Masakazu Kuroyama

Clinical efficacy of arbekacin for Gram-negative bacteria

In an analysis of methicillin-resistant Staphylococcus aureus (MRSA) infected patients treated with arbekacin (ABK) only, Gram-negative bacteria (GNB) that were inhibited by low minimal inhibitory concentrations (MICs) of amikacin (AMK) or gentamycin (GM) were eradicated by the end of the ABK treatment. On the other hand, GNB that were only inhibited by high MICs of AMK or GM persisted until the end of treatment with ABK only. Thus, ABK can be expected to be effective even in cases of mixed infection with GNB and MRSA.

Anti-angiogenic effects of valproic acid in a mouse model of oxygen-induced retinopathy

Pathological retinal angiogenesis contributes to the pathogenesis of several ocular diseases. Valproic acid, a widely used antiepileptic drug, exerts anti-angiogenic effects by inhibiting histone deacetylase (HDAC). Herein, we investigated the effects of valproic acid and vorinostat, a HDAC inhibitor, on pathological retinal angiogenesis in mice with oxygen-induced retinopathy (OIR). OIR was induced in neonatal mice by exposure to 80% oxygen from postnatal day (P) 7 to P10 and to atmospheric oxygen from P10 to P15. Mice were subcutaneously injected with valproic acid, vorinostat, or vehicle once a day from P10 to P14. At P15, retinal neovascular tufts and vascular growth in the central avascular zone were observed in mice with OIR. Additionally, immunoreactivity for phosphorylated ribosomal protein S6 (pS6), an indicator of mammalian target of rapamycin (mTOR) activity, was detected in the neovascular tufts. Both valproic acid and vorinostat reduced the formation of retinal neovascular tuft without affecting vascular growth in the central avascular zone. Valproic acid reduced the pS6 immunoreactivity in neovascular tufts. Given that vascular endothelial growth factor (VEGF) activates mTOR-dependent pathways in proliferating endothelial cells of the neonatal mouse retina, these results suggest that valproic acid suppresses pathological retinal angiogenesis by interrupting VEGF-mTOR pathways.

Determination of Serum Mexiletine Concentrations and its Protein Binding by High-performance Liquid Chromatography.

A new method to determine serum mexiletine (MX) concentrations using high-performance liquid chromatography (HPLC) was established.This method could reduce a sample volume to 100μ1 of serum and could shorten the pretreatment time to less than 10 minutes by using Chem Elut minicolumn. The results obtained by this method (n=28) correlated well with those obtained by gas chromatography method (r=0.997).Moreover, this method had a good recovery and reproducibility, suggesting that it is an excellent method for determining serum MX concentrations.Using this HPLC method, serum protein binding of MX was studied in healthy subjects and patients with chronic renal failure (CRF). The protein binding of MX was 60.83±4.37% in healthy subjects (n=6) and 52.45±6.22% in CRF (n=9).The protein binding of MX in CRF was significantly decreased, compared with healthy subjects, indicating an apparent elevation of free drug concentrations.In general, dose adjustment of MX in CRF is considered to be unnecessary. However, free drug concentrations may participate in the appearance of effects and adverse reactions. The possibility of enhanced pharmacological effects and increased adverse reactions due to such variations of protein binding in CRF should be also considered.