Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: first-in-human studies.

Background And Objectives: Fexinidazole is a 5-nitroimidazole recently included in a clinical efficacy trial as an oral drug for the treatment of human African trypanosomiasis (HAT). Preclinical studies showed it acts as a pharmacologically active pro-drug with two key active metabolites: sulfoxide and sulfone (the most active metabolite). The present studies aimed to determine the best dose regimen for the treatment of stage 2 sleeping sickness patients, which could eventually also treat stage 1 patients.

Effect of rifabutin on ethambutol pharmacokinetics in healthy volunteers.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of ethambutol was evaluated in ten healthy volunteers. The subjects received a single oral administration of 1200 mg ethambutol on days 1 and 10 and a single daily oral dose of 300 mg rifabutin from days 3 to 9. No statistically significant difference was found in plasma pharmacokinetics (C(max), t(max), AUC, half-life and MRT) and in the renal clearance, whereas a significant decrease in the amount of unchanged ethambutol excreted in urine was observed.

A study of the pharmacokinetics and tolerability of ritipenem acoxil in healthy volunteers following multiple oral dosing.

The pharmacokinetics of ritipenem acoxil, the oral prodrug of the antibiotic ritipenem, were studied in volunteers after single and repeated dosing (500 mg, three times daily for 10 days). Concentrations of ritipenem and open beta-lactam ring metabolites were measured using HPLC/UV. Ritipenem did not accumulate significantly in plasma, owing to its half-life of about 0.

Early bactericidal activity of rifabutin versus that of placebo in treatment of disseminated Mycobacterium avium complex bacteremia in AIDS patients.

Rifabutin, 600 mg/day, was compared with a placebo in the early treatment of culture-proven Mycobacterium avium bacteremia in patients with AIDS. Following 14 days' treatment, bacteriological success, defined as a negative culture or a reduction in the number of CFU of M. avium organisms per milliliter of blood by a factor of > or = 0.

Rifabutin versus placebo in combination with three drugs in the treatment of nontuberculous mycobacterial infection in patients with AIDS.

The aim of this double-blind, randomized, placebo-controlled, 12-week study was to assess the efficacy of rifabutin (450 or 600 mg/d) in the treatment of disseminated nontuberculous mycobacterial infection in patients with AIDS. Companion drugs in both arms of the study were ethambutol, clofazimine, and isoniazid. Because of low accrual, the study was prematurely terminated when a total of 382 patients had been enrolled, of which 200 were eligible (i.

Clinical experience with rifabutin in the treatment of mycobacterial infections.

Effective new therapies are required to combat the increasing incidence of mycobacterial infections. Rifabutin has been investigated in studies conducted in various countries around the world, and in the treatment of tuberculosis rifabutin in combination regimen has been shown to be as effective as rifampicin. Rifabutin is active in approximately 30% of patients with tuberculosis resistant to standard therapies, including rifampicin and/or isoniazid.

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers.

FCE 22891 is a prodrug of the penem antibiotic FCE 22101 and is suitable for oral administration. The pharmacokinetics of FCE 22891 were investigated in four healthy male volunteers following the oral administration of 500 mg of [14C]FCE 22891. Levels of radioactivity in plasma were always higher and persisted for longer than those of FCE 22101.

A study of the effects of rifabutin on isoniazid pharmacokinetics and metabolism in healthy volunteers.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of isoniazid was evaluated in 6 healthy volunteers. The subjects received on day 1 and 9 a single oral dose of 300 mg isoniazid and from day 2 to 8 a single daily oral dose of 300 mg rifabutin. Two out of 6 subjects were shown to be rapid acetylators.

Autoinduction of rifabutin metabolism in man.

1. The pharmacokinetics of the antimycobacterial agent rifabutin were studied in healthy volunteers, following single (450 mg) and repeated (450 mg once daily for 10 days) oral administration. 2.

Pharmacokinetics in healthy subjects of FCE 22101 and its acetoxymethyl ester, FCE 22891: effect of co-administration of imipenem/cilastatin on the renal metabolism of FCE 22101.

The pharmacokinetics of FCE 22101 were studied in eight healthy male subjects who received FCE 22101 intravenously alone or together with imipenem/cilastatin which was given to inhibit dehydropeptidase-I, a renal enzyme metabolizing penem and carbapenem antibiotics. The kinetics of FCE 22101 were also studied following oral administration of its acetoxymethyl ester, FCE 22891. For comparative purposes, the kinetics of imipenem and cilastatin, given alone or together with FCE 22101, were calculated.

