scholarly journals Developing in vitro assays to transform gastrointestinal safety assessment: potential for microphysiological systems

Lab on a Chip ◽  
2020 ◽  
Vol 20 (7) ◽  
pp. 1177-1190 ◽  
Author(s):  
Matthew F. Peters ◽  
Allison L. Choy ◽  
Carmen Pin ◽  
Derek J. Leishman ◽  
Annie Moisan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Safety Assessment ◽  
In Vitro Assays ◽  
Drug Induced ◽  
Gastrointestinal Safety ◽  
Microphysiological Systems

Drug-induced gastrointestinal toxicities (DI-GITs) are among the most common adverse events in clinical trials.

Gender-Based Differences in the Toxicity of Pharmaceuticals—The Food and Drug Administration's Perspective

2001 ◽  
Vol 20 (3) ◽  
pp. 149-152 ◽  
Author(s):  
Margaret Ann Miller
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Sex Difference ◽  
Qt Interval ◽  
Drug Effects ◽  
Drug Efficacy ◽  
Model Systems ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Induced

Women experience more adverse reactions to treatment with therapeutic drugs than men. Theories proposed to explain this include overdosing, different pharmacokinetics and pharmacodynamics, women are more likely to report adverse events than men, or women take more medications than men. Food and Drug Administration (FDA) Office of Women's Health (OWH) funds research to promote including women in clinical trials and understanding the biology of sex-related differences in the safety of FDA-regulated products. Including women in clinical trials advances the understanding of drug efficacy and safety in women by providing information on drug dosing, pharmacokinetics, and pharmacodynamics. A Baysian statistical analysis of sex differences in adverse events showed that although about the same number of adverse events were reported for men and women, those reported for women were more serious. One example of a sex difference in the toxicity of pharmaceuticals is the drug-induced cardiac arrhythmia, torsades de point. OWH funded studies in animals and humans to investigate the mechanism behind this sex difference. These studies demonstrated that shortening the QT interval increases the risk of developing torsades and that androgens protect against torsades by slowing cardiac repolarization and prolonging the QT interval. Understanding the mechanisms behind other reported sex-related differences in adverse drug effects requires additional research. The preliminary studies conducted to date suggest that this sex-related difference is likely to be a multifactorial problem requiring information from several fields of study. Ideally, individuals at risk for developing an adverse event should be identified prior to therapeutic intervention. The OWH plans to fund more studies to investigate the role of hormonal variations on drug metabolism and drug-drug interactions. Animal and in vitro model systems are needed to fully understand the mechanism of how gender influences drug toxicity.

Recent Progress in Prediction Systems for Drug-induced Liver Injury Using in vitro Cell Culture

2020 ◽  
Vol 14 ◽  
Author(s):  
Shogo Ozawa ◽  
Toshitaka Miura ◽  
Jun Terashima ◽  
Wataru Habano ◽  
Seiichi Ishida
Keyword(s):  
Cell Culture ◽  
Recent Progress ◽  
Inflammatory Cells ◽  
Protein Adducts ◽  
In Vitro Assays ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Culture Systems ◽  
Cell Culture Systems

Background: In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed. Objective: In this study, the recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as for the limitations of in vitro cell culture systems for DILI research. Methods: Information related to DILI was collected through a literature search of the PubMed database. Results: The initial biological event for the onset of DILI is the formation of cellular protein adducts after drugs have been metabolically activated by drug metabolizing enzymes. The damaged peptides derived from protein adducts lead to the activation of CD4+ helper T lymphocytes and recognition by CD8+ cytotoxic T lymphocytes, which destroy hepatocytes through immunological reactions. Because DILI is a major cause of drug attrition and drug withdrawal, numerous in vitro systems consisting of hepatocytes and immune/inflammatory cells, or spheroids of human primary hepatocytes containing non-parenchymal cells have been developed. These cellular-based systems have identified DILIinducing drugs with approximately 50% sensitivity and 90% specificity. Conclusion: Different co-culture systems consisting of human hepatocyte-derived cells and other immune/inflammatory cells have enabled the identification of DILI-causing drugs and of the actual mechanisms of action.

scholarly journals The Role of Vitamin C in Cancer Prevention and Therapy: A Literature Review

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1894
Author(s):  
Marcelo Villagran ◽  
Jorge Ferreira ◽  
Miquel Martorell ◽  
Lorena Mardones
Keyword(s):  
Clinical Trials ◽  
Vitamin C ◽  
Cancer Prevention ◽  
Randomized Study ◽  
Regulation Of Gene Expression ◽  
Water Soluble ◽  
In Vitro Assays ◽  
High Concentration

