Psychopharmacology (2007) 191:951–959DOI 10.1007/s00213-006-0669-8 Cognitive, psychomotor and actual driving performancein healthy volunteers after immediate and extended releaseformulations of alprazolam 1 mg Tim R. M. Leufkens & Annemiek Vermeeren &Beitske E. Smink & Peter van Ruitenbeek &Johannes G. Ramaekers Received: 8 August 2006 / Accepted: 6 December 2006 / Published online: 12 January 2007 magnitude of impairment in the driving test observed with Rationale Alprazolam extended-release (XR) is approved alprazolam XR was about half that observed with alprazo- for the treatment of panic disorder. This sustained formu- lam IR. Laboratory test results were in line with the driving lation is absorbed in a delayed manner and is therefore expected to produce fewer and less severe side effects than Conclusions The acute impairing effects of alprazolam XR its immediate release equivalent (alprazolam IR). The effect 1 mg on driving and psychomotor functions were generally of alprazolam XR on potentially dangerous daily activities, less, as compared to its immediate-release equivalent, but such as driving a car, is expected to be less as compared to still of sufficient magnitude to increase the risk of becoming involved in traffic accidents.
Objectives The present study was designed to compare theeffects of alprazolam XR (1 mg) and alprazolam IR (1 mg) Keywords Alprazolam XR . Driving . Cognition .
on actual driving ability and cognitive function.
Psychomotor performance . Serum concentration .
Method Eighteen healthy volunteers (aged 20–45 years) participated in a double-blind, placebo-controlled, three-way crossover study. At 4 h post-dose, subjects performed astandardized driving test on a primary highway in normaltraffic. Cognitive and psychomotor tests were assessed 1,2.5, and 5.5 h post-dose. Memory functioning was measured only 1 h after administration.
Results Both formulations severely impaired driving per- Daytime sedation and impairment of psychomotor and formance between 4 and 5 h after administration. The cognitive functioning is one of the main problems associ-ated with the use of benzodiazepine anxiolytics. This poses T. R. M. Leufkens A. Vermeeren P. van Ruitenbeek a crucial problem for users of these drugs who must operate vehicles. Epidemiological studies have shown that use of Experimental Psychopharmacology Unit, Brain and Behavior benzodiazepines is associated with an increased risk of car Institute, Faculty of Psychology, Maastricht University, Experimental studies have shown, however, that effects on driving performance vary depending on the drug, dose, and The Netherlands Forensic Institute (NFI), Alprazolam is the most frequently used benzodiazepine in the treatment of panic disorder and anxiety (Isbister et al.
; Moroz RxList ; Verster et al. ). It is a Department of Neurocognition, Faculty of Psychology, 1,4 triazolobenzodiazepine and available in two formula- tions, an immediate release (IR) formulation and an P.O. Box 616, 6200 MD Maastricht, The Netherlandse-mail: extended release (XR) formulation. Alprazolam IR is rapidly absorbed and has a relatively short elimination half- of studies (reviews: Ramaekers ; Vermeeren life ranging between 10 and 18 h (Greenblatt and Wright Recently, it was applied in a study to assess the effect of a ; Moroz ). After oral administration of alprazolam single dose of alprazolam IR 1 mg and placebo on actual IR 1 mg, peak plasma concentrations ranging from 12 to driving performance in 20 healthy young volunteers 22 μg/l are reached within 0.7 to 1.8 h after intake (Verster et al. ). That study showed that alprazolam (Greenblatt and Wright ). Alprazolam IR is mainly IR produced severe impairment of road tracking control prescribed in units of 0.25, 0.50, or 1.00 mg three times equivalent to the effect produced by a blood alcohol daily for patients suffering from anxiety, but daily doses can be raised to 10 mg for patients suffering from panic The primary purpose of the current study was to compare the effects of alprazolam XR with those of Patients using alprazolam IR report benzodiazepine- alprazolam IR on performance of healthy subjects in a related adverse events, such as drowsiness, dizziness, and standardized highway driving test. It was expected that reduced alertness (Verster and Volkerts A vast driving impairment would be less after alprazolam XR as amount of studies have shown that alprazolam IR in doses compared with alprazolam IR, due to differences in the of 0.5 mg and higher impairs a variety of cognitive and pharmacokinetic profiles of both formulations. The second- psychomotor skills such as memory, speed of responses, ary purpose was to compare the effects on cognitive and and tracking performance (Bertz et al. ; Ellinwood et psychomotor functioning related to driving in a controlled Scavone