Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects.

AIMS: To determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral immediate release (IR) lecozotan in healthy young and elderly subjects. METHODS: Three randomized, double-blind, placebo-controlled, sequential, ascending dose Phase I studies of lecozotan were conducted. In a single-dose study, ascending doses of 2, 5 and 10 mg were administered to cohorts of eight young subjects. In the two ascending 14-day multiple-dose studies, 41 young subjects received 0.1, 0.25, 0.5, 1 and 5 mg q12h of lecozotan or placebo and 24 elderly received 0.5 mg and 5 mg q12h of lecozotan or placebo. Assessments included safety evaluations, a complete PK profile and PD. RESULTS: Lecozotan was safe and well tolerated at steady state up to 5 mg q12. The maximum tolerated dose after multiple doses was >10 mg (5 mg q12). In the single-dose study, the maximum tolerated dose was 10 mg. Dose-limiting mild-to-moderate adverse events included paraesthesia, dizziness and visual disturbances peaking at t(max) and disappearing concomitantly with plasma concentrations. No clinically relevant changes in vital signs, ECG intervals or routine laboratory tests occurred. Lecozotan did not significantly change cognitive function, EEG or hormone levels. PK was characterized by rapid absorption, dose proportionality, extensive distribution and rapid elimination. The mean CL/F was approximately 35% lower in the elderly. CONCLUSIONS: Lecozotan IR was safe and well tolerated after administration of multiple oral doses up to 5 mg q12h in young and elderly subjects. These results support the development of lecozotan in patients with Alzheimer's disease.

Bioavailability of oral vitamin E formulations in adult volunteers and children with chronic cholestasis or cystic fibrosis.

PURPOSE: To test bioequivalence of oral vitamin E formulations, water-soluble tocofersolan (test) and water-miscible (reference), in healthy adult volunteers, and their bioavailability in children with chronic cholestasis or cystic fibrosis. METHODS: In a two-way open randomized single dose cross-over design, 1200 IU were administered in 12 healthy volunteers and 100 IU/kg in 12 children with chronic cholestasis or cystic fibrosis. RESULTS: In healthy volunteers, formulations were not bioequivalent with a higher exposure to tocofersolan. In cholestatic children tocofersolan bioavailability was significantly higher than reference formulation (maximum plasma concentration: P = 0.008 and AUC: P = 0.0026). Bioavailability was not statistically different in cystic fibrosis. CONCLUSIONS: Oral tocofersolan was more bioavailable than the reference formulation in children with chronic cholestasis and similarly bioavailable in cystic fibrosis. Tocofersolan may represent an alternative to painful intramuscular vitamin E injections in chronic cholestasis, or to other oral formulations in cystic fibrosis.

Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization.

OBJECTIVES: To examine the pharmacokinetics and the relation between plasma concentrations of the new potassium channel blocker dofetilide and QTc prolongation on the surface electrocardiogram after oral and intravenous administration. METHODS: Ten healthy volunteers received a single dose of 0.5 mg dofetilide orally and intravenously (over 30 minutes) in a randomized crossover study. The QTc interval versus dofetilide plasma concentration was analyzed by use of pharmacokinetic and pharmacodynamic modeling techniques. RESULTS: Dofetilide absolute bioavailability and systemic clearance were 92% +/- 9% and 0.35 +/- 0.05 L/hr/kg, respectively. Mean maximum increase in QTc interval duration was 99 msec (27%) and 61 msec (16%) after intravenous and oral administration, respectively. A counterclockwise hysteresis loop between dofetilide plasma concentrations and QTc interval duration was observed after intravenous infusions in all subjects, whereas direct linear relationships were observed after oral administrations in eight of 10 subjects. Pharmacokinetic-pharmacodynamic modeling showed the consistency of the effect versus concentration relationships obtained with the two routes of administration. With use of a maximum effect (Emax) model and data obtained after intravenous infusion, mean maximum QTc prolongation (Emax) was 121 +/- 57 msec and mean dofetilide plasma concentration associated with half the maximum effect (EC50) was 2.2 +/- 0.6 ng/ml. Pharmacokinetic-pharmacodynamic modeling was useful in detecting the maximum effect and in describing the plasma concentration versus effect relationship during intravenous infusion of dofetilide but was otherwise not superior to analyses performed with postdistribution data. CONCLUSION: We conclude that dofetilide prolongs QTc interval duration in a concentration-dependent manner in normal volunteers during sinus rhythm and that pharmacokinetic-pharmacodynamic modeling is useful for examination of maximum QTc prolongation induced by dofetilide.

