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991.
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993.
Therese Ericsson Antje Blank Cornelia von Hagens Michael Ashton Angela Äbelö 《European journal of clinical pharmacology》2014,70(12):1453-1463
Purpose
The purpose of this study were firstly to characterize the population pharmacokinetics of artesunate (ARS) and its active metabolite dihydroartemisinin (DHA) in patients with metastatic breast cancer during long-term (>3 weeks) daily oral ARS administration and secondly to study the relationship between salivary and plasma concentrations of DHA.Methods
Drug concentration-time data from 23 patients, receiving oral ARS (100, 150, or 200 mg OD), was analyzed using nonlinear mixed effects modeling. A combined drug-metabolite population pharmacokinetic model was developed to describe the plasma pharmacokinetics of ARS and DHA in plasma. Saliva drug concentrations were incorporated as being directly proportional to plasma concentrations.Results
A first-order absorption model for ARS linked to a combined two-compartment disposition model for ARS and one-compartment disposition model for DHA provided the best fit to the data. No covariates were identified that could explain between-subject variability. A time-dependent increase in apparent elimination clearance of DHA was observed. Salivary DHA concentrations were proportionally correlated with total DHA plasma concentrations, with an estimated slope factor of 0.116.Conclusions
Population pharmacokinetics of ARS and DHA in patients with breast cancer was well described by a combined drug-metabolite model without any covariates and with an increase in apparent elimination clearance of DHA over time. The estimated DHA saliva/plasma ratio was in good agreement with the reported DHA unbound fraction in human plasma. Saliva ARS concentrations correlated poorly with plasma concentrations. This suggests the use of saliva sampling for therapeutic drug monitoring of DHA. However, further studies are warranted to investigate the robustness of this approach. 相似文献994.
Huibing Tan Laura G. Rosen Garye A. Ng Walter J. Rushlow Steven R. Laviolette Addiction Research Group 《Psychopharmacology》2014,231(24):4669-4679
Rationale
N-Methyl-d-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood.Objective
This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA).Methods
Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings.Results
We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism.Conclusions
These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing. 相似文献995.
John Weaver Yirong Yang Rebecca Purvis Theodore Weatherwax Gerald M. Rosen Ke Jian Liu 《Toxicology and applied pharmacology》2014
Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O2 may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O2 is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO2in vivo remains largely uncharacterized. This study investigated striatal tissue pO2 changes in male C57BL/6 mice (16–20 g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO2in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO2 was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO2 to 64%. More importantly, pO2 did not recover fully to control levels even 24 h after administration of a single dose of METH and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO2 indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO2, which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults. 相似文献
996.
Conny F Waschkies Andreas Bruns Stephan Müller Martin Kapps Edilio Borroni Markus von Kienlin Markus Rudin Basil Künnecke 《Neuropsychopharmacology》2014,39(10):2331-2339
Proton magnetic resonance spectroscopy (1H-magnetic resonance spectroscopy (MRS)) is a translational modality with great appeal for neuroscience since the two major excitatory and inhibitory neurotransmitters, glutamate, and GABA, can be noninvasively quantified in vivo and have served to explore disease state and effects of drug treatment. Yet, if 1H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, 1H-MRS needs to reliably report neurobiologically relevant but rather small changes in neurometabolite levels upon pharmacological interventions and to faithfully appraise target engagement in the associated molecular pathways at pharmacologically relevant doses. Here, we thoroughly addressed these matters with a three-pronged approach. Firstly, we determined the sensitivity and reproducibility of 1H-MRS in rat at 9.4 Tesla for detecting changes in GABA and glutamate levels in the striatum and the prefrontal cortex, respectively. Secondly, we evaluated the neuropharmacological and neurobiological relevance of the MRS readouts by pharmacological interventions with five well-characterized drugs (vigabatrin, 3-mercaptopropionate, tiagabine, methionine sulfoximine, and riluzole), which target key nodes in GABAergic and glutamatergic neurotransmission. Finally, we corroborated the MRS findings with ex vivo biochemical analyses of drug exposure and neurometabolite concentrations. For all five interventions tested, 1H-MRS provided distinct drug dose-effect relationships in GABA and glutamate over preclinically relevant dose ranges and changes as low as 6% in glutamate and 12% in GABA were reliably detected from 16 mm3 volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative 1H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders. 相似文献
997.
998.
Max J. Åström Mikaela B. von Bonsdorff Maija Haanpää Minna K. Salonen Hannu Kautiainen Johan G. Eriksson 《Primary Care Diabetes》2021,15(3):561-566
AimsTo assess if individuals with diabetes or prediabetes report more pain or have increased use of pain medication compared to normoglycaemic individuals.MethodsUsing cross-sectional data, we studied 928 men and 1075 women from the Helsinki Birth Cohort Study in 2001–2004 at a mean age of 61.5 years. Glucose regulation was assessed with a 2-h 75 g oral glucose tolerance test, and applying World Health Organization criteria, participants were defined as having normoglycaemia, prediabetes (impaired fasting glucose or impaired glucose tolerance), newly diagnosed diabetes or previously diagnosed diabetes. Self-reported pain intensity and interference during the previous 4 weeks was estimated using the RAND 36-Item Health Survey 1.0. Information on use of pain medication during the past 12 months was obtained from the Social Insurance Institution of Finland.ResultsThere was no difference in pain intensity or interference between glucose regulation groups for neither men nor women after adjusting for covariates (age, body mass index, education years, Beck Depression Inventory and physical activity). In addition, use of pain medication was similar between glucose regulation groups.ConclusionsAlthough pain is a common symptom in the general population, impairments in glucose regulation alone does not seem to increase pain among older individuals. 相似文献
999.
Roland Klingenberg Oliver Schlager Andreas Limacher Marie Méan Nicolas Vuilleumier Juerg H. Beer Daniel Staub Beat Frauchiger Markus Aschwanden Bernhard Lämmle Marc Righini Michael Egloff Joseph Osterwalder Anne Angelillo-Scherrer Nils Kucher Martin Banyai Nicolas Rodondi Arnold von Eckardstein Drahomir Aujesky Marc Husmann Christian M. Matter 《European journal of clinical investigation》2019,49(9):e13154