Oral combination of eugenol oleate and miltefosine induce immune response during experimental visceral leishmaniasis through nitric oxide generation with advanced cytokine demand. (October 2021)

• Record Type: Journal Article
• Authors: Kar, Amrita; Charan Raja, Mamilla R.; Jayaraman, Adithyan; Srinivasan, Sujatha; Debnath, Joy; Kar Mahapatra, Santanu
• Is Part Of: Cytokine. Volume 146(2021)
• Publication Date: 2021-10
• Subjects: Eugenol oleate -- Miltefosine -- Additive interaction -- Oral combination -- p38MAPK; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2021.155623
• Languages: English
• ISSNs: 1043-4666

Abstract

Graphical abstract: Highlights: Eugenol oleate and miltefosine shows additive activity ( x ΣFIC 0.68) against L. donovani amastigotes. Combination therapy reduces 81.69% parasite burden in murine macrophages. In vivo oral combination therapy reduces 88.76% in liver and 80.6% in spleen parasite burden. Combination therapy induces p38MAPK dependent nitrite generation. Abstract: Conventional therapy of visceral leishmaniasis (VL) remains challenging with the pitfall of toxicity, drug resistance, and expensive. Hence, urgent need for an alternative approach is essential. In this study, we evaluated the potential of combination therapy with eugenol oleate and miltefosine in Leishmania donovani infected macrophages and in the BALB/c mouse model. The interactions between eugenol oleate and miltefosine were found to be additive against promastigotes and amastigotes with x ΣFIC 1.13 and 0.68, respectively. Significantly (p < 0.001) decreased arginase activity, increased nitrite generation, improved pro-inflammatory cytokines, and phosphorylated p38MAPK were observed after combination therapy with eugenol oleate and miltefosine. >80% parasite clearance in splenic and hepatic tissue with concomitant nitrite generation, and anti-VL cytokines productions were observed after orally administered miltefosine (5 mg/kg body weight) and eugenol oleate (15 mg/kg body weight) in L. donovani -infected BALB/c mice. Altogether, this study suggested the possibility of an oral combination of miltefosine with eugenol oleate against visceral leishmaniasis.