et al. ; Smith et al. Subhan et al. Vermeeren et al. ; Verster et al. Alprazolam XR was developed to reduce the adverse events associated with alprazolam IR. It produces peakplasma concentrations that are about 50% of a similar dose of the IR formulation and occur between 5 and 12 h afteradministration (Busto et al. ; Eller and Della-Coletta Eighteen healthy volunteers (nine men and nine women) ; Fleishaker et al. ; Glue et al. Alprazolam were recruited by means of advertisements in local news- XR produced fewer and less severe side effects than its IR papers and public buildings. Their mean ±SE age was 32.3± equivalent. Moreover, it has been shown that cognitive and 2.0 years. Volunteers were screened by a telephone inter- psychomotor performance is less impaired after alprazolam view, health questionnaire, and medical examination. The XR than after alprazolam IR (Busto et al. Mumford et medical examination included blood hematology and chem- istry, urinalysis, drug and pregnancy screening, and a 12-lead It is unclear, however, if a reduction in performance electrocardiogram. Inclusion criteria were age between 21 impairment observed in laboratory tests of psychomotor and 45 years, good physical and mental health, body mass function and cognition after alprazolam XR will have any index between 18 and 28 kg/m2, possession of a driving implications for drivers who are being treated with license for more than 3 years, and average driving alprazolam. In general, the validity of short psychomotor experience of at least 5000 km/year. Volunteers with any tests for predicting actual driving performance is limited. At cardiovascular, endocrine, psychiatric, and/or neurological best, drug-induced impairments in psychomotor tests are condition were excluded, as were subjects with a history of only moderately correlated to drug-induced impairment in drug abuse or currently using psychoactive medication, driving performance as assessed in on-the-road driving hypotension (<90/50 mmHg), liver disorder, pregnancy or tests. Consequently, it is widely accepted in the drug and lactation, and drinking more than 20 alcoholic consump- driving community that experimental studies for establish- ing the driving hazard of a medicinal drug should proceed From 1 week before participation in the study until from conventional psychomotor tests to driving simulators completion of the last treatment period, subjects were not and actual driving tests. Therefore, the final conclusions allowed to use any prescribed medicines or drugs of abuse.
concerning a drug’s impairing effect on driving should be During the study period, it was not allowed to participate in based on combined results from these studies (ICADTS any other biomedical research. Subjects had to refrain from alcohol and caffeine 24 h before testing. On test days, The present study was designed to establish the effects subjects were not allowed to consume any food 3 h before of alprazolam XR on actual driving performance as arrival. During testing, smoking was prohibited.
assessed in a standard on-the-road driving test (O’Hanlon The study’s approval was obtained from the medical ). This test has been used repeatedly for assessing ethics committee of Maastricht University. The study was medicinal drug effects on actual driving in a large number conducted according to the code of ethics on human experimentation established by the World Medical Associ- a visual search task in which the subject has to monitor 24 ation’s Declaration of Helsinki (1964) and amended in asynchronously changing single digits presented in the four Edinburgh (2000). After complete description of the study corners of a screen. The subjects are instructed to remove to the subjects, written informed consent was obtained.
their foot from a pedal as rapidly as possible whenever theydetect the digit ‘2’. The main performance parameters are average tracking error (in mm) and number of controllosses in the tracking task and number of misses and speed The study was conducted according to a double-blind, of target detection (in ms) in the visual search task. These placebo-controlled, three-way crossover design. Treatments parameters are transformed to standard (z) scores for each were single oral doses of alprazolam 1 mg IR, alprazolam task. Performance in this test has proven sensitive to the 1 mg XR, and placebo. Study medication was supplied in effects of many sedative drugs such as doses of alcohol, three capsules (double dummy) at 9 A.M. of each test day.
antidepressants, antipsychotics, antihistamines, and the Treatment orders were balanced by randomly assigning six residual effects of hypnotics (Ramaekers et al. ; Robbe treatment orders to 18 subjects. The minimum period and O’Hanlon Vermeeren et al. ; Vuurman et al.
between successive treatments was 7 days.
