Preclinical toxicity of innovative molecules: In vitro, in vivo and metabolism prediction.

The lack of predictivity of animal's models has increased the failure rate of drug candidates. Thus, the reversion of this scenario using preliminary in vitro assays and metabolism prediction can reduce the unnecessary use of animals, as well as predict toxic effects at preclinical and clinical stages. The present study aimed to evaluate safety of four biologically active molecules (RN104, RI78, ICH, PCH) with potential therapeutic applications synthesized in our laboratory. Initially, we used MTT cytotoxicity against A549, H9C2, HepG2, LLC-PK1 and NEURO-2 cell lines. RN104 showed the lowest cytotoxicity and further studies were conducted with it. The neutral red (NR) test was performed according to OECD-129 and then acute toxicity test (OECD-423). According to NR results we administered at 300 mg/kg on animals; however, no toxic effect was observed, while 2,000 mg/kg resulted in the death of one animal per group. After, metabolism prediction studies, performed using both ligand-based and structure-based, suggests three potential metabolites. In silico results suggested that potential metabolites could be fast eliminated and, then, this could be an explanation for lower observed toxicity in in vivo experiments. The results showed limitations of the NR as a predictor of the initial dose for the acute toxicity study, which may be related to metabolism. Therefore, the combination of theoretical and experimental studies is relevant to a general understanding of new molecule's toxicity.

Atividade biológica do extrato hidroalcoólico de Bauhinia forficata Link sobre Herpetomonas samuelpessoai (Galvão. ) Roitman / Biologic activity of the hydroalcoholic extract of Bauhinia forficata Link on Herpetomonas samuelpessoai (Galvão. ) Roitman

Inúmeros esforços têm sido dirigidos para conferir às plantas seu real papel e valor na terapia. Este estudo teve como objetivo avaliar a atividade antimicrobiana, mutagênica, toxicidade, e os efeitos no crescimento e diferenciação de Herpetomonas samuelpessoai, do extrato hidroalcoólico de Bauhinia forficata. Para avaliar a atividade antimicrobiana foi realizado o teste de difusão em ágar, bem como a determinação das concentrações inibitória (CIM) e microbicida mínimas (CMM). O potencial clastogênico e/ou aneugênico, in vivo, foi avaliado usando o teste do micronúcleo em medula óssea de camundongos Swiss albinus. Foi determinada também a dose letal média (DL50). O extrato inibiu o crescimento de oito bactérias, mostrando-se mais ativo para Gram-positivas e não foi eficiente para os fungos, tendo sido ativo nas concentrações de 2000, 1000, 500 e 250 mg/mL contra os microrganismos testados. Os resultados mostraram que nas concentrações administradas (500, 1000 e 2000 mg/Kg), não houve aumento estatisticamente significativo de micronúcleos. Não houve ação no crescimento e diferenciação de Herpetomonas samuelpessoai nas concentrações testadas. Com relação a DL50, o extrato não apresentou toxicidade.

Numerous efforts have been directed to discover the role and the value of plants in therapy. This work aimed to evaluate the antimicrobial activity, mutagenicity, toxicity and effects on growth and differentiation of Herpetomonas samuelpessoai of the hydroalcoholic extract of Bauhinia forficata. To evaluate the antimicrobial activity it was performed the agar diffusion test, minimum inhibitory (MIC) and microbicidal (MMC) concentrations. The in vivo clastogenic and / or aneugênic potential was evaluated using the micronucleus test in mice bone marrow Swiss albinus. It was also determined the median lethal dose (LD50). The extract inhibited the growth of eight bacteria, being more active against Gram-positiveones, and was not active against fungi. The microorganisms tested had MIC concentrations of 2000, 1000, 500 and 250 mg / mL. The results showed that the tested concentrations (500, 1000 and 2000 mg / kg) had no statistically significant increasedthe micronucleus. There was no action on the growth and differentiation of Herpetomonas samuelpessoai at the concentrations tested. In respect to the LD50, the extract showed no toxicity.