Medicinal nicotine in COVID-19 acute respiratory distress syndrome,the new corticosteroid

The cholinergic anti-inflammatory pathway (CAP) refers to the anti-inflammatory effects mediated by the parasympathetic nervous system. Existence of this pathway was first demonstrated when acetylcholinesterase inhibitors showed benefits in animal models of sepsis. CAP functions via the vagus nerve. The systemic anti-inflammatory effects of CAP converges on the α7 nicotinic acetylcholine receptor on splenic macrophages, leading to suppression of pro-inflammatory cytokines and simultaneous stimulation of anti-inflammatory cytokines, including interleukin 10. CAP offers a novel mechanism to mitigate inflammation. Electrical vagal nerve stimulation has shown benefits in patients suffering from rheumatoid arthritis. Direct agonists like nicotine and GTS-1 have also demonstrated anti-inflammatory properties in models of sepsis and acute respiratory distress syndrome, as have acetylcholinesterase inhibitors like Galantamine and Physostigmine. Experience with coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome indicates that immunomodulators have a protective role in patient outcomes. Dexamethasone is the only medication currently in use that has shown to improve clinical outcomes. This is likely due to the suppression of what is referred to as a cytokine storm, which is implicated in the lethality of viral pneumonia. Nicotine transdermal patch activates CAP and harvests its anti-inflammatory potential by means of an easily administered depot delivery mechanism. It could prove to be a promising, safe and inexpensive additional tool in the currently limited armamentarium at our disposal for management of COVID-19 induced acute hypoxic respiratory failure.     

Institutional one health and animal-human health connections in Nthongoni,Eastern Kenya

In recent years, there has been increased global advocacy for the use of a collaborative, multisectoral, and transdisciplinary approach: a One Health approach, with the goal to achieve optimal health outcomes for people, animals and their shared environment. This study explored One Health implementation and practice in Kenya. Further, I used a case study of Nthongoni, a remote rural area in Eastern Kenya, to help us to understand and think about implementation of One Health in an area where mainstream biomedical system runs parallel to or is in conflict with, a deeply entrenched indigenous health system. I used a qualitative research approach including participant observation, and key informant and general respondents' in-depth interviews. Data was transcribed verbatim, translated, checked for consistency and coded for content and thematic analysis. The findings indicate that although Kenya's One Health approach was hailed as a key strategy and a model for other countries in the region, the approach faced significant challenges including insufficient funding, competing priorities and concerns over its sustainability. But while the formal One Health is embroiled in structural and politico-economic influences that curtail its operationalization and success, this study illuminates a lay one health that is part of lived realities in Nthongoni, inviting us to reflect on the place for and status of traditional healers, and meaning of health for people and animals. The study further provokes our thoughts over whether One Health should integrate or do away with traditional health systems, or be abandoned altogether. I argue that incorporating traditional health knowledge and practitioners in One Health might help to make health care more robust and culturally responsive. The work contributes to debates on anthropology of health in general and to anthropological understanding of both the lay one health and the institutional One Health agenda.     

Mechanism of action of Orthosiphon stamineus against non-alcoholic fatty liver disease: Insights from systems pharmacology and molecular docking approaches

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of a metabolic syndrome caused by excessive accumulation of fat in the liver. Orthosiphon stamineus also known as Orthosiphon aristatus is a medicinal plant with possible potential beneficial effects on various metabolic disorders. This study aims to investigate the in vitro inhibitory effects of O. stamineus on hepatic fat accumulation and to further use the computational systems pharmacology approach to identify the pharmacokinetic properties of the bioactive compounds of O. stamineus and to predict their molecular mechanisms against NAFLD. Methods: The effects of an ethanolic extract of O. stamineus leaves on cytotoxicity, fat accumulation and antioxidant activity were assessed using HepG2 cells. The bioactive compounds of O. stamineus were identified using LC/MS and two bioinformatics databases, namely the Traditional Chinese Medicine Integrated Database (TCMID) and the Bioinformatics Analysis Tool for the Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Pathway enrichment analysis was performed on the predicted targets of the bioactive compounds to provide a systematic overview of the molecular mechanism of action, while molecular docking was used to validate the predicted targets. Results: A total of 27 bioactive compounds corresponding to 50 potential NAFLD-related targets were identified. O. stamineus exerts its anti-NAFLD effects by modulating a variety of cellular processes, including oxidative stress, mitochondrial β-oxidation, inflammatory signalling pathways, insulin signalling, and fatty acid homeostasis pathways. O. stamineus is significantly targeting many oxidative stress regulators, including JNK, mammalian target of rapamycin (mTOR), NFKB1, PPAR, and AKT1. Molecular docking analysis confirmed the expected high affinity for the potential targets, while the in vitro assay indicates the ability of O. stamineus to inhibit hepatic fat accumulation. Conclusion: Using the computational systems pharmacology approach, the potentially beneficial effect of O. stamineus in NAFLD was indicated through the combination of multiple compounds, multiple targets, and multicellular components.     

