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61.
Dagmar Busse Jose Cosme Philippe Beaune Heyo K. Kroemer Michel Eichelbaum D. Busse H. K. Kroemer M. Eichelbaum 《Naunyn-Schmiedeberg's archives of pharmacology》1995,353(1):116-121
The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile]), and verapamil N-demethylation (formation of norverapamil [2,8-bis(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)6-methyl-2-isopropyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (111) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18.In human liver microsomes (n=4), the intrinsic clearance (CLint), as derived from the ratio of V
max/Km, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9±1.0 vs 2.4±0.6 ml*min-1
*g-1 mean±SD; p<0.05), S-Verapamil (16.8±3.3 vs 2.2±1.2 ml* mini*g-1, p<0.05) and R-verapamil (12.1±2.9 vs 3.6 ±1.3 ml*min-1
* g-1; p<0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CLint of D-703 formation in human liver microsomes showed a modest but significant degree of stereo selectivity (p<0.05) with a S/R-ratio of 1.41±0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5±4.5% and 45%, that of D-702 by 52.7±7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703.In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes. 相似文献
62.
The possible occurrence of benzodiazepine-like substances in human breast milk was investigated in 35 healthy, newly delivered women who were known not to be taking benzodiazepines. Maternal blood samples and a sample of breast milk were obtained on the fifth post partum day. A radioreceptor technique (lower limit of detection 1.5 ng/ml; difference between duplicates at various concentrations <7%) was used for measuring benzodiazepine-like substances in blood and breast milk (with and without prior extraction). No benzodiazepine-like substances could be demonstrated in any of the blood samples taken from the 35 women. Measurable concentrations of benzodiazepine-like substances were demonstrated in all but 1 of the 35 breast milk samples. The mean concentration of benzodiazepine-like substances for all 35 women was 4.3±2.3 ng/ml (range 0–9.3 ng/ml) expressed as lorazepam. The corresponding value for extracted breast milk was 2.6±1.5 ng/ml (range 0–7.0 ng/ml). There was no association between concentrations of benzodiazepine-like substances in breast milk and maternal age, weight, height and body mass or parity, or the sex of the infant and infant birth weight. We suggest that non-detectable amounts of benzodiazepine-like substances in serum are concentrated in the mammillary glands and excreted in a higher concentration in breast milk. It is less likely that the relevant benzodiazepines are produced in the mammillary glands. 相似文献
63.
Signals generated from muscles other than the muscle(s) of interest (cross talk) can confound the interpretation of surface electromyograms (EMGs). In this study, the amount of cross talk in surface EMGs of human hamstring muscles was estimated using a protocol in which the quadriceps femoris was electrically stimulated via the femoral nerve. EMGs were recorded from the vastus lateralis and the medial and lateral hamstring muscle groups. The amplitude of the EMG response of the vastus lateralis to electrical stimulation was adjusted to match that of its maximum voluntary effort (MVE) under isometric conditions. Subsequent power density spectrum analysis showed that the median frequencies of the signals generated by electrical stimulation and MVE were not significantly different. In conventional bipolar recordings, cross talk in lateral hamstring EMGs averaged 17.1% MVE and in medial hamstring EMGs 11.3% MVE (average-rectified values). The double differential technique significantly reduced cross talk to 7.6% MVE for the lateral hamstrings, and to 4.2% MVE for the medial hamstrings. The double differential technique appears to be more selective than the bipolar technique when recording EMGs from muscles with highly active neighbors and thus should be used in such situations. Software simulations of the double differential technique also appear to be more selective than the bipolar technique and may be used when the number of amplifiers available is limited. 相似文献
64.
J. R. Buscombe I. Khalkhali G. R. Mason D. Rauh J. Meatherall W. J. G. Oyen F. H. M. Corstens 《European journal of nuclear medicine and molecular imaging》1994,21(10):1148-1150
Functional imaging is ideally suited to monitoring the effect of specific therapy on disease processes. In this pilot study five patients with AIDS and Pneumocystis carinii pneumonia (PCP) were imaged with Indium-111 labelled pooled human immunoglobulin (111In-HIG) during infection and after therapy for PCP. The lung activity of t t tln-HIG, measured as a lung/heart ratio, was calculated in a study performed during infection with PCP and after therapy. In all five patients the lung/heart ratio of t t 1ln-HIG was reduced after treatment. The mean reduction in heart/lung ratio was 27% (range 12%-53%). If these results are confirmed by a larger study, 11In-HIG will be useful in monitoring the response of PCP to therapy in patients with AIDS. 相似文献
65.
66.
人胎盘提取组织凝血活酶及其质量评价 总被引:2,自引:2,他引:0
利用人胎盘抽提得组织凝血活酶,并对其质量进行了评价,同时初步应用于临床。结果显示:用含表面活性剂的抽提剂粉碎抽提的效果较好,所得组织凝血活酶重复性、灵敏度、稳定性均令人满意;与上海荣盛生物制品厂生产的PT试剂盒比较相关性好:Y=2.75+0.905x,r=0.9253,经相关系数t检验,t=26.5469,P<0.001,呈直线正相关。临床初步应用显示:肝病及抗凝治疗等病人PT时间明显延长,93例正常人x=11.3秒,s=0.96秒,正常范围9.42-13.18秒。 相似文献
67.
聚合酶链反应检测尖锐湿疣皮损内人乳头瘤病毒 总被引:7,自引:0,他引:7
13个皮损组织取自13例尖锐湿疣(CA)患者,13例基底细胞上皮瘤(BCC)组织作为对照,用溴化钠液分离表真皮,从组织中提出的 DNA和溴化钠液分别用聚合酶链反应检测 HPV DNA。11例CA表皮中检出 HPV DNA,HPV6有7例,HPV11有4例。3例CA真皮中发现有HPV DNA,HPV6有2例,HPV11有1例。2例标本因溴化钠液被HPV污染未作统计。在BCC组织中未发现有HPV DNA。在某些CA真皮内含有 HPV DNA可以解释散发病例的复发性。 相似文献
68.
69.
70.
人胎盘脂多糖辅助治疗支气管哮喘临床疗效观察 总被引:1,自引:0,他引:1
目的观察人胎盘脂多糖辅助治疗儿童支气管哮喘的临床疗效。方法将我院91例支气管哮喘患儿随机分成2组,治疗组46例,采用综合疗法,发作期应用沙丁胺醇、普米克令舒、氨茶碱治疗,缓解期肌内注射人胎盘脂多糖、气雾吸入倍氯米松;对照组45例,发作期用沙丁胺醇、普米克令舒、氨茶碱治疗,缓解期气雾吸入倍氯米松。结果治疗2周后治疗组、对照组对改善喘息、咳嗽症状比较,差异有显著性意义(P<0.05)。随访1年,治疗组复发率与对照组比较,差异有显著性意义(P<0.05)。结论人胎盘脂多糖辅助治疗支气管哮喘疗效确切,复发率低,值得临床推广应用。 相似文献