The Stop Signal Task assesses inhibitory control, defined as the ability to stop a pending thought or action (Logan). The paradigm consists of two concurrent tasks, i.e., Before the first treatment period, all subjects received a a stop and a go task. The current test was adapted from an comprehensive training of the driving and laboratory tasks.
earlier version by Fillmore et al. (and has been The standardized highway driving test was undertaken validated for showing stimulant and sedative drug effects between 4 and 5 h after dosing, i.e., the time plasma (Ramaekers and Kuypers ). The go signals are four concentrations of the XR formulation were expected to be letters (A, B, C, or D) presented one at a time in the center at a maximum. The Stop Signal Task and a Divided of a computer screen. Subjects are required to respond to Attention Task were performed at 1, 2.5, and 5.5 h after each letter as quickly as possible by pressing one of two dosing. A Word Learning Task was performed at 1 h post- response buttons by either the left (A or C) or right (B or D) dose. Subjects consumed two standardized light meals 0.5 h index finger. In the stop task, subjects are required to withhold any response in case a stop signal (a visual cueappearing in one of the four corners of the screen) is presented. Stop signals are presented 12 times at each of thefour delays after the onset of a letter: 50, 150, 250, 350 ms In the 1-h driving test (O’Hanlon subjects operate a The dependent variables are reaction times to go signals specially instrumented vehicle over a 100-km (61-mi) (Go RT), the average delay needed to inhibit successfully primary highway circuit while maintaining a constant speed the ongoing response (stop signal reaction time, SSRT) and of 95 km/h (58 mi/h) and a steady lateral position between the delineated boundaries of the right (slower) traffic lane.
The Word Learning Task assesses memory for verbal Subjects are accompanied by a licensed driving instructor information (Rey In this test, 15 monosyllabic nouns with access to dual controls. During the test, the car’s speed are sequentially presented on a computer screen for 2 s, and and lateral position with respect to left lane-line are the subject is required to read the words aloud. At the end continuously recorded. These signals are edited off-line to of the sequence, the subject is asked to recall as many yield the Standard Deviation of Lateral Position (SDLP in words as possible in any order. This procedure is repeated centimeters) which is taken as the primary outcome five times, and the total number of correct recalls in five variable. SDLP is a measure of road tracking error or trials is referred to as the Immediate Recall Score (IRS).
‘weaving’. SDLP has proven to be sensitive to the sedative After a delay of at least 20 min, the subject is again and stimulating effects of various psychoactive drugs such required to recall as many words as possible. During this as anxiolytics (O’Hanlon et al. Verster et al. ), trial, the nouns are not presented. The total number of hypnotics (Vermeeren antidepressants (Ramaekers correct recalls is referred to as the Delayed Recall Score ), and antihistamines (O’Hanlon and Ramaekers (DRS). Finally, a sequence of 30 monosyllabic nouns is presented, containing 15 nouns from the original set and 15 The Divided Attention Task measures the ability to per- new nouns in random order. The subject has to indicate form two tasks simultaneously during 12 min (Moskowitz whether a noun originates from the old or from the new set.
