In vitro activity of iron-binding compounds against Senegalese isolates of Plasmodium falciparum.
OBJECTIVE
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 (IC(50)) values of FR160 ranged from 0.1 to 10 microM and the geometric mean IC(50) was 1.48 microM (95% CI = 1.29-1.68 microM). The geometric mean IC(50) of doxycycline for 121 isolates was 18.9 microM (95% CI = 16.8-21.3 microM) and that of desferrioxamine for 73 isolates was 20.7 microM (95% CI = 17.3-24.8 microM). FR160 was significantly less active against the chloroquine-resistant isolates (P < 0.0001). The mean IC(50)s 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 (r(2) < 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.
Pradines
B
B
Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Le Pharo, 13998 Marseille, France. bruno.pradines@free.fr
Tall
A
A
Ramiandrasoa
F
F
Spiegel
A
A
Sokhna
C
C
Fusai
T
T
Mosnier
J
J
Daries
W
W
Trape
J F
JF
Kunesch
G
G
Parzy
D
D
Rogier
C
C
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D003676:Deferoxamine / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D020128:Inhibitory Concentration 50; D007502:Iron Chelating Agents / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D012675:Senegal; D013095:Spermidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013223:Statistics as Topic
D000962:Antimalarials; C108048:FR 160; D007502:Iron Chelating Agents; D003676:Deferoxamine; D004318:Doxycycline; D013095:Spermidine