Next-generation Metabolomics in the Development of New Antidepressants: Using Albiflorin as an Example

2018 ◽  
Vol 24 (22) ◽  
pp. 2530-2540 ◽  
Author(s):  
Jian Han ◽  
Yonghong Xia ◽  
Lejun Lin ◽  
Zuoguang Zhang ◽  
Hui Tian ◽  
...  
Keyword(s):  
Safety Evaluation ◽  
The United States ◽  
Drug Candidate ◽  
Next Generation ◽  
Drug Induced ◽  
Analytical Instruments ◽  
Drug Safety Evaluation ◽  
Technical Advances ◽  
Botanical Medicine ◽  
New Generation

Depression is a highly prevalent disorder that affects more than 300 million adults worldwide in 2015. Depression also frequently coexists with many other conditions such as osteoporosis and one-third of the Intensive Care Unit (ICU) survivors had depressive symptoms. Antidepressants have become the most commonly prescribed drugs in the United States. In addition to the regular process, drug discovery and development (R&D) for depression presents extra challenges because of the heterogeneity of the symptoms and various co-occurring disorders. Botanical medicine with multi-functional nature has been proposed to be more effective, providing rapid control of core and comorbid conditions of depression. With the technical advances in analytical instruments, metabolomics is entering into a “new generation”. Next-generation metabolomics (NGM) has the capability to comprehensively characterize drug-induced metabolic changes in the biological systems. NGM has demonstrated great potential in all the stages of pharmaceutical R&D in the last 10 years. Albiflorin isolated from Peony roots is a promising drug candidate with multi-target for depression and is currently under development by Beijing Wonner Biotech. In this work, we summarized the common analytical platforms for NGM and its main applications in drug R&D. We used albiflorin as an example to illustrate how NGM improves our understanding of drug candidate actions and facilitates drug safety evaluation. Future directions on how to expand the use of NGM for new antidepressant development in pharmaceutical industry were also discussed.

scholarly journals Sex Differences in Drug-Induced Arrhythmogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Mathias Peirlinck ◽  
Francisco Sahli Costabal ◽  
Ellen Kuhl
Keyword(s):  
Sex Differences ◽  
Safety Evaluation ◽  
New Drugs ◽  
Specific Response ◽  
Drug Induced ◽  
Tissue Conductivity ◽  
Male And Female ◽  
Drug Safety Evaluation ◽  
Qt Intervals ◽  
Drug Concentrations

The electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.

scholarly journals How drugs modulate the performance of the human heart

2021 ◽  
Author(s):  
Mathias Peirlinck ◽  
Jiang Yao ◽  
Francisco Sahli Costabal ◽  
Ellen Kuhl
Keyword(s):  
Safety Evaluation ◽  
Heart Rhythm ◽  
Cardiac Cells ◽  
Drug Induced ◽  
Drug Safety Evaluation ◽  
Drug Concentrations ◽  
Heart Rhythm Disorders ◽  
Whole Heart ◽  
Tissue Relaxation ◽  
And Personalized Medicine

Many drugs interact with ion channels in the cells of the heart and trigger heart rhythm disorders with potentially fatal consequences. Computational modeling can provide mechanistic insight into the onset and propagation of drug-induced arrhythmias, but the effect of drugs on the mechanical behavior of the heart remains poorly understood. Here we establish a multiphysics framework that integrates the biochemical, electrical, and mechanical effects of drugs from single cardiac cells to the overall response of the whole heart. For the example of the drug dofetilide, we show that drug concentrations of 3.0x and 4.8x increase the heart rate to 122 and 114 beats per minute, increase the myofiber stretches up to 10%, and decrease tissue relaxation by 6%. Strikingly, the drug-induced interventricular and atrial-ventricular dyssynchrony results in a 2.5% decreased and 7% increased cardiac output, respectively. Our results demonstrate the potential for multiphysics, multiscale modeling towards understanding the mechanical implications of drug-induced arrhythmias. Knowing how differing drug concentrations affect the performance of the heart has important clinical implications in drug safety evaluation and personalized medicine.

THE NEW CURRICULUM STANDARDS FOR ASTRONOMY IN THE UNITED STATES

2015 ◽  
pp. 131-151
Author(s):  
Sharon P. Schleigh ◽  
Stephanie J. Slater ◽  
Timothy F. Slater ◽  
Debra J. Stork
Keyword(s):  
United States ◽  
The United States ◽  
Next Generation Science Standards ◽  
Next Generation ◽  
Curriculum Standards ◽  
Science Standards ◽  
New Curriculum

Há um grande interesse em restringir a ampla gama e vasto domínio dos possíveis temas que poderiam ser ensinados sobre astronomia em uma estrutura gerenciável. Embora não haja nenhum currículo nacional obrigatório nos Estados Unidos, uma análise dos três esforços nacionais recentes para criar uma sequência apropriada de conceitos de astronomia por idade para serem ensinados nas escolas primárias e secundárias revela uma considerável falta de consenso a respeito de quais conceitos são mais apropriados para cada idade e quais tópicos devem ser cobertos. O esquema de padronização mais recente para a educação científica dos EUA, o Next Generation Science Standards (Padrões em Ciência: Nova Geração), sugere que a maioria dos conceitos de astronomia devem ser ensinados apenas nos últimos anos de educação do aluno; e no entanto  foi recebido com críticas consideráveis. Uma comparação dos esquemas de aprendizagem da astronomia nos Estados Unidos e uma breve discussão das críticas levantadas podem proporcionar aos educadores de astronomia internacionais dados de comparação na formulação de recomendações em suas próprias regiões.

