全文获取类型
收费全文 | 564篇 |
免费 | 44篇 |
国内免费 | 6篇 |
专业分类
儿科学 | 22篇 |
妇产科学 | 8篇 |
基础医学 | 75篇 |
口腔科学 | 5篇 |
临床医学 | 88篇 |
内科学 | 141篇 |
皮肤病学 | 14篇 |
神经病学 | 10篇 |
特种医学 | 37篇 |
外科学 | 28篇 |
综合类 | 12篇 |
预防医学 | 53篇 |
眼科学 | 6篇 |
药学 | 45篇 |
中国医学 | 8篇 |
肿瘤学 | 62篇 |
出版年
2023年 | 5篇 |
2022年 | 22篇 |
2021年 | 29篇 |
2020年 | 18篇 |
2019年 | 8篇 |
2018年 | 9篇 |
2017年 | 4篇 |
2016年 | 11篇 |
2015年 | 21篇 |
2014年 | 13篇 |
2013年 | 38篇 |
2012年 | 47篇 |
2011年 | 39篇 |
2010年 | 21篇 |
2009年 | 22篇 |
2008年 | 29篇 |
2007年 | 33篇 |
2006年 | 41篇 |
2005年 | 26篇 |
2004年 | 33篇 |
2003年 | 22篇 |
2002年 | 25篇 |
2001年 | 8篇 |
2000年 | 6篇 |
1999年 | 2篇 |
1998年 | 13篇 |
1997年 | 17篇 |
1996年 | 6篇 |
1995年 | 7篇 |
1994年 | 3篇 |
1993年 | 5篇 |
1991年 | 4篇 |
1990年 | 3篇 |
1989年 | 6篇 |
1988年 | 1篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1971年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有614条查询结果,搜索用时 15 毫秒
71.
A Benakis Tran Quang Binh A Keundjian M W Scheiwe 《European journal of drug metabolism and pharmacokinetics》2006,31(1):41-45
In recent years, Artemisinin and particularly one of its derivatives--Artesunate (ART--has become an essential alternative for treatment of both uncomplicated and severe falciparum malaria in Asia and Africa as well. Therefore, these compounds are still and inccreasingly in the focus of interest because of quick acting of this drug, is able to help even unconscious to overcome the malaria attack, when administered by injection. As an alternative, RECTOCAPS have been developed and their use is meanwhile well established. From earlier studies in children, suffering from plasmodium falciparum malaria, we obtained a high level of DHART in the blood, but as expected also a rapid decline in the levels of both DHART and ART. A second administration of ART was additionally applied 4 hours after the first administration. DHART and ART plasma levels were found to last longer on an assumed therapeutic level than those obtained after one administration only. The fever clearance and the parasitemia reduction rates were found to be effective according to this dosing regimen. In view of these findings, we decided to conduct the actual described study by administering 200 mg of ART every 3 hours (0, 3, 6 and 9 h) by the rectal route. Soft geiatine capsules (RECTOCAPS) containing 200 mg of ART GMP--type each (Artesunic acid) were administered by rectal route. Each patient received four RECTOCAPS capsules (4 x 200 mg of ART) over a 3 h period. 12 adult patients with uncomplicated malaria were selected. Age, weight, height, body temperature, parasite counts before treatment and their evolution until 96 h are determined. Blood samples were taken at short time intervals after starting with the first medication: 0, 30 min, 60 min, 3 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, 84 h, 96 h and 108 h. The aliquots of all the blood samples were used for performing parasite counts. Plasma obtained following the traditional procedure was kept at -40 degrees C until analysis. HPLC technique with electrochemical detector was used for quantification of ART and DHART. From the blood concentration values of ART and DHART, the following observation can be derived: the onset of action is observed within the first half hours, therapeutic levels of the drug obtained (89 microg/ml ART compared to 84 microg/ml DHART). The DHART levels are somewhat higher than those of ART (a peak concentration after 6 h starting medication of 151 microg/ml ART as compared to 276 microg/ml DHART). The variations as a function of frequency of DHART uptake are much less marked than those observed for ART. Another finding is that after the administration, some sort of a plateau of DHART and ART is built up, lasting at least from 9 to 12 hours with DHART level of about 190 microg/ml and ART of 90 microg/ml. In the case of single-dose administration, the levels of both compounds were below the detection threshold after three hours. With regard to the parasite counts, although there were inter-individual variations, it should be noted that after 48 hours a high proportion of the patients (8 out of 12) was completely clear of parasites. Similar results were observed with regard to the body temperature (7 out of 12 returned to normal temperature 36 hours after starting the therapy). The findings of the study support the RECTOCAPS application principle resulting in effectiveness both for the velocity of drug uptake as well as for the height of plasma levels. Repeated administration of ART can extend the duration of therapeutic plasma levels of the drug. 相似文献
72.
