Effects of adinazolam and diazepam,alone and in combination with ethanol,on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers

Summary Effects on psychomotor and cognitive performance of adinazolam (15 or 30 mg), alone and in combination with ethanol (0.8 g/kg), were studied in healthy male volunteers and compared to effects of 10 mg diazepam.Adinazolam 30 mg produced relatively long-lasting impairments on tests of tracking, attention, verbal and nonverbal information processing, and memory. Adinazolam 15 mg resulted in descreased visual information processing. Adinazolam decreased supine mean arterial pressure, but only the 15 mg resulted in a tendency for decreased plasma norepinephrine concentrations.After standing for 5 min, 30 mg adinazolam was associated with increased heart rate.Although ethanol consumption produced additive decrements on a continuous performance task, there was little evidence to support a synergistic effect.Adinazolam 30 mg was accompanied by increased self-reports of side effects, especially drowsiness.     

Effects of diazepam and ethanol alone and in combination on conditioned suppression of key-pecking in the pigeon.

Pigeons were intermittently given grain reinforcement for key pecks. Occasional 30-sec keylight changes (warning stimulus) were followed by a brief electric shock, which suppressed responding during the warning stimuli. This suppression was reduced by diazepam and ethanol, yet combinations of the two drugs did not reduce suppression (antagonistic effect). Each drug reduced responding in the absence of the warning stimulus, and combinations of the drug produced still greater reductions in this safe-period responding (synergistic effect).     

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.     

Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects

Single doses of alprazolam (0, 0.5, 1.5 mg) or adinazolam mesylate sustained release tablets (SR) (0, 15, 45 mg) were administered to separate groups of 12 healthy men in a crossover design. Psychomotor performance was assessed by digit symbol substitution (DSST), and memory was assessed using a test battery which reflects various aspects of memory, including attention/working memory, explicit memory (recall of categorically related words), semantic memory (fragmented picture recognition, generation of category exemplars), and implicit memory (time saved in resolving fragmented pictures on the second exposure). Maximal psychomotor performance and memory decrements for the highest active doses were significantly different from placebo for all tasks at some time after dosing. The maximum decrement in DSST was not significantly different between drugs at the high dose (P=0.288). Maximum attention/working memory decrements were significantly different between the high doses of the active compounds (P=0.031), and the difference in maximum category recall decrement was marginally significant (P=0.067). Access to knowledge memory was not significantly altered by these drugs; these results are similar to those obtained for other benzodiazepines. Both drugs exhibited slight effects on implicit memory. The results suggest that the sedative and memory effects of these triazolobenzodiazepines may not be closely related and suggest that adinazolam has a somewhat different spectrum of cognitive effects relative to alprazolam.     

Caffeine and diazepam: Separate and combined effects on mood,memory, and psychomotor performance

The effects of caffeine and diazepam on several mood, cognitive, learning, memory, and psychomotor tasks were investigated in a double-blind study of 108 young healthy adults who were randomly assigned to nine treatments; oral administration of caffeine (0, 3 and 6 mg/kg), diazepam (0, 0.15, and 0.30 mg/kg) and their combinations. Subjects completed a battery of tasks once before and twice after administration of the drugs. Caffeine alone showed no effects on cognitive, learning, and memory performance, but impaired fine motor coordination and increased anxiety and tenseness. Diazepam alone produced sedation, lowered other ratings of subjective moods, and impaired cognitive, learning, and memory performance. The two drugs did not antagonize the effects of each other, except in the symbol cancellation task.     

