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101.
Stereoselective aspects of pharmacokinetics and metabolism of a chiral nonsteroidal antiinflammatory drug, flobufen, 4-(2', 4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, were studied in male guinea pigs after p.o. administration of racemic flobufen (rac-flobufen) at a dose of 10 mg/kg. Blood samples were collected at intervals over 16 h after the administration of rac-flobufen for the quantification of flobufen enantiomers and their respective metabolites in plasma by chiral high-performance liquid chromatography (HPLC). Compartmental pharmacokinetic analysis was used to determine pharmacokinetic parameters of R- and S-flobufen. The plasma concentrations of the S- and R-enantiomers differed significantly during the experimental period. The S/R-enantiomeric ratio in 7plasma reached a maximum value of 10.1 at 240 min postdose. The oral clearance value of R-flobufen was five times higher than S-flobufen. The other pharmacokinetic parameters (K(e), T(1/2), V(SS)/F, MRT) of the enantiomers also differed substantially. All four stereoisomers of the dihydrometabolite of flobufen were detected in plasma with varying concentrations. Metabolite 17203 [4-(2,4-difluorophenyl)-phenylacetic acid] exhibited a relatively longer residence time compared to that noted for the enantiomers of the parent compound. Pharmacokinetics of the flobufen enantiomers were stereoselective in guinea pigs. The metabolism of flobufen was complex. However, metabolite 17203 seemed to be the main metabolite of flobufen that may be responsible for its relatively long-lasting antiphlogistic and immunomodulatory effects. 相似文献
102.
Bruno Chauffert Marie-Thérèse Dimanche-Boitrel Carmen Garrido Mikael Ivarsson Monique Martin François Martin Eric Solary 《Cytotechnology》1998,27(1-3):225-235
Kinetic resistance plays a major role in the failure of chemotherapy towards many solid tumors. Kinetic resistance to cytotoxic
drugs can be reproduced in vitro by growing the cells as multicellular spheroids (Multicellular Resistance) or as hyperconfluent
cultures (Confluence-Dependent Resistance). Recent findings on the cell cycle regulation have permitted a better understanding
why cancer cells which arrest in long quiescent phases are poorly sensitive to cell-cycle specific anticancer drugs. Two cyclin-dependent
kinase inhibitors (CDKI) seem particularly involved in the cell cycle arrest at the G1 to S transition checkpoint: the p53-dependent
p21cip1 protein which is activated by DNA damage and the p27kip1 which is a mediator of the contact inhibition signal. Cell quiescence could alter drug-induced apoptosis which is partly
dependent on an active progression in the cell cycle and which is facilitated by overexpression of oncogenes such as c-Myc
or cyclins. Investigations are yet necessary to determine the influence of the cell cycle on the balance between antagonizing
(bcl-2, bcl-XL...) or stimulating (Bax, Bcl-XS, Fas...) factors in chemotherapy-induced apoptosis. Quiescent cells could also be protected from toxic agents by an enhanced
expression of stress proteins, such as HSP27 which is induced by confluence. New strategies are required to circumvent kinetic
resistance of solid tumors: adequate choice of anticancer agents whose activity is not altered by quiescence (radiation, cisplatin),
recruitment from G1 to S/G2 phases by cell pretreatment with alkylating drugs or attenuation of CDKI activity by specific
inhibitors.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
103.
肽核酸的分子生物学效应及应用 总被引:2,自引:0,他引:2
肽核酸(PNA)是一类以酰胺键连接骨架替代核酸中核糖磷酸二酯键骨架构成的核酸类似物,其中N-乙基甘氨酸骨架PNA与核酸链以Waston-Crick碱基配对形式稳定互补结合,具有广泛生物学效应,包括调节DNA识别蛋白质的功能以及调节转录和翻译.在分子生物学研究中PNA作为新的工具在多方面得到应用.除它的DNA(RNA)结合特性外PNA在生物稳定性、细胞摄取、结构修饰多方面的研究进展显示出作为基因调节药物具有良好前景. 相似文献
104.
