Banca de DEFESA: JOHNY WYSLLAS DE FREITAS OLIVEIRA

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : JOHNY WYSLLAS DE FREITAS OLIVEIRA
DATE: 19/10/2023
TIME: 14:00
LOCAL: https://meet.google.com/fbw-mxrz-otq
TITLE:

CHARACTERIZATION OF SODIUM DIETYLDITHIOCARBAMATE AS A POTENTIAL DRUG FOR THE TREATMENT OF CHAGAS DISEASE

KEY WORDS:

Antiparasitic activity; Trypanosoma cruzi; Chagas disease; Sodium dietyldithiocarbamate; nanoformulations

PAGES: 160
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUBÁREA: Bioquímica dos Microorganismos
SUMMARY:

Chagas disease is an endemic zoonosis in Latin America, mainly affecting the poorer populations. The available drugs for treating both diseases have low effectiveness against intracellular forms, high toxicity, low bioavailability, and end up being unsafe for patients' health. Therefore, for several decades, efforts have been made to evaluate the possibility of using other drugs to combat this disease. One promising candidate is sodium diethyldithiocarbamate (DETC), previously described as a highly effective compound against Leishmania sp. and Trypanosoma cruzi in in vitro and in vivo models. However, in an attempt to enhance its bioavailability and reduce potential toxicity, this study evaluated the use of a nanosystem in combination with DETC through in vitro, in silico, and in vivo approaches against Trypanosoma cruzi. n this study, the nanoparticle was nanoformulated through nanoprecipitation using PLA as a polymer and tested in vitro for physicochemical characterization, cytotoxicity, cellular penetration, and antiparasitic activity. The nanoformulated PLA-DETC was found to be stable, with an average size of <200 nm and with IPD <0.3 and a zeta potential of -20 mV. It exhibited low cellular toxicity, causing no reduction of more than 20% in cell viability, had the ability to penetrate 3T3 and RAW cells within a 24-hour period, and also inhibited almost 70% of the Dm28c strain of T. cruzi within 24 hours. Additionally, it was observed that the nanosystem was capable of inducing an almost 70% increase in reactive oxygen species inside the parasites, which is a crucial factor that can lead to the parasite's death.Furthermore, an in silico analysis revealed that DETC had a more suitable ADMET profile based on physicochemical and medicinal chemistry properties compared to traditionally used drugs against Chagas disease, indicating lower toxicity. In vivo toxicity of both PLA-DETC nanoparticles and free drug at concentrations of 300 mg/kg and 1000 mg/kg was evaluated, considering hematological, biochemical, histopathological, and physical parameters following the acute toxicity characterization recommended by OECD in test 423. The results showed minimal alterations compared to the control group. A 10% reduction in platelet levels was observed, along with a slight increase in urea and AST, and a decrease in creatinine levels. Moreover, there were no significant changes in the animals' weight, behavior, or physical parameters, aligning with the control group. Finally, infection and treatment protocols were evaluated using DETC (300 mg/kg, 100 mg/kg, 0.36 mg, and 0.18 mg) and PLA-DETC nanoparticles (0.36 mg and 0.18 mg). A statistically significant reduction was observed for DETC, which exhibited a profile similar to benznidazole at a concentration of 100 mg/kg. Additionally, during the 7-day treatment, few alterations were observed, indicating low compound toxicity.

COMMITTEE MEMBERS:
Interno - 2985070 - JONAS IVAN NOBRE OLIVEIRA
Interno - 2275890 - MARCELO DE SOUSA DA SILVA
Externo ao Programa - 1639820 - ARNOBIO ANTONIO DA SILVA JUNIOR - UFRNExterna à Instituição - ALINE RIMOLDI RIBEIRO
Externa à Instituição - CLAUDIA JASSICA GONÇALVES MORENO - NOVA