Metabolism and pharmacokinetics studies of allyl methyl disulfide in rats

1. Allyl methyl disulfide (AMDS) is one of the main compounds in garlic, whereas its metabolism has not been studied yet.

2. In this work, we first identified the metabolites of AMDS in rat erythrocytes and rats using GC–MS. The transformation mechanism study among different metabolites was then conducted. The apparent kinetics of AMDS in rat erythrocytes and pharmacokinetics of AMDS by oral administration in rats were also studied.

3. The metabolic pathway study showed that AMDS was mainly metabolized in rats to allyl methyl sulfoxide (AMSO) and allyl methyl sulfone (AMSO₂) through mechanisms of reduction, methylation and oxidation. The transformation mechanism study indicated that AMDS was firstly reduced to allyl mercaptan (AM) in rat erythrocytes, and then methylated to allyl methyl sulfide (AMS) by S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), and finally oxidized to AMSO and AMSO₂ by liver microsomes. The half-life of AMDS in rat erythrocytes was 6.285?±?0.014?min while the half-lives of its active metabolites AMSO and AMSO₂ in vivo were 18.17 and 17.50?h, respectively. Also, the large AUCs of the two active metabolites were observed, indicating potential applications of AMDS for certain pharmacological effects.     

探讨太阳伤寒证是新型冠状病毒(2019-nCoV)肺炎的初始阶段—微汗解表严防疫毒内陷

在防控新型冠状病毒(2019-nCoV)肺炎的过程中,中医药可以发挥更大的作用。以生命定义核心,结合维持人体能量代谢过程和干细胞分裂过程五个基本因素就能构建人体内新型代谢模型。这个模型中,水液和热能的排泄是人体内代谢过程的最后步骤,也是太阳经的生理学基础。太阳经受到寒气后可以出现以热能排泄障碍为主的临床表现如发热,也可以出现以水液潴留为主要临床表现,如水肿等。根据新型冠状病毒(2019-nCoV)在感染人体后早期出现的上呼吸道症状和发热等辨证为太阳伤寒经证,出现肺部感染后辨证为太阳脏证。太阳经证治疗以温经散寒为主,而太阳脏证则需要采用急下、峻下及清热开窍为主的治法。太阳表证、经证未解,忌用寒凉药物和食物,这样才能将防治关口前移,避免邪毒内陷而致病情加重。     

真武汤加味联合常规西医疗法治疗Ⅰ型心肾综合征心肾阳虚兼水饮内停证临床研究

目的:观察真武汤加味联合常规西医疗法治疗Ⅰ型心肾综合征(CRS)心肾阳虚兼水饮内停证的临床疗效。方法:将80例Ⅰ型CRS心肾阳虚兼水饮内停证患者随机分为对照组和观察组各40例,对照组给予利尿剂、正性肌力药物、扩张血管药物、肾素-血管紧张素-醛固酮系统阻滞剂及连续性肾脏替代治疗(CRRT)等常规西医疗法治疗,观察组在对照组基础上服用真武汤加味,2组均连续治疗7 d。比较2组临床疗效,治疗前后心功能指标、肾功能指标,机械通气发生率及病死率。结果:观察组总有效率为87.5%,高于对照组的65.0%(P0.05)。治疗后,2组肌钙蛋白(TnI)、B型钠尿肽(BNP)、左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)与治疗前比较均降低,观察组TnI、BNP、LVEDD、LVESD低于对照组(P0.05);2组左室射血分数(LVEF)与治疗前比较均升高,观察组LVEF高于对照组(P0.05)。治疗后,2组尿素氮(BUN)、血肌酐(SCr)、血清胱抑素-C (Cys-C)与治疗前比较均降低,观察组SCr、BUN、Cys-C低于对照组(P0.05);2组24 h尿量与治疗前比较均升高,观察组24 h尿量高于对照组(P0.05)。治疗后,2组机械通气发生率、病死率比较,差异均无统计学意义(P0.05)。结论:真武汤加味联合常规西医疗法治疗Ⅰ型心肾综合征心肾阳虚兼水饮内停证,可明显改善患者心、肾功能,减轻临床症状,疗效确定。     

Acquired MET D1228N Mutations Mediate Crizotinib Resistance in Lung Adenocarcinoma with ROS1 Fusion: A Case Report

Patients with non‐small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1‐targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1‐fusion targeted therapy are acquired mutations in ROS1. Along with the use of next‐generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)‐TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74‐ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short‐term disease control for cabozantinib.Key Points

• The D1228N point mutation of MET is an acquired mutation for crizotinib resistance.
• The patient obtained short‐term clinical benefit from cabozantinib therapy after resistance to crizotinib.
• The clinical use of next‐generation sequencing could maximize the benefits of precision medicine in patients with cancer.

     

基于NF-κB信号通路探讨中医药治疗脓毒症的研究进展

脓毒症（sepsis）是重症医学科常见的急危重症，具有高发病率和高病死率的特点。目前，临床上针对脓毒症的治疗用药多以西药为主，长期使用存在抗生素耐药、激素不良反应和费用高昂等问题。因此，探寻新型、高效、安全、廉价的药物和治疗模式是现阶段研究的重点方向。中医药凭借其“整体观念、辨证论治、一人一方”的独特优势，在脓毒症的预防和治疗中积累了相当丰富的临床经验。近年来，中医药与脓毒症核转录因子-κB（NF-κB）信号通路的研究较多。该文通过筛选相关临床研究与文献，从脓毒症的病因病机，辨证论治，发病机制，NF-κB信号通路和中医药对脓毒症的干预等方面进行系统归纳整理，研究发现一些单味中药及其提取物、中药复方和中药注射液可以通过调控NF-κB信号通路的激活，调节巨噬细胞的免疫功能，有效抑制NF-κB介导的肿瘤坏死因子-α（TNF-α），白细胞介素-1（IL-1），IL-6等炎症因子及其蛋白的表达，显著减轻全身炎症反应和各脏器损伤，改善预后。但囿于客观条件的限制，部分研究也存在促炎-抗炎平衡机制模糊、药代动力学不明及药物安全性评价较低等问题，有待进一步研究与探索，以期为中医药治疗脓毒症提供新的理论基础和诊疗思路。