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Antimicrobial Agents and Chemotherapy, November 2005, p. 4628-4634, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4628-4634.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibitory Activities of Epidermal Growth Factor Receptor Tyrosine Kinase-Targeted Dihydroxyisoflavone and Trihydroxydeoxybenzoin Derivatives on Sarcocystis neurona, Neospora caninum, and Cryptosporidium parvum Development

G. Gargala,¹ A. Baishanbo,¹ L. Favennec,¹ A. François,² J. J. Ballet,^3* and J.-F. Rossignol⁴

Laboratoire de Parasitologie, and ADEN EA-3234, CHU Charles Nicolle, Rouen, France,¹ Laboratoire d'Anatomopathologie, CHU Charles Nicolle, Rouen, France,² Laboratoire d'Immunologie et Immunopathologie, UPRES EA-2128, CHU Clemenceau, Caen, France,³ Romark Laboratories, Tampa, Florida⁴

Received 25 May 2005/ Returned for modification 30 June 2005/ Accepted 30 August 2005

Several gene sequences of parasitic protozoa belonging to protein kinase gene families and epidermal growth factor (EGF)-like peptides, which act via binding to receptor tyrosine kinases of the EGF receptor (EGFR) family, appear to mediate host-protozoan interactions. As a clue to EGFR protein tyrosine kinase (PTK) mediation and a novel approach for identifying anticoccidial agents, activities against Sarcocystis neurona, Neospora caninum, and Cryptosporidium parvum grown in BM and HCT-8 cell cultures of 52 EGFR PTK inhibitor isoflavone analogs (dihydroxyisoflavone and trihydroxydeoxybenzoine derivatives) were investigated. Their cytotoxicities against host cells were either absent, mild, or moderate by a nitroblue tetrazolium test. At concentrations ranging from 5 to 10 µg/ml, 20 and 5 analogs, including RM-6427 and RM-6428, exhibited an in vitro inhibitory effect of 95% against at least one parasite or against all three, respectively. In immunosuppressed Cryptosporidium parvum-infected Mongolian gerbils orally treated with either 200 or 400 mg of agent RM-6427/kg of body weight/day for 8 days, fecal microscopic oocyst shedding was abolished in 6/10 animals (P of <0.001 versus untreated controls) and mean shedding was reduced by 90.5% (P of <0.0001) and 92.0% (P of <0.0001), respectively, higher levels of inhibition than after nitazoxanide (200 mg/kg/day for 8 days) or paromomycin (100 mg/kg/day for 8 days) treatment (55.0%, P of <0.001, and 17.5%, P of >0.05, respectively). After RM-6427 therapy (200 mg/kg/day for 8 days), the reduction in the ratio of animals with intracellular parasites was nearly significant in ileum (P = 0.067) and more marked in the biliary tract (P < 0.0013) than after nitazoxanide or paromomycin treatment (0.05 < P < 0.004). RM-6428 treatment at a regimen of 400 mg/kg/day for 12 days inhibited oocyst shedding, measured using flow cytometry from day 4 (P < 0.05) to day 12 (P < 0.02) of therapy, when 2/15 animals had no shedding (P < 0.0001) and 11/15 were free of gut and/or biliary tract parasites (P < 0.01). No mucosal alteration was microscopically observed for treated or untreated infected gerbils. To our knowledge, this report is the first to suggest that the isoflavone class of agents has the potential for anticoccidial therapy.

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* Corresponding author. Mailing address: Laboratoire d'Immunologie et Immunopathologie, CHU Avenue Georges Clemenceau, 14033 Caen Cedex, France. Phone: 33 (0)2 31 27 25 51. Fax: 33 (0)2 31 27 25 50. E-mail: ballet-jj{at}chu-caen.fr.

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Antimicrobial Agents and Chemotherapy, November 2005, p. 4628-4634, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4628-4634.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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