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991.
Ann L. Meulemans Ludo F. Helsen Jan A. J. Schuurkes 《Naunyn-Schmiedeberg's archives of pharmacology》1993,347(2):225-230
Summary Vagal stimulation of the stomach induces a relaxation mediated via non-adrenergic, non-cholinergic (NANC) nerves. The neurotransmitter which is responsible for this relaxation is still unknown. To determine whether nitric oxide (NO) or a NO related substance mediates this relaxation, an intact guinea-pig stomach was mounted in an organ bath, with electrodes surrounding the vagal nerves.Electrical stimulation of the vagal nerves, in the presence of atropine, induced frequency dependent, tetrodotoxin-(TTX) sensitive relaxations of the stomach quantified as changes in volume. These relaxations were not affected by - or -adrenoceptor antagonists or guanethidine. Thus they were evoked by non-adrenergic, non-cholinergic (NANC) inhibitory nerves. The relaxant responses could be inhibited in a concentration-dependent manner by NG-nitro-Irarginine (IrNNA) a substance that inhibits the formation of nitric oxide (NO). Addition of L-arginine, the substrate for NO-synthase, reversed the L-NNA-induced-inhibition of the relaxation.Addition of nitroglycerin (a NO-donor) to a nonstimulated stomach mimicked the relaxations observed after vagal stimulation in a concentration dependent manner. These relaxations were insensitive to TTX. Relaxation of the stomach by vagal stimulation was prevented by an inhibitor of soluble guanylate cyclase, methylene blue, further supporting our conclusions.These data indicate that NO or a substance releasing NO plays an important role in NANC-neurotransmission after vagal stimulation of the guinea-pig stomach.Correspondence to A. L. Meulemans at the above address 相似文献
992.
Ann L. Meulemans Ludo F. Helsen Jan A. J. Schuurkes 《Naunyn-Schmiedeberg's archives of pharmacology》1993,348(4):424-430
Summary In a previous study we showed that the relaxations induced after vagal stimulation of the guinea-pig stomach are mediated via nitric oxide (NO) or a NO-related substance. Intra-arterial injection (i.a.) of 5-hydroxytryptamine (5-HT) also induced relaxations in the guinea-pig stomach. Since it has been shown that in the guinea-pig colon 5-HT-induced relaxations are mediated via NO the aim of this study was to establish whether NO is involved in the 5-HT-induced relaxations in the guinea-pig stomach. Intra-arterial injection of 5-HT induced dose-dependent relaxations of the stomach. Since atropine and - and -adrenoceptor blocking agents did not influence the relaxation and since tetrodotoxin (TTX) blocked the relaxations, this effect is mediated via NANC-neurons. Administration of a NO-synthase-inhibitor NG-nitro-l-arginine (L-NNA) concentration-dependently reduced the 5-HT-induced relaxations. Haemoglobin (a NO-scavanger) did not affect the relaxations to 5-HT, while addition of methylene blue, an inhibitor of soluble guanylate cyclase, reduced the relaxations by 50%. Addition of an opioid receptor agonist (loperamide), a 5-HT1 antagonist (methiothepin or metergoline) or a 5-HT4 receptor agonist (cisapride) or-antagonist (tropisetron in micromolar concentrations) inhibited the 5-HT-induced relaxations. Neither the 5-HT4 receptor agonist renzapride, nor the novel 5-HT4 receptor antagonist SDZ 205-557, affected the relaxations to 5-HT. These data indicate that 5-HT-induced relaxations of the guinea-pig stomach are mediated via NANC-inhibitory nerves on which inhibitory opioid-receptors are present. The use of selective agonists and antagonists indicates that 5-HT does not act via 5-HT2, 5-HT3 or 5-HT4 receptors. 5-HT may act via 5-HT1 receptors but the subtype involved, if any, has not yet been identified. The inhibitory neurotransmitter which is involved is NO or a NO-related substance.
Correspondence to A. L. Meulemans at the above address 相似文献
993.
