Potential of Artesunate in the treatment of visceral leishmaniasis in dogs naturally infected by Leishmania infantum: Efficacy evidence from a randomized field trial

Abstract

Leishmaniasis is among the world’s most neglected diseases. Dogs are the main reservoirs/hosts of Leishmania infantum, causative agent of both canine and human visceral leishmaniosis. Canine leishmaniasis (CanL) represents a public health problem as one of the most prevalent zoonotic diseases worldwide. Current therapeutics present drawbacks; thus, there is a need for more effective, safer, and cheaper drugs. The aim of this study was to evaluate and to compare the efficacy of oral administration of artesunate or meglumine antimoniate/allopurinol in dogs with clinical leishmaniasis. Forty-two dogs with naturally occurring clinical leishmaniasis were included in this open-label, simple randomized positive-control clinical field trial with 6 months of follow-up. Dogs received meglumine antimoniate 100 mg/kg/day and allopurinol 30 mg/kg/day for 28 days (control group, n = 26) or artesunate 25 mg/kg/day for 6 days (test group, n = 16). The animals were evaluated for their clinical evolution, parasite load (by qPCR) and humoral response at different time points: 0, 30, 90, and 180 days after treatment. Data analyses showed a significant improvement in both groups in clinical scores, parasitemia and antibody titers after treatment. Compared to the control group, the artesunate group showed significantly lower clinical score (P = 0.0001), lower parasitemia (P = 0.0001) and antibody titers after 6 months of follow-up. Compared to baseline values, a rapid, significant reduction (P < 0.012) in antibody levels, 2.28- versus 3.04-fold for the control versus artesunate groups, respectively, was observed 30 days after treatment. Antibody levels continued to decrease further in the artesunate group, where 58% of cases became seronegative at the 6-month follow-up. All qPCR-positive dogs were negative after treatment with artesunate, while 14.3% remained positive with the appearance of two new cases in the control group. Artesunate was well tolerated, and no side effects were recorded. Treatment failures were similar in both groups with 27.27% (6/22), including 18.18% (4/22) mortality in the control group, versus 26.66% (4/15), including 13.33% (2/15) mortality in the artesunate group. This is the first report showing the potential of artesunate in the treatment of dogs with clinical leishmaniasis. Artesunate showed higher efficacy than the current first-line treatment for CanL without any adverse effects. It could be a good alternative chemotherapy for CanL, and may be considered for further studies in human leishmaniases. Further clinical trials are needed to confirm these findings, to determine if there are relapses after treatment and if dogs remain infective to sandflies, to define the ideal therapeutic dosage and duration of treatment with artesunate.

Canine Visceral Leishmaniasis in Colombia Resistant to the Treatment of Choice (Meglumine Antimoniate Plus Allopurinol)

“…Despite the WHO suggesting the exclusive use of antimonial drugs in the treatment of human leishmaniasis, choice treatment for canine leishmaniasis is currently the combined use of leishmanicidal agents used for human, as pentavalent antimonial and allopurinol (Miró et al 2017;Travi et al 2018). Since the beginning of the twentieth century, the therapeutic effects of these compounds against leishmania have been described, and therefore remain as drugs of choice against canine leishmaniasis around the world (alone or combined with allopurinol) (Medkour et al 2020). In this sense, the recommended therapeutic scheme for canine leishmaniasis is meglumine antimoniate (Glucantime) injected subcutaneously at a dose daily of 100mg/kg for one month together with allopurinol administered orally 10mg/kg twice a day for six months minimum (Solano-Gallego et al 2011;2016;Manna et al 2015;Ribeiro et al 2018).…”

“…Furthermore, parasitic factors such as structural modifications of the target proteins or mechanisms to evade the host's immune system have also been pointed out (Miro´G et al 2017). Another relevant aspect about the chemotherapeutic treatment against canine leishmaniasis is the onset of drug-resistant strains when wrong dosages are used, even failures of the combination Glucantime/allopurinol therapy have been reported, mainly due to the drug-resistance of Leishmania, but time to relapse in treated dogs has not been documented (Medkour et al 2020). In this sense, the Leishmania resistance against a given drug may be acquired when the leishmania parasites are treated with suboptimal drug doses (Vélez et al 2009).…”