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Objective: To evaluate the pharmacokinetics and tolerability of estradiol valerate 2.0mg plus dienogest 2.0mg (Climodien® 2/2). Design and Setting: This was an open single-and multiple-dose study. Study Participants: 16 healthy postmenopausal women. Interventions: Pharmacokinetic parameters were determined in plasma after single and multiple daily intake of Climodien® 2/2 for 12 weeks. Accumulation during multiple administration was calculated from the area under the plasma concentration-time curve (AUC). Changes in plasma levels of other hormones and sex hormone-binding globulin (SHBG) were also measured. Results: The observed accumulation of estradiol (accumulation ratio R1 = 3.3) and free estrone (R1 = 2.4) was higher than that predicted from single-dose data (Rtheor = 1.7 and 2.0 for estradiol and free estrone, respectively). This was thought to be due to high interindividual variability in estrogen parameters, or the degree of extrapolation required when calculating the half-life (t1/2). The observed accumulation of total estrone after multiple-drug administration was as predicted from single-dose results (R1 and Rtheor = 1.5). The pharmacokinetics of dienogest were not time dependent, the observed accumulation (AUC0–24h 627 vs 483 μg/L · h) was as predicted from single-dose results (R1 and Rtheor = 1.3). Reduced total plasma testosterone levels confirmed the antiandrogenic effect of dienogest. The main adverse events with Climodien® 2/2 (breast tension in five participants and irregular vaginal bleeding in four) reflected its hormonal content, and laboratory screening tests revealed no tolerability concerns. Conclusions: Estradiol may accumulate in plasma during multiple-drug administration with Climodien® 2/2 more than predicted from single-dose results. However, dienogest kinetics after multiple-drug administration were as predicted from single-dose results. Climodien® 2/2 demonstrated antiandrogenic effects and was well tolerated.

Twelve healthy volunteers participated in a double-blind, randomised, balanced, two-period, crossover study in which they received 5mg oral dihydroergotamine or placebo twice a day for 10 days, with a washout of at least a week between periods. On the morning of the last day of each period they also received a 10mg dose of zolmitriptan (formerly known as 311C90). There were no significant differences in baseline (pre-zolmitriptan) or post-zolmitriptan blood pressures between the two occasions and dihydroergotamine had no significant effect on any pharmacokinetic parameters of zolmitriptan or its metabolites. There were no clinically significant changes in ECGs and adverse experiences were typical of 5HT1b/1d agonists. These data suggest that zolmitriptan can be used in conjunction with oral dihydroergotamine without special precautions.

Resume Les profils pharmacocinetiques des pristinamycines composant la Pyostacine® 500 mg ont ete determines chez des volontaires sains, apres administration orale repetee pendant 7 jours, de deux comprimes le matin et de deux comprimes le soir, pris au milieu du repas, suivie d'une administration unique de deux comprimes au matin du huitieme jour. Ce schema correspond a la posologie usuelle prescrite en therapeutique. Deux methodes analytiques ont ete utilisees : dosages radioimmunologiques (RIA) des deux familles de pristinamycines P i et P ii et dosages par chromatographie liquide haute performance (CLHP) des deux principaux constituants, les pristinamycines P ia et P iia . Administrees en presence de nourriture, les pristinamycines sont absorbees rapidement, les temps d'apparition des concentrations plasmatiques maximales des composes P ia et P iia etant du meme ordre de grandeur : T MAX medians compris entre 0,5 et 1 heure. Les temps de demi-vie apparente d'elimination des pristinamycines IA et IIA, estimes au jour 1 du traitement par methode CLHP, sont respectivement de 1,9 ± 0,7 h et 1,3 ± 0,7 h. Les deux methodes analytiques RIA et CLHP donnent des resultats comparables pour decrire le profil cinetique des pristinamycines I, aussi bien en terme de vitesse d'absorption qu'en terme de biodisponibilite et de vitesse d'elimination. Les profils cinetiques des pristinamycines II, estimes par methode RIA et CLHP, sont tres differents puisque les valeurs moyennes des C MAX et SSC (0−t) de P ii trouvees par RIA sont approximativement 4,1 fois et 7,5 fois superieures aux donnees specifiques de P iia obtenues par CLHP. Cet ecart de valeurs entre les deux techniques de dosage est probablement du a la prise en compte, avec la methode RIA, de metabolites des pristinamycines II. La comparaison des parametres pharmacocinetiques, calcules a partir des donnees fournies par les deux methodes analytiques aux jours 1 et 8, met en evidence l'absence de modification de la pharmacocinetique des pristinamycines lors d'administrations repetees.

