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991.
López-Rodríguez ML Viso A Ortega-Gutiérrez S Díaz-Laviada I 《Mini reviews in medicinal chemistry》2005,5(1):97-106
The endogenous canabinoid system (ECS) is involved in the regulation of an important number of central and peripheral physiological effects. Among all these functions, the control of the cellular proliferation has become a focus of major attention as opening new therapeutic possibilities for the use of cannabinoids as potential antitumor agents. The capacity of endogenous and synthetic cannabinoids to induce apoptosis of different tumoral cells in culture and in vivo, the mechanism underlying and the potential therapeutic applications are discussed in this review. 相似文献
992.
Viganò D Rubino T Vaccani A Bianchessi S Marmorato P Castiglioni C Parolaro D 《Psychopharmacology》2005,182(4):527-536
The aim of this work was to study the mechanism of cross-modulation between cannabinoid and opioid systems for analgesia during
acute and chronic exposure. Acute coadministration of ineffectual subanalgesic doses of the synthetic cannabinoid CP-55,940
(0.2 mg/kg i.p.) and morphine (2.5 mg/kg i.p.) resulted in significant antinociception. In chronic studies, a low dose of
CP-55,940 (0.2 mg/kg, i.p.) that per se did not induce analgesia in naive animals produced a significant degree of antinociception
in rats made tolerant to morphine, whereas in rats made tolerant to CP-55,940, morphine challenge did not produce any analgesic
response. To identify the mechanism of these asymmetric interactions during chronic treatment, we investigated the functional
activity of cannabinoid and μ opioid receptors and their effects on the cyclic AMP (cAMP) cascade. Autoradiographic-binding
studies indicated a slight but significant reduction in cannabinoid receptor levels in the hippocampus and cerebellum of morphine-tolerant
rats, whereas CP-55,940-stimulated [35S]GTPγS binding showed a significant decrease in receptor/G protein coupling in the limbic area. In CP-55,940 exposed rats,
μ opioid receptor binding was significantly raised in the lateral thalamus and periaqueductal gray (PAG), with an increase
in DAMGO-stimulated [35S]GTPγS binding in the nucleus accumbens. Finally, we tested the cAMP system's responsiveness to the cannabinoid and opioid
in the striatum and dorsal mesencephalon. In vivo chronic morphine did not affect CP-55,940's ability to inhibit forskolin-stimulated
cAMP production in vitro and actually induced sensitization in striatal membranes. In contrast, in vivo chronic CP-55,940
desensitized DAMGO's efficacy in inhibiting forskolin-stimulated cAMP production in vitro. The alterations to the cAMP system
seem to mirror the behavioral responses, indicating that the two systems may interact at the postreceptor level. This might
open up new therapeutic opportunities for relief of chronic pain through cannabinoid–opioid coadministration. 相似文献
993.
Spinelli S Ballard T Gatti-McArthur S Richards GJ Kapps M Woltering T Wichmann J Stadler H Feldon J Pryce CR 《Psychopharmacology》2005,179(1):292-302
Rationale LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks.Objective In the present primate study, we used radioautography to describe the distribution and intensity of 3H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated.Methods Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3–10 mg/kg, and on the CDMP, subjects were tested at 1–3 or 3–10 mg/kg.Results Radioautography revealed a relatively low level of 3H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP.Conclusions The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functioning. 相似文献
994.
Corsini E Birindelli S Fustinoni S De Paschale G Mammone T Visentin S Galli CL Marinovich M Colosio C 《Toxicology and applied pharmacology》2005,208(2):178-185
Available data suggest that ethylenebisdithiocarbamates (EBDCs) may have immunomodulatory effects. This study aimed to investigate the immunological profile of farmers exposed to Mancozeb, an EBDC fungicide, through the determination of several serum, cellular, and functional immune parameters. Twenty-six healthy subjects entered the study, 13 vineyards exposed to Mancozeb and 13 unexposed controls. Exposure was assessed through the determination of ethylentiourea (ETU) in urine. Complete and differential blood count, serum immunoglobulins, complement fractions, autoantibodies, lymphocyte subpopulations, proliferative response to mitogens, natural killer (NK) activity, and cytokine production were measured. Post-exposure samples showed ETU urine concentration significantly higher than pre-exposure and control groups. A significant increase in CD19+ cells, both percentage and absolute number, and a significant decrease in the percentage of CD25+ cells were found in post-exposure samples compared to controls. A statistically significant increase in the proliferative response to phorbol myristate acetate plus ionomycin (PMA + ionomycin) was observed in the post-exposure group compared to controls and baseline, while a significant reduction in LPS-induced TNF-alpha release in post-exposure samples was observed. Overall, our results suggest that low-level exposure to Mancozeb has slight immunomodulatory effects, and point out a method adequate to reveal immune-modifications in workers occupationally exposed to potential immunotoxic compounds, based on a whole blood assay. 相似文献
995.
