Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches

Abstract

Concurrently, leishmaniasis and AIDS are global public health issues and the overlap between these diseases adds additional treats to the management of co-infected patients. Lopinavir (LPV) has a well characterized anti-HIV and leishmanicidal action, and to analyze its combined action with miltefosine (MFS) could help to envisage strategies to the management of co-infected patients. Here, we evaluate the interaction between LPV and MFS against Leishmania infantum infection by in vitro and in vivo approaches. The effect of the compounds alone or in association was assessed for 72 h in mouse peritoneal macrophages infected with L. infantum by the determination of the IC 50 s and FICIs. Subsequently, mice were orally treated twice daily during 5 days with the compounds alone or in association and evaluated after 30 days. The in vitro assays revealed an IC 50 of 0.24 μM and 9.89 μM of MFS and LPV, respectively, and an additive effect of the compounds (FICI 1.28). The in vivo assays revealed that LPV alone reduced the parasite load in the spleen and liver by 52 and 40%, respectively. The combined treatment of infected BALB/c mice revealed that the compounds alone required at least two times higher doses than when administered in association to virtually eliminate the parasite. Mice plasma biochemical parameters assessed revealed that the combined therapy did not present any relevant hepatotoxicity. In conclusion, the association of MFS with LPV allowed a reduction in each compound concentration to achieve the same outcome in the treatment of visceral leishmaniasis. Although a pronounced synergistic effect was not evidenced, it does not discard that such combination could be useful in humans co-infected with HIV and Leishmania parasites.

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

“…The early efforts to overcome these limitations were directed to the improvement of the drug delivery systems 27 , 28 and the formulation of more effective combination therapies. 29 However, the cost increase 30 − 32 and the rapid recurrence of resistance phenomena 33 − 37 prompted the scientific community to turn its attention toward the development of new antileishmanial drugs, 38 − 51 which should be effective, safe, and not expensive. Concerning the research and development of new improved drugs, four main approaches are exploited: (i) drug repurposing, as in the case of fexinidazole 40 ( Figure 2 ); (ii) diversity-oriented screening of collections of chemicals, such as oxaborole AN-4169 ( 39 , 52 ) and aminopyrazole amide 1 ( 39 ) ( Figure 2 ); (iii) phenotypic screening, leading to the identification of new biological targets and effective inhibitors, 53 − 56 such as 17-AAG (HSP90 inhibitor) 57 ( Figure 2 ); and (iv) use of known or new natural products with limited side effects, 58 − 61 especially those deriving from plants, such as fucoidan 58 and 11,13-dehydrocompressanolide 61 ( Figure 2 ).…”

A clioquinol-containing Pluronic® F127 polymeric micelle system is effective in the treatment of visceral leishmaniasis in a murine model

“…Miltefosine is a drug used to treat leishmaniasis [22,58]. It has been shown to be effective against various parasite species, such as those causing visceral leishmaniasis and/or tegumentary leishmaniasis [8,19,44]. However, recent reports have shown that miltefosine can cause adverse effects such as nausea and vomiting during and/or after administration as well as teratogenicity.…”

Sertraline Delivered in Phosphatidylserine Liposomes Is Effective in an Experimental Model of Visceral Leishmaniasis

“…In a previous study, miltefosine was administered to a BALB/c model infected with L . (L.) infantum (MHOM/MA67ITMAP263) and resulted in 100% suppression of the parasite burden in liver and spleen at 7.7 mg/kg (Rebello et al, 2019).…”

“…A two-step washing procedure was performed to eliminate non-adherent cells. Promastigotes were added at a ratio of 10:1, using RPMI 1640 supplemented with 2% horse serum (Rebello et al, 2019), and after 4 h, the extracellular parasites were removed by washing; fresh medium containing SERT, LP-SERT, and control were added; and the cells were incubated at 37°C for 72 h. The initial concentration of SERT and miltefosine was 100 μM, and that for LP-SERT was 20 μM. At the end of the assay, the slides were stained with Giemsa and observed using a light microscopy.…”