). The primary subtask is a compensatory tracking task The total number of correct indications is referred to as the set at a constant level of difficulty. The secondary subtask is Recognition Score (RS). The reaction time of decision is measured and is referred to as the Recognition Reaction forensic case work, calibration curves are included in each Time (RRT). Performance in this test has previously been shown to be sensitive to the effects of alprazolam IR indoses of 0.5 and 1 mg (Vermeeren et al. Sample size was based on a power calculation for detectinga clinically relevant effect of 2.4 cm in the primary measure Alprazolam was determined by measuring serum concen- of this study, the SDLP. This change corresponds to the trations. Blood samples were collected at 55 min and 6 h effects of alcohol on SDLP, whereas BACs are 0.5 g/l as after ingestion of the drug. Samples were centrifuged after a measured in a previous study (Louwerens et al. clotting period, and serum was frozen at −20°C until Given that test–retest reliability of the driving test is at least analyses for pharmacokinetic assessments. Serum was r=0.70, a group of 18 subjects should permit detection of a analyzed for serum concentrations of alprazolam and its mean change in SDLP of 2.0 cm, with a power of at least metabolite α-hydroxy-alprazolam using a Liquid Chroma- tography-Tandem Mass Spectometry Method (LC-MS-MS) The global model used in the analysis of variance (ANOVA) of all cognitive and psychomotor parameters Internal standards, d5-alprazolam and d5-α-hydroxy- included subject, period, treatment, and time of testing. In alprazolam, were added to 1.0 ml serum sample before case of a significant overall effect of treatment, a solid-phase extraction (Oasis HLB®, Waters, Etten-Leur, subsequent analysis for comparing separate drug treatments The Netherlands). The analytes were eluted from the was conducted using three simple contrasts.
cartridges with 1.5 ml acetonitrile after washing with 2 ml All statistical analyses were done by using the Statistical water and 2 ml acetonitrile/water 10% v/v. The serum Package for the Social Sciences (SPSS) statistical program extracts were evaporated and reconstituted in 50 μl aceto- (version 12.0.1 for Windows; SPSS, Chicago, IL).
nitrile/water 20% v/v before analysis.
The LC-MS system consisted of a TSP Spectra System (Finnigan, Breda, The Netherlands), including an SN4000 controller, a vacuum degasser (SCM 1000), a pump(P4000), and an auto sampler (AS3000), connected to an A summary of the cognitive, driving, and psychomotor ion trap mass spectrometer (LCQ, Finnigan). Chromato- graphic data were acquired and processed using X-calibur™ 1.2 software (Finnigan). The method used an Atlantis C18 column (150×2.1 mm, Waters, Etten-Leur,The Netherlands). Injection volume was 10 μl. The gradient Word Recognition Test data were incomplete for five used in this LC-MS (MS) method was acetonitrile/formic subjects and Stop Signal Task data were incomplete for acid (0.005 M), 10% to 90% v/v acetonitrile. The time six subjects due to technical problems. Only complete data course of the gradient was as follows: t=0–1 min (10–40% v/v acetonitrile), t=1–7 min (40 v/v % acetonitrile), t=7–8 min (40–90% v/v acetonitrile), t=8–9 min (90% v/v acetonitrile), t=9–10 min (90–10% v/v acetonitrile). Parentions (m/z 309, 314, 325, and 330 for alprazolam, d5- Ten driving tests (18.5% out of 54 comprising the complete alprazolam, α-hydroxy-alprazolam, and d5-α-hydroxy- data set) were terminated prematurely because the driving alprazolam, respectively) and product ions (m/z 274 and instructors judged the subject to be too drowsy to continue 281 for alprazolam, m/z 279 and 286 for d5-alprazolam, safely. They terminated seven rides (38.9% out of 18 m/z 279, 297, and 307 for α-hydroxy-alprazolam, and m/z comprising one condition) in the IR condition and three 284, 302, and 312 for d5-α-hydroxy-alprazolam) were rides (16.7%) in the XR condition. The SDLP scores were calculated from the data collected until termination of each The linear range for the assay was 1–10 ng/ml for alprazolam and 0.5–5 ng/ml for α-hydroxy-alprazolam. The There was a significant treatment effect [F(2,16)=31.89, limit of quantification (concentration with an intra-day p < 0.001]. Contrast analysis revealed that both drug standard deviation of 20%) was 1 ng/ml for alprazolam and formulations significantly increased SDLP [IR: F(1,17)= 0.5–1 ng/ml for α-hydroxy-alprazolam. The accuracy was 67.44, p<0.001; XR: F(1,17)=36.86, p<0.001]. However, satisfactory (deviation from calibrated external control mean SDLP after alprazolam XR was significantly lower as 10%). Inter-day precision was not determined, because in compared to alprazolam IR [F(1,17)=34.37, p<0.001].
