Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates

Introduction: There is great potential in the synthetic development of rufinamide to treat childhood-onset epilepsy known as Lennox–Gastaut syndrome (LGS).

Areas covered: 1,4-disubstituted triazole ring formed by 1,3-dipolar cycloaddition reaction is an important structural motif widely used to construct diverse chemotypes in chemical, biological, and material fields. 1,2,3-triazole ring containing rufinamide, an antiepileptic drug developed by Novartis, is useful in combination with other antiepileptic medicaments for the treatment of childhood-onset epilepsy known as LGS. There are numerous synthetic methods used to construct the rufinamide through 1,3-dipolar cycloaddition. The application claims processes for the preparation of rufinamide and their intermediates. The synthetic strategy covered for the synthesis of rufinamide using activated acetylenic esters. The activation is done using N-hydroxy succinimide, N-hydroxyphthalimide, 1-hydroxy benzotriazole, and 4-nitro phenol.

Expert opinion: The manufacturing route appears to follow the regioselective Cu catalyzed cycloaddtion of 2,6-difluro benzyl azide with or without isolated activated acetylenic esters in three steps that provide a good lead for new synthetic strategy for the rufinamide synthesis.     

Maternal reproductive performance and fetal development of the Wistar Audiogenic Rat (WAR) strain

Wistar Audiogenic Rat (WAR) strain is an animal model for epilepsy studies, the chronic multifactorial disease that affects millions of people worldwide. The animals of this strain are genetically predisposed to sound-induced seizures, called audiogenic seizures, and have been used for many years in studies to understand the mechanisms involved in the epilepsies and their neuropsychiatric comorbidities, as well as the screening of potential anti-convulsant agents. Nevertheless, little is known about the reproductive characteristics of these animals. The main goal of this study was to characterize the female reproductive performance and the fetal growth of WARs in comparison to the Wistar rats, obtaining important information for physiology and behavioral studies, as well as for the preservation of the strain. The results indicated few differences between WAR and Wistar regarding the female reproductive performance. There was no significant difference in the number of pregnant females by mating, number of live births per female, number of cells per blastocyst, and several characteristics related to reproductive performance, such as pre- and post-implantation losses. However, significant differences were observed in birth weight and weight gain until weaning, with WAR animals presenting a body weight below Wistar at birth and reduced body weight gain during the lactation period. In addition, the WAR females showed lower body weight on the day 20 of pregnancy and a larger number of corpora lutea, when compared with those of Wistar animals. Thus, we conclude that although Wistar and WAR strains have few differences in their reproductive performance, which might impact future physiological life challenges or others experimentally induced procedures, it still is a very viable strain regarding reproduction.

Abbreviations: CONCEA: National Council for the Control of Animal Experimentation; GEPR: genetically epilepsy-prone rats; WAR: Wistar Audiogenic Rat.     

术前中性粒细胞与淋巴细胞比值在临床评估急性胆管炎伴胆总管结石患者病情中的价值

目的探讨术前中性粒细胞与淋巴细胞比值(NLR)对急性胆管炎伴胆总管结石患者手术预后评估的临床意义。 方法选取江苏大学附属武进人民医院普外科2016年1月至2019年6月收治的急性胆管炎伴胆总管结石行手术治疗的患者60例为研究对象进行回顾性研究，其中男性27例，女性33例；年龄46～88岁，平均(67.93±11.46)岁。术前NLR <5.435患者作为低NLR组(31例)，NLR≥5.435患者作为高NLR组(29例)。比较两组患者术前白细胞计数、C反应蛋白、谷草转氨酶、谷氨酰转肽酶水平；同时分析两组住院总天数、术后住院天数、住院总费用等。 结果低NLR组白细胞计数低于高NLR组[(6.28±1.66)×10⁹/L比(10.59±3.55)×10⁹/L，P<0.05 ]；低NLR组C反应蛋白水平低于高NLR组[(57.63±47.68)ug/mL比(81.38±38.25)ug/mL，P<0.05 ]；低NLR组谷草转氨酶水平低于高NRL组[(96.17±71.25)U/L比(281.90±438.30)U/L，P<0.05]；低NLR组谷氨酰转肽酶水平均低于高NLR组[(297.57±255.97)U/L比(509.70±462.06)U/L，P<0.05]，差异有统计学意义(P<0. 05)。低NLR组住院总天数[(13.34±4.55)d比(15.49±3.94)d，P<0.05]、术后住院天数[(10.07±2.80)d比(11.6±3.41)d，P<0.05]及住院总费用[(26 984.78±4 316.30)元比(30 875.35＝±4 305.50)元，P<0.05]等均低于高NLR组，差异有统计学意义(P<0. 05)。 结论急性胆管炎伴胆管结石患者外周血NLR值与其炎症感染程度呈正相关，临床上可将NLR作为对其病情及手术预后进行评估的指标。     

