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31.
McGuire JJ Haile WH Valiaeva N Bartley D Guo J Coward JK 《Biochemical pharmacology》2003,65(3):315-318
A phosphorous-containing pseudopeptide folate analog (Valiaeva et al., J Org Chem 2001;66:5146-54) was designed to mimic the tetrahedral intermediate formed in the ATP-dependent reaction catalyzed by folylpolyglutamate synthetase (FPGS). This analog, methotrexate-phosphinate (MTX-phosphinate; 4-amino-4-deoxy-10-methylpteroyl-L-Glu-gamma-[psi(P(O)(OH)-CH(2))]glutarate), is a highly potent (K(is), 3.1+/-0.5 nM), competitive inhibitor of recombinant human cytosolic FPGS. Within experimental limits, FPGS inhibition was not time-dependent, and preincubation of FPGS, inhibitor, and ATP did not potentiate the inhibition. These results suggest that slow phosphorylation to produce a more potent inhibitor form is not involved. MTX-phosphinate was not growth inhibitory to human CCRF-CEM leukemia cells at 1 microM (70-fold above the concentration of MTX giving 50% growth inhibition), probably because of poor transport. Because of its exceedingly high potency as an FPGS inhibitor, MTX-phosphinate represents a lead structure from which cell-permeable analogs may be developed to test the hypothesis that FPGS inhibition is therapeutically efficacious. 相似文献
32.
Thirteen structural analogs of the potent nonpolyglutamatable dihydrofolate reductase inhibitor N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, the para-aminobenzoyl moiety, or the 9,10-bridge were evaluated for the ability to inhibit human recombinant dihydrofolate reductase (DHFR), to utilize the reduced folate carrier (RFC) for influx, and to inhibit the growth of CCRF-CEM human leukemia cells in culture. In spectrophotometric assays of the kinetics of the reduction of dihydrofolate by DHFR in the presence of NADPH, these compounds had K(i) values ranging from 0.2 to 1.3pM, and thus were not greatly different in potency from the parent drug PT523. By comparison, the K(i) values of aminopterin (AMT), methotrexate (MTX), and 10-ethyl-10-deazaaminopterin (EDX) were 3.7, 4.8, and 11pM. In assays of competitive inhibition of [3H]MTX influx into CCRF-CEM cells, the K(i) values ranged from 0.21 to 7.3 micro M, as compared with 0.71, 5.4, and 1.1 micro M for PT523, AMT, and EDX. The K(t) for MTX was also re-analyzed and found to be 4.7 micro M, in better agreement with the literature than our previously reported value of 7.1 micro M. The IC(50) values of these compounds as inhibitors of the growth of CCRF-CEM cells after 72hr of drug exposure ranged from 0.53 to 55nM, and were qualitatively consistent with the other results. 相似文献
33.
Pemetrexed (LY231514) is a new-generation antifolate that, in its polyglutamyl forms, is a potent inhibitor of thymidylate synthase and glycinamide ribonucleotide formyltransferase (GAR transformylase). This study explored the mechanisms of resistance to pemetrexed in L1210 murine leukemia cells using chemical mutagenesis with 5-formyltetrahydrofolate (5-formylTHF) as the growth substrate. A cell line, MTA-13, was identified that was 8.5-fold resistant to pemetrexed with comparable cross-resistance to ZD1694 (Tomudex) and lesser cross-resistance (5-fold) to ZD9331 [(2S)-2-(O-fluoro-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamido)-4-(tetrazol-5-yl)-butyric acid], DDATHF (dideazatetrahydrofolate) (3.5-fold), and methotrexate (MTX) (2.7-fold) but comparable sensitivity to trimetrexate. Influx of pemetrexed, MTX, and 5-formylTHF into MTA-13 cells was decreased by 56, 47, and 38% compared to wild-type cells. Folate receptor expression was negligible in both cell lines. Net drug uptake declined within 15min to a slower, constant rate over the next 45min, reflecting the rate of accumulation of pemetrexed polyglutamate derivatives. This rate in the MTA-13 line was half that of the wild-type cells. Accumulation of 50nM [3H]pemetrexed, 25nM [3H]5-formylTHF, or 50nM [3H]DDATHF after 3 days was decreased to 35, 46, and 56% the level of L1210 cells. The reduced folate carrier (RFC) message and protein were decreased by 50%, and folypolyglutamate synthetase (FPGS) message was decreased by 65% in MTA-13 cells. No mutations were detected in either protein by DNA sequence analysis. There was a slight decrease (approximately 25%) in thymidylate synthase mRNA, without mutations in the protein, and there was no change in GAR transformylase message. The data indicate that resistance to pemetrexed in the MTA-13 cell line was due to changes in both RFC and FPGS expression, two proteins that act in tandem to regulate polyglutamation of folates and antifolates in cells, resulting in cellular depletion of these active pemetrexed congeners. 相似文献
34.
