Concordance of the Toxicity of Pharmaceuticals in Humans and in Animals

Olson, Harry M.; Betton, Graham; Robinson, Denise E.; Thomas, Karluss; Monro, A. M.; Kolaja, Gerald J.; Lilly, Patrick D.; Sanders, James P.; Sipes, Glenn; Bracken, William M.; Dorato, Michael A.; Deun, Koen Van; Smith, Peter F.; Berger, Bruce E.; Heller, Allen H.

doi:10.1006/rtph.2000.1399

Cited by 1,700 publications

(1,064 citation statements)

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“…A retrospective study of concordance of human toxicity for 150 drug candidates in clinical trials was established and demonstrated close correlation with regulatory animal studies [22]. Human toxicity concordance was 71% for both rodent and nonrodent species, 63% for nonrodents alone, and 43% for rodents alone.…”

Section: In Vitro Cytotoxicity and Predicting Drug Attritionmentioning

confidence: 87%

“…The MEIC study suggested that assays with human cell lines give the best prediction and are independent of cell type, thereby indicating that the mechanism of toxicity was inhibition of a common, vital cell process. Other studies also provide further convincing evidence that in vitro cytotoxicity assays are highly predictive of acute human drug toxicity [20,21].A retrospective study of concordance of human toxicity for 150 drug candidates in clinical trials was established and demonstrated close correlation with regulatory animal studies [22]. Human toxicity concordance was 71% for both rodent and nonrodent species, 63% for nonrodents alone, and 43% for rodents alone.…”

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High-content analysis for drug delivery and nanoparticle applications

Brayden

Cryan

Dawson

et al. 2015

Drug Discovery Today

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Publication information Drug Discovery Today, 20 (8): 942-957Publisher Elsevier Item record/more information http://hdl.handle.net/10197/6636 Publisher's statementThis is the author's version of a work that was accepted for publication in Drug Discovery Today. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Drug Discovery Today, 20 (8), (2015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 26A c c e p t e d M a n u s c r i p t Sally-Ann CryanSally-Ann Cryan has a pharmacy degree and a PhD in pharmaceutics ( Jeremy SimpsonJeremy Simpson carried out his PhD at the University of Warwick, followed postdoctoral work at the Scripps Research Institute in San Diego, and the Imperial Cancer Research Fund in London. After 9 years as a staff member at the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany), he was appointed as professor of cell biology at UCD, in 2008. He currently applies high-throughput imaging technologies to study subcellular transport pathways and the internalization routes taken by nanoparticles in cells. He runs the UCD Cell Screening Laboratory and is the author of more than 80 publications.High-content analysis (HCA) provides quantitative multiparametric cellular fluorescence data. From its origins in discovery toxicology, it is now addressing fundamental questions in drug delivery. Nanoparticles (NPs), polymers, and intestinal permeation enhancers are being harnessed in drug delivery systems to modulate plasma membrane properties and the intracellular environment. Identifying comparative mechanistic cytotoxicity on sublethal events is crucial to expedite the development of such systems. NP uptake and intracellular routing pathways are also being dissected using chemical and genetic perturbations, with the potential to assess the intracellular fate of targeted and untargeted particles in vitro. As we discuss here, HCA is set to make a major impact in preclinical delivery research by elucidating the intracellular pathways of NPs and the in vitro mechanistic-based toxicology of formulation constituents. A brief recap of cytotoxicity assaysIn vitro cell-based assays have long been used to assess the cytotoxic effects of drug exposure [1]. Cells undergoing acute necrosis swell and lose metabolic capacity, thereby losing the capacity to maintain a barrier to the extracellular space and the ability ...

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Section: In Vitro Cytotoxicity and Predicting Drug Attritionmentioning

confidence: 87%

mentioning

confidence: 90%

High-content analysis for drug delivery and nanoparticle applications

Brayden

Cryan

Dawson

et al. 2015

Drug Discovery Today

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“…The evaluation of the immune response is indicated, mainly by the FDA (2002) and NTP (Luster et al, 1994), because of its higher predictive value for human toxicity (Olson et al, 2000). The possible immunotoxicological effects identified during the period of exposure to a particular drug are very important because they will be part of the assessment of its risk for use (Descotes, 2004;Olson et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the immunotoxicological effects of Dimorphandra mollis Benth., Fabaceae, in rats

Feres¹,

Toledo²,

Tagliati³

et al. 2010

Rev. bras. farmacogn.

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RESUMO: "Avaliação dos efetos imunotoxicológicos de Dimorphandra mollis Benth., Fabaceae, em ratos". A Dimorphandra mollis Benth., Fabaceae, conhecida como faveira ou favad´anta, é uma planta comum do cerrado central do Brasil, muito utilizada por suas propriedades antioxidante, antiplaquetária e, principalmente, como vasoprotetora. Seu principal marcador é a rutina. Este estudo teve como objetivo avaliar a segurança da utilização do extrato seco de D. mollis em roedores. O extrato foi extraído, padronizado e quantificado apresentando teor de 76,0±3% de rutina. Nos parâmetros bioquímicos e hematológicos avaliados, não se observou alterações nos grupos de machos e fêmeas que receberam a dose de 1000 e 2000 mg/kg de D. mollis, mas observou-se um aumento de eosinófilos. Nos estudos histopatológicos detectou-se hiperreatividade da polpa branca esplênica, no grupo que recebeu a dose de 2000 mg/kg de D. mollis. Na avaliação da resposta linfoproliferativa, com 1000 e 2000 mg/kg não foram observadas alterações, e somente nos estudos com a dose de 2000 mg/kg se observou diminuição de IgG. Os resultados obtidos, utilizando roedores, sugerem que nenhuma toxicidade existe na administração de extrato seco de D. mollis na dose de 1000 mg/kg. Unitermos: Dimorphandra mollis, rutina, imunotoxicologia, roedores.ABSTRACT: Dimorphandra mollis Benth., Fabaceae, also known as "faveira" or "fava-d´anta", is a plant common to the central woodsy meadow region of Brazil. It is well known for its antioxidant, antiplatelet and, principally, vasoprotective properties. Its principal component is rutin. The objective of this study is the evaluation of the safety of the use of the dried D. mollis extract in rodents. The rutin content of the standardized extract was 76.0±3%. With respect to the biochemical and hematological parameters evaluated, no alterations in the groups of rats that received 1000 and 2000 mg/kg doses of D. mollis were observed, but an increase in eosinophiles occurred. Hyperactivity of the white splenic pulp was detected in the group that received the 2000 mg/kg dose of D. mollis. In the evaluation of the lymphproliferative response with 1000 and 2000 mg/kg, no alterations were observed, and a decrease in IgG was only observed in the studies with a 2000 mg/kg dose. The results obtained with rodents suggest that no toxicity exists with the administration of dried D. mollis extract in a 1000 mg/kg dose.

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“…Because of ethical, economical, and scientific constraints, the use of experimental animals for toxicological purposes is indeed being increasingly discouraged. For instance, it has been documented that animal toxicity data does not necessarily correlate with human results [5,6]. In this respect, 3R (Refinement, Reduction, Replacement) strategies [6] have been introduced not only in the European legislation, but also worldwide, although to a limited extent.…”

Section: Introductionmentioning

confidence: 99%