Drug-induced skin toxicity: gaps in preclinical testing cascade as opportunities for complex in vitro models and assays

Lab on a Chip ◽  
2020 ◽  
Vol 20 (2) ◽  
pp. 199-214 ◽  
Author(s):  
Rhiannon N. Hardwick ◽  
Catherine J. Betts ◽  
Jessica Whritenour ◽  
Radhakrishna Sura ◽  
Maike Thamsen ◽  
...  

Selected skin MPS features desired to advance further adoption within the pharmaceutical industry.

Nanomaterials ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1991
Author(s):  
Rossella Bengalli ◽  
Luisa Fiandra ◽  
Claudia Vineis ◽  
Diego Omar Sanchez-Ramirez ◽  
Nuno G. Azoia ◽  
...  

Polypyrrole (PPy) nanoparticles (NPs) are used for the coating of materials, such as textiles, with biomedical applications, including wound care and tissue engineering, but they are also promising antibacterial agents. In this work, PPy NPs were used for the spray-coating of textiles with antimicrobial properties. The functional properties of the materials were verified, and their safety was evaluated. Two main exposure scenarios for humans were identified: inhalation of PPy NPs during spray (manufacturing) and direct skin contact with NPs-coated fabrics (use). Thus, the toxicity properties of PPy NPs and PPy-coated textiles were assessed by using in vitro models representative of the lung and the skin. The results from the materials’ characterization showed the stability of both the PPy NP suspension and the textile coating, even after washing cycles and extraction in artificial sweat. Data from an in vitro model of the air–blood barrier showed the low toxicity of these NPs, with no alteration of cell viability and functionality observed. The skin toxicity of PPy NPs and the coated textiles was assessed on a reconstructed human epidermis model following OECD 431 and 439 guidelines. PPy NPs proved to be non-corrosive at the tested conditions, as well as non-irritant after extraction in artificial sweat at two different pH conditions. The obtained data suggest that PPy NPs are safe NMs in applications for textile coating.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yanwen Chen ◽  
Travis B. Lear ◽  
John W. Evankovich ◽  
Mads B. Larsen ◽  
Bo Lin ◽  
...  

AbstractSARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection.


Author(s):  
Alasdair R. Irvine ◽  
Damiën van Berlo ◽  
Rawan Shekani ◽  
Rosalinde Masereeuw

2018 ◽  
Vol 14 (6) ◽  
pp. 378-393 ◽  
Author(s):  
Joanne Y.-C. Soo ◽  
Jitske Jansen ◽  
Rosalinde Masereeuw ◽  
Melissa H. Little
Keyword(s):  

2019 ◽  
Vol 93 (5) ◽  
pp. 1169-1186 ◽  
Author(s):  
Eva Gijbels ◽  
Vânia Vilas-Boas ◽  
Neel Deferm ◽  
Lindsey Devisscher ◽  
Hartmut Jaeschke ◽  
...  
Keyword(s):  

2015 ◽  
Vol 34 (12) ◽  
pp. 1304-1309 ◽  
Author(s):  
RT Naven ◽  
S Louise-May

Predictive toxicology plays a critical role in reducing the failure rate of new drugs in pharmaceutical research and development. Despite recent gains in our understanding of drug-induced toxicity, however, it is urgent that the utility and limitations of our current predictive tools be determined in order to identify gaps in our understanding of mechanistic and chemical toxicology. Using recently published computational regression analyses of in vitro and in vivo toxicology data, it will be demonstrated that significant gaps remain in early safety screening paradigms. More strategic analyses of these data sets will allow for a better understanding of their domain of applicability and help identify those compounds that cause significant in vivo toxicity but which are currently mis-predicted by in silico and in vitro models. These ‘outliers’ and falsely predicted compounds are metaphorical lighthouses that shine light on existing toxicological knowledge gaps, and it is essential that these compounds are investigated if attrition is to be reduced significantly in the future. As such, the modern computational toxicologist is more productively engaged in understanding these gaps and driving investigative toxicology towards addressing them.


2015 ◽  
Vol 30 (1) ◽  
pp. 138-165 ◽  
Author(s):  
Luise Schultz ◽  
Marie-Gabrielle Zurich ◽  
Maxime Culot ◽  
Anaelle da Costa ◽  
Christophe Landry ◽  
...  

2017 ◽  
Vol 242 (16) ◽  
pp. 1593-1604 ◽  
Author(s):  
David J Hughes ◽  
Tomasz Kostrzewski ◽  
Emma L Sceats

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.


2021 ◽  
Vol 177 ◽  
pp. S131
Author(s):  
Tamás Lőrincz ◽  
Veronika Deák ◽  
Kinga Makk-Merczel ◽  
Dóra Varga ◽  
András Szarka
Keyword(s):  

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