Midazolam 12 mg is moderately counteracted by 250 mg caffeine in man.

OBJECTIVE: Caffeine (Caf) counteracts various effects of benzodiazepines (BZDs). Since the effects of zolpidem, a short-acting atypical GABA(A)-BZD agonist, were not antagonized by Caf, we studied an interaction between Caf and midazolam (Mid) in healthy volunteers. SUBJECTS, MATERIALS AND METHODS: In Study 1, 108 healthy students divided to 6 parallel groups were given Mid 12 mg (capsule) and Caf 125 and 250 mg (in decaffeinated coffee), alone and in combinations in the double-blind placebo-controlled manner. Objective and subjective tests were done before and at 45 and 90 min after intake. Ranked delta-values (changes from baseline) were analyzed by one-way contrast ANOVA and Scheffe's tests. In Study 2, six healthy subjects took Mid 15 mg (tablet) with and without Caf 300 mg. The dynamic effects were analyzed as in Study 1 and the plasma concentrations were assayed. RESULTS: In Study 1, learn effects after placebo (ad + 15%) were seen for letter cancellation and digit symbol substitution tests. Midazolam alone significantly (p < 0.05 vs. delta-placebo) reduced letter cancellation and digit symbol substitution, lowered flicker fusion, impaired digit learning and caused subjective calmness on VAS. Caffeine alone did not differ from placebo objectively, yet improved quick-wittedness and contentedness on VAS. In the combinations, Mid + Caf 125 mg differed from placebo objectively as Mid alone, whereas Mid + Caf 250 mg did not. Mid + Caf 250 mg differed from Mid on digit substitution, but did not differ from Mid+Caf 150 mg in impairing memory and causing subjective sedation. In Study 2, Mid 15 mg caused sedation and Caf 300 mg increased plasma Mid at 45 min. Mid + Caf did not differ from Mid alone objectively, but did so subjectively on VAS (p > 0.05). CONCLUSION: In conclusion, in a parallel group study, sedative effects of Mid 12 mg were only moderately antagonized by Caf 250 mg but not by Caf 125 mg. In a cross-over study, a weak interaction was found subjectively but not in objective measures.

Driving under light and dark conditions: effects of alcohol and diazepam in young and older subjects.

OBJECTIVES: Driving at night time increases accident risk due to visual conditions, fatigue and impaired performance. In addition, the use of alcohol and benzodiazepines may enhance the risks related to night-time driving. We studied these aspects of traffic safety in a simulated driving test with young and older drivers. METHODS: In a double-blind, crossover, placebo-controlled study, nine young subjects, aged 22-24 years, performed simulated driving in both 'light' and 'dark' conditions, before and 1.5 h and 4 h after 0.8 g x kg(-1) ethanol (EOH) or 15 mg diazepam (DZ). Further, nine older subjects, aged 55-77 years, were similarly tested, but their EOH dose was 0.7 g x kg(-1) and the DZ dose was 10 mg. The tests were vigilance assessment on visual analogue scales (VAS), simulated driving under light and dark conditions for 6 min each and digit symbol substitution (DSS). RESULTS: In the young subjects, both EOH and DZ similarly impaired DSS, with DZ causing more subjective drowsiness, clumsiness, mental slowness and poor overall performance than EOH. During simulated driving, both EOH and DZ impaired simple and complex tracking (EOH > DZ) and prolonged reaction times (EOH = DZ). Impairment of performance was practically identical under light and dark conditions. In the older subjects, objective performance on DSS was poorer (-30%) than that of the young ones, and subjective impairment was marginal. During simulated driving, the baseline levels of variables in older subjects showed definite impairment (errors +100% to +500%) when compared with young subjects. Active drugs impaired several variables (EOH > DZ), but the statistical significances were fewer than in young subjects. Increase in reaction errors reached statistical significance, especially while driving in the dark. Otherwise the driving results in light and dark were not notably different. CONCLUSION: Young subjects drew good baselines but were sensitive to EOH and DZ, whilst the older subjects showed poor baselines but were less sensitive to EOH and DZ. Although the baseline driving and responses to treatments were different in young and older subjects, their driving and psychomotor impairment were unaffected by light conditions.

