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81.
GT Whiteside JM Dwyer JE Harrison CE Beyer T Cummons L Manzino L Mark GH Johnston BW Strassle A Adedoyin P Lu MJ Piesla CM Pulicicchio JCL Erve BJ Platt ZA Hughes KE Rogers DC Deecher EJ Trybulski JD Kennedy P Zhang L Leventhal 《British journal of pharmacology》2010,160(5):1105-1118
Background and purpose:
Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.Experimental approach:
In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one).Key results:
WAY-318068 is a potent and effective inhibitor of the NET with a Ki of 8.7 nM in a binding assay, and an IC50 of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits.Conclusions and implications:
Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain. 相似文献82.
83.
Percutaneous enterostomy with the Cope suture anchor 总被引:2,自引:0,他引:2
84.
Computerized radiologic reporting with voice data-entry 总被引:2,自引:0,他引:2
85.
86.
目的 探讨肿瘤坏死因子 -α(TNF -α)与 2型糖尿病胰岛素的关系。方法 用homa -R法选取有胰岛素抵抗 (IR组 )和无胰岛素抵抗 (NIR组 )的 2型糖尿病患者各 2 0例。另以 2 0名年龄及体重指数相匹配的人群的作为对照组 ,分别检测其空腹血糖、胰岛素 ,计算Homa -R值 ,用ELISA法检测TNF -α。结果 IR组的TNF -α与NIR组及对照组相比较明显增高 ,有统计学意义(P <0 0 5 ) ,IR组的空腹胰岛素水平及胰岛素抵抗指标Homa -R也显著高于NIR组及对照组 (P值为 <0 0 1) ,而三组间年龄、BMI、血脂、脂蛋白、血压均无显著性差异 (P >0 0 5 )。结论 血浆TNF -α水平与胰岛素抵抗呈密切相关 ,在 2型DM中有重要病理意义 ,可作为评估有无胰岛素抵抗的一项重要参考指标 相似文献
87.
88.
Sivaraman L; Stephens LC; Markaverich BM; Clark JA; Krnacik S; Conneely OM; O'Malley BW; Medina D 《Carcinogenesis》1998,19(9):1573-1581
One of the most consistent results in the epidemiology of human breast
cancer is the inverse relationship of risk and early full-term parity. The
goal of this study was to investigate the molecular mechanisms through
which early full-term pregnancy protects the breast from cancer
development. We used Wistar-Furth (WF) rats as our experimental system and
mimicked pregnancy using estrogen and progesterone (E/P). Sexually mature
female rats were treated with steroid hormones for 21 days and after 28
days of gland involution, the rats were administered MNU. Rats that
received a high dose of 20 microg E and 20 mg P exhibited an 82% reduction
in the incidence of mammary adenocarcinomas as compared to the rats
receiving only blank pellets. Decreasing doses of E/P were partially
protective suggesting that complete differentiation of the gland was not
required for refractoriness. We measured the RNA expression levels of
several target genes involved in the regulation of mammary cell
proliferation and/or differentiation including estrogen receptor (ER) and
progesterone receptor (PR), cyclins D1 and D2, the cell cycle inhibitors
p16, p21 and p27, and the tumor suppressor p53. At the time of MNU
treatment we found no significant differences in the expression of these
genes, with the possible exception of p21, indicating that hormone
treatment did not result in constitutive changes in expression levels. The
numbers of apoptotic cells were low and comparable in the hormone exposed
and age-matched virgin gland (AMV) at the time of carcinogen challenge and
remained low for 8 days after MNU treatment. The number of BrdU-labeled
cells at the time of carcinogen challenge were also low in both the AMV
(1.8%) and hormone exposed (0.8%) animals. In contrast, cell proliferation
in the AMV (5.7%) was significantly different from both the parous
involuted (1.2%) and the E/P-treated involuted (1.5%) animals 8 days after
MNU treatment. We interpret these data to indicate that hormone treatment
results in mammary epithelial cells that have persistent alterations in
intracellular pathways governing proliferation responses to carcinogens.
相似文献
89.
Austin CB; Young JW; Park HJ; Needleman BW; Handwerger BS; Rosenbaum RC 《Radiology》1987,164(3):787-789
Adult T-cell leukemia/lymphoma is a relatively uncommon disease, most often found in Japan, the Caribbean, the southeastern United States, and South America. To date there have been few reports of its skeletal manifestations. A case is reported in a 44-year-old man in which a short history of swelling of the hands and feet and painful motion in the fingers was followed by the rapid development of severe acroosteolysis. 相似文献
90.
羟基磷灰石溶解度等温线的测定 总被引:3,自引:0,他引:3
目的:应用微量添加固体滴定和激光散射法测定HA(37℃)溶解度等温线。方法:滴定物为HA。半导体二极管激光为发射光源,散射光源探测器用于监测超过溶解平衡点出现的沉淀。微量添加固体滴定所引发的沉淀引起散射光源显著且恒定地高于基线,由此判断溶液已处于过饱和状态,该固体滴定总量用于代表溶解度等温线的数据点。结果:HA溶解度等温线(37℃)由6次滴定合共50个滴定终点构成。与传统方法所得结果比较,本实验所得HA的溶解度约为过往结果的百份之一。结论:微量添加固体滴定和激光散射法利于研究HA的溶解平衡且能得到准确的HA溶解度等温线。 相似文献