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排序方式: 共有115条查询结果,搜索用时 15 毫秒
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Christopher R Gibson Charles Lin Rominder Singh Cheri M Brown Karen Richards Janice Brunner Kimberly Michel Jennifer Adelsberger Edward Carlini Catherine Boothe-Genthe Conrad Raab Minh Luu Aimee Michael Mona Parikh Patrice Ciecko Raju Subramanian Paul Krolikowski A David Rodrigues Thomas A Baillie Thomas H Rushmore 《Drug metabolism and disposition》2005,33(7):1044-1051
Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A. 相似文献
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Stephen A. Varvel Szilard Voros Dawn L. Thiselton James V. Pottala Tara Dall G. Russell Warnick Joseph P. McConnell Leila Ghaedi Maciek Sasinowski Timothy Graham 《Journal of cardiovascular translational research》2014,7(6):597-606
Blood-based biomarker testing of insulin resistance (IR) and beta cell dysfunction may identify diabetes risk earlier than current glycemia-based approaches. This retrospective cohort study assessed 1,687 US patients at risk for cardiovascular disease (CVD) under routine clinical care with a comprehensive panel of 19 biomarkers and derived factors related to IR, beta cell function, and glycemic control. The mean age was 53?±?15, 42 % were male, and 25 % had glycemic indicators consistent with prediabetes. An additional 45 % of the patients who had normal glycemic indicators were identified with IR or beta cell abnormalities. After 5.3 months of median follow-up, significantly more patients had improved than worsened their glycemic status in the prediabetic category (35 vs. 9 %; P?0.0001) and in the “high normal” category (HbA1c values of 5.5–5.6; 56 vs. 18 %, p?0.0001). Biomarker testing can identify IR early, enable and inform treatment, and improve glycemic control in a high proportion of patients. 相似文献
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Comprehensive morphometry of subcortical grey matter structures in early‐stage Parkinson's disease
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Ricarda A.L. Menke Konrad Szewczyk‐Krolikowski Saad Jbabdi Mark Jenkinson Kevin Talbot Clare E. Mackay Michele Hu 《Human brain mapping》2014,35(4):1681-1690
Previous imaging studies that investigated morphometric group differences of subcortical regions outside the substantia nigra between non‐demented Parkinson's patients and controls either did not find any significant differences, or reported contradictory results. Here, we performed a comprehensive morphometric analysis of 20 cognitively normal, early‐stage PD patients and 19 matched control subjects. In addition to relatively standard analyses of whole‐brain grey matter volume and overall regional volumes, we examined subtle localized surface shape differences in striatal and limbic grey matter structures and tested their utility as a diagnostic marker. Voxel‐based morphometry and volumetric comparisons did not reveal significant group differences. Shape analysis, on the other hand, demonstrated significant between‐group shape differences for the right pallidum. Careful diffusion tractography analysis showed that the affected parts of the pallidum are connected subcortically with the subthalamic nucleus, the pedunculopontine nucleus, and the thalamus and cortically with the frontal lobe. Additionally, microstructural measurements along these pathways, but not along other pallidal connections, were significantly different between the two groups. Vertex‐wise linear discriminant analysis, however, revealed limited accuracy of pallidal shape for the discrimination between patients and controls. We conclude that localized disease‐related changes in the right pallidum in early Parkinson's disease, undetectable using standard voxel‐based morphometry or volumetry, are evident using sensitive shape analysis. However, the subtle nature of these changes makes it unlikely that shape analysis alone will be useful for early diagnosis. Hum Brain Mapp 35:1681–1690, 2014. © 2013 Wiley Periodicals, Inc. 相似文献
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Inhibition of mitochondrial permeability transition enhances isoflurane-induced cardioprotection during early reperfusion: the role of mitochondrial KATP channels 总被引:10,自引:0,他引:10
Krolikowski JG Bienengraeber M Weihrauch D Warltier DC Kersten JR Pagel PS 《Anesthesia and analgesia》2005,101(6):1590-1596
Inhibition of the mitochondrial permeability transition pore (mPTP) mediates the protective effects of brief, repetitive ischemic episodes during early reperfusion after prolonged coronary artery occlusion. Brief exposure to isoflurane immediately before and during early reperfusion also produces cardioprotection, but whether mPTP is involved in this beneficial effect is unknown. We tested the hypothesis that mPTP mediates isoflurane-induced postconditioning and also examined the role of mitochondrial KATP (mKATP) channels in this process. Rabbits (n = 102) subjected to a 30-min coronary occlusion followed by 3 h reperfusion received 0.9% saline (control), isoflurane (0.5 or 1.0 MAC) administered for 3 min before and 2 min after reperfusion, or the mPTP inhibitor cyclosporin A (CsA, 5 or 10 mg/kg) in the presence or absence of the mPTP opener atractyloside (5 mg/kg) or the selective mK(ATP) channel antagonist 5-hydroxydecanoate (5-HD; 10 mg/kg). Other rabbits received 0.5 MAC isoflurane plus 5 mg/kg CsA in the presence and absence of atractyloside or 5-HD. Isoflurane (1.0 but not 0.5 MAC) and CsA (10 but not 5 mg/kg) reduced (P < 0.05) infarct size (21% +/- 4%, 44% +/- 6%, 24% +/- 3%, and 43% +/- 6%, respectively, mean +/- sd of left ventricular area at risk; triphenyltetrazolium staining) as compared with control (42% +/- 7%). Isoflurane (0.5 MAC) plus CsA (5 mg/kg) was also protective (27% +/- 4%). Neither atractyloside nor 5-HD alone affected infarct size, but these drugs abolished protection by 1.0 MAC isoflurane, 10 mg/kg CsA, and 0.5 MAC isoflurane plus 5 mg/kg CsA. The results indicate that mPTP inhibition enhances, whereas opening abolishes, isoflurane-induced postconditioning. This isoflurane-induced inhibition of mitochondrial permeability transition is dependent on activation of mitochondrial KATP channels in vivo. 相似文献
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Ovarian leiomyoma is a rare and incidentally detected neoplasm, clinically indistinguishable from subserous leiomyomas and ovarian fibromas, until histopathological confirmation. We present a case of leiomyoma arising primarily from the ovary in a 35 year old woman. 相似文献
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Use of ovulation inducing agents has increased the incidence of high order multifetal gestation. Such pregnancies are associated with increased maternal morbidity and poor perinatal outcome especially due to prematurity. Here, we report a case of sextuplet pregnancy following ovulation induction with gonadotrophins. This is the first reported case of sextuplets from Oman. 相似文献
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