Chu XJ DePinto W Bartkovitz D So SS Vu BT Packman K Lukacs C Ding Q Jiang N Wang K Goelzer P Yin X Smith MA Higgins BX Chen Y Xiang Q Moliterni J Kaplan G Graves B Lovey A Fotouhi N 《Journal of medicinal chemistry》2006,49(22):6549-6560
The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K(i) > 10 microM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K(i) = 0.001, 0.003, and 0.001 microM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC(50) = 0.08 microM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer. 相似文献
73.
Blay JY Bonvalot S Fayette J Stockle E Ray-Coquard I Coindre JM Duffaud F Taieb S Sunyach MP Ranchere D Meeus P Le Cesne A Bui BN 《Bulletin du cancer》2006,93(11):1093-1098
This document describe s the proposed clinical practices guidelines for neoadjuvant chemotherapy in soft tissue sarcomas proposed by the French Sarcoma Group.Neo-adjuvant chemotherapy remains an experimental therapeutic procedure in soft tissue sarcomas. Neo-adjuvant chemotherapy may be proposed in three different types of situations: 1) a locally advanced tumor, non accessible to R0 or 1 removal of the lesion. Its objective is there to allow for R0 or R1 surgical removal of the tumor. 2) A locally advanced tumor, accessible to R0 or 1 removal of the lesion, but with a mutilating surgery (amputation). Its objective is there to allow for R0 or R1 conservative surgical removal of the tumor. In both situation, the strategy should be discussed beforehand in a multidisciplinary specialized consultation for sarcoma. 3) In the case where complete (R0 or R1) surgical removal of the tumor can be performed, neooadjuvant chemotherapy has no demonstrated role. The only randomized phase III clinical trial testing neo-adjuvant chemotherapy in this setting, i.e. the STBSG 62871 STBSG trial, failed to demonstrate any benefit in terms of overall or progression free survival. The selection of the type of chemotherapy regimen given in the neoadjuvant setting should be discussed in a multidisciplinary setting, considering the age and the general status of the patient; young patients, without associated concomittent illnesses should be proposed for a combined chemotherapy regimen, combining doxorubicin (> or = 50 mg/m2) and ifosfamide (> 5 g/m2) on the basis of randomized trials demonstrating an improvement of response rate versus single agent therapy with doxorubine. In elderly and/or frail patients, conversely, single agent doxorubicin may be the preferred option. 相似文献
74.
