Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Bases de dados
Ano de publicação
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Regul Toxicol Pharmacol ; 138: 105309, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36481280

RESUMO

Virtual Control Groups (VCGs) based on Historical Control Data (HCD) in preclinical toxicity testing have the potential to reduce animal usage. As a case study we retrospectively analyzed the impact of replacing Concurrent Control Groups (CCGs) with VCGs on the treatment-relatedness of 28 selected histopathological findings reported in either rat or dog in the eTOX database. We developed a novel methodology whereby statistical predictions of treatment-relatedness using either CCGs or VCGs of varying covariate similarity to CCGs were compared to designations from original toxicologist reports; and changes in agreement were used to quantify changes in study outcomes. Generally, the best agreement was achieved when CCGs were replaced with VCGs with the highest level of similarity; the same species, strain, sex, administration route, and vehicle. For example, balanced accuracies for rat findings were 0.704 (predictions based on CCGs) vs. 0.702 (predictions based on VCGs). Moreover, we identified covariates which resulted in poorer identification of treatment-relatedness. This was related to an increasing incidence rate divergence in HCD relative to CCGs. Future databases which collect data at the individual animal level including study details such as animal age and testing facility are required to build adequate VCGs to accurately identify treatment-related effects.


Assuntos
Testes de Toxicidade , Ratos , Animais , Cães , Estudos Retrospectivos , Grupos Controle , Bases de Dados Factuais
2.
Arch Toxicol ; 96(2): 613-624, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34973110

RESUMO

The receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical. We have applied a state-of-the-art, multi-modal imaging platform to assess the in vivo effects of pharmacological inhibition of MERTK in mice. This involved the application of mass spectrometry imaging (MSI) to characterize the ocular spatial distribution of our highly selective MERTK inhibitor; AZ14145845, together with histopathology and transmission electron microscopy to characterize pathological and ultra-structural change in response to MERTK inhibition. In addition, we assessed the utility of a human retinal in vitro cell model to identify perturbation of phagocytosis post MERTK inhibition. We identified high localized total compound concentrations in the retinal pigment epithelium (RPE) and retinal lesions following 28 days of treatment with AZ14145845. These lesions were present in 4 of 8 treated animals, and were characterized by a thinning of the outer nuclear layer, loss of photoreceptors (PR) and accumulation of photoreceptor outer segments at the interface of the RPE and PRs. Furthermore, the lesions were very similar to that shown in the RCS rat and MERTK knock-out mouse, suggesting a MERTK-induced mechanism of PR cell death. This was further supported by the observation of reduced phagocytosis in the human retinal cell model following treatment with AZ14145845. Our study provides a viable, translational strategy to investigate the pre-clinical toxicity of MERTK inhibitors but is equally transferrable to novel chemotypes.


Assuntos
Fagocitose/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , c-Mer Tirosina Quinase/antagonistas & inibidores , Animais , Linhagem Celular , Feminino , Humanos , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Imagem Multimodal , Células Fotorreceptoras de Vertebrados/patologia , Ratos , Ratos Long-Evans , Ratos Wistar , Degeneração Retiniana/induzido quimicamente , Epitélio Pigmentado da Retina/metabolismo , Distribuição Tecidual , c-Mer Tirosina Quinase/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA