Combination effects of amphetamines under hyperthermia - the role played by oxidative stress

• Tipo: Artigo em Revista Científica Internacional
• Data: 2014

Autores

Diana Dias da Silva (Autor) Outra; Elisabete Silva (Autor) Outra; Helena Carmo (Autor) FFUP

Revista

Título: Journal of Applied Toxicology

Vol. 34 Nº 6

Páginas: 637-650

ISSN: 0260-437X

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 29 Citações

ISI Web of Science

Scopus - 48 Citações

Pubmed / Medline

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

CORDIS: Ciências da Saúde > Ciências farmacológicas > Toxicologia

Outras Informações

ID Authenticus: P-008-PJR

DOI: 10.1002/jat.2889

Abstract (EN): Rise in body temperature is a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. We evaluated the impact of hyperthermia on the cytotoxicity of combinations of MDMA and three other amphetamines, often co-ingested. For this, Hep G2 cells were exposed to MDMA, d-amphetamine, methamphetamine and 4-methylthioamphetamine, individually or combined, at 40.5 degrees C. The results were compared with normothermia data (37.0 degrees C). Mixture additivity expectations were calculated by independent action and concentration addition (CA) models. To delineate the mechanism(s) underlying the elicited effects, a range of stress endpoints was evaluated, including quantification of reactive oxygen/nitrogen species (ROS/RNS), lipid peroxidation, reduced/oxidized glutathione (GSH/GSSG), ATP and mitochondrial membrane potential (Delta psi m) changes. Our data show that, in hyperthermia, amphetamines acted additively and mixture effects were accurately predicted by CA. At 40.5 degrees C, even slight increases in the concentrations of each drug/mixture promoted significant rises in cytotoxicity, which quickly shifted from roughly undetectable to maximal mortality. Additionally, the increase of RNS/ROS production, decrease of GSH, ATP depletion and mitochondrial impairment were exacerbated under hyperthermia. Importantly, when equieffective cytotoxic concentrations of the mixture and individual amphetamines were compared for all tested stress endpoints, mixture effects did not deviate from those elicited by individual treatments, suggesting that these amphetamines have a similar mode of action, which is not altered in combination. Concluding, our data indicate that amphetamine mixtures produce deleterious effects, even when individual drugs are combined at negligible concentrations. These effects are strongly exacerbated in hyperthermia, emphasizing the potential increased risks of ecstasy intake, especially when hyperthermia occurs concurrently with polydrug abuse. Copyright (c) 2013 John Wiley & Sons, Ltd.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 14