ABSTRACT
OBJECTIVES: Antifungal triazole derivatives have been studied as possible alternatives for the treatment of Chagas' disease. Voriconazole has demonstrated in vitro activity against Trypanosoma cruzi, but its efficacy in vivo has not yet been tested. We aimed to determine the effect of voriconazole in a murine model of acute T. cruzi infection. METHODS: Treatment efficacy was evaluated by comparing parasitaemia, mortality and organ involvement (by histological examination) of infected mice. RESULTS: Treatment with voriconazole significantly lowered parasitaemia and mortality compared with controls, reduced the percentage of mice with amastigote nests in heart and skeletal muscle and moderately decreased myocardial inflammation. CONCLUSIONS: Our findings support the potential of voriconazole for the treatment of acute Chagas' disease and motivate future animal studies using varying doses and treatment schemes. Further evaluation of voriconazole for clinical use in human Chagas' patients is warranted.
Subject(s)
Antiprotozoal Agents/therapeutic use , Chagas Disease/drug therapy , Pyrimidines/therapeutic use , Triazoles/therapeutic use , Trypanosoma cruzi/drug effects , Animal Structures/parasitology , Animals , Chagas Disease/mortality , Chagas Disease/parasitology , Chagas Disease/pathology , Disease Models, Animal , Female , Histocytochemistry , Mice , Mice, Inbred BALB C , Parasitemia/drug therapy , Survival Analysis , VoriconazoleABSTRACT
With the aim of investigating if delivery of benznidazole (BNZ) to liver could be increased by incorporating the drug in multilamellar liposomes, single bolus of free BNZ or liposomal BNZ formulations (MLV-BNZ) composed of HSPC:DSPG:Chol 2:1:2 (mol/mol/mol) at 0.7% (w/w) drug/total lipid ratio, were injected by intramuscular (i.m.), subcutaneous (s.c.) and intravenous (i.v.) routes, at 0.2 mg BNZ/kg, in rats. The resulting blood concentrations were followed along 9 h post-injection (p.i.) and drug accumulation in liver was determined after 4 and 9 h p.i. Only upon i.v. injection of MLV-BNZ, a threefold higher BNZ accumulation in liver was obtained, together with blood BNZ concentrations of 1.1 microg/ml (30% lower than the blood BNZ concentration achieved upon i.v. administration of free drug) occurred 4 h p.i. However, such increased liver uptake of BNZ, raised twice a week had no effect on parasitaemia levels of mice infected with the RA strain of Trypanosoma cruzi. Our results indicate that the relationship between increased selectivity for an infected tissue and therapeutic effect is not always straightforward, at least for the MLV-BNZ regimen used in the present study.
Subject(s)
Liver/metabolism , Nitroimidazoles/administration & dosage , Nitroimidazoles/pharmacokinetics , Trypanocidal Agents/administration & dosage , Trypanocidal Agents/pharmacokinetics , Animals , Chagas Disease/drug therapy , Female , Injections, Intravenous , Liposomes , Liver/parasitology , Mice , Mice, Inbred BALB C , Nitroimidazoles/chemistry , Parasitemia/drug therapy , Particle Size , Phospholipids/chemistry , Rats , Rats, Wistar , Tissue Distribution , Trypanocidal Agents/chemistry , Trypanosoma cruzi/drug effectsABSTRACT
Th1-type immune response plays a critical role in resistance to Trypanosoma cruzi infection. We asked whether a synthetic oligodeoxynucleotide that contains immunostimulatory CpG motifs (CpG ODN), known to promote a Th1 response, could act as an adjuvant in immunization with parasite antigens. Mice immunized with a whole homogenate (WH) of T. cruzi antigens co-administered with CpG ODN presented high titers of T. cruzi antibodies (IgG2a isotype), strong delayed type hypersensitivity and a Th1-dominated (IFN-gamma and IL-12) cytokine profile. Furthermore, WH plus CpG ODN protected mice from challenge with an otherwise lethal dose of bloodstream trypomastigotes. As reported for leishmaniasis and malaria, CpG ODN holds considerable promise as an adjuvant for future vaccines against T. cruzi.
Subject(s)
Adjuvants, Immunologic/pharmacology , Antibodies, Protozoan/biosynthesis , Dinucleoside Phosphates/pharmacology , Oligodeoxyribonucleotides/pharmacology , Protozoan Vaccines/immunology , Th1 Cells/physiology , Trypanosoma cruzi/immunology , Animals , Antigens, Protozoan/immunology , Chagas Disease/prevention & control , Cytokines/biosynthesis , Female , Hypersensitivity, Delayed/etiology , Immunization , Mice , Mice, Inbred BALB CABSTRACT
An 80-kDa Trypanosoma cruzi urinary antigen (UAg) was affinity-purified from the urine of infected dogs. We demonstrated that UAg is structurally and functionally related to proteins belonging to the transferrin family, as shown by amino acid sequence and iron binding experiments. Nevertheless, monoclonal antibodies raised against UAg specifically and selectively recognized this parasite's circulating antigen. The existence of an 80-kDa T. cruzi antigen co-migrating with UAg could be confirmed when epimastigotes were metabolically labelled with [35S] methionine and then immunoprecipitated with the above mentioned antibodies. We conclude that UAg is an iron-binding T. cruzi component eliminated in the urine of the infected host.
Subject(s)
Antigens, Protozoan/metabolism , Chagas Disease/immunology , Iron/metabolism , Trypanosoma cruzi/immunology , Amino Acid Sequence , Animals , Antibodies, Monoclonal/immunology , Antigens, Protozoan/immunology , Antigens, Protozoan/isolation & purification , Chagas Disease/urine , Dogs , Electrophoresis, Polyacrylamide Gel , Epitopes , Molecular Sequence DataABSTRACT
We studied the effect of in vivo administration of anti-gamma-IFN and anti-IL-4 monoclonal antibodies on the resistance of mice against myotropic and reticulotropic strains of Trypanosoma cruzi. Anti-gamma-IFN treatment augmented the susceptibility of mice when infected with the reticulotropic RA and Tulahuén strains of T. cruzi but did not alter the course of infection with the myotropic CA-I strain of the parasite. In vivo administration of anti-IL-4 enhanced the resistance of mice when infected with either Tulahuén or RA strains but did not affect the course of parasitemia when infected with CA-I. The possible biological relevance of these observations is discussed.
