β-Adrenoceptor blocking effects and plasma levels of bornaprolol and propranolol in man

Summary The -adrenoceptor blocking effects and pharmacokinetics of bornaprolol (FM 24), a new -adrenoceptor blocking agent, have been compared with those of propranolol and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate, systolic and diastolic blood pressures and peak expiratory flow rate were measured at rest and at the end of 3 min vigorous exercise on a bicycle ergometer, before and 2, 24 and 48 h after single oral doses of bornaprolol (120, 240 and 480 mg) and propranolol (40, 80 and 160 mg). Plasma renin activity at rest and the plasma concentrations of the two drugs were determined. Bornaprolol significantly reduced resting heart rate, dose-dependently lowered exercise-induced tachycardia and decreased peak expiratory flow rate and plasma renin activity. In addition, exercise-induced tachycardia was significantly reduced by bornaprolol up to 48 hours after drug intake (pharmacodynamic half-life approximately 63–86 h) and there was a correlation between this reduction and the log plasma bornaprolol concentration over the 48-h period. Thus, bornaprolol behaved in man as a non-cardioselective and long-lasting -adrenoceptor blocking drug, probably devoid of intrinsic sympathomimetic activity.     

The acute effects of amisulpride (50 mg and 200 mg) and haloperidol (2 mg) on cognitive function in healthy elderly volunteers

In this double-blind, placebo controlled, four-way cross-over trial in 16 healthy elderly volunteers, the acute effects of haloperidol 2 mg, amisulpride 50 mg and 200 mg, were assessed on a range of tests of cognitive function. On each study day, cognitive performance was assessed prior to dosing and at 2, 4, 6, 9, 12 and 24 h after dosing with the following tests from the Cognitive Drug Research computerized assessment system: simple reaction time, digit vigilance task, choice reaction time, visual tracking, Critical Flicker Fusion, body sway, numeric working memory, immediate and delayed word recall, word recognition and self-ratings of mood and alertness. Haloperidol showed a general tendency to impair performance, and although this did not reach significance compared to placebo, for two tasks there were significant impairments with haloperidol compared to amisulpride. Amisulpride 50 mg and 200 mg, was not associated with impairment. In fact, there was some suggestion of improvement over placebo on three measures. The timings of assessment were appropriate for the study compounds. Furthermore, in a recent study in which a smaller number of elderly volunteers was tested on the same cognitive assessment system, a clear profile of acute impairments of haloperidol 3 mg, was identified. This indicates that haloperidol 2 mg, is not a sufficient dose to affect cognitive function in the elderly, supporting the general absence of effects with this dose in the young. Thus, the general absence of cognitive impairments with amisulpride at the doses used in this study suggests that this compound does not impair cognitive function in the elderly.     

Alpidem: Lack of sedative effect on psychomotor performance in therapeutic doses

This is a randomised, double blind, cross-over, placebo-controlled study carried out in 12 healthy young male volunteers. It consisted of six test days separated by two week wash-out periods. The objective was to compare the potential sedative effects of 3 single oral doses of alpidem (50 mg, 100 mg and 200 mg) versus diazepam (10 mg and 15 mg). Pharmacodynamics were assessed by objective psychometric tests (critical flicker fusion, choice-reaction time, manual dexterity, digit span) and subjective evaluation (visual analogue scales) before then 2 h, 4 h, 8 h and 24 h post-dose. Alpidem in dosages of 50 mg and 100 mg did not impair alertness or psychomotor performance; with 200 mg, psychometric tests and visual analogue scales demonstrated sedative effects 2 h post-dose. In contrast, diazepam in a therapeutic dosage (10 and 15 mg) produced similar impairments of vigilance and psychomotor performance as alpidem 200 mg, indicating a lack of dissociation between anxiolytic and sedative effects.     

Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects

A double-blind crossover study was conducted in four CYP2C19 genotype-defined metabolizer groups to assess whether increase in clopidogrel dosing can overcome reduced pharmacodynamic response in CYP2C19 poor metabolizers (PMs). Ten healthy subjects in each of four metabolizer groups were randomized to a clopidogrel regimen of a 300-mg loading dose (LD) and a 75-mg/day maintenance dose (MD) for 4 days followed by 600-mg LD and 150 mg/day MD, or vice versa. The exposure levels of clopidogrel's active metabolite H4 (clopi-H4) in PMs were 71% lower on the 75-mg/day regimen and 64% lower on the 150-mg/day regimen than the corresponding exposure levels in extensive metabolizers (EMs). In PMs, the maximal platelet aggregation (MPA) induced by adenosine diphosphate (ADP) 5 μmol/l was 10.5% lower on the 75-mg/day regimen and 7.9% lower on the 150-mg/day regimen than the corresponding values in EMs. PMs who were on the clopidogrel regimen of 600-mg LD/150 mg/day MD showed clopi-H4 exposure and MPA levels similar to those in EMs who were on the regimen of 300-mg LD/75 mg/day MD. In a pooled analysis evaluating CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A5, CYP2D6, ABCB1, and P2RY12 polymorphisms (N = 396 healthy subjects), only CYP2C19 had a significant impact on antiplatelet response. In healthy CYP2C19 PMs, a clopidogrel regimen of 600-mg LD/150 mg/day MD largely overcomes diminished clopi-H4 exposure and antiplatelet response, as assessed by MPA levels.     

