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1.
This review discusses concepts of isomers, stereoisomers, chirality, and enantiomers as applied to drugs used in anaesthesia. The inhalational anaesthetics enflurane and isoflurane are examples of stereoisomers. A chiral centre is formed when a carbon or quaternary nitrogen atom is connected to four different atoms. A molecule with one chiral centre is then present in one of two possible configurations termed enantiomers. A racemate is a mixture of both enantiomers in equal proportions. Many of the drugs used in anaesthesia are racemic mixtures (the inhalational anaesthestics, local anaesthetics, ketamine, and others). The shape of the atracurium molecule is comparable to that of a dumb-bell: the two isoquinoline groups representing the two bulky ends connected by an aliphatic chain. In each isoquinoline group there are two chiral centres, one formed by a carbon and the other by a quaternary nitrogen atom. From a geometric point of view, the connections from the carbon atom to a substituted benzene ring and from the quaternary nitrogen to the aliphatic chain may point in the same direction (cis configuration) or in opposite directions (trans configuration). The two isoquinoline groups in atracurium are paired in three geometric configurations: cis-cis, trans-trans, or cis-trans. However, the two chiral centres allow each isoquinoline group to exist in one of four stereoisomeric configurations. In the symmetrical atracurium molecule, the number of possible stereoisomers is limited to ten. Among these, 1 R-cis, 1′ R-cis atracurium was isolated and its pharmacologic properties studied. This isomer, named cis-atracurium, offers clinical advantages over the atracurium mixture, principally due to the lack of histamine-releasing propensity and the higher neuromuscular blocking potency. The ester groups appear in one of two steric configurations true and reverse esters. In the true esters, oxygen is positioned between the nitrogen atom and the carbonyl group, while in the reverse esters it is positioned on the other side of the carbonyl group. True esters, suxamethonium and mivacurium, are hydrolysed by the enzyme plasma cholinesterase (butyrylcholinesterase), albeit at different rates. The more rapid degradation of suxamethonium is responsible for its fast onset and short duration of action in comparison with mivacurium. The reverse esters, atracurium, cisatracurium, and remifentanil, are hydrolysed by nonspecific esterases in plasma (carboxyesterases). Remifentanil is hydrolysed rapidly; the degradation leads to its inactivation and short duration of action. Cis-atracurium is preferentially degraded and inactivated by a process known as Hofmann elimination. In a second step, one of the degradation products, the monoester acrylate, is hydrolysed by a nonspecific esterase. 相似文献
2.
目的 获得不易感动脉粥样硬化动物树胆固醇酯转运蛋白 (CETP)的cDNA和蛋白质序列 ,分析其结构特点 ,寻找其可能的抗动脉粥样硬化分子机制。方法 以从树肝脏mRNA反转录获得的cDNA一链为模板 ,应用SMART RACE技术 ,获得了树CETP的cDNA序列 ,并推导出其蛋白质氨基酸序列 ,应用分子生物学软件对该蛋白的一级、二级结构进行分析和比较。结果 获得的树CETPcDNA(在GenBank中的注册号为AF334 0 33)长 16 36bp ,编码 485个氨基酸 ,其成熟蛋白由 477个氨基酸组成 ,比人多一个氨基酸 (Gly318) ,该蛋白与人、家兔的同源性分别为 88%和 82 %。序列中与CETP结合和转运中性脂质功能相关的区域均非常保守 ,但在Asn34 2位的N 糖基化位点缺失 ,可能使其转运胆固醇酯的活性增加 ,利于外周组织和血浆中的胆固醇及其酯的清除。通过对不同种属蛋白序列的比较 ,初步分析了树CETP蛋白与功能相关的结构特点。结论 树CETP糖基化的特点有可能是该动物对动脉粥样硬化具有不易感性的分子机理之一 相似文献
3.
