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91.
92.
Introduction: Target-specific drugs may offer fewer side/adverse effects in comparison with other anticancer agents and thus save normal healthy cells to a greater extent. The selective overexpression of cytochrome P450 1A1 (CYP1A1) in tumor cells induces the metabolism of benzothiazole and aminoflavone compounds to their reactive species, which are responsible for DNA adduct formation and cell death. This review encompasses the novelty of CYP1A1 as an anticancer drug target and explores the possible in silico strategies that would be applicable in the discovery and development of future antitumor compounds. Areas covered: This review highlights the various ligand-based and target-based in silico methodologies that were efficiently used in exploration of CYP1A1 as a novel antitumor target. These methodologies include electronic structure analysis, CoMFA studies, homology modeling, molecular docking, molecular dynamics analysis, pharmacophore mapping and quantitative structure activity relationship (QSAR) studies. It also focuses on the various approaches used in the development of the lysyl amide prodrug of 5F-203 (NSC710305) and dimethanesulfonate salt of 5-aminoflavone (NSC710464) as clinical candidates from their less potent analogues. Expert opinion: Selective overexpression of CYP1A1 in cancer cells offers tumor-specific drug design to ameliorate the current adverse effects associated with existing antitumor agents. Medicinal chemistry and in vitro driven approaches, in combination with knowledge-based drug design and by using the currently available tools of in silico methodologies, would certainly make it possible to design and develop novel anticancer compounds targeting CYP1A1. 相似文献
93.
KS Khomane PP Nandekar B Wahlang P Bagul N Shaikh YB Pawar CL Meena AT Sangamwar R Jain K Tikoo AK Bansal 《Molecular pharmaceutics》2012,9(9):2458-2468
The present study, in general, is aimed to uncover the properties of the transport mechanism or mechanisms responsible for the uptake of NP-647 into Caco-2 cells and, in particular, to understand whether it is a substrate for the intestinal oligopeptide transporter, PEPT1 (SLC15A1). NP-647 showed a carrier-mediated, saturable transport with Michaelis-Menten parameters K(m) = 1.2 mM and V(max) = 2.2 μM/min. The effect of pH, sodium ion (Na(+)), glycylsarcosine and amoxicillin (substrates of PEPT1), and sodium azide (Na(+)/K(+)-ATPase inhibitor) on the flux rate of NP-647 was determined. Molecular docking and molecular dynamics simulation studies were carried out to investigate molecular interactions of NP-647 with transporter using homology model of human PEPT1. The permeability coefficient (P(appCaco-2)) of NP-647 (32.5 × 10(-6) cm/s) was found to be four times higher than that of TRH. Results indicate that NP-647 is transported into Caco-2 cells by means of a carrier-mediated, proton-dependent mechanism that is inhibited by Gly-Sar and amoxicillin. In turn, NP-647 also inhibits the uptake of Gly-Sar into Caco-2 cells and, together, this evidence suggests that PEPT1 is involved in the process. Docking and molecular dynamics simulation studies indicate high affinity of NP-647 toward PEPT1 binding site as compared to TRH. High permeability of NP-647 over TRH is attributed to its increased hydrophobicity which increases its affinity toward PEPT1 by interacting with the hydrophobic pocket of the transporter through hydrophobic forces. 相似文献
94.
Prajwal P. Nandekar Khaled M. Tumbi Nitu Bansal Vijay P. Rathod Leena B. Labhsetwar Neelagiri Soumya Sushma Singh Abhay T. Sangamwar 《Medicinal chemistry research》2013,22(8):3728-3742
The benzothiazole scaffold has been reported to have antitumor activity in tumor-sensitive cell lines by proposed mechanism of CYP1A1 induction. CYP1A1 has been shown to participate in metabolism of benzothiazole scaffold to its reactive metabolites. CYP1A1 has also been proposed as drug target for anti-cancer chemotherapy for its differential and selective overexpression in tumor cells. Herein, we have reported NSC745689 from the series of new pyrimidobenzothiazoles (NSC745689) for its promising antitumor activity against non-small cell lung cancer cell line in National Cancer Institute (NCI) 60 human cancer cell line screen. We confirmed CYP1A1 specificity for NSC745689 by ethoxyresorufin-O-dethylase (EROD) assay. Furthermore, we investigated the metabolism of NSC745689 using MetaSite software and quantum mechanical study. The necessary structural changes in NSC745689 scaffold to potentiate its CYP1A1 binding and antitumor activity were suggested using molecular docking and molecular dynamics analysis. 相似文献
95.