Alessandra de Cupis Paolo Pirani Laura Fazzuoli Roberto E. Favoni 《In vitro cellular & developmental biology. Animal》1998,34(10):836-843
Summary Growth rate, morphology, and responsiveness to mitogenic stimuli and pharmacological treatments were evaluated in early and
late cell passages derived from the same clone of the widely used MCF-7 human breast adenocarcinoma cell line. Our results
indicate dissimilarities between early (E) and late (L) passages for some of the parameters analyzed. The cells that underwent
many subcultivations grew faster than the others; both appeared homogeneous in size and shape. The E cells, subcultured for
almost 1 yr, displayed higher sensitivity to the mitogenic action of both estradiol, according to the level of estrogen receptor,
and insulin-like growth factor-I than did the L cells, kept in culture for more than 10 yr. Cell responsiveness to two drugs,
a novel steroid antiestrogen and a polysulfonated distamycin A derivative, was more pronounced in the early cultures only
at the longer time of exposure to the higher concentration of the estrogen antagonist. In addition, a drug-induced inhibition
of insulin-like growth factor-I binding to its receptor was shown in both E and L cells, the latter being less sensitive than
the former when exposed to the antiestrogen. Finally, MCF-7 E and L cells showed similar behavior when drug-induced apoptosis
was tested. 相似文献
105.
Hans H. Maurer Joachim W. Arlt 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1998,714(2)
A gas chromatography–mass spectrometry (GC–MS) procedure was developed for the detection of 4-hydroxycoumarin anticoagulants and their metabolites in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons after extractive methylation. The part of the phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by capillary GC and identified by computerized MS in the full scan mode. Using mass chromatography with the ions m/z 291, 294, 295, 309, 313, 322, 324, 336, 343 and 354, the possible presence of 4-hydroxycoumarin anticoagulants and/or their metabolites could be indicated. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with the reference spectra recorded during this study. This method allowed the detection of therapeutic concentrations of phenprocoumon and warfarin in human urine samples. In absence of human urine, acenocoumarol, coumachlor, coumatetrayl, pyranocoumarin (cyclocumarol) could be detected only in rat urine. 相似文献
106.
《Biological Rhythm Research》2007,38(3):247-258
The cardiovascular system is well organized in time. Mechanisms of regulation and pathophysiological events are not evenly distributed over the 24-h scale. Moreover, certain diseases may even alter the physiological circadian pattern in the cardiovascular system. This observation bares implications for drug treatment, e.g. regarding drug formulations and dosing time intervals. Pitfalls may arise from neglecting circadian phase-dependency in pharmacokinetics and in the concentration-dependent effect relationship. Moreover, different types of drugs may be superior to others when circadian time-related symptoms are concerned. There is sound evidence that “time-of-day” has to be included in our diagnostic and therapeutic strategies. 相似文献
107.
以糙皮侧耳、双孢蘑菇、金针菇、3个黑木耳品种、3个香菇品种为材料,通过测定小鼠体重、免疫器官重量、细胞免疫功能、体液免疫功能、单核-巨噬细胞的吞噬功能、血清及肝脏中谷胱甘肽过氧化物酶、超氧化物歧化酶、肝脏中白介素-6、丙二醛等指标进行小鼠免疫功能的评价研究。结果表明:"四川青川"香菇、"北神奇1号"黑木耳和"黑龙江黑29"黑木耳能显著增强小鼠的细胞免疫功能;糙皮侧耳、"辽宁恒仁"香菇、金针菇、"北神奇1号"黑木耳、"黑龙江黑29"黑木耳均能显著促进小鼠单核吞噬细胞的吞噬能力,增强小鼠机体的免疫力;糙皮侧耳、"四川青川"香菇、"辽宁恒仁"香菇、金针菇和"黑龙江黑29"黑木耳具有提高小鼠肝脏中白介素-6含量的作用;双孢蘑菇、"福建古田"香菇、"辽宁恒仁"香菇、金针菇增加小鼠血清溶血素水平,具有显著的特异性体液免疫增强作用。此外,双孢蘑菇、金针菇、"北神奇1号"黑木耳、"吉林黑29"黑木耳均可显著提高血清和肝脏中的GSH-PX活性;糙皮侧耳能提高小鼠血清中和肝脏中SOD活性;从而达到清除自由基和抗氧化损伤的作用。综合上述结果,9种食用菌超细粉均具有显著增强小鼠免疫调节能力和抗氧化作用,为食用菌功能食品产品开发利用提供支撑。 相似文献
108.
