Large changes in Pluto's atmosphere as revealed by recent stellar occultations.

Pluto's tenuous nitrogen atmosphere was first detected by the imprint left on the light curve of a star that was occulted by the planet in 1985 (ref. 1), and studied more extensively during a second occultation event in 1988 (refs 2-6). These events are, however, quite rare and Pluto's atmosphere remains poorly understood, as in particular the planet has not yet been visited by a spacecraft. Here we report data from the first occultations by Pluto since 1988. We find that, during the intervening 14 years, there seems to have been a doubling of the atmospheric pressure, a probable seasonal effect on Pluto.

The placebo effect in healthy volunteers: influence of experimental conditions on the adverse events profile during phase I studies.

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.

Pharmacokinetic and pharmacodynamic modeling of mizolastine in healthy volunteers with an indirect response model.

OBJECTIVE: The aim of this work was to model the pharmacokinetic and pharmacodynamic relationship of mizolastine, a new H1-receptor antagonist obtained from histamine-induced wheal and flare inhibition test. METHODS: Fifteen healthy volunteers participated in this double-blind crossover study and randomly received single doses of 5, 10, 15, and 20 mg of mizolastine and placebo at 1 week intervals. Simultaneous histamine tests and blood samples were performed before and at 9 different times up to 24 hours after each dosing. Pharmacokinetic and pharmacodynamic modeling were performed subject by subject for the 4 doses altogether by nonlinear regression. First, plasma concentrations were fit according to a two-compartment open model with zero order absorption and first order elimination. Then an indirect response model with inhibition of the formation rate was developed to describe the pharmacodynamic relationships between flare or wheal raw areas and plasma concentrations with the use of the pharmacokinetic parameters that were previously estimated. RESULTS: Mizolastine dose dependently inhibited the histamine-induced wheal and flare formation with a submaximum effect attained after 10 mg. The mean values of the pharmacodynamic parameters of apparent zero-order rate constant for the flare or wheal spontaneous appearance (k(in)), the first-order rate constant for the flare or wheal disappearance, the mizolastine concentration that produced 50% suppression of the maximum attainable inhibition of k(in), and the maximum attainable inhibition of the effect production were 14.1 cm2/h (coefficient of variation [CV], 32%), 0.68 h(-1) (CV, 24%), 21.1 ng/mL (CV, 77%), and 0.92 (CV, 8%), respectively, for the flare and 1.9 cm2/h (CV, 64%), 0.63 h-1 (CV, 39%), 43.9 ng/mL (CV, 68%), and 0.87 (CV, 12%), respectively, for the wheal inhibition. CONCLUSION: Pharmacokinetic and pharmacodynamic relationships of mizolastine were reliably described with the use of an indirect pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of mizolastine.

Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic.

Zolpidem is a new imidazopyridine-hypnotic that selectively binds to the central omega 1-receptor subtype. A double-blind, randomized, three-way, crossover placebo-controlled study was carried out in nine healthy male volunteers to assess the possible antagonism of central nervous system--depressant effects of zolpidem by flumazenil. Subjects received zolpidem (0.21 mg/kg) or placebo, intravenously, followed 17 minutes later by flumazenil (0.04 mg/kg) or placebo. Vigilance and performance were assessed by a trained anesthetist with use of ciliary reflex, response to a verbal instruction, subjective sedation, a tracking task, and a free recall task. Zolpidem produced a clinically relevant hypnotic effect in five subjects and significantly impaired performance in all nine subjects up to 90 minutes after dosing. Flumazenil rapidly antagonized clinical sedation in the five subjects who were asleep and significantly reversed the performance decrement within 3 minutes, without any escape phenomenon. Flumazenil did not change zolpidem plasma concentrations, confirming the pharmacodynamic nature of the interaction. Flumazenil may thus be a safe and effective antidote in patients with zolpidem overdosage.

Cognitive performance in elderly subjects after a single dose of befloxatone, a new reversible selective monoamine oxidase A inhibitor.

