Alprazolam in the elderly: pharmacokinetics and pharmacodynamics during multiple dosing

Previous studies have suggested that elderly men eliminate alprazolam more slowly than young adults. This study in the elderly was designed to determine whether a change in pharmacokinetics influences the response to alprazolam during multiple dose regimens. In addition, the study was designed to determine alprazolam pharmacokinetics and the degree to which its hydroxymetabolites accumulate, the degree of psychomotor impairment, and whether tolerance to impairment and sedation develops during three different multiple dose regimens. Twenty-six subjects completed this study. The subjects were randomized into one of three treatment groups: 0.25 mg q8h, 0.5 mg q8h, and 2 mg q12h. Subjects remained in the clinic for 8 days (day — 2-day 5). Day 0 was used as a drug free testing day to establish baseline scores for sedation, digit symbol substitution (DSS), card sorting (CS) tasks, and two computer tests. Subjects received the drug according to schedule on days 1 through 4, with day 5 as the washout day. Blood samples were assayed for alprazolam, alpha-hydroxyalprazolam and 4-hydroxyalprazolam. Alpha-hydroxyalprazolam concentrations were below assay detection limits in all subjects in the 0.25 and 0.5 mg q8h groups and 2.6 ng/ml in the 2 mg q12h group. When detectable, 4-hydroxyalprazolam concentrations were <10% of the corresponding alprazolam concentration. Mean alprazolam oral clearance values in the three treatment groups ranged between 0.54 and 0.62 ml/min/kg and half-lives were in excess of 21 h. Degree of sedation and impairment was dose related. Sedation and impairment was not higher on day 4 despite concentrations 2–3 times as great as on day 1, indicating development of tolerance. Subjects were not, however, back to baseline level of performance on day 4.     

Psychomotor effects of alprazolam and diazepam during acute and subacute treatment, and during the follow-up phase

Psychomotor effects of alprazolam (AZ) and diazepam (DZ) were compared in a controlled double-blind and cross-over trial in 24 student volunteers, who received, three times daily, placebo for the first 4 days, then an active drug (AZ) 0.25 mg or DZ 5 mg) for 7 days, and again placebo for 3 days. After a 3 week wash-out period the procedure was repeated with the comparative drug. Objective and subjective measurements were made on day 3 (placebo), on days 4 and 10 (active drug) and on days 11, 12 and 13 (follow-up placebo). Baseline levels were measured in the morning, a capsule was taken, and the tests were repeated 2 hours and 8 hours later. Blood samples were taken in the afternoon of day 10 for the bioassay of serum benzodiazepine concentrations. Single doses of both AZ 0.25 mg and DZ 5 mg showed similar degree of impairment in several objective tests. At the end of the 7-day maintenance DZ (15 mg daily) proved significantly more sedative and impaired more psychomotor performance than AZ (0.75 mg daily) did. Improvement of the complex test performances (a learning effect) was counteracted by DZ more than by AZ. No actual development of tolerance was demonstrated after either drug. During the follow-up placebo phase, DZ showed more objective residual effects than AZ. The Maddox wing test (exophoria) showed a significant DZ effect to be still present on the third post-treatment day. However, during the follow-up period subjects reported subjectively more sedation and clumsiness after AZ than after DZ, but this was not associated with impairment of objective skills.     

The effects of repeated doses of clomipramine and alprazolam on physiological,psychomotor and cognitive functions in normal subjects

Summary The effects of a 10 day administration of clomipramine (25–50 mg t.i.d.), alprazolam (0.25–0.75 mg t.i.d.) and placebo were assessed in normal volunteers in a double-blind cross-over study. A battery of physiological, psychomotor and cognitive tests was administered both before and 3 h after drug on days 1, 5 and 10.The effects of alprazolam on EEG and evoked potentials were characteristic of benzodiazepines; clomipramine had little effect. In contrast, reaction speed was markedly slowed by clomipramine but little affected by alprazolam.Neither drug produced any accumulation of effect on a verbal recall task but neither did tolerance develop to the acute impairments produced by active treatments. Alprazolam produced an increase in levels of forgetting, especially on day 5. Subjective ratings for mood and bodily symptoms were adversely affected by clomipramine but little altered by alprazolam.It is suggested that some of the differences between drug treatments may be due to differences in the speed of onset of tolerance.     

