全文获取类型
收费全文 | 446篇 |
免费 | 17篇 |
国内免费 | 9篇 |
专业分类
耳鼻咽喉 | 2篇 |
儿科学 | 4篇 |
妇产科学 | 18篇 |
基础医学 | 54篇 |
口腔科学 | 4篇 |
临床医学 | 10篇 |
内科学 | 96篇 |
皮肤病学 | 3篇 |
神经病学 | 46篇 |
特种医学 | 5篇 |
外科学 | 26篇 |
综合类 | 30篇 |
预防医学 | 20篇 |
眼科学 | 3篇 |
药学 | 133篇 |
中国医学 | 11篇 |
肿瘤学 | 7篇 |
出版年
2023年 | 2篇 |
2022年 | 13篇 |
2021年 | 7篇 |
2020年 | 9篇 |
2019年 | 12篇 |
2018年 | 8篇 |
2017年 | 8篇 |
2016年 | 15篇 |
2015年 | 9篇 |
2014年 | 15篇 |
2013年 | 28篇 |
2012年 | 16篇 |
2011年 | 27篇 |
2010年 | 14篇 |
2009年 | 13篇 |
2008年 | 19篇 |
2007年 | 23篇 |
2006年 | 18篇 |
2005年 | 28篇 |
2004年 | 11篇 |
2003年 | 17篇 |
2002年 | 12篇 |
2001年 | 17篇 |
2000年 | 13篇 |
1999年 | 12篇 |
1998年 | 12篇 |
1997年 | 13篇 |
1996年 | 8篇 |
1995年 | 12篇 |
1994年 | 10篇 |
1993年 | 2篇 |
1992年 | 8篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1987年 | 3篇 |
1986年 | 1篇 |
1984年 | 5篇 |
1983年 | 1篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1978年 | 1篇 |
1975年 | 2篇 |
1973年 | 3篇 |
1972年 | 2篇 |
1971年 | 1篇 |
排序方式: 共有472条查询结果,搜索用时 740 毫秒
141.
James E. Zadina Abba J. Kastin Lynn A. Fabre David H. Coy 《Pharmacology, biochemistry, and behavior》1981,15(6):961-964
An LHRH analog known to inhibit ovulation the rat ([N-Ac-Phe1, D-p-Cl-Phe2, D-Trp3,6]LHRH) was tested for its effects on sexual receptivity. The dose of 500 ng/rat was found in dose-response experiments to be most active and was further investigated for its behavioral effects in rats treated with either estrogen or estrogen plus progesterone. The analog significantly facilitated the behavior of rats in regimens producing low [estradiol benzoat (EB) (2μg)] and intermediate [EB (2 μg) plus progesterone (2.5 mg)] levels of sexual behavior. In rats given regimens producing high behavioral scores [EB (5 μg) plus progesterone (1 mg)], the peptide did not reduce mating behavior. In the same experiment, rats given EB (5 μg) but not progesterone showed significantly higher scores after the LHRH analog only if they had been designated ”responders” by a previous screening test with 1 μg LHRH. These results demonstrate that in animals showing low, intermediate, or high levels of sexual behavior, the LHRH analog can affect mating behavior in a direction quite different from that exerted on pituitary reproductive functions. 相似文献
142.
Savidge J Davis C Shah K Colley S Phillips E Ranasinghe S Winter J Kotsonis P Rang H McIntyre P 《Neuropharmacology》2002,43(3):450-456
We have cloned a guinea pig Vanilloid receptor 1 (VR1) from a dorsal root ganglion cDNA library and expressed it in CHO cells. The receptor has been functionally characterized by measuring changes in intracellular calcium produced by capsaicin, low pH and noxious heat.Capsaicin produced a concentration-dependent increase in intracellular calcium in guinea pig VR1-CHO cells with an estimated EC(50) of 0.17 +/- 0.0065 micro M, similar to that previously reported for rat and human VR1. Olvanil and resiniferatoxin were also effective agonists (EC(50) values of 0.0087 +/- 0.0035 micro M and 0.067 +/- 0.014 micro M, respectively), but 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) and anandamide showed little agonist activity up to 10 micro M. As with human and rat VR1, guinea pig VR1 was also activated by pH below 6.0 and by noxious heat (>42 degrees C). Capsazepine acted as an antagonist of capsaicin responses in guinea pig VR1-CHO cells (IC(50) of 0.324 +/- 0.041 micro M ), as seen at rat VR1. However, in contrast to its lack of activity against pH and heat responses at rat VR1, capsazepine was an effective antagonist of these responses at guinea pig VR1. Capsazepine displayed an IC(50) of 0.355 +/- 25 micro M against pH 5.5, and provided complete blockade of heat responses at 1 micro M. Thus, capsazepine can significantly inhibit calcium influx due to heat and pH 5.5 at guinea pig VR1 and human VR1 but is inactive against these activators at rat VR1. 相似文献
143.
