Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum: an in vitro and in vivo approach

Erika G. Pinto, Andre G. Tempone

Research output: Contribution to journalArticle

Abstract

Background
Considering the high toxicity and limited therapies available for treating visceral leishmaniasis (VL), the drug repositioning approach represents a faster way to deliver new therapies to the market.

Methods
In this study, we described for the first time the activity of a potent antiarrhythmic, amiodarone (AMD), against L. (L.) infantum and its in vitro and in vivo activity.

Results
The evaluation against promastigotes has shown that amiodarone presents leishmanicidal effect against the extracellular form, with an IC50 value of 10 μM. The activity was even greater against amastigotes in comparison with promastigotes with an IC50 value of 0.5 μM. The selectivity index in relation to the intracellular form demonstrated that the antiparasitic activity was approximately 56 times higher than its toxicity to mammalian cells. Investigation of the in vivo AMD activity in the L. infantum-infected hamster model showed that 51 days after the initial infection, amiodarone was unable to reduce the parasite burden in the spleen and liver when treated for 10 consecutive days, intraperitoneally, at 50 mg/kg/day, as determined by qPCR. Although not statistically significant, AMD was able to reduce the parasite burden by 20% in the liver when treated for 10 consecutive days, orally, at 100 mg/kg/day; no reduction in the spleen was found by qPCR.

Conclusions
Our findings may help further drug design studies seeking new AMD derivatives that may provide new candidates with an in vitro selectivity close to or even greater than that observed in the prototype delivering effectiveness in the experimental model of VL.
LanguageEnglish
Article number29
Pages1-6
Number of pages6
JournalJournal of Venomous Animals and Toxins including Tropical Diseases
Volume24
Issue number1
DOIs
Publication statusPublished - 25 Oct 2018

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Leishmania infantum
Amiodarone
Anti-Arrhythmia Agents
Visceral Leishmaniasis
Inhibitory Concentration 50
Parasites
Spleen
Drug Repositioning
Antiparasitic Agents
Drug Design
Liver
Cricetinae
In Vitro Techniques
Theoretical Models
Therapeutics
Infection

Keywords

  • Amiodarone
  • In vitro
  • In vivo
  • Leishmania
  • Visceral leishmaniasis

Cite this

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title = "Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum: an in vitro and in vivo approach",
abstract = "BackgroundConsidering the high toxicity and limited therapies available for treating visceral leishmaniasis (VL), the drug repositioning approach represents a faster way to deliver new therapies to the market.MethodsIn this study, we described for the first time the activity of a potent antiarrhythmic, amiodarone (AMD), against L. (L.) infantum and its in vitro and in vivo activity.ResultsThe evaluation against promastigotes has shown that amiodarone presents leishmanicidal effect against the extracellular form, with an IC50 value of 10 μM. The activity was even greater against amastigotes in comparison with promastigotes with an IC50 value of 0.5 μM. The selectivity index in relation to the intracellular form demonstrated that the antiparasitic activity was approximately 56 times higher than its toxicity to mammalian cells. Investigation of the in vivo AMD activity in the L. infantum-infected hamster model showed that 51 days after the initial infection, amiodarone was unable to reduce the parasite burden in the spleen and liver when treated for 10 consecutive days, intraperitoneally, at 50 mg/kg/day, as determined by qPCR. Although not statistically significant, AMD was able to reduce the parasite burden by 20{\%} in the liver when treated for 10 consecutive days, orally, at 100 mg/kg/day; no reduction in the spleen was found by qPCR.ConclusionsOur findings may help further drug design studies seeking new AMD derivatives that may provide new candidates with an in vitro selectivity close to or even greater than that observed in the prototype delivering effectiveness in the experimental model of VL.",
keywords = "Amiodarone, In vitro, In vivo, Leishmania, Visceral leishmaniasis",
author = "Pinto, {Erika G.} and Tempone, {Andre G.}",
note = "This publication was supported by the Coordination for the Improvement of Higher Education Personnel (CAPES) through Programa Editora{\cc}{\~a}o CAPES (edital n. 13/2016, aux{\'i}lio n. 0722/2017, processo n.88881.142062/2017–01) and by the National Council for Scientific and Technological Development (CNPq) through Programa Editorial CNPq/CAPES 498 (chamada n. 26/2017, proc. n. 440954/2017–7).",
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Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum : an in vitro and in vivo approach. / Pinto, Erika G.; Tempone, Andre G.

