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51.
Raddatz R Hudkins RL Mathiasen JR Gruner JA Flood DG Aimone LD Le S Schaffhauser H Duzic E Gasior M Bozyczko-Coyne D Marino MJ Ator MA Bacon ER Mallamo JP Williams M 《The Journal of pharmacology and experimental therapeutics》2012,340(1):124-133
CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H? receptor (H?R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H?R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H?R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [3?S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H?R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC?? = 0.1 ± 0.003 mg/kg), and antagonism of the H?R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED?? = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H?R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics. 相似文献
52.
Brigitte Lesur Yin G. Lin Val R. Marcy Lisa D. Aimone John Gruner Edward R. Bacon Sankar Chatterjee 《Chemical biology & drug design》2013,81(3):429-432
In search of a next generation molecule to the novel wake‐promoting agent modafinil, a series of aryl‐heteroayl‐derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually. 相似文献
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Cheng M Quail MR Gingrich DE Ott GR Lu L Wan W Albom MS Angeles TS Aimone LD Cristofani F Machiorlatti R Abele C Ator MA Dorsey BD Inghirami G Ruggeri BA 《Molecular cancer therapeutics》2012,11(3):670-679
Anaplastic lymphoma kinase (ALK) is constitutively activated in a number of human cancer types due to chromosomal translocations, point mutations, and gene amplification and has emerged as an excellent molecular target for cancer therapy. Here we report the identification and preclinical characterization of CEP-28122, a highly potent and selective orally active ALK inhibitor. CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. It induced concentration-dependent growth inhibition/cytotoxicity of ALK-positive anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cells, and displayed dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice, with substantial target inhibition (>90%) for more than 12 hours following single oral dosing at 30 mg/kg. Dose-dependent antitumor activity was observed in ALK-positive ALCL, NSCLC, and neuroblastoma tumor xenografts in mice administered CEP-28122 orally, with complete/near complete tumor regressions observed following treatment at doses of 30 mg/kg twice daily or higher. Treatment of mice bearing Sup-M2 tumor xenografts for 4 weeks and primary human ALCL tumor grafts for 2 weeks at 55 or 100 mg/kg twice daily led to sustained tumor regression in all mice, with no tumor reemergence for more than 60 days postcessation of treatment. Conversely, CEP-28122 displayed marginal antitumor activity against ALK-negative human tumor xenografts under the same dosing regimens. Administration of CEP-28122 was well tolerated in mice and rats. In summary, CEP-28122 is a highly potent and selective orally active ALK inhibitor with a favorable pharmaceutical and pharmacokinetic profile and robust and selective pharmacologic efficacy against ALK-positive human cancer cells and tumor xenograft models in mice. 相似文献
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Stefano Olmi Stefano Magnone Luigi Erba Aimone Bertolini Enrico Croce 《JSLS, Journal of the Society of Laparoendoscopic Surgeons》2005,9(2):189-195
BACKGROUND: Incisional hernia is a frequent complication of abdominal surgery. The object of this study was to confirm the safety, efficacy, and feasibility of laparoscopic treatment of abdominal wall defects. METHODS: Fifty consecutive laparoscopic abdominal and incisional hernia repairs from September 2001 to May 2003 were compared with 50 open anterior repairs. RESULTS: The 2 groups were not different for age, body mass index, or American Society of Anaesthesiologists scores. Mean operative time was 59 minutes for the laparoscopic group, 164.5 minutes for the open group. Mean hernia diameter was 10.6 cm for the laparoscopic group, 10.5 cm for the open group. Mean length of stay was 2.1 days for the laparoscopic group, 8.1 days for the open group. Complications occurred in 16% of the laparoscopic and 50% of open group. Median follow-up was 9.0 months for the laparoscopic group, 24.5 months for the open group. Recurrence rates were 2% for laparoscopic group and 0% for the open group. CONCLUSION: Results for laparoscopic abdominal and incisional hernia repair seem to be superior to results for open repair in terms of operative time, length of stay, wound infection, major complications, and overall hospital reimbursement. 相似文献
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In this issue, Alme and colleagues propose a novel hypothesis that young adult‐born neurons represent the functional population of the dentate gyrus, and that old granule cells “retire” from relevance. Here, we present several implications of this interesting theory for the function of both neurogenesis and the dentate gyrus. © 2010 Wiley‐Liss, Inc. 相似文献
59.
The dentate gyrus in the hippocampus is one of two brain regions with lifelong neurogenesis in mammals. Despite an increasing amount of information about the characteristics of the newborn granule cells, the specific contribution of their robust generation to memory formation by the hippocampus remains unclear. We describe here a possible role that this population of young granule cells may have in the formation of temporal associations in memory. Neurogenesis is a continuous process; the newborn population is only composed of the same cells for a short period of time. As time passes, the young neurons mature or die and others are born, gradually changing the identity of this young population. We discuss the possibility that one cognitive impact of this gradually changing population on hippocampal memory formation is the formation of the temporal clusters of long-term episodic memories seen in some human psychological studies. 相似文献
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