| Autor: |
Ferrante M; Laboratory of Physiology and Pharmacology, Department of Veterinary Medicine, Federal University of Lavras, Lavras 37200-000, Minas Gerais, Brazil.; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil., Leite BMM; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil., Fontes LBC; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil., Santos Moreira A; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil., Nascimento de Almeida ÉM; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil., Brodskyn CI; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil., Lima IDS; Laboratory of Structural and Molecular Pathology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil., Dos Santos WLC; Laboratory of Structural and Molecular Pathology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil.; Department of Pathology and Forensic Medicine, Bahia Medical School, Federal University of Bahia, Salvador 40110-906, Bahia, Brazil., Pacheco LV; Department of Life Sciences, State University of Bahia, Salvador 41150-000, Bahia, Brazil., Cardoso da Silva V; Department of Life Sciences, State University of Bahia, Salvador 41150-000, Bahia, Brazil., Dos Anjos JP; Integrated Campus of Manufacturing and Technology, SENAI CIMATEC University Center, Salvador 41650-010, Bahia, Brazil., Guarieiro LLN; Integrated Campus of Manufacturing and Technology, SENAI CIMATEC University Center, Salvador 41650-010, Bahia, Brazil., Landoni F; Department of Pharmacology, Faculty of Veterinary Science, National University of La Plata, Buenos Aires 1900, Argentina., de Menezes JPB; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil., Fraga DBM; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil.; Department of Preventive Veterinary Medicine and Animal Production, School of Veterinary Medicine and Animal Science, Federal University of Bahia, Salvador 40170-110, Bahia, Brazil.; National Institute of Science and Technology of Tropical Diseases (INCT-DT), National Council for Scientific Research and Development (CNPq)., Santos Júnior AF; Department of Life Sciences, State University of Bahia, Salvador 41150-000, Bahia, Brazil., Veras PST; Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador 40296-710, Bahia, Brazil.; National Institute of Science and Technology of Tropical Diseases (INCT-DT), National Council for Scientific Research and Development (CNPq). |
| Abstrakt: |
In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m 2 ) of 17-AAG or a placebo ( n = 4/dose level), using a cross-over design with a 7-day "wash-out" period; Study B: nine dogs received three IV doses of 150 mg/m 2 of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R 2 = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes-alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)-and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m 2 . After single doses of 17-AAG (50-250 mg/m 2 ), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0-8 h μg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m 2 doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m 2 . Increased levels of liver enzymes-ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)-and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0-48 h were 5254 ± 2784 μg/mL and 6850 ± 469 μg/mL × h in plasma and 736 ± 294 μg/mL and 7382 ± 1357 μg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m 2 , since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity. |
