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Pharmacokinetics may be utilized as a tool in the drug development process, either with respect to therapeutics or in allowing a drug's disposition characteristics to be defined. If two drugs of the same class have a similar dose-efficacy profile, then the favourable/unfavourable balance of the pharmacokinetic characteristics of the drugs may determine the drug of choice. Pantoprazole, a proton pump inhibitor, appears to meet the above criteria and has been found to exhibit reliable, predictable pharmacokinetic characteristics as opposed to other members of the class. The pharmacokinetics of pantoprazole over a range of intravenous and oral doses are described in healthy volunteers and are compared with values obtained for omeprazole. Studies in patients with severe cirrhosis, renal failure, and in the elderly are also described as well as potential interactions due to food and five other drugs. 相似文献
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The effects of sulfobromophthalein (SBP) and ethacrynic acid (ECA), both inhibitors of glutathione S-transferase (GST), or glyceryl trinitrate (GTN)-induced vasorelaxation were investigated in rabbit aortic strips. The aortic strips were pre-contracted with phenylephrine, followed by relaxation with 0.5 microM GTN, with or without 0.1 mM SBP or ECA. ECA was observed to inhibit GTN relaxation approximately 32%, whereas SBP did not alter the GTN activity. The dinitrate metabolites (GDN) of GTN in the tissues were also measured. The amounts of both GDNs were decreased in the ECA-treated, but not the SBP-treated group. Moreover, in the ECA-treated group, a strong correlation was obtained between the loss of GTN activity and the decrease in GTN metabolism. Concentration-response studies also revealed that ECA attenuates GTN relaxation. The slope factor of the concentration-response curves was decreased by ECA, but not by SBP, although both inhibitors caused a mild decrease in Emax. In the 9000 g supernatant of rabbit aorta, ECA was also observed to inhibit GTN metabolism more significantly than SBP. The results suggest that the mechanism of GTN activation may involve a GST isozyme that possesses high activities towards ECA. 相似文献
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Disposition of tacrolimus in isolated perfused rat liver: influence of troleandomycin, cyclosporine, and gg918. 总被引:4,自引:0,他引:4
The disposition of tacrolimus and the influence of cyclosporine, troleandomycin, and GF120918 (GG918, or N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine) on its hepatic disposition were examined in the isolated perfused rat liver. Livers from groups of rats were perfused in a recirculatory manner following a bolus dose of tacrolimus (100 microg), a substrate for P-glycoprotein (P-gp) and CYP3A, or with felodipine (200 microg), a substrate only for CYP3A. Perfusions of each substrate were also examined in groups of rats in the presence of the inhibitors: troleandomycin (20 microM, CYP3A inhibitor), GG918 (1 microM, P-gp inhibitor), or cyclosporine (10 microM, CYP3A and P-gp inhibitor). In all experiments, perfusate and bile were collected for 60 min. Tacrolimus, felodipine, and their primary metabolites were determined in perfusate and bile by liquid chromatography/tandem mass spectrometry. The area under the curve (AUC) from 0 to 30 min was determined. For the dual CYP3A and P-gp substrate, tacrolimus, AUC +/- S.D. was decreased from control (2,260 +/- 430 ng. min/ml) by GG918 (1,730 +/- 270 ng. min/ml, P < 0.05) and was increased by troleandomycin (5,200 +/- 2,470 ng. min/ml, P < 0.05) and cyclosporine (4,390 +/- 2,080 ng. min/ml, P < 0.05). For the exclusive CYP3A substrate, felodipine, AUC was unchanged from control by GG918 but increased by troleandomycin and cyclosporine. It is concluded that GG918 increased the hepatic exposure of tacrolimus by inhibiting the canalicular P-gp transport, whereas GG918 has no effect on hepatic disposition of felodipine. These results support our hypothesis that the hepatic metabolic clearance of a dual substrate will be increased by inhibiting the efflux transporter. 相似文献
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Spahn Hildegard Iwakawa Seigo Lin Emil T. Benet Leslie Z. 《Pharmaceutical research》1989,6(2):125-132
The diastereoisomeric glucuronic acid conjugates of R/S-benoxaprofen are the major benoxaprofen metabolites and are found in urine at high concentrations. The conjugates of R- and S-benoxaprofen can be separated directly on a C18 reversed-phase column using a mixture of acetonitrile and tetrabutylammonium hydroxide buffer, pH 2.5 (28:72, v/v), as the mobile phase. The k values of S- and R-benoxaprofen glucuronides are 57.5 and 63.0, respectively. Diluted urine or deproteinized plasma samples were injected without further treatment. With fluorescence detection at 313/365 nm, quantifiable limits of 50 ng equiv./ml were found for the conjugates. The intra- and interday variability was below 12%. Utilizing this analytical procedure it is possible to characterize enantioselective glucuronidation both in vivo and in vitro. For in vitro procedures, apparent rates of formation and the R/S ratio may be substrate (benoxaprofen) and cosubstrate (UDPGA) dependent. Moreover, enantioselective cleavage of the formed benoxaprofen glucuronides by alkaline hydrolysis, hydrolytic enzymes, and acyl migration must be controlled for both in vitro and in vivo studies since R-benoxaprofen glucuronide is degraded faster than the S-diastereomer under certain conditions. 相似文献
8.
