全文获取类型
收费全文 | 870篇 |
免费 | 32篇 |
国内免费 | 67篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 38篇 |
妇产科学 | 9篇 |
基础医学 | 60篇 |
口腔科学 | 8篇 |
临床医学 | 148篇 |
内科学 | 79篇 |
皮肤病学 | 13篇 |
神经病学 | 20篇 |
特种医学 | 137篇 |
外科学 | 18篇 |
综合类 | 26篇 |
预防医学 | 43篇 |
眼科学 | 1篇 |
药学 | 332篇 |
肿瘤学 | 36篇 |
出版年
2022年 | 4篇 |
2021年 | 10篇 |
2018年 | 5篇 |
2016年 | 9篇 |
2015年 | 11篇 |
2014年 | 11篇 |
2013年 | 23篇 |
2012年 | 20篇 |
2011年 | 20篇 |
2010年 | 27篇 |
2009年 | 34篇 |
2008年 | 26篇 |
2007年 | 67篇 |
2006年 | 27篇 |
2005年 | 20篇 |
2004年 | 17篇 |
2003年 | 24篇 |
2002年 | 17篇 |
2001年 | 13篇 |
2000年 | 10篇 |
1999年 | 25篇 |
1998年 | 44篇 |
1997年 | 37篇 |
1996年 | 29篇 |
1995年 | 29篇 |
1994年 | 29篇 |
1993年 | 24篇 |
1992年 | 22篇 |
1991年 | 23篇 |
1990年 | 25篇 |
1989年 | 32篇 |
1988年 | 28篇 |
1987年 | 18篇 |
1986年 | 20篇 |
1985年 | 19篇 |
1984年 | 16篇 |
1983年 | 9篇 |
1982年 | 16篇 |
1981年 | 11篇 |
1980年 | 14篇 |
1979年 | 13篇 |
1978年 | 13篇 |
1977年 | 14篇 |
1976年 | 11篇 |
1975年 | 17篇 |
1974年 | 3篇 |
1973年 | 4篇 |
1972年 | 7篇 |
1971年 | 5篇 |
1970年 | 7篇 |
排序方式: 共有969条查询结果,搜索用时 0 毫秒
61.
Alice I. Nichols F. Douglas Boudinot William J. Jusko 《Journal of pharmacokinetics and pharmacodynamics》1989,17(2):209-227
An improved model describing receptor/gene-mediated pharmacodynamics of prednisolone is presented which consists of seven differential equations. Data for plasma prednisolone concentrations, free hepatic glucocorticoid receptors, and hepatic tyrosine aminotransferase activity (TAT) following low (5 mg/kg) and high (50 mg/kg) doses of prednisolone are used to quantitate the kinetics and dynamics of this synthetic steroid in the rat. In contrast to the earlier model, the newer model provides for a coupling and simultaneous fitting of receptor and TAT data and is able to describe the recycling of receptors between cytosol and nucleus and the return of cytosolic receptors to baseline following glucocorticoid elimination. A numerical technique to determine the efficiency of TAT induction based on area under the curve calculations is presented, which supports the hypothesis that nonlinear dose-response effects are due to dose and time-dependent receptor depletion in the cytosol. Simulations are presented to examine the major determinants of corticosteroid effects and to compare the effects of single-and multiple-dose regimens in maximizing drug effects.Supported in part by Grant 24211 from the National Institutes of General Medical Sciences, National Institutes of Health. 相似文献
62.
63.
The pharmacokinetics of prednisolone after 5- and 50-mg/kg doses given as the sodium succinate salt was examined in normal and adrenalectomized rats. Prednisolone, prednisone, and corticosterone concentrations in plasma were determined by HPLC and free prednisolone measured by equilibrium dialysis. Prednisolone sodium succinate was rapidly and completely hydrolyzed to prednisolone as indicated by the absence of the ester from plasma within 5 min after intravenous injection. Prednisolone was rapidly metabolized to prednisone, while corticosterone concentrations in normal rats declined rapidly and were undetectable by 1 hr. Adrenalectomy had no effect on the disposition and protein binding of prednisolone. Dose, however, had a marked effect on prednisolone pharmacokinetics, with mean plasma clearance decreasing from 6.18 to 3.07 L/h per kg and mean steady-state volume of distribution decreasing from 2.14 to 1.05 L/kg from the lower to higher steroid dose. Half-life (0.50 hr) and mean residence time (0.35 hr) were unaffected by dose. Prednisolone plasma protein binding was nonlinear due to saturation of transcortin binding. Changes in pharmacokinetic parameters were not related to the nonlinear plasma binding, but were more likely caused by saturation of elimination pathways and tissue binding sites. 相似文献
64.
