Philippe Courtois

Nephrotoxicity of gentamicin and vancomycin given alone and in combination as determined by enzymuria and cortical antibiotic levels in rats.

The purpose of this study was to compare the nephrotoxicity of gentamicin and vancomycin alone and in combination. Thirty-two male Sprague-Dawley rats were randomized into 4 groups of 8 animals. Each group received 200mg/kg gentamicin (G) i.m., or 300 mg/kg vancomycin (V) i.v., or an association of 200 mg/kg gentamicin + 300 mg/kg vancomycin (i.m. and i.v., respectively), or 0.9% NaCl solution i.m. and i.v. (controls). To determine AAP, GGT, and NAG enzyme excretions, urine samples were taken over 24-h periods before and after the start of the experiment. A single renal cortical sample was obtained at necropsy for quantitation of antibiotic levels. No significant modifications of urinary excretions of creatinine and enzymuria were noted during the 24-h period before each drug administration or in controls. AAP, GGT, and NAG excretions were significantly increased after G and G + V injections (p < 0.001), whereas only AAP and GGT were statistically higher in rats receiving V (p < 0.05). NAG elimination (mean +/- SD) was higher in G + V (16.0 +/- 0.2 IU/mmol creatinine/24 h; p < 0.001) than g (8.8 +/- 0.6) or V (1.7 +/- 0.2). Surprisingly, mean vancomycin cortical levels decreased in the combination (827 +/- 131 vs. 1964 +/- 23 micrograms/g for V alone; p < 0.001), whereas gentamicin concentration was unchanged (826 +/- 66 vs. 839 +/- 28 micrograms/g for G alone). Determination of enzymuria allowed the nephrotoxicity of the antibiotics to be graded in the following order: vancomycin + gentamicin > gentamicin > vancomycin.

Aluminum transfer as glutamate complex through blood-brain barrier: possible implication in dialysis encephalopathy.

In vitro distribution of aluminium between plasma and erythrocytes has been studied in the presence of variable amounts of sodiuml-glutamate. With a red blood cell suspension in isotonic sodium chloride, aluminium remains confined in erythrocytes even when the sodiuml-glutamate concentration increases in the medium.Aluminium initially present in plasma penetrates red blood cells when sodiuml-glutamate increases in whole blood, showing that this metal is able in vitro to cross the erythrocyte membrane as glutamate complex. In vivo experiments with male Wistar rats prove that aluminium is also able to pass the blood-brain barrier as glutamate complex and deposit in the brain cortex.

Imipenem but not meropenem induces convulsions in DBA/2 mice, unrelated to cerebrospinal fluid concentrations

Abstract— Imipenem and meropenem CSF diffusion was comparable in DBA/2 mice but only imipenem induced convulsions, not related to CSF concentration.

Pharmacokinetic-pharmacodynamic modelling of the convulsant interaction between norfloxacin and biphenyl acetic acid in rats

Fluoroquinolones (FQs) are associated with a low incidence of central nervous system (CNS) side effects, possibly leading to convulsions, especially when co‐administered with nonsteroidal anti‐inflammatory drugs (NSAIDS). Although the in vivo pro‐convulsant activity of NSAIDS is essentially unknown, the convulsant potential of FQs is traditionally evaluated by in vitro γ‐aminobutyric acid (GABA) binding experiments in the presence of 4‐biphenyl acetic acid (BPAA), the active metabolite of fenbufen. The aim of this study was therefore to investigate the BPAA‐norfloxacin convulsant interaction in vivo. Male Sprague‐Dawley rats (n=27) were given BPAA orally, at various doses 1 h before norfloxacin infusion, which was maintained until the onset of maximal seizures, when cerebrospinal fluid (CSF) and plasma samples were collected for analysis. An inhibitory Emax effect model with a baseline effect parameter was fitted to the norfloxacin versus BPAA concentrations in the CSF, previously shown to be part of the biophase. This model includes three parameters: the concentrations of norfloxacin in the absence of BPAA (CCSF0, Nor), and when BPAA concentration tends toward infinity (CCSFbase, Nor), and the BPAA concentration for which half of the maximal effect is observed (CCSF50, BPAA). The maximal proconvulsant effect of BPAA is given by the CCSF0, Nor / CCSFbase, Nor ratio, estimated to approximately 6 in this study. Derived models were developed in plasma to account for the non‐linear CSF diffusion of norfloxacin and protein binding of BPAA. In conclusion this study has shown that the convulsant interaction between norfloxacin and BPAA in rats, can be adequately characterized by modelling of the CSF concentrations of the two drugs at the onset of activity, following their administration in various proportions.

Comparison of the Anti-Inflammatory Activity of Sodium Acexamate and Zinc Acexamate in Healing Skin Wounds in Rabbits

After obtaining an abscess on the inner thigh of rabbits, the resulting inflammatory area was treated with sodium acexamate and zinc acexamate (0.5 ml s.c. of a 7% w/v solution). All animals received labeled leukocytes (111In, 1 mCi, i.v.). The hyperfixation was measured by comparing the inflammatory areas. In the group treated with zinc acexamate, the regression of inflammation was highly significant (p less than 0.001) in comparison with the other groups. These results emphasize the importance of combining zinc with acexamic acid for healing skin wounds.

A Comparative Study of Enzymuria, in the Rat, of the Drug Combinations Amikacin/Vancomycin and Amikacin/Teicoplanin

The aim of this study was to compare nephrotoxicity of the combinations amikacin/vancomycin and amikacin/teicoplanin. Eighteen male Wistar rats were divided into 3 groups of 6 animals each. The first group received 50 mg.kg-1 of amikacin (i.m. route) and 100 mg.kg-1 of vancomycin (i.p. route). The second group received 50 mg.kg-1 of amikacin (i.m. route) and 40 mg.kg-1 of teicoplanin (i.p. route). The third group received an isotonic solution of sodium chloride. The antibiotics were injected for a period of 6 days. Urine samples of animals were taken 24 h before the beginning of the experiment, then every day, throughout the duration of the treatment (6 days), continuing for an additional 3 days following completion of the administration of the drugs. There were no significant modifications in the urinary excretions of alanine aminopeptidase and the creatinine between the 3 groups; but in the group receiving amikacin/teicoplanin, we observed between days 3 and 8 an increase in the excretion of N-acetyl-beta-D- glucosaminidase when compared to the group receiving amikacin/vancomycin (p < or = 0.05) and to the control group (p < or = 0.01).