BACKGROUND: Patients with depression often have cognitive and psychomotor performance impairments. Antidepressive treatments can correct these deficits, provided sedative and anticholinergic adverse effects do not add to the preexisting condition, particularly in elderly patients. Newly developed antidepressants therefore should be without deleterious effects on cognitive functions, including memory. Befloxatone is a new antidepressant with a potent, selective, competitive, and reversible inhibitory activity on the A isoform of monoamine oxidase (MAO-A). METHODS: The effects on cognition and psychomotor performance of single oral doses of befloxatone (10 mg) and amitriptyline (50 mg) were compared in a randomized, double-blind, placebo-controlled, three-way crossover design trial in 12 healthy elderly (65 to 85 years) volunteers. The performances of the subjects were evaluated by a comprehensive battery of validated psychometric tests that explored alertness, psychomotor performance, information processing, and memory. Subjective feelings on mood and sleep were rated on visual analog scales. MAO-A inhibition was estimated by multiple titrations of 3,4-dihydrophenylglycol (DHPG) in plasma. RESULTS: Amitriptyline displayed the expected deleterious effects on performance tasks, critical flicker fusion threshold, digit symbol substitution, and body sway, and it deteriorated memory (immediate and delayed free recall of words). In contrast, befloxatone did not impair cognition or psychomotor performance but instead significantly improved the delayed free recall. Amitriptyline adversely affected subjective feelings of alertness and contentedness, but befloxatone permitted sustained alertness and did not alter other subjective feelings or sleep. Concurrently, a single dose of 10 mg befloxatone markedly decreased the DHPG concentration in plasma. CONCLUSION: Contrary to tricyclic antidepressants, whose deleterious effects are greater in elderly subjects, this study demonstrated the safety of befloxatone on cognition and psychomotor performance in elderly subjects.

Reduction of hyperglycemia after oral glucose load by the new alpha 2-adrenergic receptor antagonist SL 84.0418 in healthy subjects.

OBJECTIVE: To assess the antihyperglycemic activity of a new peripherally acting alpha 2-adrenergic receptor antagonist, SL 84.0418 in healthy volunteers METHODS: This was a randomized, double-blind crossover study. The effects of 10, 50, and 100 mg SL 84.0418 on blood glucose, plasma insulin, C-peptide, glucagon, epinephrine, and norepinephrine were investigated in comparison with placebo and 5 mg glipizide before and after an oral glucose challenge (75 gm). RESULTS: Peak blood glucose and area under the blood-glucose curve were dose-dependently reduced by SL 84.0418; the extent of this reduction was similar with 100 mg SL 84.0418 and glipizide. Glipizide but not SL 84.0418 decreased nadir blood glucose. Plasma insulin and C-peptide were increased by glipizide but not by SL 84.0418. Treatments did not modify plasma glucagon. Plasma epinephrine increased during glipizide treatment and plasma norepinephrine increased during treatment with 50 and 100 mg SL 84.0418. Systolic and diastolic blood pressure were moderately enhanced by 50 and 100 mg SL 84.0418. Adverse effects reflecting alpha 2-adrenergic receptor blockade occurred more frequently with 100 mg SL 84.0418. The adverse effect profile of 50 mg SL 84.0418 was not different from that observed with glipizide. CONCLUSION: The alpha 2-adrenergic receptor antagonist SL 84.0418 dose dependently reduced the increase in blood glucose after glucose load without modification of plasma insulin. It may represent an alternative to sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus. Further studies are needed to assess its efficacy and tolerability in non-insulin-dependent patients.

Effects of haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers.

