Enhancement in therapeutic efficacy of miltefosine in combination with synthetic bacterial lipopeptide, Pam3Cys against experimental Visceral Leishmaniasis

Enhanced antileishmanial efficacy with pronounced transformation in host immune response was observed during the combination of in-built immunoadjuvant, Pam3Cys with miltefosine (at lower doses) as compared to individual drug. [Display omitted] ► Combination of miltefosine and immunomodulator, Pam3Cys was evaluated against VL. ► It significantly enhanced antileishmanial efficacy as compared to individual drug. ► Enhanced production of Th1 cytokines and ROS & RNS was witnessed in this group. ► Combination group also exhibited significant phagocytic responses. ► This combination therapy appears to be a good strategy for treatment of VL. Existing drugs for Visceral Leishmaniasis (VL) are partially effective, toxic, having high cost and long term treatment. Their efficacies are also compromised due to suppression of immune function associated during the course of infection. Combination therapy including a potential and safe immunostimulant with lower doses of effective drug has proven as a significant approach which is more effective than immunotherapy or drug therapy alone. In the present study, we have used the combination of Pam3Cys (an in-built immunoadjuvant and TLR2 ligand) and miltefosine. Initially dose optimization of both the agents was carried out and after that, antileishmanial effect of their combination was evaluated. All experiments were done in BALB/c mouse model. The immunomodulatory role of Pam3Cys on the immune functions of the host receiving combination treatment was also determined using immunological and biochemical parameters viz. phagocytosis, Th1/Th2 cytokines and production of ROS, RNS and H2O2. Combination group showed significant enhancement in parasitic inhibition as compared to groups receiving miltefosine and Pam3Cys separately. Enhanced production of Th1 cytokines as well as ROS, RNS and H2O2 was witnessed during the study of immunological alterations. Remarkable increase in phagocytosis index was also observed. Thus, the risk of development of drug resistance against miltefosine can be resolved through using low doses of it and Pam3Cys (single-dose) in combination and also provide a promising alternative for cure of leishmaniasis, with a pronounced transformation of the host immune response.