Vol. 24, No. 1, 29, 25.10.2018, p. 1-6.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum

T2 - an in vitro and in vivo approach

AU - Pinto, Erika G.

AU - Tempone, Andre G.

N1 - This publication was supported by the Coordination for the Improvement of Higher Education Personnel (CAPES) through Programa Editoração CAPES (edital n. 13/2016, auxílio n. 0722/2017, processo n.88881.142062/2017–01) and by the National Council for Scientific and Technological Development (CNPq) through Programa Editorial CNPq/CAPES 498 (chamada n. 26/2017, proc. n. 440954/2017–7).

PY - 2018/10/25

Y1 - 2018/10/25

N2 - BackgroundConsidering the high toxicity and limited therapies available for treating visceral leishmaniasis (VL), the drug repositioning approach represents a faster way to deliver new therapies to the market.MethodsIn this study, we described for the first time the activity of a potent antiarrhythmic, amiodarone (AMD), against L. (L.) infantum and its in vitro and in vivo activity.ResultsThe evaluation against promastigotes has shown that amiodarone presents leishmanicidal effect against the extracellular form, with an IC50 value of 10 μM. The activity was even greater against amastigotes in comparison with promastigotes with an IC50 value of 0.5 μM. The selectivity index in relation to the intracellular form demonstrated that the antiparasitic activity was approximately 56 times higher than its toxicity to mammalian cells. Investigation of the in vivo AMD activity in the L. infantum-infected hamster model showed that 51 days after the initial infection, amiodarone was unable to reduce the parasite burden in the spleen and liver when treated for 10 consecutive days, intraperitoneally, at 50 mg/kg/day, as determined by qPCR. Although not statistically significant, AMD was able to reduce the parasite burden by 20% in the liver when treated for 10 consecutive days, orally, at 100 mg/kg/day; no reduction in the spleen was found by qPCR.ConclusionsOur findings may help further drug design studies seeking new AMD derivatives that may provide new candidates with an in vitro selectivity close to or even greater than that observed in the prototype delivering effectiveness in the experimental model of VL.

AB - BackgroundConsidering the high toxicity and limited therapies available for treating visceral leishmaniasis (VL), the drug repositioning approach represents a faster way to deliver new therapies to the market.MethodsIn this study, we described for the first time the activity of a potent antiarrhythmic, amiodarone (AMD), against L. (L.) infantum and its in vitro and in vivo activity.ResultsThe evaluation against promastigotes has shown that amiodarone presents leishmanicidal effect against the extracellular form, with an IC50 value of 10 μM. The activity was even greater against amastigotes in comparison with promastigotes with an IC50 value of 0.5 μM. The selectivity index in relation to the intracellular form demonstrated that the antiparasitic activity was approximately 56 times higher than its toxicity to mammalian cells. Investigation of the in vivo AMD activity in the L. infantum-infected hamster model showed that 51 days after the initial infection, amiodarone was unable to reduce the parasite burden in the spleen and liver when treated for 10 consecutive days, intraperitoneally, at 50 mg/kg/day, as determined by qPCR. Although not statistically significant, AMD was able to reduce the parasite burden by 20% in the liver when treated for 10 consecutive days, orally, at 100 mg/kg/day; no reduction in the spleen was found by qPCR.ConclusionsOur findings may help further drug design studies seeking new AMD derivatives that may provide new candidates with an in vitro selectivity close to or even greater than that observed in the prototype delivering effectiveness in the experimental model of VL.

KW - Amiodarone

KW - In vitro

KW - In vivo

KW - Leishmania

KW - Visceral leishmaniasis

U2 - 10.1186/s40409-018-0166-7

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