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PLoS Negl Trop Dis. 2018 Jan 8;12(1):e0006183. doi: 10.1371/journal.pntd.0006183. eCollection 2018 Jan.

Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model.

Author information

1
Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont.
2
Cell, Molecular and Biomedical Sciences graduate program, University of Vermont Larner College of Medicine, Burlington, Vermont.
3
Department of Animal and Veterinary Sciences, University of Vermont College of Agriculture and Life Sciences, Burlington, Vermont.
4
Saint Louis University School of Medicine, St. Louis, MO.
5
Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine, Burlington, Vermont.

Abstract

Cryptosporidiosis causes life-threatening diarrhea in infants, but the best available treatment is only modestly efficacious. Rodents infected with relevant Cryptosporidium species do not develop diarrhea, which complicates drug development. Cryptosporidium parvum infection of dairy calves, however, causes an illness like that seen in infants. Here, the clinical and microbiologic anti-Cryptosporidium efficacy of the piperazine-based compound MMV665917 was demonstrated in neonatal calves. Oral administration of MMV665917 (22 mg/kg once daily) was begun two days after the onset of severe diarrhea and continued for seven days. Treatment resulted in prompt resolution of diarrhea, and reduced total fecal oocyst shedding by ~94%. MMV665917 was useful for treatment, rather than just prophylaxis, since it was safe and effective when administered well after the onset of diarrhea. Furthermore, even though all animals received intensive supportive care, there was a strong trend towards improved secondary health outcomes, including general health, appetite, and dehydration measures amongst treated animals. These data establish MMV665917 as an outstanding lead compound for Cryptosporidium drug development.

PMID:
29309415
PMCID:
PMC5774826
DOI:
10.1371/journal.pntd.0006183
[Indexed for MEDLINE]
Free PMC Article

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