Variations among non-sedating antihistamines: are there real differences?

Most of the modern non-sedating H1 receptor antagonists (antihistamines) penetrate the brain poorly, allowing the use of doses large enough to counteract allergic processes in peripheral tissues without important central effects. The antihistamines reviewed here are acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine. However, these drugs are not entirely free from central effects, and there are at least quantitative differences between them. Although psychomotor and sleep studies in healthy subjects in the laboratory may predict that an antihistamine does not cause drowsiness, the safety margin can be narrow enough to cause a central sedating effect during actual treatment. This might result from a patient's individual sensitivity, disease-induced sedation, or drug dosages that are for various reasons relatively or absolutely larger (patient's weight, poor response, reduced drug clearance, interactions). Mild to even moderate sedation is not necessarily a major nuisance, particularly if stimulants need be added to the regimen (e.g. in perennial rhinitis). Furthermore, patients can adjust doses themselves if needed. Sedating antihistamines are not needed for long-term itching, because glucocorticoids are indicated and more effective. It is wise to restrict or avoid using antihistamines (astemizole, terfenadine) that can cause cardiac dysrhythmias, because even severe cardiotoxicity can occur in certain pharmacokinetic drug-drug interactions. Histamine H1 receptor antagonists (antihistamines) are used in the treatment of allergic disorders. The therapeutic effects of most of the older antihistamines were associated with sedating effects on the central nervous system (CNS) and antimuscarinic effects causing dry mouth and blurred vision. Non-specific "quinidine-like" or local anaesthetic actions often led to cardiotoxicity in animals and man. Although such adverse effects varied from drug to drug, there was some degree of sedation with all old antihistamines. Non-sedating antihistamines have become available during the past 15 years. Some of them also have antiserotonin or other actions that oppose allergic inflammation, and they are not entirely free from sedative effects either. In small to moderate "clinical" concentrations they are competitive H1 receptor antagonists, although large concentrations of some of them exert non-competitive blockade. Daytime drowsiness and weakness are seldom really important, and they restrict patients' activities less than the old antihistamines. Some new antihistamines share with old antihistamines quinidine-like effects on the cardiac conducting tissues, and clinically significant interactions have raised the question of drug safety. This prodysrhythmic effect has also been briefly mentioned in comparisons of non-sedative H1 antihistamines.

Zolpidem 10 mg given at daytime is not antagonized by 300 mg caffeine in man.

OBJECTIVE: Caffeine counteracts various effects of traditional benzodiazepines (BZDs). As zolpidem, a short-acting hypnotic, is an atypical GABAA-BZD agonist, we investigated when caffeine would counteract the effects of zolpidem as well. METHODS: In daytime study I, zolpidem 10 mg (capsule) and caffeine 150 or 300 mg (in decaffeinated coffee) were given, alone and in combinations, to parallel groups (n = 15-17) of healthy students in double-blind and placebo-controlled manner. Objective and subjective tests were done before and 45 min and 90 min after intake. Ranked delta values (changes from baseline) were analysed by one-way contrast ANOVA and Scheffe's tests. In daytime study II, four healthy subjects took zolpidem 10 mg alone, and together with blinded caffeine 250 mg or (at -45 min) erythromycin 750 mg. Objective and subjective effects were measured and plasma zolpidem concentrations assayed at baseline and 45 min and 90 min after zolpidem intake. RESULTS: In study I, practice effects after placebo (ad + 30%) were seen for letter cancellation and digit symbol substitution but not for flicker fusion tests. Zolpidem alone significantly impaired (P < 0.05 vs delta placebo) letter cancellation and digit symbol substitution at 45 min and 90 min, lowered the flicker fusion threshold at 45 min, and caused subjective drowsiness, mental slowness, clumsiness and feeling of poor performance. Caffeine alone showed a non-significant trend to improve objective performance. The combined effects of zolpidem and either dose of caffeine matched those measured after zolpidem alone. Zolpidem + caffeine 300 mg was not stronger than zolpidem + caffeine 150 mg in impairing immediate memory and causing subjective sedation. In study II, zolpidem caused objective and subjective sedation; neither caffeine nor erythromycin modulated the effects of zolpidem or plasma zolpidem concentrations. CONCLUSION: The sedative effects of 10 mg of zolpidem are not antagonized by 150-300 mg of caffeine in pharmacodynamic or pharmacokinetic terms.

