Eremantholide C from aerial parts of Lychnophora trichocarpha, as drug candidate: fraction absorbed prediction in humans and BCS permeability class determination.

BACKGROUND: Lychnophora trichocarpha (Spreng.) Spreng. ex Sch.Bip has been used in folk medicine to treat pain, inflammation, rheumatism and bruises. Eremantholide C, a sesquiterpene lactone, is one of the substances responsible for the anti-inflammatory and anti-hyperuricemic effects of L. trichocarpha. OBJECTIVES: Considering the potential to become a drug for the treatment of inflammation and gouty arthritis, this study evaluated the permeability of eremantholide C using in situ intestinal perfusion in rats. From the permeability data, it was possible to predict the fraction absorbed of eremantholide C in humans and elucidate its oral absorption process. METHODS: In situ intestinal perfusion studies were performed in the complete small intestine of rats using different concentrations of eremantholide C: 960 µg/ml, 96 µg/ml and 9.6 µg/ml (with and without sodium azide), in order to verify the lack of dependence on the measured permeability as a function of the substance concentration in the perfusion solutions. RESULTS: Eremantholide C showed Peff values, in rats, greater than 5 × 10-5 cm/s and fraction absorbed predicted for humans greater than 85%. These results indicated the high permeability for eremantholide C. Moreover, its permeation process occurs only by passive route, because there were no statistically significant differences between the Peff values for eremantholide C. CONCLUSION: The high permeability, in addition to the low solubility, indicated that eremantholide C is a biologically active substance BCS class II. The pharmacological activities, low toxicity and biopharmaceutics parameters demonstrate that eremantholide C has the necessary requirements for the development of a drug product, to be administered orally, with action on inflammation, hyperuricemia and gout.

In Vitro Antitumor Activity of Sesquiterpene Lactones from Lychnophora trichocarpha / Atividade antitumoral in vitro de lactonas sesquiterpenicas de Lychnophora

The sesquiterpene lactones lychnopholide and eremantholide C were isolated from Lychnophora trichocarpha Spreng. (Asteraceae), which is a plant species native to the Brazilian Savannah or Cerrado and popularly known as arnica. Sesquiterpene lactones are known to present a variety of biological activities including antitumor activity. The present paper reports on the evaluation of the in vitro antitumor activity of lychnopholide and eremantholide C, in the National Cancer Institute, USA (NCI, USA), against a panel of 52 human tumor cell lines of major human tumors derived from nine cancer types. Lychnopholide disclosed significant activity against 30 cell lines of seven cancer types with IC100 (total growth concentration inhibition) values between 0.41 µM and 2.82 µM. Eremantholide C showed significant activity against 30 cell lines of eight cancer types with IC100 values between 21.40 µM and 53.70 µM. Lychnopholide showed values of lethal concentration 50% (LC50) for 30 human tumor cell lines between 0.72 and 10.00 µM, whereas eremantholide C presented values of LC50 for 21 human tumor cell lines between 52.50 and 91.20 µM. Lychnopholide showed an interesting profile of antitumor activity. The α-methylene-γ-lactone present in the structure of lychnopholide, besides two α,β- unsaturated carbonyl groups, might be responsible for the better activity and higher cytotoxicity of this compound in relation to eremantholide C.

As lactonas sesquiterpênicas licnofolida e eremantolida C foram isoladas de Lychnophora trichocarpha Spreng. (Asteraceae), espécie vegetal nativa do cerrado brasileiro e popularmente conhecida por arnica brasileira. As lactonas sesquiterpênicas são conhecidas por apresentarem variadas atividades biológicas, incluindo atividade antitumoral. O presente artigo relata a avaliação da atividade antitumoral in vitro de licnofolida e eremantolida C frente a um painel de 52 linhagens de células tumorais, provenientes de tumores humanos referentes a nove principais tipos de câncer. Os testes foram conduzidos no National Cancer Institute, USA (NCI, USA). Licnofolida apresentou atividade significativa frente a 30 linhagens de células tumorais referentes a sete tipos de câncer, com valores de CI100 (concentração que inibe 100% do crescimento celular) entre 0,41 µM e 2,82 µM. Eremantolida C mostrou atividade significativa frente a 30 linhagens de células tumorais referentes a oito tipos de câncer, com valores de CI100 entre 21,40 µM e 53,70 µM. Licnofolida apresentou valores de concentração letal 50% (CL50) para 30 linhagens de células tumorais humanas entre 0,72 e 10,00 µM, enquanto eremantolida C mostrou valores de CL50 para 21 linhagens entre 52,50 e 91,20 µM. Licnofolida apresentou um interessante perfil de atividade antitumoral. A presença na estrutura química da licnofolida de uma α-metileno-γ-lactona, além de dois grupos ésteres α,β-insaturados, podem ser responsáveis pela melhor atividade e maior citotoxicidade desta substância em relação à eremantolida C.

Toxicological evaluation of ethanolic extract of Lychnophora trichocarpha, Brazilian arnica

The species of the genus Lychnophora, Asteraceae, are popularly known as "arnica" and are native from Brazilian savana (Cerrado). They are widely used in Brazilian folk medicine as anti-inflammatory, to treat bruise, pain, rheumatism and for insect bites. For evaluation of acute toxicity, the ethanolic extract was given to albino female and male mice. In open-field test, the extract of Lychnophora trichocarpha (Spreng.) Spreng. (0.750 g/kg) induced a significant inhibition of the spontaneous locomotor activity and exploratory behavior of the animals were observed 1 and 4 h after administration. In traction test, the same dose reduced the muscular force 1 h after administration. The exploratory behavior reduced significantly in the group that received 0.50 g/kg, 1 and 4 h after administration of the extract. The animals that received the doses of 0.25, 0.50 and 0.75 g/kg did not show any change of blood biochemical parameters comparing to control group and showed some histopathological changes such as congestion and inflammation of kidney and liver. The dose of 1.5 g/kg caused the most serious signs of toxicity. Histopathological changes observed was hemorrhage in 62.5% and pulmonary congestion in 100% of the animals. Brain and liver congestion was found in 62.5% of the animals.

Atividade antibacteriana de furanoeliangólidos / Antibacterial activity of furanoeliangolides

As lactonas sesquiterpênicas licnofólido (1) e eremantólido C (2) e alguns derivados: 1 ,2 -epóxieremantólido C (3), 1 β -hidróxi-2,3-diidroeremantólido C (4), 3 - hidróxieremantólido C (5), cloreto de 4,5-diidroeremantólido-5-n-propilamônio (6) e 1 β -hidróxi- 2,3-diidrolicnofólido (7) foram testadas contra as bactérias Enterococus faecalis S48, Bacillus subtilis CECT 397, Staphylococus aureus ATCC 8, Salmonella typhymurium LT2, Escherichia coli U9 e Proteus sp. Os compostos 1, 4, 5 e 7 apresentaram atividade antibacteriana.

Sesquiterpene lactones lychnopholide (1) and eremantholide C (2) and some derivatives: 1 ,2 -epoxyeremantholide C (3), 1 β -hidroxy-2,3-dihydroeremantolide C (4), 3 -hydroxyeremantholide C (5), 5-n- propylamonium- 4,5-dihydroeremantholide C chloride (6) and 1 β -hydroxy-2,3- dihydrolychnopholide (7) were tested against Enterococus faecalis S48, Bacillus subtilis CECT 397, Staphylococus aureus ATCC 8, Salmonella typhymurium LT2, Escherichia coli U9 e Proteus sp. Compounds 1, 4, 5 and 7 showed activity.