The effects of TPA023, a GABAAα2,3 subtype-selective partial agonist, on essential tremor in comparison to alcohol

Essential tremor (ET) is a relatively frequent neurological disorder that responds in some patients to gamma-aminobutyric acid A (GABA(A)) agonists such as the benzodiazepines. Partial subtype-selective GABA(A) agonists may have an improved side effect profile compared to non-selective GABA(A) agonists. However, it is unknown which GABA(A) subtypes are involved in the therapeutic effects of benzodiazepines in ET. The effects of 2 mg TPA023, a GABA(A) α2,3 subtype-selective partial agonist, on ET were compared to the effects of a stable alcohol level (0.6 g/L) and placebo in nine patients with ET. Tremor evaluation included laboratory accelerometry and a performance-based scale. Additional measurements were performed to evaluate other effects on the central nervous system (CNS). Alcohol significantly diminished tremor symptoms in the postural and kinetic condition, as assessed by laboratory accelerometry, but the performance-based rating scale was unaffected. Tremor was also reduced after TPA023 treatment in the kinetic condition, albeit not significantly. Additionally, TPA023 decreased saccadic peak velocity, while alcohol decreased subjective feelings of alertness. This study showed that alcohol reduced maximum tremor power, as assessed by laboratory accelerometry, unlike TPA023, which decreased tremor symptoms to some extent but not significantly. This study showed that treatment with an α2,3 subunit-selective GABA(A) partial agonist was less effective than a stable level of alcohol in reducing ET symptoms. These results provide no support for a therapeutic role of TPA023 in the suppression of ET symptoms.     

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

Rationale

Histamine and dopamine contribute to the maintenance of wakefulness.

Objective

This study aims to conduct an exploratory analysis of the effects of 10 and 50?mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200?mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep.

Methods

A total of 25 healthy men were recruited to a double-blind, placebo-controlled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at two-hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness.

Results

After placebo, sleep deprivation was associated with enhancements in delta and theta and reductions in alpha and beta activity. Following dosing at 02:00 h, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00?h, latency to sleep onset and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1% was increased and total sleep time, SWS% and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249, the 50-mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep. After modafinil, no changes were observed for power spectra during sleep.

Conclusion

Both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.     

Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep

Summary The effects of alprazolam 0.5 mg and lorazepam 2 mg on cognitive and psychomotor skills were assessed in twelve normal volunteer subjects in a randomised, double-blind, crossover design. Single and multiple dose effects were monitored using a battery of tests comprising critical flicker fusion threshold (CFFT), choice reaction time (CRT), simulated car tracking, and subjective ratings of perceived sedation (LARS) and of sleep behaviour (LSEQ). Compared with placebo baseline scores, treatment with lorazepam 2 mg (both single and multiple doses) resulted in a widespread impairment of CRT, tracking accuracy, and CFFT. Single doses of alprazolam 0.5 mg reduced CFFT with respect to the placebo baseline. Single and multiple dose treatment with both drugs resulted in subjective reports of sedation, a reduction of sleep onset latency, and improved sleep quality. Only lorazepam 2 mg significantly disrupted the integrity of behaviour on waking from sleep. These results suggest important pharmacodynamic differences between the two drugs in the doses used.     

