全文获取类型
收费全文 | 24476篇 |
免费 | 1971篇 |
国内免费 | 939篇 |
专业分类
耳鼻咽喉 | 44篇 |
儿科学 | 559篇 |
妇产科学 | 371篇 |
基础医学 | 2791篇 |
口腔科学 | 216篇 |
临床医学 | 1982篇 |
内科学 | 4694篇 |
皮肤病学 | 136篇 |
神经病学 | 1915篇 |
特种医学 | 728篇 |
外科学 | 1903篇 |
综合类 | 2947篇 |
现状与发展 | 3篇 |
预防医学 | 1796篇 |
眼科学 | 163篇 |
药学 | 4668篇 |
6篇 | |
中国医学 | 1450篇 |
肿瘤学 | 1014篇 |
出版年
2024年 | 101篇 |
2023年 | 442篇 |
2022年 | 853篇 |
2021年 | 1065篇 |
2020年 | 850篇 |
2019年 | 726篇 |
2018年 | 747篇 |
2017年 | 725篇 |
2016年 | 812篇 |
2015年 | 848篇 |
2014年 | 1327篇 |
2013年 | 1718篇 |
2012年 | 1262篇 |
2011年 | 1223篇 |
2010年 | 1017篇 |
2009年 | 1000篇 |
2008年 | 1008篇 |
2007年 | 993篇 |
2006年 | 869篇 |
2005年 | 806篇 |
2004年 | 671篇 |
2003年 | 597篇 |
2002年 | 527篇 |
2001年 | 530篇 |
2000年 | 440篇 |
1999年 | 386篇 |
1998年 | 371篇 |
1997年 | 374篇 |
1996年 | 335篇 |
1995年 | 319篇 |
1994年 | 317篇 |
1993年 | 298篇 |
1992年 | 296篇 |
1991年 | 283篇 |
1990年 | 255篇 |
1989年 | 225篇 |
1988年 | 237篇 |
1987年 | 227篇 |
1986年 | 197篇 |
1985年 | 245篇 |
1984年 | 282篇 |
1983年 | 149篇 |
1982年 | 201篇 |
1981年 | 163篇 |
1980年 | 159篇 |
1979年 | 159篇 |
1978年 | 131篇 |
1977年 | 118篇 |
1976年 | 118篇 |
1975年 | 91篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
31.
Summary The aim of this study was to investigate imipramine-induced alterations of cytochrome P-450 and to determine whether prolonged concomitant administration of imipramine and lithium results in a pharmacokinetic interaction.Male Wistar rats received imipramine (10 mg/kg i. p.) at 12 h intervals or lithium chloride (100 mg/kg in drinking water) or they were treated with the combination of these drugs for 2 weeks. The long term treatment with imipramine produced a very complex alteration of cytochrome P-450: imipramine increased the level of the cytochrome, but it decreased the rate of its own aromatic hydroxylation in position 2. The rate of N-demethylation in the side chain was not changed. Consequently, in the case of both hydroxylation and demethylation, calculated molecular activities were decreased to 48% and 70% respectively. This differential change in activities corresponded well to the observed decrease of absorption in difference spectra (type I) produced in microsomes by imipramine. Carbamazepine-induced type I difference spectra were also decreased by imipramine pretreatment, but to a lesser extent. In contrast, hexobarbital type I binding was increased by imipramine treatment while type II difference spectra produced by metyrapone were not affected. The preliminary SDS-PAGE analysis of cytochrome P-450 isoenzymes of control and imipramine treated rats showed that the investigated antidepressant markedly intensified a protein band at 50.11 kD while bands at 51.28 kD, 56.20 kD and 56.88 kD were less intensive. These results indicate that the alteration of cytochrome P-450 by imipramine treatment is not only of quantitative but also of qualitative character. Lithium alone given to rats affected neither the concentration of cytochrome P-450 in microsomal protein nor the rate of imipramine metabolism in vitro. Lithium given jointly with imipramine reduced imipramine-induced elevation of cytochrome P-450. This, however, did not cause any change in the rate of imipramine metabolism in vitro and accordingly in imipramine pharmacokinetics in vivo. The concentration of lithium in the blood plasma tended to increase by concurrent administration of imipramine.Send offprint requests to K. J. Netter at the above address 相似文献
32.
Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine 总被引:1,自引:0,他引:1
L. C. Kirkwood R. L. Nation & A. A. Somogyi 《British journal of clinical pharmacology》1997,44(6):549-555
Aims Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated.
Methods The kinetics of formation of N- and O -demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N -demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N -demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N -demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K m values. The kinetic constants for O -demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O -demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer.
Conclusions CYP2D6 is the major enzyme mediating O -demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. 相似文献
Methods The kinetics of formation of N- and O -demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N -demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N -demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N -demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K
Conclusions CYP2D6 is the major enzyme mediating O -demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. 相似文献
33.
组织扩张术皮肤胶原的代谢改变 总被引:4,自引:0,他引:4
目的:研究常规扩张(ITE)和持续快速扩张(CTE)对皮肤胶原代谢的影响。方法用白色小家猪制作组织扩张术动物模型,用Gordeladze法测定血清和扩张组织的羟脯氨酸(HP)含量,藻酸盐印模材膜片法测量标记区面积;光镜测量真皮厚度。结果:ITE组血清HP含量升高,0.8倍,CTE组升高1.2倍,ITE和CTE组皮肤含量与正常皮肤相同,组织中HP总量均明显升高,持续扩张皮瓣组(CTEF)术后4wk皮 相似文献
34.
R. Berkels A. Bertsch T. Zuther S. Dhein K. Stockklauser P. Rsen R. Rsen 《European journal of haematology》1997,58(5):307-313
Abstract: We tried to characterize the porcine platelet nitric oxide (NO) synthase and its L-arginine (L-arg)/NO metabolism. Using RT-PCR we could show a constitutive endothelial NOS (ecNOS) and an inducible NOS (iNOS) similar mRNA in platelets. The NOS protein could be evidenced by an ecNOS specific antibody which also bound in platelets. This finding could be confirmed by Western blot showing an ecNOS in the membrane but not the cytosolic fraction; iNOS protein could not be detected. Using NADPH-diaphorase staining we could show NO synthase in preactivated platelets but not in resting platelets, indicating that the platelet NOS may be activated during platelet activation/aggregation. Porcine L-arg plasma levels (9.31 × 10–5 mol/l ± 10%) could be shown to be in the same range as human plasma levels. Moreover, we could show that the NO precursor L-arg and hydroxy-L-arginine (OHarg) concentration dependently inhibited collagen induced platelet aggregation. Summarizing these results confirm the existence of and further characterize porcine platelet NO synthases. 相似文献
35.
When administered systemically, glucose attenuates deficits in memory produced by several classes of drugs, including cholinergic antagonists and opiate agonists. Glucose also enhances memory in aged rats, mice, and humans. In addition, glucose ameliorates age-related reductions in paradoxical sleep. Because deficits in paradoxical sleep are most marked in those individual aged rats that also have deficits in memory, treatments which improve one of these functions may similarly improve the other. The present experiments show that glucose attenuates deficits in paradoxical sleep and memory after atropine administration, with similar dose-response curves for both actions. In the first experiment, rats received saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100, 250, and 500 mg/kg) 30 min before assessment on a spontaneous alternation task. In the second experiment, 3-h EEGs were assessed for spontaneous daytime sleep in rats administered saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100 and 250 mg/kg). In both experiments, glucose significantly attenuated deficits at an optimal dose of 100 mg/kg. A third experiment assessed blood glucose levels after injections of atropine + glucose (100 mg/kg) and determined that blood glucose levels were similar to those produced by other treatments which enhance memory. These results are consistent with the view that paradoxical sleep and at least one test of memory are similarly influenced by atropine and glucose. 相似文献
36.
