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51.
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
52.
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
53.
Claus Jacob Alexander Y. Safronov Sonia Wilson H.Allen O. Hill Tim F. Booth 《Journal of electroanalytical chemistry (Lausanne, Switzerland)》1997,431(1):7-10
A novel chiral redox-active ferrocene compound (FcVI) with amphiphilic properties has been synthesized. Cryogenic Transmission Electron Microscopy (cryo-TEM) has been used to estimate the shape and size of the FcVI aggregates in solution. Uni- and multi-lamellar vesicles (between 40 and 300 nm in diameter) were observed in water. Large particles (of more than 1 μm in diameter) with a hexagonal fine structure were found in 50 mM aqueous Na2SO4 solution. Sonication transformed the latter into ‘rosette’-like structures. Cyclic voltammetry has been employed to investigate the electrochemical properties of FcVI. The amphiphile adsorbed on graphite electrodes and a reversible electrochemical behaviour, characteristic of ferrocene, was observed with redox potentials between 330 and 350 mV. 相似文献
54.
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
55.
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
56.
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
57.
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
58.
高龄初产妊高征孕妇过氧化反应的研究 总被引:3,自引:0,他引:3
目的:探讨高龄初产妊高征孕妇体内过氧化反应。方法:测定正常初产妇、妊高征孕妇妊娠晚期母血过氧化脂质(LPO)、超氧化物歧化酶(DOD)的含量。结果:1.高龄初产妇母血LPO较非高龄初产妇明显升高,SOD明显下降,P<0.05。孕妇年龄与母血LPO呈明显正相关,与SOD呈明显负相关,P均<0.05。2.妊高征孕妇LPO较正常孕妇显著增高,SOD显著下降,P<0.05,并随病情加重LPO水平升高、SOD水平下降更为显著,P<0.05。3.高龄初产妊高征孕妇母血LPO含量较非高龄初产妊高征孕妇明显增高,P<0.05,而SOD则无显著变化,P>0.05。4.妊高征孕妇胎儿宫内生长发育迟缓(IUGR)发生率较正常孕妇显著升高,P<0.025,各组脐血清LPO、SOD含量无显著差异,P<0.05。结论:高龄初产妊高征孕妇体内过氧化作用明显增强,LPO水平的升高可能为高龄初产妇妊高征发生率及IUGR发生率增加的原因之一。 相似文献
59.
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
60.
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