Short-Course Treatment With Imipramine Entrapped in Squalene Liposomes Results in Sterile Cure of Experimental Visceral Leishmaniasis Induced by Antimony Resistant Leishmania donovani With Increased Efficacy.

Sandip Mukherjee,Supratim Pradhan,Shantanabha Das,Shyam Sundar,Syamal Roy,Souradeepa Ghosh,Budhaditya Mukherjee

doi:10.3389/fcimb.2020.595415

Abstract

Previously we have shown that long term oral treatment of tricyclic-antidepressant-drug, imipramine, against experimental visceral leishmaniasis, results in clearance of organ parasites, regardless of input infection, either with antimony-sensitive (SbS) or antimony-resistant (SbR) Leishmania donovani (LD) clinical isolates. Although continuous imipramine monotherapy for 28 days (5 mg/kg) results in significant clearance of organ parasites in both SbR and SbSLD infected hamsters, the dose for the sterile parasite clearance from visceral organ is comparatively higher (10 mg/kg) and shows signs of toxicity. Hence, to reduce the toxicity, we encapsulated imipramine in squalene-phosphatidylcholine (SP) liposome (Lip-Imi) and tested its efficacy for a short-course treatment (10 days) in the animal model of visceral leishmaniasis. We observed a significant reduction of hepatic toxicity coupled with sterile parasite clearance in case of this short-course treatment of Lip-Imi, which is absent with free Imi treatment. This also correlates with significant increase in serum availability of imipramine in case of Lip-Imi treatment due to sustained release. Clearance of parasite was coupled with the polarization of antileishmanial immune repertoire from Th2 to Th1 after treatment with Lip-Imi in both SbRLD and SbSLD infected mouse models of LD infection. This study showed that imipramine is effective against both SbSLD and SbRLD at a significantly lower dose with reduced time course of treatment without any toxic side effects, when encapsulated in SP-liposome. Thus, the drug has the potential to be repurposed for the treatment of Kala-azar.

Highlights

Leishmaniasis caused by different species of protozoa of genus Leishmania that are transmitted by Phlebotomine sandfly vector
Entrapment of the imipramine within liposomes had no apparent effect on the size or on the multilamellar structure
Miltefosine and AmpB is the current drug of choice with high cure rate, but high toxicity in combination with other adverse side effects and emergence of relapse cases are against these drugs have restrict their use (Pandey et al, 2009; Burza et al, 2014)

Summary

Introduction

Leishmaniasis caused by different species of protozoa of genus Leishmania that are transmitted by Phlebotomine sandfly vector. Too long half-life, large drug dose, rampant uses of drugs are the key factors that regulate resistance induction (Croft and Coombs, 2003). Approaches to overcome antimonial resistance include use of alternative drugs (Croft et al, 2006a), short-treatment regime (Sundar et al, 2000a) and better drug delivery system (Black et al, 1977; Valladares et al, 2001) to avoid side effects and resistance induction. Squalene a linear triterpene, has a very large spectrum in clinical use (Kamimura et al, 1992; Kohno et al, 1995) It is used in the adjuvant formulations in conjunction with some surfactants and administered along with vaccine to stimulate the immune system (Klucker et al, 2012). Antidepressant-Sertraline delivered in phosphatidylserine liposomes has shown effectiveness in an experimental model of VL (Romanelli et al, 2019)

Methods

Results

Conclusion