Changes in isokinetic torque and muscular activity of elbow flexors muscles with age 总被引:3,自引:0,他引:3
This study examined the influence of aging on torque–angular velocity relationships for elbow flexion and the corresponding muscular activity levels in order to target the mechanisms involved in the eccentric muscle action in older adults. Maximal constant angular torque (CAT) at 90° was measured at different angular velocities for concentric (CON; 60, 120, 180, 240° s−1), isometric (ISO) and eccentric (ECC; −60, −120° s−1) elbow flexor muscle actions in older (OG; 6 females and 4 males, 64–82 years) and young adult subjects (YG; 6 females, 6 males, 19–24 years) on an isokinetic dynamometer. Myoelectrical activity was quantified on biceps and triceps muscles, using the root mean square (RMS) procedure over a range of 30° motion (75–105°). Absolute CAT was significantly greater (p<0.04) for YG in comparison with OG for all types of actions (CON, ECC, ISO). The only effect of gender concerned absolute strength values (p=0.00007). However, the OG showed higher (p<0.001) relative CAT values (expressed as percentage of CON 60° s−1 value) during ECC muscle action than the YG. Nevertheless, RMS values for elbow flexors were significantly (p<0.03) lower in the OG than in the YG. The antagonist (triceps) co-activation was similar for both groups. The relative ECC force preservation with aging seems to be independent of a muscular activation phenomenon. 相似文献
144.
Carlos R. Plata-Salamn Sergey E. Ilyin Nicolas P. Turrin Dave Gayle Mark C. Flynn Tanya Bedard Zul Merali Hymie Anisman 《Brain research bulletin》2000,51(2)
Physical (neurogenic) stressors may influence immune functioning and interleukin-1β (IL-1β) mRNA levels within several brain regions. The present study assessed the effects of an acute or repeated naturalistic, psychogenic stressor (predator exposure) on brain cytokine and neuropeptide mRNAs. Acute predator (ferret) exposure induced stress-like behavioral effects, including elicitation of a startle response and reduced exploratory behaviors; these responses diminished after 30 sessions. Moreover, acute and repeated predator exposure, like acute restraint stress, increased plasma corticosterone levels measured 5 min later, but not 2 h after stressor exposure. In contrast, none of the stressors used influenced IL-1β, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory proteins I and II, or tumor necrosis factor-α mRNA levels in the prefrontal cortex, amygdala, hippocampus, or hypothalamus. Likewise, there were no stressor effects on transforming growth factor-β1, neuropeptide Y, glycoprotein 130, or leptin receptor mRNAs in brain regions. Thus, the naturalistic/psychogenic stressor used does not affect any of the brain cytokine component mRNAs studied. It is suggested that this type of stressor activates homeostatic mechanisms (e.g., glucocorticoid release), which act to preclude brain cytokine alterations that would otherwise favor neuroinflammatory/neuroimmunological responses and the consequent increase of brain sensitivity to neurotoxic and neurodegenerative processes. 相似文献
145.
