全文获取类型
收费全文 | 1301篇 |
免费 | 106篇 |
国内免费 | 6篇 |
专业分类
耳鼻咽喉 | 12篇 |
儿科学 | 8篇 |
妇产科学 | 19篇 |
基础医学 | 173篇 |
口腔科学 | 12篇 |
临床医学 | 125篇 |
内科学 | 474篇 |
皮肤病学 | 6篇 |
神经病学 | 91篇 |
特种医学 | 119篇 |
外科学 | 81篇 |
综合类 | 1篇 |
一般理论 | 1篇 |
预防医学 | 49篇 |
眼科学 | 4篇 |
药学 | 142篇 |
中国医学 | 1篇 |
肿瘤学 | 95篇 |
出版年
2024年 | 4篇 |
2023年 | 24篇 |
2022年 | 11篇 |
2021年 | 27篇 |
2020年 | 32篇 |
2019年 | 40篇 |
2018年 | 41篇 |
2017年 | 32篇 |
2016年 | 44篇 |
2015年 | 44篇 |
2014年 | 60篇 |
2013年 | 62篇 |
2012年 | 100篇 |
2011年 | 97篇 |
2010年 | 67篇 |
2009年 | 44篇 |
2008年 | 83篇 |
2007年 | 89篇 |
2006年 | 82篇 |
2005年 | 77篇 |
2004年 | 79篇 |
2003年 | 67篇 |
2002年 | 68篇 |
2001年 | 11篇 |
2000年 | 6篇 |
1999年 | 11篇 |
1998年 | 13篇 |
1997年 | 12篇 |
1996年 | 6篇 |
1995年 | 11篇 |
1994年 | 8篇 |
1993年 | 7篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 5篇 |
1989年 | 10篇 |
1988年 | 4篇 |
1987年 | 5篇 |
1986年 | 5篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 3篇 |
1978年 | 1篇 |
1975年 | 3篇 |
1974年 | 1篇 |
1970年 | 2篇 |
排序方式: 共有1413条查询结果,搜索用时 15 毫秒
91.
Synthesis and biological evaluation of 2,3,5-substituted [1,2,4]thiadiazoles as allosteric modulators of adenosine receptors 总被引:1,自引:0,他引:1
van den Nieuwendijk AM Pietra D Heitman L Göblyös A IJzerman AP 《Journal of medicinal chemistry》2004,47(3):663-672
A number of 2,3,5-substituted [1,2,4]thiadiazole analogues of SCH-202676 (N-(2,3-diphenyl[1,2,4]thiadiazole-5(2H)-ylidene)methanamine, 7a) were synthesized and tested as potential allosteric modulators of adenosine receptors. All compounds were capable of displacing the binding of the radiolabeled agonist [(3)H]CCPA to human A(1) adenosine receptors, whereas modest and varying effects were observed on the binding of [(3)H]DPCPX, a radiolabeled antagonist for this receptor subtype. Four compounds, 7a (SCH-202676), 7k (LUF5792), 7l (LUF5794), and 8e (LUF5789), were selected for more detailed characterization. They all proved allosteric inhibitors of agonist binding, with 7k being most potent, whereas their effects on antagonist binding were more ambiguous. Subsequently, experiments were done on human adenosine A(2A) and A(3) receptors. Compounds 7a and 7l displayed peculiar displacement characteristics of both radiolabeled agonist and antagonist binding to A(2A) receptors, whereas 7a showed some activity on A(3) receptors. 相似文献
92.
Chang LC Spanjersberg RF von Frijtag Drabbe Künzel JK Mulder-Krieger T van den Hout G Beukers MW Brussee J Ijzerman AP 《Journal of medicinal chemistry》2004,47(26):6529-6540
Adenosine receptor antagonists usually possess a bi- or tricyclic heteroaromatic structure at their core with varying substitution patterns to achieve selectivity and/or greater affinity. Taking into account molecular modeling results from a series of potent adenosine A1 receptor antagonists, a pharmacophore was derived from which we show that a monocyclic core can be equally effective. To achieve a compound that may act at the CNS we propose imposing a restriction related to its polar surface area (PSA). In consequence, we have synthesized two novel series of pyrimidines, possessing good potency at the adenosine A1 receptor and desirable PSA values. In particular, compound 30 (LUF 5735) displays excellent A1 affinity (Ki = 4 nM) and selectivity (< or =50% displacement of 1 muM concentrations of the radioligand at the other three adenosine receptors) and has a PSA value of 53 A2. 相似文献
93.