Troleandomycin-triazolam interaction in healthy volunteers: Pharmacokinetic and psychometric evaluation

Summary Seven healthy volunteers received a single oral dose of triazolam 0.25 mg after 7 days on troleandomycin 2 g/day p.o. or placebo in a double-blind cross-over study. Plasma triazolam and psychometric and memory tests (including Critical Flicker Fusion threshold, Choice Reaction Time, Digit Symbol Substitution and Self-Rating Scales) were assessed at regular intervals after the final treatment.Troleandomycin was found to prolong the psychomotor impairment and amnesia produced by triazolam.There was a significant enhancement of the AUC, the peak concentration and the delay to t_max of triazolam after 7 days treatment with troleandomycin compared to placebo.Thus, there is a pharmacokinetic interaction, and the combination of triazolam and troleandomycin should be avoided or the dose of triazolam should be adjusted. The most likely mechanism is a diminished hepatic first-pass effect, and a decrease in the apparent oral clearance of triazolam.     

A review of the pharmacokinetics,tolerability and pharmacodynamics of amisulpride in healthy volunteers

Amisulpride binds selectively to dopamine D(2) and D(3) receptors in the limbic system. Low doses of amisulpride preferentially block presynaptic D(2)/D(3)-dopamine autoreceptors, thereby enhancing dopaminergic transmission, whereas higher doses block postsynaptic receptors, thus inhibiting dopaminergic hyperactivity. Amisulpride is clinically effective on the negative symptoms of acute schizophrenia exacerbations at low dosages (50-300 mg/day), and also on the positive symptoms of the disease at high dosages (400-800 mg/day). Nineteen clinical studies involving 358 volunteers have investigated the pharmacokinetics, pharmacodynamics and tolerability of amisulpride. Amisulpride shows linear pharmacokinetics, a bioavailability of 48%, low protein binding (17%) and an elimination half-life of approximately 12 h. It is predominantly eliminated in the urine as the parent compound. It exhibits no significant detrimental effects in psychometric or memory tests up to the dose of 400 mg/day, inducing only mild impairment at high doses, whereas EEG data suggest an alertness-enhancing effect at low doses (相似文献   

Lack of interaction between amisulpride and lorazepam on psychomotor performance and memory in healthy volunteers

The potential pharmacodynamic interaction between amisulpride (a benzamide-type antipsychotic) and lorazepam was evaluated in a randomized, double-blind, cross-over, placebo-controlled study involving 18 healthy caucasian male volunteers, aged 18–35 years. They received single doses of amisulpride 50 mg and 200 mg. The interaction of the drug with a single oral dose of lorazepam 2 mg was assessed on six 1-day treatment periods separated by wash-out periods of 1 week. Pharmacodynamic criteria were: critical flicker fusion frequency, multiple choice reaction time, tapping, body sway, arithmetic calculation, Buschke's test for short and long term memory and self-ratings by ARCI scale. Prolactin as assayed for each treatment period. Statistical analysis was performed using a 3-way ANOVA. For psychometric tests and body sway, analyses were evaluated on changes from baseline. For memory test, analyses were done on raw data. Amisulpride alone, at single oral dose of 50 mg and 200 mg, was devoid of any clinically relevant impairment psychometric tests, short term and long term memory and mood. A single oral dose of lorazepam 2 mg induced marked impairment in psychometric performances, which all, except CFF test, were severely affected. Disturbances were also recorded in memory tests, and in subjective sensation (ARCI). The peak effects were 2–4 h after administration, but the majority of results were also affected up to 8 h. Prolactin levels were increased after either dose of amisulpride, but not after placebo or lorazepam. The co-administration of amisulpride plus lorazepam induced a prolactin elevation equivalent to that of amisulpride alone. In conclusion, the co-administration of amisulpride, at both doses of 50 mg and 200 mg, did not potentiate nor antagonize the detrimental effect of lorazepam 2 mg on pharmacodynamic parameters. © 1998 John Wiley & Sons, Ltd.