Gary J. Muirhead Ian H. Osterloh Steven Whaley Frans van den Berg 《The journal of sexual medicine》2019,16(2):213-222
Background
Cligosiban (formerly IX-01) is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE).Aim
To investigate the plasma pharmacokinetics, safety, and tolerability of multiple oral doses of cligosiban in healthy male subjects; measure the amount of cligosiban in semen; and evaluate the potential of cligosiban to modulate CYP3A4.Methods
Both studies were double-blind, placebo-controlled, parallel group designs involving sequential cohorts of 12 subjects each. Cligosiban dosage regimens were 100 mg, 400 mg, 800 mg, 1200 mg, 1,600 mg and 2,400 mg once daily for 10 days, administered as an aqueous dispersion.Outcomes
Blood samplings for cligosiban assays and safety assessments were performed throughout both studies. Semen was collected on day 9 at 2–4 hours postdose in study 1 only. Safety assessments included monitoring of adverse events, 12-lead electrocardiography, vital signs, and laboratory safety assessments. Urine samples for assessment of the 6β-hydroxycortisol/cortisol ratio were collected before dosing on days 1 and 10.Results
Cligosiban was rapidly absorbed after both single and multiple dosing, with maximum plasma concentrations typically measured at 1–3 hours postdose. The terminal half-life was approximately 12 hours, and steady state was achieved by day 3. Exposure increased approximately proportionally to dose after single dosing but less than proportionally after multiple dosing. Accumulation ratios were higher at the lower doses compared with higher doses (2.3 at 100 mg vs 1.1 at 2,400 mg). The mean amount of cligosiban in semen ranged from 0.22 to 2.01 μg over the 100–1,200 mg dose range (<0.0003% of the administered dose). There were no meaningful differences in the urinary 6β-hydroxycortisol/cortisol ratio after multiple dosing with cligosiban. Cligosiban appeared to be well tolerated at all dose levels.Clinical Implications
Cligosiban is well tolerated following once-daily dosing over a wide dose range and does not appear to modulate CYP3A4 activity, suggesting limited potential for perpetrating drug–drug interactions via this mechanism.Strengths & Limitations
The 2 controlled trials show good toleration and pharmacokinetic data, including negligible amounts of cligosiban in semen at doses expected to be therapeutic. Toleration of cligosiban will need to be confirmed in studies in patients with PE.Conclusion
Cligosiban showed a good safety profile at doses predicted to be therapeutic or supratherapeutic along with a pharmacokinetic profile appropriate for as-required or once-daily dosing. There was no evidence that cligosiban inhibited or induced CYP3A4 at doses up to 2,400 mg.Muirhead GJ, Osterloh IH, Whaley S, et al. Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects. J Sex Med 2019;16:213–222. 相似文献146.
Effectiveness,safety and feasibility of extended‐release naltrexone for opioid dependence: a 9‐month follow‐up to a 3‐month randomized trial 下载免费PDF全文
147.
Ronald L. Alkana Deborah A. Finn Brenda L. Jones Leigh S. Kobayashi Mario Babbini Marina Bejanian Peter J. Syapin 《Alcoholism, clinical and experimental research》1992,16(1):17-22
Hyperbaric exposure antagonizes ethanol's behavioral effects in a wide variety of species. Recent studies indicating that there are genetically determined differences in the effects of body temperature manipulation on ethanol sensitivity suggested that genotype might also influence the effects of hyperbaric exposure on ethanol intoxication. To investigate this possibility, ethanol injected long sleep (LS)/Ibg (2.7 g/kg), short sleep (SS)/Ibg (4.8 g/kg), 129/J (2.9 g/kg), and C57BL/6J (3.6 g/kg) mice were exposed to one atmosphere absolute (ATA) air or to one or 12 ATA helium-oxygen (heliox) at ambient temperatures selected to offset ethanol and helium-induced hypothermia. Hyperbaric exposure significantly reduced loss of righting reflex (LORR) duration in LS, 129, and C57 mice, but not in SS mice. A second experiment found that hyperbaric exposure significantly reduced LORR duration and increased the blood ethanol concentration (BEC) at return of righting reflex (RORR) in LS mice, but did not significantly affect either measure in SS mice. These results indicate that exposure to 12 ATA heliox antagonizes ethanol-induced LORR in LS, 129 and C57 mice, but not in SS mice. Taken with previous results, the present findings suggest that the antagonism in LS, 129, and C57 mice reflects a pressure-induced decrease in brain sensitivity to ethanol and that the lack of antagonism in SS mice cannot be explained by pressure-induced or genotypic differences in ethanol pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
148.