Pharmacodynamics of milnacipran in young and elderly volunteers

AIMS: To investigate the pharmacodynamics of milnacipran in healthy young and elderly volunteers. METHODS: Randomized double-blind crossover designs were employed and a standardized psychometric battery was administered pre and post dose for both studies. In the first study 10 healthy young volunteers received milnacipran 12.5 mg, 25 mg, 50 mg, 100 mg as a single dose or matched placebo. The test battery was administered at baseline and at 1, 2, 4 and 6 h post dose. The second study compared the effects of milnacipran 75 mg (50 mg+25 mg) per day, amitriptyline 50 mg (25 mg+25 mg) per day and placebo for 3 days' dosing in healthy volunteers aged over 65 years. The test battery was administered at baseline and at 2, 10 and 24 h post dose. The psychometric battery included critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT) and tests of short-term memory (STM), subjective sedation (LARS) and subjective sleep (LSEQ). RESULTS: Milnacipran produced no significant dose related effects in the young volunteers. For the elderly, milnacipran significantly (P<0.05) raised CFF scores compared with placebo but had no significant effects on any of the other measures used. Amitriptyline, in contrast, significantly (P<0. 05) lowered CFF threshold, lengthened CRT and increased error on the CTT. On the subjective variables, LARS and LSEQ, amitriptyline increased ratings both of sedation and of difficulty in waking from sleep. CONCLUSIONS: The results showed that milnacipran at single doses of up to 100 mg in healthy young volunteers is free from disruptive effects on cognitive function and psychomotor performance. In addition, milnacipran 75 mg (50+25 mg) appears to be free of negative effects on cognitive function in elderly volunteers, where it seemingly improves performance on CFF. In contrast, the tricyclic antidepressant amitriptyline, used here as a positive internal control, significantly impaired performance in the elderly on the majority of psychometric measures used in this study. This finding not only validated the sensitivity of this current test battery but also indicates the potential behavioural toxicity of amitriptyline in clinical use in the elderly.     

A comparison of the psychometric effects of remoxipride with those of haloperidol,thioridazine, and lorazepam in healthy volunteers

In this placebo and verum (lorazepam 2 mg) controlled double-blind crossover study the acute effects of Remoxipride 50 mg and 100 mg; Haloperidol 2·5 mg; and Thioridazine 50 mg were examined in 18 healthy volunteers. CNS function was assessed using a battery of psychometric measures, viz: Critical Flicker Fusion Threshold (CFFT); Choice Reaction Time (CRT); Tracking Accuracy (RMS) and Peripheral Reaction Time (PRT); Sternberg Memory Scanning (SMS); Word Memory (WM) as well as Line Analogue Ratings of subjective sedation (LARS) and the Leeds Sleep Evaluation Questionnaire (LSEQ). Both doses of remoxipride were associated with a reduction of CFFT: 0·9 Hz for 50 mg and 1·3 Hz for 100 mg. The 100 mg dose caused an increase (impairment) in CRT total time of 38 msec. Haloperidol reduced CFFT, while thioridazine and lorazepam impaired performance on the majority of objective measures, as expected for known sedative drugs. Thioridazine led to hypotension in three subjects, and to subjective sedation (LARS), but no treatment affected responses on the LSEQ administered the morning of the day following treatment. These results show that remoxipride has some depressant effects on CNS function, but that these are less prominent than those of sedative neuroleptics such as thioridazine.     

Cross-cultural validation of the Leeds sleep evaluation questionnaire (LSEQ) in insomnia patients

The Leeds sleep evaluation questionnaire (LSEQ) is a standardized self-reporting instrument comprising ten 100 mm visual analogue scales that pertain to the ease of getting to sleep (GTS), quality of sleep (QOS), ease of awakening from sleep (AFS) and alertness and behaviour following wakefulness (BFW). Although the LSEQ has been used in a variety of populations, published psychometric data on insomnia patients are limited. The LSEQ reliability and construct validity was evaluated in 396 French insomnia patients aged 55 years and over, who were treated with placebo (2 weeks) and melatonin (3 weeks). The results supported LSEQ internal consistency, reliability and construct validity with minor differences from those of the original English version. Then the internal consistency of the LSEQ was evaluated in 257 insomnia patients (age 20-80 years) in France and Israel who, following a 1 week placebo baseline, were randomized to placebo or melatonin treatment for 3 weeks. Cronbach's alpha and Pearson's r correlation coefficients for placebo and drug treatment conditions (p<0.001 for all) supported LSEQ internal consistency in different treatment and age groups and in different languages. It is concluded that the consistency, reliability and validity of the four LSEQ domains allows them to be singled out as independent outcome variables in cross cultural sleep research and clinical practice in adult and elderly patients with insomnia.     

