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1.
Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine 总被引:1,自引:0,他引:1
L. C. Kirkwood R. L. Nation & A. A. Somogyi 《British journal of clinical pharmacology》1997,44(6):549-555
Aims Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated.
Methods The kinetics of formation of N- and O -demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N -demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N -demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N -demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K m values. The kinetic constants for O -demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O -demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer.
Conclusions CYP2D6 is the major enzyme mediating O -demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. 相似文献
Methods The kinetics of formation of N- and O -demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N -demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N -demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N -demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K
Conclusions CYP2D6 is the major enzyme mediating O -demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. 相似文献
2.
Evans A. M. Nation R. L. Sansom L. N. Bochner F. Somogyi A. A. 《European journal of clinical pharmacology》1989,36(3):283-290
Summary We have developed a novel and reproducible method for determining the plasma protein binding of the two ibuprofen enantiomers in the presence of each other. The method involves the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of the enantiomers to diastereomeric amides, high-performance liquid chromatography, and radiochemical analysis.We have determined the plasma protein binding of R(–)- and S(+)-ibuprofen in 6 healthy male volunteers after the oral administration of 800 mg racemic ibuprofen.The mean time-averaged percentage unbound of the R(–)-enantiomer, 0.419 was significantly less than that of the S(+)-enantiomer, 0.643, consistent with stereoselective plasma protein binding.The percentage unbound of each ibuprofen enantiomer was concentration-dependent over the therapeutic concentration range and was influenced by the presence of its optical antipode. 相似文献
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Rats were exposed ad libitum to a diet containing either 500 ppm lead (Group Lead-Diet) or a control diet with no added lead (Group Control-Diet). On Day 60 both groups were presented with a 15% ethanol solution (nonchoice test) in the home cage for five days prior to placement on a choice test that presented animals with a 10% ethanol solution and tap water. Concurrently with the choice test in the home cage, animals were placed in operant chambers for one hr (pre-avoidance) prior to a 30 min free operant avoidance session (avoidance) and remained there for one hr (post-avoidance) after training. Throughout avoidance training, the choice test was conducted in the chamber as well as the home cage. In addition to evidence of greater ethanol consumption by Group Lead-Diet rats, the results showed that these animals lever pressed more frequently, but not more efficiently, than Group Control-Diet animals. 相似文献
5.
The vascularity of 49 renal masses (26 malignant and 23 benign lesions) was investigated with duplex Doppler ultrasound. Doppler signals obtained at the margins of renal masses were defined as "tumor signals" when the Doppler-shifted frequency of the lesion exceeded the frequency shift in the ipsilateral main renal artery. These exceeded 2.5 kHz with a 3-MHz insonating frequency. Among the 26 renal masses that subsequently proved to be malignant, tumor signals were obtained in 15 of 18 (83%) untreated renal cell carcinomas, in three of four Wilms tumors, and in two patients with metastases to the kidney, but not in the one patient with lymphoma. None of the 23 benign renal masses demonstrated tumor signals. Tumor vascularity in malignant lesions gives rise to abnormal, high-velocity, Doppler-shifted signals that can help in the differential diagnosis of renal masses. 相似文献
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目的 比较改良的尖头梅花针与带锁髓内针治疗胫腓骨干骨折的临床综合疗效 ,正确选取内固定物。方法 分别用改良的尖头梅花针与带锁髓内钉内固定治疗胫腓骨干骨折 74例 ,比较两组的综合疗效。结果 改良梅花针组 48例 ,轻度外旋畸形 2例 ,无骨不愈合 ,平均骨折愈合时间 3.5个月 ,平均手术时间 40 mim ,住院费用 30 0 0元 (人民币 ) ,优良率93.75 % ;带锁髓内钉组 2 1例 ,发生骨延期愈合 2例 ,平均骨折愈合时间 5个月 ,平均手术时间 6 0 mim ,住院费用 5 5 0 0元(人民币 ) ,优良率 95 .2 4%。除胫骨远端下 1/ 3或严重的粉碎性骨折外 ,两组疗效无明显差异 (P >0 .0 5 )。结论 改良尖梅花针内固定操作简单、价格低廉、疗效确切 ,仍有较高的临床使用价值 ;带锁髓内钉能满足胫骨各种类型的骨折 ,扩大了髓内固定的适应症 ,随着成本的降低 ,已逐渐成为治疗胫腓骨骨折髓内固定的方向。 相似文献
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Ashley Lacombe-Duncan PhD MSW Hannah Kia PhD MSW Carmen H. Logie PhD MSW Kieran P. Todd BA Yasmeen Persad Gabrielle Leblanc Kelendria Nation Ayden I. Scheim PhD Tara Lyons PhD Chavisa Horemans MES BFA Mona Loutfy MD FRCPC MPH 《Health & social care in the community》2021,29(5):e33-e46
Transgender (trans) women experience barriers to access to HIV care, which result in their lower engagement in HIV prevention, treatment and support relative to cisgender people living with HIV. Studies of trans women's barriers to HIV care have predominantly focused on perspectives of trans women, while barriers are most often described at provider, organisation and/or systems levels. Comparing perspectives of trans women and service providers may promote a shared vision for achieving health equity. Thus, this qualitative study utilised focus groups and semi-structured interviews conducted 2018–2019 to understand barriers and facilitators to HIV care from the perspectives of trans women (n = 26) and service providers (n = 10). Barriers endorsed by both groups included: (a) anticipated and enacted stigma and discrimination in the provision of direct care, (b) lack of provider knowledge of HIV care needs for trans women, (c) absence of trans-specific services/organisations and (d) cisnormativity in sexual healthcare. Facilitators included: (a) provision of trans-positive trauma-informed care, (b) autonomy and choice for trans women in selecting sexual health services and (c) models for trans-affirming systems change. Each theme had significant overlap, yet nuanced perspective, between trans women and service providers. Specific recommendations to improve HIV care access for trans women are discussed. These recommendations can be used by administrators and service providers alike to work collaboratively with trans women to reduce barriers and facilitators to HIV care and ultimately to achieve health equity for trans women. 相似文献