This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aviles, P.
Right arrow Articles by Gargallo-Viola, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aviles, P.
Right arrow Articles by Gargallo-Viola, D.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2000, p. 1284-1290, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vitro Pharmacodynamic Parameters of Sordarin Derivatives in Comparison with Those of Marketed Compounds against Pneumocystis carinii Isolated from Rats

Pablo Aviles,1 El-Moukhtar Aliouat,1,2 Antonio Martinez,1 Eduardo Dei-Cas,3,4 Esperanza Herreros,1 Lucien Dujardin,4 and Domingo Gargallo-Viola1,*

Department of Chemotherapy, GlaxoWellcome, S.A., Madrid, Spain,1 and Laboratoire de Parasitologie, Faculté de Pharmacie,2 Faculté de Médecine et Centre Hospitalier Regional Universitaire du Lille,3 and Department of Microbiology of Ecosystems, Institut Pasteur de Lille,4 Lille, France

Received 9 July 1999/Returned for modification 14 November 1999/Accepted 28 January 2000

Pneumocystis carinii pneumonia remains one of the most serious complications of immunosuppressed patients. In this study, the in vitro pharmacodynamic parameters of four sordarin derivatives (GM 191519, GM 237354, GM 193663, and GM 219771) have been evaluated by a new quantitative approach and compared with the commercially available drugs pentamidine, atovaquone, and trimethoprim-sulfamethoxazole (TMP-SMX). In vitro activities and in vivo therapeutic efficacies of sordarin derivatives against P. carinii were also evaluated. In vitro activity was determined by the broth microdilution technique, comparing the total number of microorganisms in treated and drug-free cultures by using Giemsa staining. The in vitro maximum effect (Emax), the drug concentrations to reach 50% of Emax (EC50), and the slope of the dose-response curve were then estimated by the Hill equation (Emax sigmoid model). Sordarin derivatives were the most potent agents against P. carinii, with EC50s of 0.00025, 0.0007, 0.0043, and 0.025 µg/ml for GM 191519, GM 237354, GM 193663, and GM 219771, respectively. The EC50s of pentamidine, atovaquone, and TMP-SMX were 0.025, 0.16, and 26.7/133.5 µg/ml, respectively. The results obtained with this approach showed GM 237354 and GM 191519 to be approximately 35- and 100-fold more active in vitro than pentamidine, the most active marketed compound. All sordarin derivatives tested were at least 5,000-fold more active in vitro than TMP-SMX. The three sordarin derivatives tested in vivo---GM 191519, GM 237354, and GM 219771---showed a marked therapeutic efficacy, defined as reduction of cyst forms per gram of lung. GM 191519 was the most potent (daily dose reducing 50% of the P. carinii burden in the lungs [ED50], 0.05 mg/kg/day) followed by GM 237354 and GM 219771 (ED50s, 0.30 and 0.49 mg/kg/day, respectively). Good agreement between in vitro parameters and in vivo outcome was obtained when P. carinii pneumonia in rats was treated with sordarin derivatives.

* Corresponding author. Mailing address: GlaxoWellcome, S.A., Parque Tecnológico de Madrid, C/ Severo Ochoa 2, 28760 - Tres Cantos, Madrid, Spain. Phone: 34 91 807 04 81. Fax: 34 91 807 05 95. E-mail: DGV28867{at}GLAXOWELLCOME.CO.UK.

Antimicrobial Agents and Chemotherapy, May 2000, p. 1284-1290, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Chabe, M., Vargas, S. L., Eyzaguirre, I., Aliouat, E. M., Follet-Dumoulin, A., Creusy, C., Fleurisse, L., Recourt, C., Camus, D., Dei-Cas, E., Durand-Joly, I. (2004). Molecular typing of Pneumocystis jirovecii found in formalin-fixed paraffin-embedded lung tissue sections from sudden infant death victims. Microbiology 150: 1167-1172 [Abstract] [Full Text]  
  • Ambrose, H. E., Keely, S. P., Aliouat, E. M., Dei-Cas, E., Wakefield, A. E., Miller, R. F., Stringer, J. R. (2004). Expression and complexity of the PRT1 multigene family of Pneumocystis carinii. Microbiology 150: 293-300 [Abstract] [Full Text]  
  • Herreros, E., Almela, M. J., Lozano, S., Gomez De Las Heras, F., Gargallo-Viola, D. (2001). Antifungal Activities and Cytotoxicity Studies of Six New Azasordarins. Antimicrob. Agents Chemother. 45: 3132-3139 [Abstract] [Full Text]  
  • Aviles, P., Falcoz, C., Guillen, M. J., San Roman, R., Gomez De Las Heras, F., Gargallo-Viola, D. (2001). Correlation between In Vitro and In Vivo Activities of GM 237354, a New Sordarin Derivative, against Candida albicans in an In Vitro Pharmacokinetic-Pharmacodynamic Model and Influence of Protein Binding. Antimicrob. Agents Chemother. 45: 2746-2754 [Abstract] [Full Text]  
  • Aviles, P., Pateman, A., San Roman, R., Guillen, M. J., Gomez De Las Heras, F., Gargallo-Viola, D. (2001). Animal Pharmacokinetics and Interspecies Scaling of Sordarin Derivatives following Intravenous Administration. Antimicrob. Agents Chemother. 45: 2787-2792 [Abstract] [Full Text]  
  • Demanche, C., Berthelemy, M., Petit, T., Polack, B., Wakefield, A. E., Dei-Cas, E., Guillot, J. (2001). Phylogeny of Pneumocystis carinii from 18 Primate Species Confirms Host Specificity and Suggests Coevolution. J. Clin. Microbiol. 39: 2126-2133 [Abstract] [Full Text]  
  • Martinez, A., Aviles, P., Jimenez, E., Caballero, J., Gargallo-Viola, D. (2000). Activities of Sordarins in Experimental Models of Candidiasis, Aspergillosis, and Pneumocystosis. Antimicrob. Agents Chemother. 44: 3389-3394 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»