Binh Au Melfort R. Boulton Phillip P. Narini Christopher A. G. McCulloch John B. Hay 《Journal of periodontal research》1996,31(8):570-578
Lymphatic drainage and circulation in periodontal tissues have been cited as important components of host defence and pathogenic mechanisms, but quantitative data are sparse because of the technical difficulties associated with small animal lymphatic studies. However, the lymphatic vessels draining the periodontal tissues and surrounding region are sufficiently large in sheep to permit surgical placement of lymphatic catheters. Consequently, lymph and recirculating lymphocytes can be continuously collected and this permits the quantitative assessment of local immune responses in these tissues. We have studied the lymphatic drainage pathways from the labial gingival tissues in sheep by two methods. First, in a series of anatomical studies (n=6), a complex of Evan's blue dye and albumin was injected into the labial gingival tissues. One hour after injection the animals were sacrificed and the submandibular and cervical regions were dissected to expose the stained lymphatics. This anatomical study demonstrated 2 major drainage pathways: 1) cervical lymph ducts and; 2) efferent prescapular lymphatics. Secondly, to compare the relative importance of these two drainage pathways, radiolabeled protein (125I-albumin) was injected directly into the gingival tissues and its appearance in the cervical and prescapular lymph was measured (n=7). Despite the technical difficulties encountered in the experiments, data collected showed that over 7.5 h, 64.7% of the injected protein was recovered in the prescapular and cervical lymph vessels (31.8±6.5% and 32.9±8.5%, respectively). In addition, 11.9±2.1% of the injected protein was transported to the blood by routes not involving the cannulated cervical and prescapular lymph vessels. With most of the remaining radiolabeled protein (17.9±4.9%) recovered from the injection site, we were able to account for approximately 95% of the injected protein. This study suggests that the lymph drainage from this region in the sheep model could provide one of the best described closed and contained systems and thus, could be a useful system for future continous monitoring of inflammatory responses during experimental periodontal diseases. 相似文献
75.
Dung TD Chang HC Binh TV Lee MR Tsai CH Tsai FJ Kuo WW Chen LM Huang CY 《International journal of molecular medicine》2012,29(6):1045-1052
Hepatocellular carcinoma is a common type of cancer that is usually associated with poor prognosis. In this study, we examined the in vitro and in vivo mechanisms of the traditional Vietnamese herb Zanthoxylum avicennae on the inhibition of HA22T human hepatocellular carcinoma cell proliferation. HA22T cells were treated with different concentrations of Zanthoxylum avicennae extracts (YBBEs) and analyzed with the MTT assay, western blot analysis, flow cytometry, siRNA transfection assays and co-immunoprecipitation assay. Additionally, the HA22T-implanted xenograft nude mouse model was applied to confirm the cellular effects. YBBEs showed a strong inhibition of HA22T cell viability in a dose-dependent manner and significantly reduced cell proliferation-related proteins as well as induced cell cycle arrest in the G2/M phase. Protein phosphatase 2A (PP2A) siRNA or okadaic acid totally blocked YBBE-mediated cell proliferation inhibition. In addition, an HA22T-implanted nude mouse model further confirmed that YBBEs inhibit HA22T tumor cell growth and downregulate the survival and cell cycle regulating proteins, as well as activate the PP2A protein. Our findings indicate that the inhibition of HA22T cell proliferation by YBBEs is mediated through PP2A activation. 相似文献
76.
Nakasone H Binh PN Yamazaki R Tanaka Y Sakamoto K Ashizawa M Sato M Terasako K Kimura S Kikuchi M Kako S Okuda S Oshima K Tanihara A Nishida J Abe Y Kanda Y 《Blood》2011,117(12):3469-3472
Recently, a growing body of evidence has suggested that adiponectin, which is secreted by adipose tissues, plays a critical role in obesity-related and autoimmune diseases. We compared the concentrations of adiponectin among 26 normal subjects and 34 allogeneic stem cell transplantation recipients. The concentrations of adiponectin were significantly higher in recipients with chronic graft-versus-host disease (cGVHD) than those in subjects without cGVHD (21.7 ± 11.0 vs 9.1 ± 6.1 μg/mL in females, P < .001; and 10.1 ± 6.8 vs 4.3 ± 2.9 μg/mL in males, P = .003). Multivariate analysis revealed that a higher concentration of adiponectin was associated with female sex (β-coefficient 8.2, P < .0001) and the severity of cGVHD (β-coefficient 6.6, 12.7, and 15.6, P < .01, each for mild, moderate, and severe cGVHD, respectively). In addition, adiponectin levels increased as cGVHD progressed, decreased as cGVHD improved, and did not change with stable cGVHD. In conclusion, adiponectin was associated with the severity of cGVHD and might play a role in the pathophysiology of cGVHD. 相似文献
77.