Subjective, psychomotor, and physiological effects of pregabalin alone and in combination with oxycodone in healthy volunteers

Pregabalin is an anticonvulsant drug indicated for neuropathic disorders and fibromyalgia. Some chronic pain patients suffering from these disorders take both this drug and an opioid for pain relief. Pregabalin is a scheduled drug under the Controlled Substances Act. The subjective effects of this drug have not been well-characterized, and the extent to which it alters the subjective effects of opioids has not been studied to the best of our knowledge. Using a double-blind, randomized, crossover design, 16 healthy volunteers were administered (in separate sessions) capsules containing placebo, 75 mg pregabalin, 150 mg pregabalin, 10 mg oxycodone, and 75 mg pregabalin combined with 10 mg oxycodone. Subjective, psychomotor, and physiological measures were assessed during each of the five sessions. Pregabalin produced dose-related increases in some subjective effects and decreased respiration rate, but did not impact on psychomotor performance. Abuse liability-related subjective effects such as drug liking and desire to take the drug again were not increased by either pregabalin dose. Oxycodone produced increases in several subjective effects, including ratings of drug liking. When 75 mg pregabalin was combined with oxycodone some subjective effects were altered relative to placebo, in contrast to when each drug was tested alone. Liking of oxycodone was not increased by 75 mg pregabalin. However, recent studies have suggested that this drug is abused, and we would recommend that further psychopharmacological studies with pregabalin are warranted, including a study assessing its abuse liability across a range of doses in sedative abusers.     

Effects of amitriptyline and zimelidine in combination with ethanol

Six healthy male volunteers took part in this three-period crossover study. In each session, a dose of trial drug —either placebo, zimelidine 200 mg, or amitriptyline 75 mg —was given at 09.00 h. Ethanol (50 g) was taken orally at 1200 h. Blood samples were taken for measurement of drug and ethanol concentrations, and body sway and subjective sedation were determined. No differences in the pharmacokinetics of ethanol were seen between the three treatment sessions. Amitriptyline and ethanol showed marked sedative effects, and the results suggest that these two effects may be additive. The combination of amitriptyline and ethanol results in a particularly marked increase in body sway. No sedative nor alerting effect of zimelidine was seen, nor was any interaction between zimelidine and ethanol apparent.     

Effects of single doses of alprazolam and alcohol alone and in combination on psychological performance

The effects of alprazolam l mg alone and in combination with 0·5 g/kg of alcohol for males and 0·42 g/kg for females were examined on a range of psychological tasks 90 and 180 min post-drug (45 and 135 min post-alcohol). Forty-eight healthy volunteers were assigned randomly to four independent groups who received: alprazolam and placebo drink, alprazolam and alcohol, placebo capsule and alcohol, placebo capsule and placebo drink, respectively. Alprazolam caused subjective sedation, unsteadiness, dizziness and physical tiredness and impaired performance on all tasks. Alcohol caused similar subjective effects but little objective impairment. The effects of the combination were generally no greater than predicted from the sum of the single effects.     

Effects of mizolastine and clemastine on actual driving and psychomotor performance in healthy volunteers

The acute effect of doses of mizolastine 5, 10, 20 and 40 mg, an active control (clemastine 2 mg) and placebo on actual car driving and psychomotor performance have been compared. Twenty four healthy volunteers were treated according to a double-blind, 6-way cross-over design. In the driving test, lasting about 1 h, lateral position control and speed were continuously measured; the psychomotor test battery, lasting 50 min, comprised critical flicker-fusion frequency, critical instability tracking, divided attention, memory search and choice reaction time, and vigilance studies; and mood changes and possible adverse-effects were rated on visual analogue scales. The results showed a dose-response relationship: mizolastine 40 and 20 mg impaired driving and psychomotor performance. The effect of mizolastine 40 mg on driving was strongly correlated with that of clemastine (r=0.78) and was comparable to the effect of a blood ethanol level of 0.8 mg·ml⁻¹. Mizolastine 5 mg and 10 mg did not have a significant effect on driving performance and psychomotor tests. It was concluded that at a 10 mg dose of mizolastine, the therapeutic dose, it could be considered a safe antihistamine, although individual adverse reactions cannot be completely ruled out.     