Veening JG Bouwknecht JA Joosten HJ Dederen PJ Zethof TJ Groenink L van der Gugten J Olivier B 《Progress in neuro-psychopharmacology & biological psychiatry》2004,28(4):699-707
In mammals, stress exposure is frequently associated with an elevated body temperature ['emotional fever', stress-induced hyperthermia (SIH)]. Rectal measurement of body core temperature of the mouse induces a rise of 1-1.5 degrees C over a 10- to 15-min time interval. This phenomenon has been exploited to design a specific test for measuring stress-induced hyperthermia: the singly-housed SIH paradigm in mice. In the present experiments, changes in body temperature and corticosterone levels were studied 10, 30, 60, 90 and 120 min after the first insertion of the rectal probe. In addition, changes in patterns of neural activation, as observed after immunostaining for Fos-immunoreactivity (Fos-IR), were studied in the brains of animals perfused at times 0, 60 or 120 min. Our results show that SIH and corticosterone levels have their peak values between 10 and 30 min and are no longer different from control values after 60 min. Patterns of Fos-IR have been studied in 11 brain areas, of which 2 brain areas (anterodorsal preoptic and periolivary nuclei) showed a continuing rise in Fos-IR after 60 and 120 min, while six nuclei, mostly hypothalamic and septal, showed a peak induction of Fos-IR after 60 min. In three brain areas, no consistent changes in Fos-IR could be observed. The authors conclude that the changes observed in the patterns of Fos-IR, after application of the singly-housed SIH-test in mice, reflect the effects of both the stressor application and the ensuing thermoregulatory responses. The role of each activated brain area in either one of these effects is discussed in view of data available from the literature. 相似文献
94.
Integrated oral bioavailability projection using in vitro screening data as a selection tool in drug discovery 总被引:2,自引:0,他引:2
Stoner CL Cleton A Johnson K Oh DM Hallak H Brodfuehrer J Surendran N Han HK 《International journal of pharmaceutics》2004,269(1):241-249
The objective of the analysis described herein is to examine the in vitro/in vivo relationship of estimated bioavailability values and also the applicability of the estimated in vitro bioavailability to lead candidate selection in drug discovery. To this end, in vitro ADME data from screening assays as well as in vivo rat pharmacokinetic (PK) data were compiled for 140 compounds across therapeutic areas from the Pfizer library in Ann Arbor. The compounds span a broad range of structural types, including neutral, basic, and acidic compounds. Solubility and Caco-2 permeability data from in vitro ADME screening were used to calculate the fraction dose absorbed (FDp) using the physiologically based IDEA model. In vitro metabolic stability (t(1/2)) from human and rat liver microsomal incubations was converted to an in vitro intrinsic clearance value (CL(int)'), which was then scaled up to reflect in vivo clearance (CL) and hepatic extraction as described by Obach et al. [J. Pharmcol. Exp. Ther. 283 (1997) 46]. Subsequently, the in vitro/in vivo relationship between the measured bioavailability (F(obs)) in rats and the estimated bioavailability (F(est)) from FDp and predicted CL values was examined. The observed data suggest that compounds with low estimated in vitro bioavailability (F(est)<15%) are more likely to have low in vivo bioavailability (F(obs)<30%). Therefore, the present study indicates that in vitro estimation of bioavailability is an efficient tool to eliminate compounds having low bioavailability prior to in vivo characterization and therefore can be used to reduce attrition due to poor ADME properties in drug development. 相似文献
95.
96.
97.
Dijkstra JB Strik JJ Lousberg R Prickaerts J Riedel WJ Jolles J van Praag HM Honig A 《Journal of affective disorders》2002,70(2):181-190
BACKGROUND: We evaluated the cognitive profile of 48 patients with major depression following their first myocardial infarction (MI). METHODS: The cognitive performance of the patients was compared with the performance of 48 non-depressed MI patients and 48 healthy controls. RESULTS: Depressed MI patients performed slower on a simple cognitive speed related measure compared with non-depressed MI patients and healthy controls. Attention and speed-related aspects of cognitive functioning were not affected. Surprisingly, (depressed) MI patients showed even better performances with respect to memory function. LIMITATION: No patients with non-MI-related depression were included. CONCLUSIONS: The cognitive profile of major depression after MI differs from that of non-cardiac-related depressive disorder, as described in the literature. This may reflect a different etiology of post MI depression from non-cardiac-related depression. 相似文献
98.
