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The accumulation of amyloid-β peptide (Aβ) in the brain is a critical hallmark of Alzheimer's disease. This high cerebral Aβ concentration may be partly caused by impaired clearance of Aβ across the blood-brain barrier (BBB). The low-density lipoprotein receptor-related protein-1 (LRP-1) and the ATP-binding cassette (ABC) protein ABCB1 (P-glycoprotein) are involved in the efflux of Aβ across the BBB. We hypothesized that other ABC proteins, such as members of the G subfamily, are also involved in the BBB clearance of Aβ. We therefore investigated the roles of ABCG2 (BCRP) and ABCG4 in the efflux of [3H] Aβ1-40 from HEK293 cells stably transfected with human ABCG2 or mouse abcg4. We showed that ABCG2 and Abcg4 mediate the cellular efflux of [3H] Aβ1-40. In addition, probucol fully inhibited the efflux of [3H] Aβ1-40 from HEK293-abcg4 cells. Using the in situ brain perfusion technique, we showed that GF120918 (dual inhibitor of Abcb1 and Abcg2) strongly enhanced the uptake (Clup, μl/g/s) of [3H] Aβ1-40 by the brains of Abcb1-deficient mice, but not by the brains of Abcb1/Abcg2-deficient mice, suggesting that Abcg2 is involved in the transport of Aβ at the mouse BBB. Perfusing the brains of Abcb1/Abcg2- and Abca1-deficient mice with [3H] Aβ1-40 plus probucol significantly increased the Clup of Aβ. This suggests that a probucol-sensitive transporter that is different from Abca1, Abcb1, and Abcg2 is involved in the brain efflux of Aβ. We suggest that this probucol-sensitive transporter is Abcg4. We conclude that Abcg4 acts in concert with Abcg2 to efflux Aβ from the brain across the BBB. [ABSTRACT FROM AUTHOR]

1 2 n -Propylquinoline (2 n PQ) is a newly developed drug for visceral antileishmaniasis and its activity has been previously evaluated in mice following oral administration. The study was carried out to investigate the kinetic formation of 2 n PQ metabolites and to characterize the human liver CYP forms involved in its oxidative metabolism. 2. The inhibition of 2 n PQ metabolite formation by specific substrates or inhibitors of CYP forms and correlation studies were performed in human liver microsomes. 2 n PQ biotransformation was then studied in human lymphoblasts expressing specific CYPs and microsomal epoxide hydrolase. 3. Three major metabolites were produced by human liver microsomes and their structures were identified by ESI-LC/MS: dihydroxy-2 n -propylquinoline, 3'-hydroxy-2 n -propylquinoline and 1'-hydroxy-2 n -propylquinoline. An intermediary metabolite, epoxy-2 n -propylquinoline, formed by CYP was also biotransformed by microsomal epoxide hydrolase into dihydroxy-2 n -propylquinoline. 4. 2 n PQ oxidation follows Michaelis-Menten kinetics. In human liver microsomes, its metabolism was extremely inhibited by pilocarpine, coumarin and diethyldithiocarbamate. From a panel of 12 human liver microsome samples, the rate of 2 n PQ oxidation was highly correlated with the activities of CYP2A6 and CYP2E1. Human lymphoblasts expressing specific CYPs showed the involvement of CYP2A6, CYP2E1 and CYP2C19. 5. The results indicate that 2 n PQ metabolites are 3'- and 1'-hydroxylated by human liver microsomes and an epoxy-2 n -propylquinoline is biotransformed into a dihydroxy-2 n -propylquinoline by microsomal epoxide hydrolase. [ABSTRACT FROM AUTHOR]

We evaluated the in vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia using a susceptible strain and one with low-level resistance (MIC/MBC of levofloxacin: 0.06/0.06 and 4/4 mg/L, respectively). As demonstrated previously with other pathogens, the AUC/MIC ratio predicted the efficacy of fluoroquinolones against A. baumannii. This parameter correlated with bactericidal effect and survival. Combination therapy did not enhance the efficacy of levofloxacin. [ABSTRACT FROM AUTHOR]

This study was designed to: (1) determine plasma midazolam concentrations producing adequate sedation in ICU patients; (2) establish an intravenous regimen to provide continuous sedation and rapid recovery after discontinuation of infusion. Initially, 13 ICU patients were given midazolam as a bolus injection, 0.20 mg·kg over 30 s in order to define the midazolam plasma concentration corresponding to an adequate level of sedation. The optimal level was reached in a mean time of 61±21 min and the mean corresponding midazolam plasma concentration was 163±62 ng·ml. Estimations of the main pharmacokinetic parameters (elimination half life: 230±102 min, total body clearance: 520±283 ml·min, total volume of distribution: 2.23±1.15 l·kg) showed no marked differences with normal patients. From those variables, an infusion regimen (loading dose and maintenance rate) to provide long term (24 to 80 h) sedation was derived in 9 patients. The mean loading dose was 0.33±0.18 mg·kg over 30 min and the mean continuous infusion dose was 0.06±0.02 mg·kg·h. The mean midazolam plasma concentration during infusion was 215±61 ng·ml, and the mean midazolam plasma concentration at the end of infusion was 199±93 ng·ml. The level of sedation was considered as optimal in most patients throughout the study. After discontinuation of infusion, the mean time for normalization of the mental state was 97 min. [ABSTRACT FROM AUTHOR]

The killing kinetics of cefuroxime against 25 Streptococcus pneumoniae isolates with penicillin MICs of <0.1, 0.1-1.0 and 2 mg/l were studied in an in vitro model simulating the serum concentration profile in healthy adults following a single intramuscular injection of 500 mg. Cefuroxime was bactericidal against the isolates with exquisite or slightly diminished susceptibility to penicillin (−4 and −3.9 log10 cfu/ml killing, respectively) during the 6 h incubation period. In contrast, there was only a 2.8 log10 cfu/ml reduction in the initial inoculum of six of the eight isolates resistant to penicillin (MIC 2 mg/l). The two remaining penicillin-resistant isolates (cefuroxime MIC 8 mg/l) only showed a 2 log10 cfu reduction in the initial inoculum. [ABSTRACT FROM AUTHOR]

The activity of ofloxacin and cefotaxime, alone or combined, against four strains of Enterobacteriaceae was evaluated both in vitro and in sera from volunteers given a single infusion over 30 min of 200 mg ofloxacin or 1 g cefotaxime. The strains showed resistance or decreased susceptibility to third-generation cephalosporins. The combination was not found to be synergistic in vitro. Analysis of the bactericidal titres and killing kinetics of sera taken at the time of the peak concentration and 6 h after the infusion, respectively, confirmed the absence of synergy between the drugs against these strains. [ABSTRACT FROM AUTHOR]