[Impact of the method and timing of administration on the systemic transport of ketoprofen]. / Répercussion du mode et du rythme d'administration sur le passage systémique du kétoprofène.

The pharmacokinetics of the non-steroidal antiinflammatory drugs are influenced by circadian rhythms and ketoprofen (K) absorption by food, to investigate the influence of these two factors, 12 subjects were treated, in random order, orally by a fast release tablet (FR 100 mg), by a fast-slow release tablet (FSR 150 mg) and by an intramuscular solution (i.m. 100 mg). The 3 treatments were administered, with a standardized meal, at 8 h a.m and 8 h p.m, and also at 1 h p.m with FR. The daily dosing was 300 mg by oral administration and 200 mg by i.m. route. Serum concentration profiles of K were determined by HPLC. The pharmacokinetic parameters of K were not modified by the time of intramuscular injection. The oral absorption of K (Tmax) was significantly delayed at 1 h p.m and more even at 8 h p.m. The maximal serum concentration (Cmax) was significantly decreased at 1 h p.m (about 50%, p < 0.001) and also at 8 h p.m. The oral bioavailability, evaluated by the area under the K serum concentration curve, was not modified, those of FSR was significantly lower than FR (6%, p < 0.05). This study shows that the time of K administration delayed the Tmax and food decreased the Cmax without loss of bioavailability.

Comparative bioavailability study of codeine and ibuprofen after administration of the two products alone or in association to 24 healthy volunteers.

The study objective was to compare the bioavailability of codeine and ibuprofen after oral administration of the two drugs alone or in association. The study was performed in three different periods, each separated by a wash-out of 6 days. Plasma concentrations were measured in 24 healthy volunteers after administration of a single oral dose of codeine phosphate (25 mg) and/or ibuprofen (200 mg). Codeine and ibuprofen assays were performed using two different HPLC methods. The relative bioavailabilities of codeine and ibuprofen (alone or in association) were 106 +/- 24% (mean +/- sd) and 101 +/- 19%, respectively. The results obtained demonstrated that bioavailabilities of codeine and ibuprofen were not modified when the two drugs were administrated alone or in association.

[Comparison between effects of morning and evening administration of effervescent calcium carbasalate (equivalent of 160 mg aspirin) on the gastroduodenal mucosa in healthy volunteers]. / Comparaison de l'effet de la prise matinale et vespérale du carbasalate calcique effervescent (equivalent a 160 mg d'aspirine) sur la muqueuse gastroduodénale chez le volontaire sain.

The aim of this randomised, cross-over trial was to compare the gastroduodenal tolerability and anti-aggregating effect of effervescent calcium carbasalate (ECC equivalent to 160 mg aspirin) given once daily either in the morning or in the evening. Twelve healthy volunteers received calcium carbasalate for 2 periods of 5 days (21 days of wash-out between the 2 periods). The principal criterion was the gastroduodenal tolerability assessed by the total number of lesions at upper gastro-intestinal endoscopy. The same treatment-blinded endoscopist performed all evaluations. Efficacy was evaluated by thromboxane B2 measurement and collagen-induced platelet aggregation tests. No difference was observed between morning and evening administration of ECC on gastroduodenal tolerability and platelet agregation. ECC was very well tolerated as assessed by upper gastrointestinal endoscopy and almost totally inhibited platelet aggregation.

Smokers' behaviour and exposure according to cigarette yield and smoking experience.

The influence of cigarette yield and length of smoking experience on smoking behaviour and biomarker levels was sought in 108 smokers who have never changed cigarette class. Smoking parameters carboxyhaemoglobin percentage (COHb), urinary nicotine, and its metabolites, mutagens, and thioethers were measured. Cigarette yield does not affect daily consumption or smoke volume puffed per cigarette. But the inhalation depth increases with decreasing cigarette yield and with length of smoking habit. The COHb level after the first cigarette in the morning increases significantly with CO cigarette yield and length of smoking experience. In the evening, only the cigarette yield has an effect on COHb level. Biomarker levels excreted in urine are generally lower for females than for males. They tend to increase with smoking history. Only COHb level and total urinary nicotine metabolites (Barlow index) are weakly correlated with cigarette yield. The absence of significant differences due to cigarette class in urinary biomarkers can be explained by changes in inhalation depth, individual differences of metabolism, and limited specificity of some markers (mutagens, thioethers).

Pressor effect of oral tyramine during treatment with befloxatone, a new reversible monoamine oxidase-A inhibitor, in healthy subjects.