Developing a Consistent,Reproducible Botulinum Toxin Type A Dosing Method for Upper Limb Tremor by Kinematic Analysis

Botulinum toxin type A (BoNT-A) injection patterns customized to each patient’s unique tremor characteristics produce better efficacy and lower adverse effects compared to the fixed-muscle-fixed-dose approach for Essential Tremor (ET) and Parkinson’s disease (PD) tremor therapy. This article outlined how a kinematic-based dosing method to standardize and customize BoNT-A injections for tremors was developed. Seven ET and eight PD participants with significant tremor reduction and minimal perceived weakness using optimized BoNT-A injections determined by clinical and kinematic guidance were retrospectively selected to develop the kinematic-based dosing method. BoNT-A dosages allocated per joint were paired to baseline tremor amplitudes per joint. The final kinematic-based dosing method was prospectively utilized to validate BoNT-A injection pattern selection without clinical/visual assessments in 31 ET and 47 PD participants with debilitating arm tremors (totaling 122 unique tremor patterns). Whole-arm kinematic tremor analysis was performed at baseline and 6-weeks post-injection. Correlation and linear regression analyses between baseline tremor amplitudes and the change in tremor amplitude 6-weeks post-injection, with BoNT-A dosages per joint, were performed. Injection patterns determined using clinical assessment and interpretation of kinematics produced significant associations between baseline tremor amplitudes and optimized BoNT-A dosages in all joints. The change in elbow tremor was only significantly associated with the elbow total dose as the change in the wrist and shoulder tremor amplitudes were not significantly associated with the wrist and shoulder dosages from the selected 15 ET and PD participants. Using the kinematic-based dosing method, significant associations between baseline tremor amplitudes and the change (6-weeks post-first treatment) in tremor at each joint with BoNT-A dosages for all joints was observed in all 78 ET and PD participants. The kinematic-based dosing method provided consistency in dose selection and subsequent tremor reduction and can be used to standardize tremor assessments for whole-arm tremor treatment planning.     

微电极引导立体定向下丘脑腹中间核毁损术治疗特发性震颤

目的探讨微电极引导立体定向下丘脑腹中间核(Vim核)毁损术治疗特发性震颤(ET)的临床疗效和并发症。方法对55例ET患者采用微电极导向技术确定Vim核的位置,进行单侧丘脑毁损术。对患者术前术后肢体震颤、生活功能改善情况及并发症进行定性评估和分析。结果手术对侧肢体震颤完全消失47例,在精神紧张时仍遗留有轻微震颤8例,头颈、躯干部震颤及声音震颤亦有所改善,同侧肢体震颤无缓解。术后复发3例,同侧二次手术后震颤完全控制。长期随访疗效稳定,患者生活质量明显提高。一过性并发症15例,均在1～3周后消失,无永久性并发症。结论微电极引导立体定向下单侧Vim核毁损术治疗ET是一种安全、高效、微创的方法,准确定位是手术成功的保障。     

The pharmacodynamics of ethanol: effects on performance and judgment

The objective and subjective effects produced by increasing and decreasing ethanol concentrations were studied in healthy volunteers on three separate occasions. A randomized, double-blind, placebo-controlled, four-way crossover study was used to determine whether there is any disparity between the time course of blood ethanol concentration and its effects on either objective test performance or self rated impairment. On each study day the subjects received one of four treatments consisting of either placebo or sufficient alcohol to achieve peak estimated blood alcohol concentration (Est.BAC) of 0.07 gm/dL, 0.1 gm/dL or 0.14 gm/dL. Est.BAC determined from breath alcohol concentrations were measured 20 minutes after each "dose" until peak Est.BAC was achieved, then 1, 2, 3.5, and 4.5 hours after peak Est.BAC. Digit symbol substitution (DSS), simulated driving reaction time (SDRT), choice reaction time (CRT) and self assessment of impairment (SRI) were measured simultaneously with Est.BAC. Changes in objective performance test scores were well correlated with Est.BAC (r2 = 0.60 P less than .01). Maximum impairment in test performance occurred at the same time as peak Est.BAC. Threshold Est.BAC needed to produce changes in objective test scores greater than placebo were 0.06 +/- 0.01 for DSS, 0.04 +/- 0.01 for SDRT, and 0.04 +/- 0.02 for CRT. There was no evidence of between dose or within dose tolerance to the effects produced by various Est.BAC on any of these performance tests. Subjects' self rated degrees of impairment at various Est.BAC were influenced by whether alcohol concentrations were rising or falling. Subjective impairment ratings were greater while alcohol concentrations were increasing compared to the same Est.BAC occurring during falling alcohol concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of alprazolam alone and combined with alcohol on central integrative activity