Dimitris Mitsouras Praveen Kumar Vemula Peng Yu Ming Tao Binh T. Nguyen Christina M. Campagna Jeffrey M. Karp Robert V. Mulkern C. Keith Ozaki Frank J. Rybicki 《Magnetic resonance in medicine》2011,65(1):176-183
An implantable MR contrast agent that can be covalently immobilized on tissue during surgery has been developed. The rationale is that a durable increase in tissue contrast using an implantable contrast agent can enhance postsurgical tissue differentiation using MRI. For small‐vessel (e.g., vein graft) MRI, the direct benefit of such permanent “labeling” of the vessel wall by modification of its relaxation properties is to achieve more efficient imaging. This efficiency can be realized as either increased contrast leading to more accurate delineation of vessel wall and lesion tissue boundaries, or, faster imaging without penalizing contrast‐to‐noise ratio, or a combination thereof. We demonstrate, for the first time, stable long‐term MRI enhancement using such an exogenous contrast mechanism based on immobilizing a modified diethylenetriaminepentaacetic acid gadolinium3+ dihydrogen complex on a human vein using a covalent amide bond. Signal enhancement due to the covalently immobilized contrast agent is demonstrated for excised human vein specimens imaged at 3 T, and its long‐term stability is demonstrated during a 4‐month incubation period. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
78.
Sébastien Salas Tetsuro Noguchi Philippe Terrier Dominique Ranchere‐Vince Pauline Lagarde Jean Benard Sébastien Forget Camille Blanchard Julien Dômont Sylvie Bonvalot Louis Guillou Agnès Leroux Agnes Mechine‐Neuville Patrick Schöffski Marik Laë Françoise Collin Olivier Verola Amelie Carbonnelle Laure Vescovo Binh Bui Véronique Brouste Hagay Sobol Alain Aurias Jean‐Michel Coindre 《Genes, chromosomes & cancer》2010,49(6):560-568
Desmoid tumors are fibroblastic/myofibroblastic proliferations. Previous studies reported that CTNNB1 mutations were detected in 84% and that mutations of the APC gene were found in several cases of sporadic desmoid tumors lacking CTNNB1 mutations. Forty tumors were analyzed by comparative genomic hybridization (CGH). Karyotype and fluorescence in situ hybridization revealed a nonrandom occurrence of trisomy 8 associated with an increased risk of recurrence. We report the first molecular characterization including a large series of patients. We performed array CGH on frozen samples of 194 tumors, and we screened for APC mutations in patients without CNNTB1 mutation. A high frequency of genomically normal tumors was observed. Four relevant and recurrent alterations (loss of 6q, loss of 5q, gain of 20q, and gain of Chromosome 8) were found in 40 out of 46 tumors with chromosomal changes. Gain of Chromosomes 8 and 20 was not associated with an increased risk of recurrence. Cases with loss of 5q had a minimal common region in 5q22.5 including the APC locus. Alterations of APC, including loss of the entire locus, and CTNNB1 mutation could explain the tumorigenesis in 89% of sporadic desmoids tumors and desmoids tumors occurring in the context of Gardner's syndrome. A better understanding of the pathogenetic pathways in the initiation and progression of desmoid tumors requires studies of 8q and 20q gains, as well as of 6q and 5q losses, and study of the Wnt/β‐catenin pathway. © 2010 Wiley‐Liss, Inc. 相似文献
79.
80.
Tumor cells transfected with strong antigenic epitopes were able to stimulate humoral response against relevant wild-type tumors. Crossreacting immune sera have been obtained by immunizing C57BL/6 mice with OVA-transfected leukemia EL-4 (subclone E.G7) and OVA-transfected melanoma B16 (subclone MO.5) stimulated with interferon-gamma. Tumors were significantly inhibited when antisera were injected subcutaneously close to the site of solid wild-type tumors EL-4 and B16 grafted onto C57BL/6 mice. 相似文献