-
J. C. Verster,
E. R. Volkerts,
A. H. Schreuder,
E. J. Eijken,
J. H. van Heuckelum,
D. S. Veldhuijzen,
M. N. Verbaten,
I. Paty,
M. Darwish, P. Danjou,
A. Patat
[show abstract]
[hide abstract]
ABSTRACT: Thirty healthy volunteers participated in this two-part study. Part 1 was a single-blind, two-period crossover design to determine the effects of a single dose of ethanol (0.03% < BAC < 0.05%) or ethanol-placebo on driving ability, memory, and psychomotor performance. Part 2 was a double-blind, five-period crossover design to measure the effects of a middle-of-the-night administration of zaleplon 10 or 20 mg, zolpidem 10 or 20 mg, or placebo on driving ability 4 hours after administration and memory and psychomotor performance 6 hours after administration. The on-the-road driving test consisted of operating an instrumented automobile over a 100-km highway circuit at a constant speed (95 km/h) while maintaining a steady lateral position between the right lane boundaries. The standard deviation of lateral position (SDLP) was the primary performance parameter of the driving test. The psychomotor and memory test battery consisted of the Word Learning Test, the Critical Tracking Test, the Divided Attention Test, and the Digit Symbol Substitution Test. Data for each part were analyzed separately using ANOVA for crossover designs. Zaleplon 10 and 20 mg did not significantly impair driving ability 4 hours after middle-of-the-night administration. Relative to placebo, after zolpidem 10 mg, SDLP was significantly elevated, but the magnitude of the difference was small and not likely to be of clinical importance. Memory and psychomotor test performance was unaffected after both doses of zaleplon and zolpidem 10 mg. In contrast, zolpidem 20 mg significantly increased SDLP and speed variability. Further, zolpidem 20 mg significantly impaired performance on all psychomotor and memory tests. Finally, driving performance, Digit Symbol Substitution Test, Divided Attention Test, and immediate and delayed free recall of the Word Learning Test were significantly impaired after ethanol. The results show that zaleplon (10 and 20 mg) is a safe hypnotic devoid of next-morning residual impairment when used in the middle of the night.
Journal of clinical psychopharmacology. 01/2002; 22(6):576-83.
-
[show abstract]
[hide abstract]
ABSTRACT: To compare the duration of the residual hypnotic and sedative effects of zaleplon with those of zolpidem and placebo following nocturnal administration at various times before morning awakening.
Zaleplon 10 mg, zolpidem 10 mg, or placebo was administered double-blind to 36 healthy subjects under standardized conditions in a six-period, incomplete-block, crossover study. Subjects were gently awakened and given medication at predetermined times 5, 4, 3, or 2 h before morning awakening, which occurred 8 h after bedtime. When the subjects awoke in the morning, a battery of subjective and objective assessments of residual effects of hypnotics was administered.
No residual effects were demonstrated after zaleplon 10 mg, when administered as little as 2 h before waking, on either subjective or objective assessments, whereas zolpidem 10 mg showed significant residual effects on DSST and memory (immediate and delayed free recall) after administration up to 5 h before waking and choice reaction time, critical flicker fusion threshold and Sternberg memory scanning after administration up to 4 h before waking. Residual effects of zolpidem were apparent in all objective and subjective measurements when the drug was administered later in the night.
The present results demonstrate that zaleplon at the dose of 10 mg is free of residual hypnotic or sedative effects when administered nocturnally as little as 2 h before waking in normal subjects. In contrast, residual effects of zolpidem are still apparent on objective assessments up to 5 h after nocturnal administration, longer than has been reported from studies involving daytime administration.