Vitamin C is a water-soluble antioxidant associated with the prevention of the common cold and is also a cofactor of hydrolases that participate in the synthesis of collagen and catecholamines, and in the regulation of gene expression. In cancer, vitamin C is associated with prevention, progression, and treatment, due to its general properties or its role as a pro-oxidant at high concentration. This review explores the role of vitamin C in cancer clinical trials and the aspects to consider in future studies, such as plasmatic vitamin C and metabolite excretion recording, and metabolism and transport of vitamin C into cancer cells. The reviewed studies show that vitamin C intake from natural sources can prevent the development of pulmonary and breast cancer, and that vitamin C synergizes with gemcitabine and erlotinib in pancreatic cancer. In vitro assays reveal that vitamin C synergizes with DNA-methyl transferase inhibitors. However, vitamin C was not associated with cancer prevention in a Mendelian randomized study. In conclusion, the role of vitamin C in the prevention and treatment of cancer is still an ongoing area of research. It is necessary that new phase II and III clinical trials be performed to collect stronger evidence of the therapeutic role of vitamin C in cancer.

scholarly journals In vitro Post-Antifungal Effect of Posaconazole and Its Impact on Adhesion-Related Traits and Hemolysin Production of Oral Candida dubliniensis Isolates

2019 ◽  
Vol 28 (6) ◽  
pp. 552-558
Author(s):  
Arjuna Nishantha Bandara Ellepola ◽  
Ranil Samantha Dassanayake ◽  
Ziauddin Khan
Keyword(s):  
Oral Candidiasis ◽  
Cell Surface Hydrophobicity ◽  
Surface Hydrophobicity ◽  
Candida Dubliniensis ◽  
In Vitro Assays ◽  
Drug Induced ◽  
Antifungal Effect ◽  
Buccal Epithelial Cells ◽  
Oral Candida

Objective: Candidal adherence to denture acrylic surfaces (DAS) and oral buccal epithelial cells (BEC), formation of candidal germ tubes (GT), candidal cell surface hydrophobicity (CSH), and hemolysin production are important pathogenic traits of Candida. The antifungal drug-induced post-antifungal effect (PAFE) also impacts the virulence of Candida. Candida dubliniensis isolates are associated with the causation of oral candidiasis which could be managed with posaconazole. Thus far there is no evidence on posaconazole-induced PAFE and its impact on adhesion-related attributes and production of hemolysin by C. dubliniensis isolates. Hence, the PAFE, adhesion to DAS and BEC, formation of GT, CSH, and hemolysin production of 20 oral C. dubliniensis isolates after brief exposure to posaconazole was ascertained. Materials and Methods: The PAFE, adherence to DAS and BEC, formation of GT, candidal CSH, and hemolysin production were investigated by hitherto described in vitro assays. Results: The mean PAFE (h) induced by posaconazole on C. dubliniensis isolates was 1.66. Exposure to posaconazole suppressed the ability of C. dubliniensis to adhere to DAS, BEC, formation of candidal GT, candidal CSH and to produce hemolysin by a reduction of 44, 33, 34, 36, and 15% (p < 0.005 to p < 0.001), respectively. Conclusion: Exposure of C. dubliniensis isolates to posaconazole for a brief period induced an antimycotic impact by subduing its growth in addition to suppressing pathogenic adherence-associated attributes, as well as production of hemolysin.

scholarly journals Concise Review: A Safety Assessment of Adipose-Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events

2017 ◽  
Vol 6 (9) ◽  
pp. 1786-1794 ◽  
Author(s):  
Navid Mohamadpour Toyserkani ◽  
Mads Gustaf Jørgensen ◽  
Siavosh Tabatabaeifar ◽  
Charlotte Harken Jensen ◽  
Søren Paludan Sheikh ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Adverse Events ◽  
Cell Therapy ◽  
Safety Assessment ◽  
Concise Review

scholarly journals Opportunities and challenges in the wider adoption of liver and interconnected microphysiological systems

2017 ◽  
Vol 242 (16) ◽  
pp. 1593-1604 ◽  
Author(s):  
David J Hughes ◽  
Tomasz Kostrzewski ◽  
Emma L Sceats
Keyword(s):  
Parenchymal Cell ◽  
Pharmaceutical Research ◽  
Hepatic Function ◽  
In Vitro Models ◽  
System Level ◽  
Primary Hepatocytes ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Microphysiological Systems

