Quinoxaline and quinoxaline‐1,4‐di‐N‐oxides: An emerging class of antimycobacterials

Tuberculosis (TB) is a highly dreaded, infectious, chronic, airborne disease affecting more than two million people all around the world, with more than eight million cases every calendar year. TB is the second leading infectious cause of death after HIV/AIDS. Over the past few decades, numerous efforts have been undertaken to develop new anti‐TB agents. The current frontline therapy for TB consists of administering three or more different drugs (usually isoniazid, rifampin, pyrazinamide, and ethambutol) over an extended period of time. But these drugs will take 6–12 months to cure TB, along with many side effects; hence, there is an urgent need to explore new anti‐TB agents. Quinoxaline derivatives are a class of compounds that show a spectrum of biological properties and the interest in these compounds is exponentially growing within the field of medicinal chemistry. Quinoxaline‐1,4‐di‐N‐oxide derivatives have shown to improve the biological results and are endowed with anti‐viral, anti‐cancer, anti‐bacterial, and anti‐protozoal activities with application in many other therapeutic areas. Since quinoxaline derivatives are regarded as a new class of effective anti‐TB candidates, their 1,4‐di‐N‐oxide analogues may show promising in vitro and in vivo anti‐TB activities and might be able to prevent the drug resistance to a certain extent. Therefore, the main aim of this review is to focus on important quinoxaline and quinoxaline‐1,4‐di‐N‐oxide analogues that have shown anti‐TB activities, and their structure–activity relationships for designing anti‐TB agents with better efficacies. The present review will be helpful in providing insights for rational designs of more active and less toxic quinoxaline‐based anti‐TB prodrugs.

     

Non‐peptide‐based new class of platelet aggregation inhibitors: Design,synthesis, bioevaluation,SAR, and in silico studies

A series of 2‐oxo‐2‐phenylethylidene linked 2‐oxo‐benzo[1,4]oxazine analogues 17a–x and 18a–o , incorporated with a variety of electron‐withdrawing as well as electron‐donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a–x and 18a–o were evaluated for their arachidonic acid (AA)‐induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC₅₀ = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i , 17x , 18f , 18g , 18h , 18i , 18l , and 18o , were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T₃ fibroblast cell lines by MTT assay of the promising compounds ( 17i , 17x , 18f–18i , 18l , and 18o ) were also performed and the compounds were found to be non‐toxic in nature. Furthermore, the results on the AA‐induced platelet aggregation inhibitory activities of these compounds ( 17i , 17x , 18f–18i , 18l , and 18o ) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non‐peptide‐based functionalized 2‐oxo‐benzo[1,4]oxazines as platelet aggregation inhibitors.

     

Dosing of caspofungin based on a pharmacokinetic/pharmacodynamic index for the treatment of invasive fungal infections in critically ill patients on continuous venovenous haemodiafiltration

Introduction

The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration.

Design,synthesis and antitumor activity evaluation of novel 2,6-dichloro-3,5-dinitrotoluene derivatives

A series of novel 2,6-dichloro-3,5-dinitrotoluene derivatives were designed, synthesized in the present study, and their antitumor activities against five cell lines (A431, HepG2, A549, HT-29 and HEK-293) were tested. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines in comparison with cisplatin. Studies on their preliminary structure-activity relationships (SARs) indicated that compounds containing phenyl (piperazin-1-yl) methanone groups, especially chlorine atom at 4-position of the phenyl ring, were more effective. Compound 4g was found to be the most potent derivative with IC₅₀ values of 1.04, 3.20, 6.93, 4.10 and 20.15 μmol/L against A431, Hep G2, A549, HT-29 and HEK-293 cell lines, respectively, which was better than positive control cisplatin, one of the most clinically used chemotherapeutic drugs.     

“加州女儿”综合征——一个被忽视的医患纠纷原因

已有诸多研究者试图从不同角度阐述医患关系紧张的原因和解决方法,但医患关系紧张情况一直没有得到有效地缓解。对医患关系的深层探索和分析可为有效地解决医患关系紧张问题提供精准可靠的策略和方法,其中"加州女儿综合征"现象作为导致部分医患矛盾案例发生的深层原因应引起重视。对"加州女儿综合征"这一现象背后原因及相关应对方法的深入探索,将有助于医护人员避免和应对此类医患纠纷的发生。     

A comprehensive review on Brigatinib – A wonder drug for targeted cancer therapy in non-small cell lung cancer

The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using N-[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90?mg of brigatinib for 7?days and then 180?mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need.     

对中国药典2015年版硫酸庆大霉素原料及其注射液标准中存在问题的探讨

中国药典2015年版中对硫酸庆大霉素原料和注射液标准进行了修订,其中在有关物质检查项下二者的限度数值相同。但由于原料和注射液中硫酸庆大霉素有关物质含量的含义和量纲(单位)不同,使得可能出现合格原料生产出不合格注射液的尴尬局面。本文从庆大霉素含量表征的特点入手,通过阐述原料和其制剂有关物质含量表述方式和量纲(单位)方面的差异,并以量效统一化研究为基础,讨论可以确保两标准限度间相互匹配的解决方案,从而为该品种的合理修订提供理论支撑。     

The relationship between smartphone addiction predisposition and impulsivity among Korean smartphone users

Background: The smartphone ownership rate has been growing steeply worldwide, and there are various adverse effects of smartphone overuse. Previous studies suggest that adolescents are vulnerable to addiction because they lack the ability to control impulsive behavior. However, only a few studies have investigated psychological factors related to smartphone addiction predisposition (SAP) among adolescents. This study compared the prevalence of SAP in adolescents and adults and investigated associations between impulsivity and SAP.

Methods: A total of 7003 participants answered the entire set of questionnaires. Participants completed self-report Korean questionnaires regarding demographic characteristics, level of SAP, and trait impulsivity. They were divided into three groups based on age: an adolescent group (14–18?years old), an early adulthood group (19–25?years old), and an adulthood group (over 26?years old). SAP was assessed with the Smartphone Addiction Proneness Scale (SAPS), and impulsivity was assessed with Dickman’s Impulsivity Inventory (DII).

Results: The level of SAP was significantly different between age groups, with the adolescent group having the highest percentage of SAP. Dysfunctional DII score was highest in the adolescent group, and there was a significant difference between the adolescent group and the other two age groups. Moreover, the higher the level of SAP, the greater the dysfunctional impulsivity score.

Conclusions: Result suggests that adolescents are vulnerable to SAP, which is similar to substance addiction and other types of behavioral addiction. In addition, impulsivity may be one of the factors contributing to this vulnerability, as it does to other addictions.