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991.
Savegnago L Jesse CR Pinto LG Rocha JB Barancelli DA Nogueira CW Zeni G 《Pharmacology, biochemistry, and behavior》2008,88(4):418-426
This study investigated the possible antidepressant-like and anxiolytic-like effects of diphenyl diselenide, (PhSe)(2) in mice. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the antidepressant-like effect was also evaluated. The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced by (PhSe)(2) (5-100 mg/kg; oral route, p.o.). The antiimmobility effect of (PhSe)(2) (5 mg/kg, p.o.) in the TST was prevented by pretreatment of mice with L-arginine [a substrate for nitric oxide synthase (NOS)], methylene blue [an inhibitor of NO synthase and sGC] and sildenafil [a phosphodiesterase 5 inhibitor]. Furthermore, a sub-effective dose of (PhSe)(2) (0.1 mg/kg, p.o.) produced a synergistic antidepressant-like effect with N(G)-nitro-L-arginine [L-NNA; 0.3mg/kg, i.p. inhibitor of NOS], (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ; 30 pmol/site i.c.v., a specific inhibitor of soluble guanylate cyclase (sGC)], fluoxetine and imipramine in the TST. (PhSe)(2) (50-100 mg/kg, p.o.) induced anxiolytic-like effect in the elevated plus-maze test and light/dark box. Together the results indicate that (PhSe)(2) elicited significant antidepressant-like and anxiolytic-like effects. The antidepressant-like action caused by (PhSe)(2) seems to involve an interaction with L-arginine-NO-cGMP pathway. 相似文献
992.
Castro NG Costa RS Pimentel LS Danuello A Romeiro NC Viegas C Barreiro EJ Fraga CA Bolzani VS Rocha MS 《European journal of pharmacology》2008,580(3):339-349
LASSBio-767 [(−)-3-O-acetyl-spectaline] and LASSBio-822 [(−)-3-O-tert-Boc-spectaline] were recently described as cholinesterase inhibitors derived from the natural piperidine alkaloid (−)-spectaline, obtained from the flowers of Senna spectabilis (Fabaceae). We investigated their mechanism of inhibition of acetylcholinesterase and their efficacy in reversing scopolamine-induced amnesia. Competition assays with the substrate acetylthiocholine showed a concentration-dependent reduction in rat brain cholinesterase Vmax without changes in apparent Km. The kinetic data for LASSBio-767 and LASSBio-822 were best fit by a model of simple linear noncompetitive inhibition with Ki of 6.1 μM and 7.5 μM, respectively. A dilution assay showed a fast and complete reversal of inhibition, independent of incubation time. Simulated docking of the compounds into the catalytic gorge of Torpedo acetylcholinesterase showed interactions with the peripheral anionic site, but not with the catalytic triad. Anti-amnestic effects in mice were assessed in a step-down passive avoidance test and in the Morris water maze 30 min after injection of scopolamine (1 mg/kg i.p.). Saline, LASSBio-767, or LASSBio-822 was administered 15 min before scopolamine. Both compounds reversed the scopolamine-induced reduction in step-down latency at 0.1 mg/kg i.p. LASSBio-767 reversed scopolamine-induced changes in water maze escape latency at 1 mg/kg i.p. or p.o., while its cholinergic side effects were absent or mild up to 30 mg/kg i.p. (LD50 above 100 mg/kg i.p.). Thus, the (−)-spectaline derivatives are potent cholinergic agents in vivo, with a unique profile combining noncompetitive cholinesterase inhibition and CNS selectivity, with few peripheral side effects. 相似文献
993.
Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity 总被引:1,自引:0,他引:1
Alig L Alsenz J Andjelkovic M Bendels S Bénardeau A Bleicher K Bourson A David-Pierson P Guba W Hildbrand S Kube D Lübbers T Mayweg AV Narquizian R Neidhart W Nettekoven M Plancher JM Rocha C Rogers-Evans M Röver S Schneider G Taylor S Waldmeier P 《Journal of medicinal chemistry》2008,51(7):2115-2127
The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed. 相似文献
994.
Barroso EM Costa LS Medeiros VP Cordeiro SL Costa MS Franco CR Nader HB Leite EL Rocha HA 《Planta medica》2008,74(7):712-718
Fucan is a term used to denominate a family of sulfated L-fucose-rich polysaccharides. The brown alga Spatoglossum schr?ederi (Dictyotaceae) has three heterofucans namely fucan A, B and C. The 21 kDa fucan A is composed of a core of a beta (1-3) glucuronic acid-containing oligosaccharide of 4.5 kDa with branches at C4 of the fucose chains alpha (1-3) linked. The fucose is mostly substituted at C4 with a sulfate group and at C2 with chains of beta (1-4) xylose. This fucan has neither anticoagulant (from from 0.1 to 100 microg) nor hemorrhagic activities (from 50 to 800 microg/mL). The antithrombotic test in vivo showed that fucan A has no activity in any of the concentrations (from 0.2 to 20 microg/g/day) tested 1 h after polysaccharide administration. However, when fucan A was injected endovenously 24 h before the ligature of the venae cavae, we observed a dose-dependent effect, reaching saturation at around 20 microg/g of rat weight. In addition, this effect is also time-dependent, reaching saturation around 16 h after fucan administration. In addition, regardless of the administration route, fucan A displayed antithrombotic activity. The exception was the oral pathway. Of particular importance was the finding that fucan A stimulates the synthesis of an antithrombotic heparan sulfate from endothelial cells like heparin. The hypothesis has been raised that the in vivo antithrombotic activity of fucan A is related to the increased production of this heparan. Taken together with the fact that the compound is practically devoid of anticoagulant and hemorrhagic activity, the data suggest that it may be an ideal antithrombotic agent in vivo. 相似文献
995.