DalBó S Jürgensen S Horst H Ruzza AA Soethe DN Santos AR Pizzolatti MG Ribeiro-do-Valle RM 《The Journal of pharmacy and pharmacology》2005,57(6):765-771
The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate soluble fraction of the crude extract of Croton celtidifolius bark presented a high content of total proanthocyanidins (75.0+/-2.3%). HPLC analysis of 63SF revealed a dimeric profile (e.g.catechin-(4alpha-->8)-catechin and gallocatechin-(4alpha-->8)-catechin) and polymeric proanthocyanidins. In pharmacological investigations, 63SF administered intraperitoneally exhibited dose-dependent antinociceptive activity against several chemical stimuli, including the intraperitoneal injection of acetic acid (ID50 (the dose of 63SF which was able to reduce the nociceptive response by 50% relative to the control value)=0.9 (0.5-1.6)) and the intraplantar injection of capsaicin (ID50=13.0 (10.0-17.0)), glutamate (ID50=4.0 (2.0-7.0)) and formalin (ID50 first phase=36.0 (24.0-53.0) and late phase=11.0 (8.0-14.0)). 63SF administered orally exhibited an antinociceptive effect in the formalin test (ID50 first phase=125.0 (89.0-177.0) and late phase=65.0 (33.0-95.0)). In the same test, 63SF was effective when given soon after the first phase, as well as exhibiting therapeutic activity. Furthermore, 63SF was effective in models of thermal nociception including tail-flick and hot-plate tests. When the mice were treated in the neonatal period with capsaicin, the antinociceptive effect of 63SF in the first phase of the formalin test was abolished, but pretreatment with naltrexone did not change the antinociceptive effect of 63SF. Together, these results provide evidence that 63SF exerted a pronounced systemic antinociception against chemical (acetic acid, formalin, glutamate and capsaicin tests) and thermal (hot-plate and tail-flick tests) nociceptive models of pain in mice at a dose that did not interfere with the locomotor activity. The mechanism by which this sub-fraction produced antinociception remains unclear, but it is unlikely to involve the activation of the opioid system. However, unmyelinated C-fibres sensitive to treatment with capsaicin are likely to participate in antinociception caused by 63SF. 相似文献
996.
Quik M Vailati S Bordia T Kulak JM Fan H McIntosh JM Clementi F Gotti C 《Molecular pharmacology》2005,67(1):32-41
Nicotinic acetylcholine receptors (nAChRs) represent an important modulator of striatal function both under normal conditions and in pathological states such as Parkinson's disease. Because different nAChR subtypes may have unique functions, immunoprecipitation and ligand binding studies were done to identify their subunit composition. As in the rodent, alpha2, alpha4, alpha6, beta2, and beta3 nAChR subunit immunoreactivity was identified in monkey striatum. However, distinct from the rodent, the present results also revealed the novel presence of alpha3 nAChR subunit-immunoreactivity in this same region, but not that for alpha5 and beta4. Relatively high levels of alpha2 and alpha3 subunits were also identified in monkey cortex, in addition to alpha4 and beta2. Experiments were next done to determine whether striatal subunit expression was changed with nigrostriatal damage. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment decreased alpha6 and beta3 subunit immunoreactivity by approximately 80% in parallel with the dopamine transporter, suggesting that they are predominantly expressed on nigrostriatal dopaminergic projections. In contrast, alpha3, alpha4, and beta2 subunit immunoreactivity was decreased approximately 50%, whereas alpha2 was not changed. These data, together with those from dual immunoprecipitation and radioligand binding studies ([(3)H]cytisine, (125)I-alpha-bungarotoxin, and (125)I-alpha-conotoxin MII) suggest the following: that alpha6beta2beta3, alpha6alpha4beta2beta3, and alpha3beta2* nAChR subtypes are present on dopaminergic terminals and that the alpha4beta2 subtype is localized on both dopaminergic and nondopaminergic neurons, whereas alpha2beta2* and alpha7 receptors are localized on nondopaminergic cells in monkey striatum. Overall, these results suggest that drugs targeting non-alpha7 nicotinic receptors may be useful in the treatment of disorders characterized by nigrostriatal dopaminergic damage, such as Parkinson's disease. 相似文献
997.
Dalla Pellegrina C Rizzi C Mosconi S Zoccatelli G Peruffo A Chignola R 《Toxicology and applied pharmacology》2005,207(2):170-178
Wheat germ agglutinin (WGA) is a plant protein that binds specifically to sugars expressed also by gastrointestinal epithelial cells. WGA is currently investigated as an anti-tumor drug and as a carrier for oral drugs. Information on whether it can cross the gastrointestinal epithelium and on its possible effects on the integrity of the epithelial layer is however scanty or lacking, and herein we address these issues. Differentiated Caco2 cells have been used as a model of polarized intestinal epithelium. WGA concentration at both the apical and the basolateral side of the epithelium has been quantified using a sensitive ELISA assay (sensitivity threshold 0.84 nM). Trans epithelial electrical resistance (TEER) has been measured to evaluate the integrity of the epithelium upon treatments with WGA. (3)H-Mannitol (182.2 Da) and FITC-dextran (3000 Da) have been used to measure the permeability of the epithelium. Cell viability has been measured by the MTT, by 7-AAD uptake, and Annexin-V binding assays. Up to a concentration of 5.6 microM, approximately 0.1% of intact WGA molecules only could cross the epithelial layer. WGA perturbed the integrity of the epithelium and increased the permeability of the tissue in a dose- and time-dependent manner. WGA did not induce cell death but increased the permeability of individual cells to 7-AAD which is normally not uptaken by viable cells. These data allowed us to define a toxicity threshold for WGA on epithelial cells. WGA suitability as a carrier for oral drugs can therefore be evaluated on a rational basis. 相似文献
998.
Folic Acid does not limit endothelial dysfunction induced by ischemia and reperfusion: a human study
Dragoni S Gori T Di Stolfo G Sicuro S Forconi S Parker JD 《Journal of cardiovascular pharmacology》2005,46(4):494-497
Nitric oxide synthase (NOS) uncoupling is a condition of increased production of superoxide anion associated with a decreased production of nitric oxide (NO) by this enzyme. Folic acid can prevent and/or reverse NOS uncoupling in the setting of diabetes, smoking, hypercholesterolemia, and nitrate tolerance. Whereas animal studies showed a protective effect of folic acid in ischemia and reperfusion (IR) injury, no study tested whether folic acid administration limits IR-induced endothelial dysfunction in humans. In a double-blind, parallel study, 20 healthy young male volunteers were randomized to receive folic acid, 10 mg/d for 7 days, or matching placebo. At the end of the treatment period, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR injury (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). There was no difference at baseline between groups in any variable. In the placebo group, IR significantly blunted FMD (before IR, 6.7+/-1.0%; after IR, 1.5+/-1.3%, P<0.01). A similar effect was observed in the folic acid group (before IR, 6.3+/-1.1%; after IR, 2.1+/-1.0%, P=ns compared with placebo). As opposed to animal studies, high-dose folic acid does not protect the vascular endothelium from IR injury in humans. 相似文献
999.
A mutated p53 status did not prevent the induction of apoptosis by sulforaphane,a promising anti-cancer drug 总被引:2,自引:0,他引:2
Fimognari C Sangiorgi L Capponcelli S Nüsse M Fontanesi S Berti F Soddu S Cantelli-Forti G Hrelia P 《Investigational new drugs》2005,23(3):195-203
Summary We investigated apoptosis induction by sulforaphane on three cell lines characterized by a different p53 status. In particular, we used p53-knock-out fibroblasts from newborn mice transfected with the p53-Ser220 mutation, observed in Li-Fraumeni Syndrome patients, as a model of mutated p53 status. Moreover, immortalized fibroblasts from newborn mice expressing or lacking p53 (p53 +/+ andp53-/-, respectively) have been used to verify whether mutated p53 status could prevent sulforaphane-induced apoptotic events. Sulforaphane was able to induce apoptosis on all three cell lines. Indeed, the caspase-3 assays and poly(ADP-ribose)polymerase (PARP) cleavage data indicated that sulforaphane stimulated caspase-3-like activity and degradation of PARP. However, cells with a wild-type or mutated p53 appeared to be more sensitive to the effects of sulforaphane than cells lacking p53. Taken together, our results suggest that sulforaphane could act by a p53-independent pathway. For this reason, sulforaphane can be viewed as a novel agent useful not only in the treatment of Li-Fraumeni-associated tumors but also drug resistant tumors where p53 dysregulation is a feature. 相似文献
1000.
Cassiani SH 《Revista brasileira de enfermagem》2005,58(1):95-99
Administering medication to patients is a complex process with various phases which contemplate a series of inter-related decisions and actions involving professionals from a number of disciplines as well as patients themselves. Errors may occur in any phase of such process. This article describes the indexes, terminology and classification of medication errors and determines the approaches which explain their occurrence, namely the person-centered approach and the system-centered approach. The aim of the paper was to contribute, through theoretical elements, to the strategic discussions concerning the improvement of care standards in health care institutions in our country, focusing on patient safety related to drug therapy. 相似文献