Comparison of Two Dosing Regimens of Miltefosine, Both in Combination With Allopurinol, on Clinical and Parasitological Findings of Dogs With Leishmaniosis: A Pilot Study

Iarussi, Fabrizio; Paradies, Paola; Manzillo, Valentina Foglia; Gizzarelli, Manuela; Caratozzolo, Mariano Francesco; Navarro, Christelle; Greco, Béatrice; Rubino, Giuseppe; Oliva, Gætano; Sasanelli, Mariateresa

doi:10.3389/fvets.2020.577395

Cited by 6 publications

(6 citation statements)

References 45 publications

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“…Above all, the use of the MIL-AL protocol has found excellent compliance by the owners, both for the simple mode of administration and for the limited adverse reactions. In fact, as already demonstrated by several authors [ 16 , 28 ]. Miltefosine has shown good tolerability, with the exception of mild and self-limiting gastrointestinal side effects.…”

Section: Discussionsupporting

confidence: 63%

Retrospective Long-Term Evaluation of Miltefosine-Allopurinol Treatment in Canine Leishmaniosis

Gizzarelli

Manzillo

Inglese³

et al. 2023

Pathogens

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Miltefosine-Allopurinol (MIL-AL) combination is reported to be one of the most effective treatments for canine leishmaniosis, thanks to its oral administration and MIL-documented low impact on renal function. However, MIL-AL is considered a second-choice treatment when compared to meglumine-antimoniate—allopurinol combination, mainly due to the risk of earlier relapses. The aim of this study was to evaluate the efficacy of the MIL-AL protocol during a long-term follow-up with an average duration of nine years. Dogs were living in Southern Italy (Puglia, Italy) in an area considered endemic for Canine leishmaniosis (CanL). Inclusion criteria were clinical and/or clinicopathological signs consistent with CanL; positive result to Leishmania quantitative ELISA; and negativity to the most frequent canine vector-borne infections. All dogs received 2 mg/kg MIL for 28 days, and 10 mg/kg AL, BID, for a period varying between 2 and 12 months. Ancillary treatments were allowed according to the clinical condition of the dog. A total clinical score and a total clinicopathological score were calculated at each time point by attributing one point to each sign or alteration present and then by adding all points. Improvement after each treatment was defined by the reduction of at least 50% of the total score. A survival analysis (Kaplan–Meier curve) was performed for quantifying the probability of the events occurring during the study follow-up. The following events were considered: decreased and negative ELISA results; improvement/recovery of the clinical and clinicopathological alterations; and relapse of leishmaniasis. One hundred seventy-three dogs (75f and 98m) were retrospectively included in the study by examining their clinical records since the first diagnosis of CanL. One hundred forty-three (83%) dogs were under five years of age. The mean duration of the follow-up period was 5.4 (±1.1) years with a minimum of 3.2 years and a maximum of 9 years. All dogs received a first treatment of MIL-AL at inclusion; then, during the follow-up course, 30 dogs required a second treatment, 2 dogs required a third treatment and 1 dog required a fourth and a fifth treatment. The mean time interval between the first and the second treatment was 27.2 (±18.3) months. After the first treatment, all dogs had decreased ELISA levels, in an average interval of 2.6 (±1.6) months. One hundred seventy dogs (98%) experienced a clinical improvement (mean time 3.0 ± 4.9 months); 152 (88%) dogs were considered clinically recovered after a mean time of 16.7 ± 13.5 months. A similar trend was observed for clinicopathological alterations; interestingly, proteinuria decreased in most dogs (p < 0.0001—Chi-square for trends). Thirty dogs experienced relapses, the earliest after 4.8 months. The mean time without relapse was 90.4 (±2.5) months. In relapsed dogs, the mean time for clinical improvement after the second treatment was 8.6 (±12.6) months, whereas it was 11.0 (±15.4) months for clinicopathological alterations. Five dogs had limited gastrointestinal side effects associated with MIL treatment. The present study confirms that the MIL-AL protocol can be considered one of the most effective treatments for CanL therapy, mainly for its capacity to provide a long-time clinical improvement in a large majority of treated dogs. As reported in the literature, the clinical stabilization of dogs does not occur immediately after treatment, probably due to the particular pharmacokinetic properties of MIL. The efficacy of MIL-AL decreases in dogs that need more than one treatment, suggesting the necessity to alternate anti-Leishmania drugs for the treatment of relapses. Side effects were transient and slight, even in dogs that required several treatments.

