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目的 研究洛伐他汀对大鼠血管平滑肌合成一氧化氮的影响及其机理。方法 血管平滑肌取自SpragueDawley大鼠 (2 0 0 - 2 5 0g)的胸主动脉。大鼠血管平滑肌细胞培养液中亚硝酸盐水平由比色法测定。结果 洛伐他汀 (10 5mol/L)明显增加白细胞介素 1β(IL 1β ,10ng/mL)诱导的一氧化氮合成 ,呈时间 (0 - 2 4小时 )依赖型。外源性甲羟戊酸 (10 4 mol/L)和芒牛儿芒牛儿焦磷酸 (GGPP ,10 μmol/L)可完全逆转洛伐他汀的上述作用。而且用C3外酶 (2 5 - 5 0 μg/mL)抑制Rho可引起类似上述洛伐他汀的作用。结论 洛伐他汀上调受IL 1β刺激的大鼠SMCs合成NO ,其机理可能与Rho蛋白活性抑制有关 相似文献
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Masahiko Igarashi Yuki Takeda Seijiro Mori Naoko Ishibashi Eiichi Komatsu Kentaro Takahashi Tsunekazu Fuse Mikako Yamamura Kazuki Kubo Yasuo Sugiyama Yasushi Saito 《British journal of pharmacology》1997,120(6):1172-1178
- The aim of this study was to determine whether BAYw6228 (BAYw), a newly developed 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, could suppress an atherogenic process such as intimal thickening by a mechanism other than lowering the level of serum cholesterol.
- First, we evaluated the in vitro effect of BAYw on the proliferation of vascular smooth muscle cells (SMC) from various species: Sprague-Dawley (SD) rats, New Zealand (NZ) white rabbits, intimal cells from Watanabe hereditary hyperlipidemic (WHHL) rabbit and SMC from the new-born human aorta. The increasing rate of total protein content of these cells was inhibited by the addition of BAYw in a dose-dependent fashion. In the presence of 2% foetal calf serum (FCS), the value of IC50 was 1.0 μM in SD rats. 2.1 μM in NZ white rabbits, and 0.3 μM in WHHL rabbits. With human SMC, the value was 0.02 μM in the presence of 10% FCS and 0.2 μM with a mixture of growth factors.
- Based on these above in vitro findings, we next examined the in vivo effect of the agent to determine whether it could suppress rabbit intimal thickening induced by balloon catheterization. A balloon catheter was inserted from a peripheral branch of the left external carotid artery to the aorta to denude the endothelium of the left common carotid artery in Japanese white rabbits. After 12 days they were divided into control and BAYw groups. The former were subcutaneously injected with saline and the latter with BAYw 1 mg kg−1 day−1. Two days after the beginning of treatment, a second balloon injury was performed to the previously injured left common carotid artery in both groups. After another two weeks, the left common carotid artery was removed and variously stained. Although the total serum cholesterol in the BAYw group was significantly lower than in the control (P<0.05), the difference was not enough to affect intimal thickening. In addition, the BAYw group had a smaller intima/media ratio than the control group, decreasing to 45% of control (P<0.05). By anti-α smooth muscle actin antibody staining, these intimal thickening areas were entirely occupied by SMCs, and their amount was attenuated by BAYw. By anti-rabbit macrophage antibody (RAM 11) staining, the number of positive cells in the intimal thickening was markedly decreased in the BAYw group compared to control (P<0.01).
- These results indicate that BAYw has an inhibitory effect on intimal thickening by attenuating intimal SMC proliferation and infiltration of macrophages, suggesting that BAYw could be effective in the prevention of the progression of atherosclerotic plaque-like restenosis after angioplasty.