SummaryThe present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin®), nadroparin (Fraxiparin®), and enoxaparin (Love- nox®) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 2,500 IU (= 2,500 IU anti-Xa), nadroparin 7,500 ICU (= 3,075 IU anti-Xa), enoxaparin 20 mg (= 2,000 IU anti-Xa) and enoxaparin 40 mg (= 4,000 IU anti-Xa). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest®, anti-thrombin (aIIa) activity and anti-Xa (aXa) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aXa activity. We demonstrated that dalteparin, nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aXa), the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater (p < 0.001) than that of nadroparin and 2.28 times greater (p < 0.001) than that of dalteparin while the plasma amount induced by nadroparin is 1.54 times greater (p < 0.001) than that of dalteparin. The apparent total body clearance of enoxaparin doses (CL/F = 16.7 ± 5.5 and 13.8 ± 3.2 ml/min) is significantly smaller than those of nadroparin (CL/F = 21.4 ± 7.0 ml/min ; p < 0.01) and dalteparin (CL/F = 33.3 ±11.8 ml/min ; p < 0.001) while dalteparin apparent clearance is about 1.5-fold greater (p < 0.001) than that of nadroparin. These LMMHs also differ by their renal excretion pattern : more fragments exhibiting an anti-Xa activity are recovered in urine following enoxaparin doses (6.4 and 8.7 % of the dose, respectively) than following nadroparin (3.9 %) and dalteparin (3.4 %) injection. These differences in the disposition profiles explain why the apparent elimination half life t1/2 values of the LMMHs compared here are different: dalteparin: 2.8 h; nadroparin: 3.7 h; and enoxaparin: 4.1 h. Whether or not these differences may contribute to explain the different safety/efficacy balance of each of these antithrombotic medications remains to be discussed and needs further studies.

A single blind placebo controlled, cross-over study comparing a new microencapsulated potassium chloride tablet (MET) with two reference formulations of oral potassium, potassium chloride solution (PS) and potassium chloride wax-matrix tablets (WMT), was performed in 12 normal healthy volunteers. Urinary potassium excretion was the main criterion of comparison. Results showed that all three formulations have excellent bioavailability. This indicates that potassium absorption in the stomach is similar to that in more distant portions of the gut. The slow-release characteristics of both MET and WMT were confirmed. Clinical and pharmacological tolerance was excellent and no side-effects were reported with any of the potassium formulations studied.

As the therapeutic use of interferon-alpha (IFN-alpha) is limited by a dose-dependent toxicity and variable efficacy, ways of improving the therapeutic index of the cytokine are being sought. Murabutide (N-acetyl muramyl-L-alanyl-D-glutamine-O-n-butyl-ester) (ISTAC Biotechnology, Lille, France) is a safe synthetic and clinically acceptable immunomodulator that enhances the biologic activities of IFN-alpha in different experimental models. We evaluated in healthy human volunteers tolerance of the coadministration of Murabutide with increasing doses of IFN-alpha. The simultaneous administration of the two drugs was well tolerated without any increased or prohibiting toxicity, and all recipients experienced side effects that were similar to those observed after the administration of IFN-alpha alone. We also profiled the serum levels of cytokines induced following coinjection of the two drugs. We mostly detected an induction of anti-inflammatory cytokines and of human immunodeficiency virus type 1 (HIV-1)-suppressive beta-chemokines, in the absence of release of key proinflammatory cytokines. Therefore, the simultaneous administration of Murabutide and IFN-alpha is well tolerated and does not lead to increased toxicity. In addition, the selectivity in the profile of cytokines and chemokines induced following the coadministration of Murabutide and IFN-alpha points to the potential use of this combination in the treatment of inflammatory diseases and chronic viral infections.