Summary The effects of alprazolam 1 mg both alone and in combination with 0.5 g/kg of alcohol were examined on self-ratings of intoxication and measures of central and peripheral activity such as EEG, auditory evoked response, tremor at 90, 150 and 210 min post drug. Forty-eight healthy volunteers were assigned randomly to 4 independent groups who received: alprazolam and placebo drink, alprazolam and alcohol, placebo capsule and alcohol, placebo capsule and placebo drink respectively.Alprazolam decreased the amplitudes of the 3 potentials of the evoked response, decreased activity in the 8–13 Hz and increased activity in the 13.5–26 Hz wavebands of the EEG and decreased the frequency at which fusion was perceived. Alcohol prolonged reaction time and increased tremor. The effects were not always additive and alprazolam was dominant in the combination.     

Effects of tianeptine and mianserin on car driving skills

RATIONALE: Tianeptine is a novel antidepressant which enhances the reuptake of serotonin (5-HT). Previous studies suggest that tianeptine has a non-sedative side-effect profile, but its effects on everyday activities including car driving have not been fully explored. OBJECTIVES: To assess the effects of tianeptine on tests related to car driving performance. METHOD: Sixteen healthy volunteers received acute doses of tianeptine 12.5 mg and 37.5 mg, mianserin 30 mg and placebo in a double blind four-way crossover study. The effects of treatment on self assessed ratings of sedation (LARS), two valid and reliable laboratory performance measures, critical flicker fusion (CFF) and choice reaction time (CRT) and an "on-the-road" measure of one aspect of car driving performance, brake reaction time (BRT) were examined. The BRT test was administered at baseline and at 1.5, 3, 4.5 and 6 h post-dose, while LARS, CFF and CRT were administered at baseline and at 1, 2, 4 and 5 h post-dose. For all data, the maximum change from baseline was calculated and used in the analysis. RESULTS: Tianeptine had no measurable effect on performance, compared to placebo, on any of the variables investigated. Compared to placebo, mianserin was shown to lower CFF thresholds (P = 0.01), increase reaction times on both the CRT (P = 0.001) and the BRT (P = 0.01) tests and was subjectively rated as more sedative than placebo (P = 0.01). CONCLUSION: The apparent lack of counter-therapeutic side-effects produced by an acute dose of tianeptine suggest that it may be a suitable antidepressant for use in an ambulant population.     

Separate and combined effects of the social drugs on psychomotor performance

Ten female subjects (five smokers and five non-smokers) performed a choice reaction time task (CRT), a compensatory tracking task (CTT), a short-term memory task (STM) and were tested for their critical flicker fusion threshold (CFF) at set points over 4 h after the administration of each possible combination of nicotine (2 mg gum or placebo), caffeine (250 mg capsule or placebo) and alcohol (30 g or placebo). Memory and motor function were shown to be facilitated by nicotine or caffeine, and the debilitating effects of alcohol were frequently antagonised by either drug. In spite of the differences in their neuropharmacological actions, combinations of nicotine, caffeine and alcohol may be compared through their effects on common information processing mechanisms involved in psychomotor performance.     

The effects of single and repeated administration of ebastine on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers

OBJECTIVE: The cognitive and psychomotor effects of 10 mg, 20 mg and 30 mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10 mg (as a verum) and placebo in 10 healthy volunteers in a double-blind, randomised cross-over study. METHODS: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1 h, 2 h, 4 h and 8 h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ). RESULTS: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p < 0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the difference with placebo reaching statistical significance on day 1, 8 h post-dose (p < 0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8h on day 1 (p < 0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4 h and 8 h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2 h and 4 h following triprolidine administration on day 1 and ebastine (30 mg) was rated as sedative 4 h following administration on day 5. The perceived sedative activity of ebastine 30 mg was also reflected in the subjective reports on the LSEQ on day 1 (p < 0.05). CONCLUSIONS: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10-20 mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10 mg.     