The effects of a typical neuroleptic, haloperidol (1 and 2 mg orally), of an atypical neuroleptic, amisulpride (50 and 100 mg) and of a placebo on motor and cognitive skill learning were assessed in 60 healthy volunteers using repeated testing on the Tower of Toronto puzzle. Subjects were asked to solve three blocks of eight trials and, at distance from drug administration, a fourth block. The puzzle was connected to a computer in order to obtain a precise timing of individual moves. Two components of cognitive skill learning were assessed, the ability to learn to solve the puzzle and the acquisition of a problem-solving routine. Subjective feelings of effort and automatisation of the task were assessed using a questionnaire. Like placebo-treated subjects, neuroleptic-treated subjects were able to acquire a motor skill, to learn to solve the puzzle and to acquire a routine. However, haloperidol 2 mg-treated subjects needed significantly more moves to solve the puzzle in blocks 3 and 4, some of them having routinised a non-optimal solution. A significant cognitive slowing was observed in the haloperidol 1 mg group in block 4. The performance pattern and verbal reports suggested that haloperidol impaired the higher cognitive functions such as the ability to shift from one strategy to another and/or to assess one's performance accurately, possibly leading to the development of compensatory strategies. The only deleterious amisulpride effect was a cognitive slowing in block 4, which was observed in the lower dose group.

EEG profile of intravenous zolpidem in healthy volunteers.

Zolpidem is an imidazopyridine which binds specifically to the omega 1 receptor. Zolpidem demonstrated potent hypnotic activity at a dose of 10 mg. Pharmacodynamics and pharmacokinetics of zolpidem were studied after daytime administration in a randomised, double-blind, placebo-controlled, cross-over trial. Single doses of zolpidem (10 mg IV as a 3-min infusion and 20 mg orally) and placebo were firstly tested in 12 healthy young male volunteers. Two other doses (5 mg IV and orally) were then evaluated in 6 out of these 12 subjects. EEG (4 leads = Fp2-T4, Fp1-T3, T4-02 and T3-01), and Stanford Sleepiness Scale (SSS) were measured up to 5 h postdosing. Blood samples were also collected up to 24 h. The time course of the hypnotic activity of zolpidem, assessed by the score obtained on SSS, showed a similar profile whatever the route or the dose administered: slightly earlier onset after IV but sedative scores were reached at 30 min and the effect peaked between 1 and 1.5 h and lasted 4 h in both conditions. The EEG profile of zolpidem was characterised by a decrease of alpha activity and an increase in delta and in beta activity. The effect on beta activity was marked within the first hour and then disappeared. The time course of delta and alpha activities indicated a rapid onset (10 min after IV, 30 min after oral route) and a duration of 3-4 h. The amplitude of these relative EEG changes and their duration were independent of the route of administration and the dose administered. AUC and Cmax increased proportionally to the administered dose and elimination half life (2h), clearance and volume of distribution did not change according to the dose or the route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of histamine-induced skin wheal and flare after 5 days of mizolastine.

Mizolastine is a new, nonsedating antihistamine providing satisfactory symptomatic relief in allergic rhinitis and urticaria. The purpose of this study was to use inhibition of wheal and flare formation after 2-mu g intradermal histamine injections as a measure of the antihistamine effect of repeated doses of mizolastine. Eight volunteers were enrolled in this four-arm, double-blind, cross-over, randomized study. Three dose levels of once-daily mizolastine (5 mg, 10 mg, and 15 mg) were compared with placebo during 5-day dose periods. Histamine tests were performed before drug intake on days 1 and 5, and then 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours after drug intake on day 5. All 3 doses of mizolastine were more effective than placebo in suppressing wheal and flare reactions, and the antihistamine activity was highest at both the 10- and 15-mg dose levels. The effect on the flare reaction appeared within 1 hour, reached a maximum effect 4 hours after administration, and persisted for as long as 24 hours. The relative changes in wheal and flare areas were correlated with mizolastine trough plasma levels on day 5. Safety was satisfactory in all groups. This study confirms that mizolastine is a rapid and potent antihistamine; and its long-lasting effectiveness indicates that a once-daily regimen is acceptable for clinical use.

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.

Clinical pharmacology of befloxatone: a brief review.