Table 1 Summary of the results of the Road Tracking Test and Cognitive and Psychomotor Tests in healthy subjects in a crossover trial ofalprazolam IR (1 mg), alprazolam XR (1 mg), and placebo (n=18) PLA Placebo, IR alprazolam Immediate Release, XR alprazolam Extended Release, NS not significant, SDLP standard deviation of lateral position, SDS standard deviation of speed, IRS immediate recall score, DRS delayed recall score, RS recognition score, RRT recognition reaction time, FAfalse alarms, z-AE z-score of average tracking error, z-ln(cl) z-score of log transformed total number of control losses, z-RT z-score of reactiontime, z-ln(mi) z-score of log transformed total number of misses Figure shows that SDLP increased with approximately showed that tracking performance was significantly im- 8 cm in the IR condition and 4 cm in the XR condition as paired at 1, 2.5, and 5.5 h after administration of alprazolam IR 1 mg [1 h: F(1,17)=15.88, p<0.001; 2.5 h: F(1,17)= No overall differences between placebo and drug were 15.14, p < 0.001; 5.5 h: F(1,17) = 12.40, p < 0.01] and found on mean speed and speed variability.
alprazolam XR 1 mg [1 h: F(1,17) =6.31, p<0.05; 2.5 h F(1,17) =7.00, p<0.05; 5.5 h: F(1,17) =12.26, p<0.01]. The effects of the XR formulation were less severe, however, thanthose of the IR formulation at 1 h [F(1,17)=15.42, p<0.05] The distributions of control losses and misses were and 2.5 h post-dose [F(1,17)=21.32, p<0.05] but no longer at highly skewed. Therefore, they were transformed to their natural log (ln) scores before transformation to z-scores.
A significant overall treatment effect in target detection ANOVA of the sum score of the z-scores of the average performance, as measured by the sum of the z-scores of the error and natural log of the total number of control losses reaction time and natural log of total number of misses, was revealed a significant overall treatment effect [F(2,16)= found [F(2,16) =5.72, p<0.05]. Analyses at separate times 11.74, p<0.001]. Effects of treatments were further ana- after administration revealed a significant impairment on lyzed at separate times after drug intake. These analyses target detection by alprazolam IR compared to placebo at Fig. 1 Mean (±SE) StandardDeviation of Lateral Position(SDLP) in each drug condition.
a is significantly different fromplacebo (p<0.001) and b issignificantly different fromalprazolam XR (p<0.001) all times of measurement [F(1,17) =6.89, p<0.05]. Alpra- after ingestion [F(1,11)=109.92, p<0.001; F(1,11)=6.44, zolam XR did not differ significantly from placebo 1 h p<0.05, respectively] but no longer at 5.5 h post-dose.
post-dose. On 2.5 and 5.5 h post-dose, target detection For the total number of false alarms data, analyses differed significantly between placebo and alprazolam XR [respectively, F(1,17)=4.46, p<0.05; F(1,17)=6.49, p<0.05]. Comparisons between both treatment conditions revealed significant differences at 1 h and 2.5 h post-dose[respectively, F(1,17)=5.84, p<0.05; F(1,17)=6.72, p< Analysis of the total number of words correctly recalled 0.05]. At 5.5 h after ingestion, target detection was not over five memory trials, as reflected by the IRS, showed a significantly different between both treatment conditions.
significant overall treatment effect [F(2,16)=9.08, p<0.01].
Placebo-drug comparisons revealed a significant impairing effect of alprazolam IR at 1 h after administration but not ofalprazolam XR. No significant difference was found Analysis revealed a significant overall treatment effect on between alprazolam IR and alprazolam XR.
the go reaction time [F(2,10) =6.20, p<0.05]. Separate The DRS also revealed a significant overall treatment analyses for each time of testing revealed significant effect, as delayed recall under the alprazolam IR condition differences between treatments at 2.5 h post-dose. At that was significantly lower than under the placebo condition [F time, relative to placebo, the go reaction time was (1,17) =10.22, p<0.01]. Delayed recall after alprazolam XR significantly longer after alprazolam IR [F(1,11)=22.87, p ingestion did not significantly differ from placebo. The < 0.001] but not after alprazolam XR. Moreover, the difference between alprazolam IR and alprazolam XR was increment in reaction time after alprazolam IR was also significant [F(1,17)=4.64, p<0.05).