Effects of clobazam and clonazepam on saccadic eye movements and other parameters of psychomotor performance

Summary The effects of two benzodiazepine anti-convulsants clobazam (20 mg) and clonazepam (2 mg) in a variety of psychomotor performance tests were compared in a placebo controlled double-blind acute oral dose study in ten healthy volunteers. Assessments included critical flicker fusion (CFF) threshold, the Sternberg memory scanning and choice reaction time (CRT), peak saccadic velocity (PSV) and visual analogue scales, all previously shown to be sensitive to the effects of benzodiazepines.Clobazam did not significantly impair saccadic eye movements, CFF threshold, Sternberg memory scanning and CRT compared to placebo. Clonazepam significantly lowered PSV, reduced the CFF threshold, slowed the Sternberg CRT and decreased an alertness factor in the visual analogue scales compared to placebo. Clonazepam significantly increased memory scanning time compared to clobazam. Clobazam was remarkably free of cognitive and psychomotor side-effects.     

The effects of repeated doses of temazepam taken in conjunction with alcohol on aspects of psychomotor performance the morning following night time medication.

A study to compare the morning-after effects of three dose levels of temazepam (Euhypnos capsules) given with alcohol, was carried out in 18 healthy volunteers. Matched placebos were given for two days before and four days after the four nights on active drug and a standard dose of alcohol was given on all ten nights of the study. Objective measurements made on the mornings after days 2, 4, 6 and 10 were critical flicker fusion threshold (CFF), choice reaction time (CRT) and digit symbol substitution tasks (DSST). The administration of 10 or 20 mg temazepam with alcohol produced no significant change inany of these measurements. 30 mg produced no change in DSST and although there was some impairment of CRT at this dose, it was not statistically significant. The combination of 30 mg temazepam and alcohol significantly depressed CFF following four nights on these drugs.     

Metabolism of the TRH analog L-pyro-2-aminoadipyl-L-histidyl-[3H]-L-thiazolidine-4-carboxamide (MK-771) in gut and brain tissue of rats: the implications for its bioavailability

Hydrolysis of the terminal amide group of L-pyro-2-aminoadipyl-L-histidyl-[3H]-L-thiazolidine-4-carboxamide ([3H]MK-771) in rat brain homogenates was rapid and yielded the corresponding [3H] tripeptide carboxylic acid (III). Brain proteolytic enzymes may limit the bioavailability of [3H]MK-771. In contrast MK-771 degradation in a rat gut homogenate (where the radiolabeled product of hydrolysis was [3H]thioproline) was much slower and intestinal proteolytic enzymes probably did not prevent the absorption of MK-771 into the systemic circulation. However, the majority of an oral dose of MK-771 was not absorbed and intact MK-771 represented only 2% of the fecal radioactivity. Degradation of unabsorbed MK-771 occurred mainly in the large intestine of normal rats presumably because of the action of gut flora. Eighty percent of the oral dose remained in the intestine of germ-free rats as intact MK-771 and it was concluded that the limited absorption of MK-771 was caused by its inefficient transportation across gut membranes.     

Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized,Double-Blind,Placebo-Controlled Study

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial ({"type":"clinical-trial","attrs":{"text":"NCT02207946","term_id":"NCT02207946"}}NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn–Tolosa–Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p = 0.003) and Week 8 (p = 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p = 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.     

A preliminary investigation of “albert 285” (HWA 285) on psychomotor performance,mood, and memory

Eight healthy female volunteers received 150, 300, and 450 mg of HWA 285 and placebo according to a randomized, double-blind crossover design. The subjects completed a battery of psychological tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings of drug effects (LARS), and a Sternberg memory scanning test (SMST) 1 and 2 hr following treatment. No statistically significant changes from placebo were observed on CFF, CRT, or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was significantly improved with respect to placebo 1 hr following treatment with HWA 285 at 150, 300, and 450 mg dose levels. The action of the drug was found to be specific in its effects on the central serial comparison stage of the information processing model.     