Prediction of sotalol-induced maximum steady-state QTc prolongation from single-dose administration in healthy volunteers.

The relationship between racemic sotalol plasma concentrations and QTc interval prolongation after both single-dose and repeated administration of three sotalol oral doses was studied in a randomized crossover protocol performed in 10 healthy volunteers. QTc interval increase was significant after the three single-dose sotalol administrations and was significantly related to the administered dose (p < 0.0001). In 21 of 30 analyses, QTc interval was linearly correlated with sotalol plasma concentrations. After the 320 mg dose, the linear model was a best fit for 90% of the cases, and no hysteresis was observed. After repeated sotalol administration, 69 of 87 QTc interval measurements at steady state could be predicted from the plasma concentration versus effect relationship established after single-dose 320 mg administration. Seventeen of 18 errors (94%) corresponded to QTc intervals that were significantly lower than predicted. These findings suggest that a short-term individual linear model determined after a 320 mg test dose of sotalol allows a good prediction of expected maximal increase in QTc duration in healthy subjects.

Postmarketing surveillance of zopiclone in insomnia: analysis of 20,513 cases.

The subjective response to the prescription drug zopiclone, an hypnotic agent belonging to the cyclopyrrolone family, was assessed under the usual conditions of prescription of an hypnotic in general practice. The study included 20,513 insomniac outpatients with at least two of the following symptoms: sleep onset latency longer than 1 hour, more than two nocturnal awakenings, early morning awakening 1 hour or more before scheduled time, total sleep time of less than 6 hours, complaint of tiredness on awakening. Insomniac patients were treated with zopiclone and followed for 21 consecutive days within the context of a follow-up surveillance study. The population was predominantly female (62.6%), and the mean age was 52.3 years. The dosage of zopiclone prescribed at the inclusion visit was 7.5 mg per day in 87.5% of the cases and 3.75 mg per day in 10.5%. A total of 93.8% of the patients completed the survey. Spiegel questionnaire improved during the 21-day survey, and 9.2% of the patients reported at least one adverse event that led to treatment discontinuation in only 2.8% of the population. No serious or unexpected adverse events were reported.

Antidepressants and cognition: comparative effects of moclobemide, viloxazine and maprotiline.

The respective effects of three antidepressant drugs (moclobemide, 450 mg/j; viloxazine, 300 mg/j; maprotiline, 150 mg/j) on vigilance, attention, and memory were compared. Young depressed outpatients (n = 46) entered a double-blind, randomized, monocentre clinical trial lasting for 6 weeks. Drug actions were assessed through the regular determination of critical flicker fusion point (CFF), reaction times (SRT), and a battery to measure memory components. None of the three drugs caused deterioration in cognitive functions. On the other hand, moclobemide improved both vigilance and attention (CFF, SRT) and some crucial components of memory (general memory scores, delayed word recall, recognition of familiar faces). This effect was rapid, stable, and superior to those of viloxazine and maprotiline. It may be explained by moclobemide's selective and reversible inhibition of monoamine oxidase A, as well as by the lack of any anticholinergic action.

Absolute bioavailability and electroencephalographic effects of conventional and extended-release formulations of venlafaxine in healthy subjects.

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.

Pharmacodynamics and pharmacokinetics of two dose regimens of befloxatone, a new reversible and selective monoamine oxidase inhibitor, at steady state in healthy volunteers.

The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO-A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double-blind, three-way crossover, placebo-controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3-4 dihydroxyphenylglycol (DHPG), as measured by high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose-related reduction in plasma DHPG levels, as shown by the decrease in the 24-hour area under the concentration-time curve (AUC0-24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO-A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration-time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady-state levels of DHPG.

Effect of bromazepam versus placebo on inhibition and waiting capacity in young women with traits of anxiety.