Resolving a 150-year-old paternity case in Mormon history using DTC autosomal DNA testing of distant relatives

Although autosomal DNA testing has been available for a number of years, its use to reconstruct genetic profiles of people that lived centuries in the past is relatively recent and there are no published cases where it was employed to verify a kinship relation, likely to be an alleged paternity, that occurred one and a half century ago.DNA testing has already been employed to study the ancestry and posterity of Joseph Smith Jr., founder of the Latter-day Saint (Mormon) movement. Thanks to information found on the paternally inherited Y chromosome, a number of alleged paternities have been disproved, but obviously this analysis is not effective for alleged daughters. Likewise, his reconstructed mitogenome sequence, reported here for the first time, provides information about his maternal ancestry, but is useless in any paternity questions due to the strict maternal inheritance. Among all the children attributed to Joseph Smith Jr., Josephine Lyon, born in 1844, is perhaps the most frequently mentioned.In the current study, 56 individuals, mostly direct descendants of Joseph Smith Jr. and Josephine Lyon, had their autosomal DNA tested to verify Josephine’s biological paternity. Nearly 600,000 autosomal SNPs from each subject were typed and detailed genealogical data were compiled. The absence of shared DNA between Josephine’s grandson and Joseph Smith Jr.’s five great-grandchildren together with various amounts of autosomal DNA shared by the same individual with four other relatives of Windsor Lyon is a clear indication that Josephine was not related to the Smith, but to the Lyon’s family. These inferences were also verified using kinship analyses and likelihood ratio calculations.     

A population of descending tyraminergic/octopaminergic projection neurons of the insect deutocerebrum

In this study, we describe a cluster of tyraminergic/octopaminergic neurons in the lateral dorsal deutocerebrum of desert locusts (Schistocerca gregaria) with descending axons to the abdominal ganglia. In the locust, these neurons synthesize octopamine from tyramine stress-dependently. Electrophysiological recordings in locusts reveal that they respond to mechanosensory touch stimuli delivered to various parts of the body including the antennae. A similar cluster of tyraminergic/octopaminergic neurons was also identified in the American cockroach (Periplaneta americana) and the pink winged stick insect (Sipyloidea sipylus). It is suggested that these neurons release octopamine in the ventral nerve cord ganglia and, most likely, convey information on arousal and/or stressful stimuli to neuronal circuits thus contributing to the many actions of octopamine in the central nervous system.     

Epidermal growth factor receptor (EGFR)-targeted therapies in mesothelioma

Introduction: Malignant mesothelioma (MM) is an aggressive malignancy arising from the mesothelial cells lining the pleura and other serosal membranes. It is associated with an extremely poor prognosis and has limited therapeutic options.

Areas covered: Epidermal growth factor receptor (EGFR) is known to be highly overexpressed in mesothelioma with reported EGFR overexpression between 44 to 97%. Given this, several anti-EGFR agents have been trialed in mesothelioma. In this review, we provide an overview of the current available data on anti-EGFR therapies in MM and future directions of investigation with these targeted agents in MM.

Expert opinion: While many anti-EGFR therapies have failed to show significant efficacy in the management of MM, the pathway is biologically active and its abrogation preclinically points toward it being a valid target. Toward targeting the pathway, many novel EGFR-based therapies are still being investigated. Current ongoing research of interest in MM include EGFR-targeted nanotechnology approach for drug delivery, antibodies targeting the extracellular EGFR and potentially anti-EGFR antibody drug conjugates.     

Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2

BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.     

民族医药移动信息平台设计与实现

以广西中医药大学已建成的民族医药专业数据库作为依托，基于微信公众平台设计和实现一个功能完善、简单易用的民族医药移动信息平台。介绍平台设计思路、设计原则、功能模块、关键技术、预期结果等方面。