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121.
Ben E. Evans 《Drug development research》1993,29(4):255-261
Peptide receptors represent important targets for a variety of potentially important disease modifying drugs. Over the past 20 years, considerable effort has been spent on modifying the natural ligands for peptide receptors, the peptides themselves, with limited success. Using a targeted screen, namely cholecystokinin (CCK)-A receptor binding, the Merck group in 1984 discovered asperlicin, a potent non-peptide cholecystokinin antagonist selective for peripheral tissues, that was isolated from Aspergillus alliaceaus. This compound was used as a lead to develop MK-329, a CCK-A receptor antagonist, the evolution of which is discussed within the context of the drug discovery process and receptor modeling strategies. © 1993 Wiley-Liss, Inc. 相似文献
122.
兴奋性氨基酸在缺血性海马神经元损害中的作用的研究 总被引:7,自引:0,他引:7
采用大鼠全脑缺血模型,研究脑缺血再灌流海马氨基酸含量的动态变化及相应病理改变,观察NMDA(N-甲基-D-门冬氮酸)受体拮抗剂MK-801的疗效,提示兴奋性氨基酸(Glu,Asp)可能参与海马神经元损害,MK-801能有效防止海马CA_1区迟发性神经元坏死。兴奋性氨基酸受体拮抗剂的研究,将为临床缺血性中风治疗提供新的途径。 相似文献
123.
氯丙嗪对紫杉醇协同作用的实验研究 总被引:1,自引:0,他引:1
目的 观察氯丙嗪与紫杉醇联合应用对人肺巨细胞癌株(PLA801D)增殖抑制及对其细胞周期的影响。方法 采用MTT法检测不同浓度紫杉醇单独及与氯丙嗪联合使用时对PLA801D细胞的生长抑制率;应用流式细胞术分析单独及联合用药后,PLA801D细胞周期的变化和凋亡率。结果 单药组诱导的凋亡率随紫杉醇剂量增加而升高,当紫杉醇浓度为24μg/ml时,诱导的凋亡率最高为13.2%;而两药联用(紫杉醇剂量不变,氯丙嗪剂量为4μg/ml),诱导的凋亡率明显高于紫杉醇单用组为55.8%,两组比较差异显著(P〈0.01)。同时,两药联用比单用抑瘤率亦有不同程度的提高(P〈0.05),且呈时间、剂量依赖性。结论 在一定浓度范围内,氯丙嗪在增强紫杉醇诱导PLA801D细胞凋亡及增殖抑制作用上具有明显的协同效应。 相似文献
124.
Christine Brideau Chi-Chung Chan Diane Guevremont John H. Hutchinson Joseph McDonnell Vernon Moore 《Drug development research》1993,29(3):188-194
The effect of a leukotriene biosynthesis inhibitor (MK-0591) on LTB4 synthesis was examined in a rabbit model of joint inflammation. Intra-articular (ia) injection of human recombinant interleukin-1β (rlL-1β, 50–400 ng/joint) resulted in dose-dependent infiltration of leukocytes into the synovium but produced only background levels of LTB4 over a time course of 14–16 h, suggesting that the leukocytes were not activated with respect to LTB4 metabolism. The influx of leukocytes in the synovial space was not inhibited by MK-0591. Injection of A23187 (100 nmol/joint, ia) in addition to rlL-1β elicited significant LTB4 release in the synovial fluid. MK-0591 given iv 30 min before A23187 significantly inhibited the release of LTB4 (ED50 = 0.3 mg/kg), without affecting the number of leukocytes in the synovium. In rabbit whole blood challenged with A23187 in vitro, MK-0591 also potently inhibited LTB4 synthesis (IC50 = 126 ± 29 nM). The in vivo inhibitory action of MK-0591 was in good agreement with the plasma levels of the compound (0.62 μM in the group treated with MK-0591 at 3 mg/kg) and its biochemical efficacy in vitro (100% inhibition of LTB4 synthesis). The effect of MK-0591 was comparable to that of another leukotriene biosynthesis inhibitor, MK-886. Indomethacin at dose up to 3 mg/kg iv did not affect the production of LTB4 in the joint. The present study demonstrates that MK-0591 inhibits LTB4 biosynthesis with high potency in the rabbit synovium, a microenvironment rich in protein and leukocytes. It would be of interest to determine whether such an action would be beneficial in the management of rheumatoid arthritis or other inflammatory conditions in humans. ©1993 Wiley-Liss, Inc. 相似文献
125.