The effect of 3 dosages of bromazepam administered as single oral doses (1.5, 3 and 6 mg) on anxious inhibition phenomena was studied in a population of 16 young women (18-30 years) with anxiety-traits, selected on the criteria of Cattell's anxiety scale supported by two personality inventory (Eysenck's, MMPI). A double-blind, placebo study design was chosen. The main assessment criteria were based on the go/no-go test (Logan's procedure), slow response rate (SRR) and a task of forced or unforced decision (use of the CFF). Attentional processes and declarative memory were analyzed as secondary criteria. None of the three dosages modified inhibition or acting-out. Sustained attention was reduced with 1.5 mg and 6 mg, as was memory performance with 3 and 6 mg, 3.5 h after drug administration. In contradistinction with studies carried out in healthy volunteers or with other benzodiazepine compounds, bromazepam at single low dosages does not modify inhibition capacity in these subjects with traits of anxiety, in this particular procedure.

Lack of effect of mizolastine on the safety and pharmacokinetics of digoxin administered orally in repeated doses to healthy volunteers.

The effects of mizolatine, a new H1 receptor antagonist, on safety and pharmacokinetics of digoxin were studied in a double-blind placebo-controlled crossover study. After administration of digoxine alone (0.25 mg o.d. for 7 days), 12 healthy young male volunteers (23+/-2 years) received either placebo and digoxin (0.25 mg o.d.) or mizolastine (10 mg o.d.) and digoxin (0.25 mg o.d.) during 7 days. The assessment criteria consisted in hemodynamic and ECG parameters recordings and the pharmacokinetics of digoxin during the last day of coadministration (day 14). No difference between the 2 treatment groups was evidenced on ECG, hemodynamic, and clinical and laboratory safety parameters. No change in AUC and tmax was recorded. No clinically relevant effect of mizolastine on the digoxin pharmacokinetics was found. However, a statistically significant increase in digoxin Cmax (3.03+/-0.18 nmolxl(-1) vs 2.52+/-0.19 nmolxl(-1), p < 0.05) and Cmin (0.99+/-0.08 nmolxl(-1) vs 0.87+/-0.07 nmolxl(-1), p=0.05) occurred after the coadministration vs digoxin alone. It can be concluded that mizolastine and digoxin at therapeutic dosages can be safely coadministered.

Comparative study of the effects of zopiclone (7.5 mg), zolpidem, flunitrazepam and a placebo on nocturnal cognitive performance in healthy subjects, in relation to pharmacokinetics.

The effect of zopiclone (7.5 mg) on attention, vigilance and memory components was evaluated during a nocturnal period in comparison to a placebo, to zolpidem (10 mg) and to flunitrazepam (1 mg) in a double blind, randomized study, after administration of a single dose in 16 young healthy volunteers. It appears that there is a clear effect on attention and vigilance; this effect is apparent during the kinetic phase of the absorption of the medication. The effect on memory is transient and is absent four hours after the ingestion of the drug. The objective results are not strictly consistent with the chronology of the subjective parameters (Leeds scale - Visual Analogue Scale). The three hypnotics under comparison do not fundamentally differ except in their kinetic/pharmacodynamic effect relationship. One important fact, taking the parameters as a whole, is that there is no objective "residual" effect.

[The elderly healthy volunteer: a necessity]. / Le volontaire sain âgé: une nécessité.

Phase I and II clinical studies performed in healthy elderly volunteers appear as a necessity in the design of any drug development. This is particularly true for drugs which will be indicated in age-related disorders. The essential aim is to obtain a maximum of results on kinetics, dosage and tolerance in this target population. Difficulties and specificities of these studies will be developed. This issue will contribute to improve the quality of Phase III studies and appears as a money-saving strategy.

[Randomized double-blind comparative study of minaprine (200mg/j) and of placebo on memory loss]. / Etude comparative en double aveugle randomisée de la minaprine (200 mg/j) et du placebo sur la plainte mnésique.

