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71.
72.
Mepyramine对肝脏疾病肝微粒体膜流动性的影响 总被引:1,自引:0,他引:1
目的:探讨Mepyramine对肝脏疾病肝微粒体膜流动性的影响.方法:以1,6-diphenyl-1,3,5-hexatriene(DPH)作为荧光探剂,应用荧光偏振技术研究大鼠急性肝炎、大鼠肝硬化肝微粒体膜流动性(LMMF)的变化,并在体外实验观察mepyramine(MPR)对LMMF的影响.结果:①LMMF在大鼠发生急性肝炎时升高,与对照组相比有显著性差异(P<0.o1),而大鼠发生肝硬化时降低,与对照组相比有显著性差异(P<0.05).②10-4mol/L MPR可使正常大鼠、大鼠肝硬化及人体肝癌组织LMMF升高(P分别小于0.01,0.01,0.05).结论:肝病时LMMF出现异常;MPR可以升高LMMF,其机制可能与阻断抗组胺药敏感性细胞色素P450(HP-450)有关. 相似文献
73.
Casley William L.; Menzies Allan; Girard Michel; Larocque Lyse; Mousseau Nicole; Whitehouse Larry W.; Moon Thomas W. 《Toxicological sciences》1997,40(2):228-237
The 3-demethylation of caffeine can be used as an index of cytochromeP450 CYP1A2 activity in vivo. We compared the plasma levelsof caffeine and the 3-demethylated metabolite, 1,7-dimethylxanthine,in six common inbred strains (A/J, P/J, BALB/cJ, C3H/HeJ, AKR/J,and SWR/J) and one inbred strain (APN) derived in our laboratoryfrom outbred Swiss-Webster mice on the basis of its relativesusceptibility to acetaminophen-induced hepatotoxicity. We foundsignificant variations between a number of the common strains,all of which produced significantly higher caffeine 3-demethylationindices than our APN strain. In three of the six common strains,there was a significant difference between males and females,with the females having consistently lower 1,7-xanthine/caffeineratios. Hepatic Cyp1a2 expression was compared between APN andC3H/HeJ males. Microsomal methoxyresorufin O-demethylation,acetanilide 4-hydroxylation, and CYP1A2 immunoreactive proteinlevels were significantly higher in C3H/HeJ relative to APNmice, as were hepatic CYP1A2 mRNA levels. These results indicatethe importance of strain and gender to the outcome of pharmacologicalor toxicological studies involving CYP1A2-mediated metabolism,as well as the suitability of the plasma 1,7-dimethylxanthine/caffeineratio as a marker of CYP1A2 activity in the mouse. The strikingdifferences observed between the APN and C3H/HeJ mice suggestthat these strains may be suitable for a genetic analysis ofthe regulation of the basal expression of CYP1A2, a key enzymeIn procarcinogen activation. 相似文献
74.
The number of published reports associating hepatotoxicity with paracetamol ingestion at therapeutic or near-therapeutic dose levels is small but is, nevertheless, suggestive of a relationship. There is however, mounting evidence that certain groups of patients, such as alcohol-dependent people, patients receiving enzyme-inducing drugs (particularly anti-convulsant and anti-tuberculosis medications) as well as those with certain infectious diseases, are rendered more susceptible to paracetamol-induced hepatotoxicity. Seventy-four case reports where therapeutic or near-therapeutic doses of paracetamol resulted in hepatic injury are reviewed and factors and mechanisms which might explain this apparently increased vulnerability to damage are discussed. 相似文献
75.
I. Ieiri W. Goto S. Higuchi K. Hirata A. Toshitani S. Imayama Y. Ohyama H. Yamada K. Ohtsubo 《European journal of clinical pharmacology》1995,49(1-2):51-56
The purpose of this study was to assess the possible role of the (R)- and (S)- enantiomers of the phenytoin metabolite p-HPPH in the pathogenesis of gingival hyperplasia (GH). About 98% of circulating p-HPPH is in the (S)-form. There were significant differences between patients with and without GH in (R)-p-HPPH level (0.055 vs 0.042 g·ml–1), both enantiomer/racemate level ratios, and R/S enantiomeric ratio (0.0313 vs 0.0232); an increase in serum (R)-p-HPPH level was observed in patients with GH. In separate experiments, the effect of p-HPPH enantiomers on the proliferation of the normal human dermal fibroblast was studied. The in vitro study showed that (R)-p-HPPH selectively stimulated fibroblast growth. The results suggest that the least abundant metabolite, (R)-p-HPPH, is the most toxic with respect to gingival hyperplasia. 相似文献
76.
