individual differences in the subjective response to alcohol exist and exaggerated cardiac response to alcohol has been suggested to be a marker of increased sensitivity to the stimulant properties of alcohol. OBJECTIVES: The present investigation examines the relationship between cardiac reactivity to alcohol measured on the ascending limb of the Blood Alcohol Concentration (BAC) curve and the subjective stimulant and sedative effects of alcohol throughout the BAC curve. METHODS: The stimulant and sedative effects of alcohol anticipatory to alcohol and during the ascending and descending limbs of the BAC curve were evaluated using the Biphasic Alcohol Effects Scale in 39 male social drinkers. RESULTS: Cardiac response to ethanol measured on the ascending limb of the BAC curve was positively correlated with intoxicated stimulant effects at numerous time points during the ascending and descending limbs of the BAC curve (ps < 0.01). No associations were found between cardiac change following alcohol and alcohol-related sedative effects at any time point. CONCLUSIONS: Objective and subjective reports of stimulation post-alcohol ingestion may increase risk for problematic drinking.     

Comparative effects of conventional B-blockers and nebivolol on psychomotor performances in healthy volunteers: a preliminary report

The present study was under taken to assess the comparative effects of nebivolol with propranolol and atenolol on psychomotor performances. Thirty healthy volunteers were randomized into three groups with n=10 in each group. Each subject received single dose of one of the three medications (nebivolol 5 mg, atenolol 50 mg and propranolol 40 mg) in morning (9:00 AM). Just before administering the drug, the pre-drug scores were taken, followed by post drug score obtained for consecutive six hours. Psychomotor assessment was carried out by three tests Simple Reaction Timer (SRT), Critical Flicker Fusion Frequent Threshold (CFFT) and Digit Cancellation Test (DCT). The results of present study indicate that single doses of atenolol and propranolol produced significant impairment of psychomotor performance. Nebivolol also impaired psychomotor performance tests in the similar fashion to atenolol and propranolol. Hence, the findings of the present study correlate with the lipophilic nature of the nebivolol.     

Relationship between facial flushing and blood acetaldehyde levels after alcohol intake.

Normal subjects were divided into two groups, i.e., those showing, and those not showing, facial flushing after consuming a small amount of alcohol. In the flushing group, increases of pulse rate, facial skin temperature and carotid arterial pressure and blood flow rate, as well as changes of digital plethysmogram and electrocardiogram, were found together with a conspicuous rise in blood acetaldehyde levels after the drinking. However, significant changes of the signs as mentioned above and elevation of blood acetaldehyde did not occur in the non-flushing group. The maximum blood alcohol levels and the rate of alcohol elimination showed not difference between these two groups. Furthermore, urinary excretions of epinephrine and norepinephrine increased in the flushing cases after the drinking.     

Interactions between alcohol and caffeine in relation to psychomotor speed and accuracy

Unlike other CNS depressants, alcohol intoxication can be associated with increased error rates, coupled with unaffected (or speeded) response rates during psychomotor and cognitive processing. The present study examined whether concurrent consumption of caffeine may differentially affect these aspects of alcohol and performance.A randomised, double-blind, placebo-controlled design was utilised in which 64 healthy young volunteers received either 0.66 g/kg alcohol, caffeine (110-120 mg), both or neither. Performance was assessed using a four choice reaction time task (FCRT) with elements of repetitive (predictable) and random stimuli sequences and the digit symbol substitution task (DSST). Individuals on alcohol made significantly more errors during both fixed and random FCRT sequences, and there was evidence of weak antagonism of these effects by caffeine on the latter measure. On the DSST test of psychomotor speed, alcohol was associated with a significant slowing, the caffeine group were significantly faster and there was clear antagonism of the effects of alcohol by caffeine. These findings confirm that alcohol consumption is associated a greater number of errors and provide some evidence for task-specific antagonism of alcohol's cognitive effects by caffeine.     

Effects of desloratadine and alcohol coadministration on psychomotor performance

ABSTRACT

Objective: This study was set up to evaluate the effects of desloratadine 7.5?mg daily, with and without alcohol, on sedation and psychomotor performance.

Research methods: In a double-blind, placebo-controlled, four-way crossover trial, 25 adult patients were randomized to desloratadine 7.5?mg, desloratadine 7.5?mg plus alcohol, placebo, or placebo plus alcohol. Alcohol was weight adjusted to an average blood alcohol concentration of 0.1%. Assessments included the modified Romberg test, Stanford Sleepiness Scale, Digit Symbol Substitution Test, Serial Add Subtract Reaction Time Test, and the Psychomotor Vigilance Test. The primary variable was the mean score of each of the five tests averaged over the treatment period, expressed as the mean percent change from baseline.

Results: Across these assessments, differences between desloratadine alone or with alcohol versus placebo alone or without alcohol, were not significant, whereas most differences between desloratadine and placebo alone versus desloratadine and placebo with alcohol were significant (?p < 0.01). Thus, with or without alcohol, desloratadine 7.5?mg does not increase sedation or impair psychomotor performance. Most adverse events (AEs) were mild-to-moderate in severity, with the most frequently reported individual AEs being headache, fatigue, nausea, vomiting, and dry mouth. The study does have potential limitations. The measures used are restricted to a particular profile of the known effects of alcohol only, and the relatively high doses of alcohol used alone demonstrate effects on psychomotor function and attention.

Conclusions: A single dose of desloratadine does not potentiate alcohol-mediated CNS impairment. Desloratadine alone or in combination with alcohol was safe and well tolerated.