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1.
《Vaccine》2022,40(41):5882-5891
BackgroundMethamphetamine (METH) addiction is a major public health concern globally with limited management options. The development of a METH vaccine through hapten design has received significant attention as a promising platform for the potential treatment of METH addiction and overdose, however there is yet to be a successful candidate in human trials.Research design and methods: In this study, we developed a novel conjugated METH vaccine using oxidized mannan (a polymannose) as an immunogenic carrier. A METH hapten was synthesized by using amphetamine and conjugated to mannan with a (Lysine-Glycine-Lysine-Glycine-lysine-Glycine-Lysine-Glycine-Lysine-Glycine) (KG)5 peptide linker.ResultsThe reaction between amphetamine and (KG)5, oxidation of mannan, and conjugation of amphetamine-(KG)5 with oxidized mannan were confirmed by color tests, Fourier-transform infrared spectroscopy, gas and liquid chromatography mass spectrometry, thin-layer chromatography, and ultraviolet spectrophotometer. Additionally, the ability of the vaccine to generate antibodies was confirmed in C57BL/6 mice.ConclusionsThe successful development and characterization of the METH-mannan conjugate vaccine, provides a potential therapeutic intervention to curb METH substance use disorders. Each step of vaccine development was characterized to aid in future research on these vaccines, and the immunogenicity shown in the animal models supports future evaluation of the approach. Future studies of the conjugated METH vaccine should evaluate the efficacy in animal models of acute and chronic METH to pave the way for human studies.  相似文献   
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BackgroundIn this paper we capture and synthesize the unique knowledge of experts so that choices regarding policy measures to address methamphetamine consumption and dependency in Australia can be strengthened. We examine perceptions of the: (1) influence of underlying factors that impact on the methamphetamine problem; (2) importance of various models of intervention that have the potential to affect the success of policies; and (3) efficacy of alternative pseudoephedrine policy options.MethodsWe adopt a multi-criteria decision model to unpack factors that affect decisions made by experts and examine potential variations on weight/preference among groups. Seventy experts from five groups (i.e. academia (18.6%), government and policy (27.1%), health (18.6%), pharmaceutical (17.1%) and police (18.6%)) in Australia participated in the survey.ResultsSocial characteristics are considered the most important underlying factor, prevention the most effective strategy and Project STOP the most preferred policy option with respect to reducing methamphetamine consumption and dependency in Australia. One-way repeated ANOVAs indicate a statistically significant difference with regards to the influence of underlying factors (F(2.3, 144.5) = 11.256, p < .001), effectiveness of interventions (F(2.4, 153.1) = 28.738, p < .001) and policy options (F(2.8, 175.5) = 70.854, p < .001).ConclusionA majority of respondents believed that genetic, biological, emotional, cognitive and social factors are the most influential explanatory variables in terms of methamphetamine consumption and dependency. Most experts support the use of preventative mechanisms to inhibit drug initiation and delayed drug uptake. Compared to other policies, Project STOP (which aims to disrupt the initial diversion of pseudoephedrine) appears to be a more preferable preventative mechanism to control the production and subsequent sale and use of methamphetamine. This regulatory civil law lever engages third parties in controlling drug-related crime. The literature supports third-party partnerships as it engages experts who have knowledge and expertise with respect to prevention and harm minimization.  相似文献   
4.
Methamphetamine (METH), an illicit drug, is widely abused in many parts of the world. Mounting evidence shows that METH exposure contributes to neurotoxicity, particularly for the monoaminergic neurons. However, to date, only a few studies have tried to unravel the mechanisms involved in METH‐induced non‐monoaminergic neural damage. Therefore, in the present study, we tried to explore the mechanisms for METH‐induced neural damage in cortical neurons. Our results showed that METH significantly increased intracellular [Ca2+]i in Ca2+‐containing solution rather than Ca2+‐free solution. Moreover, METH also upregulated calmodulin (CaM) expression and activated CaM‐dependent protein kinase II (CaMKII). Significantly, METH‐induced neural damage can be partially retarded by CaM antagonist W7 as well as CaMKII blocker KN93. In addition, L‐type Ca2+ channel was also proved to be involved in METH‐induced cell damage, as nifedipine, the L‐type Ca2+ channel‐specific inhibitor, markedly attenuated METH‐induced neural damage. Collectively, our results suggest that Ca2+‐CaM‐CaMKII is involved in METH‐mediated neurotoxicity, and it might suggest a potential target for the development of therapeutic strategies for METH abuse. Copyright © 2016 John Wiley & Sons, Ltd.  相似文献   
5.

Background

The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of sustained-release methylphenidate (MPH-SR) in treatment of methamphetamine dependence.

