Clinical tolerance and profile of cytokine induction in healthy volunteers following the simultaneous administration of ifn-alpha and the synthetic immunomodulator murabutide.

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.

Improved delivery of ipratropium bromide using Respimat (a new soft mist inhaler) compared with a conventional metered dose inhaler: cumulative dose response study in patients with COPD.

Respimat (RMT) is a reusable, propellant-free, soft mist inhaler (SMI), a novel device for inhalation therapy. We conducted a three-period cross-over study to evaluate the safety and efficacy of cumulative doses of ipratropium bromide inhaled from RMT (Two dose levels) or from a pressurized metered dose inhaler (MDI), in 36 patients with chronic obstructive pulmonary disease (COPD). The bronchodilator effect of ipratropium bromide was greater when administered via RMT (10 or 20 microg per puff, given double-blind within device, to total doses of 160 or 320 microg) than via MDI (20 microg per puff, total dose 320 microg). The bronchodilator effects of the 160 and 320 microg doses delivered via RMT were similar. Cumulative ipratropium bromide doses of 320 microg given via MDI or RMT and 160 microg given via RMT produced similar safety profiles. Between 45 min after the first drug inhalation and 45 min after the final dose, greater bronchodilatory effect was obtained from half the cumulative dose of ipratropium (RMT 10 microg per puff) when compared with the MDI (20 microg per puff). Therefore, ipratropium bromide delivered by RMT is as safe as, and can be more effective than, the MDI on acute administration in patients with COPD.

Pharmacokinetics of estradiol valerate 2mg + dienogest 2mg (climodien® 2/2) after single and repeated oral administration in healthy postmenopausal women.

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 R(1) = 3.3) and free estrone (R(1) = 2.4) was higher than that predicted from single-dose data (R(theor) = 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 (R(1) and R(theor) = 1.5). The pharmacokinetics of dienogest were not time dependent, the observed accumulation (AUC(0-24h) 627 vs 483 µg/L · h) was as predicted from single-dose results (R(1) and R(theor) = 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.

Repeated-dose pharmacodynamics of clopidogrel in healthy subjects.

The effect of repeated doses of clopidogrel, a novel platelet ADP-receptor antagonist, on platelet aggregation and its tolerance were assessed in two randomized, double-blind studies in healthy male adults. In each of the four successive dose groups in Study I, 6 subjects received either clopidogrel 25, 50, 100, or 150 mg once daily and 2 received placebo for 16 days, according to a rising dose design. In each of the three successive treatment groups of Study II, 9 subjects received clopidogrel (50, 75, or 100 mg once daily) in the morning, 3 received triclopidine 250 mg twice daily and 3 received placebo for 14 days. In both studies, the inhibition of platelet aggregation induced by 5 microM of ADP was measured before dosing (baseline), then at regular intervals during and after treatment. Bleeding time was generally assessed at the same time points as platelet aggregation. In both studies, the inhibition of platelet aggregation reached steady state after day 6 dosing. Mean steady-state percent inhibition of platelet aggregation was 30%, 46%, 53%, and 73% for clopidogrel 25, 50, 100, and 150 mg, respectively, in Study I; and 54%, 52%, 47%, and 43% for clopidogrel 50, 75, 100 mg, and for ticlopidine, respectively, in Study II. After treatment discontinuation, statistically significant inhibition of platelet aggregation persisted for up to 8 days. In Study I, up to 75 mg repeated doses, mean bleeding time prolongation factor did not exceed 2, but increased further to 3.5 and 5.5 at a clopidogrel dose of 100 mg and 150 mg, respectively. In study II, prolongation factors during treatment did not exceed 2.2 for clopidogrel (in the 75 mg dose group) and 1.6 for ticlopidine 500 mg. Recovery of bleeding time was observed within 7-8 days. Treatments were well tolerated, and no serious clinical events or important changes in laboratory parameters were recorded. These data were consistent with those obtained in atherosclerotic patients and showed that the plateau response for the inhibition of platelet aggregation was reached at the 75 mg dose, for which bleeding time prolongation was approximately 2.