The Insidious Momentum of American Mass Incarceration

2020 ◽  
Author(s):  
Franklin E. Zimring
Keyword(s):  
United States ◽  
Public Policy ◽  
Twentieth Century ◽  
Mass Incarceration ◽  
The United States ◽  
Next Generation ◽  
Single Generation ◽  
American Life ◽  
Peak Rate ◽  
Or Practice

The phenomenal growth of penal confinement in the United States in the last quarter of the twentieth century is still a public policy mystery. Why did it happen when it happened? What explains the unprecedented magnitude of prison and jail expansion? Why are the current levels of penal confinement so very close to the all-time peak rate reached in 2007? What is the likely course of levels of penal confinement in the next generation of American life? Are there changes in government or policy that can avoid the prospect of mass incarceration as a chronic element of governance in the United States? This study is organized around four major concerns: What happened in the 33 years after 1973? Why did these extraordinary changes happen in that single generation? What is likely to happen to levels of penal confinement in the next three decades? What changes in law or practice might reduce this likely penal future?

scholarly journals The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer?

2011 ◽  
Vol 301 (3) ◽  
pp. G401-G424 ◽  
Author(s):  
M. Andrea Azcárate-Peril ◽  
Michael Sikes ◽  
José M. Bruno-Bárcena
Keyword(s):  
Colorectal Cancer ◽  
Intestinal Microbiota ◽  
Defense Mechanisms ◽  
High Throughput Sequencing ◽  
Safety Evaluation ◽  
Health Benefit ◽  
The United States ◽  
Dietary Factors ◽  
Colorectal Adenomas ◽  
Food Allergies

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and, even though 5–15% of the total CRC cases can be attributed to individual genetic predisposition, environmental factors could be considered major factors in susceptibility to CRC. Lifestyle factors increasing the risks of CRC include elevated body mass index, obesity, and reduced physical activity. Additionally, a number of dietary elements have been associated with higher or lower incidence of CRC. In this context, it has been suggested that diets high in fruit and low in meat might have a protective effect, reducing the incidence of colorectal adenomas by modulating the composition of the normal nonpathogenic commensal microbiota. In addition, it has been demonstrated that changes in abundance of taxonomic groups have a profound impact on the gastrointestinal physiology, and an increasing number of studies are proposing that the microbiota mediates the generation of dietary factors triggering colon cancer. High-throughput sequencing and molecular taxonomic technologies are rapidly filling the knowledge gaps left by conventional microbiology techniques to obtain a comprehensive catalog of the human intestinal microbiota and their associated metabolic repertoire. The information provided by these studies will be essential to identify agents capable of modulating the massive amount of gut bacteria in safe noninvasive manners to prevent CRC. Probiotics, defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” ( 219 ), are capable of transient modulation of the microbiota, and their beneficial effects include reinforcement of the natural defense mechanisms and protection against gastrointestinal disorders. Probiotics have been successfully used to manage infant diarrhea, food allergies, and inflammatory bowel disease; hence, the purpose of this review was to examine probiotic metabolic activities that may have an effect on the prevention of CRC by scavenging toxic compounds or preventing their generation in situ. Additionally, a brief consideration is given to safety evaluation and production methods in the context of probiotics efficacy.

scholarly journals Inflammatory responses of C57BL/6NKorl mice to dextran sulfate sodium-induced colitis: comparison between three C57BL/6 N sub-strains

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Sou Hyun Kim ◽  
Doyoung Kwon ◽  
Seung Won Son ◽  
Tae Bin Jeong ◽  
Seunghyun Lee ◽  
...  
Keyword(s):  
Animal Model ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Inflammatory Responses ◽  
Inbred Mouse ◽  
Clinical Signs ◽  
Safety Evaluation ◽  
Inbred Mouse Strain ◽  
Drug Safety Evaluation ◽  
Factor Α

Abstract Background Inflammatory bowel disease (IBD), including both Crohn’s disease and ulcerative colitis, are chronic human diseases that are challenging to cure and are often unable to be resolved. The inbred mouse strain C57BL/6 N has been used in investigations of IBD as an experimental animal model. The purpose of the current study was to compare the inflammatory responsiveness of C57BL/6NKorl mice, a sub-strain recently established by the National Institute of Food and Drug Safety Evaluation (NIFDS), with those of C57BL/6 N mice from two different sources using a dextran sulfate sodium (DSS)-induced colitis model. Results Male mice (8 weeks old) were administered DSS (0, 1, 2, or 3%) in drinking water for 7 days. DSS significantly decreased body weight and colon length and increased the colon weight-to-length ratio. Moreover, severe colitis-related clinical signs including diarrhea and rectal bleeding were observed beginning on day 4 in mice administered DSS at a concentration of 3%. DSS led to edema, epithelial layer disruption, inflammatory cell infiltration, and cytokine induction (tumor necrosis factor-α, interleukin-6, and interleukin-1β) in the colon tissues. However, no significant differences in DSS-promoted abnormal symptoms or their severity were found between the three sub-strains. Conclusions These results indicate that C57BL/6NKorl mice responded to DSS-induced colitis similar to the generally used C57BL6/N mice, thus this newly developed mouse sub-strain provides a useful animal model of IBD.

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