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. 2008 Sep;52(9):3106-12.
doi: 10.1128/AAC.00207-08. Epub 2008 Jun 30.

Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model

Autumn S Downey  1 , Curtis R Chong, Thaddeus K Graczyk, David J Sullivan
Affiliations

Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model

Autumn S Downey et al. Antimicrob Agents Chemother. 2008 Sep.

Abstract

No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients. Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 microM paromomycin or 27 microM chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.

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Figures

FIG. 1.
FIG. 1.
Effects of pyrvinium, chloroquine, and paromomycin on C. parvum growth in HCT-8 cells. Drugs were added to cultures 1.5 h after the addition of 5 × 103 oocysts/well and were incubated for 48 h. Parasite growth was determined by an ELISA using rat polyclonal anti-Cryptosporidium sera. The percentages of inhibition by pyrvinium (squares), chloroquine (triangles), and paromomycin (circles) are from biologic replicate experiments. Error bars, representing standard deviations, are from triplicate wells with the biologic duplicates.
FIG. 2.
FIG. 2.
Representative H&E-stained intestinal sections from C. parvum-infected neonatal mice. Trophozoites are shown covering the intestinal epithelial cells in the ileum, appendix, and colon in control mice, while only a few trophozoites are present in pyrvinium- or paromomycin-treated mice. Size bars, 50 μm. Magnification, ×400.
FIG. 3.
FIG. 3.
Effects of drug treatment for 6 consecutive days on levels of C. parvum trophozoites in individual intestinal sections. (A) At necropsy, 1-cm-long intestinal sections were taken from the ileum, appendix, cecum, and colon and were stained with H&E for histological analysis to determine the extent of mucosal infection in drug-treated versus untreated mice. Results are mean numbers of trophozoites per 1,000 epithelial cells ± standard deviations (error bars). Experiments testing paromomycin at 100 mg/kg (n = 9) (light shaded bars) against its no-drug controls (n = 11) (dark shaded bars) and pyrvinium at 5 mg/kg (n = 10) (open bars) against its no-drug controls (n = 9) (filled bars) were performed at different times. Control mice had few trophozoites in the proximal ileum, with levels peaking in the terminal ileum and decreasing again in the colon. Oocysts in fecal matter were not counted. In paromomycin-treated mice, trophozoites were observed only in the terminal ileum, appendix, and colon. (B) Percentages of inhibition by pyrvinium in different intestinal sections for each of 10 individual mice (circles). Horizontal bars represent means. A single pyrvinium-treated mouse had little inhibition in the ileum but more-marked inhibition in the appendix and colon. Percentages of inhibition by paromomycin were greater than 90% in all sections (data not shown).
FIG. 4.
FIG. 4.
Intestinal epithelium infection summary scores for C. parvum-infected neonatal mice in different treatment groups. The cumulative score for the extent of intestinal infection was calculated as the sum of the numbers of trophozoites per 1,000 epithelial cells from all of the tissue sections for each mouse. Treatment group data are presented in box plots displaying the median values (21,159, 10, 13,750, and 63 for the paromomycin no-drug control, paromomycin, the pyrvinium no-drug control, and pyrvinium, respectively). A Kruskal-Wallis nonparametric test of equality and pairwise comparisons using a nonparametric two-sample Mann-Whitney test showed that the levels of trophozoites in both the pyrvinium and the paromomycin treatment group were significantly (P < 0.05) lower than those in their respective controls but not significantly different from each other (P = 0.2682).
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