Effects of alcohol, zolpidem, and some other sedatives and hypnotics on human performance and memory.

Zolpidem (Zol), an omega1-agonist, acts via GABA(A) receptors but may differ qualitatively from diazepam (Dz) and other benzodiazepines (BZDs). We conducted a placebo-controlled, randomized, double-blind, and crossover study to compare the psychomotor and cognitive effects of 15 mg Zol with those of 15 mg Dz, 30 mg oxazepam (Ox), 7.5 mg zopiclone (Zop), and ethanol (EOH; 0.65 + 0.35 g x kg(-1)) given to 12 subjects at 1-week intervals. Psychomotor tests (symbol digit substitution, simulated driving, flicker fusion, body sway) were done before and 1, 3.5, and 5 h after intake; immediate and delayed memory were measured between 1.5 and 3.5 h. The plasma concentrations of drugs were measured by gas chromatography and by radioreceptor assay (RRA). The mean values of EOH in blood at 1.5, 4, and 5.5 h were 0.82, 0.88, and 0.6 g x l(-1), and the mean values of RRA-assayed plasma Dz were 470, 330, and 210 microg x l(-1), respectively. The corresponding values of other hypnosedatives, in Dz equivalents (microg x l(-1)), were 550, 750, and 330 for Ox; 350, 270, and 70 for Zol; and 160, 210, and 70 for Zop. The standard RRA graph for Zol was significantly flatter than those for other hypnotics. Zol impaired coordinative, reactive, and cognitive skills at 1 and 3.5 h more clearly than the other agents did, the most sensitive performance (tracking) still being impaired by Zol at 5 h. Dz and Zop were less active than Zol objectively; subjective sedation after Dz and Zol was stronger than after Zop. Compared to placebo, all active agents tended to impair learning and memory, their decremental effects, in declining order, being Zol, Dz > EOH, Ox > Zop. During the delay, Dz and Zol caused similar losses of material that had been learned. When separating "true" delayed memory from immediate memory (attention important), Dz and Zol had equieffects on delayed memory and were more detrimental than Zop. When contrasting that against the impaired psychomotor performances, it is possible that 15 mg Zol impairs memory relatively less than 15 mg Dz does.

GABA(A)-receptor subtypes: clinical efficacy and selectivity of benzodiazepine site ligands.

The main inhibitory neurotransmitter receptor of the brain, the gamma-aminobutyric acid type A receptor (GABA[A]), mediates the actions of several classes of clinically important drugs, such as benzodiazepines, barbiturates and general anaesthetics. This review summarizes the current knowledge on how classical benzodiazepines and novel nonbenzodiazepine compounds act on the benzodiazepine site of GABA(A) receptors and on their clinical pharmacology related to anxiolytic, sedative, hypnotic and cognitive effects or side-effects. Partial agonism, receptor subtype selectivity and novel binding sites are discussed as possible strategies to develop new drugs with fewer adverse effects than are seen in the clinical use of benzodiazepines.

Effects of alcohol and hypnosedative drugs on digit-symbol substitution: comparison of two different computerized tests.