Single-dose pharmacodynamics of clopidogrel.

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.

Clopidogrel does not affect the pharmacokinetics of theophylline.

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.

Pharmacokinetics of estradiol and of estrone during application of three strengths of an estradiol transdermal patch with active matrix.

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.

Comparative wheal and flare study of mizolastine vs terfenadine, cetirizine, loratadine and placebo in healthy volunteers.

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.

Comparison of the pharmacokinetic profiles of three low molecular mass heparins--dalteparin, enoxaparin and nadroparin--administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism).

The 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 (Lovenox) 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.

Pharmacokinetics of sparfloxacin in humans after single oral administration at doses of 200, 400, 600, and 800 mg.

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.

[Gastroduodenal tolerance of methylprednisolone. Study of oral versus intravenous administration in healthy volunteers]. / Tolérance gastro-duodénale de la méthylprednisolone. Etude de la voie orale versus voie veineuse chez le volontaire sain.

OBJECTIVES: To endoscopically evaluate the tolerance of gastroduodenal mucosa to methylprednisolone given orally and intravenously. METHODS: Thirty two healthy volunteers (age range 18-39 years) were divided randomly into two groups of 16 each (8 males and 8 females). All were Caucasians, gave their informed consent and were considered normal after a complete clinical and laboratory work-up including gastroduodenal fibroscopy. Methylprednisolone (500 mg) was administered for three consecutive days at 9 a.m., orally in one group and intravenously in the second group. No other drugs were being taken and alcohol and smoking were prohibited from day 0 to day 11. Tolerance was evaluated on days 4 and 11 based on clinical examination, blood pressure, heart rate, oral temperature, body weight, blood and urine chemistry and by video-recorded gastroduodenal endoscopy. Two independent endoscopists, uninformed of the patient's regimen, scored lesions from 0 (normal) to 5 (more than 25 lesions including at least 2 erosions). In case of abnormal findings, follow-up was continued to normalization. RESULTS: Endoscopically detectable lesions (stage I) attributed to corticosteroid therapy were observed in 4 subjects in the oral group and in 5 in the intravenous group. All regressed spontaneously. Duodenal lesions were observed only after oral administration while lesions of gastric mucosa were mostly found after intravenous administration. Systemic effects included abdominal pain after oral intake, 1 case of insomnia and bitter taste in the mouth after intravenous administration. CONCLUSIONS: These findings suggest that the effect of corticosteroid therapy, on the gastric mucosa, is basically systemic, and on the duodenal mucosa, basically local. No severe manifestations were observed after high-dose methylprednisolone given orally or by intravenous injection.

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)

EEG profile of litoxetine after single and repeated administration in healthy volunteers.

1. Litoxetine is a selective serotonin reuptake inhibitor with antidepressant activity in animal models and in depressed patients. 2. This double-blind, cross-over, placebo-controlled study was carried out in 12 healthy young male volunteers. The aim was to assess the EEG profile of litoxetine in parallel with its pharmacokinetics after a single dose or multiple administrations for 4 days (6 doses) of two dosages (10 mg and 25 mg). Spectral analysis of four EEG leads (F4-T4, F3-T3, T4-02 and T3-01) was done up to 12 h post-dose. 3. In single or multiple doses, litoxetine induced EEG changes characterised by a dose-related increase in fast beta energies, mainly beta 2, without any changes in slow waves (delta and theta). A slight reduction in alpha activity occurred only after repeated doses. 4. EEG changes occurred after a single oral administration and lasted at least 12 h with litoxetine blood concentrations ranging from 4 to 10 ng ml-1. With repeated administrations, the pharmacodynamic steady-state was achieved as the increase in beta 2 energies was the same before and 12 h post-dose. These effects occurred with litoxetine blood concentrations ranging from 3 to 7 ng ml-1 with the 10 mg dosage and from 8 to 18 ng ml-1 with the 25 mg dosage. The EEG profile did not change after 4 days of repeated administration, indicating that tolerance did not develop. 5. Cmax and AUC showed proportionality between the administered dosages of 10 and 25 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of 2-(alpha-thenoylthio)-propionylglycine (TTPG) in healthy volunteers--an oral dose-proportionality investigation.