Khema R. Sharma Jane Kent-Braun Mark A. Mynhier Michael W. Weiner Robert G. Miller 《Muscle & nerve》1995,18(12):1403-1411
The goals of this study were to investigate muscle fatigue in patients with multiple sclerosis (MS), and to determine the relationships between muscle fatigue, clinical status, and perceived fatigue. The fatigability of the anterior tibial muscle was quantitated in patients and controls during 9 min of intermittent stimulation (used to eliminate central sources of muscle fatigue). During exercise, the decline in tetanic force, phosphocreatine, and intracellular pH was greater in patients than in controls. The compound muscle action potential amplitude did not decrease during exercise, indicating that there was no failure of neuromuscular transmission during fatigue. Thus, the excessive fatigue in MS developed from sources beyond the muscle membrane. Following exercise, the recovery of tetanic force was delayed in patients (a pattern that suggests abnormal excitation–contraction coupling), whereas the recovery of metabolites was complete in both groups. Muscular fatigue was correlated with clinical disability but not with perceived fatigue. These results suggests that fatigue in MS has both central (perception, upper motor neuron dysfunction) and peripheral (impaired metabolism and excitation–contraction coupling) components.© 1995 John Wiley &Sons, Inc. 相似文献
37.
HELEN J. GILL JAMES L. MAGGS STEPHEN MADDEN MUNIR PIRMOHAMED & B. KEVIN PARK 《British journal of clinical pharmacology》1996,42(3):347-353
1 Cytochrome P450-mediated bioactivation of sulphamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV-infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulphamethoxazole hydroxylamine.
2 Ten healthy male volunteers were given co-trimoxazole (800 mg sulphamethoxazole and 160 mg trimethoprim) alone or 1 h after either fluconazole (150 mg) or ketoconazole (200 mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24 h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS.
3 Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly ( P <0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N4 -acetyl sulphamethoxazole, or sulphamethoxazole N1 -glucuronide excreted in urine.
4 The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points. 相似文献
2 Ten healthy male volunteers were given co-trimoxazole (800 mg sulphamethoxazole and 160 mg trimethoprim) alone or 1 h after either fluconazole (150 mg) or ketoconazole (200 mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24 h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS.
3 Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly ( P <0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N
4 The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points. 相似文献
38.
在动物实验的基础上,比较了抗AFP单克隆抗体(mAb)和抗AFP多克隆抗体(pAb)两种不同抗体双弹头标记物在肝癌患者体内的生物代谢情况。结果显示,两种抗体标记物的血浆清除半衰期均在24h左右,mAb标记物的清除较pAb标记物略慢。尿清除的半衰期,mAb标记物约为120h,而pAb标记物则约为18h,表明二者的体内生物代谢不同,疗效可能不一。 相似文献
39.
Dario Roccatello Marco Formica Guido Cavalli Maria C. Amprimo Maria G. Pignatelli Paolo Costa Ruggero de Paulis Giacomo Quattrocchio rea Molino Gianbeppe Giordano 《Artificial organs》1990,14(1):69-72
Neutrophil oxidative metabolism, C3d and beta 2 microglobulin levels, were assessed in nine consecutive patients undergoing cardiopulmonary bypass surgery with polypropylene hollow fiber oxygenators for open cardiac operations. Generation of oxygen free radicals by neutrophils was measured as luminol-enhanced chemiluminescence after stimulation with opsonized Zymosan and phorbol myristate acetate. A significant increase in light emission was detected by using both of the chemiluminescence stimulators. Moreover, a remarkable and significant increase in C3d levels was found already at 10 min. Conversely minimal changes in levels of beta 2 microglobulin were detected during cardiopulmonary bypass surgery. These data suggest that the impact of the patient blood with the foreign surface of cardiopulmonary bypass results in activation of phagocyte cells with increased potential in oxygen consumption. These effects could be partially complement-mediated. 相似文献
40.
报道对链脲佐菌素(STZ)诱导的实验性糖尿病大鼠几种重要脏器(肝、肾、心、脑)卵磷脂、脑磷脂中脂肪酸构成的变化。不饱和脂肪酸变化的模式(C18:2n-6,C20:3n-6,C22:5n-3,C22:6n-3增加,C20:4n-6降低)基本相同,改变的先后顺序是肝→心、肾→脑。 相似文献