British Journal of Clinical Pharmacology 10/1999; 48(3):367-74. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Venlafaxine is currently marketed for treatment of depressive disorders as a conventional tablet formulation with a twice or three times daily dosage regimen. The absolute bioavailability of the conventional (CF) and extended-release (XR) formulations and their effects on electroencephalograms (EEG) and on a visual analog scale (VAS) for nausea were assessed in a randomized, double-blind, four-way crossover, placebo-controlled study of 16 healthy young men who were given either a single oral dose of 50 mg of CF venlafaxine, 75 mg of XR venlafaxine, or an intravenous dose of 10 mg of venlafaxine, or a placebo at 1-week intervals. The absolute bioavailability of venlafaxine was between 40% and 45% and was similar for both the CF and XR formulations. Venlafaxine produced central effects of a desipramine-like antidepressant. Regardless of formulation tested, the main EEG changes were an increase in fast beta (20-30 Hz) energy, which was more pronounced over the frontotemporal regions and extended within the full beta range (16-40 Hz). Maximum effect was reached at 6 hours for the CF and reached a plateau from 10 to 24 hours for the XR formulation. A dose-proportional increase in central activity, expressed as area under the effect curve (AUE) of the beta band, was observed between the CF (50 mg) and XR (75 mg) formulations. Compared with the CF tablet, the XR formulation also produced a much less intense maximum effect and a decrease of 63% in the AUE of nausea normalized by dose. The XR formulation has the same absolute bioavailability and the same central activity as assessed by EEG, but produced less intensive nausea than CF venlafaxine. The present findings suggest that a once-daily dosage regimen should be sufficient. This was confirmed by several clinical trials in depressive patients.
The Journal of Clinical Pharmacology 03/1998; 38(3):256-67. · 2.91 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The main metrological characteristics of a French version of the 49-item addiction research center inventory (ARCI) were evaluated using data collected in three controlled studies in healthy subjects. An analysis of variance showed no study effect, so the three studies were pooled. The test-retest reliability coefficients after placebo evaluated by a Spearman rank correlation test were 0.64 (P < 0.0001) for subscale A, 0.49 (P < 0.0001) for subscale BG, 0.55 (P < 0.0001) for MBG, 0.58 (P < 0.0001) for PCAG and 0.27 for LSD (not significant). Using the same test, the test-retest reliability coefficients after amphetamine were 0.73 (P < 0.0001) for subscale A, 0.61 (P < 0.0001) for subscale BG, 0.71 (P < 0.0001) for MBG, 0.46 (P < 0.0001) for PCAG and 0.66 for LSD (P < 0.0001). In order to assess the predictive validity of the translated questionnaire, areas under curves were calculated from the ROC diagrams for the three scores, amphetamine (A), benzedrine group (BG) and morphine benzedrine group (MBG). Two criteria validity were used: the desire to take amphetamine another time and the discrimination of the allocated treatment (amphetamine or placebo). The calculated areas under curves indicated a good capacity of prediction of the three ARCI subscales (A, BG, MBG) for both criteria.
Drug and Alcohol Dependence 05/1997; 45(3):177-83. · 3.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate plasma and skin suction-blister-fluid pharmacokinetics of oral mizolastine in order to determine whether the drug concentration in the fluid of suction-induced skin blisters could better predict the antihistamine activity than the plasma concentration.
Department of Internal Medicine, Université Paris 6.
Ten healthy male volunteers.
The volunteers (mean age 26.8 years, mean weight 75.8 kg) received a single 10-mg oral dose of mizolastine at 1000 hours. The pharmacokinetic study included 11 plasma and 9 blister fluid samples and blister epidermal-roof specimens. Mizolastine was assayed by high-performance liquid chromatography (HPLC). Each volunteer also received nine intradermal injections of 5 micrograms histamine. Antihistamine activity was assessed as the post-treatment percentages of changes in the histamine-induced relative wheal and flare areas versus baseline.
Mizolastine mean Cmax (SD) and median tmax were, respectively, 380 ng.ml-1 and 0.8 h in plasma, and 21.8 ng.ml-1 and 10 h in blister fluid. Mizolastine could not be quantified in the epidermis. The maximal histamine-induced relative flare inhibition was 72.5% and was attained at the median time of 3 h post-dosing and therefore was delayed by 2.2 h with respect to the plasma tmax. Mean relative wheal inhibition, although lower, showed the same time profile. A direct relationship could not be found between drug concentrations in blister fluid and antihistamine activity. Simulated concentrations in the peripheral compartment better explain the maximum inhibition effect on flare, observed 3 h post-dosing, with a flatter hysteresis loop obtained when plotting relative flare inhibition versus plasma or blister-fluid drug concentrations.