Development and validation of standardized severity rating scale to assess the consistency of drug-drug interaction severity among various drug information resources

BackgroundThe consistency in reporting the severity of drug interactions across the drug information resources is important in guiding the appropriate clinical use of drug-pairs, to minimize the associated adverse events. This necessitates the need of a standardized severity rating scale, that can accommodate the different severity ratings of the same interacting drug-pair into a reasonable severity category, that can ease the consistency assessment among different drug information resources.ObjectiveTo develop and validate a standardized severity rating scale that can ease the consistency assessment among the various drug information resources.MethodsThe definitions of various severity rating categories as documented in the eight drug information resources was consolidated to develop a standardized severity rating scale. Thus developed rating scale was validated using twenty commonly used drug-pairs. Fleiss' kappa score was used as an indicator for assessing overall consistency among various drug information resources, whereas, Cohen's kappa was used as an indicator of level of consistency between two drug information resources and between individual drug information resource and newly developed standardized severity rating scale.ResultsThe newly developed standardized severity rating scale classifies the severity of drug-drug interactions into three categories namely mild, moderate and major. The Fleiss' kappa score was improved from 0.047 to 0.176, indicating improved strength of agreement [Average pairwise agreement: 16% Vs 36.7%] among various drug information resources. The average pairwise Cohen's kappa was 0.082 [Strength of agreement: poor] in original severity ratings whereas it was improved to 0.198 [Strength of agreement: almost equal to fair] in standardized severity rating scale.ConclusionThe newly developed standardized severity rating scale can be used as a tool to assess the consistency of severity rating categories among the various drug information resources.     

基于高通量测序技术研究药食两用薏苡仁中污染真菌多样性

目的:调查药食两用薏苡仁中污染真菌多样性,为其安全使用提供参考依据。方法:收集薏苡仁样品18批,提取真菌DNA并扩增ITS2序列,基于Illumina MiSeq PE250平台进行高通量测序。结果:共检测到4门18纲44目99科149属的真菌,子囊菌门Ascomycota是最优势菌门,镰刀菌属Fusarium(3.05%~60.32%)是属水平最优势属,其次是曲霉属Aspergillus(2.20%~45.44%)、白僵菌属Beauveria(0.07%~63.21%)、链格孢属Alternaria(0.80%~11.92%)、Arachnomyces(0.03%~39.36%)和青霉属Penicillium(0.24%~8.03%)。此外,共检测到5种潜在产毒真菌,分别是烟曲霉A.fumigatus、土曲霉A.terreus、梨孢镰刀菌F.poae、囊状青霉P.capsulatum和展青霉P.paxilli。结论:高通量测序技术可以快速有效地检测薏苡仁中污染真菌种类,为薏苡仁污染真菌毒素提供风险预警。     

Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters

Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CL_h) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CL_h involving OATP1B-mediated hepatic uptake. CL_h can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CL_h and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction.     

Piperazine derivatives with central pharmacological activity used as therapeutic tools

Medicinal chemistry is a science applied to the search and discovery of new therapeutic agents for the treatment of various diseases. Therefore, promising structures have been identified; one of these structures is the piperazine moiety, a cyclic molecule containing two nitrogen atoms in positions 1 and 4 as well as four carbon atoms. Many piperazine derivatives have central pharmacological activity that mainly involves the activation of the monoamine pathway. Thus, piperazine derivatives have been the subject of research for many central therapeutic applications, including antipsychotic, antidepressant and anxiolytic applications. Benzylpiperazine is the prototype of piperazine derivatives; this substance is the main component of recreational drugs, partly due to its stimulant and euphoric effects. This paper describes some piperazine derivatives used therapeutically as antipsychotic (clozapine), antidepressant (vortioxetine) and anxiolytic (buspirone) drugs.