Efficacy of Combined Therapy with Liposome-Encapsulated Meglumine Antimoniate and Allopurinol in Treatment of Canine Visceral Leishmaniasis

Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 03/2012; 56(6):2858-67. DOI: 10.1128/AAC.00208-12
Source: PubMed

ABSTRACT An innovative liposomal formulation of meglumine antimoniate (LMA) was recently reported to promote both long-term parasite suppression and reduction of infectivity to sand flies in dogs with visceral leishmaniasis. However, 5 months after treatment, parasites were still found in the bone marrow of all treated dogs. In order to improve treatment with LMA, the present study aimed to evaluate its efficacy in combination with allopurinol. Mongrel dogs naturally infected with Leishmania infantum were treated with six doses of LMA (6.5 mg Sb/kg of body weight/dose) given at 4-day intervals, plus allopurinol (20 mg/kg/24 h per os) for 140 days. Comparison was made with groups treated with LMA, allopurinol, empty liposomes plus allopurinol, empty liposomes, and saline. Dogs remained without treatment from day 140 to 200 after the start of treatment. The drug combination promoted both clinical improvement of dogs and significant reduction in the parasitic load in bone marrow and spleen on days 140 and 200 compared to these parameters in the pretreatment period. This is in contrast with the other protocols, which did not result in significant reduction of the bone marrow parasite load on day 200. Strikingly, the combined treatment, in contrast to the other regimens, induced negative quantitative PCR (qPCR) results in the liver of 100% of the dogs. Both xenodiagnosis and skin parasite determination by qPCR indicated that the drug combination was effective in blocking the transmission of skin parasites to sand flies. Based on all of the parasitological tests performed on day 200, 50% of the animals that received the combined treatment were considered cured.

Download full-text


Available from: Sydnei Magno da Silva, Sep 28, 2015
20 Reads
  • Source
    • "Moreover, prolonged or repeated use of this drug can induce resistance in Leishmania clones (73). Currently, an important strategy for therapy in dogs is the use of liposome-encapsulated SbV, which promotes improved clinical status and reduced parasite load in infected animals (74). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Leishmaniasis has several clinical forms: self-healing or chronic cutaneous leishmaniasis or post-kala-azar dermal leishmaniasis; mucosal leishmaniasis; visceral leishmaniasis (VL), which is fatal if left untreated. The epidemiology and clinical features of VL vary greatly due to the interaction of multiple factors including parasite strains, vectors, host genetics, and the environment. Human immunodeficiency virus infection augments the severity of VL increasing the risk of developing active disease by 100-2320 times. An effective vaccine for humans is not yet available. Resistance to chemotherapy is a growing problem in many regions, and the costs associated with drug identification and development, make commercial production for leishmaniasis, unattractive. The toxicity of currently drugs, their long treatment course, and limited efficacy are significant concerns. For cutaneous disease, many studies have shown promising results with immunotherapy/immunochemotherapy, aimed to modulate and activate the immune response to obtain a therapeutic cure. Nowadays, the focus of many groups centers on treating canine VL by using vaccines and immunomodulators with or without chemotherapy. In human disease, the use of cytokines like interferon-γ associated with pentavalent antimonials demonstrated promising results in patients that did not respond to conventional treatment. In mice, immunomodulation based on monoclonal antibodies to remove endogenous immunosuppressive cytokines (interleukin-10) or block their receptors, antigen-pulsed syngeneic dendritic cells, or biological products like Pam3Cys (TLR ligand) has already been shown as a prospective treatment of the disease. This review addresses VL treatment, particularly immunotherapy and/or immunochemotherapy as an alternative to conventional drug treatment in experimental models, canine VL, and human disease.
    Frontiers in Immunology 06/2014; 5(272). DOI:10.3389/fimmu.2014.00272
  • Source
    • "Amphotericin B Visceral leishmaniasis Dog Oliva et al., 2004 Trifluralin Marques et al., 2004; Carvalheiro et al., 2009 Meglumine antimoniate Ribeiro et al., 2008; da Silva et al., 2012 Antitumoral Doxorubicin Sarcoma Cat, dog, Teske et al., 2011, Kleiter et al., 2010 Meta-tetra (hydroxyphenyl) "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this book the authors present current research in the study of liposomes. Topics discusses in this compilation include liposome mediated malaria vaccine development; liposomal delivery of antimicrobial agents in advances in liposome research; trends on microfluidic liposome production through hydrodynamic flow-focusing and microdroplet techniques for gene delivery applications; liposomes as important drug carriers in cancer therapy; liposome application in the veterinary field; and design of liposomes with a pH-sensitive fluorescent dye and gramicidin channels for immune-sensing. (Imprint: Nova)
    Advances in Liposomes Research, Edited by Lauren Finney, 01/2014: chapter Liposome Applications in the Veterinary Field; , ISBN: 978-1-63117-074-4
  • Source
    • "A mixed-breed adult dog of unknown age was obtained from the Control Zoonosis Center of the Municipality of Ribeirão das Neves, Belo Horizonte Metropolitan area, Minas Gerais, Brazil. It was diagnosed with Leishmania (L.) infantum infection serologically and parasitologically [22]. The indirect immunofluorescence antibody test (IFAT) titer was >1∶40 dilution and the enzyme linked immunosorbent assay (ELISA) showed optical density >100 (1∶400 dilution). "
    [Show abstract] [Hide abstract]
    ABSTRACT: American tegumentary leishmaniasis (ATL) is endemic in Latin America, where Brazil has over 27 thousand cases per year. The aim of the present study was to develop an immunohistochemical method (IHC) for ATL diagnosis. For this purpose, we used serum from a dog naturally infected with Leishmania (L) infantum (canine hyperimmune serum) as the primary antibody, followed by a detection system with a secondary biotinylated antibody. Skin samples were obtained from 73 patients in an endemic area of Caratinga, Minas Gerais (MG) State, Brazil all testing positive for ATL with the Montenegro skin test, microscopy, and PCR. Canine hyperimmune serum of a dog naturally infected with Leishmania (L.) infantum was employed as a primary antibody in an immunohistochemical diagnostic method using streptavidin-biotin peroxidase. To assess the specificity of this reaction, IHC assays employing two monoclonal antibodies were carried out. As the polymer-based technology is less time-consuming and labor intensive than the IHC labeled streptavidin-biotin peroxidase method, we compared the two methods for all samples. The IHC method detected ATL in 67 of the 73 cases (91.8%). Immunolabeled parasites were primarily detected inside macrophages either in the superficial or the deep dermis. Detection was facilitated by the high contrast staining of amastigotes (dark brown) against the light blue background. A lower detection rate (71.2%) was observed with the both of the monoclonal Leishmania antibodies compared to the canine hyperimmune serum. This may have been due to a non-specific background staining observed in all histological samples rendering positive detection more difficult. The higher efficacy of the canine hyperimmune serum in the IHC method was confirmed by the method using streptavidin-biotin peroxidase as well as that with the polymer-based technology (biotin-avidin-free system). The data are encouraging with regard to validating IHC as a standard alternative method for ATL diagnosis.
    PLoS ONE 05/2013; 8(5):e63343. DOI:10.1371/journal.pone.0063343 · 3.23 Impact Factor
Show more