Banca de DEFESA: LÍVIA BRITO COELHO

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
DISCENTE : LÍVIA BRITO COELHO
DATA : 04/09/2020
HORA: 14:00
LOCAL: Webconferência
TÍTULO:

Evaluation of the safety of 17-AAG for its use as a chemotherapy in the treatment of canine visceral leishmaniasis.

PALAVRAS-CHAVES:

Toxicity; pharmacokinetics; dogs; tanespymicin.

PÁGINAS: 70
GRANDE ÁREA: Ciências da Saúde
ÁREA: Medicina
RESUMO:

INTRODUCTION: In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficiencies in existing treatments and the lack of an effective vaccine, euthanasia in dogs is one of the main strategies for controlling the disease, making the development of new therapeutic interventions mandatory. Previously, our group has shown that 17-AAG, an HSP90 inhibitor, has demonstrated potential for use in the treatment of leishmaniasis. OBJECTIVE: The present study aimed to test the safety of 17-AAG in dogs, evaluating the plasma pharmacokinetics, dose proportionality and tolerability of 17-AAG in response to one or more intravenous (IV) doses in healthy dogs. MATERIAL AND METHODS: Two research protocols were used. Protocol 1 (P1): healthy dogs received variable doses (50, 100, 150, 200 or 250 mg / m²) of 17-AAG or placebo (n = 4) intravenously, using a cross-over design with a wash-out period seven days between treatments. Protocol 2 (P2) involved nine healthy dogs that received three doses of 150 mg / m² 17-AAG administered IV at 48 hour intervals. RESULTS: All dogs successfully completed both protocols. At P1, 17-AAG was well tolerated, however, increased levels of liver enzymes and diarrhea were observed in all four dogs that received a dosage of 250 mg / m². The parameters maximum plasma concentrations (Cmax) and area under the curve (AUC) were proportional to the dose administered between the doses of 50 and 200 mg / m². Regarding P2, 17-AAG was considered to be well tolerated at multiple doses of 150 mg / m². Increased levels of liver enzymes and diarrhea were observed in 3/9 and 1/9 of these dogs, respectively. CONCLUSION: Our results demonstrated safety for conducting the 17-AAG efficacy test in dogs with VL when administered in concentrations equal to or less than 150 mg / m² at intervals of 48 hours. However, the hepatotoxicity observed with the interval dosing scheme, despite being reversible, points to efforts to reduce toxicity such as the use of nanoformulations or liposomes.

MEMBROS DA BANCA:
Externo ao Programa - 2663064 - DANIELA FARIAS LARANGEIRA
Presidente - 2573399 - DEBORAH BITTENCOURT MOTHE FRAGA
Interno - 005.343.193-60 - JAIME RIBEIRO FILHO - Fiocruz - RJ