Thirty five subjects (age: 45-69 years) with subjective memory loss, without any other neuropsychiatric or somatic disease, were recruited in a phase II study. This double blind randomized versus placebo controlled study compared the effects of minaprine (200 mg/d) with placebo, in two parallel groups, during 2 months, on memory, attention and vigilance. Three psychometric tests were the main criteria of assessment: a standardized battery of memory tests (SM 5), the dual-coding test, the analysis of choice reaction times (CRT) and the critical flicker fusion point (CFF). A positive effect of minaprine was detected on words delayed recall (p = 0.028) and immediate recognition of words (p = 0.049). The global clinical tests (CGI, MacNair scale) were not statistically modified. Tolerability of minaprine and placebo were comparable. A positive pharmacodynamic activity on mnemonic performance is thus demonstrated in favour of minaprine (200 mg/d) in this specific population characterized by a memory complaint. These results would lead to a phase III study in which the main criteria would be global scales in order to confirm the clinical reliability of the present results.

[Pregnancy and delivery satisfaction of 424 patients in Perinatal Health Network « Sécurité Naissance ¼ of Pays-de-la-Loire area]. / Satisfaction de 424 usagers pendant la grossesse et à l'accouchement dans le Réseau de santé en périnatalité « Sécurité Naissance ¼ des Pays-de-la-Loire.

BACKGROUND: One method of evaluating a perinatal policy measuring user satisfaction is an important issue. The objective of the study was to measure satisfaction with the monitoring of pregnancy, childbirth and maternity stay. METHODS: Each volunteer maternity received a list of all births during one week in March-April 2008. The first mailing of questionnaires was conducted by post with stamped envelopes for the reply, after 2months in May and June 2008. A second reminder was made in July 2008. Responses to questions were coded using a Likert scale with four degrees with "very satisfied", "satisfied," "not very satisfied" and "not satisfied" with a quote by 4 to 1. The results are presented with the proportions of satisfied women, with radar diagrams. Transformation of responses with scores of 20 was established. RESULTS: In total, 424 responses were obtained in 22 maternities (/24), on 524 questionnaires sent (response rate 80.9 %). A comparison of mothers who responded to those who did not respond showed an over-representation of senior and middle managers and department. The average response time from birth was ten weeks±1 (8-26). The early prenatal care (known as the 4th month) was ignored (the word) by 58 % of women, but satisfying for those who have had while preparing for the birth, information on ultrasounds, tests on blood testing were satisfactory. A total of 13.2 % of women were hospitalized, and 94.9 % of cases, the information was obtained with 96.5 % satisfaction for the explanations. Mothers were met for the monitoring of pregnancy to 95.4 %. At delivery, the reception was well received with 94.7 % of satisfaction, like attention paid to patients with 93.5 % satisfied. The satisfaction score for delivery in general (with or without cesarean) was 16.5±4.0 (out of 20) with 92.5 % satisfied. The score for the cesarean section was 16.3 versus 16.6 for the low channels (not significant [NS]) in the case of anesthesia of 16.5 versus 16.7 (NS) in case of episiotomy of 15.9 versus 16.9 (P<0.05). The length of postpartum stay was found too short in case of 4.8 % (4.7 days), correct in 78.6 % (4.8 days), too long in 15.9 % (4.8 days). The satisfaction score for delivery in general (with or without cesarean) was 16.5 out of 20 with 92.5 % of satisfied. Also, 73.1 % of mothers tended to agree about the useful information for baby; 77.8 % thought that breastfeeding went well. The total score for pregnancy and childbirth is averaging 16.1, with 95.7 % of satisfied. The dissatisfying factors for 17 women have been linked in univariate to a department, the choice of maternity proximity and the existence of an episiotomy. Multivariate analysis was not significant criteria of discontent. CONCLUSION: Users respond to this type of investigation and seem satisfied with the care provided, in accordance with published data. The analysis of satisfaction and sources of dissatisfaction can improve treatments. The limits of the notion of satisfaction are analyzed.

Rate dependence of sotalol-induced prolongation of ventricular repolarization during exercise in humans.