A noncompartmental approach for determination of the apparent zero-order absorption rate constant (k
0) has been developed. The procedure evolves from the convolution integral and requires individual oral-dose plasma concentration values and calculation of area intervals under the plasma concentration–time curves after intravenous administration. The proposed method was evaluated and compared with the Wagner–Nelson, Loo–Riegelman, deconvolution, nonlinear regression, and moment methods using errorless and errant simulation data for one- or two-compartment models. The area function method is generally equal to the best of these techniques (nonlinear regression) and superior to the weaker methods (moment, deconvolution, Loo–Riegelman), especially for errant two-compartment data. Coupled with a companion procedure for constructing fraction absorbed versus time plots and assessing first-order absorption rate constants, the area function methods offer direct and accurate means of discerning drug absorption kinetics without the need for assignment of a disposition model for drugs with linear elimination kinetics. 相似文献
65.
66.
67.
Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics. 总被引:1,自引:0,他引:1
J A Wald D E Salazar H Y Chen W J Jusko 《Journal of pharmacokinetics and biopharmaceutics》1991,19(5):521-536
A two-compartment closed model was used to characterize the movement of basophils between blood and extravascular sites resulting from methylprednisolone (MP) exposure. This model is consistent with the view that corticosteroids cause a decrease in the recirculation of these cells from peripheral compartments. Methylprednisolone (Solu-Medrol) was given to healthy males at doses of 10, 25, and 40 mg. Blood samples were collected and assayed for MP by HPLC for pharmacokinetic analysis. Whole blood histamine, an index of circulating basophils, was assessed by RIA over 32 hr. Nonlinear least-squares analysis was carried out to solve for the model parameters reflecting cell movement between compartments and sensitivity (IC50) to the steroid. This model quantitiates the fall and return pattern of biologic response to corticosteroids with a minimal number of parameters which jointly fit several dose/response curves and yields a mean IC50 value of 8.1 ng/ml similar to receptor binding of MP. Properties of the temporal and integrated response curve and model extrapolations over a wide dose range were explored with simulations. Because corticosteroids exert similar effects on other cells in blood, this model may be applicable to various regulatory and immunosuppressive effects. 相似文献
68.
Factors most likely contributing to reduced ceftriaxone plasma protein binding in patients undergoing open heart surgery (OHS) were examined. Binding was determined by equilibrium dialysis. It was found that ceftriaxone does not bind significantly to red blood cells, alpha 1-acid glycoprotein, or to protamine, and that the pH of serum did not significantly affect binding. Albumin is the major protein to bind ceftriaxone, and binding decreases with lower albumin concentrations due to fewer binding sites. The binding of ceftriaxone was not affected by the in vitro addition of heparin or methylprednisolone, but high concentrations of methylprednisolone hemisuccinate increased the free fraction of ceftriaxone. Increased concentrations of free fatty acids (FFA) were demonstrated in several patients undergoing OHS. The in vitro addition of palmitic, stearic, linoleic, and oleic acids in high concentrations decreased the binding of ceftriaxone. Ceftriaxone binding in patient samples correlated with the molar ratio of FFA to albumin, but not to either individually. The dual effect of increased FFA and decreased albumin concentrations in OHS patients appears responsible for most of the observed binding alterations. 相似文献
69.
Charles B. Davis Leeann P. Tobia Deborah C. Kwok Christine M. Oishi Neil Kheterpal Timothy W. Hepburn Lisa J. Benincosa Fung-Sing Chow William J. Jusko 《Drug delivery》1999,6(3):171-179
SB-249417, a humanized monoclonal antibody (Mab) specific for the Gla domain of Factor IX, inhibits activation of this zymogen and blocks the activity of Factor IXa on Factor X, the subsequent enzyme in the clotting cascade. In the present study, the pharmacokinetics and pharmacodynamics of SB-249417 were investigated in male Sprague-Dawley rats after IV administration of single doses of 10, 50, or 250 mg/kg. Blood samples were collected for up to six weeks to assess total plasma Mab concentration and activated partial thromboplastin time (aPTT). A PK/PD model was developed using an empirical relationship between aPTT and the concentration of free Factor IX (inhibitory Emax model). The model assumed natural synthesis and degradation of the endogenous zymogen that was interrupted by the complexation of Factor IX with the antibody. Following antibody administration, aPTT values increased 5-fold above baseline at the earliest sampling time in all dose groups. Higher doses led to a longer duration of prolonged clotting time. Estimates of model parameters yielded a Kd for antibody-antigen interaction (38 nM) that was similar to the in vitro value. The estimated degradation half-life of Factor IX (8 hr) was consistent with historical estimates. The PK/PD model predicted that the maximum concentration of antibody-Factor IX complex (Cmax) and the time to Cmax (Tmax) would increase with increasing dose. The extent of accumulation, up to 10-fold greater than the concentration of endogenous Factor IX at baseline, was confirmed by Western Blot analysis of Protein A extracts. Complex Tmax was similar to the duration of pharmacological effect and suggests effects persisted until Factor IX synthesis produced sufficient antigen to saturate the antibody. 相似文献
70.