The mizolastine concentrations in the skin suction-blister fluid were not predictive of the antihistamine activity.
European Journal of Clinical Pharmacology 02/1996; 50(4):327-33. · 2.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Noradrenergic stimulation of pineal beta-adrenoceptors results in melatonin secretion. To investigate beta-adrenoceptor mediated plasma melatonin responses in humans, ritodrine, salbutamol (beta 2-adrenoceptor agonists) and dobutamine (beta 1-adrenoceptor agonist) were infused from 0900 to 1200 h to 8 healthy subjects (four men and four women) in a double blind, crossover, placebo controlled study. Ritodrine and salbutamol significantly increased plasma cyclic AMP and decreased serum potassium concentrations indicating the presence of beta 2-adrenoceptor stimulation. Dobutamine substantially increased systolic blood pressure corresponding to its beta 1-adrenoceptor agonist propriety. However, neither beta 2- nor beta 1-adrenoceptor stimulation modified plasma melatonin concentration. These results show that beta-adrenoceptor agonists do not increase daytime plasma melatonin concentration.
Life Sciences 04/1995; 56(17):PL325-31. · 2.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Potential interactions between the imidazopyridine anxiolytic alpidem and the full benzodiazepine agonist lorazepam were assessed in a randomized, double-blind, four-way cross-over, placebo-controlled study in 16 healthy young male volunteers. Each volunteer received alpidem, 50 mg, or a placebo twice daily for 8 days with a 1- week wash-out interval. The interaction between alpidem, at the steady state, and a single oral dose of lorazepam 2 mg or a placebo was assessed after concomitant administration on days 7 or 9 of each treatment period. Psycho motor performance and cognitive function were evaluated before and 2, 4, 6 and 8 h post-dose, using objective tests [critical flicker fusion threshold (CFF), choice reaction time (CRT), digit-symbol substitution (DSST), body sway and short-term memory (Sternberg memory scanning)] and self-ratings [line analogue rating scales: (LARS)]. Long-term memory (delayed free recall and recognition of pictures) was assessed before the dose and 2 and 4 h post-dose. Pharmacodynamic interactions were evaluated by applying repeated measures ANOVA to a 2 x 2 factorial interaction model. Alpidem, 50 mg twice daily at the steady state, was free of any clinically relevant detrimental effects on skilled performance, information processing or memory. In contrast, a single 2 mg dose of lorazepam induced marked impairment of psychomotor performance and cognitive function (significant reductions in CFF and DSST and increases in CRT and body sway), as well as subjective sedation from 2 to 8 h post-dose, depending on the test used. In addition, lorazepam induced anterograde amnesia, characterized by a decrease in delayed free recall and recognition, and a deficit in short-term memory. Finally, alpidem 50 mg did not potentiate the detrimental effects of lorazepam 2 mg. On the contrary, alpidem significantly antagonized the lorazepam-induced CRT increase and anterograde amnesia, and produced similar trends on most of the other cognitive parameters; thus, the results obtained with the combination of alpidem and lorazepam consistently indicated less impairment than those measured after lorazepam alone. These results are consistent with the suggested partial agonsist properties of alpidem at the benzodiazepine receptor and indicate that such properties can be assessed in humans based on antagonism of the effects of a full agonist.
Journal of Psychopharmacology 01/1995; 9(2):91-101. · 3.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The possible effects on memory, psychomotor performance and mood of eliprodil, a new non-competitive NMDA receptor antagonist acting through the polyamine modulatory site, was assessed in a randomized, double-blind, cross-over, placebo-controlled study involving 11 healthy young male volunteers. Eliprodil 30 mg, a placebo and midazolam 15 mg, a positive control, were administered as a single oral dose at 1 week wash-out intervals. Objective tests evaluated both memory (Sternberg memory scanning and paired words for short-term memory, delayed free recall of pictures for long-term memory) and psychomotor functions and arousal (critical flicker fusion threshold, choice reaction time, body sway). Mood was assessed using self-ratings (LARS, POMS, ARCI). Statistical analysis was performed using an ANOVA with pairwise comparisons using Tukey's method. A single dose of eliprodil 30 mg was free of any detrimental effect on memory and skilled performance and did not produce either subjective sedation or excitation or psychotomimetic effects in comparison with placebo. In contrast, a single dose of midazolam 15 mg induced a marked impairment in psychomotor performance and cognitive functions (significant reduction in CFF, increase in CRT and body sway, disruption of short- and long-term memory). The potent sedative activity of midazolam, peaking 1 to 3 h post-dose, was confirmed by subjective evaluation and had disappeared 8 h post-dose.
