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 (
The acute effect of doses of mizolastine 5, 10, 20 and 40 mg, an active control (clemastine 2 mg) and placebo on actual car driving and psychomotor performance have been compared. Twenty four healthy volunteers were treated according to a double-blind, 6-way cross-over design. In the driving test, lasting about 1 h, lateral position control and speed were continuously measured; the psychomotor test battery, lasting 50 min, comprised critical flicker-fusion frequency, critical instability tracking, divided attention, memory search and choice reaction time, and vigilance studies; and mood changes and possible adverse-effects were rated on visual analogue scales. The results showed a dose-response relationship: mizolastine 40 and 20 mg impaired driving and psychomotor performance. The effect of mizolastine 40 mg on driving was strongly correlated with that of clemastine (r = 0.78) and was comparable to the effect of a blood ethanol level of 0.8 mg.ml-1. Mizolastine 5 mg and 10 mg did not have a significant effect on driving performance and psychomotor tests. It was concluded that at a 10 mg dose of mizolastine, the therapeutic dose, it could be considered a safe anti-histamine, although individual adverse reactions cannot be completely ruled out.
The primary objective of this study was to compare the objective and subjective effects of amisulpride with those of a classic antipsychotic, haloperidol, when both were given to healthy volunteers in representative therapeutic doses over 5 days. The secondary objective was to compare the effects of relatively low and high doses of amisulpride to confirm the suspected duality of its pharmacologic activity. Twenty-one subjects participated in the four-way, randomized, double-blind, crossover study with repeated daily doses of amisulpride 50 mg, amisulpride 400 mg, haloperidol 4 mg, and placebo. Subjects were institutionalized during treatment periods and were under 24-hour medical supervision. They underwent a series of psychomotor and cognitive tests 1 hour before and 3 and 6 hours after dosing on days 1 and 5. Their extrapyramidal disturbances and drug-related feelings were assessed at the end of each replication. Psychiatric interviews and ratings of depression, subjective well-being, and negative symptoms occurred on day 4. Amisulpride 50 mg had no significant effect on any parameter. Amisulpride 400 mg had several adverse effects on psychomotor and, although less severe, on cognitive performance on the fifth day only. Amisulpride 400 mg produced no significant extrapyramidal disturbances in the group as a whole, although it may have in some individual subjects. Also, it produced no signs of mental disturbances on clinical rating scales or during a structured psychiatric interview. Haloperidol ubiquitously impaired psychomotor and cognitive performance in a similar fashion after the first and the final doses. It produced extrapyramidal disturbances in nearly every subject, the most common being akathisia and the most severe, in the case of one individual, being acute dystonia. Unlike amisulpride, haloperidol produced a number of mental disturbances, the most noteworthy being negative symptoms. Amisulpride seems to be a well-tolerated drug. Its side effects should be much less troublesome to patients using the drug on a long-term basis than those of classic antipsychotics, like haloperidol.
In contrast to the plethora of publications on placebo effects in patients, very little is known about placebo effects in healthy volunteers during clinical pharmacology studies. We therefore reviewed the adverse events spontaneously reported during placebo administration in 109 double-blind, placebo-controlled studies involving 1228 volunteers. The overall incidence of adverse events in the healthy volunteers during placebo administration was 19%. As expected, complaints were more frequent after repeated dosing (28%) and in elderly subjects (26%). Overall, the most frequent adverse events were headache (7%), drowsiness (5%), and asthenia (4%), with some variation depending on study design and population. In conclusion, these data shed new light on the impact of experimental conditions on the results of safety evaluations in healthy volunteers participating in clinical pharmacology studies.
Ca}eine is a widely!consumed psychoactive substance whose stimulant e}ects on mood\ attention and performance are largely recognised[ The central nervous system pharmacodynamic pro_le of a single oral dose of a new slow release "SR# ca}eine formulation "599 mg# was assessed in a randomised\ double!blind\ crossover\ placebo!controlled study[ Twelve young\ health\ male\ sleep!deprived "for 25 h# subjects were studied using EEG and various measures of psychomotor and cognitive functions\ including critical~icker fusion "CFF#\ choice reaction task "CRT#\ tracking\ continuous performance task "CPT#\ Stroop test\ body sway and subjective evaluation "Stanford Sleepiness Scale#[ Ca}eine signi_cantly "p ³ 9=94# antagonised the detrimental e}ects of sleep!deprivation on EEG "i[e[ produced a signi_cant decrease in delta and theta relative power and a signi_cant increase in alpha and beta "01Ð39 Hz# relative power# and psychomotor performance "signi_cant increase in speed of reaction on the CRT and Stroop tests\ signi_cant decrease in body sway\ signi_cant increase in accuracy of the CPT and signi_cant reduction in subjective sedation# compared to placebo[ The e}ect peaked 3 h after dosing and was maintained until the end of sleep deprivation "i[e[ 13 h after dosing#[ In conclusion\ the present results demonstrate that a single dose of ca}eine SR possesses alerting e}ects which are able to reverse the deleterious e}ect of 25 h sleep deprivation for at least 13 h[
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