为揭示胆囊结石病与遗传因素的关系,运用聚合酶链反应技术(PCR)和基因限制性片段长度多态性分析法(RFLPs)对104例胆囊结石患者和68例健康人进行了研究。结果显示:胆囊结石组B1等位基因频率52.3%,B1B1基因型频率28.8%,大于对照组B1等位基因频率34.6%(P<0.05),B1B1基因型频率11.76%(P<0.05),胆囊结石组B2等位基因频率47.7%,B2B2基因型频率24.2%小于对照组B2等位基因频率65.4%(P<0.05),B2B2基因型频率42.6%(P<0.05)。胆囊结石组H1等位基因频率20%,H1H1基因型频率5%,H2H2基因型频率65%,H2等位基因频率80%与对照组H1等位基因频率17.9%,H1H1基因型频率2%,H2H2基因型频率65.9%,H2等位基因频率82.1%比较无显著性差异(P>0.05)。提示:B1等位基因是胆囊结石患者主导基因。B2等位基因是对照组的主导基因。H1及H2等位基因频率在胆囊结石患者及对照组中分布相同,无显著性差异(P>0.05)。 相似文献
4.
《Expert opinion on drug delivery》2013,10(3):337-348
ABSTRACTObjective: The aim of this study was to improve the drug loading (DL) and stability of clarithromycin (CLA)-loaded liposomes, and reduce the irritation caused by intravenous administration of CLA.Methods: A CLA–cholesteryl hemisuccinate (CHEMS) ion pair (CIP) was prepared by the solvent evaporation method and confirmed by fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance, differential scanning calorimetry and X-ray powder diffraction. Subsequently, CIP liposomes (CIP-Lip) were prepared by the thin-film dispersion method and evaluated in terms of their size, zeta-potential, in vitro release, stability, in vitro antimicrobial activity and irritation.Results: The CIP-Lip exhibited a homogeneous round shape, and their size, ζ-potential, encapsulation efficiency (EE) and DL were 71.89 ± 2.6 nm, ?9.91 ± 0.82 mV, 95.1 ± 1.5% and 7.8 ± 0.3%, respectively. The physical appearance and drug content of CIP-Lip over a three-month storage remained almost unchanged. The release of CLA in CIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4. Although the in vitro antimicrobial activity of CIP-Lip was comparable with free CLA, the irritation produced by CIP-Lip was significantly reduced compared with CLA solution.Conclusions: These findings suggest that CIP-Lip is a promising intravenous drug delivery system, especially on account of its high DL and reduced irritation. 相似文献
5.
CETP is a determinant of serum LDL-cholesterol but not HDL-cholesterol in healthy Japanese 总被引:2,自引:0,他引:2
Makoto Kinoshita Tamio Teramoto Nobuko Shimazu Kazuko Kaneko Masato Ohta Toru Koike Shigemi Hosogaya Yukio Ozaki Shoji Kume Masami Yamanaka 《Atherosclerosis》1996,120(1-2):75-82
Cholesteryl ester transfer protein (CETP) is one of the factors that regulate plasma levels of HDL-cholesterol. To identify the factors that may regulate CETP activity, and to determine to what extent CETP is correlated with physiologic concentrations of lipoprotein, we performed an epidemiologic study in 586 healthy volunteers (317 males and 269 females, mean age 52.2 ± 10.9 years). CETP activity in these subjects was 192.96 ± 48.73 (mean ± S.D.) nmol/ml/h and distributed to a wide range (60–450 nmol/ml/h). Using multiple regression analysis, we found significant positive correlations between CETP activity and LDL-cholesterol (P < 0.03), apolipoprotein (apo) E (P < 0.005) and LCAT activity (P < 0.001). CETP activities showed significant negative correlation with apo A-I (P < 0.03). However, CETP activity showed no significant correlation either with HDL cholesterol or with apo B. One-way layout analysis of variance showed that alcohol drinking and cigarette smoking significantly reduced CETP activity, but there was no significant association between CETP activity and body mass index. Although CETP activities were significantly higher in females than in males (P < 0.001), multiple regression analysis showed no correlation between CETP activity and age in either the males or the females. Our results suggest that CETP activity regulates the concentration of apo A-I and LDL-cholesterol, and that such activity may be influenced by gender, alcohol consumption and cigarette smoking. 相似文献
6.