significantly different from that after alprazolam XR [F No significant effects were found on performance in the (1,11)=23.70, p<0.001]. No interaction was found between A significant interaction effect between treatment and time of measurement in SSRT was found [F(2,10)=58.94,p<0.001]. Placebo drug comparisons for each time of Mean (SE) serum concentrations for alprazolam at 55 min testing showed that alprazolam IR increased SSRT signif- post-dose were 4.9 (1.0) μg/l after alprazolam IR adminis- icantly at each time of testing [F(1,11)=6.01, p<0.05], tration and 1.7 (0.2) μg/l after alprazolam XR administra- whereas alprazolam XR did not. SSRT after alprazolam XR tion. After approximately 6 h of drug ingestion, mean (SE) was significantly faster than after alprazolam IR 1 and 2.5 h serum concentrations for alprazolam were 10.6 (0.5) μg/l after alprazolam IR and 9.0 (0.6) μg/l after alprazolam XR.
and delayed recall in the word learning task. In contrast, The alprazolam metabolite α-hydroxy-alprazolam was not alprazolam XR only impaired performance in the divided detectable in the serum. The metabolite is expected to be attention task but not in the stop signal and memory tests, present in plasma in unconjugated form at less than 10% of indicating a reduction in adverse effects.
This reduction in impairing effects was most pronounced within the first 4 h after administration of both formula-tions, when blood levels of alprazolam XR were still rising and those of alprazolam IR were at their peak, as shown bythe serum concentrations. Within this time period, the Results from the present study show that both alprazolam effects of alprazolam XR were significantly less severe in 1 mg formulations administered as single doses to healthy the majority of the tests as compared with those of nonanxious volunteers significantly impair performance on alprazolam IR. At 5.5 h, post-dosing performance effects the standardized highway driving test. The IR formulation and serum concentrations became comparable. At this point produced a mean increase in SDLP of 8.2 cm and the XR in time, alprazolam XR achieves peak plasma concentra- formulation produced an increase of 3.9 cm. Although the tions, whereas alprazolam IR plasma levels are already magnitude of effect on SDLP was reduced by about 50% descending. Thus, peak effects of alprazolam XR are less after alprazolam XR, the impairment was still severe. The acute effects of alprazolam IR and alprazolam XR would be A potential limitation of the present study might be that the equivalents of driving with a BAC above the legal limit the effects were assessed only after a single dose adminis- for alcohol in most industrialized countries, i.e., 0.5 g/l tration of study treatments. Alprazolam-induced impairment (Louwerens et al. BACs of above 0.5 g/l have been may become less severe after chronic administration of shown to progressively increase the risk of becoming alprazolam, as it is well known that tolerance to the involved in a serious traffic accident by a factor of 2 or sedating effects of benzodiazepines can develop after more (Borkenstein ). The number of driving tests that repeated use (Curran ). However, it has also been were prematurely terminated supported the SDLP data.
shown that tolerance to the impairing effects of benzodia- Under the alprazolam XR condition, three (16.7%) subjects zepines is never complete. An epidemiological study by were not able to complete the driving test. Alprazolam IR Neutel ) demonstrated that benzodiazepines increase caused an early ending of the test in seven (38.9%) the relative risk of becoming involved in traffic accidents subjects. The most frequent reason for aborting the test during the first week of treatment and that this risk remains, prematurely was excessive sleepiness.
