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Antimicrobial Agents and Chemotherapy, March 2005, p. 1160-1168, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1160-1168.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antiamoebic and Toxicity Studies of a Carbamic Acid Derivative and Its Therapeutic Effect in a Hamster Model of Hepatic Amoebiasis

Cynthia Ordaz-Pichardo,¹ Mineko Shibayama,² Saúl Villa-Treviño,¹ Myriam Arriaga-Alba,³ Enrique Angeles,⁴ and Mireya de la Garza^1*

Departamento de Biología Celular,¹ Departamento de Patología Experimental, Centro de Investigación y de Estudios Avanzados del IPN,² Laboratorio de Investigación en Microbiología, Hospital Juárez de México, Mexico City,³ Laboratorio de Química Medicinal, Unidad de Postgrado Campo 1, FES Cuautitlán, UNAM, Cuautitlán Izcalli, Estado de México, Mexico⁴

Received 27 May 2004/ Returned for modification 5 August 2004/ Accepted 26 October 2004

Amoebiasis is an important public health problem in developing countries. Entamoeba histolytica, the causative agent of amoebiasis, may develop resistance to nitroimidazoles, a group of drugs considered to be the most effective against this parasitic disease. Therefore, research on new drugs for the treatment of this common infection still constitutes an important therapeutic demand. In the present study we determined the effects of a carbamate derivative, ethyl 4-chlorophenylcarbamate (C4), on trophozoites of E. histolytica strain HM-1:IMSS. C4 was subject to various toxicity tests, including the determination of mutagenicity for bacterial DNA and changes in the enzymatic activities of eukaryotic cells. Genotoxicity studies were performed by the mutagenicity Ames test (plate incorporation and preincubation methods) with Salmonella enterica serovar Typhimurium, with or without metabolic activation produced by the S9 fraction of rat liver. C4 toxicity studies were performed by measuring enzymatic activity in eukaryotic cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-formazan test with Fischer 344 rat hepatocytes. C4 did not induce either frame-shift mutations in S. enterica serovar Typhimurium TA97 or TA98 or base pair substitutions in strains TA100 and TA102. The compound was not toxic for cultured rat hepatic cells. Trophozoites treated with 100 µg of C4 per ml were inhibited 97.88% at 48 h of culture; moreover, damage to the amoebae was also confirmed by electron microscopy. The antiamoebic activity of C4 was evaluated by using an in vivo model of amoebic liver abscess in hamsters. Doses of 75 and 100 mg/100 g of body weight reduced the extent of the amoebic liver abscess by 84 and 94%, respectively. These results justify further studies to clearly validate whether C4 is a new suitable antiamoebic drug.

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* Corresponding author. Mailing address: Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Apdo. Postal 14-740, México D.F. 07000, México. Phone: (52) 55-50613987. Fax: (52) 55-57477081. E-mail: mireya{at}cell.cinvestav.mx.

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Antimicrobial Agents and Chemotherapy, March 2005, p. 1160-1168, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1160-1168.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.