A comparative pharmacokinetic and dynamic evaluation of alprazolam sustained-release, bromazepam, and lorazepam

Sustained-release (SR) alprazolam may facilitate compliance with oral benzodiazepine treatment of panic disorders that currently requires doses administered three or four times daily. To compare the pharmacokinetic, psychomotor performance, and subjective effects of alprazolam SR (1.5 mg), bromazepam (3 mg taken three times daily), and lorazepam (1 mg taken three times daily), 13 male volunteers (aged 20-45 years) randomly received on four separate occasions one of these medications or placebo. Once before and 11 times after drug administration, the subjects were tested using psychomotor performance tests (manual tracking and digit-symbol substitution test [DSST]) and computerized questionnaires (such as the Tufts University Benzodiazepine Scale [TUBS], the Addiction Research Center Inventory, and the visual analog scales) to determine the subjective effects of the drugs. Blood samples for the determination of the plasma levels of the drugs were collected before and 17 times after the drug was administered. A peak plateau of plasma alprazolam began approximately 6 hours after the dose, which was later than the initial peaks for lorazepam and bromazepam (1-2 hours after the dose). Once this plateau had begun, alprazolam SR sustained that concentration better than did the other two formulations. Of the 10 measures on which the response averaged for the first 14 hours differed among drugs (p < 0.05), bromazepam differed from placebo on two measures, lorazepam on four (including DSST Performance and TUBS Sedation), and alprazolam SR on nine (including all four affected by lorazepam). Lorazepam and alprazolam, but not bromazepam, produced significantly more sedation than placebo. The doses of the three drugs were not equipotent in sedation and mood effects. None of the drugs tested differed from placebo on measures relevant to abuse liability.     

Effects of alprazolam and diazepam on the daytime sleepiness of non-anxious subjects

Eighteen non-anxious volunteers underwent sleep recordings and daytime tests of sleepiness, performance, and mood while receiving, either alprazolam 0.5 mg b.i.d. or diazepam 5 mg b.i.d. for 7 consecutive days. Recordings and tests were done before treatment and on the 1st and 7th days of treatment. Nocturnal sleep changes were similar for both groups; there were no statistically significant changes in mood. However, levels of daytime sleepiness differed. Alprazolam subjects showed more daytime sedation than diazepam subjects on treatment day 1, but showed a significant decreased in Day 1–7 daytime sedation. Although diazepam subjects were less sedated at the onset, they showed no tolerance to this effect; thus by treatment day 7, the two groups did not differ in levels of daytime sleepiness. Results suggested that tolerance to alprazolam's sedative effects (which develops during the 1st week of treatment) may be separable from tolerance to its antianxiety effects (which develops after at least 4 weeks). As daytime sedation is common and potentially dangerous with most anxiolytics, selective tolerance to this side effect is highly desirable.     

Does tolerance develop to the sedative and amnesic effects of antidepressants?

Summary The psychomotor, sedative and memory effects of a sedative, anticholinergic antidepressant (amitriptyline), a sedative antidepressant (trazodone) and placebo were compared in a double-blind, cross-over study with 12 healthy volunteers. Amitriptyline (37.5 mg) and trazodone (100 mg) were administered for the first 7 days of treatment and in double-dosage for the next 7 days of treatment. Subjects completed a battery of tests before and 2 h after drug administration on days 1, 8 and 14.Over the 2 weeks of treatment, there was no accumulation of effects but subjects experienced marked sedation and psychomotor impairments following a daily dose of both active drugs. Although both amitriptyline and trazodone produced impairments on memory tasks, the effect of amitriptyline was significantly greater and may reflect its anticholinergic action over and above global sedative effects. Tolerance to the effects of amitriptyline built up differentially over measures of sedation, psychomotor function and memory.     

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.     