albeit to a lesser extent with passage of time. During the The detrimental effect of alprazolam IR on driving in the first week of treatment, the benzodiazepine users’ relative present study is similar to that found in a previous study risk was 13.5. After 1 month, the relative risk had declined employing the same standardized highway driving test. In to 2.6. The implication thus seems to be that benzodiaze- that study, Verster et al. ) found a mean increment in pine impairment persists over time but to a lesser degree as SDLP of approximately 9 cm between 1–2 h after a single observed after initial dosing. A similar pattern was found in dose of alprazolam IR 1 mg. This indicates that sensitivity an experimental study assessing the effects on driving of the subjects in the present study to the effects of performance of diazepam 5 mg treatment during 4 consecutive weeks in 12 patients with generalized anxiety Although the laboratory tests are not expected to disorder (Van Laar et al. Diazepam significantly strongly predict driving performance, they usually provide impaired driving performance as reflected by an elevated some insight as to what extent driving is affected after drug SDLP in the first 3 weeks of treatment. Therefore, it was intake. Driving ability is not one distinct skill but a concluded that driving performance of patients will be combination of a series of mental and behavioral functions affected at least during early, chronic treatment.
(Vermeeren and De Gier ). Therefore, performance in It might be argued that performance of healthy subjects laboratory tests assessing different aspects of driving can may be different from performance of patients suffering provide insight into what aspects of driving behavior are from anxiety of panic disorder. Moreover, as healthy most sensitive to the effects of a particular drug, although volunteers do not have a history of benzodiazepine use, performance in any single test is not highly correlated to the effect of alprazolam may be stronger than that in driving performance itself. As expected, alprazolam IR patients who have already been using alprazolam for an significantly impaired performance on all tasks as com- extended period of time. Yet, these notions have never been pared with placebo. It impaired tracking and peripheral confirmed in scientific research. On the contrary, O’Hanlon visual search in the divided attention task, response speed et al. (have shown that driving performance after and inhibitory control in the stop signal task, and immediate both single and repeated doses of benzodiazepine anxio- lytics did not differ in healthy volunteers and patients.
Greenblatt DJ, Harmatz JS, Dorsey C, Shader RI (1988) Comparative Moreover, these authors showed that baseline and placebo single-dose kinetics and dynamics of lorazepam, alprazolam,prazepam, and placebo. Clin Pharmacol Ther 44:326–334 performances were comparable between both groups. This ICADTS (1999) Guidelines on experimental studies undertaken to implies that healthy volunteer models can be used for determine a medicinal drug’s effect on driving or skills related to predicting drug effects on driving in patient populations.
driving. Bundes Anstalt fuer Strassenwesen (BASt), Köln Therefore, if the effects of both formulations of alprazolam Isbister GK, O’Regan L, Sibbritt D, Whyte IM (2004) Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br observed in the present study also apply to anxious individuals receiving the medications as clinical treatment, Kroboth PD, Folan MM, Bauer KS, Tullock W, Wright CE, Sweeney the risk of becoming involved in a car accident may be JA (1998) Do alprazolam-induced changes in saccadic eye movement and psychomotor function follow the same timecourse? J Clin Pharmacol 38:337–346 In conclusion, the impairing effects of alprazolam XR Logan GD (1994) On the ability to inhibit thought and action: a users’ 1 mg on driving and cognition were generally less as com- guide to the Stop Signal Paradigm. In: Dagenbach D, Carr TH pared to its IR equivalent but still of sufficient magnitude to (eds) Inhibitory processes in attention, memory, and language.
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Louwerens JW, Gloerich ABM, de Vries G, Brookhuis KA, O’Hanlon JF (1987) The relationship between drivers’ blood alcohol This research was supported by a grant from concentration (BAC) and actual driving performance during high speed travel. Alcohol Drugs Traffic Saf 86:183–186 We like to thank Anita van Oers, Janneke Guijaux, Roland Otten, Moroz G (2004) High-potency benzodiazepines: recent clinical Henk Brauers, Willy Jeurissen, Irma Brauers and Cees van Leeuwen results. J Clin Psychiatry 65(Suppl 5):13–18 for their assistance in data collection.
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Journal of Xinjiang University(Natural Science Edition)LIN Hui-qiu, MENG Ji-xiang † , TIAN Ying-zhi( College of Mathematics and Systems Science, Xinjiang University, Urumqi, Xinjiang 830046, China )A subset S ⊂ E ( G ) is called a 4-restricted-edge-cut of G , if G − S is disconnected and everycomponent contains at least 4 vertices. The minimum cardinality over all 4-restricted-edge-c

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