Methods

Fifty-six individuals who met DSM-IV-TR criteria for methamphetamine dependence participated in this 10-week trial. The participants were randomly allocated into two groups and received 18 to 54 mg/day sustained-released methylphenidate or placebo for 10 weeks. Craving was evaluated by a visual analogue craving scale every week. Urinary screening test for methamphetamine was carried out each week. The Beck Depression Inventory-II (BDI-II) was used to monitor participant depressive symptoms at baseline and bi-weekly during the treatment period.

Results

At the end of the trial, the MPH-SR group was less methamphetamine positive compared to the placebo group and the difference was significant (p = 0.03). By the end of the study, MPH-SR group showed significantly less craving scores compared to the placebo group [MD (95% CI) = -10.28(0.88-19.18), t(54) = 2.19, p = 0.03]. There was greater improvement in the depressive symptoms scores in the intervention group compared to the placebo group [MD (95% CI) =2.03(0.31-3.75), t (54) =2.37, p = 0.02].

Conclusion

Sustained-released methylphenidate was safe and well tolerated among active methamphetamine users and significantly reduced methamphetamine use, craving and depressive symptoms.

Trial registration

IRCT201202281556N38  相似文献   
6.
目的 观察甲基苯丙胺与HIV-Tat蛋白协同对大鼠血脑屏障的作用机制.方法 雄性SD大鼠每天2次腹腔注射给予MA10 mg/kg的同时尾静脉注射给予HIV-Tat 400 ng/kg,连续7d,给药结束24 h后随机取10只大鼠尾静脉注射伊文思蓝检测脑组织EB含量,随机取5只大鼠断颈取脑,用于SOD活力、GSH和MDA含量的测定.余下2只大鼠快速断颈取脑,戊二醛-锇酸溶液固定前额叶皮质部分,透射电镜观察结构变化.结果 与正常对照组相比,实验组脑组织中EB含量不同程度增加,提示实验组血脑屏障通透性增加(P<0.05);MDA含量升高、SOD活力和GSH含量不同程度降低,提示实验组氧化应激反应增强(P<0.05).MA+Tat组与MA组、Tat组相比,EB含量升高明显,提示MA与HIV-Tat蛋白联用能协同增加血脑屏障通透性;MDA含量显著升高,SOD活力、GSH含量明显下降,提示MA与HIV-Tat蛋白联用能协同增强大鼠脑组织氧化应激反应(P<0.01);NAC+MA+Tat组与MA+Tat组相比,EB含量降低,提示NAC能一定程度拮抗MA与HIV-Tat蛋白对血脑屏障通透性的影响(P<0.01);MDA含量下降,SOD活力、GSH含量明显升高,反映NAC能在一定程度拮抗MA与HIV-Tat蛋白对大鼠脑内氧化应激反应增强作用(P<0.01).各实验组在电镜下观察到血脑屏障一系列超微结构改变,如脑微血管内皮细胞肿胀变薄,血管周围胶质细胞和星形胶质细胞肿胀,胞饮小泡增加等,这些改变以MA+Tat组最为显著.结论 MA和HIV-Tat蛋白能改变血脑屏障通透性,两者具有协同作用,协同作用机制可能与氧化应激有关.  相似文献   
7.
Animal studies have consistently observed neuronal death following methamphetamine (MA) administration, however, these have not been systematically reviewed. This systematic review aims to present the evidence for MA-induced neuronal death in animals (rodents) and identify the regions affected. Locating the brain regions in which neuronal death occurs in animal studies will provide valuable insight into the linkage between MA consumption and the structural alterations observed in the human brain. The data were collected from three databases: Scopus, Ovid, and the Web of Science. Thirty-seven studies met the inclusion criteria and were divided into two sub-groups, i.e. acute and repeated administration. Twenty-six (of 27) acute and ten (of 11) repeated administration studies observed neuronal death. A meta-analysis was not possible due to different variables between studies, i.e. species, treatment regimens, withdrawal periods, methods of quantification, and regions studied. Acute MA treatment induced neuronal death in the frontal cortex, striatum, and substantia nigra, but not in the hippocampus, whereas repeated MA administration led to neuronal loss in the hippocampus, frontal cortex, and striatum. In addition, when animals self-administered the drug, neuronal death was observed at much lower doses than the doses administered by experimenters. There is some overlap in the regions where neuronal death occurred in animals and the identified regions from human studies. For instance, gray matter deficits have been observed in the prefrontal cortex and hippocampus of MA users. The findings presented in this review implicate that not only does MA induce neuronal death in animals, but it also damages the same regions affected in human users. Despite the inter-species differences, animal studies have contributed significantly to addiction research, and are still of great assistance for future research with a more relevant model of compulsive drug use in humans.  相似文献   
8.
Methamphetamine, a highly addictive psychostimulant drug, is widely used by substance users who are not motivated to undergo treatment throughout the world, including Iran. This research was conducted to evaluate the effectiveness of a brief home-based social work motivational intervention (HSWMI) to encourage male methamphetamine users to participate in a treatment program. Method: Fifty-six unmotivated male methamphetamine users participated in a randomized controlled trial. The case group received the HSWMI in addition to the usual consulting services in the clinic; the control group just received the usual consulting services. Data were collected 7 and 90 days after the intervention to evaluate participation and retention in a treatment program. Data were analyzed using the chi-square test. Results: Drug users with a mean age of 32.55 years and mean duration of drug use of 7.73 years, participated in the case (n = 28) and control (n = 28) groups. The case group participated in treatment programs significantly more than the control group and the retention rate for the case group was significantly higher than for the control group. Conclusion: This brief HSWMI was effective to increase the motivation of methamphetamine users to participate and remain in treatment programs. This intervention can be implemented by social workers in substance use treatment centers.  相似文献   