The interaction between tyramine and befloxatone, a new selective, reversible monoamine oxidase-A (MAO-A) inhibitor, was studied in a single-blind, parallel-group study in 30 healthy male volunteers whose fasting tyramine 30 dose (Tyr30) was 400 or 600 mg. Each subject completed a placebo run-in period followed by a befloxatone period. Befloxatone was given in repeated doses according to one of three regimens: befloxatone 20 mg once daily at the end of a meal rich in tyramine or befloxatone 10 or 20 mg twice daily 2 hours before a meal rich in tyramine. Subjects were given increasing daily doses of tyramine mixed with the meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (Tyr30). The mean Tyr30 decreased from 1220 mg (range, 600-1800 mg) during placebo to 290 mg (range, 150-500 mg) during befloxatone 20 mg once daily, 250 mg (range, 100-300) during befloxatone 10 mg twice daily, and 155 mg (range, 100-250 mg) during befloxatone 20 mg twice daily; corresponding to a potentiation factor of 5.2-, 6.5-, and 7.9-fold, respectively. The extent and the duration of the systolic blood pressure increase did not significantly differ between the placebo and the befloxatone regimens, except for a longer duration with the 20-mg twice daily regimen. These results are similar to those reported with the therapeutic dosage of other selective MAO-A inhibitors. They suggest that there would be little risk of hypertensive crisis in patients treated in clinical studies with befloxatone, and thus dietary restrictions appear to be unnecessary when the drug is given in a regimen of up to 20-mg once daily after meals.

Lack of amnestic, psychotomimetic or impairing effect on psychomotor performance of eliprodil, a new NMDA antagonist.

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.

[Pharmacokinetics of low-dose lithium in healthy volunteers]. / Pharmacocinétique du lithium administré à doses faibles chez le volontaire sain.

The pharmacokinetics of lithium in healthy volunteers receiving low doses of lithium as Lithium Oligosol by sublingual route were investigated in two randomized crossover studies (lithium vs placebo) with a two week wash-out period. In the first study, 8 volunteers received a single dose (1.68 mg) of lithium and in the second 8 another volunteers received repetitive doses of lithium (0.56 mg twice a day) during 11 days. The plasma concentration of lithium was determined by an electrothermal atomic absorption spectrometry. The plasma concentrations of lithium measured during the placebo period were about 1 microgram/L, the peak concentration was 99.4 +/- 22.2 micrograms/L in the single dose study and 49.6 +/- 5.4 micrograms/L in the multiple doses study. In this last one, the residual plasma levels of lithium were between 20 and 25 micrograms/L. The pharmacokinetics parameters measured were: T1/2 = 22.6 +/- 3.1 h; Vd/F = 0.70 +/- 0.09 L/kg and Cl/F = 1.53 +/- 0.12 L/h. The plasma concentrations of lithium are strictly dependent on intake from food or drugs.

Pharmacokinetics of diacerein in patients with liver cirrhosis.

The pharmacokinetics of diacerein following a single oral dose of 50 mg was studied in 12 healthy volunteers, 10 patients with a mild liver cirrhosis (Child Pugh's grade A), and 6 patients with a more severe liver cirrhosis (Child Pugh's grade B to C). Statistical analysis using a Kruskal-Wallis test showed no significant differences between the three groups for the following parameters: median Cmax was 3.9 mg l-1 for the cirrhotic patients group I (CPI) and 3.2 mg l-1 for the cirrhotic patients group II (CPII) versus 3.2 mg l-1 for the healthy volunteers (HV); median t1/2 was 4.9 h for CPI and 4.3 h for CPII versus 4.3 h for HV; median Cl/F was 2.1 l h-1 for CPI and 2.5 l h-1 for CPII versus 1.6 l h-1 for HV; median Vdss/F was 12.6 l for CPI and 14.0 l for CPII versus 13.21 for HV. The urinary parameters were comparable. It was concluded that, from a pharmacokinetic point of view, no reduction in the initial dosage of diacerein need be proposed in liver cirrhosis.

Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects.

