Avaliação dos aspectos farmacológicos, toxicológicos e esquistossomicida da benzofenona 7-epiclusianona

Abstract

Schistosomiasis is a disease caused by helminths of the genus Schistosoma, which threatens about 230 million people worldwide. Recently, strains of Schistosoma mansoni have developed tolerance and resistance against praziquantel (PZQ), which is the only drug available on the market, used to treat this disease. These related resistance problems justify studies that seek alternatives for the prevention, treatment and cure of the disease. The objective of this study was to evaluate the chemical stability, pharmacokinetics, toxic and schistosomicidal effects of 7- epiclusianone (7-epi), a substance isolated from Garcinia brasiliensis. Assays for chemical stability using HPLC-UV-VIS, pharmacokinetics using UPLC-MS/MS, biochemists evaluating hepatic function markers (aspartate-aminotransferase, alanine-aminotransferase, albumin, total proteins and glucose) and renal (creatinine) function, in vivo toxicity By the comet test, micronucleus of marrow and colon and apoptosis were carried out with the objective of evaluating the effects of these substances in murine models. 7-epi was shown to be stable in the forced degradation tests, however in the presence of 0,3% (v / v) hydrogen peroxide degradation occurred to give the oxidized form of this compound. In turn, pharmacokinetic tests analyzed 7-epi in plasma from mice infected by Schistosoma mansoni, showed an increase in area under the plasma concentration versus time curve (20846 vs 32438 ng.h / mL), a decrease in apparent total clearance (0.006 vs 0.004 L / h / kg), increased half-life (1.73 vs 6.11 h) and maximum plasma concentration was reduced (5427.5 vs. 3321.0 ng / mL) compared to the uninfected group, but the time to reach maximum plasma concentration did not present significant difference. In toxicological tests using comet assay, micronucleus test of marrow and colon, bisides to the apoptosis tests, 7-epi did not cause DNA damage and was still able to protect the cell from damage caused by doxirubicin and N, N'-dimethylhydrazine. While in the biochemical evaluation although 7-epi did not cause toxic effects to the host, it was not able to correct the damage caused by S. mansoni eggs. In the in vivo schistosomicidal tests, no significant effects were observed in the adult worm, when infected mice were treated with 7-epi, but there was a reduction in the area of granuloma (46.0%) and eosinophil count in hepatic tissue (45.0%). 7-epi showed no toxicity in the evaluated parameters and was still able to protect the cells against damage caused by the damaging agents. The results obtained showed a significant schistosomicidal activity in vivo at the dose of 300 mg / kg. In addition, there was a reduction in the size of granumloma. Therefore, these results are preliminary and point out the importance of assessing in vivo the activity of this substance using different treatment regimens and 7-epi liposome formulations to improve its efficacy.