Studies in animals have shown that drug-induced action potential prolongation with class III antiarrhythmic agents increases with slow pacing rates. We studied the physiological rate dependence of sotalol effects on ventricular repolarization, measured as QT interval duration on the surface electrocardiogram at rest and during a maximal exercise test, in 10 normal volunteers. In a randomized, crossover study, three dosages of sotalol (160 mg/24 hr, 320 mg/24 hr, and 640 mg/24 hr) were administered during 4 days to each subject. In a control period, no drug was administered. During each period, 50-100 QT intervals were measured over a wide range of RR intervals recorded at rest and during the course of a maximal exercise test. Plasma sotalol concentration and beta-adrenoceptor blockade (percent reduction in peak exercise heart rate from control) were also measured. The QT-versus-RR relation was fitted to several formulas, and the overall best fit was used to calculate QT interval duration normalized for a heart rate of 60 beats/min (QTc) and to analyze the rate dependence of QT prolongation with sotalol. Sotalol-induced beta-adrenoceptor blockade and QTc prolongation were dose and concentration dependent. Sotalol reduced peak exercise heart rate by 13.8 +/- 7% at the dosage of 320 mg/24 hr and by 25.4 +/- 8% at the dosage of 640 mg/24 hr (both p less than 0.01). Sotalol prolonged QTc interval by 5.8 +/- 3.7% and 11.8 +/- 3% at these respective dosages (both p less than 0.01). The concentration of sotalol required to produce minimal (mean QTc prolongation, 5.6%; confidence interval, 0-11.2%) QTc prolongation (680 ng/ml) tended to be lower than that required for minimal (mean percent reduction in maximal exercise heart rate, 13.9%; confidence interval, 0-27.8%) beta-blockade (840 ng/ml). QT prolongation with sotalol increased with increasing RR intervals (i.e., decreasing heart rate) at all dosages. QT prolongation became statistically significant for RR of 800 msec or more at all dosages and for RR intervals of 600 msec or more at the dosage of 640 mg/24 hr. This rate dependence altered the relation between QT interval duration and sotalol plasma concentrations. These results suggest that sotalol prolongs QTc interval in humans at dosages and concentrations similar to those required to produce beta-adrenoceptor blockade, QT prolongation with sotalol is more pronounced when heart rate decreases and is not apparent during exercise-induced tachycardia, and the relation between QT prolongation with sotalol and plasma concentrations of the drug depends on the heart rate at which measurements are made.

Oral pharmacokinetics of bisoprolol in resting and exercising healthy volunteers.

The effects of exercise on bisoprolol oral pharmacokinetics were studied in eight healthy male volunteers in an open, randomized, three-period, crossover trial. Oral bisoprolol (20 mg) was given either at rest during 24 h or with iterative stress tests before and 2.5, 5, 10, and 24 h after dosing. Exercise tests were repeated on a third placebo period. Bisoprolol was assayed in plasma and urines, and plasma catecholamines were measured before and after stress tests, Cmax, Tmax, elimination t1/2, and renal clearance of bisoprolol were not significantly modified by exercise. AUC0-infinity significantly decreased by 7.5% (p less than 0.05) with stress test resulting in an increase in apparent oral clearance. The beta-blocking effect peaked at 2.5 h, lasted greater than 24 h, and was related to plasma levels. The exercise-induced increase in plasma norepinephrine levels was significantly augmented with bisoprolol. These results suggest that repeated exercise tests exerted only limited effects on the oral pharmacokinetics of bisoprolol.

Comparison of three regimens of Parlodel-SRO in levodopa-treated parkinsonians: a randomized double-blind crossover study.

Parlodel-SRO is a newly developed slow-release formulation of bromocriptine, which prevents initial plasma peak--a known source of adverse events--and extends the half-life of the compound, an interesting feature for the management of motor symptoms in Parkinsonians. This study was designed to determine the best daily administration schedule for 30 mg Parlodel-SRO in 18 parkinsonians previously treated with levodopa and standard Bromocriptine (Br). The 30 mg dose was replaced from one day to the next, in a randomized, double-blind latin square design trial. Three consecutive 7-day courses were implemented, during which a total daily dose of 30 mg P-SRO was administered in one dose, two intakes (b.i.d.) and three intakes, (t.i.d.) respectively. The b.i.d. schedule produced the best improvement in UPDRS scores, especially as to postural stability, walking, bradykinesia; it also provided greater pharmacological stability throughout the assessment day. Adverse event analysis was not in favor of a single daily dose. It appeared that P-SRO administered in two 15 mg intakes (morning and evening) produces the best benefit-risk ratio in Parkinsonians who were already being treated with levodopa.