Gonçalves H Rocha AP Ayres-de-Campos D Bernardes J 《Cardiovascular & hematological disorders drug targets》2008,8(2):91-98
Recently, frequency domain and entropy analysis of fetal heart rate (FHR) have been assessed in several studies, providing new insights into physiologic regulatory mechanisms, constituting appealing tools for pharmacodynamic assessment, namely during fetal life. There is evidence that entropy and frequency domain analysis convey information on cortical and autonomic nervous system activities, respectively. Use of internal versus external FHR acquisition sensors and the signal sampling frequency may dramatically affect results. Most FHR frequency domain indices are significantly increased with rising fetal activity, namely during active wakefulness and active sleep, whereas the opposite occurs with nonlinear indices. This is in favour of increased activity of the autonomous nervous system and decreased activity of the central nervous system complexity control systems, during periods of fetal activity. Progression of labor is associated with a significant increase in FHR frequency domain indices, whereas entropy indices are significantly decreased. This denotes activation of the autonomic nervous system in the final minutes of labour, associated with decreased central nervous system activity. The emerging knowledge on FHR frequency domain and entropy analysis substantiates a continued interest of these methods in evaluation of the fetal pathophysiologic regulatory mechanisms, and opens new perspectives for clinical and pharmacodynamic assessment. 相似文献
996.
997.
de Vargas Barbosa NB Nogueira CW Guecheva TN Bellinaso Mde L Rocha JB 《Archives of toxicology》2008,82(9):655-663
The effect of dietary diphenyl diselenide (1 ppm) on N-nitroso-N-methylurea (NMU)-induced mammary carcinogenesis was examined in female Wistar rats. Beginning at 5 weeks of age, the animals were fed with either control or diphenyl-diselenide-supplied diets until the end of the study (210 days). At 50 days of age, mammary tumor was induced by the administration of three doses of NMU (50 mg/kg body wt, intraperitoneally) once a week for 3 weeks. In experimental trials, latency to tumor onset was extended in rats fed with diet supplemented with diphenyl diselenide (P < 0.05). The incidence and frequency of tumors were significantly small in animals supplemented with diphenyl diselenide. However, the multiplicity of tumors was not altered by dietary diphenyl diselenide. Diphenyl diselenide supplementation also restored superoxide dismutase (SOD) activity and vitamin C levels altered in the NMU group (P < 0.05). Our results suggest that diphenyl diselenide can be considered a chemopreventive agent, even when supplemented at a relatively low concentration. 相似文献
998.
N.M.H. Bulow E. Colpo R.P. Pereira E.F.M. Correa E.P. Waczuk M.F. Duarte J.B.T. Rocha 《Brazilian journal of medical and biological research》2016,49(4)
Cardiopulmonary bypass (CPB) with extracorporeal circulation produces changes in the
immune system accompanied by an increase in proinflammatory cytokines and a decrease
in anti-inflammatory cytokines. We hypothesize that dexmedetomidine (DEX) as an
anesthetic adjuvant modulates the inflammatory response after coronary artery bypass
graft surgery with mini-CPB. In a prospective, randomized, blind study, 12 patients
(4 females and 8 males, age range 42-72) were assigned to DEX group and compared with
a conventional total intravenous anesthesia (TIVA) group of 11 patients (4 females
and 7 males). The endpoints used to assess inflammatory and biochemical responses to
mini-CPB were plasma interleukin (IL)-1, IL-6, IL-10, interferon (INF)-γ, tumor
necrosis factor (TNF)-α, C-reactive protein, creatine phosphokinase, creatine
phosphokinase-MB, cardiac troponin I, cortisol, and glucose levels. These variables
were determined before anesthesia, 90 min after beginning CPB, 5 h after beginning
CPB, and 24 h after the end of surgery. Endpoints of oxidative stress, including
thiobarbituric acid reactive species and delta-aminolevulinate dehydratase activity
in erythrocytes were also determined. DEX+TIVA use was associated with a significant
reduction in IL-1, IL-6, TNF-α, and INF-γ (P<0.0001) levels compared with TIVA
(two-way ANOVA). In contrast, the surgery-induced increase in thiobarbituric acid
reactive species was higher in the DEX+TIVA group than in the TIVA group (P<0.01;
two-way ANOVA). Delta-aminolevulinate dehydratase activity was decreased after CPB
(P<0.001), but there was no difference between the two groups. DEX as an adjuvant
in anesthesia reduced circulating IL-1, IL-6, TNF-α, and INF-γ levels after mini-CPB.
These findings indicate an interesting anti-inflammatory effect of DEX, which should
be studied in different types of surgical interventions. 相似文献
999.
1000.
Graça Casal Sónia Rocha Graça Costa Saleh Al-Quraishy Carlos Azevedo 《Parasitology research》2016,115(10):3963-3972