Use este identificador para citar ou linkar para este item:
https://www.arca.fiocruz.br/handle/icict/46987
Tipo de documento
ArtigoDireito Autoral
Acesso restrito
Coleções
- IOC - Artigos de Periódicos [12596]
Metadata
Mostrar registro completo
EFFECT OF ITRACONAZOLE-EZETIMIBE-MILTEFOSINE TERNARY THERAPY IN MURINE VISCERAL LEISHMANIASIS
Azoles
Ezetimibe
Miltefosina
Reposição de drogas
Terapia combinada
Azoles
Ezetimibe
Miltefosine
Drug repurposing
Combined therapy
Afiliação
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Estudos Integrados em Protozoologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Estudos Integrados em Protozoologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Resumo em Inglês
Drug combination therapy is an interesting approach to increase the
success of drug repurposing for neglected diseases. Thus, the objective of this work
was to evaluate binary and ternary therapies composed of itraconazole, ezetimibe,
and miltefosine for the treatment of visceral leishmaniasis. Intracellular Leishmania
infantum amastigotes were incubated with the drugs alone or in combination for
72 h. For in vivo experiments, we tested long-course (21 days, once per day) and
short-course (5 days, twice per day) treatments for the binary combination of itraco nazole and ezetimibe. For the ternary therapy including miltefosine, we adopted the
short-course treatment and varied the vehicle. None of the combinations were toxic
to macrophages. The binary combination of itraconazole plus ezetimibe and the ter nary combination of itraconazole, ezetimibe, and miltefosine had synergistic effects
in intracellular amastigotes, for some of the proportions evaluated. Although the in
vivo long-course therapy had been more effective than the short-course protocol, it
showed hepatic toxicity signs. Ezetimibe has been proven to be able to reduce the
parasite burden alone or in combination. Both suspensions of the ternary combina tion were active, but when the drugs were suspended in the commercial Ora-Plus
formulation instead of purified water, the parasite burden was reduced by 98% in
the liver and spleen. Altogether, the results demonstrate for the first time the activity
of ezetimibe in a viscerotropic species of Leishmania and indicate that ternary treat ment composed of miltefosine, itraconazole, and ezetimibe at low doses is a promis ing therapeutic alternative for the treatment of visceral leishmaniasis.Drug combination therapy is an interesting approach to increase the
success of drug repurposing for neglected diseases. Thus, the objective of this work
was to evaluate binary and ternary therapies composed of itraconazole, ezetimibe,
and miltefosine for the treatment of visceral leishmaniasis. Intracellular Leishmania
infantum amastigotes were incubated with the drugs alone or in combination for
72 h. For in vivo experiments, we tested long-course (21 days, once per day) and
short-course (5 days, twice per day) treatments for the binary combination of itraco nazole and ezetimibe. For the ternary therapy including miltefosine, we adopted the
short-course treatment and varied the vehicle. None of the combinations were toxic
to macrophages. The binary combination of itraconazole plus ezetimibe and the ter nary combination of itraconazole, ezetimibe, and miltefosine had synergistic effects
in intracellular amastigotes, for some of the proportions evaluated. Although the in
vivo long-course therapy had been more effective than the short-course protocol, it
showed hepatic toxicity signs. Ezetimibe has been proven to be able to reduce the
parasite burden alone or in combination. Both suspensions of the ternary combina tion were active, but when the drugs were suspended in the commercial Ora-Plus
formulation instead of purified water, the parasite burden was reduced by 98% in
the liver and spleen. Altogether, the results demonstrate for the first time the activity
of ezetimibe in a viscerotropic species of Leishmania and indicate that ternary treat ment composed of miltefosine, itraconazole, and ezetimibe at low doses is a promis ing therapeutic alternative for the treatment of visceral leishmaniasis.
Palavras-chave
Leishmania infantumAzoles
Ezetimibe
Miltefosina
Reposição de drogas
Terapia combinada
Palavras-chave em inglês
Leishmania infantumAzoles
Ezetimibe
Miltefosine
Drug repurposing
Combined therapy
Compartilhar