The dose linearity of 2-(alpha-thenoylthio)-propionylglycine (TTPG) pharmacokinetics after a single oral administration at three different TTPG doses (180, 540 and 1080 mg) was evaluated in 12 healthy volunteers according to an open, randomized, cross-over study with a 1-week wash-out period between each administration. The duration of the study, for each subject, was 4 weeks. Plasma concentration and urinary excretion of TTPG and its two systemic metabolites, namely propionylglycine (tiopronin) and thiophenecarboxylic acid (TCA) were assayed by a previously well validated HPLC method. Due to differences in the physical and chemical properties of these compounds, two assays were needed, one to measure TTPG and TCA as such, and one to measure derivatized tiopronin. Both used UV detection. TTPG, tiopronin and TCA were quickly detected in plasma, suggesting that the drug administered is rapidly absorbed and biotransformed, in part, in the systemic circulation into the two metabolites noted above. Time-to-peak for all three analytes showed a trend to increase with increasing doses of TTPG, being: 0.42, 0.40 and 0.67 h (P < 0.01) with TTPG; 0.53, 0.47 and 0.73 h (P < 0.05) with TCA; and 1.33, 2.13 and 2.58 h (P < 0.01) with tiopronin. Cmax showed the opposite behaviour with values (ng ml-1) normalized to the dose of 540 mg: 1235, 905 and 513 (P < 0.001) with TTPG; 888, 547 and 383 (P < 0.001) with TCA; and 7290, 6950 and 5170 (P < 0.01) with tiopronin.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamics and pharmacokinetics of mizolastine (SL 85.0324), a new nonsedative H1 antihistamine.

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.

The pharmacokinetics of tiopronin and its principal metabolite (2-mercaptopropionic acid) after oral administration to healthy volunteers.

We have studied the pharmacokinetics of tiopronin and its principal metabolite, 2-mercaptopropionic acid (2-MPA) in healthy volunteers after the oral administration of 500 mg (2 Acadione tablets), followed by simultaneous assay of the two compounds in plasma over a period of 48 h using a new method (emission of fluorescence after HPLC and post-column derivatization by pyrene-maleimide). The absorption of tiopronin was slow (tmax between 4 and 6 h) and the plasma concentrations subsequently fell biexponentially. The principal metabolite 2-MPA appeared later in the plasma (tmax between 10 and 12 h after a lag-time of 3 h) then disappeared monoexponentially. About 15% of the tiopronin was metabolized to 2-MPA.

A single blind normal volunteer bioavailability study of a new microencapsulated potassium chloride tablet compared with two reference potassium formulations.

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.

Pharmacokinetics of pyrimethamine in healthy young volunteers using a new solid phase extraction/HPLC method.

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.

Comparative bioequivalence study of a new levothyroxine solution versus a reference L-thyroxine solution in normal healthy volunteers.

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.

Comparative bioavailability study of cefixime administered as tablets or aqueous solution.

The relative bioavailability of cefixime was studied in 24 healthy male volunteers, with each subject receiving a single 400mg dose of cefixime administered as an aqueous solution, a 400mg tablet and two 200mg tablets, in a randomised crossover sequence. Serum and urine samples were analysed using high-performance liquid chromatography. Peak cefixime levels were achieved 3 hours after administration of the solution vs 4 hours for the 2 tablet formulations; however, the extent of absorption was only slightly improved with the solution (by 14 and 7% compared with the 1 x 400 and 2 x 200mg tablets, respectively). The 400mg and 2 x 200mg tablets were found to be bioequivalent. The pharmacokinetic profile of the 400mg cefixime tablet (mean maximum plasma concentrations of 4.4 mg/L at 4 hours, area under the concentration-time curve of 34.4 mg/L.h, and apparent terminal elimination half-life of 3.7 hours) supports the clinical evaluation of a 400mg once-daily dosage regimen for cefixime.