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991.
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993.
Singer W Panford-Walsh R Watermann D Hendrich O Zimmermann U Köpschall I Rohbock K Knipper M 《Molecular pharmacology》2008,73(4):1085-1091
994.
Fedorenko O Strutz-Seebohm N Henrion U Ureche ON Lang F Seebohm G Lang UE 《Psychopharmacology》2008,199(1):47-54
RATIONALE: Evidence for an association between phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) and schizophrenia was recently obtained and replicated in several samples. PIP5K2A controls the function of KCNQ channels via phosphatidylinositol-4,5-bisphosphate (PIP2) synthesis. Interestingly, recent data suggest that KCNQ channels suppress basal activity of dopaminergic neurons and dopaminergic firing. Activation of KCNQ accordingly attenuates the central stimulating effects of dopamine, cocaine, methylphenidate, and phenylcyclidine. OBJECTIVE: The aim of this study was to explore the functional relevance of PIP5K2A, which might influence schizophrenic behavior. MATERIALS AND METHODS: Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3, and KCNQ3/KCNQ5 in the Xenopus expression system. RESULTS: We find that wild-type PIP5K2A but not the schizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5, the molecular correlate of neuronal M channels. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence of KCNQ3 in the channel complex is required for the kinase-mediated effects. Acute application of PI(4,5)P2 and a PIP2 scavenger indicates that the mutation N251S renders the kinase PIP5K2A inactive. CONCLUSIONS: Our results suggest that the schizophrenia-linked mutation of the kinase results in reduced KCNQ channel function and thereby might explain the loss of dopaminergic control in schizophrenic patients. Moreover, the addictive potential of dopaminergic drugs often observed in schizophrenic patients might be explained by this mechanism. At least, the insufficiency of (N251S)-PIP5K2A to stimulate neuronal M channels may contribute to the clinical phenotype of schizophrenia. 相似文献
995.
May K Westphal K Giessmann T Wegner D Adam U Lerch MM Oertel R Warzok RW Weitschies W Braeter M Siegmund W 《Journal of clinical pharmacology》2008,48(5):570-579
Propiverine extended release is expected to be better tolerated compared to immediate release tablets because of slower drug release and reduced formation of active metabolites in the colon. CYP3A4 and ABCC2, the major variables in pharmacokinetics of propiverine, are less expressed in the colon. Therefore, disposition and pharmacodynamics of propiverine were measured in a double-blind, double-dummy, crossover study with administration of 15 mg immediate release 3 times daily for 7 days compared to 45 mg extended release once daily for 7 days in 24 healthy subjects. Twelve subjects also received 15 mg propiverine intravenously. Serum and urine propiverine levels were measured repeatedly following oral administration on day 7 for up to 72 hours and correlated to duodenal expression of CYP3A4, ABCB1, and ABCC2. Propiverine immediate release 3 times daily was not different to extended release once daily in areas under the serum concentration-time curve (0-24 hours) and peak-trough fluctuation. The areas under the serum concentration-time curve of propiverine immediate release was circadian-time-dependent, with the lowest values during the night. Disposition of intravenous propiverine and propiverine immediate release administered in the night was influenced by intestinal expression of ABCC2. We concluded that oral absorption of propiverine is site-dependent and influenced by dosage form and circadian-time-dependent elimination processes. 相似文献
996.
997.
Dixon R Job S Oliver R Tompson D Wright JG Maltby K Lorch U Taubel J 《British journal of clinical pharmacology》2008,66(3):396-404
AIM
To characterize the effects of lamotrigine on QT interval in healthy subjects.METHODS
Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic–pharmacodynamic (PK–PD) modelling.RESULTS
Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo −7.48 ms, 90% CI −10.49, −4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK–PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied.CONCLUSIONS
Therapeutic doses of lamotrigine (50–200 mg b.d.) were not associated with QT prolongation in healthy subjects.WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
- Drugs that inhibit the human cardiac delayed rectifier potassium current may lead to prolongation of the cardiac QT interval and are associated with a fatal, polymorphic, ventricular tachycardia known as torsades de pointes.
- Lamotrigine is indicated in the treatment of epilepsy and the prevention of mood episodes in patients with bipolar disorder.
- Lamotrigine inhibits the human cardiac delayed rectifier potassium current in vitro, and it has been hypothesized that QT prolongation may contribute to the risk of sudden unexpected death in epilepsy patients.
WHAT THIS STUDY ADDS
- This is the first reported thorough QT/QTc study with lamotrigine conducted to International Conference on Harmonization guidelines.
- The mean QTc interval was not prolonged by lamotrigine in healthy subjects, as assessed by the standard heart rate correction methods (Fridericia''s and Bazett''s).
- The in vitro inhibition of the delayed rectifier potassium current does not translate into an effect on QT in man.
998.
Reiß Franziska Kaman Anne Napp Ann-Kathrin Devine Janine Li Lydia Y. Strelow Lisa Erhart Michael Hölling Heike Schlack Robert Ravens-Sieberer Ulrike 《Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz》2023,66(7):727-735
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Ein kontinuierliches bundesweites Gesundheitsmonitoring ist wichtig, um das Wohlbefinden von Kindern und Jugendlichen im Blick zu... 相似文献
999.
Induced Microphase Separation in Hybrid Composite Polymer Electrolytes Based on Poly(acrylonitrile‐r‐butadienes) and Ionic Liquids 下载免费PDF全文
Michael Wirey Marcus Hunt Tyler Blensdorf Barry D. Stein Ulrike Werner‐Zwanziger Margaret A. Hanson Waleed E. Mahmoud Ahmed A. Al‐Ghamdi John Carini Lyudmila M. Bronstein 《Macromolecular chemistry and physics.》2016,217(6):794-803
Novel hybrid, composite polymer electrolytes (HCPEs) based on poly(acrylonitrile‐r‐butadiene) (PAN‐r‐PB), CN‐modified silica nanoparticles (CN‐MSNs), Li triflate, and ionic liquids (ILs) are synthesized. Using a combination of methods, it is demonstrated that these materials segregate into PAN‐rich and PB‐rich phases, the behavior of which changes depending on the IL type. The incorporation of ILs containing hexyl and octyl substituents at the imidazolium rings leads to a higher mobility of the PB‐rich phase and a decrease of the density of the neighboring PAN‐rich phase, allowing an improvement of the Li ion conductivity. However, with an increase of the substituent length from decyl to dodecyl, ordering of the hydrophobic tails in the PB‐rich phase leads to both stiffening of the latter and corresponding ordering of the ionic pairs of ILs, resulting in a decreased conductivity. The results of this work are broadly applicable for controlling the structure and properties of polymeric materials exhibiting microphase segregation.
1000.