International Clinical Psychopharmacology 10/1994; 9(3):155-62. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Zolpidem, an imidazopyridine derivative, is a chemically novel, non-benzodiazepine hypnotic agent. Many uraemic patients complain of sleep disorders and ask for hypnotic medication which is well tolerated both clinically and biologically in such patients. We studied the pharmacokinetics and pharmacodynamics of zolpidem in 12 end-stage renal patients regularly treated by hemodialysis three times a week. Zolpidem (10 mg) was given orally for 14 or 21 days. Pharmacokinetic and pharmacodynamic evaluations were repeated at the end of the study on day 14 or day 21. Cmax, Tmax, t1/2 and the area under the curve were not modified in hemodialyzed patients. After daytime dosing, zolpidem induced the same level of sleepiness after the first and last dose and was well tolerated as a hypnotic agent after the night-time dosing. From these results, it can be said that zolpidem may be administered safely to patients with severe renal impairment without any modification of the dosage regimen.
Fundamental and Clinical Pharmacology 02/1993; 7(1):1-9. · 1.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The new potential anxiolytic ritanserin was studied in a double-blind manner vs. alprazolam, diazepam and placebo in 23 healthy subjects. The subjects belonged either to a high anxiety level group or a low anxiety level group, in order to study the effect of the anxiety level on the pharmacodynamic responses. The assessments included cognitive function (memory tests), psychomotor performance [Critical Flicker Fusion (CFF), Choice Reaction Time (CRT)], subjective ratings of alertness and overnight sleep and stress paradigm. Ritanserin (10 mg), alprazolam (0.75 mg), diazepam (10 mg) and placebo were given as single oral doses following a latin square design. Groups were well contrasted on the Cattell anxiety scale and were not overlapping. On no psychometric variable have there been any interactions between the anxiety level and the drug factor. At baseline an anxiety-related difference between the two groups was observed: lower CFF value in the high anxiety group (-1.4 Hz). Both benzodiazepines impaired psychomotor assessment and memory function and increased sleepiness. Ritanserin decreased CFF values without significantly affecting CRT on which nevertheless a trend to impairment was observed. Memory tests, and subjective ratings of alertness were unaffected by ritanserin. A trend to an antistress effect was observed on electrodermogram after ritanserin. Both benzodiazepines decreased central nervous system arousal and memory while ritanserin was inactive except on CFF. Recent data support the hypothesis that 5-HT2 blockers decrease pupil diameter which is a well known covariate of flicker frequency.
International Clinical Psychopharmacology 12/1992; 7(2):73-9. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 1. Twelve healthy subjects were enrolled in a double-blind placebo controlled cross-over study in order to assess the possible anticholinergic effects of four doses of a new antihistamine compound, mizolastine, compared with hyoscine butylbromide (HBB) used as a reference anticholinergic drug. 2. Although mizolastine, a potent and selective H1-receptor blocker has no affinity for muscarinic receptors and does not antagonize the effects of carbachol in rodents, a study was initiated to investigate its effects on various effectors possessing muscarinic receptors (eye, heart, sweat gland, salivary gland). 3. HBB (40 mg, s.c.) impaired accommodation, decreased salivary flow and inhibited cardiac sinus arrhythmia. Pupil diameter and maximum constriction speed, carbachol-induced skin sweating and Valsalva ratio were unaffected. 4. Mizolastine (5, 10, 20, 40 mg p.o.) did not affect any parameter at any time point, demonstrating a lack of anticholinergic effect.
