ABSTRACT
The aim of the present study was to evaluate the impact of a multiple dose regimen of a liposomal formulation of meglumine antimoniate (LMA) on the pharmacokinetics of antimony in the bone marrow of dogs with visceral leishmaniasis and on the ability of LMA to eliminate parasites from this tissue. Dogs naturally infected with Leishmania chagasi received 4 intravenous doses of either LMA (6.5 mg antimony/kg body weight, N = 9), or empty liposomes (at the same lipid dose as LMA, N = 9) at 4-day intervals. A third group of animals was untreated (N = 8). Before each administration and at different times after treatment, bone marrow was obtained and analyzed for antimony level (LMA group) by electrothermal atomic absorption spectrometry, and for the presence of Leishmania parasites (all groups). There was a significant increase of antimony concentration from 0.76 æg/kg wet organ (4 days after the first dose) to 2.07 æg/kg (4 days after the fourth dose) and a half-life of 4 days for antimony elimination from the bone marrow. Treatment with LMA significantly reduced the number of dogs positive for parasites (with at least one amastigote per 1000 host cells) compared to controls (positive dogs 30 days after treatment: 0 of 9 in the LMA group, 3 of 9 in the group treated with empty liposomes and 3 of 8 in the untreated group). However, complete elimination of parasites was not achieved. In conclusion, the present study showed that multiple dose treatment with LMA was effective in improving antimony levels in the bone marrow of dogs with visceral leishmaniasis and in reducing the number of positive animals, even though it was not sufficient to achieve complete elimination of parasites.
Subject(s)
Animals , Male , Dogs , Antiprotozoal Agents/administration & dosage , Organometallic Compounds/administration & dosage , Dog Diseases/drug therapy , Leishmaniasis, Visceral/veterinary , Bone Marrow/chemistry , Meglumine/administration & dosage , Antiprotozoal Agents/pharmacokinetics , Organometallic Compounds/pharmacokinetics , Dog Diseases/parasitology , Liposomes , Leishmaniasis, Visceral/drug therapy , Leishmaniasis, Visceral/parasitology , Bone Marrow/parasitology , Meglumine/pharmacokinetics , Spectrophotometry, AtomicABSTRACT
The aim of the present study was to evaluate the impact of a multiple dose regimen of a liposomal formulation of meglumine antimoniate (LMA) on the pharmacokinetics of antimony in the bone marrow of dogs with visceral leishmaniasis and on the ability of LMA to eliminate parasites from this tissue. Dogs naturally infected with Leishmania chagasi received 4 intravenous doses of either LMA (6.5 mg antimony/kg body weight, N = 9), or empty liposomes (at the same lipid dose as LMA, N = 9) at 4-day intervals. A third group of animals was untreated (N = 8). Before each administration and at different times after treatment, bone marrow was obtained and analyzed for antimony level (LMA group) by electrothermal atomic absorption spectrometry, and for the presence of Leishmania parasites (all groups). There was a significant increase of antimony concentration from 0.76 microg/kg wet organ (4 days after the first dose) to 2.07 microg/kg (4 days after the fourth dose) and a half-life of 4 days for antimony elimination from the bone marrow. Treatment with LMA significantly reduced the number of dogs positive for parasites (with at least one amastigote per 1000 host cells) compared to controls (positive dogs 30 days after treatment: 0 of 9 in the LMA group, 3 of 9 in the group treated with empty liposomes and 3 of 8 in the untreated group). However, complete elimination of parasites was not achieved. In conclusion, the present study showed that multiple dose treatment with LMA was effective in improving antimony levels in the bone marrow of dogs with visceral leishmaniasis and in reducing the number of positive animals, even though it was not sufficient to achieve complete elimination of parasites.
