全文获取类型
收费全文 | 698篇 |
免费 | 43篇 |
国内免费 | 1篇 |
专业分类
儿科学 | 8篇 |
妇产科学 | 1篇 |
基础医学 | 28篇 |
临床医学 | 47篇 |
内科学 | 35篇 |
皮肤病学 | 1篇 |
神经病学 | 6篇 |
特种医学 | 3篇 |
外科学 | 3篇 |
预防医学 | 12篇 |
药学 | 337篇 |
中国医学 | 1篇 |
肿瘤学 | 260篇 |
出版年
2022年 | 2篇 |
2021年 | 3篇 |
2020年 | 4篇 |
2019年 | 4篇 |
2018年 | 4篇 |
2017年 | 8篇 |
2016年 | 17篇 |
2015年 | 16篇 |
2014年 | 13篇 |
2013年 | 26篇 |
2012年 | 34篇 |
2011年 | 39篇 |
2010年 | 19篇 |
2009年 | 26篇 |
2008年 | 28篇 |
2007年 | 34篇 |
2006年 | 47篇 |
2005年 | 53篇 |
2004年 | 29篇 |
2003年 | 27篇 |
2002年 | 56篇 |
2001年 | 50篇 |
2000年 | 41篇 |
1999年 | 44篇 |
1998年 | 8篇 |
1997年 | 16篇 |
1996年 | 12篇 |
1995年 | 13篇 |
1994年 | 19篇 |
1993年 | 14篇 |
1992年 | 8篇 |
1991年 | 7篇 |
1990年 | 6篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 1篇 |
排序方式: 共有742条查询结果,搜索用时 161 毫秒
1.
Sanne C. F. A. Huijberts Robin M. J. M. van Geel Emilie M. J. van Brummelen Frans L. Opdam Serena Marchetti Neeltje Steeghs Saskia Pulleman Bas Thijssen Hilde Rosing Kim Monkhorst Alwin D. R. Huitema Jos H. Beijnen Ren Bernards Jan H. M. Schellens 《Cancer chemotherapy and pharmacology》2020,85(5):917-930
KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated. 相似文献
2.
3.
J H Beijnen L T Vlasveld J Wanders W W ten Bokkel Huinink S Rodenhuis 《The Annals of pharmacotherapy》1992,26(4):488-490
OBJECTIVE: A case in which a possible cisplatin interference with lithium pharmacokinetics is evaluated. DATA SYNTHESIS: A 36-year-old woman with disseminated cervical cancer and multiple metastatic lesions in both kidneys was being treated with five courses of bleomycin, vindesine, mitomycin C, and cisplatin. The patient had also been taking lithium carbonate for the management of a manic-depressive disorder. Serum and urinary lithium concentrations were measured daily during the first course of chemotherapy and on a periodic basis during and between the consecutive courses. Lithium concentrations remained within the therapeutic range during the first course and increased later in association with deterioration of the patient's renal function secondary to progressive disease in both kidneys. This required dose adjustments of lithium. CONCLUSIONS: Lithium therapy should be guided by serial serum concentrations in such patients. 相似文献
4.
The chemical stability of members of two groups of cytostatics, mitomycins and anthracyclines, has been studied in four different cell culture media enriched with serum. Stability was determined with the use of high performance liquid chromatography. In the group of mitomycins, the 7-aminomitosanes appeared to be relatively stable during a seven days incubation period at 37 degrees C when compared to the 7-methoxy congeners. The anthracycline derivatives, 4-demethoxy-daunorubicin, doxorubicin and its 4'-analogues showed half-lives of about 10-20 hours. Doxorubicinol and daunorubicin were found to be more stable. Anthracycline degradation products could be traced with the use of thin layer chromatography. All main degradation products originate from hydrolytic reactions. No enzymatic conversions could be observed. These observations may be of importance for the correct interpretation of the effects of mitomycins or anthracyclines on cells incubated in a cell culture medium. 相似文献
5.
Application of a radioimmunoassay for determination of levels of zalcitabine (ddC) in human plasma, urine, and cerebrospinal fluid. 总被引:1,自引:1,他引:0 下载免费PDF全文
D M Burger H Rosing C H ten Napel T Duyts P L Meenhorst J W Mulder C H Koks A Bult J H Beijnen 《Antimicrobial agents and chemotherapy》1994,38(12):2763-2767
A specific and sensitive radioimmunoassay for the determination of levels of zalcitabine in human plasma, urine, and cerebrospinal fluid has been developed. Commercially available radiolabel and antiserum (Sigma Chemicals) were used after dilution in assay buffer. Prior to the immunoassay, standard and patient samples were subjected to solid-phase extraction on silica columns in order to obtain purified samples. The lower limit of quantitation was determined to be 1 ng/ml. Intra- and interassay variations were less than 11% for a number of quality control samples of drug in plasma and urine. Results from parallelism studies with plasma and urine demonstrated that samples outside the standard range (1 to 30 ng/ml) could be diluted by blank plasma or assay buffer, respectively. A large number of related compounds and potentially coadministered drugs were tested for cross-reactivity. Stability tests showed that heat treatment for 30 min at 60 degrees C or storage for 1 month at -30 degrees C did not affect zalcitabine concentrations in plasma or urine. The radioimmunoassay with solid-phase extraction for sample cleanup discussed here has been successfully applied in a pharmacokinetic study of a single patient, demonstrating its applicability for clinical pharmacokinetic research with zalcitabine. 相似文献
6.