目的:研究长期使用青光眼药物对患者眼表结构的影响,为正确选择青光眼治疗药物提供依据。方法:将采用青光眼药物治
疗≥ 3 个月的青光眼患者40 例(62 只眼)设为病例组,以同期健康志愿者30 例(30 只眼)设为对照组,比较两组基础泪液分泌长
度(ST)、泪膜破裂时间(BUT)、角膜荧光染色评分(FB)及结膜印记细胞评级(IC)。结果:病例组ST、BUT 分别为(6.12± 3.63)mm、
(5.21± 2.13)s,均短于对照组的(10.72± 4.62)mm、(11.45± 5.12)s(P<0.01);病例组FB 评分为(2.19± 0.42)分,高于对照组(0.62±
0.04)分(P<0.01);病例组IC 评级为Ⅱ~Ⅲ级比例为54.84%,高于对照组的5.00%(P<0.01)。结论:青光眼患者长期使用青光眼药物
会导致泪液分泌减少,泪膜稳定性下降,并加快结膜细胞鳞状上皮化进程,对泪膜、角膜及结膜均有损伤,应引起重视。 相似文献
109.
Heggodu G. RohitKumar Kittur R. Asha Hulihalli N. KiranKumar Laxmi S. Inamdar 《Nucleosides, nucleotides & nucleic acids》2015,34(8):525-543
Circular dichroism, topological studies, molecular docking, absorbance, and fluorescence spectral titrations were employed to study the interaction of 4-morpholinopyrimido [4′,5′:4,5] selenolo (2,3-b) quinoline (MPSQ) with DNA. The association constants of MPSQ–DNA interactions were of the order of 104 M?1. Melting temperature, topological, and docking studies confirmed that the mode of interaction was by intercalation with preference to d(GpC)–d(CpG) site of DNA. Cytotoxicity studies showed the MPSQ-induced dose-dependent inhibitory effect on the proliferation of different cancer cells. Colon adenocarcinoma (COLO 205) cells are more sensitive among the cell lines tested, with an IC50 value of 15 μM. Flow cytometry revealed that MPSQ affects the cell cycle progression by arresting at G2M phase. Further, Annexin V staining, mitochondrial membrane potential assay, and caspase-3 activity assay confirmed that MPSQ leads to mitochondria-mediated apoptotic cell death in COLO 205 cells. 相似文献
110.
Cryosurgery with liquid nitrogen is one of the most used treatments for actinic keratosis. We aimed to study the effectiveness of two consecutive sessions of cryosurgery for actinic keratosis and investigate factors associated with its therapeutic success. Hence, we conducted a longitudinal study including 92 patients of both sexes, aged 50–75 years with 5–50 actinic keratosis on the face and forearms, who underwent cryosurgery and treatment with sunscreen SPF 30, at baseline and after 120 days. The lesions were counted in duplicate by the same examiner before the start of treatment and after 120 (N = 92) and 300 days (N = 33), represented by their medians and quartiles and compared using the generalized linear mixed effects model (negative binomial). Treatment behavior was investigated in relation to sex, age, education, skin type, smoking, sun exposure at work and the use of aspirin, anti-inflammatory and angiotensin-converting enzyme inhibitors. There was a significant reduction in the actinic keratosis count on the face and forearms (p < 0.05). Our results confirmed the effectiveness of cryosurgery for actinic keratosis, with a 57% reduction in the number, and size of the lesions. Higher education levels (p = 0.02) and less sun exposure at work (p = 0.02) independently promoted a significant reduction in the actinic keratosis count. Different population groups showed characteristic responses to the treatment, which may be explained by the degree of adherence to the use of photoprotection. In two sessions, cryosurgery with liquid nitrogen reduced the actinic keratosis count. 相似文献