Randomized, allopurinol-controlled trial of the effects of dietary nucleotides and active hexose correlated compound in the treatment of canine leishmaniosis

Abstract

First-line treatment for canine leishmaniosis (CanL) is N-methylglucamine antimoniate (MGA) combined with allopurinol. However, in some dogs allopurinol may induce hyperxanthinuria leading to urolithiasis. Moreover, allopurinol resistance has recently been described in Leishmania infantum isolates from treated dogs with a relapse of the disease. Alternative treatments are thus needed. Since the type of host immune response strongly influences CanL progression and prognosis, dogs could benefit from treatments targeted at modulating such response, such as nucleotides and active hexose correlated compound (AHCC). The aim of this study was to evaluate the effects of an oral combination of nucleotides and AHCC in dogs with clinical leishmaniosis. Sixty-nine dogs with naturally-occurring clinical leishmaniosis were included in this multicenter, open-label, positively-controlled clinical trial and randomized to receive 10mg/kg allopurinol PO BID (allopurinol group) or 17mg/kg AHCC plus 32mg/kg nucleotides PO SID (supplement group) for 180 days. All dogs were also given 50mg/kg MGA SC BID during the first 28 days. At the time points 0, 30, and 180 days of the trial, dogs underwent a clinical examination, and blood, urine, and bone marrow samples were submitted for analytical tests. Final data analyses (allopurinol group: n=29; supplement group: n=24) revealed a significant improvement in both groups in clinical scores and ELISA-determined antibody titers after treatment. However, the supplement group showed a significantly lower clinical score (P=0.005) and significantly higher antibody titers (P=0.032) after 180 days, compared to the allopurinol group. RT-PCR parasite loads were reduced in groups (mean±SD supplement: 0.38±0.56 vs 5.23±18.9; allopurinol: 0.45±1.47 vs 3.09±8.36 parasites/ng of DNA), but there were no significant differences over time or between groups. During the study, 12 dogs in the allopurinol group developed xanthinuria (41%) compared to no dogs (0%) in the supplement group (P=0.000). Both treatments led to significantly increased CD4+/CD8+ ratio, and improvements in protein electrophoretic pattern and acute phase response. In conclusion, 6-month oral treatment with nucleotides and AHCC in addition to MGA showed similar efficacy to the current first-line treatment for CanL, without producing xanthinuria. This combination could be a good alternative to MGA-allopurinol combination treatment for CanL, especially for dogs suffering allopurinol-related adverse events.

Keywords: AHCC; Allopurinol; Canine leishmaniosis; Dietary nucleotides; Hyperxanthinuria; Xanthine.