Urinary recovery and tolerability of FCE 22101 following single intravenous administration under restricted and high fluid intake.

The urinary recovery and tolerability of FCE 22101, a broad spectrum injectable penem, were investigated in a multicentre single-blind randomized crossover study of 60 healthy male volunteers. Single 1 g doses of FCE 22101 or placebo were given by intravenous bolus at weekly intervals. FCE 22101 was given either after intake of 750 ml water (treatment A) or after 8 h of water restriction (treatment B).

Pharmacokinetics and tolerance of a new penem antibiotic, FCE 22101, in healthy volunteers after a single intravenous dose.

The clinical tolerance and pharmacokinetics of FCE 22101 (sodium (5R, 6S)-6-[(1R)-hydroxyethyl]-2-carbamoyloxymethyl-2-penem-3-carboxylate), a new penem antibiotic, have been studied after giving a single i.v. dose of 4 mg.

Comparative effects of roxithromycin and erythromycin on cellular immune functions in vitro. 2. Chemotaxis and phagocytosis of 3H-Staphylococcus aureus by human macrophages.

The in vitro effects of roxithromycin on human macrophage activity were compared with those of erythromycin. Half the MIC of roxithromycin significantly enhanced the phagocytosis of 3H-labelled Staphylococcus aureus by human macrophages. Bacterial phagocytosis was also increased after pre-incubation of staphylococci with roxithromycin.

Toxicity, uptake, and subcellular distribution in rat hepatocytes of roxithromycin, a new semisynthetic macrolide, and erythromycin base.

Rat hepatocytes were used to study the toxicity of a new semisynthetic macrolide, roxithromycin, in comparison with erythromycin base and erythromycin estolate. Roxithromycin caused lactate dehydrogenase leakage close to that of erythromycin estolate and higher than erythromycin base after 21 h of exposure to the drugs. This effect was, at least in part, explained by the higher uptake: roxithromycin was two to three times more concentrated by liver cells than erythromycin base.

Roxithromycin disposition in tonsils after single and repeated administrations.

Levels of roxithromycin in serum and tissue were investigated in 29 subjects undergoing tonsillectomy. A total of 13 subjects received a single oral dose of 300 mg, and 16 received four oral doses 12 h apart as follows: a 300-mg loading dose followed by three 150-mg doses. Measurable levels of roxithromycin were present in tonsil samples of 11 of 13 subjects in the first group.

Effects of roxithromycin, a new semisynthetic macrolide, and two erythromycins on drug metabolizing enzymes in rat liver.

The effects of a new semisynthetic macrolide, roxithromycin, on drug metabolizing enzymes of rat liver were compared with two erythromycins, the base (EB) and the estolate (EE), after 7 days' treatment with high oral doses (400 and 800 mg/kg daily). Dose-related higher concentrations of roxithromycin were reached in serum and liver than after EB or EE. The two reference erythromycins induced the synthesis of microsomal enzymes and formed inactive cytochrome P-450-metabolite complexes.

Gastric antisecretory and cytoprotective activity of MDL 646, a 16-methyl-16-methoxy prostaglandin E1 analog in man.

MDL 646 is a 16-methyl-16-methoxy PGE analog with gastric antisecretory and cytoprotective activity in rats following oral administration. The efficacy of MDL 646 in inhibiting pentagastrin-stimulated acid secretion in man was investigated in a pilot crossover study in 10 male subjects given single oral doses of 500-1,000 mcg of the compound or placebo in randomized order. The doses showing consistent antisecretory effects in all subjects were 800 and 1,000 mcg, which caused a reduction in acid output of at least 25% over the whole test period (2.

Double-blind multicenter trial of a rifampicin-trimethoprim combination and rifampicin alone in urinary tract infections.

A double-blind multicenter trial was carried out in 146 patients with urinary tract infections in order to compare the combination of rifampicin and trimethoprim (450 mg plus 120 mg twice daily) with rifampicin alone (450 mg twice daily). The success rate on the day after a 10-day course of treatment was significantly higher after the combination than after rifampicin alone (72% of 60 cases vs. 45% of 55 cases).

Plasma levels and urinary elimination of diftalone, paracetamol, and their metabolites after single oral administration in man.

The plasma levels of diftalone, its metabolite 7-hydroxydiftalone, unconjugated and total paracetamol have been assessed in 6 healthy volunteers after oral administration of diftalone 0.75 g and of paracetamol 1.0 g, given alone and in combination in a cross-over fashion.