Miltefosine is an alkylphosphocholine compound that has been observed to induce apoptosis, although the precise mechanisms by which this occurs remain unclear. Allopurinol is a purine analog of adenosine nucleotide that inhibits RNA synthesis, thereby impeding the growth of Leishmania. Thus far, meglumine antimoniate in combination with allopurinol has been regarded as the primary treatment option in Europe, while miltefosine plus allopurinol has been considered a second-line intervention. However, there has been a growing interest in miltefosine therapy, as evidenced by its recent authorization in 2017 for the treatment of canine leishmaniosis (CanL) in Brazil, a country with a high prevalence of both canine and human leishmaniosis.
Despite elevated AST and ALT levels, combined treatment with miltefosine and allopurinol resulted in a reduction of AST and ALT in dogs from the MT+A group, although at a slower rate. This led to a return of urinalysis values to within the normal range. However, increased gene expression of pro-inflammatory cytokines persisted after treatment with miltefosine in combination with allopurinol.
Notwithstanding the generalized tendency of treated canines to achieve normal levels, the upregulation of pro-inflammatory cytokines (IFN-γ and IL-2) in conjunction with the trend toward the normalization of anti-inflammatory (IL-4 and IL-5) and regulatory cytokines (IL-10 and TGF-β) indicate the persistence of an inflammatory immune response throughout the three-month treatment period.
The combined therapies of miltefosine and meglumine antimoniate have been observed to exert an influence on the expression of cytokine genes.
MG+A has been observed to induce the overexpression of cytokines in both the blood and lymph nodes. It is plausible that allopurinol plays a pivotal role in the enhancement of cytokine generation. In the bone marrow, the drugs appear to exert an inhibitory effect on cytokine gene expression. Additionally, MT+A appears to facilitate the expression of cytokine genes. However, following the cessation of miltefosine administration, there was a notable decline in the expression of IL-4 in lymph node and IL-10 in bone marrow tissue.
Miltefosine therapy does not reduce the inflammatory immune response. Instead, it normalizes the anti-inflammatory response and suppresses the immune response.
With miltefosine now used to treat leishmaniosis in Brazil, a country with a high incidence of the disease in both humans and dogs, it is important to ensure the best possible protection for public health.