The inhibition of platelet aggregation by clopidogrel, a novel platelet ADP-receptor antagonist, was evaluated in healthy male volunteers in two single-dose studies. In one study, 10 subjects received, in increasing order, single doses of 100, 200, 400 and 600 mg of clopidogrel or placebo in five study periods, according to a randomized, doubleblind, protocol design. In the second study, 12 subjects received a single 400 mg dose of clopidogrel as capsules and as tablets, according to an open-label, randomized, crossover design. The interval between the two administrations was seven days. Platelet aggregation induced by ADP (2, 5 and 10 microM) and by collagen (0.5 and 1 microg/mL; rising-dose study only) was assessed from blood samples collected over a period of 24 hours to 72 hours postdose. The inhibition of platelet aggregation was expressed as the mean percent change from baseline in maximum platelet aggregation. The effect of clopidogrel on bleeding time was also assessed. Clopidogrel induced a statistically significant inhibition of ADP-induced platelet aggregation at all doses. With 5 microM of ADP, the inhibition was dose-related up to a dose of 400 mg, with no further increase at a dose of 600 mg. At 2 hours, mean inhibition ranged from 12+/-6% (100 mg) to 42 +/-6% (400 mg), and at 24 hours, it ranged from 17+/-7% (100 mg) to 43+/-9% (400 mg). After 400 mg, the inhibition of platelet aggregation remained stable from 2 hours up to 72 hours, with mean percentages of inhibition ranging from 49 to 39%. Clopidogrel only showed a slight-to-moderate inhibitory effect on collagen-induced platelet aggregation. A mean bleeding time prolongation of 1.7 was observed 5 hours after the 400 mg and 600 mg doses; it was statistically significant only following the higher dose. Individual bleeding time prolongations ranged from 1 to 2.85. Clopidogrel was well tolerated at all doses. The results of these studies were part of the rational for the choice of the loading dose.

The potential influence of clopidogrel on the pharmacokinetics of theophylline was evaluated in 15 healthy male subjects during the pharmacokinetic steady state of theophylline, after single and multiple doses. Theophylline was administered orally as one 300-mg capsule in the morning before breakfast and one in the evening before dinner for 13 days (day 1 through day 13), and one capsule on the morning of day 14. Clopidogrel was administered orally as one 75-mg tablet in the morning before breakfast from day 5 through day 14. Plasma concentration of theophylline was determined at the following times: before the morning dose on days, 1, 6-9, and 12; before administration, then at 0.5, 1,2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after administration on days 4, 5, and 14. Tests of hemostasis (ADP-induced platelet aggregation and bleeding time) were carried out 2 hours after clopidogrel dosing on days 5, 7, 9, 11, and 14. The curves of the mean plasma concentration of theophylline over 12 hours post-morning dose on day 4 (drug alone), day 5 (after a single dose of clopidogrel), and day 14 (after 10 days of clopidogrel coadministration) were superimposable, indicating the absence of an effect of clopidogrel on the steady-state pharmacokinetics of theophylline. There were no statistically significant differences between the days of administration for the log-transformed values of theophylline C(bt) (concentration before treatment) Cmax, AUC(0-12h), and Cmin; and the 90% confidence intervals of the day 5/day 4, day 14/day 4, and day 14/day 5 ratios of the geometric means of C(bt) all fell within the (0.80; 1.25) interval. These results show that the administration of clopidogrel during steady state theophylline administration had no effect on the plasma concentration of the latter drug. The average steady-state (days 11-14) percentage of inhibition of ADP-induced platelet aggregation by clopidogrel with respect to day 1 was 46%. The geometric mean of the bleeding time prolongation factor was about 2 at steady state. The latter results indicate that the pharmacodynamics of clopidogrel were not affected by concomitant theophylline.

The pharmacokinetic pattern of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) during and after application of three strengths of a new transdermal estradiol patch (Dermestril) with active matrix was investigated in a cross-over study in 24 women in natural or surgical menopause. Free estradiol and estrone were assayed by GC-MS on plasma samples obtained during a 4-day application on the upper buttocks of the patches with 3 strengths and release rates of 25, 50 and 100 micrograms/day estradiol. The estradiol concentrations in plasma increased from 0-10 pg/ml typical of menopause to average concentrations of 23, 40 and 79 pg/ml during the application of the new estradiol transdermal patches with the three strengths. The concentrations of estradiol are in the range of those during the early follicular phase in women in fertile age. The increases were linearly related with the strength of the patches. Upon removal of the patches the estradiol concentrations returned to the basal low values in 8-24 h. Retarded with regard to estradiol, there was also an increase of estrone, from basal average concentrations of 22-32 pg/ml up to 31, 39 and 60 pg/ml. The increase of estrone was less pronounced than that of estradiol. Also estrone returned to its basal concentrations 24 h after removal of the patches. The estradiol/ estrone ratio from very low values typical of postmenopause increased to values of about 1, i.e. in the range of those found during the fertile age of woman. The adhesion of the patches was satisfying, provided that direct rough frictions were avoided. The patches were locally well tolerated, with rare mild and transient irritating effects on the skin. Also the systemic tolerability was good, with occasional mild or moderate side effects typical of estradiol (headache, mastodynia and pelvic heaviness) which in the practical use can be easily avoided by the application of patches of lower strength.

