RESUMEN
The cost for the development of new active and safe drugs is higher than ever and continues to increase. At the same time, both the pharmaceutical industry and the Regulatory Authorities are, despite the increasing effort to develop safer drugs, concerned by the risk of unexpected side effects observed in the late steps of the development of new drugs, either in late clinical development or after marketing approval. Then, the early knowledge of any potential toxic effect of a new drug is a key issue to allow adequate decision making. This means that current approaches based on the determination of the No-Adverse-Effect-Level and the Human-Equivalent-Dose are far from being perfect, and fail mainly to detect toxic phenomena of low intensity and/or low frequency. To improve the predictability of the existing experimental models, Toxicogenomics could be included into the in vitro candidate-selection steps and/or during the regulatory preclinical (or clinical) studies. In this communication, the authors present an example of the use of Toxicogenomic data to support decision making when selecting a new candidate to regulatory development. The authors also present a second example of integration of Toxicogenomics with the animal regulatory studies within the preclinical development of a new drug.
Asunto(s)
Investigación Biomédica/métodos , Descubrimiento de Drogas , Industria Farmacéutica , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Toxicogenética/métodos , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Valor Predictivo de las Pruebas , Pruebas de ToxicidadRESUMEN
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Asunto(s)
Animales , Compuestos Químicos , Sistema de Registros , Evaluación de Medicamentos/métodos , Animales de Laboratorio , Experimentación Animal/normas , Administración de la Seguridad/tendencias , Aprobación de Drogas , Industria Farmacéutica/tendenciasAsunto(s)
Alternativas a las Pruebas en Animales/métodos , Pruebas de Toxicidad/métodos , Alternativas a las Pruebas en Animales/legislación & jurisprudencia , Animales , Muerte Celular/efectos de los fármacos , Cosméticos/toxicidad , Europa (Continente) , Guías como Asunto , Dosificación Letal Mediana , Enfermedades de la Boca/inducido químicamente , Sistema de Registros , Reproducibilidad de los Resultados , Pruebas de Toxicidad Aguda , Estados UnidosRESUMEN
Early toxicity screening of new drugs is performed to select candidates for development. Many cell models are used to assess basic cytotoxicity and to show a good correlation with acute toxicity. However, their correlation with chronic in vivo exposure is inadequate. The new hepatoma cell line (HBG BC2) possesses the capacities of being reversibly differentiated in vitro, and of maintaining a relatively higher metabolic rate when in the differentiated phase (3 weeks) as compared to Hep G2 cells. MTT reduction was used to evaluate the toxicity of propranolol, perhexiline, aspirin and paracetamol, after both single and repeated treatments (three times a week for 2 weeks). Under conditions of repeated treatment, cytotoxicity was observed at lower doses when compared with single administration. Moreover, the first non-toxic doses were in the same range as plasma concentrations measured in humans during therapeutic use. Our results suggest that the new human hepatoma HBG BC2 cell line may be of interest for the evaluation of cell toxicity under repeated treatment conditions.