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S. NYLANDER B. KULL J. A. BJÖRKMAN J. C. ULVINGE N. OAKES B. M. EMANUELSSON M. ANDERSSON T. SKÄRBY T. INGHARDT O. FJELLSTRÖM D. GUSTAFSSON 《Journal of thrombosis and haemostasis》2012,10(10):2127-2136
Nylander S, Kull B, Björkman JA, Ulvinge JC, Oakes N, Emanuelsson BM, Andersson M, Skärby T, Inghardt T, Fjellström O, Gustafsson D. Human target validation of phosphoinositide 3‐kinase (PI3K)β:effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor. J Thromb Haemost 2012; 10: 2127–36. See also Jackson SP, Schoenwaelder SM. Antithrombotic phosphoinositide 3‐kinase β inhibitors in humans – a ‘shear’ delight! This issue, pp 2123–6. Summary. Background: Based on in vitro and animal data, PI3Kβ is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear. Objective: To strengthen the PI3Kβ target validation using the novel, short‐acting inhibitor AZD6482. Methods and results: AZD6482 is a potent, selective and ATP competitive PI3Kβ inhibitor (IC50 0.01 μm ). A maximal anti‐platelet effect was achieved at 1 μm in the in vitro and ex vivo tests both in dog and in man. In dog, in vivo AZD6482 produced a complete anti‐thrombotic effect without an increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3‐h infusion. The ex vivo anti‐platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin‐induced human adipocyte glucose uptake in vitro (IC50 of 4.4 μm ). In the euglycemic hyperinsulinemic clamp model, in rats, glucose infusion rate was not affected at 2.3 μm but reduced by about 60% at a plasma exposure of 27 μm . In man, the homeostasis model analysis (HOMA) index increased by about 10–20% at the highest plasma concentration of 5.3 μm . Conclusions: This is the first human target validation for PI3Kβ inhibition as anti‐platelet therapy showing a mild and generalized antiplatelet effect attenuating but not completely inhibiting multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at ‘supratherapeutic’ plasma concentrations may attenuate insulin signaling, most likely through PI3Kα inhibition. 相似文献
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L Thors JJ Burston BJ Alter MK McKinney BF Cravatt RA Ross RG Pertwee RW Gereau th JL Wiley CJ Fowler 《British journal of pharmacology》2010,160(3):549-560
Background and purpose:
Inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of the endogenous cannabinoid (CB) receptor ligand anandamide (AEA), are effective in a number of animal models of pain. Here, we investigated a series of isoflavones with respect to their abilities to inhibit FAAH.Experimental approach:
In vitro assays of FAAH activity and affinity for CB receptors were used to characterize key compounds. In vivo assays used were biochemical responses to formalin in anaesthetized mice and the ‘tetrad’ test for central CB receptor activation.Key results:
Of the compounds tested, biochanin A was adjudged to be the most promising. Biochanin A inhibited the hydrolysis of 0.5 µM AEA by mouse, rat and human FAAH with IC50 values of 1.8, 1.4 and 2.4 µM respectively. The compound did not interact to any major extent with CB1 or CB2 receptors, nor with FAAH-2. In anaesthetized mice, URB597 (30 µg i.pl.) and biochanin A (100 µg i.pl.) both inhibited the spinal phosphorylation of extracellular signal-regulated kinase produced by the intraplantar injection of formalin. The effects of both compounds were significantly reduced by the CB1 receptor antagonist/inverse agonist AM251 (30 µg i.pl.). Biochanin A (15 mg·kg−1 i.v.) did not increase brain AEA concentrations, but produced a modest potentiation of the effects of 10 mg·kg−1 i.v. AEA in the tetrad test.Conclusions and implications:
It is concluded that biochanin A, in addition to its other biochemical properties, inhibits FAAH both in vitro and peripherally in vivo.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x 相似文献444.
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The assessment of new radiologic tests can be seriously hampered by the presence of systematic bias. Biases can arise from incomplete verification of the sample population; omission of uninterpretable tests; absence of a definitive reference test; extraneous factors affecting interpretation; and extrapolation factors including variations in test efficacy among patients, hospitals, and the radiologists who interpret the tests. The authors review these biases that affect the results of efficacy studies and provide guidelines to avoid these problems. 相似文献
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BJ Poiesz ; S Dube ; B Jones ; V Bryz-Gornia ; MT Dean ; T Spicer ; J Hengst ; K Sayre ; E Esteban ; JF Ferrer 《Transfusion》1997,37(1):52-59
BACKGROUND : Human T-cell lymphoma/leukemia viruses types I and II (HTLV- I and HTLV-II) are related exogenous human retroviruses. The former is definitely pathogenic while disease association with the latter is unclear. There are two subtypes of HTLV-II, A and B. Currently, enzyme- linked immunosorbent assays (ELISAs) based on HTLV-I antigens are used to screen for the presence of HTLV-I and -II antibodies. Confirmation and subtyping are accomplished by Western blot (WB) or ELISAs based on HTLV-I whole viral antigens and/or HTLV-I and HTLV-IIA peptides. The sensitivity and specificity of these serologic assays were compared to those of HTLV-I and-II-specific polymerase chain reaction (PCR) assays in tests on samples from Indians from South America in whom the HTLV- IIB subtype is endemic. STUDY DESIGN AND METHODS : Sera from 246 Gran Chaco Indians were evaluated for HTLV antibodies with the use of four ELISAs (Retrotek HTLV-I; Cambridge Biotech rgp21 enhanced HTLV-I/II; Vironostika HTLV-I/II; and Select HTLV-I/II), and a WB assay. Peripheral blood leukocyte DNA from each Indian was analyzed for HTLV-I or HTLV-II pol DNA via PCR. Fifteen of the PCR-positive samples were further subtyped via cloning and sequencing and/or oligomer restriction. RESULTS : Ninety-seven samples (39%) were positive for HTLV- II by serologic and/or PCR assays. All 15 positive DNA samples that were further analyzed were of the HTLV-IIB subtype and were clustered as a highly conserved phylogenetic group. Comparative analyses indicate that the sensitivity and specificity of the various assays were: PCR, 97 and 100 percent; Retrotek, 70 and 91 percent; Cambridge Biotech, 74 and 96 percent; Vironostika, 73 and 99 percent; Select 72 and 98 percent; and WB, 70 and 100 percent. CONCLUSION : The sensitivities of the tested HTLV serologic assays were comparable. However, the specificity of the Retrotek ELISA was significantly lower than that of the others. When positive, the subtyping assays were very specific. However, PCR assays would seem preferable or to be a necessary adjunct for the sensitive detection of HTLV-IIB infection. 相似文献
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