WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Co‐administration of proton pump inhibitors (PPIs) increases plasma methotrexate (MTX) concentration in cancer patients receiving high‐dose MTX (HDMTX) therapy. • There is controversy as to whether or not co‐administration of PPIs affects plasma MTX elimination in HDMTX therapy. • Inhibitory activity of PPIs on breast cancer resistance protein (BCRP) is a possible mechanism for the drug interaction between MTX and PPIs. WHAT THIS STUDY ADDS • Co‐administration of a PPI (omeprazole, lansoprazole, or rabeprazole) was more frequently observed in the delayed MTX elimination group than in the normal MTX elimination group. • Multiple logistic regression analysis with adjustment for significant covariates revealed that PPI co‐administration was a significant risk factor for delayed plasma MTX elimination. • The half‐maximal inhibitory concentration of each PPI in inhibiting BCRP function was much higher than the therapeutic unbound concentration in the plasma. AIM To assess whether or not co‐administration of proton pump inhibitors (PPIs) is a risk factor for delayed elimination of plasma methotrexate (MTX) in high‐dose MTX (HDMTX) therapy for malignant diseases. METHODS To assess the effects of PPI co‐administration on elimination of plasma MTX, we examined plasma MTX concentration data on 171 cycles of HDMTX therapy performed in 74 patients. We performed multiple logistic regression analysis to evaluate PPI co‐administration as a risk factor. Inhibitory potencies of omeprazole, lansoprazole, rabeprazole and pantoprazole on MTX transport via breast cancer resistance protein (BCRP, ABCG2) were also investigated in an in vitro study using membrane vesicles expressing human BCRP. RESULTS We identified co‐administration of PPIs as a risk factor for delayed elimination (odds ratio 2.65, 95% confidence interval 1.03, 6.82) as well as renal and liver dysfunction. All four PPIs inhibited BCRP‐mediated transport of MTX, with half‐maximal inhibitory concentrations of 5.5–17.6 µM – considerably higher than the unbound plasma concentrations of the PPIs. CONCLUSIONS Our results support previous findings suggesting that PPI co‐administration is associated with delayed elimination of plasma MTX in patients with HDMTX therapy. This drug interaction, however, cannot be explained solely by the inhibitory effects of PPIs on BCRP‐mediated MTX transport.

Introduction: The large number casualties caused by the 1995 Great Hanshin and Awaji Earthquake created a massive demand for medical care. However, as area hospitals also were damaged by the earthquake, they were unable to perform their usual functions. Therefore, the care capacity was reduced greatly. Thus, the needs to: (1) transport a large number of injured and ill people out of the disaster-affected area; and (2) dispatch medical teams to perform such wide-area transfers were clear. The need for trained medical teams to provide medical assistance also was made clear after the Niigata-ken Chuetsu Earthquake in 2004. Therefore, the Japanese government decided to establish Disaster Medical Assistance Teams (DMATs), as "mobile, trained medical teams that rapidly can be deployed during the acute phase of a sudden-onset disaster". Disaster Medical Assistance Teams have been established in much of Japan. The provision of emergency relief and medical care and the enhancement and promotion of DMATs for wide-area deployments during disasters were incorporated formally in the Basic Plan for Disaster Prevention in its July 2005 amendment. Results: The essential points pertaining to DMATs were summarized as a set of guidelines for DMAT deployment. These were based on the results of research funded by a Health and Labour Sciences research grant from the, Labour and Welfare (MHLW) of the Ministry of Health. The guidelines define the basic procedures for DMAT activities-for example: (1) the activities are to be based on agreements concluded between prefectures and medical institutions during non-emergency times; and (2) deployment is based on requests from disaster-affected prefectures and the basic roles of prefectures and the MHLW.The guidelines also detail DMAT activities at the disaster scene of the, support from medical institutions, and transportation assistance including "wide-area" medical transport activities, such as medical treatment in staging care units and the implementation of medical treatment onboard aircraft. Conclusions: Japan's DMATs are small-scale units that are designed to be suitable for responding to the demands of acute emergencies. Further issues to be examined in relation to DMATs include expanding their application to all prefectures, and systems to facilitate continuous education and training. http://pdm.medicine.wisc.edu Prehospital and Disaster Medicine Kondo, Koido, Morino, et al 557 http://pdm.medicine.wisc.edu Prehospital and Disaster Medicine Kondo, Koido, Morino, et al http://pdm.medicine.wisc.edu Prehospital and Disaster Medicine Kondo, Koido, Morino, et al http://pdm.medicine.wisc.edu Prehospital and Disaster Medicine Kondo, Koido, Morino, et al

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A novel [Ile7]surfactin (1), which showed anti-human immunodeficiency virus activity, has been isolated from Bacillus subtilis natto. Structural and conformational analysis of the peptide backbone of [Ile7]surfactin was conducted by a combination of various two-dimensional (2D) nuclear magnetic resonance (NMR), circular dichroism (CD) spectroscopy and simulated annealing calculations, compared with a known [Leu7]surfactin (2). Both surfactins were shown to exist in different conformational states in both polar and apolar solvents.

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Ribavirin is an antiviral agent used in the treatment of chronic hepatitis C virus infection. One of the limitations associated with the use of ribavirin is a reversible anemia caused by its accumulation in erythrocytes. Therefore, it is of interest to determine ribavirin levels in erythrocytes, as well as in plasma, as these measurements may be predictive of hematotoxicity. In the present study, we describe a high-performance liquid chromatographic (HPLC) assay for ribavirin in whole blood to estimate concentrations of free ribavirin and phosphorylated anabolites in erythrocytes. Since ribavirin exists primarily as phosphorylated anabolites (mono-, di-, and triphosphates) in erythrocytes, whole-blood extracts were initially dephosphorylated with acid phosphatase. The enzyme-treated samples were subjected to phenyl boronic acid column extraction for cleanup. The purified fraction was analyzed by reversed-phase HPLC, which was optimized for determination of ribavirin levels in whole blood. The recoveries of ribavirin from whole blood ranged from 63.1 to 90.7% at concentrations ranging from 1.67 to 40.0 μM. Intra- and interassay variations estimated at these concentrations were 3.2 to 10.4 and 4.7 to 11.7%, respectively. This method was used to quantitate ribavirin in samples both treated and untreated with acid phosphatase to estimate the extent of intracellular phosphorylation in erythrocytes. The method was also used to evaluate the effects of dipyridamole, a nucleoside transporter inhibitor, on ribavirin disposition in erythrocytes in in vitro experiments.

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