No association of CCK and CCK(B) receptor polymorphisms with alcohol dependence.

Cholecystokinin (CCK) is the most widely distributed neuropeptide in the central nervous system. One of its several functions is to modulate the release of dopamine in brain areas involved in reinforcement and reward behavior. The aim of this study was to investigate the association of CCK system genes (CCK, CCK(A) and CCK(B) receptor genes) with alcohol dependence using single nucleotide polymorphisms (SNPs) as genetic markers. A total of 257 psychiatrically interviewed Finns were genotyped for CCK (-45C>T), CCK(A) (Val365Ile) and CCK(B) (Val125Ile) receptor polymorphisms. Allele frequencies were compared between 150 unrelated healthy Finnish controls and 107 unrelated alcohol-dependent subjects (DSM-III-R criteria), who were also criminal offenders. The frequency of the CCK -45T allele was not significantly different between controls [0.07] and alcoholics [0.09]. The CCK(B) receptor polymorphism Val125Ile was also not associated with alcoholism and the Ile125 allele frequencies were 0.05 in controls vs. 0.06 in alcohol-dependent subjects. A CCK(A) receptor marker, Val365Ile, was uninformative in this Finnish dataset; all subjects were Val365/Val365 homozygous. The results suggest that CCK -45C>T and CCKBR Val125Ile polymorphisms do not have a major role in alcohol dependence in the population studied. The role of the CCK(A) the receptor in alcohol dependence remains open until additional DNA sequence variants for this gene become available.

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.

An abundant proneurotensin polymorphism, 479A>G, and a test of its association with alcohol dependence in a Finnish population.

BACKGROUND: Neurotensin is a 13-amino acid neuropeptide that endogenously modulates dopamine release in the central nervous system. In substance dependence, the mesolimbic dopamine system has been postulated to be a central structure that mediates rewarding and reinforcing effects. Neurotensin receptors in the neurons of the ventral tegmental area facilitate dopamine release, making the neurotensin gene an excellent candidate gene for alcohol dependence and for other behaviors that involve reinforcement. METHODS: A total of 639 psychiatrically interviewed Finns were genotyped for proneurotensin 479A>G polymorphism. We used the polymorphism as a marker to study the association between proneurotensin gene and alcohol dependence by comparing 229 unrelated Finnish healthy controls to 134 unrelated alcohol-dependent (DSM-III-R criteria) subjects who were also criminal offenders. In addition, 276 relatives of the alcohol-dependent and control subjects were genotyped. RESULTS: The frequencies of the genotypes in the whole sample (n = 639) were 0.84 for 479A/A, 0.16 for 479A/G, and 0.003 for 479G/G. The frequency of the rarer 479G allele was 0.07 and 0.06 in controls and alcohol-dependent subjects, respectively, and this difference was not statistically significant (chi2 = 0.264, df = 1, p = 0.61, controls vs. alcohol-dependent subjects). CONCLUSIONS: The results of the comparison between psychiatrically interviewed controls and alcoholics from a relatively well defined population indicate that the proneurotensin 479A>G polymorphism is not strongly associated with alcohol dependence. The results do not rule out a role for this gene in the pathogenesis of alcoholism or in differential vulnerability.

The effect of sedation on weaning following coronary artery bypass grafting: propofol versus oxycodone-thiopental.

BACKGROUND: Propofol has been advocated for sedation in intensive care because of superior recovery characteristics. We hypothesised that the use of two totally different sedation methods after coronary artery bypass grafting should result in differences not only in extubation time, but also in breathing pattern and gas exchange during weaning and after extubation. METHODS: Thirty patients participated in this randomised and controlled study. We used propofol infusion and oxycodone-thiopental bolus dosage, titrated to sedation level 4 or 5 according to Ramsey. Weaning was performed using protocol-based pressure support trials. RESULTS: Total (SD) fentanyl dose during operation was 33 (6) microg x kg(-1) for propofol and 34 (6) microg x kg(-1) for oxycodone-thiopental (ns). The target sedation was achieved equally with both methods. The time from admission to intensive care unit to extubation was 494 (100) min for propofol and 521 (98) min for oxycodone-thiopental (ns). Weaning times were 63 (24) min and 112 (63) min in the propofol and oxycodone-thiopental groups, respectively (P<0.05). Breathing frequency increased and tidal volume decreased from weaning to 2 h postextubation. CONCLUSION: Propofol infusion and oxycodone-thiopental bolus dosages, titrated to the same sedation end point, resulted in similar time from admission to extubation, although the weaning period was shorter in the propofol group. In terms of breathing pattern, gas exchange, blood gases and haemodynamics, the methods were similar. Propofol, despite its attractive pharmacological profile, may offer no clinical benefit in short-term sedation after a moderate dose fentanyl anaesthesia in cardiac surgery.

The effects of quinine and 4-aminopyridine on conditioned place preference and changes in motor activity induced by morphine in rats.

