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21.
目的 探讨布鲁顿酪氨酸激酶(Bruton,s tyrosine kinase,BTK)抑制剂依鲁替尼(ibrutinib)和AVL-292单药及联合蛋白酶体抑制剂硼替佐米对人多发性骨髓瘤细胞系H929和RPMI8226的作用及其机制.方法 用不同浓度的依鲁替尼、AVL-292单药以及联合硼替佐米处理H929、RPMI8226细胞.采用CCK-8法检测细胞增殖情况,流式细胞术检测细胞凋亡情况,蛋白质印迹法检测药物处理前后细胞内BTK信号通路蛋白及凋亡相关蛋白的表达水平.结果 依鲁替尼和AVL-292均可抑制H929、RPMI8226细胞增殖,其抑制作用呈浓度依赖性,依鲁替尼对H929、RPMI8226细胞48 h的半数抑制浓度(median inhibitory concentration,IC50)分别为(10.41±3.29) μmol/L和(51.65±13.58) μmol/L,AVL-292对H929、RPMI8226细胞48 h的IC50分别为(7.77±2.99) μmol/L和(6.44±1.06) μmol/L.不同浓度的依鲁替尼(5、10 μmol/L)和AVL-292(5、10 μmol/L)分别与不同浓度的硼替佐米(5、10、20、50 nmol/L)联合应用对H929、RPMI8226细胞增殖的抑制率均高于相应浓度单药组(P<0.05,P<0.01),不同组合的协同系数R均>1.0.10 μmol/L依鲁替尼、10 μmol/L AVL-292和20 nmol/L硼替佐米单独作用48 h后,H929细胞的凋亡率分别为(15.12±1.59)%、(18.23±6.38)%和(10.71±1.62)%,均高于对照组[(6.46±1.18)%;P<0.05,P<0.01];RPMI8226细胞的凋亡率分别为(9.29±1.44)%、(15.01±4.99)%和(7.58±1.13)%,10 μmol/L依鲁替尼和10 μmol/L AVL-292单药组与对照组[(5.54±1.61)%]比较差异均有统计学意义(P<0.05);10μmol/L依鲁替尼和10 μmol/L AVL-292分别与20 nmol/L硼替佐米联合后,H929细胞凋亡率分别为(40.31±3.94)%和(51.55±6.39)%,RPMI8226细胞凋亡率分别为(31.86±1.93)%和(43.23±4.03)%,均高于相应单药组(P<0.01).10 μmol/L依鲁替尼单药和10 μmol/L AVL-292单药作用24 h后,H929细胞内BTK、NF-κB p65、Akt和ERK的磷酸化水平及Bcl-XL蛋白表达水平均较对照组降低(P<0.05),cleaved caspase-3表达水平均较对照组升高(P<0.01);两药分别联合20 nmol/L硼替佐米后,对上述蛋白的调节作用均较相应单药组增强(P<0.05,P<0.01).结论 BTK抑制剂依鲁替尼和AVL-292对多发性骨髓瘤细胞系H929、RPMI8226有增殖抑制和凋亡诱导作用,并与蛋白酶体抑制剂硼替佐米有协同作用,其机制可能与抑制细胞内BTK活性及下游NF-κB、Akt、ERK信号通路活性,下调抗凋亡蛋白Bcl-xL表达、激活caspase-3依赖的凋亡途径有关. 相似文献
22.
Synergism of amlodipine and candesartan on blood pressure reduction and organ protection in hypertensive rats 下载免费PDF全文
Xu‐Hong Yu Wen‐Zhe Dong Ding‐Feng Su De‐Qiu Zhu Ai‐Jun Liu 《Clinical and experimental pharmacology & physiology》2018,45(6):514-524
This study was designed to investigate the possible synergism of amlodipine and candesartan on the reduction of blood pressure (BP) in hypertensive rats. The end organ protection was also observed. In acute experiment, spontaneously hypertensive rats (SHRs) were treated with intragastric administration of amlodipine (0.5, 1, 2, 3 mg/kg), candesartan (1, 2, 3, 4, 6, 8 mg/kg), and 14 different combinations to find the possible ratio of synergistic interaction. In two kidneys, one clip (2K1C) rats, the effects of amlodipine (1 mg/kg), canderastan (2 mg/kg) and their combination on BP reduction were also observed. In chronic study, SHRs were treated with amlodipine (1 mg/kg), candesartan (2 mg/kg), and their combination for 5 months. Organ damage evaluation was performed after BP recording. The probability sum test (q test) was used to evaluate the synergistic action. There is a synergistic interaction between amlodipine and candesartan on BP reduction. The optimal dose ratio is 1:2. The synergistic effect was also confirmed by 2K1C hypertensive rats. In chronic study, this combination (1:2) possessed an obvious synergism on the reduction of BP and BP variability (BPV) and protection on end organs. Multiple regression analysis showed that heart and aortic hypertrophy indexes and glomerular damage parameters were positively related to BP and BPV. In conclusion, combination of amlodipine and candesartan exhibited a potent antihypertensive effect and possessed an obvious synergism on BP reduction and organ protection in hypertension. The optimal proportion was 1:2. BP and BPV reduction may both importantly contribute to end organ protection. 相似文献
23.