1. Mizolastine, a new benzimidazole derivative with potent selective, non-sedative H1-histamine antagonist activity was compared with terfenadine, cetirizine and loratadine using the histamine-induced wheal and flare model in healthy volunteers. 2. Study design was a five way double-blind crossover design using a single dose of mizolastine 10 mg, terfenadine 120 mg, cetirizine 10 mg, loratadine 10 mg and placebo. 3. Histamine tests were performed on 10 occasions up to +24 h after dosing using an intradermal injection of histamine 2 micrograms with concommittant contralateral injection of a saline control. 4. Mizolastine, terfenadine, cetirizine and loratadine significantly (P < 0.001 vs placebo) inhibited the wheal and flare formation starting 1 to 2 h after dosing up to 24 h after dosing. 5. Mizolastine was significantly more active than loratadine on the wheal (P < 0.01) and flare (P < 0.05) inhibition from 3 up to 6 and 8 h respectively, as active as terfenadine on both parameters and as active as cetirizine on wheal inhibition while less active (P < 0.01) than cetirizine on flare inhibition at 2 and 12 h post-dosing.

The pharmacokinetics of sparfloxacin at oral doses of 200, 400, 600, and 800 mg were studied in 12 healthy volunteers in a randomized double-blind crossover study. Each dose administration was separated by a 1-week washout period. Plasma and urine samples were collected up to 120 hours postdosing, for determination of free and total (free plus glucurono-conjugated) sparfloxacin levels by high-performance liquid chromatography assay and ultraviolet detection. Mean Cmax values ranged from 705 +/- 158 to 1966 +/- 620 ng/mL for the 200 to 800 mg doses, at median tmax ranging from 4 to 5 hours. A slight decrease of sparfloxacin bioavailability with increasing dose was observed because AUC was 87% to 88% of the expected area when the dose was doubled. The elimination half-life values were constant over the dose range (with values ranging from 18 to 21 hours) as well as the renal clearance. The metabolic ratio conjugated/free drug was not modified by increasing dose.

The antihistaminic activity, clinical safety, and pharmacokinetics of mizolastine (SL 85.0324) were studied in a 5-way, double-blind crossover study of ten healthy volunteers with doses of 1 to 75 mg. Inhibition of the histamine-induced wheal and flare showed clear dose-dependent antihistaminic activity beginning from the 2-mg dose with a maximum attained between 10 and 20 mg. The onset of action was rapid (one hour) and the effect persisted for more than 24 hours after a 10-mg dose or more. Mizolastine was well tolerated at doses up to 75 mg; subjective and objective signs of transient sedative activity were not observed at doses below 30 mg. The pharmacokinetic profile (rapid absorption with Tmax congruent to 1 h and elimination T1/2 of about eight hours) parallels the pharmacodynamic activity. Within the considered dose range, the pharmacokinetics was linear with no saturation phenomena.

A bioequivalence study between a new Levothyroxine solution and a reference solution was performed in 12 healthy volunteers after one single 3000 g oral administration. Administrations were done according to a cross-over schedule with a three week wash-out period. Plasma profile of Levothyroxine was determined for 72 hours, clinical tolerance being appreciated for 10 days after each administration. No statistical difference was reported for pharmacokinetic parameters and clinical tolerance was good.