T. Kokufu N. Ihara N. Sugioka H. Koyama T. Ohta S. Mori K. Nakajima 《European journal of clinical pharmacology》1995,48(5):391-395
The effect of the new substituted benzimidazole proton pump inhibitor, lansoprazole, on pharmacokinetics and metabolism of theophylline has been studied in healthy adults given oral lansoprazole 30 mg once daily for 11 days. On Days 4 and 11 of 300 mg aminophylline was simultaneously administered orally and blood samples for theophylline analysis were taken over 24 h. Urine samples were collected for up to 24 h and were assayed for theophylline and its major metabolites 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX). The pharmacokinetic parameters of theophylline were determined, and the urinary recovery of unchanged theophylline and its major metabolites were calculated.After administration of lansoprazole for 4 days, no significant alteration in the terminal elimination half-life (t
1/2) or the mean residence time (MRT) was detected. However, there was a significant decrease of about 13% in the area under the plasma concentration-time curve (AUC) and a significant increase of about 19% in the apparent clearance (CLapp). Lansoprazole treatment for 11 days caused a significant decrease of approximately 12% in t
1/2 and about 10% in the MRT of theophylline, although neither AUC nor CLapp showed a significant alteration. The excretion of 3-MX in the urine was significantly increased by about 20% after lansoprazole treatment for 4 and 11 days, although there was no significant alteration in the excretion of unchanged theophylline, 1,3-DMU or 1-MU.The results indicate that repeated administration of lansoprazole to humans induces the hepatic microsomal P-450-dependent drug oxidation system that mediates N-1-demethylation of theophylline, consequently increasing its metabolism. 相似文献
77.
为研究地西泮在两组基因型(wt/ml和ml/ml)的国人体内代谢的差异,采用PCR法筛选12位符合基因型要求的受试 ,6位为CYP2C19突变型纯合子(ml/ml),6位为CYP2C19的杂合子(wt/ml)。每位受试者口服5mg地西泮片,然后用气相色谱法测定其血浆中地西泮的浓度,计算其药代动力学参数,结果显示两组受试者之间地西泮代谢有显著性差异。结论:遗传因素是决定地西泮代谢的重要因素。 相似文献
78.
目的:探讨中国广东籍汉族人细胞色素P4502E1基因5′侧翼区的多态性分布规律。方法:利用聚合酶链反应和RsaⅠ、PstⅠ限制性片段长度多态性(PCRRFLP)技术对82名正常中国广东籍汉族人的细胞色素P4502E1基因5′侧翼区的多态性进行了检测。结果:82名正常中国广东籍汉族人的细胞色素P4502E1基因5′侧翼区C1(RsaⅠ+,PstⅠ)、C2(RsaⅠ,PstⅠ+)等位基因频率分别为0854,0146;基因型C1C1、C1C2、C2C2的比率分别为0732、0244、0024,符合HardyWeinberg平衡分布。结论:中国广东籍汉族人细胞色素P4502E1基因5′侧翼区RsaⅠ和PstⅠ多态性分布规律与欧美人显著不同。 相似文献
79.
The cytochrome P450 isoenzymes are a superfamily of haemoprotein enzymes that catalyse the metabolism of a large number of endogenous and exogenous compounds. Recently, the cytochrome isoenzymes have been shown to be important in the synthesis of steroid hormones and bile acids, the arachidonic acid cascade and in central nervous function. These enzymes are a major determinant of the pharmacokinetic behaviour of numerous drugs. Furthermore, alterations in cytochrome P450 activity have been implicated in some diseases. 相似文献
80.
Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 总被引:8,自引:0,他引:8
Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms
of schizophrenia and produces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone,
an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism
of risperidone (100 μM) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8,
CYP2C9-arg144, CYP2C9-cys144, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by
a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the
ones capable of metabolising risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol–1 CYP min–1, respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone
is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone
at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine
(inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore,
inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone
is highly correlated with testosterone 6β-hydroxylase activities, suggesting that inducible CYP3A contributes significantly
to the metabolism of risperidone in rat.
Received: 4 May 1998 / Accepted: 26 October 1998 相似文献