7.
Renske M.T. ten Ham Merel van Nuland Rick A. Vreman Laurens G. de Graaf Hilde Rosing André M. Bergman Alwin D.R. Huitema Jos H. Beijnen Anke M. Hövels 《Value in health》2021,24(1):121-128
ObjectivesAbiraterone acetate is registered for the treatment of metastatic castration-sensitive and resistant prostate cancer (mCRPC). Treatment outcome is associated with plasma trough concentrations (Cmin) of abiraterone. Patients with a plasma Cmin below the target of 8.4 ng/mL may benefit from treatment optimization by dose increase or concomitant intake with food. This study aims to investigate the cost-effectiveness of monitoring abiraterone Cmin in patients with mCRPC.MethodsA Markov model was built with health states progression-free survival, progressed disease, and death. The benefits of monitoring abiraterone Cmin followed by a dose increase or food intervention were modeled via a difference in the percentage of patients achieving adequate Cmin taking a healthcare payer perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainties and their impac to the incremental cost-effectiveness ratio (ICER).ResultsMonitoring abiraterone followed by a dose increase resulted in 0.149 incremental quality-adjusted life-years (QALYs) with €22 145 incremental costs and an ICER of €177 821/QALY. The food intervention assumed equal effects and estimated incremental costs of €7599, resulting in an ICER of €61 019/QALY. The likelihoods of therapeutic drug monitoring (TDM) with a dose increase or food intervention being cost-effective were 8.04%and 81.9%, respectively.ConclusionsMonitoring abiraterone followed by a dose increase is not cost-effective in patients with mCRPC from a healthcare payer perspective. Monitoring in combination with a food intervention is likely to be cost-effective. This cost-effectiveness assessment may assist decision making in future integration of abiraterone TDM followed by a food intervention into standard abiraterone acetate treatment practices of mCRPC patients. 相似文献
8.
Alexander Sparreboom Manon T. Huizing Jan J. B. Boesen Willem J. Nooijen Olaf van Tellingen Jos H. Beijnen 《Cancer chemotherapy and pharmacology》1995,36(4):299-304
Three metabolites of the cytotoxic drug paclitaxel (Taxol) were isolated and purified from the feces of cancer patients receiving the agent as an intravenous infusion. The procedures involved sample homogenization in water followed by liquid-liquid extraction with diethyl ether and high-performance liquid chromatography (HPLC). Approximately 1–3.5 mg of each metabolite was obtained from 100 g of feces. As judged from the chromatographic traces of analytical HPLC with ultraviolet (UV) detection at 227 nm, the purity of each compound was >97%. On-line photodiode-array detection demonstrated that the UV spectrum of the isolated compounds closely resembles that of the parent drug. Mass spectrometry provided evidence that these metabolites are mono- and dihydroxy-substituted derivatives, namely, 6-hydroxypaclitaxel, 3-p-hydroxypaclitaxel, and 6,3-p-dihydroxypaclitaxel. The two 6-hydroxy-substituted metabolites were shown to have lost their cytotoxicity in in vitro clonogenic assays using the A2780 human ovarian carcinoma and the CC531 rat colon-carcinoma tumor cell lines. In addition, the metabolites showed reduced myelotoxic effects as compared with paclitaxel in an in vitro hemopoietic progenitor toxicity assay. Our procedure for the isolation and purification of paclitaxel metabolites in milligram quantities should be useful for testing the biological activities of these compounds and for the preparation of calibration standards essential for pharmockinetics studies. 相似文献
9.
10.
van Asperen J van Tellingen O Schinkel AH Beijnen JH 《The Journal of pharmacology and experimental therapeutics》1999,289(1):329-333
To determine the tissue-specific impact of P-glycoprotein on the accumulation of a substrate drug, we have studied the tissue distribution of vinblastine in mdr1a(-/-) and wild-type mice at approximately similar, relatively low plasma levels. Vinblastine was administered as a 96-h continuous infusion at dose rates of 1 to 10 microgram/h, which were delivered by a s.c.-implanted osmotic pump. Drug concentrations were determined in plasma and tissues by HPLC. In comparison to wild-type mice, 4.4- to 9.6-fold higher drug concentrations were observed in the brains of mdr1a(-/-) mice (p =. 014), whereas a 2-fold increase was found in the heart (p =.014) and the intestinal tissues (p =.028). No or only slight differences were observed in all other tissues. These results indicate that, except for the brain and, to a lesser extent, the heart and the intestinal tissues, P-glycoprotein does not protect individual organs against vinblastine. Given its polarized cell-specific and organ-specific distribution and its affinity for a broad range of compounds, it is suggested that P-glycoprotein has mainly evolved to provide a general protection of the complete organism against potentially toxic substrates by inhibiting their uptake and by mediating their transport from the internal to the external environment. For the clinical application of reversal agents, these data indicate that, in general, a blockade of endogenous P-glycoprotein will probably not result in an increased accumulation of the coadministered anticancer drug in complete organs, but, possibly, only in classes of cells making up a fraction of an organ. 相似文献