Computerized symbol-digit substitution tests (SDSTs) and 'yes/no' digit-symbol substitution tests (YNDSTs), together with a digit-digit copying test (DDCT) were compared in a double-blind crossover study for hypnosedative and alcohol effects in 12 young healthy subjects. The tests were carried out before and 1, 3.5 and 5 h after intake of 15 mg diazepam, 30 mg oxazepam, 7.5 mg zopiclone, 15 mg zolpidem or 0.65+0.35 g/kg ethanol, these impaired performance by varying extents. The drug-induced decrements were similar in the YNDSTs and SDSTs; the errors were subject-related and increased with alcohol intake in the YNDSTs but not in the SDSTs. Pooled baseline values in YNDSTs correlated well (Pearson) with those in the SDSTs. The SDSTs also correlated well with the DDCTs. The same correlations were seen when comparing absolute performances after ethanol and hypnosedatives. When using the delta-values (changes from baseline), the correlation between YNDSTs and SDSTs was high after placebo but low after alcohol and hypnosedatives. When using ANCOVA to measure the responses to drugs (delta-drug-delta-placebo), the correlation between YNDSTs and SDSTs was fairly significant after most but not all active drugs. Subjective visual analogue variables did not correlate with objective performances. By comparing absolute performances with hypnosedatives we conclude that YNDSTs and SDSTs are similar, with the delta-values indicating differences between them.

Grapefruit juice does not enhance the effects of midazolam and triazolam in man.

OBJECTIVES: Since grapefruit juice (Gra) inhibits hepatic P450 (CYP3A4), we studied its potential to enhance the effects of midazolam (Mid) and triazolam (Trz), which are metabolized by the CYP3A4 isoenzyme. METHODS: In Study I parallel groups of healthy students were given orally Mid 10 mg with water or grapefruit juice (GraMid), two placebo groups receiving water or Gra. The effects of Mid were measured by psychomotor tests and by self-rating on visual analogue scales before and 30 and 90 min after intake. Study II was similar, but the post-treatment tests were at 45 and 90 min, and the active drugs used were 0.250 mg Trz, GraTrz, and Mid 10 mg. In the crossover Study III, 6 subjects took Mid 10 mg alone and with Gra (GraMid) and 750 mg erythromycin (EryMid). Performance tests were made and blood was sampled before and 30, 60 and 90 min after intake. Midazolam and its active metabolite alpha-OH-midazolam were assayed by gas chromatography (GC) and radioreceptor assay (RRA). RESULTS: In Study I, both Mid and GraMid impaired digit symbol substitution (DSS), letter cancellation (LC) and flicker fusion (CFF) at 90 min. GraMid had more effect (P < 0.05) than Mid on the DSS performance. Mid caused drowsiness at 30 and 90 min. Both Mid and GraMid caused clumsiness and a feeling of impaired performance at 90 min. In Study II, the active drugs impaired objective test performances (DSS, LC, CFF) at 90 min, without having a clear subjective effect. In Study III, Mid, EryMid and GraMid impaired performance in the DSS, LC and CFF tests. EryMid proved stronger than Mid and GraMid on DSS and LC tests at 30 min. Mean values of plasma midazolam (and alpha-OH-midazolam) at 30, 60, 90 and 120 min after Mid 10 mg were 68(19), 61(19), 43(14) and 42(12) micrograms.l-1. The corresponding values after EryMid were 164(14), 137(13), 104(10) and 89(10) micrograms.l-1, and after GraMid 60(12), 69(16), 61(15) and 57 (14) micrograms.l-1. CONCLUSIONS: The grapefruit juice used did have any particular interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in healthy young subjects.

Single oral doses of amisulpride do not enhance the effects of alcohol on the performance and memory of healthy subjects.

