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1.
Toxicol In Vitro ; 30(1 Pt B): 373-82, 2015 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-26439184

RESUMO

The U-SENS™ is a test method based on the human myeloid U937 cell line to assess the skin sensitisation potential of substances. To demonstrate its robustness, a multicentre validation study with four laboratories testing 24 coded substances has been conducted according to internationally agreed principles. The primary objective of the study was to enlarge the U-SENS™'s reproducibility database. Secondary objectives were to provide additional evidence on its transferability and its predictive capability. Reproducibility within laboratories was approximately 92%, while the reproducibility between laboratories was 87.5%. Predictivity for the 24 validation substances was high, with sensitivity, specificity and accuracy being on average at least 93.8%. Similar performances are obtained for 38 substances when combining the study results with those of an earlier multicentre study, as well as with an automated version of the U-SENS™. With reliability and relevance similar to comparable non-animal skin sensitisation test methods, which have achieved regulatory acceptance, it is concluded that the U-SENS™ is a well reproducible and predictive test method. This profiles the U-SENS™ as a valuable addition to the suite of non-animal testing methods for skin sensitisation with the potential to significantly contribute to the development of integrated testing strategies.


Assuntos
Pele/efeitos dos fármacos , Testes de Toxicidade/métodos , Alternativas aos Testes com Animais , Humanos , Estudos Prospectivos , Reprodutibilidade dos Testes , Testes Cutâneos , Células U937
2.
J Appl Toxicol ; 21(5): 431-4, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11746187

RESUMO

The measurement of natural killer (NK) cell activity often is recommended as an endpoint for inclusion in the non-clinical immunotoxicity evaluation of environmental chemicals and pharmaceuticals. To date, most data on the impact of immunotoxicants on NK cell activity have been obtained in the rat. Because non-human primates often are used in the safety evaluation of new medicinal products, there is a need to compare chemically induced changes in NK cell activity between rats and primates. In this study, the in vitro effects of nickel chloride and morphine hydrochloride were investigated on NK cell activity in the rat and the cynomolgus monkey. Despite some species-specific differences in the techniques used, rather similar results were obtained in the two species. At the higher concentration, nickel chloride induced a significant decrease in NK cell activity in the ranges of 21.6-24.3% (rat) and 34.4-42.2% (monkey), depending on the effector-to-target cell ratio used, and morphine hydrochloride induced a decrease in the ranges of 23.7-34.7% (rat) and 59.1-68.0% (monkey). These results suggest that NK cell activity can be used as a reliable endpoint for the assessment of immune effects during safety evaluation studies in the cynomolgus monkey.


Assuntos
Citotoxicidade Imunológica/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Morfina/toxicidade , Níquel/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromo/metabolismo , Testes Imunológicos de Citotoxicidade , Relação Dose-Resposta a Droga , Feminino , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Macaca fascicularis , Masculino , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Baço/citologia , Baço/efeitos dos fármacos
3.
Toxicol Lett ; 119(3): 183-92, 2001 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-11246171

RESUMO

Although cutaneous adverse drug reactions (ADRs) are relatively frequent and potentially severe, their mechanisms are poorly understood and no validated predictive experimental model is available. Sulfamethoxazole (SMX) is commonly used to treat infections in HIV-positive patients and severe cutaneous ADRs have been described. This study was undertaken to test whether sensitization to SMX could be achieved in mice using a combination of in vivo and in vitro endpoints. No delayed-type hypersensitivity (DTH) response could be evidenced following SMX injection in the back and subsequent challenge into the footpad or onto the ear. Pretreatment with the enzymatic inducers phenobarbitone and betanaphtoflavone, or depletion in CD4(+) T-lymphocytes were not successful either. In contrast, the injection of SMX/S9 mix in the back and challenge with SMX/S9 mix induced a significant increase in footpad thickness. A significant proliferation of spleen cells from SMX- or SMX/S9 mix-treated mice was evidenced following incubation with SMX/S9 mix, but not SMX alone. This study provides indirect evidence that SMX metabolites are involved and confirms previous in vitro results obtained with lymphocytes from patients with a history of SMX-induced ADRs cultured with murine microsomes. Further investigations using other drugs known to induce similar ADRs are warranted to establish the predictive value of this murine model.


Assuntos
Anti-Infecciosos/toxicidade , Hipersensibilidade a Drogas , Hipersensibilidade Tardia/induzido quimicamente , Sulfametoxazol/toxicidade , Animais , Anti-Infecciosos/metabolismo , Contagem de Linfócito CD4 , Modelos Animais de Doenças , Determinação de Ponto Final , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Especificidade da Espécie , Sulfametoxazol/metabolismo
4.
Toxicology ; 105(1): 81-90, 1995 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-8638287

RESUMO

Lymphocyte subset counts and cytokine assays are useful to investigate the interactions of pharmaceuticals, particularly new biotechnology products, with the immune system. As no specific reagents are available to label monkey lymphocytes or to assay monkey cytokines by ELISA, cross reactivities of a panel of monoclonal antibodies specific for human lymphocytes or cytokines were studied in the Cynomolgus monkey. The proportions of B, T, CD4+ and CD8+ cells were determined by flow cytometry using a whole blood technique with at least one monoclonal antibody for each subset. Background data were obtained for more than 300 samples. Monkey and human cultured white blood cells were stimulated with standard mitogens. PHA + LPS in humans and Con A + PWM in monkeys triggered the greatest proliferation. IL-1 beta IL-2, IL-6, IL-8, TNF-alpha, TNF-beta and IFN-gamma, but not IL-1 alpha, were detected in the monkey using human reagents. In addition, the cytokine profile and the kinetics of cytokine production compared well in humans and Cynomolgus monkeys.


Assuntos
Citocinas/análise , Subpopulações de Linfócitos , Macaca fascicularis/imunologia , Animais , Anticorpos Monoclonais/imunologia , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Macaca fascicularis/sangue
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