Vassilios I. Avramis Kenneth K. Chan Michelle M. Solorzano Zhan-liu Chen 《Cancer chemotherapy and pharmacology》1993,33(3):197-202
O-6-methylguanine (O6-mG), a guanine analog recently shown to be a potent inhibitor of alkylguanine-DNA alkyltransferase, has been found to potentiate the antitumor activity of nitrosoureas, in particular, carmustine (BCNU), in resistant cell lines (HT-29 mer+) and is targeted for development as a modulating agent with chloroethyl nitrosoureas. A high-performance liquid chromatography (HPLC) assay of O6-mG in plasma has been developed using a C18 reverse-phase column. O6-mG and the internal standard deoxyguanosine (dGuo) were eluted with a linear gradient of from 15% to 35% methanol in 0.5M ammonium acetate (pH 6.5) at a flow rate of 1 ml/min. The assay was linear over a 4-log concentration range with a detection limit of 0.1 g/ml. The within-run and between-run coefficients of variation (CV) were found to be 8.1% and 9.3%, respectively. The pharmacokinetics (PK) of O6-mG were investigated in healthy CDF1 mice following separate i.v. and i.p. administrations. At 20 mg/kg i.v., plasma O6-mG gave a biexponential profile with a terminal half-life (t1/2) of 24 min and a total clearance (CLT) of 23.7 ml min–1 kg–1. Higher doses (40–80 mg/kg) revealed a fluctuating third phase, probably due to enterohepatic cycling. Dose-dependent kinetics as measured by CLT and area under the plasma-concentration curve (AUC) values were also seen. Following i.p. dosing, O6-mG was completely absorbed and available to the circulation. No acute toxicity was observed in the animals, except for mild sedation, a possible side effect of the 10% ethanol used in the formulation. Studies on the cellular metabolism of highly purified [3H]-O6-mG have shown that the compound is not anabolized by a human lymphoblastoid cell line (CEM). Biochemistry studies have shown that the parent molecule is inactivating the alkylguanine-DNA alkyltransferase (AGT), thus exerting its pharmacological effect.Abbreviations O6-mG
O-6-methylguanine
- HPLC
high-performance liquid chromatography
- PK
pharmacokinetics
- CLT
total clearance
- AUC
area under the plasma concentration curve
- AGT
alkylguanine-DNA alkyltransferase
- dGuo
deoxyguanosine
This work was supported in part by contract NO1-CM-97620 from the National Cancer Institute (NIH) and by the Neil Bogart Memorial Laboratories by the T. J. Martell Foundation for Cancer, Leukemia, and AIDS Research 相似文献
994.
Candace S. Johnson Ming-Jei Chang Wei-Dong Yu Ruth A. Modzelewski Jennifer R. Grandis Daniel R. Vlock Philip Furmanski 《Cancer chemotherapy and pharmacology》1993,32(5):339-346
Administration of interleukin-1 (IL-1 ) plus certain cytotoxic drugs causes substantially greater clonogenic tumor-cell kill and tumor-regrowth delay than does treatment with either agent alone. IL-1 itself has little effect on tumor growth despite its ability to induce acute hemorrhagic necrosis, restrict tumor blood flow, and cause microvascular injury in a variety of murine model systems. To investigate further IL-1 's ability to enhance the antitumor activity of cytotoxic drugs, we initiated studies to examine the effect of IL-1 on cisplatin (cDDP)-mediated cytotoxicity using the RIF-1 tumor system. The antitumor activity of IL-1 and cDDP was quantitated through standard clonogenic tumor-cell survival assays, a tumor hemorrhagic necrosis assay and tumor-regrowth delay studies, with the interaction between IL-1 and cDDP being analyzed through median dose-effect. In vitro, IL-1 had no enhancing effect on the cDDP-mediated tumorcell kill. For examination of the in vivo efficacy of this regimen. RIF-1 tumor-bearing C3H/HeJ mice (14 days postimplantation) were treated concurrently with single i.p. injections of IL-1 and/or cDDP at various doses. The increased clonogenic tumor-cell kill obtained with IL-1 /cDDP was dose-dependent, with significant enhancement by IL-1 being observed (P<0.001), even at the lowest doses tested (2 mg/kg and 6 g/kg for cDDP and IL-1 , respectively), but it did not correlate with an increase in tumor hemorrhage. Using median dose-effect analysis, this interaction was determined to be strongly synergistic. When treated animals were monitored for long-term antitumor effects, combinations with IL-1 significantly increased the tumor-regrowth delay and decreased the fractional tumor volume (P<0.001). These results demonstrate that IL-1 synergistically enhances cDDP mediated in vivo antitumor activity and suggest that the combination of IL-1 and cDDP may have potential therapeutic application in the design of effective treatment modalities for cancer.Abbreviations IL-1
interleukin-1
- cDDP
cis-diamminedichloroplatinum (cisplatin)
- BRMs
biological response modifiers
- TNF
tumor necrosis factor
- IFN
interferon
- Fa
traction affected
- Dm or ED50
drug concentration necessary to produce Fa=0.5 as compared with untreated controls
- CI
combination index; SF, surviving fraction
- ANOVA
oneway analysis of variance
This work was supported in part by Public Health Service grant CA-48077 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, by the Mary Hillman Jennings Foundation, and by the Ramona DeSantis Cancer Research Fund 相似文献
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