腹腔镜联合甲氨喋呤(MTX)与单纯MTX保守治疗异位妊娠的疗效比较 总被引:2,自引:2,他引:2
目的比较腹腔镜联合MTX与单纯MTX保守治疗异位妊娠的临床疗效。方法选取2005年1月~2006年1月在四川省妇女儿童医院住院治疗的89例异位妊娠患者,分为腹腔镜联合MTX保守手术治疗组(A组)和单纯MTX保守治疗组(B组),分别观察两组患者治疗前血清β—HCG值、附件包块大小、住院天数、住院费用、出院时血中β—HCG浓度、输卵管通水情况、再次宫内妊娠以及再次同侧异位妊娠情况。结果A组比B组住院天数短(P〈0.01),血中β—HCG下降快(P〈0.01),再次宫内妊娠率高(P〈0.05)。结论相对于单纯MTX药物保守治疗,腹腔镜联合MTX保守手术治疗异位妊娠疗效快,住院时间短,远期并发症少,再次宫内妊娠率高,具有良好的临床应用价值。 相似文献
35.
两种不同治疗方法对异位妊娠预后影响的临床分析 总被引:15,自引:0,他引:15
目的:分析评价药物保守治疗和手术治疗异位妊娠对患者预后的影响。方法:对有生育要求的171例异位妊娠患者,分别对其中65例实施肌内注射MTX(药物组),106例行输卵管切除术(手术组)。结果:药物组中,在经过1或2个疗程MTX化疗后,彻底治愈51例,治愈率为78.5%,平均治疗时间为21±7天。手术组,治愈率为100%。随访2年,两组再次宫内受孕的成功率药物组45.1%,手术组51.9%,差异无显著性(P>0.05)。结论:肌内注射MTX治疗未破裂异位妊娠是一种安全而较为有效的治疗措施,其治疗后再次宫内受孕的成功率与手术组相比无明显差异。 相似文献
36.
ACNU, MTX And 5-FU Penetration of Rat Brain Tissue and Tumors 总被引:2,自引:0,他引:2
The distribution of radio-labeled ACNU, MTX and 5-FU in brain and tumor tissue was studied in female Wistar rats by macroautoradiography after intrathecal administration. In normal rats, ACNU and 5-FU, administered intracisternally, distributed rapidly in the subarachnoid space, ventricular system and cerebrospinal fluid (CSF). 5-FU and MTX penetrated the brain deeply; the diffusional transport of ACNU was limited to a depth of 1 or 2mm from the CSF surface of the brain. MTX and 5-FU clearance into the blood circulation was rather slow while ACNU cleared relatively quickly. The half time of ACNU, 5-FU and MTX radioactivity at the ventricular surface was 10, 21, and 110min, respectively, at their maximal concentration after intracisternal administration. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 cells, the distribution patterns of ACNU, 5-FU, and MTX were essentially the same as in normal rats despite 10–20 cell layers of tumor growing in the subarachnoid space. 5-FU and MTX were able to penetrate tumor masses in the subarachnoid space; MTX penetration was slower than that of 5-FU and ACNU failed to penetrate to more than a depth of 1 or 2mm from the tumor surface. 相似文献
37.
化学治疗是恶性肿瘤治疗的主要方法之一,治疗期间病人易出现不同程度的口腔溃疡,使患者承受着巨大的痛苦,由此产生惧怕化疗的心理压力.因此在化疗时应采取有效的措施,以预防、减轻其毒性反应. 相似文献
38.
大剂量MTX联合化疗淋巴系统恶性肿瘤的临床和药动学研究 总被引:3,自引:0,他引:3
目的:探讨大剂量甲氨蝶呤(HD-MTX3~4g/m^2)连续24小时静脉输注,第36 小时CF解救联合其它化疗药物治疗淋巴系统恶性肿瘤的临床耐受性和药动学研究。方法:分别对11例淋巴系统恶 性肿瘤进行共30个疗程大剂量MTX3~4g/m^2连续24小时静脉输注,第36小时CF解救,同时行血药浓度监测。其中22个疗程HD-MTX在G-CSF支持与其它化疗药物联合应用。结果:一般出现2~3级中性粒细胞减少,1~ 相似文献
39.
目的利用宫腔镜插管对输卵管妊娠保守治疗,探讨其临床价值。方法2006~2008年24例宫外孕患者行患侧输卵管插管注入MTX 20~40mg,成功杀死胚胎。结果方法简便可行,费用少,值得推广。结论采用宫腔镜输卵管妊娠插管保守治疗成功率高,消除了手术的痛苦,保存了完整输卵管,减少并发症。 相似文献
40.