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81.
82.
The involvement of NMDA receptors in rats with peripheral inflammation and hyperalgesia was evaluated by administration of the non-competitive NMDA receptor antagonist, MK-801. Inflammation and hyperalgesia was induced by intradermal injection of complete Freund's adjuvant (CFA) or carrageenan into the left hind paw. The latency of paw withdrawal from a thermal stimulus was used as a measure of hyperalgesia in awake rats. MK-801 (1.6 mg/kg, i.p., or 31.5 μg, intrathecal) significantly attenuated thermal hyperalgesia and reduced its duration in comparison to saline-injected rats (P < 0.05). The receptive field size of nociceptive-specific and wide-dynamic-range neurons in the superficial and deep spinal dorsal horn recorded 24 h after injection of CFA was significantly reduced to 73 ± 6% (P < 0.05, n = 8) and 74 ± 4% (P < 0.05, n = 8) of control values, respectively, by a cumulative dose of 3 mg/kg of MK-801 (i.v.). MK-801 (2 mg/kg) prevented the expansion of the receptive fields of dorsal horn neurons recorded 5 ± 0.4 h (n = 5) after intradermal injection of CFA as compared to saline-injected rats (P < 0.05). MK-801 had no significant effect on receptive field size of dorsal horn neurons in rats without CFA-induced inflammation but blocked a transient expansion of the receptive fields induced by 1 Hz, C-fiber intensity electrical stimulation of the sciatic nerve. The background activity and noxious heat-evoked response of dorsal horn neurons in rats with CFA-induced inflammation were primarily inhibited and noxious pinch-evoked activity was both facilitated and inhibited by the administration of MK-801. These results support the hypothesis that NMDA receptors are involved in the dorsal horn neuronal plasticity and behavioral hyperalgesia that follows peripheral tissue inflammation. 相似文献
83.
84.
Herman GA Mistry GC Yi B Bergman AJ Wang AQ Zeng W Chen L Snyder K Ruckle JL Larson PJ Davies MJ Langdon RB Gottesdiener KM Wagner JA 《British journal of clinical pharmacology》2011,71(3):429-436
AIMS
Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males.METHODS
In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20–46 years) in each panel received single oral doses of 5–400 mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0–48 h post dose and plasma DPP-4 inhibition from 0–24 h post dose. The results were compared with historical data from young, healthy non-Japanese males.RESULTS
Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2–6 h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9–14 h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73–1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50 mg resulted in weighted average DPP-4 inhibition from 0–24 h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia.CONCLUSIONS
The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes. 相似文献85.
目的探讨大鼠脊髓损伤后应用兴奋性氨基酸受体非竞争性拮抗剂地卓西平马来酸盐(MK-801)对热休克蛋白27(HSP27)、半胱氨酸蛋白酶3(Caspase-3)表达及细胞凋亡的影响。方法 20只SD大鼠平均分为2组,采用Al-len’s法造成SD大鼠脊髓损伤模型,分别给予MK-801及生理盐水治疗,24h后取材,用免疫组化染色检测Caspase-3阳性细胞及HSP27阳性细胞,用流式细胞学检测细胞凋亡。结果两组均发现Caspase-3、HSP27表达及凋亡细胞,损伤组Caspase-3表达及神经细胞凋亡指数均高于MK-801组(P<0.01),而HSP27表达MK-801组高于损伤组(P<0.01)。结论脊髓损伤后,MK-801能上调HSP27的表达,抑制Caspase-3表达及神经细胞凋亡。 相似文献
86.
目的探讨2-甲氧基雌二醇(2ME2)对全脑缺血大鼠HIF-1α及凋亡相关基冈RTP801的作用。方法将成年雄性SD大鼠104只随机分为对照组(n=8)、全脑缺血组(n=48)和全脑缺血2-甲氧基雌二醇干预组(n=48),后两组按再灌注时间不同各分为6个亚组。采用改良的Pulsineli4-VO方法行全脑缺血大鼠模型制作。Nissl染色进行海马神经元计数,免疫组化及RT—PCR技术进行HIF-1α及RTP801mRNA表达检测。结果全脑缺血2ME2干预组与全脑缺血组相应时间点亚组相比,神经细胞计数明显增加,HIF-1α表达减少,RTP801mRNA表达减低(P〈O.05)。结论在全脑缺血急性期.2ME2抑制HIF-1α及凋亡相关基因RTP801表达,具有一定的神经保护作用。 相似文献
87.
Schizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H(3)-receptor (H(3)R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, i.p.) and clobenpropit (15 mg/kg, i.p.), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apomorphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (AChE) activity. Results of the present study demonstrate that ciproxifan and clobenpropitwere able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain AChE activity demonstrated positive results with these protypical imidazole H(3)R-antagonists/inverse agonists. 相似文献
88.
The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist (+)MK-801 is widely used in animal research (over 3000 publications), however its extracellular brain concentration has never been reported. Here, we show using in vivo microdialysis that systemic injection of (+)MK-801 at doses of 0.05, 0.1 or 0.2 mg/kg resulted in peak brain ECF concentration of 6, 14 or 34 nM, respectively. Moreover, (+)MK-801 resulted in a dose-dependent learning impairment in the Morris water maze as well as hyperactivity in the open field. These data demonstrate for the first time that (+)MK-801 at doses producing behavioural alterations expected from NMDA receptor blockade reaches extracellular brain concentrations corresponding to the affinity at NMDA receptors. 相似文献
89.
Brazg R Xu L Dalla Man C Cobelli C Thomas K Stein PP 《Diabetes, obesity & metabolism》2007,9(2):186-193
AIM: The aim of this study was to assess the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on 24-h glucose control when added to the regimen of patients with type 2 diabetes who had inadequate glycaemic control on metformin therapy. METHODS: In a double-blind, randomized, placebo-controlled, two-period crossover study, patients with type 2 diabetes with inadequate glycaemic control on metformin monotherapy (i.e. on a stable dose of > or = 1500 mg/day for > or = 6 weeks prior to the screening visit and an haemoglobin A(1c) (HbA(1c)) > or = 6.5% and <10% and fasting plasma glucose (FPG) < or = 240 mg/dl) were recruited for participation. A total of 28 patients (baseline HbA(1c) range = 6.5-9.6%) receiving metformin were randomized into one of two treatment sequences: the addition of placebo for 4 weeks followed by the addition of sitagliptin 50 mg twice daily (b.i.d.) for 4 weeks, or vice versa. At the end of each treatment period, patients were domiciled for frequent blood sampling over 24 h. The primary endpoint was 24-h weighted mean glucose (WMG) and secondary endpoints included change in FPG, mean of 7 daily self-blood glucose measurements (MDG) and fructosamine. beta-cell function was assessed from glucose and C-peptide concentrations were measured during the 5-h period after a standard breakfast meal by using the C-peptide minimal model. RESULTS: Despite a carryover effect from period 1 to period 2, the combined period 1 and period 2 results for glycaemic endpoints were statistically significant for sitagliptin relative to placebo when added to ongoing metformin therapy. To account for the carryover effect, the period 1 results were also compared between the groups. Following period 1, there were significant least-squares (LS) mean reductions in 24-h WMG of 32.8 mg/dl, significant LS mean reduction from baseline in MDG of 28 mg/dl, FPG of 20.3 mg/dl and fructosamine of 33.7 mmol/l in patients treated with sitagliptin relative to placebo (p < 0.05). When added to ongoing metformin therapy, parameters of beta-cell function were significantly improved with sitagliptin compared with placebo. No weight gain or increases in gastrointestinal adverse events or hypoglycaemia events were observed with sitagliptin relative to placebo during this study. CONCLUSIONS: In this study, the addition of sitagliptin 50 mg b.i.d. to ongoing metformin therapy improved 24-h glycaemic control and beta-cell function, and was generally well tolerated in patients with type 2 diabetes. 相似文献
90.
Hermansen K Kipnes M Luo E Fanurik D Khatami H Stein P;Sitagliptin Study Group 《Diabetes, obesity & metabolism》2007,9(5):733-745
AIM: To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA(1c)) >or=7.5% and or=4 mg/day) monotherapy and 229 were on glimepiride (>or=4 mg/day) plus metformin (>or=1,500 mg/day) combination therapy. Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period were provided open-label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated the change in HbA(1c) from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG), 2-h post-meal glucose and lipid measurements. RESULTS: Mean baseline HbA(1c) was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced HbA(1c) by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA(1c) by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment-beta, a marker of beta-cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. -0.4 kg; p < 0.001). CONCLUSIONS: Sitagliptin 100 mg once daily significantly improved glycaemic control and beta-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy. The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement. 相似文献