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Fukushima-shi, Japan

Urabe D.,University of Tokyo | Todoroki H.,University of Tokyo | Masuda K.,Shionogi and Co. | Inoue M.,University of Tokyo
Tetrahedron | Year: 2012

Resolvin E3, 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid, is a potent anti-inflammatory lipid mediator. To determine the stereochemistries of the C17- and C18-hydroxy groups of resolvin E3 and to supply a sufficient amount of material for future biological studies, we developed a highly convergent and practical route to its four possible stereoisomers. The key reactions employed here were the Horner-Wadsworth-Emmons coupling, the two copper(I)-mediated reactions between the alkynes and the propargyl tosylates, and the simultaneous reduction of the three triple bonds to the three Z-olefins. © 2012 Elsevier Ltd. All rights reserved. Source


Kido Y.,University of California at San Francisco | Kido Y.,Shionogi and Co. | Matsson P.,University of California at San Francisco | Matsson P.,Uppsala University
Journal of Medicinal Chemistry | Year: 2011

Drug-drug interactions (DDIs) are major causes of serious adverse drug reactions. Most DDIs have a pharmacokinetic basis in which one drug reduces the elimination of a second drug, leading to potentially toxic drug levels. As a major organ of drug elimination, the kidney represents an important site for DDIs. Here, we screened a prescription drug library against the renal organic cation transporter OCT2/SLC22A2, which mediates the first step in the renal secretion of many cationic drugs. Of the 910 compounds screened, 244 inhibited OCT2. Computational analyses revealed key properties of inhibitors versus noninhibitors, which included overall molecular charge. Four of six potential clinical inhibitors were transporter-selective in follow-up screens against additional transporters: OCT1/SLC22A1, MATE1/SLC47A1, and MATE2-K/SLC47A2. Two compounds showed different kinetics of interaction with the common polymorphism OCT2-A270S, suggesting a role of genetics in modulating renal DDIs. © 2011 American Chemical Society. Source


In recent years, immunological science has evolved, and cancer vaccines are available for treating existing cancers. Because cancer vaccines require time to elicit an immune response, a delayed treatment effect is expected. Accordingly, the use of weighted log-rank tests with the Fleming-Harrington class of weights is proposed for evaluation of survival endpoints. We present a method for calculating the sample size under assumption of a piecewise exponential distribution for the cancer vaccine group and an exponential distribution for the placebo group as the survival model. The impact of delayed effect timing on both the choice of the Fleming-Harrington's weights and the increment in the required number of events is discussed. Copyright © 2014 John Wiley & Sons, Ltd. Copyright © 2014 John Wiley & Sons, Ltd. Source


Wang M.,Sanford Burnham Institute for Medical Research | Hayakawa J.,Sanford Burnham Institute for Medical Research | Hayakawa J.,Shionogi and Co. | Yang K.,University of Washington | Han X.,Sanford Burnham Institute for Medical Research
Analytical Chemistry | Year: 2014

Diacylglycerols (DAGs) are important intermediates of lipid metabolism and cellular signaling. It is well-known that the mass levels of DAG are altered under disease states. Therefore, quantitative analysis of DAGs in biological samples can provide critical information to uncover underlying mechanisms of various cellular functional disorders. Although great efforts on the analysis of individual DAG species have recently been made by utilizing mass spectrometry with or without derivatization, cost-effective and high throughput methodologies for identification and quantification of all DAG species including regioisomers, particularly in an approach of shotgun lipidomics, are still missing. Herein, we described a novel method for directly identifying and quantifying DAG species including regioisomers present in lipid extracts of biological samples after facile one-step derivatization with dimethylglycine based on the principles of multidimensional mass spectrometry-based shotgun lipidomics. The established method provided substantial sensitivity (low limit of quantification at amol/μL), high specificity, and broad linear dynamics range (2500-fold) without matrix effects. By exploiting this novel method, we revealed a 16-fold increase of total DAG mass in the livers of ob/ob mice compared to their wild type controls at 4 months of age (an insulin-resistant state) versus a 5-fold difference between 3 month old mice (with normal insulin). These results demonstrated the importance and power of the method for studying biochemical mechanisms underpinning disease states. © 2014 American Chemical Society. Source


Clotet B.,University of Vic | Feinberg J.,University of Cincinnati | Van Lunzen J.,Universitatsklinikum Hamburg Eppendorf | Antinori A.,National Institute for Infectious | And 9 more authors.
The Lancet | Year: 2014

Background Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor (NNRTI). In FLAMINGO, we compared dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy. Methods In this multicentre, open-label, phase 3b, non-inferiority study, HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were randomly assigned (1:1) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir.emtricitabine or abacavir.lamivudine. Randomisation was stratifi ed by screening HIV-1 RNA (.100 000 or >100 000 copies per mL) and nucleoside reverse transcriptase inhibitor (NRTI) selection. The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL (Food and Drug Administration [FDA] snapshot algorithm) at week 48 with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, NCT01449929. Findings Recruitment began on Oct 31, 2011, and was completed on May 24, 2012, in 64 research centres in nine countries worldwide. Of 595 patients screened, 484 patients were included in the analysis (242 in each group). At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted diff erence 7E1%, 95% CI 0E9.13E2), non-inferiority and on pre-specifi ed secondary analysis dolutegravir was superior (p=0E025). Confi rmed virological failure occurred in two (<1%) patients in each group; we recorded no treatment-emergent resistance in either group. Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir (four [2%] patients) than for darunavir plus ritonavir (ten [4%] patients) and contributed to the diff erence in response rates. The most commonly reported (.10%) adverse events were diarrhoea (dolutegravir 41 [17%] patients vs darunavir plus ritonavir 70 [29%] patients), nausea (39 [16%] vs 43 [18%]), and headache (37 [15%] vs 24 [10%]). Patients receiving dolutegravir had signifi cantly fewer low-density lipoprotein values of grade 2 or higher (11 [2%] vs 36 [7%]; p=0E0001). Interpretation Once-daily dolutegravir was superior to once-daily darunavir plus ritonavir. Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected, treatment-naive patients. Funding ViiV Healthcare and Shionogi & Co. © Chataway et al. Open Access article distributed under the terms of CC BY. Source

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