OBJECTIVES: Amisulpride is a benzamide antipsychotic that binds selectively to dopamine D2- and D3-receptors, preferentially in limbic and hippocampal structures. Since other substituted benzamides have a limited or negligible interaction with alcohol on human performance, amisulpride was studied for this potential. METHODS: In a randomised double-blind crossover study, 18 young, non-smoking men took single oral doses of placebo and amisulpride 50 mg and 200 mg, without and with ethanol (0.8 g. kg-1) taken 30 min later. Objective performance tests and self-ratings were done at baseline and 1.5, 3.5 and 6.5 h after drug intake. Memory (immediate and delayed recall) was tested 2 h after dosing. Breath ethanol and the plasma concentrations of amisulpride and prolactin were measured. Three-way ANOVA + Newman-Keul tests were used for statistical analyses; interactions were confirmed by factorial contrast ANOVA. RESULTS: Mean blood ethanol was 0.94, 0.62 and 0.26 g.1(-1) at the three test times. It produced significant impairment in all performance tests (symbol digit substitution, simulated driving, body sway, flicker fusion, tapping, nystagmus), reduced both immediate and delayed recall in memory tests, and caused subjective clumsiness, muzziness and mental slowness, mainly between 1.5 to 4.5 h after dosing. Amisulpride, 50 and 200 mg elevated plasma prolactin but had minimal or no effect on performance, attention and memory. The decreases in immediate free recall after the 50 mg dose and in delayed free recall after the 200 mg dose were slight. Amisulpride neither modified blood ethanol concentrations nor enhanced the detrimental effect of ethanol on skilled and cognitive performance; it slightly antagonised ethanol in the digit copying test. Ethanol did not modify the effect of amisulpride on plasma prolactin, and the plasma concentrations of amisulpride were little changed by ethanol. CONCLUSIONS: Amisulpride in single oral doses of 50 and 200 mg did not interact significantly with the effects of high, moderate or low concentrations of ethanol on human skilled and cognitive performance. The drugs did interact pharmacokinetically.

150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects.

Fluconazole, an azole antifungal agent, moderately inhibits the CYP3A-mediated metabolism of midazolam in vitro. We therefore studied whether such an interaction takes place in vivo following oral administration of these drugs, given as relevant double blinded doses in capsule form. In study I parallel groups of healthy subjects received oral midazolam 10 mg (MID 10) or 15 mg (MID 15), placebo, or MID 10 mg + 150 mg fluconazole (FLU) given 2 h earlier. Objective and subjective performance tests were made before, and 30 and 90 min after the intake of midazolam. MID 10 and MID 15 moderately impaired performance on digit symbol substitution, letter cancellation and flicker fusion tests, and visual analogue scales revealed mild sedation. FLU + MID 10 had similar or slightly stronger effects than MID 10; it differed from MID 10 in that it lowered the flicker fusion threshold and produced subjective slowness and overall impairment. In study II 5 subjects received MID 10 after placebo, after FLU, and after 750 mg erythromycin (ERY) at 1-week intervals, following a crossover and double-blinded study design. Blood was sampled before MID intake and 30, 60 and 90 min after it, and performance was measured. FLU and ERY increased the effect of MID on flicker fusion and letter cancellation performances, and increased the HPLC-assayed plasma midazolam (ERY + 100%, FLU + 50%) in comparison to that measured after MID ingested alone. When the concentrations of midazolam together with its active metabolite alpha-OH-midazolam were assayed by radioreceptor technique the increases caused by ERY and FLU were less and compatible with the pharmacodynamic data.(ABSTRACT TRUNCATED AT 250 WORDS)

Lorazepam and diazepam differently impair divided attention.

Effects of ethanol (EtOH, 0.65 + 0.35 g.kg-1), diazepam (DZ, 15 and 30 mg), lorazepam (LZ, 2 mg) on divided attention were measured in two placebo-controlled crossover studies with healthy young subjects. The test comprised four parallel computer screens with a ball moving along a circular obstacle course on each screen at different rates. When the ball entered an obstacle on any screen, the subject had to press the respective button. The obstacles varied in numbers and shapes, and randomly changed their location every 10 s. Concomitant aural stimuli were responded to by pushing the foot pedals. The primary visual variables were the absolute and percent numbers of correct responses on each screen. Concentrated attention was measured with a symbol digit substitution (SDST) and digit copying (DDCT) tests, for 3 min each. In Study I, with 12 subjects, the tests (4 min) were made before the treatment (placebo, EtOH, DZ) and 1, 3, and 6 h after intake. EtOH impaired attention on the lateral but not on medial screens, with and without aural stimuli, the "special" obstacles of deviating shape being the most sensitive targets to EtOH effects. DZ 15 mg did not modify divided attention whereas it impaired SDST performance and was subjectively slightly more potent than EtOH on visual analog scales. DZ 30 mg impaired attention on the lateral screens, with and without aural stimuli, but without preference to "special" obstacles. It also reduced responses to aural stimuli, strongly impaired SDST and DDCT, and caused subjective sedation. In Study II, with 9 subjects, the test run without aural stimuli was easier but lasted for 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of oxicam nonsteroidal anti-inflammatory agents.

Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of structurally closely related substances with anti-inflammatory, analgesic and antipyretic activities. They have a weakly acidic character and are extensively bound to plasma proteins. Piroxicam, the most widely used oxicam, is well absorbed after oral administration. Peak plasma concentrations (Cmax) of the drug are reached within 2 to 4 hours. Piroxicam has a small volume of distribution and a low plasma clearance. It undergoes hepatic metabolism and only 5 to 10% is excreted unchanged in urine. The elimination half-life varies between 30 and 70 hours. Age of the patient and renal or hepatic dysfunction do not seem to have any major effect on the pharmacokinetics of piroxicam. The drug reduces the renal excretion of lithium to a clinically significant extent, but the clinical significance of piroxicam-aspirin (acetylsalicylic-acid) and piroxicam-acenocoumarol interaction has not been established. Ampiroxicam, droxicam and pivoxicam are prodrugs of piroxicam that have been synthesised to reduce piroxicam-related gastrointestinal irritation. All prodrugs are well absorbed, but Cmax values are reached later than those following administration of piroxicam. Tenoxicam is used in the management of rheumatic and inflammatory diseases. Mean Cmax values are achieved 2 hours postdose. Food reduces the rate but not the extent of absorption. The oral bioavailability of tenoxicam is 100% and rectal bioavailability is 80%. Like piroxicam, tenoxicam has a low volume of distribution and low plasma clearance. It is eliminated through hepatic metabolism. The mean elimination half-life is 60 to 75 hours. The pharmacokinetics of tenoxicam are independent of patient age, or concurrent liver or renal diseases. High doses of aspirin have been shown to increase the elimination of tenoxicam, but this has little clinical significance. Isoxicam was in widespread clinical use until its worldwide marketing was suspended because of fatal skin reactions. Isoxicam is completely absorbed, but Cmax values are not reached until 10 hours postdose. It has a low plasma clearance, approximately 5 ml/min (0.3 L/h), and low volume of distribution. The mean elimination half-life is 30 hours and does not appear to be affected by the age of the patient. Isoxicam potentiated the anticoagulant effect of warfarin, necessitating a 20% dosage reduction. Lornoxicam differs from other oxicam NSAIDs because it has a short elimination half-life of 3 to 4 hours. On the basis of limited data, some individuals seem to eliminate lornoxicam very slowly, suggesting the presence of polymorphic metabolism. The pharmacokinetics of cinnoxicam and sudoxicam have not been studied thoroughly.(ABSTRACT TRUNCATED AT 400 WORDS)

Azithromycin does not alter the effects of oral midazolam on human performance.

Since macrolide antibiotics inhibit the oxidative hepatic metabolism of various drugs, including midazolam, the present double blind studies were conducted to find out if azithromycin, a new macrolide of the azalide type, would inhibit the metabolism of midazolam and enhance the effects of midazolam on human performance. In Study I, 64 healthy medical students, divided in four parallel groups received placebo, midazolam (10 mg or 15 mg), and midazolam 10 mg combined with azithromycin (500 mg + 250 mg). In Study II, three males received oral midazolam 10 mg in combination with placebo, azithromycin or erythromycin 750 mg (as a positive control) in a cross-over trial. Objective and subjective tests were done before the intake of midazolam and 30 and 90 min after it, and venous blood was sampled for the assay of midazolam. In the placebo group in Study I, the mean numbers of letters cancelled (LC) at baseline, 30 min and 90 min were 21, 20 and 20, respectively, and the corresponding mean numbers of correct digit symbol substitutions (DSS) were 126, 137 and 140, indicating a practice effect. Midazolam 10 mg impaired these performances (21, 13 and 12 for LC, and 127, 113 and 111 for DSS). Either dose of midazolam produced clumsiness, mental slowness and poor subjective performance, midazolam 15 mg being slightly more active. The corresponding, scores in the azithromycin+midazolam group were 21, 16, 16 for LC, and 132, 121 and 119 for DSS, the only significant difference from placebo being the impairment of DSS at 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol antagonism by atipamezole on motor performance in mice.

