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61.
62.
Annette Hambrock Cornelia L?ffler-Walz Yoshihisa Kurachi Ulrich Quast 《British journal of pharmacology》1998,125(3):577-583
- The binding of modulators of the ATP-sensitive K+ channel (KATP channel) to the murine sulphonylurea receptor, SUR2B, was investigated. SUR2B, a proposed subunit of the vascular KATP channel, was expressed in HEK 293 cells and binding assays were performed in membranes at 37°C using the tritiated KATP channel opener, [3H]-P1075.
- Binding of [3H]-P1075 required the presence of Mg2+ and ATP. MgATP activated binding with EC50 values of 10 and 3 μM at free Mg2+ concentrations of 3 μM and 1 mM, respectively. At 1 mM Mg2+, binding was lower than at 3 μM Mg2+.
- [3H]-P1075 saturation binding experiments, performed at 3 mM ATP and free Mg2+ concentrations of 3 μM and 1 mM, gave KD values of 1.8 and 3.4 nM and BMAX values of 876 and 698 fmol mg−1, respectively.
- In competition experiments, openers inhibited [3H]-P1075 binding with potencies similar to those determined in rings of rat aorta.
- Glibenclamide inhibited [3H]-P1075 binding with Ki values of 0.35 and 2.4 μM at 3 μM and 1 mM free Mg2+, respectively. Glibenclamide enhanced the dissociation of the [3H]-P1075-SUR2B complex suggesting a negative allosteric coupling between the binding sites for P1075 and the sulphonylureas.
- It is concluded that an MgATP site on SUR2B with μM affinity must be occupied to allow opener binding whereas Mg2+ concentrations ⩾10 μM decrease the affinities for openers and glibenclamide. The properties of the [3H]-P1075 site strongly suggest that SUR2B represents the drug receptor of the openers in vascular smooth muscle.
63.
- The aim of this study was to characterize the KATP channel of intact rat skeletal muscle (rat flexor digitorum brevis muscle). Changes in membrane currents were recorded with two-electrode voltage-clamp of whole fibres.
- The KATP channel openers, levcromakalim and pinacidil (10–400 μM), caused a concentration-dependent increase in whole-cell chord conductance (up to approximately 1.5 mScm−2). The activated current had a weak inwardly rectifying current-voltage relation, a reversal potential near EK and nanomolar sensitivity to glibenclamide – characteristic of a KATP channel current. Concentration-effect analysis revealed that levcromakalim and pinacidil were not particularly potent (EC50 ∼186 μM, ∼30 μM, respectively), but diazoxide was completely inactive.
- The ability of both classical KATP channel inhibitors (glibenclamide, tolbutamide, glipizide and 5-hydroxydecanoic acid) and a number of structurally related glibenclamide analogues to antagonize the levcromakalim-induced current was determined. Glibenclamide was the most potent compound with an IC50 of approximately 5 nM. However, the non-sulphonylurea (but cardioactive) compound 5-hydroxydecanoic acid was inactive in this preparation.
- Regression analysis showed that the glibenclamide analogues used have a similar rank order of potency to that observed previously in vascular smooth muscle and cerebral tissue. However, two compounds (glipizide and DK13) were found to have unexpectedly low potency in skeletal muscle.
- These experiments revealed KATP channels of skeletal muscle to be at least 10× more sensitive to glibenclamide than previously found; this may be because of the requirement for an intact intracellular environment for the full effect of sulphonylureas to be realised. Pharmacologically, KATP channels of mammalian skeletal muscle appear to resemble most closely KATP channels of cardiac myocytes.
64.
目的:建立了二甲双胍格列本脲胶囊(Ⅱ)中基因毒性杂质N-亚硝基二甲胺(NDMA)的测定方法。方法:采用气相色谱-三重四级杆质谱仪,以多反应监测模式(MRM)进行测定,按外标法定量。仪器条件:EI源温度:230℃;电子能量:70 eV;碰撞气:高纯氮气,碰撞气流速:1.5 mL/min。载气:高纯氦气,载气流速为1.0 mL/min。结果:NDMA在0.243~48.626 ng/mL的浓度范围内呈良好的线性相关,相关系数(R2)大于0.9997,方法检出限均为0.005μg/g,定量限为0.01μg/g,平均回收率为92.41%~101.02%(n=9),RSD为2.4%,重复性试验RSD(n=6)为3.0%,NDMA在定量限浓度及限度浓度的精密度试验RSD(n=6)分别为4.2%和3.2%。结论:方法适合用于二甲双胍格列本脲胶囊(Ⅱ)中基因毒性杂质NDMA的检测。 相似文献
65.