目的为了延缓和克服蚊虫抗性的发生和发展,更好地选用卫生杀虫剂控制蚊虫,测定了常用杀虫剂复配对采自济宁市部分地区现场淡色库蚊幼虫的敏感性及增效作用。方法采用WHO生物测试法,计算LC50、回归方程、增效系数。结果DDVP+三氯杀虫酯、残杀威+三氯杀虫酯复配共毒系数分别为123.24~212.40和171.80~335.80,显示出较好的增效作用。DDVP+残杀威复配效果较差。结论当淡色库蚊产生抗药性后,采用有机磷或氨基甲酸酯类杀虫剂与有机氯类杀虫剂混用的方法,能取得较好效果。 相似文献
24.
Orsolic N Giles FJ Gourdeau H Golemovic M Beran M Cortes J Freireich EJ Kantarjian H Verstovsek S 《British journal of haematology》2004,124(6):727-738
The in vitro and in vivo activity of a deoxycytidine analogue, troxacitabine, alone or in combination with imatinib mesylate (IM), was evaluated against human chronic myeloid leukaemia (CML) cell lines both sensitive (KBM5 and KBM7) and resistant (KBM5-R and KBM7-R) to IM. These cell lines differ in their sensitivity to IM but all showed similar sensitivity to treatment with troxacitabine (IC50 = 0.5-1 micromol/l). Combined treatment with troxacitabine and IM revealed additive or synergistic effects. Greater apoptotic response was seen with combined treatment than with either agent alone in KBM7-R cells. In clonogenic assays, troxacitabine showed activity against mononuclear cells from CML patients (IC50 = 0.01 micromol/l) with either IM-sensitive or resistant disease. In vivo efficacy studies were carried out in severe combined immunodeficient mice bearing KBM5 or KBM5-R cells. Troxacitabine was administered i.p. daily for 5 d starting on day 20, at doses of 5, 10, 20, or 25 mg/kg. IM was administered i.p. twice a day for 10 d at a dose of 50 mg/kg starting on day 25. In this setting of late stage disease, troxacitabine led to a significant increase in life span, while IM did not. When IM was combined with troxacitabine at 10 and 25 mg/kg in the KBM5 xenograft model, a further increase in life span was observed and some mice achieved long-term survival. These data indicate that the combination of troxacitabine and IM has significant preclinical activity in advanced CML and that clinical evaluation of this combination is warranted. 相似文献
25.
《Journal de Mycologie Médicale》2020,30(1):100921
AimAmong the most common mechanisms of multidrug resistance (MDR) in prevalent human fungal pathogen, Candida albicans, overexpression of drug efflux pumps remains the predominant mechanism. Hence to inhibit efflux pumps and chemosensitize C. albicans against traditional antifungal drugs still represents an attractive approach. The present study aimed to analyze the effect of Vanillin (Van), a natural food flavoring agent, on drug efflux pump activity of Candida albicans.Methods and resultsWe observed that Van specifically inhibits Candida drug resistance protein 2 (CaCdr2p) activity belonging to ATP Binding Cassette (ABC) superfamily as revealed by abrogated rhodamine 6G efflux and nile red accumulation assay with CaCdr2p over expressing strain. Insight studies into the mechanisms suggested that abrogated efflux by CaCdr2p is due to competitive mode of inhibition by Van as depicted by Lineweaver-Burk plot. RT-PCR, western blot and confocal microscopy further unraveled that Van leads to reduced expression of CDR2 and CaCdr2p mislocalization respectively. Furthermore, Van sensitizes the azole sensitive and resistant clinical matched pair of isolates Gu4/Gu5 and led to abrogated rhodamine 6G efflux and depleted ergosterol. Furthermore, Van synergizes with membrane targeting drugs fluconazole and amphotericin B as their fractional inhibitory coefficient index was less than 0.5.ConclusionVan being a potent inhibitor of CaCdr2p and chemosensitizing of drug resistant C. albicans warrants further studies to be exploited as effective antifungal agent. 相似文献
26.
目的 探讨他克莫司与伊曲康唑、特比萘芬联合对皮炎外瓶霉的体外抗真菌效果.方法 参考美国临床实验室标准化研究所M38-A2方案,测定特比萘芬和伊曲康唑对12株皮炎外瓶霉的最低抑菌浓度;利用棋盘法,测定他克莫司和伊曲康唑或特比萘芬的联合抗皮炎外瓶霉效果.结果 特比萘芬和伊曲康唑对皮炎外瓶霉最低抑菌浓度范围分别为(0.06 ~0.125) mg/L和(0.5 ~1) mg/L.他克莫司和特比萘芬联合对5株皮炎外瓶霉、他克莫司和伊曲康唑联合对10株皮炎外瓶霉有协同作用.两组均无拮抗作用.结论 他克莫司在体外与伊曲康唑或特比萘芬联合应用时,能够增加皮炎外瓶霉对伊曲康唑和特比萘芬的敏感性. 相似文献
27.
