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Claudia Linde Cornelia Löffler Christina Kessler U. Quast 《Naunyn-Schmiedeberg's archives of pharmacology》1997,356(4):467-474
In vascular smooth muscle, openers of ATP-dependent potassium channels (K
ATP channels), such as P1075 (N-cyano-N’-(1,1-dimethylpropyl)-N’’-3-pyridylguanidine), produce relaxation. In this study we have investigated the effects of thiol-modifying agents on the
binding of P1075 and on the 86Rb+ efflux stimulating and vasorelaxant effects of the opener in rat aortic rings. The increase in 86Rb+ efflux induced by P1075 was taken as a qualitative measure of K+ channel opening. The hydrophilic SH-group-oxidizing substance, thimerosal (1 to 100μM), abolished specific binding of [3H]-P1075 with an IC50 value of 7.6±1.2μM; at 30μM, the half time for inhibition was 38min. Two other thiol-oxidizing agents, PMB (4-hydroxy-mercuribenzoic
acid) and DTBNP (2,2’-dithio-bis(5-nitropyridine)), inhibited binding up to 86% and 44%, respectively. The disulphide bond
reducing substance, DTT (1,4-dithiothreitol, 0.1 to 1mM), reduced [3H]-P1075 binding by up to 20% and partially reversed the inhibitory effect of thimerosal. In 86Rb+ efflux experiments, thimerosal (3 to 100μM) concentration-dependently increased basal efflux but inhibited P1075-stimulated
tracer efflux with an IC50 value of 7±1μM. The inhibitory effect occurred with a half-time of approximately 8min and was essentially reversed by DTT.
In rings precontracted with noradrenaline, thimerosal inhibited the vasorelaxant effect in a noncompetitive manner, shifting
the concentration-relaxation curves to the right and reducing maximum relaxation.The data show that oxidation of thiol groups
interferes with the binding of the K
ATP channel opener, P1075; concomitantly, the 86Rb+ efflux stimulating and the vasorelaxant effects are inhibited. Reduction of disulphide bonds by DTT has only minor effects
on the action of P1075. Collectively, the results suggest that intact thiol groups are essential for the functioning of the
KATP channel in rat aorta. The different kinetics governing the inhibition of opener binding and of opener-stimulated 86Rb+ efflux suggest that the SH-groups involved in the two processes differ in their accessibility to thimerosal and/or in their
reactivity.
Received: 7 April / Accepted: 9 July 1997 相似文献
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Structure-activity studies of potassium channel opening in pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas. 总被引:3,自引:0,他引:3
Potassium channel opening activity for pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas, has been assessed through simultaneous measurement of spontaneous contractile activity and stimulation of 86Rb+ efflux from rat portal veins loaded with 86Rb+. The good correlation between these two effects suggests that the vasodilator activity of the compounds is directly attributable to an increased opening of potassium channels. The resulting quantitative in vitro data has been used to analyze the structure-activity relationships for potassium channel opening, allowing the biological activity to be rationalized in terms of a pharmacophore involving a hydrogen-bond-acceptor element, a hydrogen-bond-donor element, and a lipophilic binding group. A model for the binding of pinacidil-related compounds to their potassium channel receptor has been developed, and compounds designed to test this model have been synthesized and tested. Prototropic equilibria are implicated as playing a fundamental role in determining the hydrogen-bonding ability of the compounds, and conformational changes in the receptor are invoked to explain disparities in the chiral recognition of lipophilic groups in different compounds. 相似文献
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Surgery of spinal nerve schwannoma. Risk of neurological deficit after resection of involved root 总被引:6,自引:0,他引:6
When surgically removing a spinal nerve schwannoma, preservation of the involved root is attempted and may be feasible. However, in large tumors, sacrifice of the nerve root is often required to achieve total removal of the tumor, and the resection does not always result in postoperative neurological deficit. The present study was designed to determine the incidence and extent of neurological deficit as correlated with resection of the root, performed between 1976 and 1987 in 86 cases at the time of total removal of spinal schwannoma. Thirty-one patients underwent sacrifice of a root critical for the function of the upper (C5-T1, 14 cases) or the lower extremities (L3-S1, 17 cases). This report is limited to these 31 cases. Only seven patients (23%) developed detachable motor or sensory deficits postoperatively. All deficits were no more than partial loss of strength or sensation. Fifteen of the 31 patients had large tumors with extradural components, which necessitated sacrifice of the entire motor and sensory radix; however, 11 (76%) of these 15 did not develop any deficits referrable to the involved myotome or dermatome. Six cases showed histological characteristics of "neurofibroma," with axons intermingled in the tumor, and none developed a postoperative deficit. Preoperative electromyography was performed in 23 cases. Of 13 patients with findings of denervation, five developed deficits after surgery; the other 10 patients showed no evidence of denervation, and none had deficits after surgery. These results indicate that the spinal roots giving origin to schwannoma are frequently nonfunctional at the time of surgery, and risks of causing disabling neurological deficit after sacrificing these roots are small. 相似文献