Dose-response evaluation of the interaction between sertraline and alprazolam in vivo

In vitro data show the inhibition of alprazolam metabolism by sertraline via CYP3A4; therefore, using a randomized, double-blind, placebo-controlled design, the authors conducted this study to assess the potential for similar in vivo inhibition in humans. Ten healthy volunteers participated in two test sessions (placebo/alprazolam 1 mg orally) before the initiation of sertraline treatment. Blood samples were obtained over a 32-hour period and pharmacodynamic measures (sedation, psychomotor performance, memory function) were obtained over an 8-hour period. After a minimum of 2 weeks of daily sertraline self-administration (50, 100, or 150 mg/day), test sessions were repeated. Alprazolam concentrations (N = 6, 4, and 6 at sertraline doses of 50, 100, and 150 mg/day, respectively) showed no significant changes based on peak concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (t1/2[beta]), and area under the concentration-time curve (AUC(0-8)), with the exception of a reduced Cmax in the 50 mg/day group. Similarly, dynamic data showed no significant variations based on peak effect, Tmax, and AUC(0-infinity), with the exception of increased peak impairment in one measure of psychomotor performance. No differences were detected between placebo alone and placebo plus sertraline. These findings suggest that sertraline (50-150 mg/day) does not alter the single-dose kinetics or dynamics of alprazolam; therefore, the combination may be prescribed without an increased risk of alprazolam toxicity.     

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

The effect of carbamazepine, an inducer of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics of alprazolam was examined in a double-blind, randomized crossover study with two phases. Seven healthy male subjects took carbamazepine 300 mg/day or matched placebo orally for 10 days, and on the 8th day they took a single oral 0.8 mg dose of alprazolam. Blood samples were taken and psychomotor function was assessed by the Digit Symbol Substitution Test, Visual Analog Scale, and UKU Side Effect Rating Scale up to 48 h after alprazolam dosing. Carbamazepine significantly (p < .01 to .001) decreased the plasma alprazolam concentrations during the elimination phase. Carbamazepine significantly (p < .001) increased the apparent oral clearance (0.90 ± 0.21 vs. 2.13 ± 0.54 ml/min/kg) and shortened the elimination half-life (17.1 ± 4.9 vs. 7.7 ± 1.7 h), with no significant effect on the peak plasma concentration (11.7 ± 1.5 vs. 13.0 ± 3.5 ng/ml). The majority of psychomotor function parameters during the carbamazepine treatment were not significantly different from those during the placebo treatment, probably because of the sedative effect of carbamazepine itself. The present study suggests that carbamazepine decreases plasma concentration of alprazolam by inducing its metabolism. It also supports the previous studies, suggesting that alprazolam is metabolized predominantly by CYP3A4.     

Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine

The pharmacokinetic and pharmacodynamic effects of concomitant administration of alprazolam and fluoxetine were studied in this double-blind parallel study in 80 healthy, male volunteers. Subjects were randomly assigned to one of four treatment groups. Drug treatments consisted of 4-day regimens of 1 mg alprazolam four times daily, 60 mg fluoxetine every morning, 1 mg alprazolam four times daily and 60 mg fluoxetine every morning, and placebo four times daily. Psychomotor performance, mood status, and degree of sedation were evaluated at designated times. Combined administration of alprazolam and fluoxetine resulted in an approximate 30% increase in plasma alprazolam concentrations relative to plasma concentrations following the administration of alprazolam alone. There were no significant differences in fluoxetine or norfluoxetine plasma concentrations between the alprazolam/fluoxetine and fluoxetine treatments. Psychomotor decrements increased when fluoxetine was administered with alprazolam relative to alprazolam administration alone. Psychomotor performance of the fluoxetine treatment group was not significantly different from that of the placebo group. No significant changes were observed in mood status, and sedation was minimal in all treatment groups. As when any two psychoactive drugs are administered together, increased patient monitoring and patient education is recommended when alprazolam and fluoxetine are prescribed concurrently.     