Makoto Tsuda Norifumi Shimizu Yoshinori Yajima T. Suzuki Miwa Misawa 《Naunyn-Schmiedeberg's archives of pharmacology》1998,357(3):309-315
The present study investigated the role of NMDA (N-methyl-D-aspartate) receptors in the hypersusceptibility to seizures induced
by the benzodiazepine inverse agonist DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) during diazepam withdrawal
The seizure threshold of DMCM was markedly decreased during diazepam withdrawal, reflecting withdrawal hyperexcitability in
response to physical dependence. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was inhibited by
the non-competitive NMDA receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate;
50 μg/kg, s.c.) and ifenprodil (20 mg/kg, i.p.). The effective doses of these compounds were lower than those required to
prevent DMCM-induced seizures in chronically vehicle-treated mice. Since MK-801 and ifenprodil do not only bind to NMDA receptors
but also to σ receptors, the present study also investigated the effects of σ receptor ligands. The decrease in the seizure
threshold of DMCM in diazepam-withdrawn mice was not modified by the σ receptor agonist, (+)-pentazocine (5 mg/kg, s.c.),
or the σ receptor antagonist, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride; 5
mg/kg, i.p.). Furthermore, the latency to the expression of wild running induced by intracerebroventricular administration
of NMDA (60 ng/mouse) was also significantly lower in diazepam-withdrawn mice than in vehicle-treated control mice. On the
other hand, there was no difference in the spermidine concentration between vehicle-treated control and diazepam-withdrawn
mice. In a receptor binding experiment, the Bmax value for [3H]-MK-801 binding was significantly increased in cerebrocortical tissues from diazepam-withdrawn mice, while the Kd value did not change in either group. However, the acute addition of a high concentration of diazepam (10 and 100 μM) in
vitro did not alter [3H]-MK-801 binding in cerebrocortical membrane preparations. The behavioral experiments suggest that NMDA receptor antagonists
may suppress benzodiazepine withdrawal responses, while the biochemical study reveals upregulation of the NMDA receptor, which
may play an important role in the hypersusceptibility to DMCM-induced seizure in diazepam-withdrawn mice.
Received: 23 July 1997 / Accepted: 27 November 1997 相似文献
126.
目的 探讨地卓西平 (Dizocilpine ,MK 80 1)对局灶性脑缺血大鼠海马N 甲基 D 天门冬氨酸 (N methyl D asparticacid ,NM DA)受体的影响。方法 线栓法研制大脑中动脉阻断 (MCAO)大鼠模型 ,观察MK 80 1对局灶性脑缺血大鼠神经功能缺损评分、梗死体积以及脑海马NMDA受体结合位点数的影响。结果 MK 80 1组缺血 1、6、2 4小时各时相NMDA受体数量明显低于模型组 ;缺血 2 4小时MK 80 1组神经功能缺损评分及梗死体积明显低于模型组 (P <0 .0 1)。结论 MK 80 1对局灶性脑缺血大鼠的神经保护作用可能与下调脑缺血后兴奋性氨基酸受体结合位点数的上调有关。 相似文献
127.
Repeated amphetamine administration produced behavioral sensitization to subsequent amphetamine challenge. The development of sensitization was blocked by coadministration of the N-methyl-d-aspartate (NMDA) antagonist MK-801. Conditioned locomotion, as revealed by saline challenge, was also blocked by MK-801, suggesting that behavioral sensitization and conditioned locomotion may share a requirement for NMDA receptor stimulation. Repeated MK-801 administration produced behavioral sensitization to MK-801 but not amphetamine challenge, suggesting that MK-801 itself produces sensitization through a different mechanism than amphetamine. 相似文献
128.
Norio Himori Yushiro Tanaka Mitsue Kurasawa Kenichi Mishima Nobuhide Akaike Mayumi Imai Ken-ichi Ueno Takeo Matsukura Hiroshi Watanabe 《Psychopharmacology》1993,111(2):153-162
The acute anti-ischemic and anti-anoxic effects of dextrorphan (DX) were compared with those of dizocilpine (MK-801) in a variety of animal models, and in vivo and in vitro testings under anoxic conditions. DX reduced the incidence of death in ischemic mice and improved the rotarod performance of mice with brain ischemia. The ischemically-impaired memory of mice treated with DX markedly improved, as shown in the step-through type passive avoidance test, Morris water maze and in the habituation of exploratory behavior test. MK-801 likewise improved the water maze performance of the ischemically-impaired mice, but to a lesser extent. The step-through type passive avoidance performance of ischemic mice was not improved by MK-801. In the passive avoidance task with normal mice, DX, like MK-801, produced anterograde amnesia at doses higher than those needed to attenuate the behavioral effects of ischemia. DX, intravenously or centrally administered, markedly and dose-dependently reduced the incidence of death in mice receiving potassium cyanide (KCN). DX lessened the reduction in adenosine triphosphate (ATP) and increased lactate contents in mice dosed with KCN and also lessened the reduction in ATP in the TCA cycle and oxidative phosphorylation reactions caused by KCN (0.58 mmol/l), whereas MK-801 failed to show any effect on ATP formation pathways in vivo and in vitro, and failed to protect mice against KCN-induced lethal toxicity in vivo. In the in vitro studies, DX increased the adenylate kinase activity of the rat brain homogenate. DX was found to be a cerebroprotectant with anti-ischemic and anti-anoxic actions, the effects probably stemming from its N-methyl-d-aspartate receptor antagonistic property in cooperation with its ATP replenishing action. 相似文献
129.