British Journal of Clinical Pharmacology 11/1992; 34(4):328-31. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A method of assessment of the erection in man, using numeric penile plethysmography, is presented. The data concerning the sensor, the electronic circuit, and the computer interfacing with an IBM PC are described. As a validation of this method, apomorphine (0.009 mg/kg) was tested in a double-blind, placebo-controlled study, carried out in healthy volunteers. Apomorphine induced an erection starting, as a mean, at the fourth minute postinjection. The treatment increased the penis volume without any other stimulation (p = 0.0008) and potentiated the physiologic response induced by visual erotic stimulation (p = 0.0012). The limits of plethysmography are discussed in reference to rigidimetry.
Journal of Pharmacological Methods 04/1989; 21(1):61-9.
-
Psychopharmacology series 02/1989; 7:296-302.
-
[show abstract]
[hide abstract]
ABSTRACT: Following the infusion of 15 micrograms/kg of dihydroergotamine (DHE) a 50-fold rise in growth hormone plasma levels was observed in 9 healthy volunteers. Prolactin (PRL) secretion was depressed 240 minutes post infusion. For 170 min, diastolic blood pressure was increased reaching a peak of +19 mmHg at the end of the infusion. Mild sedation and nausea were induced by the treatment for a total duration of 60 min.
International Clinical Psychopharmacology 02/1989; 4(1):71-83. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 1. In a four period, double-blind, placebo-controlled study, apomorphine (0.009 mg kg-1 subcutaneous route) and yohimbine (0.30 mg kg-1 i.v. route) were administered to 10 male healthy volunteers. Penile circumference was monitored using plethysmography and subjective sexual arousal was self-assessed. Data were collected before, during and after a stimulation session during which 50 erotic slides were projected to the subjects. 2. Apomorphine induced an erection starting from the fourth minute post-injection, and potentiated the visually-induced response. Self assessment showed increased tumescence and rigidity without modifications of sexual arousal. 3. Yohimbine did not modify penile diameter without stimulation and did not affect the physiological response to erotic stimuli. 'Sexual excitement' was decreased by yohimbine during the post-stimulation phase. One subject experienced severe anxiety while he was infused with yohimbine. 4. These results are discussed with reference to animal data and to recent studies carried out in impotent patients.
British Journal of Clinical Pharmacology 01/1989; 26(6):733-9. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The effect of tyramine, used as eye-drops, was assessed in 2 ethnic groups of healthy young adults, 6 Africans and 6 Caucasians. Tyramine-induced mydriasis in the Caucasian group was 5 times greater than in the African group. Similar differences were observed for indirect sympathominetic amines (ephedrine and cocaine) used as mydriatics, as well as for the effects of alpha 1 blocking drugs on the vascular system. (French abstract) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Psychiatrie & Psychobiologie. 09/1987;
-
[show abstract]
[hide abstract]
ABSTRACT: In a double-blind, placebo-controlled crossover trial, propranolol 80 mg did not show any hypnotic properties and even increased the insomnia in a sample of 37 patients previously treated chronically with hypnotic medication (mostly benzodiazepines). This worsening of the insomnia is consistent with the observations of sleep disturbance at the beginning of treatment with beta-blocking drugs. This lack of efficacy suggests that the anti-stress or anxiolytic properties of propranolol do not apply to the rebound insomnia seen when stopping treatment with hypnotic drugs.
International Clinical Psychopharmacology 05/1987; 2(2):135-40. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study evaluated the effects of acute doses of zopiclone (7.5 mg), triazolam (0.25 mg) and placebo on memory and psychomotor performance of 12 normal volunteers. The subjects received both drugs in a repeated measure, double-blind Latin square design. The tests (CFF, CRT, DSST, memory assessments) were performed before and 2 and 6 hr after treatment. Zopiclone and triazolam induced an anterograde amnesia affecting short-term and long-term memory which lasted less than 6 hr. No retrograde amnesia was observed. Two hr after drug intake of both hypnotics psychomotor performances were significantly altered compared with placebo. The subjects also felt more drowsy, dizzy, clumsy and tired, and less alert and energetic 2 hr after zopiclone and triazolam compared to placebo. There was no difference between the effects of the two hypnotics at the doses studied.
Fundamental and Clinical Pharmacology 02/1987; 1(2):145-52. · 1.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 tmax 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.
European Journal of Clinical Pharmacology 01/1987; 32(4):389-93. · 2.85 Impact Factor
-
Thérapie 43(2):93-6. · 0.30 Impact Factor
