Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Toxicol Pathol ; 49(2): 235-260, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33455525

RESUMO

The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple ("uncomplicated") increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators.


Assuntos
Produtos Biológicos , Hipersensibilidade , Administração por Inalação , Animais , Produtos Biológicos/efeitos adversos , Líquido da Lavagem Broncoalveolar , Inflamação , Pulmão , Macrófagos Alveolares , Coelhos
2.
Toxicol Pathol ; 49(2): 349-369, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33167784

RESUMO

This paper presents a review of the nature, range, and incidences of background pathology findings in the respiratory tract of cynomolgus monkeys and rats. Data were collected from 81 inhalation studies and 133 non-inhalation studies evaluated at 3 geographically distinct contract research organization facilities. The inhalation studies were comprised of 44 different small molecule pharmaceuticals or chemicals which were also analyzed in order to understand the patterns of induced changes within the respiratory tract. The lung was the most frequently affected organ in both species, with increased alveolar macrophages being the most common background and test article-related finding. In the upper respiratory tract (URT), inflammatory cell infiltrates were the most common background findings in the nasal cavity in monkeys. Induced URT findings were more frequent in rats than monkeys, with squamous metaplasia in the larynx, and goblet cell hyperplasia in the nasal cavity being the most common. Overall, the data revealed a limited pattern of response to inhaled molecules in the respiratory tract, with background and test article-related findings often occurring in the same regions. It is hoped that these data will assist in the interpretation of findings in the respiratory tract induced by novel inhaled small molecule entities.


Assuntos
Poluentes Atmosféricos , Pulmão , Traqueia , Administração por Inalação , Poluentes Atmosféricos/toxicidade , Animais , Pulmão/efeitos dos fármacos , Macaca fascicularis , Ratos , Ratos Endogâmicos F344 , Traqueia/efeitos dos fármacos
3.
J Aerosol Med Pulm Drug Deliv ; 29(4): 362-77, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26859446

RESUMO

BACKGROUND: Understanding the relationship between dose, lung exposure, and drug efficacy continues to be a challenging aspect of inhaled drug development. An experimental inhalation platform was developed using mometasone furoate to link rodent lung exposure to its in vivo pharmacodynamic (PD) effects. METHODS: We assessed the effect of mometasone delivered directly to the lung in two different rodent PD models of lung inflammation. The data obtained were used to develop and evaluate a mathematical model to estimate drug dissolution, transport, distribution, and efficacy, following inhaled delivery in rodents and humans. RESULTS: Mometasone directly delivered to the lung, in both LPS and Alternaria alternata rat models, resulted in dose dependent inhibition of BALf cellular inflammation. The parameters for our mathematical model were calibrated to describe the observed lung and systemic exposure profiles of mometasone in humans and in animal models. We found that physicochemical properties, such as lung fluid solubility and lipophilicity, strongly influenced compound distribution and lung retention. CONCLUSIONS: Presently, we report on a novel and sophisticated mathematical model leading to improvements in a current inhaled drug development practices by providing a quantitative understanding of the relationship between PD effects and drug concentration in lungs.


Assuntos
Alternariose/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Cálculos da Dosagem de Medicamento , Pneumopatias Fúngicas/tratamento farmacológico , Pulmão/efeitos dos fármacos , Modelos Biológicos , Furoato de Mometasona/administração & dosagem , Pneumonia/tratamento farmacológico , Administração por Inalação , Aerossóis , Alternaria , Alternariose/metabolismo , Alternariose/microbiologia , Alternariose/fisiopatologia , Animais , Anti-Inflamatórios/farmacocinética , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/fisiopatologia , Pneumopatias Fúngicas/metabolismo , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/fisiopatologia , Masculino , Furoato de Mometasona/farmacocinética , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Ratos Endogâmicos BN , Ratos Sprague-Dawley , Especificidade da Espécie , Distribuição Tecidual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...