Effects of single dose of gamma-hydroxybutyric acid and lorazepam on psychomotor performance and subjective feelings in healthy volunteers

Objective: This study investigated the possible effects of gamma-hydroxybutyric acid (GHB) on human psychomotor performance and subjective feelings important for the safety of skilled performance. Methods: Twelve healthy volunteers, six males and six females, aged 22–36 years, participated as subjects. Drugs and placebo were administered according to a single-dose, double-blind, balanced, four-way, cross-over design. Treatments were separated by a wash-out period of 1 week and consisted of placebo, lorazepam 0.03 mg · kg⁻¹, GHB 12.5 mg · kg⁻¹ and GHB 25 mg · kg⁻¹. Subjects' psychomotor performance was assessed at baseline and at 15, 60, 120 and 180 min after treatment. Mood was assessed using 16 visual analogue scales, before treatment and 120 min later. Psychomotor performance was measured using the following tests: Critical Flicker Fusion. Response Competition Test, Critical Tracking Task, Choice Reaction Time and Visual Vigilance Task. Results: GHB at both doses had no effects on attention, vigilance, alertness, short-term memory or psychomotor co-ordination (Δ-placebo, P > 0.05); calmness increased with the lower dose and contentedness decreased significantly at both doses (Δ-baseline, P < 0.05); adverse effects were limited to slight subjective feelings of dizziness and dullness, which disappeared 30–60 min after administration of the dose. Lorazepam caused impairment of psychometric functions. Conclusion: After single therapeutic doses, GHB does not induce changes in psychomotor performance and therefore the drug does not influence the ability to drive or work. However, repeated reports of the abuse potential of GHB and its usefulness in treating ethyl alcohol addiction indicate that it may play an “agonist-like” role, which means that it should only used under close medical supervision. Received: 11 May 1998 / Accepted in revised form: 13 September 1998     

Tofisopam,a novel 3,4,-benzodiazepine: Multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol

Twelve healthy male volunteers were treated (double-blind crossover design) with tofisopam (a new 3,4-benzodiazepine), diazepam, or placebo, on 2 consecutive days each. Psychomotor skills were impaired after a single dose of diazepam (10 mg) given on day 1. Measurements on day 2 showed that some tolerance had developed to the diazepam-induced impairment of reactive and coordinative skills, but not to its effects on flicker fusion or on the extraocular muscle balance. Tofisopam failed to impair performance both as a single dose (100 mg) and after repeated doses (100+50+50+100 mg). The subjects felt more fatigue, dizziness, calmness, and passiveness after diazepam than after tofisopam. When either drug was given together with 0.8 g/kg ethanol on day 2, the breath ethanol concentrations were 0.7–1.0 mg/ml and all psychomotor skills were impaired. Diazepam+ethanol particularly impaired memory and learning as well. After this combination the subjects were classified (time anticipation test) as disqualified drivers more often than after placebo. It is concluded that diazepam,as well as either benzodiazepine with ethanol, may reduce the ability to drive vehicles or operate machinery.     

The interactions of ethanol with single and repeated doses of suriclone and diazepam on physiological and psychomotor functions in normal subjects

Summary The effects of diazepam (5 mg t.i.d.), suriclone (0.2 and 0.4 mg t.i.d.) and placebo (t.i.d.) were assessed in 12 normal, healthy volunteer subjects after a single dose and after treatment for a period of 8 days. A battery of physiological, psychomotor and subjective tests was administered on days 1 and 8 both before and after drug and after a measured dose of ethanol. The effects of diazepam on the EEG were characteristic of benzodiazepines — a decrease in the slow frequency wave-bands, an increase in fast frequency wave-band and diminished evoked response amplitude. Suriclone had similar effects on fast frequency activity and evoked response amplitude but, in contrast to diazepam, also increased the slow frequency wave-bands after 7 days treatment.Some improvements in performance were seen with suriclone on critical flicker fusion, tapping speed, spiral maze and digit cancellation. In contrast, suriclone impaired performance to a greater extent than diazepam on digit symbol substitution and symbol copying. Body sway was also enhanced by suriclone to a greater extent than diazepam.Subjective ratings for mood and adverse-effects showed few differences between suriclone or diazepam. However, suriclone caused greater gastro-intestinal disturbances than diazepam, especially after ethanol, and subjects rated themselves as more antagonistic and more irritable on suriclone. Ratings for calmness suggested that in contrast to diazepam, suriclone had no anxiolytic effect.Several of the parameters tested showed a build up of effect with diazepam over the treatment period which was not seen with suriclone. It is suggested that this difference may be due to differences in elimination rate.There was little evidence of interaction with ethanol with any of the treatments, most effects being simply additive.The profile of effects of suriclone was similar to that of diazepam but with some differences. The effects of suriclone were usually dose-related, the 0.4 mg dose having equivalent or greater effects than diazepam.     

Effects of single doses of quinapril and atenolol on autonomic nervous function and exercise capacity in healthy volunteers

Summary The effects of single oral doses of the angiotensin converting enzyme (ACE) inhibitor quinapril (CI-906) 40 mg and the cardioselective -adrenoceptor blocker atenolol 100 mg on sympathetic and parasympathetic function and on exercise capacity have been studied in 8 healthy young men. The trial followed a double-blind, placebo controlled, randomized cross-over design, with at least one week between treatments.Blood pressure (BP) and heart rate (HR) at rest were slightly reduced by atenolol but were not affected by quinapril. Atenolol impaired the sympathetically mediated increases in HR and BP caused by standing, immersion of the hand into melting ice, the Valsalva manoeuvre and isometric forearm exercise. Quinapril did not influence those responses nor the vagally mediated bradycardia of the diving reflex. Atenolol, however, augmented the vagal bradycardia, presumably by sympathetic inhibition. In a dynamic bicycle ergometer test with a stepwise increasing work load, exercise performance was decreased by atenolol but not by quinapril. Inhibition of the renin-angiotensin system by quinapril was shown by a marked decrease in serum ACE activity and a several-fold increase in plasma renin activity (PRA). Atenolol produced a moderate reduction in PRA. Before or during exercise, plasma noradrenaline and adrenaline were not influenced by either drug.The results indicate that, unlike the atenolol-induced -adrenoceptor blockade, ACE inhibition by a single dose of quinapril had no clear effect on autonomic nervous function or exercise capacity.Preliminary results from this study were presented at the XX Congress of the Nordic Society of Military Medicine, Helsinki, 14–16 May, 1987, and were published in 1988 in Ann Milit Med Fenn, 63 (1–2)     

Effects of sibutramine alone and with alcohol on cognitive function in healthy volunteers

AIMS: To investigate the effects of sibutramine in combination with alcohol in a double-blind, randomised, placebo-controlled, four-way crossover study in 20 healthy volunteers. METHODS: On each study day each volunteer received either: sibutramine 20 mg+0.5 g kg-1 alcohol; sibutramine 20 mg+placebo alcohol; placebo capsules+0.5 g kg-1 alcohol; or placebo capsules+placebo alcohol. Alcohol was administered 2 h following ingestion of the study capsules. During each study day, assessments of cognitive performance were made prior to dosing, and at 3, 4.5, 6 and 10 h post dosing. Blood alcohol concentration was estimated using a breath alcometer immediately prior to each cognitive performance test session. Each study day was followed by a minimum 7 day washout period. RESULTS: Alcohol was found to produce statistically significant impairments in tests of attention (maximum impairment to speed of digit vigilance=49 ms) and episodic memory (maximum impairment to speed of word recognition=74 ms). Alcohol also increased body sway (maximum increase 17.4 units) and lowered self rated alertness (maximum decrease 13.6 mm). These effects were produced by an inferred blood alcohol level of 53.2 mg dl-1. Sibutramine was not found to potentiate any of the effects of alcohol. There was a small, yet statistically significant, interaction effect observed on the sensitivity index of the picture recognition task. In this test, the combined effects of sibutramine and alcohol were smaller than the impairments produced by alcohol alone. Sibutramine, when dosed alone, was associated with improved performance on several tasks. Sibutramine improved attention (mean speed of digit vigilance improved by 21 ms), picture recognition speed (improvement at 3=81) and motor control (tracking error at 3 h reduced by 1.58 mm). Also sibutramine improved postural stability (reducing body sway at 3 h by 14.2 units). Adverse events reported were unremarkable and consistent with the known pharmacology of sibutramine and alcohol. CONCLUSIONS: There was little evidence of a clinically relevant interaction of sibutramine with the impairment of cognitive function produced by alcohol in healthy volunteers. The single statistically significant interaction indicated a reduction, rather than a worsening, of alcohol-induced impairment when sibutramine is taken concomitantly. Sibutramine when administered alone is associated with improved performance on several tasks.     

Adverse effects of single therapeutic doses of diazepam on performance in normal geriatric subjects: Relationship to plasma concentrations

Elderly normal volunteers (N=12, mean age 70.4 years) were administered placebo or diazepam 2.5, 5, 10 mg in four consecutive sessions separated by at least a 1-week interval. Memory and psychomotor performance and plasma diazepam concentrations were assessed at baseline and at 1 and 3 h following drug administration. Significant impairments were found in response to all doses of diazepam. The maximum impairment occurred at 1 h, which coincided with the highest plasma concentration of the drug.     

The effects on memory of pipequaline,alone or in combination with diazepam

Pipequaline (PK 8165) is a putative mixed agonist/antagonist at benzodiazepine receptors. The effects of pipequaline and diazepam on memory were assessed in 12 normal volunteers. Diazepam 10 mg or placebo was added to two doses of pipequaline, 50 and 150 mg, or to placebo in a double-blind crossover design. Diazepam produced impairments of episodic memory. In contrast, the effects of pipequaline were minor. Addition of diazepam to pipequaline increased drowsiness and general lethargy, with a less marked effect occurring for the higher dose of pipequaline alone. Pipequaline did not antagonise any of the effects of diazepam.     

The effect of caffeine on human performance,alone and in combination with ethanol

The effect of caffeine (300 mg/70 kg) on cognitive, perceptual and motor functions was investigated both alone and in combination with ethanol (0.75 g/kg) in 68 healthy student volunteers of both sexes. A test battery consisting of standing steadiness, simple and complex reaction time, manual dexterity, numerical reasoning, perceptual speed and verbal fluency was used. Placebos for both drugs were included. Caffeine was administered in decaffeinated coffee immediately after finishing drinking the alcoholic beverage. A peak plasma ethanol concentration of 92 ± 4 mg/100 ml occurred at 40 min which was not modified by caffeine. Caffeine did not antagonise the ethanol-induced decrement in performance except in the reaction time tests. Caffeine alone caused a significant increase in body sway at 40 min.     

Lack of interaction between two antihistamines,mizolastine and cetirizine,and ethanol in psychomotor and driving performance in healthy subjects

The pharmacodynamic interaction between mizolastine, a new H₁ antihistamine, and ethanol was assessed in a randomized, double-blind, three-way crossover, placebo-controlled study. Eighteen healthy young male volunteers received mizolastine 10 mg, or cetirizine 10 mg or placebo once daily for 7 days with a 1-week wash-out interval. An oral dose of ethanol or ethanol placebo, given 2 h after dosing on days 5 or 7 of each treatment period, was administered to achieve a peak blood alcohol concentration (BAC) of 0.7 g/l, then maintained for 1 h by two further doses of ethanol. Driving ability and psychomotor performance were evaluated using actual and simulated driving tests, critical flicker fusion threshold (CFF), adaptive tracking and divided attention (DAT) tasks. Ethanol produced a significant decrement in all tasks up to 5.5 h after administration: an increase in steering movements of 4.6, in lateral deviation of 0.45 m, in braking reaction time of 80 ms, in driving test and DAT performance of +3.2; and a decrease in CFF and in tracking speed of 2.6 m·s^–1. Neither mizolastine nor cetirizine significantly impaired driving ability or arousal (CFF) compared with the placebo. However, both drugs significantly impaired DAT performance 6:00 h post-dose (increase of +2.1 for mizolastine and +2.4 for cetirizine). The tracking speed was significantly decreased 7:50 h after mizolastine administration (-1.3 m·s^–1) and more consistently from 1:30 to 7:50 h after cetirizine administration (-1.4 m·s^–1). No significant adverse interaction, i.e potentiation, occurred between ethanol and either antihistamine. No pharmacokinetic interaction occurred in BAC. In conclusion, treatment with a therapeutic dose of mizolastine or cetirizine has minimal or no effect on human performance, does not impair driving task performance and does not interact with ethanol at concentrations of 0.7 g·^–1.