1. The effects of two unselective potassium (K(+)-) channel blockers, quinine (12.5, 25 and 50 mg/kg) and 4-aminopyridine (1 and 2 mg/kg), on conditioned place preference and biphasic changes in motor activity induced by morphine (10 mg/kg) were tested in Wistar rats. Quinine is known to block voltage-, calcium- and ATP-sensitive K(+)-channels while 4-aminopyridine is known to block voltage-sensitive K(+)-channels. 2. In the counterbalanced method, quinine attenuated morphine-induced place preference, whereas 4-aminopyridine was ineffective. In the motor activity test measured with an Animex-activity meter neither of the K(+)-channel blockers affected morphine-induced hypoactivity, but both K(+)-channel blockers prevented morphine-induced secondary hyperactivity. 3. These results suggest the involvement of quinine-sensitive but not 4-aminopyridine-sensitive K(+)-channels in morphine reward. It is also suggested that the blockade of K(+)-channels sensitive to these blockers is not sufficient to prevent morphine-induced hypoactivity whereas morphine-induced hyperactivity seems to be connected to both quinine- and 4-aminopyridine-sensitive K(+)-channels.

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.

Creatine and caffeine in anaerobic and aerobic exercise: effects on physical performance and pharmacokinetic considerations.

The pharmacokinetics and effects of creatine and caffeine administration on anaerobic and aerobic performance of 7 trained athletes were studied in a randomized, placebo-controlled, double-blind crossover design. The treatments were: placebo (PLA), a single oral dose (7 mg x kg(-1)) of caffeine (CAF), repeated oral doses (3 x 100 mg x kg(-1) x day(-1)) of creatine for 3 days (CRE), or the combination of caffeine and creatine (CAF + CRE) before physical exercise. In one session CAF was administered without exercise. Drug administration was followed by 3 repetitive 1-minute exercise bouts on a bicycle ergometer at maximal speed (anaerobic exercise) starting 70 min after drug administration. Anaerobic exercise was followed by 45 min of cycling at constant pedalling speed and workload (aerobic exercise). CRE and CAF, alone or in combination, did not improve maximal pedalling speed (rpm), maintenance of maximal speed (rpm) or total work output (kJ) during the 1 -minute bouts, when compared with PLA. In addition, no statistically significant differences in heart rate or blood lactate were observed between the treatments either during anaerobic or aerobic exercise bouts. Creatine was rapidly and efficiently absorbed, as reflected by plasma concentrations. The mean +/-SEM value for creatine Cmax was 1.22+/-0.14 mmol x l(-1), tmax 92+/-7 min and plasma half-life (t1/2beta) 172+/-21 min. Caffeine pharmacokinetics were not affected by concomitant administration of creatine or by physical exercise. In conclusion, neither maximal performance and subsequent recovery nor aerobic performance were enhanced by oral creatine supplementation in the study.

Heat exposure and drugs. A review of the effects of hyperthermia on pharmacokinetics.

Acute heat loading is encountered in several everyday situations, during physical exercise or work in a hot climate are just 2 examples. Special forms of heat exposure include different types of steam baths and saunas. External heating induces changes in haemodynamics, body fluid volume and blood flow distribution, which in turn may affect the pharmacokinetics of a drug and the therapeutic response. Documentation of the effects of heat exposure on the pharmacokinetics of drugs in humans is very limited, but based on the documentation some general conclusions can be drawn. The effects of external heating on absorption and elimination of those orally administered drugs which have been studied (e.g. midazolam, ephedrine, propranolol and tetracycline), have been minor. Systemic absorption of transdermally and subcutaneously administered drugs [insulin, nitroglycerin (glyceryl trinitrate) and nicotine] is in most cases enhanced by external heating, leading to higher plasma drug concentrations. In general, pharmacokinetic interactions between heat exposure and drug therapy are rare and limited to special situations, in which local blood flow (for example, over the skin) is enhanced many-fold because of hyperthermia. When pharmacodynamics are concerned, in most cases the probability of interactions is low, but in the treatment of malignant tumours hyperthermia may potentiate cytotoxic effects of drugs without enhancement of myelosuppressive effects.

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.

Renal excretion of tetracycline is transiently decreased during short-term heat exposure.