The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, has been shown to block the development of sensitization of the behavioral activating effects of amphetamine. Three experiments were designed to determine in rats whether MK-801 had its effects through interference with long-term changes underlying sensitization, per se, or through interference with the development of conditioning of the drug effect to the environment where the drug was given. In experiment 1, conditioning was promoted by explicitly pairing amphetamine (1.5 mg/kg, IP) with the testing environment. In experiment 2, a random-pairing procedure was used to eliminate the possibility of association between the drug and a specific context. Experiment 3 was carried out to assess the duration of the blockade of sensitization by MK-801. The effect of MK-801 (0.25 mg/kg, IP) during amphetamine pre-exposure was studied in tests for conditioning (following saline injections, experiment 1) and in tests for sensitization (following 0.75 mg/kg amphetamine, experiments 1, 2 and 3). It was found in experiment 1 that MK-801 given with amphetamine during the amphetamine pre-exposure phase blocked the development of both conditioning activity and environment-specific sensitization to amphetamine. The results of experiment 2, showing that sensitization to amphetamine was blocked by MK-801 even when conditioning was prevented, suggest that the two effects of MK-801 are independent, and may implicate different sites of action. Experiment 3 showed that the blockade of sensitization by MK-801 was evident in tests made 10 days after pre-exposure to amphetamine, supporting the view that MK-801 interferes with long-term changes underlying sensitization to amphetamine. 相似文献
130.
Katsuhiro Yamashita Peter Vogel Klaus Fritze Tobias Back Konstantin-Alexander Hossmann Christoph Wiessner 《Brain research》1996,735(2):285
We investigated the temporo-spatial expression of astrocyte glial fibrillary acidic protein (gfap) and sulfated glycoprotein 2 (sgp-2) mRNAs in comparison to 70-kDa heat shock protein (hsp70) mRNA by in situ hybridisation in rats subjected to permanent occlusion of the middle cerebral artery (MCA).Gfap mRNA started to increase in the cingulate cortex of the lesioned hemisphere 6 h after MCA occlusion and gradually spread over the lateral part of the ipsilateral cortex and the striatum from 12 h to 3 days, peaking at 3 days after MCA occlusion.Gfap mRNA also increased in the contralateral cingulate cortex and corpus callosum at 12 and 24 h.Hsp70 mRNA increased markedly in the ipsilateral cortex adjacent to the ischemic lesion, and slightly within the lesion area from 3 to 24 h and disappeared after 3 days. By 7 days,gfap andsgp-2 mRNAs were increased markedly in the peri-infarct area, and in the ipsilateral thalamus parallel with the delayed neuronal damage, whereas the widespread increase ofgfap mRNA in the ipsilateral hemisphere declined. Post-occlusion treatment with the glutamate receptor antagonists MK-801 and NBQX slightly attenuated the induction ofgfap but did not qualitatively affect the topical expression pattern. Within the cingulate cortex MK-801 treatment resulted in a significant decrease of the signal intensity at all survival times, reflecting most likely an attenuation of lesion-induced spreading depression like depolarization waves by MK-801. The area ofhsp70 expression was reduced by both MK-801 and NBQX, most likely reflecting the decrease of the lesion area by both treatment regimens. Our study thus revealed an early and widespread increase ofgfap mRNA in the non-ischemic areas including the contralateral hemisphere starting between 3 and 6 h, and a delayed circumscribed expression in the peri-infarct border zone after 1 week. Comparison with the expression ofhsp70 mRNA suggests that the absence of an earlygfap mRNA induction in the peri-lesion zone reflects an impairment of astrocytic function which may be of importance for infarct growth during the early evolution of the pathological process. 相似文献