Ajay Madan rew Parkinson Morris D. Faiman 《Alcoholism, clinical and experimental research》1998,22(6):1212-1219
Diethyldithiocarbamate methyl ester (DDTC-Me) is a precursor to the formation of S-methyl-N,N-diethyliolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P-450 (CYP) enzymes in sulfoxidation and thiono-oxidation of DDTC-Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P-450 enzyme(s) involved in the sulfoxidation and thiono-oxidation of DDTC-Me. These approaches included the use of cDNA-expressed human P-450 enzymes, correlation analysis with sample-to-sample variation in human P-450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P-450 enzymes (CYP3A4, CYPlA2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC-Me, as determined with cDNA-expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC-Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC-Me sulfoxidation and testosterone 6β-hydroxylation; (2) increased DDTC-Me sulfoxidation in the presence of α-naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC-Mesulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono-oxidation of DDTC-Me by human liver microsomes is catalyzed in part by CYPlA2, CYP266, CYPPEl, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA-expressed enzymes; (2) a high correlation between DDTC-Me thiono-oxidation and testosterone 6β-hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti-CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC-Me thiono-oxidation by furafylline and anti-CYPlA antibody suggested involvement of CYPlA2, and (5) inhibition of DDTC-Me thiono-oxidation by DDTC and anti-CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC-Me by human liver microsomes, and CYPlA2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC-Me thiono-oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153–1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent. 相似文献
7.
《Digestive and liver disease》2020,52(4):359-367
Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited disorders caused by loss-of-function mutations in genes encoding for lysosomal enzymes/proteins. The consequence is a progressive accumulation of substrates in these intracellular organelles, resulting in cellular and tissue damage. The overall incidence is about 1/8000 live births, but is likely underestimated. LSDs are chronic progressive multi-systemic disorders, generally presenting with visceromegaly, and involvement of the central nervous system, eyes, the skeleton, and the respiratory and cardiovascular systems. The age at onset and phenotypic expression are highly variable, according to the specific enzymatic defect and tissues involved, the residual activity, and the disease-causing genotype. Enzyme-replacement therapies and substrate-reduction therapies have recently become available, leading to the improvement in symptoms, disease progression and quality of life of affected individuals. Liver involvement and hepatosplenomegaly are frequent features of LSDs and a hallmark of adult-onset forms, frequently leading to medical attention. LSDs should therefore be considered in the differential diagnosis of liver disease with organomegaly. The present document will provide a short overview of adult-onset LSDs with hepatic involvement, highlighting the specificities and systemic manifestations of the ones most frequently encountered in clinical practice, which may hint at the correct diagnosis and the appropriate treatment. 相似文献
8.
9.
John J. Albers John H. Tollefson Gertrud Wolfbauer Robert E. Albright Jr 《International Journal of Clinical & Laboratory Research》1992,21(2-4):264-266
Summary The evidence that apolipoproteins are found in the cerebrospinal fluid and low-density lipoprotein receptor is found in the
brain suggests that the brain may have an active lipid transport system. In plasma, cholesteryl ester transfer protein mediates
the exchange and net transfer of cholesteryl ester and triglycerides among lipoproteins. Cholesteryl ester transfer activity
was measured in the cerebrospinal fluid and plasma of ten neurologically normal subjects. Cholesteryl ester transfer activity
was readily detectable in cerebrospinal fluid (7.4±13% cholesteryl ester was transferred per 20 μl), and this activity was
completely abolished with specific antibody against the plasma cholesteryl ester transfer protein. The concentration of cholesteryl
ester transfer activity in the cerebrospinal fluid was about 12% of that found in plasma, whereas the concentration of albumin
in cerebrospinal fluid was only about 0.6% of that in plasma, suggesting direct synthesis of cholesteryl ester transfer protein
within the brain. Cholesteryl ester transfer activity was found in conditioned medium from human neuroblastoma and neuroglioma
cells and sheep choroid plexus. The data suggest that cholesteryl ester transfer protein is synthesized and secreted in the
brain. This protein could play an important role in the transport and redistribution of lipids within the central nervous
system.
Deceased January 1991 相似文献
10.
Ana Cenarro José Puzo Juan Ferrando Rocío Mateo-Gallego Ana M. Bea Pilar Calmarza Estíbaliz Jarauta Fernando Civeira 《Metabolism: clinical and experimental》2014