Determination of fosmidomycin in human serum and urine by capillary electrophoresis.

A capillary electrophoresis method with direct UV detection was developed for the determination of fosmidomycin, a promising new anti-malarial drug, in human serum and urine. Optimization of the separation parameters resulted in a buffer system adjusted to pH 10.8 containing a cationic reagent and an organic modifier. Under these conditions, the migration time of fosmidomycin was 5.2 min with serum and 7.4 min with urine samples. Validation of the method revealed good recoveries, precision and accuracy. The limit of quantification was 0.5 microg/ml in serum and 10 microg/ml in urine. The determination of fosmidomycin in serum was linear over a range of 0.1-150 microg/ml. Short and long-term stability tests resulted in no significant loss of fosmidomycin. The described technique will provide a fast and accurate analytical method for future pharmacokinetic studies.

Amatoxins in wood-rotting Galerina marginata.

Amatoxins, bicyclic octapeptide derivatives responsible for severe hepatic failure, are present in several Basidiomycota species belonging to four genera, i.e. Amanita, Conocybe, Galerina and Lepiota. DNA studies for G. autumnalis, G. marginata, G. oregonensis, G. unicolor and G. venenata (section Naucoriopsis) determined that these species are the same, supporting the concept of Galerina marginata complex. These mostly lignicolous species are designated as white-rot fungi having a broad host range and capable of degrading both hardwoods and softwoods. Twenty-seven G. marginata basidiomes taken from different sites and hosts (three sets) as well as 17 A. phalloides specimens (three sets) were collected in French locations. The 44 basidiomes were examined for amatoxins and phallotoxins using high-performance liquid chromatography. Toxinological data for the wood-rotting G. marginata and the ectomycorrhizal A. phalloides species were compared and statistically analyzed. The acidic and neutral phallotoxins were not detected in any G. marginata specimen, whereas the acidic (ß-Ama) and neutral (α-Ama and γ-Ama) amanitins were found in all basidiomes from either Angiosperms or Gymnosperms hosts. The G. marginata amatoxin content varied from 78.17 to 243.61 µg.mg(-1) of fresh weight and was elevated significantly in one set out of three. The amanitin amounts from certain Galerina specimens were higher than those from some A. phalloides basidiomes. Relationship between the amanitin distribution and the chemical composition of substrate was underlined and statistically validated for the white-rot G. marginata. Changes in nutritional components from decayed host due to enzymatic systems and genetic factors as well as environmental conditions seem to play a determinant role in the amanitin profile. Variability noticed in the amanitin distribution for the white-rot G. marginata basidiomes was not observed for the ectomycorrhizal A. phalloides specimens.

The effect of rifampin on the pharmacokinetics of vinorelbine in the micropig.

BACKGROUND: Vinorelbine has been shown to be metabolised by CYP3A4 in vitro. To evaluate the impact of CYP3A in the disposition of vinorelbine in vivo, we compared the kinetics of the alkaloid given intravenously alone and combined with rifampin, a potent CYP3A inducer, in the micropig. ANIMALS AND METHODS: Four healthy Yucatan micropigs, about 20 kg, received a first infusion of vinorelbine (0.5 mg/kg). During the next week they were injected rifampin (600 mg daily) and a second vinorelbine infusion (0.5 mg/kg) on the 7th day of rifampin dosing. Serum concentrations of vinorelbine and rifampin were measured by high performance liquid chromatography. RESULTS: The mean peak concentrations of vinorelbine were 274.2 ng/ml (Standard Deviation or SD: 90) and 458 ng/ml (SD: 448), the mean areas under the serum concentration-time curve were 8,344 ng.min.ml-1 (SD: 2,604) and 14,093 ng/ml.min-1 (SD: 10,000) and the total clearances were 1.146 l/min (SD: 0.333) and 1.003 l/min (SD: 0.714) when the Catharanthus alkaloid was given alone or was combined with rifampin, respectively. CONCLUSION: We did not observe an increase in vinorelbine elimination by rifampin related to a CYP3A induction in an animal model physiologically close to humans. Although the number of animals was small, these results suggest that CYP3A metabolism constitutes a minor pathway of elimination of intravenous vinorelbine in the micropig.

Moxifloxacin efficacy and vitreous penetration in a rabbit model of Staphylococcus aureus endophthalmitis and effect on gene expression of leucotoxins and virulence regulator factors.

Bacterial endophthalmitis is a serious complication of ocular surgery and of eye trauma; the leading causative organisms are Staphylococcus aureus strains. Tissue damage is due both to the host inflammatory response and to toxin synthesis by bacteria. Systemic treatment remains difficult because most antibiotics show poor ocular penetration. Moxifloxacin (MXF), a novel fluoroquinolone, was evaluated for its penetration into the vitreous of normal rabbit eyes and of eyes of rabbits infected for 24 h with methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA) following a single intravenous administration of 5 or 20 mg/kg. MXF penetration was rapid and efficient regardless of the dose, ranging from 28 to 52%. An inflammatory state of the vitreous significantly increased penetration after the 20-mg/kg dose, with penetration reaching 52%. Concentrations determined in the vitreous cavity following a 20-mg/kg administration showed a 3.5-fold decrease of the bacterial density within 5 h for MSSA (MIC, 0.125 micro g/ml) and a 1.6-fold decrease for MRSA (MIC, 4 micro g/ml) strains, respectively. By using a semiquantitative reverse transcription-PCR method, the expression of luk-PV and hlgCB, but not hlgA, encoding staphylococcal leukotoxins, was detected in the vitreous without MXF treatment. A slight decrease in the expression of leucotoxins and sarA, agr, and sigB virulence regulatory factors was observed 1 h following the administration of 5 mg of MXF per kg.