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Antimicrobial Agents and Chemotherapy, April 2007, p. 1440-1445, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01537-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species

Shu-Hua Xiao,^1, Jennifer Keiser,^2, Jacques Chollet,^2, Jürg Utzinger,² Yuxiang Dong,³ Yvette Endriss,² Jonathan L. Vennerstrom,³ and Marcel Tanner^2*

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai 200025, People's Republic of China,¹ Swiss Tropical Institute, CH-4002 Basel, Switzerland,² College of Pharmacy, University of Nebraska Medical Center, Nebraska 68198-6025³

Received 10 December 2006/ Accepted 28 January 2007

Schistosomiasis is a parasitic disease that remains of considerable public health significance in tropical and subtropical environments. Since the mainstay of schistosomiasis control is chemotherapy with a single drug, praziquantel, drug resistance is a concern. Here, we present new data on the antischistosomal properties of representative synthetic 1,2,4-trioxolanes (OZs). Exposure of adult Schistosoma mansoni for 24 h to a medium containing 20 µg/ml OZ209 reduced worm motor activity, induced tegumental alterations, and killed worms within 72 h. While exposure of S. mansoni to OZ78 had no apparent effect, addition of hemin reduced worm motor activity and caused tegumental damage. Administration of single 200-mg/kg of body weight oral doses of OZ78, OZ209, and OZ288 to mice harboring a juvenile S. mansoni infection resulted in worm burden reductions of 82.0 to 95.4%. In the adult infection model in mice, single 400-mg/kg doses of these compounds resulted in a maximum total worm burden reduction of 52.2%. High worm burden reductions (71.7 to 86.5%) were observed after administration of single 200-mg/kg doses of OZ78 and OZ288 to hamsters infected with either juvenile or adult S. mansoni. A single 200-mg/kg dose of OZ78 to hamsters infected with adult Schistosoma japonicum resulted in total and female worm burden reductions of 94.2 to 100%. Our results, along with the low toxicity, metabolic stability, and good pharmacokinetic properties of the OZs, indicate the potential for the development of novel broad-spectrum antischistosomal OZ drug candidates.

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* Corresponding author. Mailing address: Swiss Tropical Institute, CH-4002 Basel, Switzerland. Phone: 41-61-2848287. Fax: 41-61-2848105. E-mail: marcel.tanner{at}unibas.ch

Published ahead of print on 5 February 2007.

S.-H.X., J.K., and J.C. contributed equally to this work.

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Antimicrobial Agents and Chemotherapy, April 2007, p. 1440-1445, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01537-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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