JAC Advance Access published online on April 4, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl117
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1 Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Le Pharo, 13998 Marseille, France; Institut Fédératif de la Recherche no 48, 13385 Marseille, France
* To whom correspondence should be addressed. Objectives: The in vitro activities of FR160, a synthetic catecholate siderophore, and two iron-binding agents, desferrioxamine and doxycycline, were evaluated against Plasmodium falciparum isolates. Correlations between these compounds and standard antimalarial drugs (chloroquine, quinine, amodiaquine, pyronaridine, artemether, artesunate, atovaquone, cycloguanil and pyrimethamine) were assessed to determine any degree of cross-resistance. Methods: Between October 1997 and February 1998, and September and November 1998, 189 P. falciparum isolates were obtained in Dielmo and Ndiop (Dakar). Their susceptibilities were assessed using an isotopic, microwell format, drug susceptibility test. Results: The 137 inhibitory concentrations (IC50) values of FR160 ranged from 0.1 to 10 µM and the geometric mean IC50 was 1.48 µM (95% CI = 1.29-1.68 µM). The geometric mean IC50 of doxycycline for 121 isolates was 18.9 µM (95% CI = 16.8-21.3 µM) and that of desferrioxamine for 73 isolates was 20.7 µM (95% CI = 17.3-24.8 µM). FR160 was significantly less active against the chloroquine-resistant isolates (P < 0.0001). The mean IC50s of doxycycline were significantly higher for the chloroquine-susceptible isolates than for the resistant parasites (P = 0.0447). There was a weak correlation between the responses to FR160, desferrioxamine or doxycycline and those to the other antimalarial compounds (r2 < 0.22). Conclusions: The activities of FR160 and desferrioxamine, determined for P. falciparum clones, were confirmed against 137 isolates. The coefficients of determination between the responses to FR160, doxycycline or desferrioxamine and those to all the antimalarial drugs tested are too weak to suggest cross-resistance. FR160 could be a rationale partner to use in combination with doxycycline.
Received September 27, 2005
Revised January 9, 2006
Accepted March 12, 2006
Original article
In vitro activity of iron-binding compounds against Senegalese isolates of Plasmodium falciparum
B. Pradines 1 *,
A. Tall 2,
F. Ramiandrasoa 3,
A. Spiegel 4,
C. Sokhna 5,
T. Fusai 1,
J. Mosnier 1,
W. Daries 1,
J. F. Trape 5,
G. Kunesch 3,
D. Parzy 6,
and
C. Rogier 1
2 Service d'Epidémiologie, Institut Pasteur, Dakar, Sénégal
3 Laboratoire de Chimie Bioorganique et Bioinorganique, CNRS URA 1384, Institut de Chimie Moléculaire d'Orsay, 91405 Orsay, France
4 Service d'Epidémiologie, Institut Pasteur, Dakar, Sénégal; Département d'Epidémiologie et de Santé Publique, Ecole d'Application du Service de Santé des Armées, 94998 Saint Mandé, France
5 UR 077 de Paludologie Afrotropicale, Institut pour la Recherche et le Développement, Dakar, Sénégal
6 Institut Fédératif de la Recherche no 48, 13385 Marseille, France; Unité de Recherche en Physiopathologie et de Pharmacogénétique Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Le Pharo, 13998 Marseille, France
B. Pradines, E-mail: bruno.pradines{at}free.fr
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