9.
Objective: Interaction of methamphetamine and sigma (σ) receptors lead to up-regulation and activation of thesereceptors. The σ receptors induced apoptosis in some parts of the brain by increasing calcium, dopamine, ROS,mitochondrial pores and caspase activity. Ibudilast is a phosphodiesterase inhibitor and anti-inflammatory drug,which can decrease the inflammatory cytokines. Also, it has a neuroprotective effect. It seems that ibudilast canreduce the methamphetamine-induced cell death due to inhibition of σ receptors. Materials and Methods: Therewere seven treatments including; control: culture medium, Treatment 1: 1mM methamphetamine, Treatment 2: 1mMmethamphetamine and 1nM ibudilast, Treatment 3: 1mM methamphetamine and 10nM ibudilast, Treatment 4: 1mMmethamphetamine and 100nM ibudilast, Treatment 5: 1mM methamphetamine and 1uM ibudilast, Treatment 6: 1mMmethamphetamine and 10uM ibudilast, and Treatment 7: 1mM methamphetamine and 100uM ibudilast. Finally, forinhibition of PKA, CREB, IP3 receptor, NMDA receptor, Sigma receptor antagonist, sigma receptor agonist, cellswere preincubated with adding H89 dihydrochloride, 666-15, Heparin, Ketamine, BMY 14802, and Pentazocine.MTT and LDH tests were performed for cell viability and cytotoxicity measurement, respectively. In continuing, thecaspase activity colorimetric assay kit used for caspase 3 activity diagnosis. Rhodamine-123 performed to detection ofmitochondrial membrane potential. TUNEL test used to DNA fragmentation and apoptosis, Fura-2 used to Measurementof (Ca2+) ic and (Ca2+) m, and fluorescence microscope used to Measurement of antioxidant enzyme activities. Results:Ibudilast increased the cell viability and the rhodamine-123 absorbance in methamphetamin-treated PC12 cells. Itreduced cell cytotoxicity, caspase 3 activity, ic and m Ca2+ concentration, (OH) generation and DNA fragmentation inall concentrations of 1 nM t0 100 μM (p<0.05) by the optimal concentration of 100 μM, between our tested treatments.Conclusion: Ibudilast as a phosphodiesterase inhibitor can reduce the methamphetamine-induced cell death due toinhibition of σ receptors through cAMP production.  相似文献   
10.
ObjectiveMethamphetamine is used extensively around the world as a psychostimulant. The complications related to methamphetamine include methamphetamine-induced neurotoxicity, mainly involving intraneuronal processes, such as oxidative stress and excitotoxicity. Curcumin is effective against neuronal injury due to its antioxidant, anti-inflammatory effects. In this study, we examined the protective effects of curcumin against methamphetamine neurotoxicity.MethodsSixty male Wistar rats were divided into the following groups: control (n = 12), DMSO (n = 12), methamphetamine (n = 12), and methamphetamine + curcumin (100 and 200 mg/kg, respectively, intraperitoneal [IP]; n = 12). Neurotoxicity was induced by 40 mg/kg of methamphetamine administrated through 4 injections (4 × 10 mg/kg, q2h, IP). Curcumin (100 and 200 mg/kg) was administered at 7 days after the last methamphetamine injection. By using a Morris water maze task, the hippocampus-dependent memory and spatial learning were evaluated 1 day after the last curcumin injection. Then, the animal brains were isolated for biochemical measurements, as well as glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1(Iba-1) and caspase-3 immunohistochemical staining.ResultsThe current study demonstrated that administration of curcumin significantly attenuates spatial memory impairment (P < 0.01) following methamphetamine neurotoxicity. Curcumin caused a significant increase in the levels of superoxide dismutase and glutathione peroxidase (P < 0.05). However, it decreased tumor necrosis factor (TNF-α) (P < 0.05) and malondialdehyde (P < 0.01) levels as compared to the methamphetamine group. Also, curcumin significantly reduced Iba-1 (P < 0. 01), GFAP and caspase-3 positive cells in the hippocampus (P < 0.001).ConclusionCurcumin exerted neuroprotective effects on methamphetamine neurotoxicity because of its antioxidant and anti-inflammatory effect.  相似文献   
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