长春瑞滨对人肺腺癌973细胞放射增敏作用的实验研究 总被引:2,自引:0,他引:2
目的:探讨长春瑞滨(NVB)对非小细胞肺癌细胞放射效应影响及其与放射的最佳结合序贯。方法:以指数生长期的人肺腺癌973细胞为研究对象,采用克隆形成分析法进行0.1nM及1nMNVB与放射不同结合序贯实验,研究NVB与放射结合效应,利用"多靶单击"数学模型(SF=1-(1-е-D/D0)N)进行曲线拟合,获得细胞存活曲线及平均致死剂量、准阈剂量、D0比和增敏比等参数,进行效应评估。结果:0.1nM及1nMNVB照前、照后给药组的增敏比(SER)分别为0.957和0.989,1.295和1.042;0.1nM及1nMNVB照前、照后给药组的D0比分别为1.073和1.099,1.374和1.106。表明0.1nMNVB照前、照后给药时均无放射增敏作用;1nMNVB照前、照后给药时均与放射效应具有较明显协同作用,且照前给药组的协同作用明显强于照后给药组。结论:0.1nMNVB不具有增强放射效应的作用,1nMNVB具有较明显放射效应增强作用,且照前给药组的协同作用明显强于照后给药组。 相似文献
28.
29.
颐康冲剂对阿霉素、丝裂霉素、氟尿嘧啶的增效作用及其对毒性影响的实验研究 总被引:1,自引:0,他引:1
颐康冲剂由香菇、当归、红参等16味药材提制而成。实验结果表明,颐康冲剂与阿霉素、丝裂霉素及氟尿嘧啶分别伍用,能明显提高对小鼠移植肿瘤S180、H22及Lewis抑瘤率,与单用3种化疗药物相比,P值<0.05~0.001。对3种化疗药物所致免疫器官萎缩、巨噬细胞吞噬功能下降、染色体畸变及白细胞减少等均有显著保护作用,同时还能显著提高NK细胞活性。说明颐康冲剂不仅是一种有效的肿瘤化疗药物增效剂,而且能提高机体免疫功能,显著降低化疗药物的毒副反应。 相似文献
30.
Enhancement of camptothecin-induced cytotoxicity with UCN-01 in breast cancer cells: abrogation of S/G2 arrest 总被引:3,自引:0,他引:3
Purpose: To determine the ability of UCN-01 to abrogate the cell cycle arrest induced by camptothecin (CPT) in tumor cells that lack
p53 function, and therefore enhance the cytotoxicity of CPT in these cells in relation to normal cells with wild-type p53.
Methods: The responses of MDA-MB-231 and GI 101A breast cancer cells were compared to those of normal bovine endothelial cells. Cytotoxicity
was assessed by the MTT assay, and the resulting data were modeled using median-effect analysis. Inhibition of DNA synthesis
was determined by loss of [3H]thymidine incorporation, and cell cycle status was determined by flow cytometric analysis of propidium-iodide-stained nuclei.
Results: UCN-01, a specific inhibitor of protein kinase C (PKC) presently in clinical trials, abrogated CPT-induced activation of
S and G2 checkpoints in human MDA-MB-231 and GI 101A breast carcinoma cells, both of which are mutants for the p53 gene. This abrogation
occurred with the use of sublethal doses (100 nM) of UCN-01 and correlated with the enhancement of CPT-induced cytotoxicity. Median-effect analysis showed that synergistic
cytotoxic interactions existed between CPT and UCN-01 against these tumor cells. In normal cells, however, abrogation of the
S phase arrest caused accumulation in G0/G1 phase, perhaps by the presence of wild-type p53 activity, with no change in CPT-induced cytotoxicity. Conclusion: We have shown previously that the cytotoxicity of CPT is correlated with cell cycle response in normal and tumor cells.
Low doses of CPT arrest cells in the G2/M phase and inhibit DNA synthesis, but higher doses cause arrest of cells in S phase. Thus modulation of events at the S
and G2 checkpoints may provide an opportunity to enhance CPT-induced cytotoxicity in tumor cells. The results of this study indicate
that UCN-01 enhances the progression of tumor cells through S phase thus greatly increasing CPT-induced cytotoxicity. Normal
cells, however, are able to arrest in G0/G1 and thus avoid the increased toxicity induced by CPT. Our findings suggest potential usefulness of combining UCN-01 in topoisomerase
I inhibitor-based drug therapy for the treatment of breast cancer with a dysfunctional p53 gene.
Received: 25 February 1999 / Accepted: 4 October 1999 相似文献