Therapeutic Efficacy of a Mixed Formulation of Conventional and PEGylated Liposomes Containing Meglumine Antimoniate, Combined with Allopurinol, in Dogs Naturally Infected with Leishmania infantum

Abstract

The treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote a marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP plus Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg of body weight/dose) at 4-day intervals plus allopurinol at 30 mg/kg/12 h per os (p.o.) during 130 days (LCP+Allop); LC plus Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) plus allopurinol during 130 days (LC+Allop); Allop, treated with allopurinol only; and a nontreated control. Parasite loads were evaluated by quantitative PCR in liver, spleen, and bone marrow tissue and by immunohistochemistry in the ear skin, before treatment, just after treatment, and 4 months later. The LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen, and bone marrow 4 months after treatment compared to the pretreatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin in comparison to the control group. On the basis of clinical staging and parasitological evaluations, the LCP formulation exhibited a more favorable therapeutic profile than the LC one, being therefore promising for the treatment of canine visceral leishmaniasis.

Formulation of Amphotericin B in PEGylated Liposomes for Improved Treatment of Cutaneous Leishmaniasis by Parenteral and Oral Routes

“…On the other hand, a different profile was observed by our group using anionic liposomes containing dicetylphosphate, with or without 5 mol% of DSPE-PEG2000. The PEGylated liposomes promoted a prolonged circulation time of encapsulated antimonial drug, in comparison with non-PEGylated liposomes, and were more effective in reducing the skin parasite load in canine leishmaniasis [ 25 , 26 ]. Nevertheless, it is possible that distinct drug release profiles from liposomes may contribute to the therapeutic difference between the PEGylated formulation and AmBisome ® .…”

Clinical and parasitological impact of short-term treatment using miltefosine and allopurinol monotherapy or combination therapy in canine visceral leishmaniasis

“…Currently, miltefosine is the only drug authorized for canine treatment in Brazil and is clinically effective (Nogueira et al, 2019). In several studies, the efficacy of miltefosine has been associated with the use of allopurinol which is administered mainly to prevent the disease recurrence (Pennisi et al, 2005;Yasur-Landau et al, 2017;Santos et al, 2020), although allopurinol effectively reduces the parasite load used alone (Nascimento et al, 2020). However, in Brazil, allopurinol is not yet authorized as a veterinary drug for canine VL (CVL) therapy and has been used only in research (Dias et al, 2020).…”