Effects of ravuconazole treatment on parasite load and immune response in dogs experimentally infected with Trypanosoma cruzi.
In this work, we investigated the in vivo activity of ravuconazole against the Y and Berenice-78 Trypanosoma cruzi strains using acutely infected dogs as hosts. Ravuconazole was well tolerated, as no significant side effects were observed during the treatment using 6.0 mg/kg twice a day (12 mg/kg/day) for up to 90 days. In all treated animals, parasitemia was permanently suppressed by the first day of treatment, independently of the parasite strain. Cultures of blood obtained posttreatment were negative for 90% of the animals, confirming that the drug induced a marked reduction in the parasite load. The results of PCR tests for T. cruzi in blood performed 1 month posttreatment were consistently negative for three of five and two of five animals infected with the Y and Berenice-78 strains, respectively. All ravuconazole-treated dogs consistently had negative serological test results during and until 30 days after treatment, regardless of the therapeutic scheme used. However, after the end of treatment, an increase in specific antibody levels was observed in all treated animals, although the antibody levels were always significantly lower than those of the nontreated control dogs. Despite being unable to induce a parasitological cure, ravuconazole treatment led to significant reductions in the levels of gamma interferon expression and lesions in cardiac tissues in animals infected with the Y strain, while the level of interleukin-10 mRNA expression increased. We conclude that ravuconazole has potent suppressive but not curative activity in the canine model of acute Chagas' disease, probably due to its unfavorable pharmacokinetic properties (half-life, 8.8 h). The longer half-life of ravuconazole in humans (4 to 8 days) makes it a promising drug for assessment for use as chemotherapy in human Chagas' disease.
Diniz
Lívia de Figueiredo
Lde F
Departamento de Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil.
Caldas
Ivo Santana
IS
Guedes
Paulo Marcos da Matta
PM
Crepalde
Geovam
G
de Lana
Marta
M
Carneiro
Cláudia Martins
CM
Talvani
André
A
Urbina
Julio Alberto
JA
Bahia
Maria Terezinha
MT
D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000276:immunology* / Q000469:parasitology; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D016133:Polymerase Chain Reaction; D013844:Thiazoles / Q000627:therapeutic use*; D014230:Triazoles / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*
D007074:Immunoglobulin G; D013844:Thiazoles; D014230:Triazoles; D014344:Trypanocidal Agents; D016753:Interleukin-10; D007371:Interferon-gamma; C104066:ER 30346
Bull World Health Organ. 1976;53(1):55-65
1085667
Parasitol Res. 2008 Jul;103(2):413-21
18454349
Vet Immunol Immunopathol. 2008 Jul 15;124(1-2):163-8
18439688
Arch Oral Biol. 2004 Jun;49(6):443-50
15099801
Mem Inst Oswaldo Cruz. 1993 Jan-Mar;88(1):171-2
8246754
Antimicrob Agents Chemother. 2004 Jul;48(7):2379-87
15215084
Rev Soc Bras Med Trop. 2006;39 Suppl 3:59-62
17605209
Antimicrob Agents Chemother. 2001 Apr;45(4):1210-5
11257036
Rev Soc Bras Med Trop. 1989 Jan-Mar;22(1):19-23
2517801
Trends Parasitol. 2003 Nov;19(11):495-501
14580960
Am Heart J. 1994 Jan;127(1):151-62
8273735
Rev Inst Med Trop Sao Paulo. 2002 Jan-Feb;44(1):29-37
11896410
Circulation. 2007 Mar 6;115(9):1109-23
17339569
Chemotherapy. 2002 Mar;48(1):7-9
11901249
Mem Inst Oswaldo Cruz. 2003 Jul;98(5):577-91
12973523
Exp Parasitol. 1998 Jan;88(1):28-33
9571142
Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:311-8
19753490
Cad Saude Publica. 2007;23 Suppl 1:S13-22
17308713
Life Sci. 2004 Dec 24;76(6):685-97
15567193
Rev Inst Med Trop Sao Paulo. 2000 May-Jun;42(3):157-61
10887376
Acta Trop. 2002 Oct;84(1):9-17
12387906
Vet Immunol Immunopathol. 2009 Jul 15;130(1-2):43-52
19211152
Int J Parasitol. 2001 May 1;31(5-6):550-4
11334941
Antimicrob Agents Chemother. 2003 Apr;47(4):1193-9
12654646
Antimicrob Agents Chemother. 2004 Nov;48(11):4286-92
15504854
Am J Trop Med Hyg. 2000 Sep-Oct;63(3-4):111-8
11388500
Antimicrob Agents Chemother. 1993 Mar;37(3):580-91
8460926
Int J Antimicrob Agents. 2003 Jan;21(1):27-38
12507835