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Section: Discussionsupporting

confidence: 63%

Retrospective Long-Term Evaluation of Miltefosine-Allopurinol Treatment in Canine Leishmaniosis

Gizzarelli

Manzillo

Inglese³

et al. 2023

Pathogens

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“…The evolution of the infection was also monitored by measuring the parasite burden of the visceral infection using qPCR and microscopy, as reported in similar studies [34]. These measurements were made in bone marrow, and in skin (only by microscopy) to assess the cutaneous dissemination.…”

Section: Discussionmentioning

confidence: 99%

Effective immuno-therapeutic treatment of Canine Leishmaniasis

Ramos

Giannelli²,

Fasquelle³

et al. 2023

PLoS Negl Trop Dis

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Background Canine Leishmaniasis (CanL) caused by the L. infantum species is one of the biggest threats to the health of the South American canine population. Chemotherapeutics currently used for the treatment of CanL fail to induce a total parasite clearance while inducing numerous side effects. As CanL is an immunomodulated disease, the use of immuno-treatments should strengthen the deficient immune response of infected dogs. In this study, we evaluated a nasally administered immunotherapy in dogs naturally infected with L. infantum (stage 2), with both visceral and cutaneous manifestations. Noteworthy, some of them were also infected by other parasites (E. canis, D. immitis, A. platys), what worsen their chance of survival. Methodology/Principal findings The treatment was based on 2 intranasal (IN.) administrations of a killed L. infantum parasite loaded into maltodextrin nanoparticles, which treatment was compared with the classical oral administration of Miltefosine (2 mg/kg) for 28 days, as well as a combination of these 2 treatments. The results showed that two IN administrations significantly reduced the serology, and were at least as efficient as the chemotherapy to reduce the skin and bone marrow parasite burden, as well as clinical scores, and that unlike Miltefosine treatments, this nasally administered nanoparticle vaccine was without side effects. Conclusions These results confirm the feasibility of a simple therapeutic immuno-treatment against L. infantum infected dogs, which is a promising tool for future developments.

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“…Miltefosine and allopurinol have been used in several studies as therapies for CVL, with varying results (Manna et al, 2008;Miró et al, 2009Miró et al, , 2011Woerly et al, 2009;Nogueira et al, 2019;Iarussi et al, 2020). In clinical practice, the primary goal of CVL treatment is to improve the quality of life of the animal, as no cure is available.…”

Section: Discussionmentioning

confidence: 99%

“…Antibody titer was not a relevant parameter for monitoring treatment in this study, as the protocols did not reduce antibody levels in 28 days. The reduction of antibody titers to non-significant levels usually occurs over time with continued allopurinol therapy (Miró et al, 2009;Santos et al, 2019;Iarussi et al, 2020). One of the criteria for long-term treatment discontinuation is the reversal to a negative antibody titer or a significant decrease in the initial titer (Kasabalis et al, 2020).…”

Section: Correlation Between Variablesmentioning

confidence: 99%

“…This indicates that, over time, the treatment effects can become more significant due to the prolonged activity of miltefosine. The combination of these drugs is the protocol recommended by several studies since the synergistic effect of the drugs, one leishmanicidal and the other leishmaniostatic, improves clinical symptoms and reduces the parasite load in several tissues over long periods (Manna et al, 2009(Manna et al, , 2015Dias et al, 2020;Iarussi et al, 2020). However, the prognosis varies according to the clinical status of the dog and the immune response to the treatment (Dantas- Torres et al, 2012).…”

Section: Correlation Between Variablesmentioning

confidence: 99%

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

Sorte

Dias

Monteiro

et al. 2022

Rev. Bras. Parasitol. Vet.

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Canine visceral leishmaniasis is an endemic zoonosis in Brazil. Dogs are the main hosts in urban environments. The treatment has gained popularity since the Brazilian government authorized miltefosine for canine treatment. The aim of this study was to investigate the clinical and parasitological impact of short-term treatment with miltefosine and allopurinol, alone and in combination. We evaluated the ability of pharmacotherapy to reduce clinical signs of disease, antibody levels using the indirect fluorescence antibody test (IFAT) and skin parasite load via qPCR after 28 days of treatment. The therapeutic protocols promoted a significant decline in clinical signs and in the skin parasite load in dogs (p < 0.01). We observed a moderate correlation between the skin parasite load and the clinical score in all three treatment groups (r > 0.5) Antibody levels did not decrease in this short period. It was concluded that the treatment with allopurinol reduced the number of parasites in the skin of dogs with visceral leishmaniasis in the short term. However, its efficiency is potentiated when associated with miltefosine.

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Comparison of Two Dosing Regimens of Miltefosine, Both in Combination With Allopurinol, on Clinical and Parasitological Findings of Dogs With Leishmaniosis: A Pilot Study

Cited by 6 publications

References 45 publications

Retrospective Long-Term Evaluation of Miltefosine-Allopurinol Treatment in Canine Leishmaniosis

Retrospective Long-Term Evaluation of Miltefosine-Allopurinol Treatment in Canine Leishmaniosis

Effective immuno-therapeutic treatment of Canine Leishmaniasis

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

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