The single dose pharmacokinetics of pyrimethamine were determined in 12 healthy young volunteers using a newly developed fully automated analytical system which combines liquid solid extraction on disposable extraction columns and high performance liquid chromatography. This technique is highly sensitive (detection 1 ng/ml) and reproducible. Following a 50mg dose of the drug, the plasma concentration peaked at 0.48 0.13 g/ml (msd) and was attained 2.5 hours (median value) post dosing. Thereafter, the plasma level of pyrimethamine decreased slowly, the level at 336 hours after administration being still about 40 ng/ml. The area under the plasma concentration-time curve (AUC0-inf) was 56.8 18.4 h.mg/ml. The volume of distribution Vd was: 2.42 1.25 l/kg and the total clearance: 15.55 4.48 ml/h/kg. Urinary excretion represented about 20% to 40% of the dose after seven days of the administered dose.

Food-induced changes in the absorption of Theostat 300, a controlled release formulation of theophylline, have been studied in healthy volunteers. This open, randomised, 3-way, single-dose study involved 12 volunteers who received the drug either while fasting, or with a standardised low-fat (10g), or high-fat (60g) breakfast. Each subject was studied over a 3-week period, with 3 separate days of oral treatment and a 7-day washout period between treatments. The results showed no differences in AUC0-24 and tmax values between the 3 kinds of diet. The only differences observed concerned absorption. Food intake increased Cmax values by 20%. The steady-state peak concentration obtained by means of simulated plasma levels was not influenced by food intake. This slight food-drug interaction of Theostat 300 seemed to be of no clinical significance.

Studies are reviewed of the inhibitory effect of flurbiprofen, given in doses ranging from 50 mg to 200 mg per day for 1 week, on platelet aggregation measured by biological tests (adenosine diphosphate and collagen methods). Flurbiprofen at doses of 50 mg and 100 mg daily had a peak time of action of between 1 and 2 hours, the effects usually disappearing after 24 hours, and 100 mg flurbiprofen caused a similar decrease in platelet aggregation to 1 g aspirin daily. In a clinical study of 72 patients with chronic glomerulonephritis treated with doses of flurbiprofen up to 200 daily there was a significant correlation between the parameters of aggregation measured and treatment, and between proteinuria and adenosine disphosphate aggregation when the flurbiprofen dose did not exceed 100 mg daily.

Pharmacokinetics of ornidazole, a nitroimidazole derivative, was studied after intravenous injection in 10 patients with severe alcoholic cirrhosis and 10 healthy volunteers. Plasma concentrations of ornidazole and its two major hydroxylated metabolites, M1 (alpha-(chloromethyl)-2-hydroxymethyl-5-nitroimidazole-1-ethanol) and M4 (3-(2-methyl-5-nitroimidazole 1-yl) 1,2 propane diol), were measured by HPLC. The t1/2 of ornidazole was 14.1 +/- 0.5 hours for normal subjects and 21.9 +/- 2.9 hours for patients with cirrhosis. Mean plasma clearance was 50.6 +/- 2.1 ml/min in control subjects and 34.9 +/- 4.9 ml/min in patients, whereas apparent V SS was not modified in hepatic insufficiency. In healthy volunteers, M1 and M4 levels are well below levels of the parent drug; in cirrhosis both metabolites accumulate in plasma as a result of decreased elimination. Hepatic cirrhosis prolongs ornidazole elimination, and to avoid cumulation the interval between repeated doses could be doubled.

Dilitazem, a coronary vasodilating agent, after oral administration of four different doses, was well and rapidly absorbed. The pharmacokinetics of the drug followed a two-compartment model, with a rapid distribution and an elimination with a half-life of 4-7 hours. After chronic treatment the pharmacokinetic parameters were practically unchanged and therefore no accumulation of the drug was observed. The comparison between capsule and tablet preparations showed that both forms had a similar bioavailability. Diltiazem was extensively metabilized and only a few percent of the drug was found in urine. Several metabolites, also present as conjugates, have been identified by means of gas chromatography-mass spectrometry.

(+/-)-1-(Isopropylamino)-3-[p-(2-cyclopropyl-methoxyethyl)-phenoxy]-2-propanol HCl (betaxolol, SL 75212) was given to groups of healthy volunteers, 10 mg daily for 7 days followed by 20 mg daily 7 days in one group, and increasing daily doses up to 60 mg/day for a total of 15 days in the other group. The pharmacokinetics were studied during dosing and in the washout period. The pharmacokinetic characteristics were unchanged after repeated doses, T/2 16-22 h, Vd 7.7-8.8 l/kg; clearance 0.28-0.33 l/h/kg.