Amiodarone and itraconazole improve the activity of pentavalent antimonial in the treatment of experimental cutaneous leishmaniasis

Anversa, Laís; Tibúrcio, Monique Gomes Salles; Batista, Lara Rocha; Cuba, Marília Beatriz de; Nascentes, Gabriel Antônio Nogueira; Martins, Tábata Yamasaki; Richini-Pereira, Virgínia Bodelão; Ruiz, Luciana da Silva; Silva, Valdo José Dias da; Ramı́rez, Luı́s Eduardo

doi:10.1016/j.ijantimicag.2017.06.007

Cited by 10 publications

(3 citation statements)

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“…The combination of meglumine antimoniate with 8.8 mg/kg/day of spironolactone was more effective than treatment with meglumine antimoniate alone. Some studies have shown that the use of meglumine antimoniate associated with other drugs is effective; for example, combinations with lapachone derivatives, azoles, amiodarone, and aminosidine sulfate have shown a greater effectiveness when compared to the use of meglumine antimoniate alone (Oliva et al, 1998;Anversa et al, 2017;Gonçalves-Oliveira et al, 2019). Giannitrapani et al (2009) described the case of a patient with visceral leishmaniasis who was previously diagnosed with cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

et al. 2021

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Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. In the search for new drugs, we performed a drug screening of L. amazonensis promastigotes and intracellular amastigotes of fifty available drugs belonging to several classes according to their pharmacophoric group. Spironolactone, a potassium-sparing diuretic, proved to be the most promising drug candidate. After demonstrating the in vitro antileishmanial activity, we evaluated the efficacy on a murine experimental model with L. amazonensis and L. infantum. The treatment controlled the cutaneous lesion and reduced the parasite burden of L. amazonensis significantly, as effectively as meglumine antimoniate. The treatment of experimental visceral leishmaniasis was effective in reducing the parasite load on the main affected organs (spleen and liver) via high doses of spironolactone. The association between spironolactone and meglumine antimoniate promoted better control of the parasite load in the spleen and liver compared to the group treated with meglumine antimoniate alone. These results reveal a possible benefit of the concomitant use of spironolactone and meglumine antimoniate that should be studied more in depth for the future possibility of repositioning for leishmaniasis co-therapy.

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Section: Discussionmentioning

confidence: 99%

Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

et al. 2021

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“…The administration of amiodarone at 50 mg/kg/day + miltefosine at 20 mg/kg/day resulted in a “parasitological cure” in 90% of the animals, as evaluated by optical microscopy, PCR and cell culture [ 38 ]. Furthermore Anversa et al [ 39 ] showed that amiodarone used either on its own or in combination was unable to stop the development of cutaneous lesions caused by L. amazonensis ; however, an improvement of pentavalent antimonial activity in the lesions has been observed with no side effects [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

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

Pinto

Tempone

2018

J Venom Anim Toxins Incl Trop Dis

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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.

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“…Other promising results were found when combining antimonials with drugs intended for other diseases, for example, antifungals and antiparasitics, such as amiodarone and itraconazole (Anversa et al, 2017), levamisole (Bamorovat et al, 2019) and oxiranes (epoxy-α-lapachone and epoxymethyl-lawsone) (Gonçalves-Oliveira et al, 2019), as well as the anticancer drug tamoxifen (Machado et al, 2018) (Trinconi et al, 2018). Añez et al proposed as an alternative treatment the intralesional infiltration of a generic pentavalent antimonial compound combined with lidocaine, based on the successful results in a study including 122 lesions caused by L. braziliensis (Añez et al, 2018) Shanehsaz and Ishkhanian found a good response to a treatment based on a lower dose of systemic meglumine antimoniate supplemented with oral cimetidine, although it was less effective than the standard dose (Shanehsaz and Ishkhanian, 2015).…”

Section: Intralesionalmentioning

confidence: 99%

An appraisal of the scientific current situation and new perspectives in the treatment of cutaneous leishmaniasis

et al. 2021

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Amiodarone and itraconazole improve the activity of pentavalent antimonial in the treatment of experimental cutaneous leishmaniasis

Cited by 10 publications

References 30 publications

Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

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

An appraisal of the scientific current situation and new perspectives in the treatment of cutaneous leishmaniasis

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