Zolpidem is a rapid-onset, short-duration imidazopyridine hypnotic drug and is specific agonist of the omega-1 (BZD1) receptors. Its hypnotic characteristics resemble those of triazolam. The aims of this study were to assess the effects of zolpidem on memory (the main objective), psychomotor performances, and postural sway (secondary objectives) in 18 healthy subjects and to compare them with those of triazolam and placebo. Short- and long-term memory (paired words associate and pictures test), psychomotor performances (critical flicker fusion frequency, choice reaction time, digit symbol substitution test), and postural sway were evaluated before and 1.5, 4, 6, and 8 h after the administration of a single dose of zolpidem (10 mg), triazolam (0.25 mg), and placebo. For each assessment, the maximal effect for both hypnotic drugs occurred 1.5 hour after intake. Both drugs decreased psychomotor performance, impaired memory, and increased postural sway. The effects of both hypnotic agents were short lasting, and no alterations were found 6 and 8 hours, respectively, after drug intake. No clinically relevant differences were found between zolpidem and triazolam for memory, psychomotor performance, postural sway, or adverse effects. It may be concluded that zolpidem, like triazolam, impairs short- and long-term memory, psychomotor performances, and postural sway and that these effects are of short duration.

Influence of renal function on the pharmacokinetics of diacerein after a single oral dose.

The pharmacokinetics of diacerein (a new anti-inflammatory analgesic antipyretic drug) following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups of eight patients with mild or severe renal insufficiency. Statistical analysis using a Kruskal-Wallis rank sum test showed a significant difference between the three groups for the following parameters. In severely uraemic patients, median AUC0-infinity was multiplied by a factor of ca 2: 40.5 mg h/l versus 21.3 in healthy subjects, P = 0.04; and t1/2 was prolonged by the same factor: 9.6 h versus 4.3 in the control group, P = 0.003. Apparent drug availability and renal clearance assessed through urinary data decreased with renal failure, respectively: 14.5% and 0.045 l/h versus 35.4% (P = 0.01) and 0.13 l/h (P = 0.008) in healthy subjects. Amounts of glucuro and sulfo conjugates in urine were lower in severely uraemic patients. Intermediate values were observed for mildly uraemic patients. Other parameters: lag-time, Cmax, tmax, Vss/F, urinary glucuro- to sulphoconjugate ratios did not change significantly. Apparent total clearance of rhein was poorly correlated with creatinine clearance and this was related to a decrease of non-renal clearance of rhein in renal insufficiency. It was concluded that, from a pharmacokinetic point of view, a reduction (50%) in the maintenance dosage of diacerein should be considered in severe renal failure.

Assessment of the anticholinergic effect of the new antihistamine mizolastine in healthy subjects.

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.

Dose ranging study of lansoprazole, a new proton pump inhibitor, in patients with high gastric acid secretion.

The effects of single doses and of 7 days of lansoprazole 10, 20 and 30 mg PO versus placebo on gastric acid secretion have been evaluated in 8 patients with high gastric acid secretion. The double blind crossover period was followed by a simple blind 7 days on placebo to detect any rebound phenomenon. After the first dose lansoprazole did not modify basal acid output (BAO) but it significantly and dose dependently inhibited peak acid output (PAO) and increased the time during which nocturnal intragastric pH was greater than 3. After 7 days of treatment the same significant, dose-dependent suppression of gastric acid was found, but BAO was also blocked. One week after cessation of lansoprazole administration no rebound increase in gastric acid-secretion was observed. The plasma gastrin concentration remained unchanged throughout the study.

Evaluation and comparison of the interaction between alcohol and moclobemide or clomipramine in healthy subjects.

The interaction of clomipramine and moclobemide with alcohol was compared in a double blind parallel groups study in 24 healthy volunteers. Moclobemide was given at the highest recommended therapeutic dose (200 mg t.i.d.) and clomipramine in a subtherapeutic dose (25 mg b.i.d.) because of its poor tolerance in healthy subjects. Psychometric evaluations were performed during a placebo run-in phase; after a 5-day treatment period; assessments were made before, and again 1 h and 4 h after alcohol ingestion. Alcohol doses were pre-determined for each subject in order to produce a blood alcohol concentration of 0.6 g/l 1 h after alcohol intake and this individual alcohol dose was given on test days. The day before alcohol intake tests for autonomic functions were made to assess the anticholinergic effects of the drugs. Alcohol significantly increased body sway, decreased critical flicker fusion frequency, prolonged choice reaction time, impaired copying skills, impaired memory and increased the subjective feelings of satisfaction and tension. Drugs increased the effect of alcohol on body sway and this was essentially due to clomipramine. Clomipramine both without and with alcohol increased body sway, prolonged choice reaction time more than did moclobemide. Clomipramine seemed to diminish alcohol-induced memory impairment in one of the memory tests used. Subjects taking clomipramine had significantly more adverse effects after alcohol ingestion than did subjects of the moclobemide group. In contrast to moclobemide, clomipramine produced a moderate but significant drop in standing systolic blood pressure and a clear inhibition of salivary excretion.(ABSTRACT TRUNCATED AT 250 WORDS)