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Kaymak Hakan Graff Birte Schaeffel Frank Langenbucher Achim Seitz Berthold Schwahn Hartmut 《Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie》2021,259(10):3083-3092
Graefe's Archive for Clinical and Experimental Ophthalmology - Several randomized controlled studies have demonstrated the beneficial effects of 0.01% atropine eye drops on myopia progression... 相似文献
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Amelia N. Deitchman Ravi Shankar Prasad Singh Hartmut Derendorf 《Journal of pharmaceutical sciences》2018,107(7):1754-1760
Nonlinear protein binding is traditionally thought of as an increasing fraction unbound with increasing total drug concentration. In the past several years, research into the protein binding of several tetracyclines has shown that an unexpected and counterintuitive phenomenon has been observed, specifically that of decreasing unbound drug fraction with increasing total concentrations of drug over certain concentration ranges. Although several studies of tigecycline have shown the importance calcium and its chelation may play in the protein-drug interaction, the potential clinical implications and relevance have not been explored. Here, we define typical and atypical nonlinear protein binding, overview protein binding theory, and discuss theoretical implications on pharmacokinetics. Using tigecycline as an example, in silico simulations and calculations show how when atypical nonlinear protein binding is not accounted for free drug exposure, and drug tissue penetration may be overestimated. It is important to revisit the impacts of nonlinearity in protein binding on clinical pharmacokinetics and pharmacodynamics, and ultimately, clinical efficacy. Although this phenomenon could potentially warrant clinical dose adjustment for certain compounds, it also presents a potential opportunity to exploit underlying mechanisms to develop new therapies and better understand molecular interactions of xenobiotics within the physiological system. 相似文献
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Amelia N. Deitchman Ravi Shankar Prasad Singh Kenneth H. Rand Hartmut Derendorf 《International journal of antimicrobial agents》2018,51(5):799-802
The lack of availability of novel antibiotic agents and the rise of resistance to existing therapies has led clinicians to utilise combination therapy to adequately treat bacterial infections. Here we examined how chelators may impact the in vitro activity of tigecycline (TIG) against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined by broth dilution with and without various combinations of chelators (EDTA and other tetracyclines) and metal ions (i.e. calcium, magnesium). Trimethoprim (TMP) was used as a non-chelating control. Addition of metal ions led to increases in MICs, whilst addition of EDTA led to decreases in MICs. The chelating effects of EDTA were reversed by addition of magnesium and most profoundly calcium. Similar effects of EDTA and calcium were observed for tetracycline (TET) and TMP. When other tetracyclines (TET, oxytetracycline (OXY) and chlortetracycline (CHL)) were used as chelators at concentrations below their MICs, TIG MICs decreased for P. aeruginosa but not for E. coli. Some decreases in TIG MICs were observed for K. pneumoniae when TET and CHL were added. A dose-dependent decrease in TIG MIC was observed for TET and was reversed by the addition of calcium. The presence of effects of EDTA and calcium on TMP MICs indicates that mechanisms outside of TIG chelation likely play a role in enhanced activity. Full characterisation of an unexpected interaction such as TIG–TET with different microorganisms could provide valuable insights into the underlying mechanisms and design of physiologically viable chelators as candidates for future combinations regimens. 相似文献
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Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer 总被引:10,自引:0,他引:10 下载免费PDF全文
Ciampi R Knauf JA Kerler R Gandhi M Zhu Z Nikiforova MN Rabes HM Fagin JA Nikiforov YE 《The Journal of clinical investigation》2005,115(1):94-101
Genes crucial for cancer development can be mutated via various mechanisms, which may reflect the nature of the mutagen. In thyroid papillary carcinomas, mutations of genes coding for effectors along the MAPK pathway are central for transformation. BRAF point mutation is most common in sporadic tumors. By contrast, radiation-induced tumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1. We report here a rearrangement of BRAF via paracentric inversion of chromosome 7q resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene and exons 9-18 of BRAF. The fusion protein contains the protein kinase domain and lacks the autoinhibitory N-terminal portion of BRAF. It has elevated kinase activity and transforms NIH3T3 cells, which provides evidence, for the first time to our knowledge, of in vivo activation of an intracellular effector along the MAPK pathway by recombination. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations were absent in this group. These data indicate that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations. 相似文献
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Sherwin K. B. Sy Eduardo Asin-Prieto Hartmut Derendorf Emil Samara 《The AAPS journal》2014,16(6):1372-1379
The empirical scaling from adult to pediatric using allometric size adjustments based on body weight continued to be the mainstream method for pediatric dose selection. Due to the flexibility of a polynomial function to conform to the data trend, an empirical function for simulating age-matched weight and body mass index by gender in the pediatric population is developed by using a polynomial function and a constant coefficient to describe the interindividual variability in weight. A polynomial of up to fifth order sufficiently described the pediatric data from the Center for Disease Control (CDC) and the World Health Organization (WHO). The coefficients of variation to describe the variability were within 17%. The percentages of the CDC simulated weights for pediatrics between 0 and 5 years that fell outside the WHO 90% and 95% confidence boundaries were well within the expected percentage values, indicating that the CDC dataset can be used to substitute for the WHO dataset for the purpose of pediatric drug development. To illustrate the utility of this empirical function, the CDC-based age-matched weights were simulated and were used in the prediction of the concentration–time profiles of tenofovir in children based on a population pharmacokinetic model whose parameters were allometrically scaled. We have shown that the resulting 95% prediction interval of tenofovir in newborn to 5 years of age was almost identical whether the weights were simulated based on WHO or CDC dataset. The approach is simple and is broadly applicable in adjusting for pediatric dosages using allometry.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9657-9) contains supplementary material, which is available to authorized users.KEY WORDS: Age, Allometry, BMI, Pediatric, Weight 相似文献80.
Andrea M. Isidori Jacques Buvat Giovanni Corona Irwin Goldstein Emmanule A. Jannini Andrea Lenzi Hartmut Porst Andrea Salonia Abdulmaged M. Traish Mario Maggi 《European urology》2014