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1.
《Drug metabolism and pharmacokinetics》2019,34(5):308-316
LC-MS quantification of drug metabolites is sometimes impeded by the availability of internal standards that often requires customized synthesis and/or extensive purification. Although isotopically labeled internal standards are considered ideal for LC-MS/MS based quantification, de novo synthesis using costly isotope-enriched starting materials makes it impractical for early stage of drug discovery. Therefore, quick access to these isotope-enriched compounds without chemical derivatization and purification will greatly facilitate LC-MS/MS based quantification. Herein, we report a novel 18O-labeling technique using metabolizing enzyme carboxylesterase (CES) and its potential application in metabolites quantification study. Substrates of CES typically undergo a two-step oxygen exchange with H218O in the presence of the enzyme, generating singly- and doubly-18O-labeled carboxylic acids; however, unexpected hydrolytic behavior was observed for three of the test compounds – indomethacin, piperacillin and clopidogrel. These unusual observations led to the discovery of several novel hydrolytic mechanisms. Finally, when used as internal standard for LC-MS/MS based quantification, these in situ labeled compounds generated accurate quantitation comparable to the conventional standard curve method. The preliminary results suggest that this method has potential to eliminate laborious chemical synthesis of isotope-labeled internal standards for carboxylic acid-containing compounds, and can be developed to facilitate quantitative analysis in early-stage drug discovery. 相似文献
2.
K. Norpoth W. Stücker E. Krewet G. Müller 《International archives of occupational and environmental health》1988,60(3):163-168
Summary From preliminary experiments it was known that radiolabelled benzene and some of its metabolites during its metabolic activation process produce different in vitro DNA-phenyladducts in mitoplasts [5, 11].As we reported previously [9] at least one of these adducts, N-7-phenylguanine, is excreted in the urine of rats in measurable amounts, probably through an excision-repair mechanism after an inhalation experiment. Now we found, after i.p. application of benzene in the urine of rats, a compound separated by cation-exchange chromatography that behaves like a synthezised N-7-phenylguanine reference substance with respect to its retention index and the UV-absorption. This finding could be confirmed by HPLC-measurements with reversed-phase carrier materials. Silylation and gaschromatographic/mass spectrometric (GC/MS) separation of the fraction, which contains the phenylguanine, revealed that these fractions contain further phenyl adducts. Furthermore we studied the time-dependent excretion of the DNA-base adduct. Surprisingly the excretion dropped to zero on the fourth day and showed a new increase thereafter. 相似文献
3.
TuberculosisandSchistosomiasisarethemajorcontagiousdiseaseswhicharethemostdangeroustothepeople’shealth Inordertogetridofthem ,wemustlookforamoreusefulvaccine Bythetech niquesofmolecularbiology ,2 6 0 0 0DaGlutathionStransferase (GST) genewasclonedintotheE coli MycobacteriumtransferringandexpressionvectorpBCG 2 0 0 0totransformittoMycobacteriumsmeg matismc2 15 5 (MS)andBCGseparatelyinordertoconstructrMS Sj2 6GSTvaccineandrBCG Sj2 6GSTvaccine Inthisstudy ,theBALB/cmicewereimmu niz… 相似文献
4.
Ruri Aoki Tetsuya Arinobu Takeshi Kumazawa Hideki Hattori Hiroshi Noguchi 《Forensic Toxicology》2007,25(1):8-15
An automated on-line method for simultaneous analysis of five phenothiazine drugs by high-performance liquid chromatography
(HPLC)/sonic spray ionization mass spectrometry (SSI-MS) has been established, using backflush column switching. A 400-μl
portion of serum sample diluted 81-fold with distilled water was subjected to the on-line system. In the system, an Oasis
HLB cartridge was used as the precolumn for extraction; large molecules such as proteins in serum were discarded by use of
distilled water containing 0.1% formic acid as a mobile phase. After switching a valve, the analytes trapped in the precolumn
were eluted in the backflush mode and separated by a Chromolith Performance RP-18e column, which is composed of C18-bonded monolithic silica. The column effluents were then introduced into the SSI-MS. The present method provided successful
separation and determination of six phenothiazines including an internal standard. Satisfactory linearities, reproducibility,
and sensitivity were obtained at concentration levels that matched the toxic levels of phenothiazines. All drug peaks appeared
within 18 min, and the system could be reequilibrated in only about 8 min for the next run. Because of the simplicity and
rapidness of the method, it is likely to be useful in the fields of emergency medicine and forensic toxicology. 相似文献
5.
健康志愿者10名,随机交叉口服硫酸吗啡控释片(CRMS)30mg(30mg×1)和硫酸吗啡普通片(IRMS)20mg(10mg×2),分别于服药前后各时点取静脉血,用GCMS测定血浆中吗啡含量。以药代软件程序处理,分别求得CRMS和IRMS的Cmax为19.38±3.80和21.27±6.21ng/ml;tmax为2.36±0.37h和0.55±0.16h;t1/2β为3.53±0.87h和3.03±0.74h,曲线下面积AUC为145.15±17.65和93.08±16.65ng·h/ml。癌症病人多次口服硫酸吗啡至稳态,CRMS和IRMS的峰浓度分别为27.43±0.33ng/ml,22.68±0.16ng/ml;谷浓度分别为19.45±1.44ng/ml;18.14±0.49ng/ml。 相似文献
6.
Yossi Gilgun-Sherki Yael Barhum Daphne Atlas Eldad Melamed Daniel Offen 《Journal of molecular neuroscience : MN》1996,27(1):125-135
Accumulating data from experimental studies indicate that oxidative stress has a major role in the pathogenesis of multiple
sclerosis (MS). It has been suggested that local production of reactive oxygen species, probably by macrophages, mediates
axonal damage in both MS patients and the mouse model experimental autoimmune encephalomyelitis (EAE). We have shown previously
that our novel brain-penetrating antioxidant, N-acetylcysteine amide (AD4), reduces the clinical and pathological symptoms, including inflammation and axonal damage in myelin
oligodendrocyte glycoprotein (MOG)-induced chronic EAE in mice. The aim of this study was to examine the molecular mechanism
by which AD4 exerts protection in MOG-induced EAE mice. Therefore, we analyzed gene-expression profile in the spinal cords
of MOG-induced chronic EAE mice and compared them with MOG-induced mice treated with AD4, using a cDNA microarray. We found
that MOG treatment up-regulated genes encoding growth factors, cytokines, death receptors, proteases, and myelin structure
proteins, whereas MOG- and AD4-treated mice demonstrated gene expression profiles similar to that seen in na?ve healthy mice.
In conclusion, our study shows that chronic AD4 administration suppresses the induction of various pathological pathways that
play a role in EAE and probably in MS. 相似文献
7.
Chun Chang John Lipian Dennis A. Barnes Larry Seger Cheryl Burns Brian Bennett Laura Bonney Larry F. Rhodes George M. Benedikt Robert Lattimer Shyhchang S. Huang Victor W. Day 《Macromolecular chemistry and physics.》2005,206(19):1988-2000
Summary: Homopolymers of a bis‐trifluorocarbinol substituted norbornene ( 1 ) (α,α‐bis(trifluoromethyl)bicyclo[2.2.1]hept‐5‐ene‐2‐ethanol or HFANB) and copolymers of 1 with t‐butyl ester of 5‐carboxylic acid ( 2 , t‐BuEsNB) were produced using palladium catalysts and olefinic chain transfer agents such as 1‐hexene and ethylene to control molecular weight. However, these low‐molecular‐weight polymers exhibited relatively low optical transparencies at 193 nm. In fact, the opacity (measured as optical densities in absorbance units per micron) of thin films of these homo‐ and co‐polymers was inversely proportional to their molecular weight. This relationship is consistent with an end group contribution to the film opacity. Spectroscopic analysis of these polymers by 1H NMR and MALDI‐TOF MS confirmed that 1‐hexene and ethylene chain transfer agents generated olefin‐terminated vinyl addition polymers. The olefinic end group contribution to optical density can be eliminated by appropriate chemical modification. Both epoxidation and hydrogenation of the polymer olefinic end groups generated very low optical density materials, independent of molecular weight, that are suitable as 193‐nm photoresist binder resins.
8.
T cell epitope spreading to myelin oligodendrocyte glycoprotein in HLA-DR4 transgenic mice during experimental autoimmune encephalomyelitis 总被引:2,自引:0,他引:2
Klehmet J Shive C Guardia-Wolff R Petersen I Spack EG Boehm BO Weissert R Forsthuber TG 《Clinical immunology (Orlando, Fla.)》2004,111(1):53-60
Epitope spreading has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS). T cell epitope spreading has been demonstrated in rodents for myelin basic protein (MBP) and proteolipid protein (PLP) determinants, but not for myelin oligodendrocyte glycoprotein (MOG), another important myelin antigen. Moreover, the role of human autoimmunity-associated MHC molecules in epitope spreading, including HLA-DR2 and DR4, has not been formally examined. To address these questions, we investigated epitope spreading to MOG determinants in HLA-DR4 (DRB1*0401) transgenic mice during EAE. The data show that upon induction of EAE in HLA-DR4 transgenic mice with the immunodominant HLA-DR4-restricted MOG peptide 97-108 (MOG(97-108); TCFFRDHSYQEE), the T cell response diversifies over time to MOG(181-200) (core: MOG(183-191); FVIVPVLGP) and MBP. The spreading epitope MOG(181-200) binds with high affinity to HLA-DRB1*0401 and is presented by human HLA-DRB1*0401+antigen presenting cells. Moreover, this epitope is encephalitogenic in HLA-DRB1*0401 transgenic mice. This study demonstrates intra- and intermolecular epitope spreading to MOG and MBP in "humanized" HLA-DR4 transgenic mice. 相似文献
9.
Nobuhiko Okamoto Mashiro Nakayama Chie Narahara Han-suk Kim Masashi Fujioka Isao Imada Tatsuya Arai Soichiro Toda 《Journal of human genetics》1997,42(3):441-444
Summary Mevalonic acidemia is a rare metabolic disorder due to mevalonate kinase deficiency which affects the biosynthesis of cholesterol
and nonsterol isoprenes. We report the first case of Japan. The clinical course is characterized by intrauterine growth retardation,
postnatal growth failure, intractable diarrhea, liver dysfunctions and death at three months of age. Dysmorphic features including
triangular face, protrusion of forehead, hypertelorism, low set ears and micrognathism were noted. High mevalonic acid level
was found by GC/MS. 相似文献
10.
琥珀酸美托洛尔HPMC骨架片释放影响因素研究 总被引:3,自引:0,他引:3
以羟丙基甲基纤维素(HPMC)为骨架材料,乙基纤维素(EC)为阻滞剂,采用湿颗粒压片法制备琥珀酸美托洛尔亲水凝胶骨架片,考察HPMC用量、HPMC黏度、EC用量、制备方法、压片压力、释放介质及转速对琥珀酸美托洛尔(MS)骨架片体外释药的影响。结果表明,MS骨架片体外释药符合Higuchi方程,药物释放机制是骨架溶蚀和药物扩散的综合效应;HPMC用量与黏度、阻滞剂用量、制备方法、压片压力对释放速率均有显著性影响;释放介质的pH值及转速对释放速率无显著性影响。 相似文献