Renal blood flow is known to be reduced during intensive external heating, which may have clinical relevance for renal drug elimination as well. The effects of heat exposure in a sauna bath on tetracycline pharmacokinetics were studied in 8 healthy volunteers in an open, randomized crossover study. The subjects were given a single oral dose of tetracycline (500 mg) both in a control session and in a sauna bathing session. The heat exposure consisted of three 10-minute stays in a sauna bath (temperature 76-87 degrees C, relative humidity 27-33%) starting 20 minutes after drug administration. The stays in the steam room were separated by two 5-minute cooling periods at 23 degrees C. Venous blood samples for determination of plasma tetracycline concentrations were taken 15 min before the drug intake, 20, 40, 60 min, and 2, 3, 4, 6, 8, and 24 h after it. The control session at room temperature (23 degrees C) followed the same sampling protocol. No statistically significant differences in tetracycline plasma concentrations, Cmax, Tmax, or AUC0-24h were seen. In addition, urine was collected (0-2 h, 2-5 h, 5-8 h, and 8-24 h) for determination of the amount of tetracycline excreted unchanged. Urinary tetracycline excretion was transiently (2-5 h after drug intake) reduced in the sauna session (P < 0.05 vs. control, Wilcoxon). The other collection periods and the total urinary excretion of tetracycline (24 h) did not differ from the control session. It is concluded that urinary tetracycline excretion was transiently decreased during short-term heat exposure, but otherwise the effects of external heating on tetracycline pharmacokinetics were negligible.

Exposure to high ambient temperature increases absorption and plasma concentrations of transdermal nicotine.

Absorption and plasma concentrations of transdermally delivered drugs may be increased during heat exposure. We studied the effects of short-term heat exposure in a sauna bath on the pharmacokinetics of transdermal nicotine, 25 mg/16 hr, in 12 healthy smokers in an open, randomized crossover study that consisted of a control session and a sauna bathing session. In the sauna session the subjects stayed seated in a sauna bath (mean temperature 82 degrees C (180 degrees F); mean relative humidity 28%) for three 10-minute periods separated by two 5-minute breaks. Sauna bathing significantly (p < 0.01 versus control) increased peak plasma concentration, area under the plasma concentration-time curve from 0 to 1 hour, the amount of nicotine absorbed, and the mean plasma nicotine concentrations during heat exposure. No significant difference in nicotine area under the plasma concentration-time curve from 0 to 3 hours was observed. In addition, the combined effects of transdermal nicotine and sauna bathing on hemodynamics, some psychomotor skills, and subjective symptoms were evaluated. We concluded that absorption and plasma concentrations of transdermally delivered nicotine may be increased during exposure to high ambient temperature, probably because of enhanced skin blood flow. However, no adverse symptoms were recorded.

Exposure to high environmental temperature in the sauna does not change plasma indocyanine green (ICG) clearance in healthy subjects.

Indocyanine green (ICG) was given intravenously (0.5 mg kg-1) to seven healthy male volunteers in random order during a control session and a session in the sauna bath. The sauna bathing session consisted of three 10 min. stays in the sauna (temperature 85-95 degrees, relative humidity 25-30%), separated by two 5-min. periods of resting at 22 degrees. Blood samples were taken for 60 min. in order to calculate ICG plasma clearance (CI), volume of distribution (Vss) and elimination half-life (t1/2 beta). The mean +/- S.E.M. values of ICG plasma clearance, Vss and t1/2 beta for the control session and the sauna bathing session were 0.47 +/- 0.08 1 min.-1 versus 0.39 +/- 0.04 1 min.-1, 2.4 +/- 0.4 1 versus 2.3 +/- 0.2 1 and 3.9 +/- 0.3 min. versus 4.4 +/- 0.3 min., respectively. No statistically significant differences in the CI, t1/2 beta or Vss of ICG were detected between the control and sauna bathing sessions. The results suggest that short-term exposure to high ambient temperatures during sauna bathing does not affect hepatic blood flow. Consequently, short-term hyperthermia and associated changes in hepatic blood flow are assumed to have little, if any, effect on the hepatic clearance of drugs.

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.

Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam.

OBJECTIVE: The effect of short-term heat exposure in a Finnish sauna on hepatic first-pass metabolism and the capacity to metabolize midazolam were studied in a crossover trial. Midazolam oral (15 mg) and intravenous (0.05 mg.kg-1) was given to 6 healthy young male volunteers, in random order, during a control session and a sauna bathing session (temperature 85-100 degrees C, relative humidity 25-30%). Blood samples for the determination of plasma midazolam and alpha-hydroxy midazolam concentrations were taken for 6 h after drug administration. RESULTS: After oral administration, the bioavailability and clearance of midazolam were not affected by sauna bathing, nor was there a significant difference in alpha-hydroxy midazolam plasma concentration or the alpha-hydroxy midazolam/midazolam AUC-ratio between the sessions. Midazolam Cmax was increased and its t1/2 beta was prolonged during the sauna session, but the clinical relevance of the findings appears to be modest. The pharmacokinetics of intravenous midazolam were not affected by sauna bathing. CONCLUSIONS: Short-term heat exposure may not affect the first-pass metabolism or hepatic capacity to metabolize midazolam.

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)

Effects of a Finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers.

The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo, propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85-100 degrees C, relative humidity 25-35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (Cmax 41 vs. 28 ng.ml-1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC0-5h (119 vs 71 micrograms.h.l-1) of propranolol from 0 to 5 hours tmax, t1/2 beta and AUC0-24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase.(ABSTRACT TRUNCATED AT 250 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)