The effects of paroxetine and other antidepressants in combination with alcohol in psychomotor activity related to car driving

Ten healthy female volunteers received single doses of amitriptyline 50 mg (AMI); mianserin 20 mg (MIA); trazodone 50 mg (TRA); paroxetine 30 mg (PAR) and placebo (PLA), with or without a ‘social’ dose of alcohol (ALC) in a double-blind, balanced crossover study where each subject acted as her own control. Psychomotor activity related to car handling ability was measured on a battery of tests at 1.5 and 4 h following study drug. The tests included tracking accuracy (RMS) and latency of response to a peripheral stimulus (RT) as measures of sensorimotor co-ordination; the Maddox Wing test (MW) for the balance of extraocular muscles; critical flicker fusion threshold (CFF) for overall levels of CNS activity; choice reaction time (CRT) for psychomotor performance and the latency of brake reaction time (BRT) measured in a driving simulator. Subjective ratings of sedation were measured on line analogue ratings scales (VARS) and the Leeds Sleep Evaluation Questionnaire (LSEQ). When compared to PLA on objective tests, AMI significantly impaired RMS, RT, MW and CFF at 4 h post-drug and AMI + ALC similarly impaired the same measures and BRT. MIA produced a significant impairment of RT, MW, CFF and CRT at both 1.5 and 4 h. MIA + ALC further impaired RMS at 1.5 and 4 h and BRT at 4 h. TRA showed a detrimental activity on CFF at 1.5 h and CFF, RT, MW and BRT at 4 h. TRA + ALC produced a greater effect than TRA alone at 1.5 h and significantly impaired RT, MW, TRT, BRT. There were no significant effects of TRA + ALC at 4 h. PAR alone had no measurable effect on any of the test measures at either 1.5 or 4 h after treatment. PAR + ALC impaired RT at 1.5 and 4 h but had no effect on any other measures at either test times. Indeed, compared to PLA, CFF levels were significantly improved at 4 h following both PAR and PAR + ALC and improvements in RRT were also measured 4 h after taking PAR. Subjective measures (VARS) compared to placebo, show AMI at 4 h and AMI + ALC at 1.5 and 4 h, both MIA and MIA + ALC after 1.5 and 4 h, TRA + ALC after 1.5 h and PAR + ALC at 4 h to have significant sedative activity. In this placebo-controlled study, acute doses of AMI 50 mg, MIA 20 mg and TRA 50 mg alone and with alcohol showed evidence both of significant impairment of psychomotor skills related to vehicle handling and of perceived sedation at 1.5 and / or 4 h following treatment. Under identical circumstances PAR 30 mg produced no detrimental effect on any of the test measures, there was an impairment with PAR + ALC of one component of a divided attention task and on a subjective measurement of sedation.     

A clinical laboratory paradigm for evaluating medication effects on alcohol consumption: naltrexone and nalmefene.

Opiate antagonist medications have been shown to improve alcoholism treatment, but few human laboratory-based studies investigating mechanisms for these effects have been conducted on alcohol dependent persons. The present study was designed to determine the impact of two opiate antagonists on alcohol consumption among nontreatment-seeking alcoholics (n=125) and social drinkers (n=90). Participants were randomly assigned to receive placebo, naltrexone (titrated to 50 mg/day), or nalmefene (titrated to 40 mg/day) for 8 days with an alcohol laboratory session on the final day. Alcohol consumption was monitored in the natural environment during the first 5 medication days, and during a choice consumption paradigm following a standard 'priming' alcohol dose in a bar-laboratory setting. Social drinkers consumed less alcohol than alcoholics during the prelab medication period and the laboratory choice consumption paradigm, and they attained lower blood alcohol levels than alcoholics following the priming drink. Both opiate antagonist medications equally reduced drinking amounts and frequency among alcoholics but not social drinkers, relative to placebo, during natural environment and bar-lab alcohol consumption evaluations. Greater medication side effects, mostly mild in nature, were observed in participants taking nalmefene. These findings demonstrate that both naltrexone and nalmefene can lead to reductions in alcohol consumption among alcoholics who are not attempting to reduce drinking. Similar laboratory paradigms may offer substantial advantages for observing these effects during evaluation of other medications as well.