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61.
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Hend Kothayer Samy M. Ibrahim Moustafa K. Soltan Samar Rezq Shireen S. Mahmoud 《Drug development research》2019,80(3):343-352
In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED50) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED50 values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABAA binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.
相似文献
Hit, Lead & Candidate Discovery |
64.
Jennifer Wang Jonathan G. Stine Scott L. Cornella Curtis K. Argo Steven M. Cohn 《临床与转化肝病杂志(英文版)》2015,3(4):254-259
Background and Aims: Gastric antral vascular ectasia (GAVE) is commonly found in patients with cirrhosis, but it is also associated with other diseases in the absence of cirrhosis. Whether GAVE confers a different severity of gastrointestinal (GI) bleeding between patients with and without cirrhosis remains unknown. We aim to examine whether there is a difference in clinically significant GI bleeding due to GAVE in patients with or without cirrhosis. Methods: This is a retrospective case-control study of patients who were diagnosed with GAVE between January 2000 and June 2014. Patients were categorized into cirrhosis and noncirrhosis groups, and those with an additional GI bleeding source were excluded. Univariate comparisons and multivariable models were constructed using logistic regression. Results: In total, 110 patients diagnosed with GAVE on esophagogastroduodenoscopy (EGD) were included in our analysis; 84 patients had cirrhosis (76.4%) and 26 (23.6%) did not. Active GI bleeding was more prevalent in patients without cirrhosis (63.4% vs. 32.1%, p=0.003) despite similar indications for EGD, and endoscopic treatment with argon plasma coagulation (APC) was required more often in this group, approaching statistical significance (27% vs. 10.7%, p=0.056). There was no difference in bleeding severity, as evidenced by similar re-bleeding rates, surgery, or death attributed to uncontrolled bleeding. The strongest independent risk factor for GI bleeding was the absence of cirrhosis (odds ratio (OR): 5.151 (95% confidence interval (CI): 1.08-24.48, p=0.039). Conclusions: Patients with GAVE in the absence of cirrhosis are at higher risk for active GI bleeding and require more frequent endoscopic treatment than similar patients with cirrhosis. It may be worthwhile to treat GAVE in this population even in the absence of active bleeding. 相似文献
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Interaction effects between the 5‐hydroxy tryptamine transporter‐linked polymorphic region (5‐HTTLPR) genotype and family conflict on adolescent alcohol use and misuse 下载免费PDF全文
67.
Hanna Lee Mary K. Tan Andrew T. Yan Paul Angaran Paul Dorian Claudia Bucci Jean C. Gregoire Alan D. Bell Martin S. Green Peter L. Gross Allan Skanes Charles R. Kerr L. Brent Mitchell Jafna L. Cox Vidal Essebag Brett Heilbron Krishnan Ramanathan Carl Fournier Shaun G. Goodman 《The Canadian journal of cardiology》2019,35(2):160-168
Background
Physicians treating nonvalvular atrial fibrillation (AF) assess stroke and bleeding risks when deciding on anticoagulation. The agreement between empirical and physician-estimated risks is unclear. Furthermore, the association between patient and physician sex and anticoagulation decision-making is uncertain.Methods
We pooled data from 2 national primary care physician chart audit databases of patients with AF (Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation and Coordinated National Network to Engage Physicians in the Care and Treatment of Patients with Atrial Fibrillation Chart Audit) with a combined 1035 physicians (133 female, 902 male) and 10,927 patients (4567 female and 6360 male).Results
Male physicians underestimated stroke risk in female patients and overestimated risk in male patients. Female physicians estimated stroke risk well in female patients but underestimated the risk in male patients. Risk of bleeding was underestimated in all. Despite differences in risk assessment by physician and patient sex, > 90% of patients received anticoagulation across all subgroups. There was modest agreement between physician estimated and calculated (ie, CHADS2 score) stroke risk: Kappa scores were 0.41 (0.35-0.47) for female physicians and 0.34 (0.32-0.36) for male physicians.Conclusions
Our study is the first to examine the association between patient and physician sex influences and stroke and bleeding risk estimation in AF. Although there were differences in agreement between physician estimated stroke risk and calculated CHADS2 scores, these differences were small and unlikely to affect clinical practice; further, despite any perceived differences in the accuracy of risk assessment by sex, most patients received anticoagulation. 相似文献68.
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C. Lukannek S. Shaefi K. Platzbecker D. Raub P. Santer S. Nabel H.S. Lecamwasam T.T. Houle M. Eikermann 《Anaesthesia》2019,74(9):1165-1174
Postoperative pulmonary complications are associated with an increase in mortality, morbidity and healthcare utilisation. The Agency for Healthcare Research and Quality recommends risk assessment for postoperative respiratory complications in patients undergoing surgery. In this hospital registry study of adult patients undergoing non-cardiac surgery between 2005 and 2017 at two independent healthcare networks, a prediction instrument for early postoperative tracheal re-intubation was developed and externally validated. This was based on the development of the Score for Prediction Of Postoperative Respiratory Complications. For predictor selection, stepwise backward logistic regression and bootstrap resampling were applied. Development and validation cohorts were represented by 90,893 patients at Partners Healthcare and 67,046 patients at Beth Israel Deaconess Medical Center, of whom 699 (0.8%) and 587 (0.9%) patients, respectively, had their tracheas re-intubated. In addition to five pre-operative predictors identified in the Score for Prediction Of Postoperative Respiratory Complications, the final model included seven additional intra-operative predictors: early post-tracheal intubation desaturation; prolonged duration of surgery; high fraction of inspired oxygen; high vasopressor dose; blood transfusion; the absence of volatile anaesthetic use; and the absence of lung-protective ventilation. The area under the receiver operating characteristic curve for the new score was significantly greater than that of the original Score for Prediction Of Postoperative Respiratory Complications (0.84 [95%CI 0.82–0.85] vs. 0.76 [95%CI 0.75–0.78], respectively; p < 0.001). This may allow clinicians to develop and implement strategies to decrease the risk of early postoperative tracheal re-intubation. 相似文献