The interactions of an alpha 2-adrenoceptor antagonist, atipamezole, and an alpha 2-adrenoceptor agonist, dexmedetomidine, with ethanol were studied in male NIH Swiss mice. The mice were given (i.p.) atipamezole 0.1, 0.3, 1, 3 and 10 mg/kg and dexmedetomidine 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 mg/kg; the ethanol doses were 1, 2 or 3 g/kg. Motor performance was measured by spontaneous locomotor activity and rotarod test. Dexmedetomidine impaired performance in both tests. The effect of dexmedetomidine peaked at the dose of 1 mg/kg. Three mg/kg of atipamezole abolished totally the effects of 0.3 mg/kg of dexmedetomidine and partially those of 1 mg/kg of dexmedetomidine. Atipamezole counteracted and dexmedetomidine enchanced ethanol effects in both tests. The interactions were not of pharmacokinetic origin since blood and brain ethanol and dexmedetomidine levels were unaltered at the time of testing. The results suggest that ethanol effects on motor performance in mice are mediated in part via central noradrenergic mechanisms, and blockade of alpha 2-adrenoceptors by atipamezole leads to considerable antagonism of these ethanol effects.

Suriclone enhances the actions of chlorpromazine on human psychomotor performance but not on memory or plasma prolactin in healthy subjects.

Twelve healthy subjects received single oral doses of 0.4 mg suriclone (SU), 7.5 mg zopiclone (ZO) and placebo, alone and together with 50 mg chlorpromazine (CP), double blind and crossover, in Latin square order, at one-week intervals. Performance tests administered before and 1.5, 3.5 and 6 h after drug intake included digit symbol substitution and simulated driving combined in a "Global test", flicker fusion frequency, body balance and memory and subjective assessments. Changes from baseline were examined statistically. Performance and memory data were analysed from only 11 subjects. Compared to placebo, SU minimally affected "global" performance, although it slowed reactions and tended to impair digit substitution. ZO impaired "global" performance at 1.5 h, affected performance in several separate tests, and produced subjective muzziness. CP did not impair "global" performance, although it did impair digit substitution and render the subjects drowsy, weak and dreamy. The combinations SU + CP and ZO + CP definitely impaired "global" performance more than CP alone. This difference was also found in most objective tests but less so in the subjective tests. CP and its combinations produced similar increases in plasma prolactin. Active drugs and their combinations variably lowered blood pressure and increased heart rate, and one subject collapsed after CP. The treatments irregularly impaired spatial memory and learning acquisition. No pharmacokinetic interactions were seen in the plasma levels of suriclone, zopiclone and chlorpromazine. The impairment of performance after these combinations resembles that previously encountered after 2.5 mg lorazepam, or 15 mg diazepam + 100 mg remoxipride.

Effects of psychotropic drugs on digit substitution: comparison of the computerized symbol-digit substitution and traditional digit-symbol substitution tests.

