Human plasma metabolic profiles of benzydamine,a flavin-containing monooxygenase probe substrate,simulated with pharmacokinetic data from control and humanized-liver mice

1.?Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir.

2.?Following oral administration of benzydamine (10?mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide.

3.?Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high.

4.?The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.     

Female reproductive factors and risk of all-cause and cause-specific mortality among women: The Japan Public Health Center–based Prospective Study (JPHC study)

Purpose

We investigated the association between reproductive history and mortality from all and major causes among Japanese women.

Bacteremia due to high-level daptomycin-resistant Corynebacterium striatum: A case report with genetic investigation

Corynebacterium striatum, generally considered an opportunistic organism in humans, has recently been known to develop high-level daptomycin resistance (HLDR) shortly after drug exposure. To date, however, only several such clinical isolates have been described in the literature and clinical background of the resistant pathogen remains to be elucidated. Here, we report a case involving a C. striatum strain with HLDR harboring novel nucleotide mutations, together with a review of the relevant literature. To the best of our knowledge, this is the first well-investigated clinical report from Japan including a genetic investigation. Considering the rapid emergence of HLDR C. striatum in vitro experiment, there could be a number of underreporting cases. Scrupulous attention is required when administering daptomycin for the treatment of C. striatum infections, even if the organism has initially exhibited susceptibility.     

Changing the mind? Not really—activity and connectivity in the caudate correlates with changes of choice

Changes in preference are inherently subjective and internal psychological events. We have identified brain events that presage ultimate (rather than intervening) choices, and signal the finality of a choice. At the first exposure to a pair of faces, caudate activity reflected the face of final choice, even if an initial choice was different. Furthermore, the orbitofrontal cortex and hippocampus exhibited correlations only when the subject had made a choice that would not change.     

Disseminated Mycobacterium avium Infection Complicated with Chylous Ascites in a Patient with Neutralizing Autoantibodies to Interferon-γ

A 68-year-old man visited our hospital due to anorexia, weight loss and a fever. We diagnosed the patient with disseminated Mycobacterium avium complex (MAC) and confirmed the presence of interferon (IFN)-γ neutralizing autoantibodies (IFN-γAb). His lesions improved following antibiotic therapy, but chylous ascites (CA) developed seven months after treatment. CA was able to be controlled by subcutaneous octreotide and diet therapy. IFN-γAb is recognized as having a critical role in the pathogenesis of disseminated MAC disease, but its clinical features are not fully understood. CA may be a complication that develops during the treatment of disseminated MAC infection.