Prajwal Lourdes Lobo Boja Poojary Manjunatha Kumsi Vinaya Chandra Nalilu Sucheta Kumari K. R. Chandrashekar 《Medicinal chemistry research》2013,22(4):1689-1699
In this study, various substituted chalcones, prepared by condensing substituted acetophenones with substituted aldehydes/arylfurfurals, were treated with thiosemicarbazide in basic media to produce 1-thiocarbonyl-3,5-disubstituted pyrazolines which on further reaction with substituted phenacyl bromides afforded the title compounds in good yield. Structures of the newly synthesized compounds were assigned on the basis of elemental analyses, IR, 1H NMR, and mass spectral studies. The newly synthesized compounds were tested for their in vitro antibacterial and antifungal activities against a variety of microorganisms and antioxidant activities by diphenylpicrylhydrazyl radical scavenging assay. Among the derivatives, compounds 3b, 3e, 6a, and 6h were identified as potent antioxidants. Compounds 3d, 3e, and 6a–f have emerged as the most promising antimicrobial agents displaying the maximum activity against all the tested microorganisms. 相似文献
96.
97.
Regmi PR Metzler-Zebeli BU Gänzle MG van Kempen TA Zijlstra RT 《The Journal of nutrition》2011,141(7):1273-1280
Diets containing different starch types can affect enzymatic digestion of starch and thereby starch availability for microbial fermentation in the gut. However, the role of starch chemistry in nutrient digestion and flow and microbial profile has been poorly explained. Eight ileal-cannulated pigs (29.4 ± 0.9 kg body weight) were fed 4 diets containing 70% purified starch (amylose content, <5, 20, 28, and 63%; reflected by in vitro maximal digestion rate; 1.06, 0.73, 0.38, and 0.22%/min, respectively) in a replicated 4 × 4 Latin square. Ileal and fecal starch output, postileal crude protein yield, fecal total SCFA and total butyrate content, and gene copies of Bifidobacterium spp. in feces were higher (P < 0.05) when pigs consumed the slowly digestible starch diet than the remaining 3 starch diets. The in vitro starch digestion rate had a negative, nonlinear relationship with ileal starch flow (R(2) = 0.98; P < 0.001). Ileal starch flow was positively related to Bifidobacterium spp. (R(2) = 0.27; P < 0.01), Lactobacillus group (R(2) = 0.22; P < 0.01), and total butyrate content (R(2) = 0.46; P < 0.01) but was not related to Enterobacteriaceae (R(2) < 0.00; P = 0.92). In conclusion, starch with high amylose content and low in vitro digestibility increased postileal nutrient flow and microbial fermentation and selectively promoted Bifidobacterium spp. in the distal gut. 相似文献
98.
Diets containing different starch types affect peripheral glucose and insulin responses. However, the role of starch chemistry in kinetics of nutrient absorption and insulin and incretin secretion is poorly understood. Four portal vein-catheterized pigs (35.0 ± 0.2 kg body weight) consumed 4 diets containing 70% purified starch [0-63.2% amylose content and 0.22 (slowly) to 1.06%/min (rapidly) maximum rate of in vitro digestion] for 7-d periods in a 4 × 4 Latin square. On d 7, blood was collected for 12 h postprandial with simultaneous blood flow measurement for determining the net portal appearance (NPA) of nutrients and hormones. The NPA of glucose, insulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) during 0-4 h postprandial were lower (P < 0.05) and those of butyrate and total SCFA were higher (P < 0.05) when pigs consumed the diet containing slowly digestible compared with rapidly digestible starch. The peak NPA of insulin occurred prior to that of glucose when pigs consumed diets containing rapidly digestible starch. The kinetics of insulin secretion had a linear positive relation with kinetics of NPA of glucose (R(2) = 0.50; P < 0.01). In conclusion, starch with high amylose and low in vitro digestibility decreases the kinetics of glucose absorption and insulin and GIP secretion and increases SCFA absorption and glucagon-like peptide-1 secretion. In conclusion, starch with high amylose content and a lower rate and extent of in vitro digestion decreased glucose absorption and insulin secretion and increased SCFA absorption. 相似文献
99.