High-dose fluoxetine: efficacy and activating-sedating effects in agitated and retarded depression

The effects of high-dose fluoxetine (median 80 mg/day), standard-dose imipramine (median 200 mg/day), and placebo were studied in 706 outpatients meeting DSM-III criteria for major depressive disorder. Baseline psychomotor activity of each patient was prospectively categorized as agitated, retarded, or neither. Rates of occurrence of total and significant (leading to discontinuation) activating adverse events (insomnia, agitation, anxiety, nervousness) and sedating events (somnolence, asthenia) were compared between treatments on an overall basis and within categories of baseline psychomotor activity. Additionally, these rates were compared across baseline psychomotor activity for each treatment. Efficacy was evaluated on an overall basis and with respect to baseline psychomotor activity. There was more total activation with fluoxetine than placebo (p = 0.008), but total activation with fluoxetine (28%) showed only a trend (p = 0.092) for being greater than with imipramine (21%). Discontinuations for activation with fluoxetine (5%) did not differ from imipramine (5%). Sedation and discontinuations for sedation with both fluoxetine and imipramine significantly exceeded placebo. The only drug-drug difference in discontinuations was for sedation where imipramine (11%) exceeded fluoxetine (5%; p = 0.008). Only for the occurrence of sedation with imipramine (47% among patients retarded at baseline) was there a significant association with baseline psychomotor activity (p = 0.021). Both fluoxetine and imipramine were superior to placebo and equal in efficacy in decreasing total Hamilton Rating Scale for Depression (HAM-D), the sleep disturbance HAM-D factor, and the anxiety/somatization HAM-D factor scores. These improvements were independent of baseline psychomotor activity.     

Effects of alprazolam and lorazepam on catecholaminergic and cardiovascular activity during supine rest,mental load and orthostatic challenge

Effects of oral alprazolam (0.5 and 1 mg) and lorazepam (2 mg) on sympathetic adrenomedullary activity and sedation were studied during supine rest, mental load (Color Word Test, CWT) and active standing (OCT), in 12 male volunteers in a randomized double-blind placebo-controlled cross-over design. Compared to placebo, alprazolam significantly increased subjective sedation, reduced plasma adrenaline and noradrenaline concentrations and mean blood pressure (MBP) during supine rest, and attenuated plasma adrenaline responses during the CWT and the OCT; these effects during the CWT and OCT appeared to be dose-dependent. In comparison with lorazepam (2 mg), alprazolam (1 mg) showed reduced MBP levels during supine rest, whereas lorazepam showed a higher heart rate level during supine rest, a reduced plasma noradrenaline response to the OCT and a performance deterioration to the CWT. There were no differences between alprazolam (1 mg) and lorazepam regarding subjective sedation. Although the benzodiazepines were similar regarding their increase of sedation, alprazolam and loraze- pam induced differential effects on sympathetic adrenomedullary activity during rest and stress, whereby suppression of adrenomedullary activity may be specific for alprazolam. Received: 13 March 1996 / Final version: 6 June 1996     

The Effects of Single and Repeated Administration of Ebastine on Cognition and Psychomotor Performance in Comparison to Triprolidine and Placebo in Healthy Volunteers

Summary

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 10mg (as averum) and placebo in 10 healthy volunteers in a double-blind, randomised crossover 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 I 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 8?h 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.     

