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排序方式: 共有6142条查询结果,搜索用时 15 毫秒
991.
992.
Ibe S Shigemi U Sawaki K Fujisaki S Hattori J Yokomaku Y Mamiya N Hamaguchi M Kaneda T 《AIDS research and human retroviruses》2008,24(8):1121-1125
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996.
Imanishi M Nakajima Y Tomishima Y Hamashima H Washizuka K Sakurai M Matsui S Imamura E Ueshima K Yamamoto T Yamamoto N Ishikawa H Nakano K Unami N Hamada K Matsumura Y Takamura F Hattori K 《Journal of medicinal chemistry》2008,51(15):4804-4822
We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys. 相似文献
997.
Hasegawa T Kawazome A Matsumoto K Yanagimoto G Hayashi T Akimoto M Todo H Sugibayashi K 《Biological & pharmaceutical bulletin》2008,31(1):85-89
The skin disposition and metabolism of topically applied ethyl nicotinate (EN) were evaluated in dual agar gel disc-inserted hairless rats, which have two agar gel discs subcutaneously inserted into the abdominal region as drug receptors, and a topical formulation containing EN placed on either side of the gel disc through the skin. Plasma and agar levels of EN and its metabolite, nicotinic acid (NA), were followed every 2 h over 6 h. EN permeated through the skin barrier and partly metabolized to NA with 89.4% of the metabolite ratio [NA/(EN+NA)] at 6 h. Some EN and NA in the skin moved to the systemic circulation, and the remainder migrated into the agar gel below the formulation. The total amount (EN+NA) in the skin that distributed from the formulation directly to the systemic circulation and the application side of the gel corresponded to 95.2% and 4.8% of the total skin permeation at 6 h, respectively. Only NA was distributed from the systemic circulation to both agar gel discs. The NA fraction in the application side of the gel from the circulation was only 1% of the total amount in the agar gel. The metabolite ratio on the application side of the agar gel was higher than that in the receiver for the in vitro skin permeation using excised hairless rat skin. This difference was probably related to a lower EN ratio in viable skin in situ than in vitro. These results suggest that the present in situ method is useful to evaluate the skin disposition and metabolism of topically applied drugs. 相似文献
998.
Imanishi M Tomishima Y Itou S Hamashima H Nakajima Y Washizuka K Sakurai M Matsui S Imamura E Ueshima K Yamamoto T Yamamoto N Ishikawa H Nakano K Unami N Hamada K Matsumura Y Takamura F Hattori K 《Journal of medicinal chemistry》2008,51(6):1925-1944
A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists. 相似文献
999.
Niitsu Y Sugidachi A Ogawa T Jakubowski JA Hashimoto M Isobe T Otsuguro K Asai F 《European journal of pharmacology》2008,579(1-3):276-282
Antiplatelet and antithrombotic activity of multiple oral dosing of prasugrel were evaluated in several animal species. Prasugrel's active metabolite concentration-relatedly inhibited in vitro ADP-induced aggregation of rat, rabbit, dog, monkey and human platelets. Oral administration of prasugrel to dogs (0.03-0.3 mg/kg/day) and monkeys (0.1 and 0.3 mg/kg/day) once a day for 14 days resulted in potent, dose-related and cumulative inhibition of ADP-induced platelet aggregation. The inhibitory effects reached a plateau on days 3 to 5 and thereafter were maintained during dosing. Inhibition decreased gradually after cessation of dosing with near full recovery by 7 days after last dose. Antiplatelet and antithrombotic activity of prasugrel and clopidogrel were further examined in rats. Multiple oral dosing of prasugrel (0.3-3 mg/kg/day) to rats resulted in more potent inhibition of platelet aggregation compared to clopidogrel (3-30 mg/kg/day) and ticlopidine (30-300 mg/kg/day). Separate experiments confirmed that platelet inhibition was associated with inhibition of [(3)H]-2-methylthio-ADP binding to rat platelets. In a rat model of electrically-induced arterial thrombosis, prasugrel (0.1-1 mg/kg/day, p.o.) significantly prolonged the time to arterial occlusion and increased the duration of arterial patency. The inhibition of platelet aggregation of prasugrel was about 10 and 300 times more potent than clopidogrel and ticlopidine, respectively. Overall these results show that in several species multiple oral administration of prasugrel results in more potent inhibition of platelet aggregation and thrombus formation than clopidogrel and ticlopidine, and that these effects are mediated by inhibition of platelet ADP receptors. 相似文献
1000.
The growth of human breast cancer-derived MCF-7 cells was affected by oil-in-water lipid emulsions prepared with fish oil (FO) rich in n-3 fatty acids (FAs) and egg-yolk phosphatides (EYP) (FO-emulsions), but not by lipid emulsions prepared with soybean oil (SO) and EYP (SO-emulsions). On the other hand, the growth of human hepatocarcinoma HepG2 cells was affected by neither SO-emulsions nor FO-emulsions. The growth inhibition of MCF-7 cells in the presence of FO-emulsions was not affected by trolox, but was inhibited by alpha-lipoic acid, and was even potentiated by ebselen, which works as an antioxidant as well as a lipoxygenase inhibitor. Since prostaglandin E(3), generated from n-3 FAs by cyclooxygenases, has a suppressive effect on tumour cell growth, and increases when lipoxygenases are inhibited, these findings suggest that lipid emulsions incorporating triglycerides of n-3 FAs might be effective in suppressing the growth of MCF-7 cells, possibly via oxidative stress and through eicosanoid production with anti-proliferating activity against cancer cells. 相似文献