Effects of flunitrazepam on responses to lateralized visual stimuli: evidence for cerebral asymmetry of execution of manual movements to targets in contralateral and ipsilateral visual space.

In order to examine the effects of benzodiazepines on response execution by the left and right hemisphere, flunitrazepam (1 mg) or placebo was administered to healthy, right handed volunteers in two separate experiments. In experiment 1, drug was administered daily during a treatment period of 8 days, and subjects were instructed to fixate vision centrally and to execute laterally directed manual responses corresponding to the position of visual stimuli presented in either the right or left hemifield. Experiment 2 was performed with a single dose and cross-over design, and subjects responded to the laterally presented visual stimuli by key press of a centrally positioned response device, i. e. neither detection of position of the stimulus in space nor response selection was required before initiation of the response. In experiment 1, intake of flunitrazepam generally increased reaction time more during response execution by the left as compared to the right hemisphere, and the most pronounced effect was observed on responses with the right hand, directed across the body axis, to visual stimuli presented in the left visual field. In contrast to these observations, in experiment 2, flunitrazepam impaired responses with the right and left hand practically to the same extent. Together, the results indicate that benzodiazepines may affect manual responses executed by left and right hemisphere differently, and that this asymmetry may be related to a stimulus-response compatibility effect in tasks that require response selection.

Relationship between unbound plasma concentrations and various psychomotor and subjective effects after intakes of diazepam and flunitrazepam.

Unbound plasma concentrations of diazepam and flunitrazepam were related to psychomotor and subjective effects of the two drugs. The interindividual variability in plasma protein binding of both diazepam (98.5 +/- 0.14%) and flunitrazepam (84.5 +/- 1.2%) was relatively small, and high correlations were therefore observed between the individual unbound and total drug plasma concentrations after a particular dose. However, poor correlations were seen between individual unbound drug plasma concentrations and psychomotor or subjective effects. This observation indicates that factors other than individual variability in drug plasma concentration, account for the pronounced individual differences in, for example, psychomotor impairment frequently observed after intake of benzodiazepines. Furthermore, based on a linear relationship between unbound drug plasma concentrations and increase in either complex choice or simple reaction time, the potency of flunitrazepam was calculated to be about seven times higher than the potency of diazepam. This is approximately two times higher than expected from the reported in vitro affinity of the two drugs for the benzodiazepine receptor. This finding may indicate that flunitrazepam may have a higher apparent in vivo intrinsic efficacy than diazepam when assessed by psychomotor impairment.

Development of acute tolerance after oral doses of diazepam and flunitrazepam.

Flunitrazepam (1 and 2 mg), diazepam (10 and 20 mg) or placebo was administered to healthy, male volunteers, and the time course of psychomotor impairment, as indicated by simple and complex choice reaction time and movement time, was studied during a period of 6 h after drug intake. To examine whether acute tolerance developed, the observed performance during decreasing drug plasma concentration was compared to the predicted performance based on kinetic-dynamic modelling of the observed performance during the first 1.5 h after intake when the drug plasma concentrations were increasing or at peak level. Placebo corrections of the test scores were accomplished to adjust for diurnal variation and the possible influence of learning during the test day. After the flunitrazepam treatments, the predictions overestimated the actual performance significantly with respect to simple and choice reaction time at the 6-h session after intake. After the diazepam treatments, however, no significant deviation was detected between predicted and observed performance. The results indicate that acute tolerance develops with respect to impairment of attention demanding performance after medium to large doses of flunitrazepam, and that tolerance is expressed after approximately 4-6 h following intake.

Amnesic effects and subjective ratings during repeated dosing of flunitrazepam to healthy volunteers.

Flunitrazepam (1 mg) or placebo was administered once daily over a treatment period of 8 days to healthy, male volunteers to study the time course of the effects on memory functions and on subjective ratings of alertness and tension. The plasma level of flunitrazepam increased by approximately 40% (P < 0.05) during the treatment period. The mean pre-dose level of flunitrazepam on day 4 and day 8 was approximately 0.005 microM, and no residual effects on memory functions were observed. Intake of flunitrazepam decreased the number of freely recalled words by about 85% (P < 0.05) and significantly affected the subjects' rating of attention when tested during the first few hours after drug intake on day 1 of treatment. However, no significant effect on the subjects' rating of relaxation was observed. When tested similarly after 8 days treatment, flunitrazepam significantly affected the subjects' rating of relaxation (P < 0.01). Furthermore, no tolerance developed for the effect of flunitrazepam on free recall (P > 0.3) and the subjects' rating of attention (P > 0.7), and these effects had nearly equal time courses during the treatment period. This may indicate that the amnesic effect of benzodiazepines is at least partially mediated through the effects on attention or general arousal. Two of the subjects in the active drug group reported adverse reactions or incidents of discomfort during the 1st week following the treatment period, whereas none in the placebo group reported such reactions.