格列吡嗪和格列本脲对氯沙坦药动学的影响 总被引:3,自引:3,他引:0
目的 研究格列吡嗪和格列本脲对氯沙坦在大鼠体内药动学的影响。方法 将15只大鼠随机分成对照组、格列吡嗪组和格列本脲组,分别灌胃给予0.5% CMC、10 mg·kg-1格列吡嗪和10 mg·kg-1格列本脲,0.5 h后灌胃给予5 mg·kg-1氯沙坦钾,经尾静脉予不同时间点采集血样,采用HPLC测定血样中氯沙坦及其代谢产物E-3174的浓度。采用DAS计算各组主要的药动学参数,并进行统计学分析。结果 合用格列吡嗪后,氯沙坦和E-3174的AUC、MRT和峰浓度均明显增加,氯沙坦的清除率减小;合用格列本脲后,氯沙坦的达峰时间提前,E-3174的MRT延长。结论 与同剂量的格列本脲相比,格列吡嗪对氯沙坦及其代谢产物在大鼠体内的药动学影响较大。临床上合用氯沙坦和格列吡嗪时,应注意潜在的药物相互作用所致的药物不良反应。 相似文献
66.
目的:研究格列本脲对脑缺血再灌注损伤小鼠后期神经运动功能障碍的影响?方法:应用C57BL/6小鼠,制备局灶性脑缺血再灌注损伤模型,经灌胃给予格列本脲(20 mg/kg)连续治疗5周,每周监测小鼠的空腹血糖与体重变化?通过角测试?圆柱体测试?转棒实验及踏空实验等观察小鼠的行为学改变,免疫组织化学染色法观察缺血脑区星形胶质细胞的变化?结果:格列本脲(20 mg/kg)连续治疗5周,不影响小鼠的空腹血糖;与对照组比较,从治疗第2周开始,能显著增加小鼠的体重(P < 0.01);从治疗第3周开始,能减少踏空实验中小鼠的足失误率(P < 0.05)及延长转棒实验中的棒上停留时间(P < 0.05),并减少缺血脑区胶质瘢痕的形成范围(P < 0.05)?结论:格列本脲连续治疗能够促进小鼠脑缺血再灌注损伤后期神经运动功能的恢复? 相似文献
67.
目的 :研究硝苯吡啶以及硝苯吡啶与格列本脲合用对空腹大鼠和肾上腺素诱发高血糖大鼠血糖水平的影响。方法 :本实验采用葡萄糖氧化酶法测定血糖含量。结果 :硝苯吡啶 2 .5mg/kgig使空腹大鼠血糖水平显著升高(P <0 .0 1 ) ,并加重肾上腺素诱发的高血糖反应。而硝苯吡啶与降糖药格列本脲 0 .9mg/kg合用时不影响空腹大鼠的血糖水平 ,硝苯吡啶对肾上腺素诱发高血糖大鼠灌胃格列本脲后的降血糖作用亦无明显影响。结论 :尽管硝苯吡啶对空腹大鼠以及肾上腺素诱发高血糖大鼠有显著升高血糖的作用 ,但对格列本脲的降血糖作用无明显不良影响 相似文献
68.
69.
Viswanathaswamy AH Koti BC Gore A Thippeswamy AH Kulkarni RV 《Indian journal of pharmaceutical sciences》2011,73(2):139-145
The present study was undertaken to investigate the antihyperglycemic and antihyperlipidemic effects of ethanol extract of Plectranthus amboinicus in normal and alloxan-induced diabetic rats. Diabetes was induced in Wistar rats by single intraperitoneal administration of alloxan monohydrate (150 mg/kg). Normal as well as diabetic rats were divided into groups (n=6) receiving different treatments. Graded doses (200 mg/kg and 400 mg/kg) of ethanol extract of Plectranthus amboinicus were studied in both normal and alloxan-induced diabetic rats for a period of 15 days. Glibenclamide (600 μg/kg) was used as a reference drug. Oral administration with graded doses of ethanol extract of Plectranthus amboinicus exhibited hypoglycemic effect in normal rats and significantly reduced the peak glucose levels after 120 min of glucose loading. In alloxan-induced diabetic rats, the daily oral treatment with ethanol extract of Plectranthus amboinicus showed a significant reduction in blood glucose. Besides, administration of ethanol extract of Plectranthus amboinicus for 15 days significantly decreased serum contents of total cholesterol, triglycerides whereas HDL-cholesterol, total proteins and calcium were effectively increased. Furthermore, effect of ethanol extract of Plectranthus amboinicus showed profound elevation of serum amylase and reduction of serum lipase. Histology examination showed ethanol extract of Plectranthus amboinicus exhibited almost normalization of damaged pancreatic architecture in rats with diabetes mellitus. Studies clearly demonstrated that ethanol extract of Plectranthus amboinicus leaves possesses hypoglycemic and antihyperlipidemic effects mediated through the restoration of the functions of pancreatic tissues and insulinotropic effect. 相似文献
70.
Early potassium channel blockade improves sepsis-induced organ damage and cardiovascular dysfunction