Clinical pharmacology studies of befloxatone, a new selective reversible inhibitor of monoamine oxidase-A (MAO-A), have addressed safety, with special emphasis on tyramine interactions, and have also investigated pharmacokinetics (PK) and pharmacodynamics in terms of both MAO-A inhibition (using 3,4-dihydroxyphenylglycol, DHPG, as a pharmacological activity marker) and effects on psychomotor and cognitive function, in young and elderly healthy volunteers. Clinical and laboratory safety data were satisfactory in healthy volunteers given single doses of up to 160 mg or repeated doses of up to 80 mg/day for 7 days. Tyramine interaction studies showed that the expected potentiation of the tyramine pressor effect occurred with a safety margin that was so wide as to make dietary restrictions unnecessary with dosages of up to 20 mg once daily in clinical settings. Absorption was rapid (tmax = 2 h), terminal halflife was about 11 h, and PK parameters increased linearly with the dose. Befloxatone induced a dose-dependent decrease in plasma DHPG levels from 2.5 mg upwards, and a 10-mg dose provided sub-maximal activity (80% DHPG decrease) of 24 h duration. No sedative or stimulant effects were detected using several batteries of psychometric tests. Befloxatone was devoid of deleterious effects on memory in young volunteers, and exhibited the EEG profile of a non-sedative antidepressant. In summary, available clinical pharmacology studies confirm that befloxatone is a safe and potent RIMA with no potential for inducing deleterious CNS effects.

Effects of 50mg amisulpride on EEG, psychomotor and cognitive functions in healthy sleep-deprived subjects.

Amisulpride, a substituted benzamide, binds selectively to the dopamine D2- and D3-receptors. It has higher affinity for limbic compared to striatal dopamine receptors in vivo. At low doses, amisulpride facilitates dopamine transmission via a selective blockade of presynaptic D2- and D3-receptors. Amisulpride is an active antipsychotic compound effective at low doses for negative symptoms and at high doses for positive symptoms of schizophrenia. The CNS profile of multiple doses of a low dosage regimen of amisulpride (50 mg once daily for 4 days) was assessed in a randomised, double-blind, 3-way crossover, placebo-controlled study carried out in 12 young sleep-deprived (for 36 h) subjects, using EEG and various measures of psychomotor and cognitive functions. Caffeine slow release (600 mg) was used as a positive reference. Multiple doses of 50 mg amisulpride once daily were devoid of any detrimental effects on EEG and psychomotor performance and cognitive function after total sleep deprivation. In addition, 50mg amisulpride partially antagonized the deleterious effects of sleep deprivation on EEG and subjective sedation as shown by trends, and a significant increase in EEG relative beta power and a decrease in subjective sedation. These effects were more pronounced at the end of sleep deprivation, suggesting possible alerting effects of amisulpride at this dose level. Caffeine significantly antagonized the detrimental effects of sleep deprivation on vigilance (increase in EEG beta waves, speed of reaction, sustained attention and reduction in subjective sedation). In conclusion, the present results demonstrate that 50 mg amisulpride is devoid of detrimental effects on EEG, psychomotor and cognitive performance after sleep deprivation, a situation well-known to amplify such effects if they exist. Moreover, some data suggest possible alerting effects of this low dosage regimen of amisulpride.

Pharmacokinetics and pharmacodynamics of zolpidem following repeated doses in hemodialyzed uraemic patients.

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.

Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers.

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.

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.

Effects of mizolastine, a new antihistamine, on psychomotor performance and memory in elderly subjects.

The effects of a single 10 mg dose of the new H1 antihistamine mizolastine on psychomotor performance and memory in the elderly were assessed in a double-blind, cross-over, placebo-controlled study in 15 elderly female volunteers aged 66-77 years, using clemastine 2 mg as a positive control. Objective (critical flicker fusion, choice reaction time, digit symbol substitution, immediate and delayed free recall) and subjective (linear analogue rating scales) assessments were done on each test day before the dose, then 4 and 8 h post-dose. Plasma samples were also collected. A single oral dose of mizolastine within the range of recommended daily therapeutic dosages (10 mg) failed to induce subjective drowsiness and produced no detrimental effects on psychomotor performance or on short-term and long-term memory in the elderly subjects. In contrast, 2 mg clemastine induced significant impairments (decrease in critical flicker fusion, increase in recognition reaction time) in comparison with placebo and mizolastine, although it did not impair memory. The pharmacokinetic profile of mizolastine in the elderly study subjects was similar to that observed in healthy young volunteers. Therefore, it can be concluded that mizolastine 10 mg could be used safely in elderly out-patients as it preserves functions involved in activities of daily living.

