全文获取类型
收费全文 | 220篇 |
免费 | 2篇 |
国内免费 | 5篇 |
专业分类
耳鼻咽喉 | 1篇 |
基础医学 | 21篇 |
临床医学 | 21篇 |
内科学 | 30篇 |
皮肤病学 | 4篇 |
神经病学 | 1篇 |
特种医学 | 91篇 |
外科学 | 31篇 |
综合类 | 2篇 |
预防医学 | 7篇 |
眼科学 | 1篇 |
药学 | 2篇 |
肿瘤学 | 15篇 |
出版年
2022年 | 1篇 |
2021年 | 2篇 |
2020年 | 2篇 |
2019年 | 4篇 |
2018年 | 4篇 |
2017年 | 6篇 |
2015年 | 4篇 |
2014年 | 7篇 |
2013年 | 9篇 |
2012年 | 12篇 |
2011年 | 18篇 |
2010年 | 11篇 |
2009年 | 11篇 |
2008年 | 22篇 |
2007年 | 22篇 |
2006年 | 18篇 |
2005年 | 21篇 |
2004年 | 11篇 |
2003年 | 10篇 |
2002年 | 14篇 |
2001年 | 6篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 1篇 |
1991年 | 3篇 |
1989年 | 1篇 |
排序方式: 共有227条查询结果,搜索用时 0 毫秒
131.
Sameera Senaweera Tiffany C. Edwards Jayakanth Kankanala Yan Wang Rajkumar Lalji Sahani Jiashu Xie Robert J. Geraghty Zhengqiang Wang 《药学学报(英文版)》2022,12(4):1671-1684
Current drugs for treating human cytomegalovirus (HCMV) infections are limited by resistance and treatment-associated toxicities. In developing mechanistically novel HCMV antivirals, we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit (8a) inhibiting HCMV in submicromolar range. We describe herein the structure–activity relationship (SAR) for 8a, and the characterization of potent analogs for cytotoxicity/cytostatic property, the preliminary mechanism of action, and the absorption, distribution, metabolism and excretion (ADME) properties. The SAR revealed a few pharmacophore features conferring optimal antiviral profile, including the 5-OH, the N-1 benzyl, at least one –CH2− in the linker, and a di-halogen substituted phenyl ring in the amide moiety. In the end, we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index. The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay, a virus entry assay, a time-of-addition assay, and a compound withdrawal assay. ADME profiling measuring aqueous solubility, plasma and liver microsomal stability, and parallel artificial membrane permeability assay (PAMPA) permeability demonstrated largely favorable drug-like properties. Together, these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.KEY WORDS: Human cytomegalovirus, N-Benzyl hydroxypyridone carboxamides, Structure–activity relationship, Mechanism of action 相似文献
132.
133.
134.
Hepatocellular carcinoma (HCC), the most common primary liver tumor, is notoriously resistant to systemic therapies, and often recurs even after aggressive local therapies. HCCs rely on the formation of new blood vessels for growth, and VEGF is critical in this process. A hallmark of new vessel formation in tumors is their structural and functional abnormality. This leads to an abnormal tumor microenvironment characterized by low oxygen tension. The liver is perfused by both arterial and venous blood and the resulting abnormal microenvironment selects for more-aggressive malignancies. Anti-VEGF therapy with sorafenib was the first systemic therapy to demonstrate improved survival in patients with advanced-stage HCC. This important development in the treatment of HCC raises hope as well as critical questions on the future development of targeted agents including other antiangiogenic agents, which hold promise to further increase survival in this aggressive disease. 相似文献
135.
136.
137.
Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue--initial experience 总被引:10,自引:0,他引:10
PURPOSE: To prospectively assess computed tomographic (CT) perfusion for evaluation of tumor vascularity of advanced hepatocellular carcinoma (HCC) and to correlate CT perfusion parameters with tumor grade and serum markers. MATERIALS AND METHODS: The study was HIPAA compliant and was approved by the institutional review board. Patients provided informed consent. Thirty patients (22 men, eight women; mean age, 60 years; range, 28-79 years) with unresectable or metastatic HCC were studied. Dynamic first-pass CT perfusion was performed in primary (n=25) and metastatic (n=5) HCCs after intravenous injection of contrast medium. Data were analyzed to calculate tissue blood flow, blood volume, mean transit time, and permeability-surface area product. Repeat examination was performed in four patients within 30 hours to test reproducibility of CT perfusion. CT perfusion parameters were compared among tumors of different grades, with presence or absence of portal vein invasion, with presence or absence of cirrhosis, and of various extrahepatic metastases. Parameters were correlated with HCC serum markers. One-way analysis of variance was used to calculate variations in CT perfusion parameters. RESULTS: Good correlation (r=0.9, P<.01) was observed between repeat examination results and first CT examination results. There was a significant difference (P 相似文献
138.
139.
BACKGROUND: Recent reports indicate increased incidence of Clostridium botulinum infections, particularly among drug abusers and tissue allograft recipients. Botulinum toxin also has potential application in biochemical warfare. The neurotoxin-induced paralysis often requires mechanical ventilation with and without muscle relaxants. The authors investigated the long-term effects of botulinum toxin on muscle function, expression of nicotinic acetylcholine receptors (nAChRs), and their interaction with muscle relaxant, atracurium. METHODS: Rats (n=30) were injected with varying doses (0.625, 2.5, and 10 U) of botulinum toxin into the tibialis muscle. Control animals (n=9) received an equivalent volume of saline. At 128 days after injection, neuromuscular function, pharmacodynamics of atracurium, and nAChRs were evaluated. RESULTS: Nerve-evoked tensions, including tetanic tension and muscle mass, were decreased on the toxin-injected side in a dose-dependent manner relative to saline-injected controls as well as the contralateral side. Specific muscle tension and specific tetanic muscle tension (tensions/muscle mass) were not reduced. The ED10 of atracurium was reduced, the ED50 was unchanged, and the ED90 was increased in the highest (10-U) dose of toxin group. The atracurium plasma concentration to maintain a steady state 50% paralysis was significantly reduced in the 10-U toxin group. The nAChR concentrations in the tibialis muscle were significantly increased in a dose-dependent manner in all experimental groups. CONCLUSION: Botulinum toxin causes dose-dependent long-term neuromuscular changes. The loss of tension generating capacity is almost exclusively related to muscle atrophy, because the specific tension did not change. The decreased ED10, unaltered ED50, and increased ED90 to atracurium suggest its interactions with different isoforms of receptors having varying sensitivity to atracurium. The absence of fade, despite the persistent botulinum toxin-induced denervation (increased nAChRs), suggests that the up-regulated nAChRs may have compensated for the prejunctional effects of botulinum toxin. 相似文献
140.