Subject(s)
Antiprotozoal Agents/administration & dosage , Bone Marrow/chemistry , Dog Diseases/drug therapy , Leishmaniasis, Visceral/veterinary , Meglumine/administration & dosage , Organometallic Compounds/administration & dosage , Animals , Antiprotozoal Agents/pharmacokinetics , Bone Marrow/parasitology , Dog Diseases/parasitology , Dogs , Leishmaniasis, Visceral/drug therapy , Leishmaniasis, Visceral/parasitology , Liposomes , Male , Meglumine/pharmacokinetics , Meglumine Antimoniate , Organometallic Compounds/pharmacokinetics , Spectrophotometry, AtomicABSTRACT
The achievement of complete cure in dogs with visceral leishmaniasis is currently a great challenge, since dogs are the main reservoir for the transmission of visceral leishmaniasis to humans and they respond poorly to conventional treatment with pentavalent antimonials. In order to improve the efficacy of treatment, we developed a novel formulation for meglumine antimoniate based on the encapsulation of this drug in freeze-dried liposomes (LMA). The aim of the present study was to evaluate the biodistribution of antimony (Sb) in dogs following a single intravenous bolus injection of LMA. Four healthy male mongrel dogs received LMA at 3.8 mg Sb/kg body weight and were sacrificed 3, 48 and 96 h and 7 days later. Antimony was determined in the blood, liver, spleen and bone marrow. In the bone marrow, the highest Sb concentration was observed at 3 h (2.8 microg/g wet weight) whereas in the liver and spleen it was demonstrated at 48 h (43.6 and 102.4 microg/g, respectively). In these organs, Sb concentrations decreased gradually and reached levels of 19.1 microg/g (liver), 28.1 microg/g (spleen) and 0.2 microg/g (bone marrow) after 7 days. Our data suggest that the critical organ for the treatment with LMA could be the bone marrow, since it has low Sb levels and, presumably, high rates of Sb elimination. A multiple dose treatment with LMA seems to be necessary for complete elimination of parasites from bone marrow in dogs with visceral leishmaniasis.
Subject(s)
Antiprotozoal Agents/pharmacokinetics , Dog Diseases/drug therapy , Leishmaniasis, Visceral/veterinary , Meglumine/pharmacokinetics , Organometallic Compounds/pharmacokinetics , Animals , Antiprotozoal Agents/administration & dosage , Biological Availability , Chemistry, Pharmaceutical , Dog Diseases/metabolism , Dogs , Freeze Drying , Leishmaniasis, Visceral/drug therapy , Leishmaniasis, Visceral/metabolism , Liposomes , Male , Meglumine/administration & dosage , Meglumine Antimoniate , Organometallic Compounds/administration & dosageABSTRACT
The achievement of complete cure in dogs with visceral leishmaniasis is currently a great challenge, since dogs are the main reservoir for the transmission of visceral leishmaniasis to humans and they respond poorly to conventional treatment with pentavalent antimonials. In order to improve the efficacy of treatment, we developed a novel formulation for meglumine antimoniate based on the encapsulation of this drug in freeze-dried liposomes (LMA). The aim of the present study was to evaluate the biodistribution of antimony (Sb) in dogs following a single intravenous bolus injection of LMA. Four healthy male mongrel dogs received LMA at 3.8 mg Sb/kg body weight and were sacrificed 3, 48 and 96 h and 7 days later. Antimony was determined in the blood, liver, spleen and bone marrow. In the bone marrow, the highest Sb concentration was observed at 3 h (2.8 æg/g wet weight) whereas in the liver and spleen it was demonstrated at 48 h (43.6 and 102.4 æg/g, respectively). In these organs, Sb concentrations decreased gradually and reached levels of 19.1 æg/g (liver), 28.1 æg/g (spleen) and 0.2 æg/g (bone marrow) after 7 days. Our data suggest that the critical organ for the treatment with LMA could be the bone marrow, since it has low Sb levels and, presumably, high rates of Sb elimination. A multiple dose treatment with LMA seems to be necessary for complete elimination of parasites from bone marrow in dogs with visceral leishmaniasis