Suman S Thapa Rosa VD Berg Shankar Khanal Indira Paudyal Pooja Pandey Nhukesh Maharjan Shankha N Twyana Govinda Paudyal Reeta Gurung Sanduk Ruit Ger HMBV Rens 《BMC ophthalmology》2011,11(1):1-9
Background
The present study investigates two different treatment options for convergence insufficiency CI for a group of children with reading difficulties referred by educational institutes to a specialist eye clinic in Vienna.Methods
One hundred and thirty four subjects (aged 7-14 years) with reading difficulties were referred from an educational institute in Vienna, Austria for visual assessment. Each child was given either 8Δ base-in reading spectacles (n = 51) or computerised home vision therapy (HTS) (n = 51). Thirty two participants refused all treatment offered (clinical control group). A full visual assessment including reading speed and accuracy were conducted pre- and post-treatment.Results
Factorial analyses demonstrated statistically significant changes between results obtained for visits 1 and 2 for total reading time, reading error score, amplitude of accommodation and binocular accommodative facility (within subjects effects) (p < 0.05). Significant differences were also demonstrated between treatment groups for total reading time, reading error score and binocular accommodative facility (between subjects effects) (p < 0.05).Conclusions
Reading difficulties with no apparent intellectual or psychological foundation may be due to a binocular vision anomaly such as convergence insufficiency. Both the HTS and prismatic correction are highly effective treatment options for convergence insufficiency. Prismatic correction can be considered an effective alternative to HTS. 相似文献100.
Prajwal Boddu Guillermo Garcia‐Manero Farhad Ravandi Gautam Borthakur Elias Jabbour Courtney DiNardo Nitin Jain Naval Daver Naveen Pemmaraju Paolo Anderlini Simrit Parmar Devendra KC Mary Akosile Sherry A. Pierce Richard Champlin Jorge Cortes Hagop Kantarjian Tapan Kadia 《American journal of hematology》2017,92(12):1295-1302
Newer treatment modalities are being investigated to improve upon historical outcomes with standard immunosuppressive therapy (IST) in aplastic anemia (AA). We analyzed outcomes of adult patients with AA treated with various combinatorial anti‐thymoglobulin‐based IST regimens in frontline and relapsed/refractory (R/R) settings. Pretreatment and on‐treatment clinical characteristics were analyzed for relationships to response and outcome. Among 126 patients reviewed, 95 were treatment‐naïve (TN) and 63, R/R (including 32 from the TN cohort); median ages were 49 and 50 years, respectively. Overall survival (OS) was superior in IST responders (P < .001). Partial response to IST was associated with shorter relapse‐free survival (RFS), as compared with complete response (P = .03). By multivariate analysis, baseline platelet and lymphocyte count predicted for IST response at 3 and 6 months, respectively. While additional growth factor interventions led to faster count recovery, there were no statistically significant differences in RFS or OS across the various frontline IST regimens (i.e., with/without G‐CSF or eltrombopag). While marrow cellularity did not correlate with peripheral‐blood counts at 3 months, cytomorphological assessment revealed dyspoietic changes in all nonresponders with hypercellular‐marrow indices. Covert dysplasia, identified through early bone marrow assessment, has implications on future therapy choices after IST failure. Salvage IST response depended upon prior response to ATG: prior responders (46%) vs. primary refractory (0%) (P < .01). In the R/R setting, there was no survival difference between IST and allogeneic stem cell transplant groups, with a trend toward superior OS in the former. Transplant benefits in the R/R setting may be underrealized due to transplant‐related mortality. 相似文献