Liver disease represents a growing global health burden. The development of in vitro liver models which allow the study of disease and the prediction of metabolism and drug-induced liver injury in humans remains a challenge. The maintenance of functional primary hepatocytes cultures, the parenchymal cell of the liver, has historically been difficult with dedifferentiation and the consequent loss of hepatic function limiting utility. The desire for longer term functional liver cultures sparked the development of numerous systems, including collagen sandwiches, spheroids, micropatterned co-cultures and liver microphysiological systems. This review will focus on liver microphysiological systems, often referred to as liver-on-a-chip, and broaden to include platforms with interconnected microphysiological systems or multi-organ-chips. The interconnection of microphysiological systems presents the opportunity to explore system level effects, investigate organ cross talk, and address questions which were previously the preserve of animal experimentation. As a field, microphysiological systems have reached a level of maturity suitable for commercialization and consequent evaluation by a wider community of users, in academia and the pharmaceutical industry. Here scientific, operational, and organizational considerations relevant to the wider adoption of microphysiological systems will be discussed. Applications in which microphysiological systems might offer unique scientific insights or enable studies currently feasible only with animal models are described, and challenges which might be addressed to enable wider adoption of the technologies are highlighted. A path forward which envisions the development of microphysiological systems in partnerships between academia, vendors and industry, is proposed. Impact statement Microphysiological systems are in vitro models of human tissues and organs. These systems have advanced rapidly in recent years and are now being commercialized. To achieve wide adoption in the biological and pharmaceutical research communities, microphysiological systems must provide unique insights which translate to humans. This will be achieved by identifying key applications and making microphysiological systems intuitive to use.

scholarly journals Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and post-marketing reports

2020 ◽  
Author(s):  
Ines A. Smit ◽  
Avid M. Afzal ◽  
Chad H. G. Allen ◽  
Fredrik Svensson ◽  
Thierry Hanser ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Adverse Event Reporting System ◽  
Quantitative Information ◽  
Carbonic Anhydrases ◽  
Systematic Analysis ◽  
Post Marketing Surveillance ◽  
Post Marketing

AbstractAdverse drug reactions (ADRs) are undesired effects of medicines that can harm patients and are a significant source of attrition in drug development. ADRs are anticipated by routinely screening drugs against secondary pharmacology protein panels. However, there is still a lack of quantitative information on the links between these off-target proteins and the risk of ADRs in humans. Here, we present a systematic analysis of associations between measured and predicted in vitro bioactivities of drugs, and adverse events (AEs) in humans from two sources of data: the Side Effect Resource (SIDER), derived from clinical trials, and the Food and Drug Administration Adverse Event Reporting System (FAERS), derived from post-marketing surveillance. The ratio of a drug’s in vitro potency against a given protein relative to its therapeutic unbound drug plasma concentration was used to select proteins most likely to be relevant to in vivo effects. In examining individual target bioactivities as predictors of AEs, we found a trade-off between the Positive Predictive Value and the fraction of drugs with AEs that can be detected, however considering sets of multiple targets for the same AE can help identify a greater fraction of AE-associated drugs. Of the 45 targets with statistically significant associations to AEs, 30 are included on existing safety target panels. The remaining 15 targets include 8 carbonic anhydrases, of which CA5B was significantly associated with cholestatic jaundice. We include the full quantitative data on associations between in vitro bioactivities and AEs in humans in this work, which can be used to make a more informed selection of safety profiling targets.

scholarly journals Kidney-based in vitro models for drug-induced toxicity testing

2019 ◽  
Vol 93 (12) ◽  
pp. 3397-3418 ◽  
Author(s):  
João Faria ◽  
Sabbir Ahmed ◽  
Karin G. F. Gerritsen ◽  
Silvia M. Mihaila ◽  
Rosalinde Masereeuw
Keyword(s):  
Adverse Effects ◽  
Drug Disposition ◽  
Drug Effects ◽  
Toxicity Testing ◽  
Cell Types ◽  
In Vitro Assays ◽  
Vascular Effects ◽  
Drug Induced

Abstract The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs’ microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and response to environmental signals. Cell polarity is dependent on communication between cells, which includes paracrine and autocrine signals, as well as biomechanic and chemotactic processes. These processes all influence kidney cell proliferation, migration, and differentiation. For drug disposition studies, this microenvironment is essential for prediction of toxic responses. This review provides an overview of drug-induced injuries to the kidney, details on relevant and translational biomarkers, and advances in 3D cultures of human renal cells, including organoids and kidney-on-a-chip platforms.

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