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1.
G. Toffoli I. Robieux D. Fantin M. Gigante S. Frustaci G. L. Nicolosi M. De Cicco & M. Boiocchi 《British journal of clinical pharmacology》1997,44(3):255-260
Aims In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic monitoring. We report the pharmacokinetics of escalating doses of verapamil.
Methods We studied nine patients [
seven males, two females; median age 46 years (range, 31–57)] with advanced adenocarcinoma of the colon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg−1 followed by 12 h continuous i.v. infusion at 0.20 mg kg−1 h−1 ), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg−1 h−1 ). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n=4) or 60 to 108 h (n=5). Blood samples and urine collections were taken every 12 h. Verapamil and nor-verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL=ko/Css ) and renal clearance (CLr) of verapamil and nor-verapamil. The Cssvs rate relationship was fitted to a Michaelis-Menten equation: Css=ko(Km+Css )/(V Vm ).
Results CL was dose-dependent and in all nine patients a significant reduction in CL was observed over the dose range (mean CL±s.d. were 0.51±0.31, 0.38±0.16, 0.32±0.18, and 0.27±0.11 l h−1 kg−1, respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg−1 h−1; P=0.0001). Css increased more than proportionally to the dose rate and the Cssvs rate relationship was best defined by a Michaelis-Menten equation (Km=730 μg l−1; V Vm=0.55 mg kg−1 h−1 ), (r=0.994; P=0.006). CLr of verapamil and nor-verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose.
Conclusions These findings suggest a non-linear, capacity-limited metabolic clearance of high-dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500–2500 ng ml−1 ) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses. 相似文献
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LN Weinberger MJ Zirwas JC English III 《Journal of the European Academy of Dermatology and Venereology》2007,21(2):156-162
Male genital oedema can be defined as swelling or the appearance of swelling of the scrotum and/or the penile shaft and prepuce. Despite the various causes of genital oedema reported in the published work, a concise approach to the evaluation and management has not been sufficiently addressed. 相似文献
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Drago F Frisina M Grech M Nicolosi A Micale V Nicosia A Medico M Foti F 《Neuroscience letters》2001,300(3):176-178
Melatonin affects the circadian sleep/wake cycle, but it is not clear whether it may influence drug-induced narcosis. Sodium thiopenthal was administered intraperitoneally into male rats pre-treated with melatonin (0.05, 0.5, 5 and 50 mg/kg). Melatonin pre-treatment affected in a dual manner barbiturate narcosis, however, no dose-effect correlation was found. In particular, low doses reduced the latency to and prolonged the duration of barbiturate narcosis. In contrast, the highest dose of melatonin (50 mg/kg) caused a paradoxical increase in the latency and produced a sustained reduction of the duration of narcosis, and a reduction in mortality rate. Melatonin 0.5 and 5 mg/kg influenced the duration but not the latency of ketamine- or diazepam-induced narcosis. Thus, the dual action of melatonin on pharmacological narcosis seems to be specific for the barbiturate mechanism of action. 相似文献
8.
E Moro G L Nicolosi C Burelli G L Rellini G Grenci D Zanuttini 《Giornale italiano di cardiologia》1987,17(4):306-310
In order to assess the reliability of Doppler echocardiography in the determination of mean mitral gradient 38 consecutive patients (pts) affected by rheumatic mitral valve stenosis (MS) were analyzed by continuous wave Doppler echocardiography (CWD). Cardiac catheterization (CATH) was performed within 24 hours from echocardiographic examination. The mean diastolic mitral gradient (MG) at CATH was calculated by planimetry from simultaneously recorded left ventricular and pulmonary artery wedge pressure. The maximal velocity profile through the mitral valve was used to calculate pressure gradient by CWD. A mean mitral gradient was calculated for each patient by the planimetered velocity profile throughout diastole. MG determined by CATH ranged from 6 to 31 mmHg (mean 15.2 +/- 6.0); MG determined by CWD ranged from 4 to 18 mmHg (mean 10 +/- 3.7). The correlation between CWD and CATH by linear regression analysis was: y = 0.53 X + 1.8; r = 0.85; p less than 0.001. Mean % error of CWD in the assessment of MG was 34.7%. In conclusion this study indicates that CWD seems systematically underestimate MG with respect to CATH. The identification of CWD flow tracings "optimal" for analysis could not represent the maximal velocity of transmitral jet, which is a complex three dimensional entity. In addition non-simultaneous determinations of gradient and day-to-day variations in cardiac output may account for discrepancies between CWD and CATH measurements. 相似文献
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Yang PY Almofti MR Lu L Kang H Zhang J Li TJ Rui YC Sun LN Chen WS 《第二军医大学学报》2006,27(6):637-637
Polygonum multiflorum stilbeneglycoside (PMS) is a water-soluble fraction of Polygonum multiflorum Thunb. , one of the most famous tonic traditional Chinese medicines, that has protective effects on the cardiovascular system. The purpose of the present study is to elucidate the effects of PMS on macrophage-derived foam cell functions and the reduction of severity of atherosclerosis in hypercholesterolemic New Zealand White (NZW) rabbits. NZW rabbits were fed for 12 weeks with a normal diet, a high cholesterol diet, or a high cholesterol diet associated with irrigation with different doses of PMS (25, 50, or 100 mg/kg). Treatment of NZW rabbits fed with high cholesterol diet with 100 mg/kg PMS attenuated the increase in plasma cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and plasma triglyceride. Treatment with 50 and 100 mg/kg PMS caused 43% and 60% decrease in atherosclerotic lesioned area ratio to total surface area, respectively. In U937 foam cells, PMS could decrease the high expression of intercellular adhesion molecule (ICAM)-1 protein and the vascular endothelial growth factor (VEGF) protein levels in the medium induced by oxidized lipoprotein when analyzed by flow cytometry. The results proved that PMS is a powerful agent against atherosclerosis and that PMS action could possibly be through the inhibition of the expression of ICAM-1 and VEGF in foam cells. 相似文献