The digit-symbol substitution test (DSST), performed with paper and pencil or computerized, is widely used to reveal decrements in human attention and cognition. We programmed sets of adjustable tasks (digit-symbol, digit-digit, symbol-digit, symbol-symbol) into a microcomputer and compared the symbol-digit substitution (SDST) and the digit copying test (DDCT) with the traditional DSST in two placebo-controlled double-blind studies of psychotropic drugs with pre-trained young healthy subjects. Performances were measured before drug intake and several times after it; matched, different codes were used at consecutive tests. DSST and SDST substitutions remained at the baseline level after placebo, while the simple DDCT performance improved during the placebo session. The prolonged (3 min) test was not exhaustive because interim counts at 90 s predicted the final performance well. In Trial I, 15 mg diazepam orally reduced DSST and SDST functions in a similar way, but it also impaired simple copying in the DDCT, though to a lesser extent. Ebastine, an H(1)-antihistamine, proved inert alone and failed to increase the effects of diazepam on these variables. In Trial II, 7.5 mg zopiclone, 0.4 mg suriclone and 50 mg chlorpromazine, alone and in combinations, impaired the DSST performance in the manner expected. The drug effects were similar in the SDST, and somewhat less in the DDCT, while the substitution errors were subject related and not altered significantly by any treatment. The simple correlation matrices (Pearson, Spearman), confirmed by analysis of covariance, showed that the results of DSST correlated fairly well with those of SDST after zopiclone, chlorpromazine and their combination, but not after suriclone or its combination with chlorpromazine. The DDCT results correlated with those of the substitution tests when analysing pooled baseline values, but not when analysing the performances after drug intake. Subjective visual analogue variables correlated poorly or not at all with objective performances. Our results suggest that manual dexterity in these computerized tests might contribute significantly to the total impairment of performance in response to different drugs. The DSST and SDST matched each other fairly well in their sensitivity to drug effects, yet this similarity may depend on the drug used.

Oral single doses of erythromycin and roxithromycin may increase the effects of midazolam on human performance.

Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolam in vitro and in vivo. To find out if significant interactions take place after single oral doses of these agents to man, 0.25 mg triazolam and 5, 10 and 15 mg of midazolam in capsule from were given with and without 750 mg erythromycin or 300 mg roxithromycin to parallel groups of healthy subjects in four placebo-controlled double-blind studies. Objective tests and subjective assessments were made before the intake of hypnotics and 30 and 90 min after it. In Study I, triazolam impaired letter cancellation, the combination triazolam+erythromycin impaired digit symbol substitution and letter cancellation, and triazolam+roxithromycin impaired digit symbol substitution, all at 90 min. In Study II, midazolam 5 mg and midazolam 10 mg proved quite inert but the combination midazolam 5 mg+erythromycin impaired digit symbol substitution. In Study III, both midazolam 10 mg and midazolam 15 mg impaired digit substitution and letter cancellation, the effects of 15 mg being more prominent. The strongest drug effects were found with midazolam 10 mg+erythromycin which differed from placebo and midazolam (10 mg and 15 mg) in several objective and subjective test variables. In Study IV, the combination midazolam 10 mg+roxithromycin impaired several objective and subjective variables but it was not stronger than midazolam 15 mg. These results were supported by the direct measurements of plasma midazolam in three subjects: erythromycin increased plasma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Diazepam effects on the performance of healthy subjects are not enhanced by treatment with the antihistamine ebastine.

1. We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a randomized double-blind and crossover study for 1 week each. The subjects were tested for drug effects on day 6 of each period, and for interactions of ebastine with oral 15 mg diazepam (DZ) on day 7. On both days, the testing runs were at baseline and 1.5, 3, 4.5 and 6 h after intake. 2. The performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, simulated driving, body balance) and subjectively (visual analogue scales, questionnaires). Venous blood was sampled daily during the maintenance and during each testing round for the assay of plasma carebastine (the active metabolite of ebastine) by high pressure liquid chromatography and plasma diazepam by radioreceptor assay. Three-way ANOVA, paired t-test, Wilcoxon rank sign test and Fisher's fourfold table test were used for data analysis. 3. Plasma carebastine reached steady levels from day 3 onwards. The mean concentrations in the morning were 82 micrograms l-1 on day 6 and 85 micrograms l-1 on day 7. The rise (+ 150%) in plasma carebastine after an extra 20 mg ebastine was not modified by DZ. Ebastine did not affect performance objectively or subjectively, yet borderline drowsiness was recorded during the first 3 h. On day 7, plasma DZ concentrations peaked (mean 480 micrograms l-1) at 1.5 h after the intake. DZ produced impaired performance in various objective tests, and drowsiness, weakness, clumsiness, mental slowness and poor performance were reported on visual analogue scales.(ABSTRACT TRUNCATED AT 250 WORDS)