The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare

AIM: To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (L-CTZ), cetirizine (CTZ), loratadine (LOR) and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction. PRM was included in the study as a positive internal control to validate the sensitivity of the psychometric test battery to the CNS effects of the various treatments. METHODS: Twenty healthy volunteers (18-50 years) received L-CTZ 5mg, CTZ 10 mg, LOR 10 mg, PRM 30 mg and placebo once daily for four days in a five-way, double-blind, crossover study. For each treatment condition, subjects were assessed using a psychometric test system and a pinprick weal and flare response to 100 mg/ml histamine solution at baseline and at 1, 2, 3 ,4, 6, 8, 10 and 122 hours post-dose on days 1 and 4. The psychometrics comprised critical flicker fusion (CFF), choice reaction time (CRT), a continuous tracking task (CTT) and subjective rating scales for sedation (LARS). On days 2 and 3, subjects took their medication at pre-designated times while out of the unit. RESULTS: The verum (PRM) established the sensitivity of the test battery: a significant overall reduction in CFF thresholds on both days 1 and 4 (p < 0.05); an overall significant increase (impairment) in recognition, motor and total reaction times on day 1 (p < 0.05); a significant impairment of both the tracking accuracy and reaction time aspects of the CTT task on day 1 (p < 0.005) and significantly higher ratings of subjective sedation on day 1 (p < 0.05). L-CTZ, CTZ and LOR were not distinguishable from placebo in any of the objective and subjective tests at any time point on either day 1 or day 4. With regards to the peripheral inhibitory effects, L-CTZ inhibited both the weal and flare reaction, with maximum inhibition (almost 100%) occurring within two hours of drug ingestion. CTZ also showed evidence of potent peripheral inhibition of histamine, whereas PRM, and especially LOR, showed only a weak weal and flare reaction which had completely attenuated at day 4. CONCLUSIONS: In a study where the psychometric assessments were shown to be sensitive to impairment, L-CTZ 5 mg was found following both initial and repeated doses, but also to be demonstrably free from disruptive and sedative effects on objective measures of psychomotor and cognitive function. Similarly, CTZ showed evidence of pronounced antihistaminic activity and significantly reduced weal and flare scores after both acute and repeated doses, again without evidence of cognitive or psychomotor impairment. LOR also was non-sedative but the antihistaminic reaction was demonstrably weak.     

Physiological and psychological effects of clorazepate in man

1 In the first study, eight healthy volunteers were given single oral doses of 5, 7.5 and 15 mg clorazepate dipotassium (Tranxene), a precursor of n-desmethyldiazepam, and placebo. Drug effects up to 5 h after administration were assessed on a battery of physiological, psychomotor and subjective tests.2 Psychotropic effects were not marked but decreases in EEG auditory responses and increases in EEG fast-wave activity were detected. Some psychomotor impairment was apparent after the 15 mg dose. Subjective effects comprised some lowering of alertness and changes in sociability. Plasma concentrations of n-desmethyldiazepam 3 h after ingestion were related to dose and correlations were found with the other variables.3 In the second study, nine subjects received clorazepate 7.5 and 15 mg, and placebo, in a single daily dose for 14 days, with at least 5 weeks between courses. Psychotropic effects were evaluated on the first and last days of drug administration, for up to 5 h following the daily dose. After 15 days, EEG auditory responses were diminished and fast-wave activity increased. Anxiety was diminished but psychomotor effects were minimal.4 Psychotropic effects following the dose of clorazepate dipotassium on day 15 were compared with those on day 1. Objective measures, the EEG auditory response, fast-wave activity and critical flicker fusion, were significantly less affected on day 15 than on day 1 whereas subjective ratings and the digit-symbol substitution test were more affected.5 Plasma concentrations of n-desmethyldiazepam increased in a dose-related way over the 2 weeks. Increases following the drug on day 15 were at least as large as those on day 1 suggesting that pharmacokinetic factors could not account for the physiological tolerance noted above.6 It was concluded that clorazepate dipotassium in doses of 7.5 mg/day provided useful anxiolytic actions without undue sedation.     

A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine

We have assesed the pharmacokinetic and pharmacodynamic interaction between fluvoxamine, a serotonin reuptake inhibitor, and alprazolam, a triazolobenzodiazepine.Healthy men took fluvoxamine maleate daily for 10 days (50 mg on days 1–3, 100 mg on days 4–10) (n=20), 1 mg of alprazolam four times daily for four days (days 7–10 of the study period) (n=20), or a combination of the two (n=20), according to a parallel study design. Alprazolam and fluvoxamine concentrations were measured in serial plasma samples by HPLC and gas chromatography respectively, and psychomotor performance and memory were assessed on days 1, 7, and 10.Fluvoxamine increased plasma alprazolam concentrations by 100%. The mean apparent half-life of alprazolam was increased from 20 h to 34 h after fluvoxamine co-administration.The increased plasma concentrations of alprazolam resulted in significantly greater reductions in psychomotor performance evident on day 10. Mean fluvoxamine plasma concentrations were about 25% lower in those who took the combination than in those who took only fluvoxamine; this was more likely due to heterogeneity between the treatment groups than to an effect of alprazolam.The dosage of alprazolam should be reduced during co-administration with fluvoxamine.     

