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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
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Critical illness polyneuromyopathy after artificial respiration. 总被引:3,自引:0,他引:3
A A Op de Coul G A Verheul A C Leyten R L Schellens J L Teepen 《Clinical neurology and neurosurgery》1991,93(1):27-33
Up to now, 71 critically ill patients have been reported with neuromuscular complications after artificial respiration. The authors review the literature and present data of a personal series of 22 patients all suffering from severe flaccid tetraparesis and muscle atrophy, which developed after an average of two weeks artificial respiration. The prognosis was relatively good in those surviving the primary disease. The multiconditional causes are discussed with emphasis on the combination of polyneuropathy and myopathy. Tumor necrosis factor (TNF), a key mediator of sepsis, which also has an influence on muscle and nerves, is mentioned as a possible cause of this illness. 相似文献
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Adverse reaction to intravenous gadoteridol 总被引:1,自引:0,他引:1
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Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects. 下载免费PDF全文
J H Schellens J H van der Wart D D Breimer 《British journal of clinical pharmacology》1990,29(6):665-671
1. In a phenotyped panel of healthy subjects correlations were studied between the oxidation of mephenytoin, phenytoin, methylphenytoin and phenobarbitone, with respect to the formation of their 4-hydroxy metabolites (OH-). 2. On different occasions phenotyped extensive metabolizers (EM; n = 16) and poor metabolizers (PM; n = 4) of mephenytoin received phenytoin (100 mg), methylphenytoin (100 mg) and phenobarbitone (50 mg) and urine was collected up to 24 h. The excreted 4-hydroxy metabolites of all compounds were measured by h.p.l.c. 3. Urinary recovery of OH-phenytoin was 31.0 +/- 11.7%, of OH-methylphenytoin 3.4 +/- 2.7% and of OH-phenobarbitone 1.4 +/- 1.2%. No correlation was found between the recovery of OH-mephenytoin and OH-phenytoin. A subject who produced virtually no OH-phenytoin was an EM of mephenytoin, confirming a dissociation of mephenytoin polymorphism and phenytoin hydroxylation. 4. The correlation coefficient for OH-mephenytoin and OH-methylphenytoin recovery was 0.71 (Spearman rank, P = 0.002). The PMs of mephenytoin excreted the least amount of OH-methylphenytoin, suggesting a cosegregation of the 4-hydroxylation pathways. No correlation was found between the urinary recovery of OH-phenobarbitone and that of the other 4-hydroxy metabolites. 相似文献
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Intestinal schistosomiasis japonica: CT-pathologic correlation 总被引:1,自引:0,他引:1
Lee RC; Chiang JH; Chou YH; Rubesin SE; Wu HP; Jeng WC; Hsu CC; Tiu CM; Chang T 《Radiology》1994,193(2):539