RESUMO
Atovaquone, a hydroxynaphthoquinone, is an anti-parasite drug, selectively targeting the mitochondrial respiratory chain of malaria parasite. It is used for both the treatment and prevention of malaria, usually in a fixed combination with proguanil. Although atovaquone has not often been associated with severe adverse reactions in the recommended dosages and has a relatively favorable side effect profile, the present study was undertaken to evaluate its cytogenotoxic potential towards human peripheral blood lymphocytes. Two different concentrations of atovaquone found in plasma when used in fixed-dose combination with proguanile hydrochloride were used with and without S9 metabolic activation: 2950 ng ml(-1) used for prophylactic treatment and 11 800 ng ml(-1) used in treatment of malaria. The results showed that lymphocyte viability was not affected after the treatment, suggesting that atovaquone was not cytotoxic in the given concentrations. With the alkaline comet assay we demonstrated that in human peripheral blood lymphocytes no significant changes in comet parameters occurred after the treatment. There were no differences in tested parameters with the addition of S9 metabolic activation, indicating that atovaquone either has no metabolite or it is not toxic in the given concentrations. Since no effects were observed after the treatment, it is to be concluded that atovaquone is safe from the aspect of genototoxicity in the recommended dosages.
Assuntos
Antimaláricos/toxicidade , Atovaquona/toxicidade , Ensaio Cometa , Dano ao DNA , Linfócitos/efeitos dos fármacos , Mutagênicos/toxicidade , Adulto , Atovaquona/classificação , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Humanos , Linfócitos/patologia , Masculino , Mutagênicos/classificação , Proteína S9 Ribossômica , Proteínas Ribossômicas/efeitos dos fármacosRESUMO
The oxidative phosphorylation inhibitor atovaquone (ATO) and the photosensitizer new indocyanine green (IR820) were self-assembled into carrier-free nanodrugs (IR820/ATO NPs) to achieve superior photothermal therapy (PTT), offering an attractive mitochondrial metabolism-regulatable approach for breast cancer treatment, where adenosine triphosphate (ATP) was downregulated along with downregulating the expression of heat shock proteins (HSPs) to amplify the sensitivity of PTT.
Assuntos
Antineoplásicos/farmacologia , Atovaquona/farmacologia , Neoplasias da Mama/tratamento farmacológico , Verde de Indocianina/análogos & derivados , Nanopartículas/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Atovaquona/química , Atovaquona/toxicidade , Linhagem Celular Tumoral , Feminino , Verde de Indocianina/química , Verde de Indocianina/farmacologia , Verde de Indocianina/toxicidade , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/toxicidade , Fosforilação Oxidativa/efeitos dos fármacos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/toxicidade , Terapia FototérmicaRESUMO
The acute toxicities of five naphthoquinone compounds to Photobacterium phosphoreum were determined. We evaluated the mechanism of toxicity using the structure-activity relationship technique. The results showed that some factors, including the species of substituents, shape/size of molecule and oil-water partition coefficient (log P) played the important roles in the interaction between the naphthoquinones and the target. Among of these, the toxicities of Atovaquone and Buparvaquone were lower than the other naphthoquinones we tested because of the alkyl-substitution with the bigger volume and strong hydrophobicity. Conversely, Menadione had the highest toxicity because of the appropriate log P and shape/size of molecule resulting in the easier interaction with the target.