Preliminary report on the use of desferrioxamine in the treatment of <i>Plasmodium falciparum</i> malaria

Ousmane, Traore; Coriat, Pierre; Kaptue-Noche, Lazar; Mbede, J.; Desfontaine, M; Élion, Jacques; Labie, Dominique; Nagel, Ronald L.

doi:10.1002/ajh.2830370316

Cited by 47 publications

(17 citation statements)

References 4 publications

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“…The suggestion that iron chelation might represent a useful approach to antimicrobial therapy is not new (13,41,42), yet only recently has it been intensively investigated, most successfully in malaria research (16,19,40). The current work confirms previous observations that iron chelation with DFO inhibits the growth of P. carinii in vitro (46) and in vivo (11), and also demonstrates that alterations in ultrastructure parallel the inhibitory effect.…”

Section: Discussionsupporting

confidence: 80%

“…It has been suggested, therefore, that manipulation of iron availability be exploited as a therapeutic tool (13,41,42). In fact, several iron chelators, among them deferoxamine (DFO), demonstrate antimalarial activity in cell culture and animal models (14,33,47,48), and recently, iron chelation with DFO has been shown to be an effective adjunct to traditional antimalarial therapy in asymptomatic parasitemic adults and children with cerebral malaria (16,19,40).Clarkson et al (11) examined the effects of DFO on the progression of reactivated latent P. carinii pneumonia in rats and showed that DFO therapy reduces the lung cyst count in a dose-dependent manner. A subsequent preliminary study from the laboratory of Weinberg and Shaw (46) showed that DFO suppresses the growth of P. carinii in an established cell culture model at concentrations safely achievable in human serum.…”

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confidence: 99%

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Iron chelators as therapeutic agents against Pneumocystis carinii

Weinberg

1994

Antimicrob Agents Chemother

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Iron plays a critical role in host-parasite interactions, and iron chelators have been demonstrated to serve as effective adjunct therapeutic agents against malaria. The effects of the parenteral iron chelator deferoxamine (DFO) on the growth of rat-derived Pneumocystis carinii were studied in a human fibroblast cell culture model and in two in vivo models of experimental infection. In addition, the effects of the investigational oral iron chelator CP20 and its 3-hydroxypyridin-4-one analogs CP51, CP94, and CP96 on the growth of P. carinii in vitro were assessed. DFO suppressed the growth of P. carinii in vitro in a dose-dependent manner, and daily injections of DFO markedly reduced the intensity of P. carinii infection in both mice and rats. Cell cultures treated with iron chelators that are administered orally to humans also showed substantial P. carinii growth inhibition. Reduction of P. carinii numbers after iron chelator therapy correlated with alterations in P. carinii morphology, as viewed by transmission electron microscopy. Since the use of current anti-P. carinii drugs is limited by toxicity or incomplete efficacy, or both, the role of iron chelation as adjunctive anti-P. carinii chemotherapy merits additional investigation.In the absence of specific antimicrobial prophylaxis, Pneumocystis carinii causes pneumonia in the majority of individuals infected with human immunodeficiency virus and remains an important pathogen in persons treated with immunosuppressive therapy for malignancy and after organ transplantation (6). The toxicity and the incomplete efficacy of the standard treatment regimens for P. carinii pneumonia have prompted the development of new or adjunctive modes of therapy (6, 27).The availability of iron plays a critical role in host-parasite interactions (13,28,29,41,42). Iron is required for the growth of nearly all forms of bacterial, fungal, protozoal, plant, and animal cells (43,44). Vertebrate animals have developed elaborate strategies to withhold growth-essential iron from microbial invaders while retaining their own access to the metal (41,42,45). It has been suggested, therefore, that manipulation of iron availability be exploited as a therapeutic tool (13,41,42). In fact, several iron chelators, among them deferoxamine (DFO), demonstrate antimalarial activity in cell culture and animal models (14,33,47,48), and recently, iron chelation with DFO has been shown to be an effective adjunct to traditional antimalarial therapy in asymptomatic parasitemic adults and children with cerebral malaria (16,19,40).Clarkson et al. (11) examined the effects of DFO on the progression of reactivated latent P. carinii pneumonia in rats and showed that DFO therapy reduces the lung cyst count in a dose-dependent manner. A subsequent preliminary study from the laboratory of Weinberg and Shaw (46) showed that DFO suppresses the growth of P. carinii in an established cell culture model at concentrations safely achievable in human serum. However, despite the efficacy and safety of DFO as a chelator, i...

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Iron chelators as therapeutic agents against Pneumocystis carinii

Weinberg

1994

Antimicrob Agents Chemother

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“…This truism also applies to iron chelators, which have already scored success in the management of various diseases ( 1 ), including malaria (9). To gain knowledge on the mode of action of iron chelators as antimalarial agents and to determine the basis for their specific effects on infected cells it is necessary to delineate the routes by which they permeate into cells and to identify the critical iron pools.…”

Section: Discussionmentioning

confidence: 99%

“…Recently it was shown that DFO congeners display effective antimalarial activity both in vitro (2)(3)(4)(5) and in vivo (4,(6)(7)(8)(9), but as with many other drugs, their mode of action has remained elusive (1). The information available indicates that DFO acts without affecting serum (4,10) or normal red cell iron pools (3,10), that it gains a restricted access to infected cells ( 11 ), and that its antimalarial action is manifested only in the advanced stages of parasite development and only after prolonged exposure of cells to drug (3,12).…”

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confidence: 99%

The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites.

Loyevsky

Lytton²,

Mester³

et al. 1993

J. Clin. Invest.

102

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We designed the N-methylanthranilic-desferrioxamine (MA-DFO) as a fluorescent iron(III) chelator with improved membrane permeation properties. Upon binding of iron(III), MA-DFO fluorescence is quenched, thus allowing traceability of drug-iron(III) interactions. MA-DFO is well tolerated by mammalian cells in culture. Its antimalarial activity is pronounced: IC50 values on in vitro (24-h) growth of Plasmodium fakciparum were 3±1 MM for MA-DFO compared with 30±8 for DFO. The onset of growth inhibition of rings or trophozoites occurs 2-4 h after exposure to 13 gM MA-DFO. This effect is commensurate with MA-DFO permeation into infected cells. In a 24-h exposure to MA-DFO or DFO, trophozoites take up either compound to -10% of the external concentration, rings to 5%, and noninfected cells to < 1%. Red cells encapsulated with millimolar concentrations of DFO or MA-DFO fully support parasite invasion and growth. We conclude that extracellular MA-DFO and DFO gain selective access into parasites by bypassing the host. The rate-limiting step is permeation through the parasite membrane, which MA-DVO accomplishes faster than DFO, in accordance with its iigher hydrophobicity. These views are consistent with the proposed duct, which apparently provides parasitized cells with a window to the external medium. (J. Clin. Invest. 1993. 91:218-224.)

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“…Studies in human malaria showed that DFO alone, or in combination with standard therapy, enhances parasite clearance in asymptomatic and severe malaria (Traore et al, 1991;Gordeuk et al, 1992;Mabeza et al, 1996). Continuous infusion of DFO over a 3 day period is required to obtain enhanced parasite clearance in human malaria (Mabeza et al, 1996).…”

Section: Discussionmentioning

confidence: 99%