A double-blind,placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers

Rationale Pregabalin potently and selectively binds to the alpha₂-delta subunit of voltage-dependent calcium channels, reducing calcium influx and modulating release of downstream excitatory neurotransmitters, such as glutamate. Pregabalin has demonstrated robust efficacy for several disease states, but its neuropharmacology is still being elucidated.Objective This study was conducted to evaluate the cognitive and psychomotor effects of oral pregabalin (150 mg t.i.d.) using alprazolam (1 mg t.i.d.) as a positive internal control and placebo.Methods Twenty-four healthy volunteers were randomised to a double-blind, three-way crossover study. Each period consisted of 3-day double-blind treatment followed by 1 day of single-blind placebo. Psychometrics included tests of Choice Reaction Time (CRT), CNS arousal (Critical Flicker Fusion, CFF), vigilance (Rapid Visual Information Processing, RVIP), serial memory scanning (Sternberg Short-Term Memory Scanning Test, STM), divided attention (Compensatory Tracking Task, CTT), Brake Reaction Time (BRT) in an on-the-road vehicle, and subjective Line Analogue Rating Scales (LARS) for sedation.Results Pregabalin showed no significant effects on the objective psychometrics—CRT, BRT, RVIP, STM—compared with placebo. Pregabalin produced a limited, significant decrement on CFF and CTT and a significant effect on the LARS. Pregabalin was associated with improvement relative to placebo in BRT. The positive control, alprazolam, produced significant impairment on all objective measures and significant impairment on the LARS, thus establishing the sensitivity of the test battery used in the study.Conclusions Pregabalin did not differ on most assessments from placebo, producing only minor, transient impairment on some objective cognitive and psychomotor measures, suggesting a relatively benign CNS side-effect profile.     

An investigation of the effects of lofepramine, nomifensine, amitriptyline and placebo on aspects of memory and psychomotor performance related to car driving

Ten healthy, female volunteers took part in a double-blind, placebo-controlled study to investigate the effects of lofepramine 70 mg, lofepramine 140 mg, nomifensine 100 mg, amitriptyline 50 mg and placebo on psychomotor performance related to driving. One subject failed to complete the study for reasons unrelated to the medications. Each subject received each of the treatments in random order at weekly intervals and was then assessed for psychomotor performance, sedation and quality of sleep. Amitriptyline 50 mg served as a positive control producing results consistent with its known sedative properties. In contrast, lofepramine 70 mg and 140 mg and nomifensine 100 mg were generally free from any significant effect on psychomotor performance.     

Pharmacokinetics and pharmacodynamics of alprazolam following single and multiple oral doses of a sustained-release formulation

The pharmacokinetics and pharmacodynamics of alprazolam after IV and oral sustained-release (SR) tablet administration were evaluated in 42 healthy, normal, male volunteers. All 42 subjects received a single 1-mg intravenous (IV) alprazolam dose. After a 1-week washout period, the subjects received one of three SR treatments as a single dose: one 1-mg SR tablet, three 1-mg SR tablets, or six 1-mg SR tablets. Beginning 2 days after single-dose SR treatment, each subject received the above SR doses for 3 days. The daily dose for the multiple-dose study was the same as the subject received in the single-dose study. Serial blood samples were collected after each treatment (single-dose IV, single-dose SR, and after the last SR multiple dose), and plasma samples were analyzed by high performance liquid chromatography. Sedation was assessed by a blinded observer at each blood sampling time. Mean pharmacokinetic parameters for IV administration were consistent with previous results. Pharmacokinetic parameters for the SR doses were consistent with linear kinetics over the dosage range studied. The mean absolute bioavailabilities of the SR tablets were greater than 0.84 after single SR doses. Maximal sedation was related to dose after single-dose SR administration. During multiple dosing, chronic tolerance was observed. Maximal sedation scores after 3 days of alprazolam SR administration were independent of the dose administered and were lower after multiple-dose administration than scores observed after single oral SR doses, although plasma alprazolam concentrations were at least 1.5 times higher with multiple dosing. Sedation data indicate that oral SR doses were well tolerated in multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)