Udai P. Singh Narendra P. Singh Hongbing Guan Brandon Busbee Robert L. Price Dennis D. Taub Manoj K. Mishra Raja Fayad Mitzi Nagarkatti Prakash S. Nagarkatti 《Immunobiology》2013
Background
Although the etiology of two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are unknown and evidence suggests that chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens. Previous studies support the role for TGF-β1 through 3 in the initiation and maintenance of tolerance via the induction of regulatory T cells (Tregs) to control intestinal inflammation. Leptin, a satiety hormone produced primarily by adipose tissue, has been shown to increase during colitis progression and is believed to contribute to disease genesis and/or progression.Aim
We investigated the ability of a pegylated leptin antagonist (PG-MLA) to ameliorate the development of chronic experimental colitis.Results
Compared to vehicle control animals, PG-MLA treatment of mice resulted in an (1) attenuated clinical score; (2) reversed colitis-associated pathogenesis including a decrease in body weight; (3) reduced systemic and mucosal inflammatory cytokine expression; (4) increased insulin levels and (5) enhanced systemic and mucosal Tregs and CD39+ Tregs in mice with chronic colitis. The percentage of systemic and mucosal TGF-β1, -β2 and -β3 expressing CD4+ T cells were augmented after PG-MLA treatment. The activation of STAT1 and STAT3 and the expression of Smad7 were also reduced after PG-MLA treatment in the colitic mice. These findings clearly suggest that PG-MLA treatment reduces intestinal Smad7 expression, restores TGF-β1-3 signaling and reduces STAT1/STAT3 activation that may increase the number of Tregs to ameliorate chronic colitis.Conclusion
This study clearly links inflammation with the metabolic hormone leptin suggesting that nutritional status influences immune tolerance through the induction of functional Tregs. Inhibiting leptin activity through PG-MLA might provide a new and novel therapeutic strategy for the treatment of IBD. 相似文献149.
目的开发基于TNF功能表位的新型人源单链抗体。方法利用自主研制的鼠抗TNF-α中和单抗Z12能特异性识别TNF-α的141~146位功能表位特性,通过理论模拟构建TNF/抗体Z12相互作用的复合物模型设计获得功能性拮抗肽(PT2、PT3、PT4、PT7)以及单域抗体PTVH5(以人抗体可变区重链框架VH5为支架合理展示PT2、PT3、PT4),利用计算机辅助分子设计以及同源模建、分子对接方法,进一步合理选择人抗体可变区轻链框架(Vκ1)作为展示支架,通过构象判别、作用能比较以及识别区域确认并选择合适的连接肽设计新型单链分子ScFv_AB1。结果理论分析发现,ScFv_AB1稳定性较好,识别TNF-α的141~146功能位点(即Z12识别的位点)。生物学实验证明,ScFv_AB1能与TNF-α结合、抑制TNF-α与TNFR的结合、抑制TNF-α介导的细胞毒作用。结论初步验证了"借助计算机模建,基于人抗体可变区的框架结构和拮抗肽设计单链抗体分子"的策略是可行的,从而为人源小分子抗体的制备提供了一条可供选择的途径。 相似文献
150.
目的:研究高选择性内皮素受体A型拮抗剂安立生坦对肺动脉高压患者近期疗效和安全性的初步观察。方法回顾性分析2012.12-2013.08武汉亚洲心脏病医院肺高压中心特发性肺高压5例,结缔组织病相关性肺高压2例共7例患者,口服安立生坦5mg每日一次,连续服用24周。分别于安立生坦治疗前及治疗24周进行右心导管、心脏超声、患者WHO FC分级、6MWT及查静脉血测NT-proBNP及肝功能(丙氨酸转氨酶,ALT)。结果安立生坦治疗24周时,右心导管检查全肺阻力由(1899±753)dyn.s-1.cm-5降为(1005±642)dyn.s-1. cm-5(p=0.03)。超声心动图测得右室EF值由934±7)%增为(41±8)%(P=0.043)。治疗前WHO FC Ⅲ-IV级患者为5例,治疗后为1例,较前减少(p=0.03)。6MWT由(419±26)m增加为(508±28)m(P=0.001)。NT-proBNP由(235±164)ng/L下降至(147±129)ng/L(P=0.014)。24周内7例患者无死亡及病情恶化,无患者出现转氨酶异常。结论安立生坦可明显降低肺血管阻力,改善患者心功能,提高运动耐量,降低NT-proBNP水平,且对右室EF值有改善,并且安全性,耐受性良好。 相似文献