Ouhibi Nadia; Menezo Yves; Benet Gerard; Nicollet Bernard 《Human reproduction (Oxford, England)》1989,4(3):229-235
This study proposes a procedure for the isolation and cultureof oviduct epithelial cells of several species. In-vitro cultureon such a feeder seems to allow full embryonic development andviability. The inner linings of Fallopian tubes from mouse,rabbit, cow and human were trypsinized and the epithelial cellswere enriched with Percoll gradient. Isolated cells, obtainedin high yield with good viability, were maintained in monolayerculture in B2-Menezo medium supplemented with serum, which alsosupports early embryonic development in vitro. The plated primarycultures reached confluence within 8 days, producting a monolayerof cohesive polygonalcells. Associated with this large epithelialcall population, ciliated cells as wellas polykaryotic cellsand few fibroblastic nestswere observed. After the first sub-culture,the ciliated cells disappeared and the epithelial cell monolayergrew rapidly to confluence with in 3 days and displayed contactinhibition. No epithelial cell growth could be obtained inculturein the absence of serum. The addition of oestrogens had no effecton any of the cultured oviductal epithelial cells. A sponotaneousalteration was observed in morphology and growth after severalpassages, the number of which depends mainly upon the species 相似文献
9.
Aliño SF Crespo J Tarrasón G Blaya C Adán J Escrig E Benet M Crespo A Peris JE Piulats J 《Xenobiotica; the fate of foreign compounds in biological systems》1999,29(12):1283-1291
1. The effect of the method employed to prepare liposomes and their lipid composition were evaluated in terms of the encapsulation efficiency and pharmacokinetic features of two oligodeoxynucleotides of a 21 mer: the normal (N-Odn) and the phosphorothioate (S-Odn) oligodeoxynucleotide. 2. Liposomes were prepared by the classical method of multilamellar vesicles (MV) and by the dehydration-rehydration method (DR). Two lipid mixtures were used to prepare liposomes--the predominant lipid being phosphatidylcholine (PC) and sphingomyelin (SM) respectively. 3. The DR method for liposome preparation provided the highest encapsulation efficiency, regardless of liposome lipid composition and the type of oligodeoxynucleotide involved (N-Odn or S-Odn). 4. The pharmacokinetics of free and liposome encapsulated oligodeoxynucleotides was studied in mouse following i.v. administration. Liposome encapsulated oligodeoxynucleotides exhibited a significantly lower plasma clearance and longer half-life and residence time than free oligodeoxynucleotides. The method used to obtain the liposomes affected plasma clearance, which was lower for liposomes elaborated by the DR method than for liposomes prepared with the MV method. The use of S-Odn in place of N-Odn decreased the plasma clearance of oligodeoxynucleotide when administered encapsulated in liposomes, regardless of the lipid composition and method used to obtain the liposomes. 相似文献
10.
Furosemide 1-O-acyl glucuronide (Fgnd) was reversibly bound to a single class of binding sites on human serum albumin (HSA), and the binding of Fgnd decreased with increasing F concentrations, suggesting that Fgnd binds to the same warfarin binding sites on HSA as F binds. The rate of Fgnd degradation (hydrolysis and acyl migration) decreased in the presence of HSA. Although the formation of acyl migration isomers of Fgnd was slower in the presence of HSA than in its absence, hydrolysis of Fgnd to F was faster in the presence of HSA. Rapid minor irreversible binding of Fgnd to HSA within 30 min was followed by slow major irreversible binding. Slow irreversible binding of Fgnd to HSA was decreased by F, though not significantly. This suggests that major irreversible binding may proceed via reversible binding. It has been reported that acyl migration is a prerequisite for irreversible binding. Therefore, these results indicate that HSA decreases irreversible binding of Fgnd to protein by suppressing acyl migration. Furthermore, these results suggest that HSA may prevent irreversible binding of Fgnd to other proteins in the body by decreasing the concentration of reactive Fgnd in the unbound form. HSA eliminates reactive Fgnd by hydrolysis to F. Therefore, it is concluded that HSA works as a scavenger to decrease reactive compounds by reversible binding or eliminates reactive compounds by irreversible binding. 相似文献