An animal model of postmortem amitriptyline redistribution.

An experimental rat model was developed to study postmortem changes of drug concentration after an acute overdose. Overnight fasted rats were fed 75 mg of amitriptyline (AMI). Two h after dosing, the rats were anaesthetized and blood samples were drawn from the femoral vein (peripheral blood--PB) and the heart (HB). The rats were sacrificed by CO2 and left at room temperature for either 0.1, 0.5, 1, 2, 5, 10, 24, 48, or 96 hours, when samples of heart blood, blood from the inferior vena cava (PB) and tissue samples from different liver lobes, heart, lungs, kidney, thigh muscle, and brain were taken. Samples were analyzed by high performance liquid chromatography. The AMI concentration in HB increased fairly rapidly within the first 2 h postmortem and from then the average ratio was 6.4 +/- 0.8 (mean +/- sem) (n = 31). In PB, the post/antemortem AMI concentration ratio followed an approximately exponential rise; at 2 h postmortem the ratio was 1.6 +/- 0.3 (n = 5), and at 96 h 55.1 +/- 23.8 (n = 4). For the main metabolite nortriptyline (NOR), the concentration changes followed the same pattern, but to a lesser extent. Among the tissues, the liver lobes had high, but variable drug concentrations; lobes lying closest to the stomach had the highest drug concentrations. The drug concentration in the lungs declined significantly. This animal model demonstrates postmortem drug concentration changes similar to those described in humans. Probable mechanisms include drug diffusion from the stomach and GI tract to the surrounding tissues and blood; and postmortem drug release from the lungs and possibly other drug-rich tissues into the blood.

Measuring ethanol in blood and breath for legal purposes: variability between laboratories and between breath-test instruments.

We determined the concentrations of ethanol in nearly simultaneous specimens of venous blood (BAC) and end-expired breath (BrAC) after healthy volunteers drank moderate amounts of alcohol. BAC was measured at two laboratories and BrAC was analyzed with two instruments (Intoxilyzer 5000) from the same manufacturer. The mean difference in BAC between laboratories was 0.0105 mg/g (SD 0.0219); 95% of the differences ranged from -0.0333 to 0.0543 mg/g. The mean difference in BrAC between instruments was 0.0153 mg/L (SD 0.0136), and 95% of the differences ranged from -0.0119 to 0.0425 mg/L. The coefficient of variation (CV) between laboratories was 2.9% compared with 4.5% between breath-test instruments. Venous BAC (y) and BrAC (x) were highly correlated (r = 0.978). However, when the Intoxilyzer instruments indicated that BrAC had reached zero, the actual BAC was 0.135 mg/g, according to the average forensic laboratory reports. The Intoxilyzer 5000 breath analyzers used in this study seem to have a constant analytical bias.

[Neurobiological aspects of addictive drugs]. / Neurobiologiske aspekter ved avhengighetsdannende stoffer.

Increasing insight into the molecular and cellular mechanisms of drugs of abuse has been obtained during the last decade. Such drugs exert several of the effects related to their abuse potential by interacting with the mesocorticolimbic dopaminergic system. Single doses of several drugs of abuse increase dopamine activity in nucleus accumbens, which is related to reward and reinforcement. Repeated administration may result in development of tolerance, but also in behavioral sensitization and conditioning. These processes alter subsequent drug-related behaviours and may contribute to relapse to drug taking.

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.

[Intravenous abuse of crushed tablets. A case with fatal outcome]. / Intravenøst misbruk av knuste tabletter. Et tilfelle med dødelig utgang.

We present a case of fatal vascular destruction and granulomatosis of the lungs from intravenous injections of dissolved tablets containing microcrystalline cellulose as filler material. Numerous microcrystalline cellulose pulmonary emboli and foreign body granulomas were detected, and the pulmonary parenchyma showed signs of disturbed circulation with focal necrosis and oedema.