Multicenter studies on the pharmacokinetic profile of sustained-release oral diltiazem (300 mg) after once a day repeated administration: influence of age.

The influence of age on the pharmacokinetics of the oral sustained release diltiazem Mono-Tildiem LP 300 mg was investigated in 12 middle-aged (40-64 years), 12 elderly (65-80 years) patients and compared to a control group of 54 young healthy volunteers (18-36 years). Each subject received daily a single dose of diltiazem slow release (300 mg) in the morning for 5 consecutive days. On the fifth day of treatment, the pharmacokinetic parameters of diltiazem and of 2 of its circulating metabolites (N-monodemethyldiltiazem and deacetyldiltiazem) were evaluated. The mean diltiazem Cmax was 199.3 +/- 117.8 ng/ml, 254.8 +/- 85.2 ng/ml and 154.5 +/- 63.2 ng/ml in middle-aged, elderly, and young healthy subjects, respectively. Mean plasma Cmin concentration was also higher in elderly subjects than in middle-aged and young subjects: 129.7 +/- 77.9 ng/ml versus 66.8 +/- 56.8 and 66.3 +/- 32.3 ng/ml, respectively. The AUC0-24 showed the same trend: 4,042 +/- 1,136 ng/ml.h in elderly, 2,995 +/- 1,905 ng/ml.h in middle-aged, and 2,564 +/- 1,205 ng/ml.h in young subjects. These parameters were statistically higher (p < 0.01) in the elderly subjects than those obtained in younger people. No statistical difference was observed between young volunteers and middle-aged patients. The Tmax did not differ significantly with age (5.1 +/- 4.4, 6.8 +/- 2.8, 6.1 +/- 3.5 hours, respectively). The ratios between the AUC of each metabolite and that of the parent compound did not vary with the age. These results suggest that in elderly people (> 65 y) the bioavailability of diltiazem is increased, probably due to a reduction of the first-pass effect. Based on the pharmacokinetic results, although safety data did not show any specific trend with age, a precautionary reduction of the dose at the start of the treatment seems advisable.

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.

Effects of zolpidem versus diazepam and placebo on breathing control parameters in healthy human subjects.

The following study explores the possibility that zolpidem, a new hypnotic agent derived from imidopyridine, may induce changes in ventilatory function in normal subjects. The study, conducted double-blind on 16 subjects (eight men and eight women, aged 21 to 33 years) was undertaken in two successive phases: phase A with a cross-over, intended to compare the ventilatory effects of 10 mg oral dose of diazepam with a placebo, and then phase B, with a Latin square design, intended to compare the effects of 10 and 20 mg oral doses of zolpidem with 10 mg oral doses of diazepam and a placebo. Central inspiratory drive was assessed by occlusion pressure (P0.1) and breathing pattern in air and during carbon dioxide rebreathing. Measurements were performed one and three hours after each drug or placebo administration. Zolpidem did not affect tidal volume (Vt), slopes S1, S2 or P0.1, but decreased the duration of the phases of the respiratory cycle ti by 14% (p less than 0.01) and ttot by 15% (p = 0.03) after three hours post dosing without any change in ventilation, Vt/ti or ti/ttot. Nevertheless, these timing changes, although statistically significant, seem to have no clinical relevance to overall ventilation regulation in normal subjects. On the other hand, diazepam slightly changed S2 at three hours post dosing (0.14 +/- 0.07 versus 0.17 +/- 0.10 after the placebo; p = 0.06) without modifying the other parameters.