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In aqueous solutions, dalvastatin (1) undergoes epimerization as well as hydrolysis. The transformation of the drug was studied as a function of pH at 25°C in aqueous solutions containing 20% acetonitrile. At all pH values, first-order plots for the conversion are biphasic, indicating rapid equilibration of 1 with its epimer (2) and slower hydrolysis of 1 to the corresponding -hydroxy acid (3). Apparent first-order rate constants for the biexponential equation are given as a function of pH. The alkyl–oxygen cleavage of the lactone ring results in the epimerization of 1 to 2, whereas the acyl–oxygen cleavage results in the hydrolysis of 1 to 3. The epimerization is an SN1 reaction reaching an equilibrium of [l]
eq/[2]
eq = 1.27. The epimerization rate is increased with an increase in the water content of the solvent. The hydrolysis of 1 to 3 is acid and base catalyzed. The hydrolysis is reversible in acidic media and irreversible in neutral and basic media. At pH values greater than 9, the hydrolysis reaction proceeds more rapidly than the epimerization. 相似文献
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4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-羧酸甲酯的合成 总被引:1,自引:0,他引:1
目的 合成罗苏伐他汀的关键中间体4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-羧酸甲酯。方法 以异丁酰乙酸甲酯为起始原料,经与对氟苯甲醛缩合、S-甲基异硫脲硫酸盐环合、高锰酸钾氧化,再经甲胺基、甲磺酰基取代全盛的目标化合物。结果 5步反应总收率为25.0%。结论 改进了合成路线,有助于罗苏伐他汀的合成。 相似文献
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《Expert opinion on pharmacotherapy》2013,14(2):211-219
Background: Colorectal cancer (CRC) is one of the most common cancers worldwide and a prevalent cause of morbidity and mortality. CRC has a natural history of transition from a precursor lesion, ie adenomatous polyp to cancer, that spans over 10 to 15 years providing an extended opportunity for intervention and cancer prevention. Suppression of the carcinogenic process by use of pharmacological or natural agents is the cornerstone of chemoprevention. Objectives: The aim of this review was to give an up-to-date overview on the different agents that had been studied, over the last decade, as chemopreventive agents and the current status of chemoprevention. Methods: Articles were identified by searches of PubMed and the Internet and reviewed. All articles and other referenced materials were retrieved using the keywords “colon cancer”, “adenoma”, “chemoprevention”, “non steroidal anti-inflamatory drugs”, “aspirin”, “HMG-CoA reductase inhibitors”, “bile acids”, “Difluoromethylornithine”, “hormone replacement therapy”, “mesalamine”, “curcumin”, and “calcium”. Papers were published between 1960 and 2008, with older references selected for historical significance. Only papers published in English were reviewed. Results: Recent preclinical as well as clinical trials have provided data on the potential benefit of a number of drugs and nutritional elements in the field of CRC prevention. Currently, only celecoxib is FDA approved for chemoprevention of CRC and only for high-risk patients with Familial Adenomatous Polyposis (FAP). This is mainly due to cardiovascular toxicity reported in individuals with a personal history of sporadic adenomas. Aspirin and sulindac have also repeatedly demonstrated efficacy in this setting. However, due to increased risk of associated GI toxicity their benefit will have to be weighed against their risk. Combination therapy, using lower doses of each medication, is drawing a great deal of attention and many studies utilizing a variety of chemopreventive agents are presently under study. Promising results have recently been published using sulindac and DFMO. Conclusion: Many agents have shown positive results in the field of chemoprevention however, the ideal chemopreventive agent remains to be discovered with great emphasis on need not to harm. Combining different agents may maximize effectiveness while limiting drug toxicity. 相似文献
7.
《Expert opinion on pharmacotherapy》2013,14(5):819-830
Atorvastatin (Lipitor?, Pfizer) is a safe and effective 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin). It is the most potent currently available statin in terms of lowering low-density lipoprotein (LDL) and total cholesterol levels. It was the first statin shown to lower triglycerides in patients with isolated hypertriglyceridaemia. It has a good safety profile. In common with other statins, it has non-lipid-lowering effects including improving endothelial function, antiproliferative actions on smooth muscle and reducing platelet aggregation. It also has anti-inflammatory effects and may reduce plasma glucose levels. Clinical trial evidence with this statin is currently limited. It did slightly reduce events in the AVERT trial comparing patients receiving coronary angioplasty with those receiving high-dose atorvastatin therapy and in the MIRACL study reduced ischemia in patients with acute coronary syndromes. Other end point trials are in progress. 相似文献
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