The rectus femoris muscle in the rabbit represents a reliable flap for experimental work in many aspects of microsurgery. The operative exposure of the flap is often tricky for those unfamiliar with the anatomy, as is isolation of its neurovascular pedicle. Experience with 59 consecutive rectus femoris flaps demonstrated five separate patterns of arteral and venous pedicles. The nervous anatomy was found to be constant. Once recognized, these vessel patterns can be used to facilitate pedicle dissection, thus minimizing intraoperative mistakes which may endanger the viability of the flap. 相似文献
99.
Beukers MW Wanner MJ Von Frijtag Drabbe Künzel JK Klaasse EC IJzerman AP Koomen GJ 《Journal of medicinal chemistry》2003,46(8):1492-1503
Four subtypes of adenosine receptors are currently known, that is, A(1), A(2A), A(2B), and A(3) receptors. Interestingly, quite substantial species differences exist especially between human and rat A(3) receptors. As a result, ligands such as CCPA, which are very selective for the rat A(1) receptor versus the human A(3) receptor, are substantially less selective when the human A(1) and A(3) receptors are compared. New 2-substituted and 2,N(6)-disubstituted adenosines were synthesized, and their affinities for the human adenosine A(1), A(2A), A(2B), and A(3) receptors were determined. Although large substituents on the C2-position are generally thought to yield adenosine A(2A) receptor selective ligands, the reported series of 2-triazeno-substituted adenosines had a very high affinity for the A(1) receptor. For example, 2-(3-phenylaminocarbonyltriazene-1-yl)adenosine had an affinity of 6.1 +/- 1.3 nM for the human adenosine A(1) receptor. Introduction of a diphenethyl substituent at the N(6)-position of this compound resulted in a high-affinity agonist, 3.1 +/- 0.9 nM, for the human adenosine A(1) receptor with 316- and 45-fold selectivity versus the human A(2A) and human A(3) receptors, respectively. The most selective, high-affinity human adenosine A(1) receptor agonist was the disubstituted compound N(6)-cyclopentyl-2-(3-phenylaminocarbonyltriazene-1-yl)adenosine (TCPA). TCPA had an affinity of 2.8 +/- 0.8 nM for the human adenosine A(1) receptor and was 75-fold and 214-fold selective versus the human A(2A) and human A(3) receptors, respectively. In addition, TCPA was a full agonist and inhibited the forskolin-induced cAMP production of CHO cells stably transfected with the human adenosine A(1) receptor with an IC(50) of 1.5 +/- 0.5 nM. 相似文献
100.
Voors AA Oosterga M Buikema H Mariani M Grandjean JG van Gilst WH 《Journal of cardiovascular pharmacology》2003,41(2):178-184
The current study aimed to demonstrate differences between angiotensin (Ang)-converting enzyme (ACE) inhibition and Ang II-AT1 receptor antagonism on full concentration-contraction responses to Ang I. Contraction responses to increasing concentrations of Ang I (1 nM-1 microM) were evaluated in organ baths in the presence of captopril (10 microM-1 mM) with or without a chymase inhibitor (1 microM soybean trypsin inhibitor), or irbesartan (0.1 nM-microM), in internal mammary arteries from 25 patients undergoing coronary bypass surgery. Responses were expressed as a percentage of the control response to 10 microM phenylephrine. Captopril did not change the maximum response to Ang I (control: 46.3 +/- 6.3%, captopril: 43.0 +/- 4.6%). In contrast, 0.1 microM irbesartan completely blocked the maximum response to Ang I (from 45.8 +/- 6.7% to 1.9 +/- 1.9%, p < 0.001). However, addition of soybean trypsin inhibitor to captopril more effectively shifted -log pD2 than captopril alone (0.47 +/- 0.06 vs 0.95 +/- 0.14 log units, p = 0.007). Ang I-mediated effects are much more effectively inhibited by Ang II antagonism than by ACE inhibition. The incomplete effects of captopril on the inhibition of Ang II formation might be caused by alternative Ang II forming enzyme(s), as was demonstrated by the additive effects of soybean trypsin inhibitor added to captopril. 相似文献