Effect of Iron Chelation Therapy on Recovery from Deep Coma in Children with Cerebral Malaria

Gordeuk, Victor R.; Thuma, Philip E.; Brittenham, Gary M.; McLaren, Christine E.; Parry, Dean; Backenstose, Anita; Biemba, Godfrey; Msiska, R; Holmes, Laura; McKinley, Elizabeth D.; Vargas, Linda; Gilkeson, Robert C.; Poltera, A. A.

doi:10.1056/nejm199211193272101

Cited by 192 publications

(88 citation statements)

References 18 publications

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“…DEF, a trihydroxamic acid siderophore produced by Streptomyces pilosus (40), is the only iron-chelating agent approved for clinical use. This drug has been used successfully as an adjunct in the treatment of malaria, in which it was found to hasten the clearance of parasitemia and enhance recovery from deep coma in patients with cerebral malaria (20). The only other iron chelator that has been extensively studied in humans is CP20, also known as L1 or deferiprone.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

Newman

Gootee

Stroobant

et al. 1995

Antimicrob Agents Chemother

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Histoplasma capsulatum requires intracellular iron to survive and multiply within human and murine macrophages (M). Thus, iron chelators may be useful compounds in the treatment of histoplasmosis. In the present study we compared the efficacies of five different iron chelators with deferoxamine (DEF) for their capacity to inhibit the growth of H. capsulatum yeast cells in culture medium and within human M. Of the agents tested, only one, VUF 8514, a 2,2-bipyridyl analog, was found to be effective. VUF 8514 inhibited the growth of yeast cells in tissue culture medium and within M in a dose-response fashion. In tissue culture medium, the 50% effective dose (ED 50 ) of VUF 8514 was 30 nM and the ED 50 of DEF was 1 mM. In human M, the ED 50 of VUF 8514 was 520 nM and the ED 50 of DEF was 4 mM. Thus, VUF 8514 was effective at a concentration 7.7 ؋ 10 The mechanism used by Histoplasma capsulatum yeast cells to survive and multiply within human macrophages (M) are poorly understood. Phagocytosis of H. capsulatum yeast cells by human monocyte/M stimulates both the respiratory burst (6, 33, 39) and phagolysosomal fusion (37). Nevertheless, ingested yeast cells multiply within M phagolysosomes (17,34,36).Original studies on the interaction of H. capsulatum yeast cells with murine peritoneal M suggest that acquisition of intracellular iron may be important for yeast survival. Thus, coculture of H. capsulatum-infected murine peritoneal M in the presence of the iron chelator deferoxamine (DEF) suppresses the intracellular growth of yeast cells, and this effect is reversed by iron-saturated transferrin (holotransferrin) (25). More important, one mechanism by which gamma interferonactivated mouse peritoneal M (25) and gamma interferonlipopolysaccharide-activated murine splenic M (26) inhibit the intracellular growth of H. capsulatum is by the restriction of intracellular iron.Even though gamma interferon does not activate the antifungal activity of human M (17, 34), iron is a critical requirement for the intracellular survival of H. capsulatum yeast cells in human M (35). Thus, coculture of H. capsulatum-infected M with DEF suppresses the growth of the yeast cells, an effect that is reversed by holotransferrin, confirming the studies in murine M. In addition, chloroquine, a weak base that prevents the release of iron from transferrin by raising endocytic and lysosomal pH (2,18,24,44), induces human M to kill H. capsulatum. The effect of chloroquine is reversed by iron nitriloacetate (FeNTA), an iron compound that is soluble at neutral to alkaline pH (1), but not by holotransferrin, which releases iron only in an acidic environment. Furthermore, chloroquine is an effective therapeutic agent in a murine model of histoplasmosis (35).These data suggest that agents that interfere with the ability of H. capsulatum yeast cells to acquire intracellular iron may be useful in the treatment of histoplasmosis. Currently, DEF is the only metal chelator that is available for clinical use, and it has been used mainly in patients with hematol...

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Section: Discussionmentioning

confidence: 99%

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

Newman

Gootee

Stroobant

et al. 1995

Antimicrob Agents Chemother

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“…6,[15][16][17][18] Most deaths occur within 24 hr of starting treatment 6,7,16,[19][20][21] and most of those who survive recover fully within 48 hr of starting treatment. 6,15,16,20,21 To be credible, theories of fatal malaria pathogenesis must explain the rapidity with which these syndromes develop and then either kill the patient or resolve, leaving only 9-12% of survivors with neurologic sequelae. 6,17,22 Malaria hyperpneic syndrome.…”

Section: Descriptionmentioning

confidence: 99%

“…26 Patients are excluded if they improve within 1 hr of a convulsion, or of being restored to a normoglycemic state. 6,7,15,16 A less stringent definition, where any impairment of consciousness is sufficient justification for intensifying the clinical management (parenteral antimalarials, assiduous nursing care) is more appropriate in usual clinical settings. 26 The neurologic manifestations of CM span the spectrum from diffuse cortical involvement to specific brainstem abnormalities.…”

Section: Descriptionmentioning

confidence: 99%

Pathophysiology of fatal falciparum malaria in African children.

Newton¹,

Taylor²,

Whitten³

1998

Am J Trop Med Hyg

122

121

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Abstract. Children living in sub-Saharan Africa bear the brunt of the mortality from falciparum malaria, yet there is a dearth of relevant post-mortem data. Clinical studies from centers in Africa suggest that the pathophysiology of severe malaria is different in children and adults. Three overlapping clinical syndromes, metabolic acidosis manifesting as hyperpnea, cerebral malaria, and severe anemia, are responsible for nearly all the deaths in African children. Despite improvements in antimalarial treatment, there has not been a significant reduction in mortality. We review the pathology and pathophysiology of fatal falciparum malaria in African children. Many questions remain, the answers to which would facilitate the development and evaluation of new approaches to the management of this disease.Severe and complicated Plasmodium falciparum infections continue to threaten the survival of young children in sub-Saharan Africa: one in 15 children on the Kenyan coast will have experienced an episode of severe malaria before the age of five, 1 and 1% of Gambian children less than five years of age will die of malaria. 2 The annual death toll is estimated to be one million children across the continent; 90% of the annual worldwide malaria mortality. 3 Although most children die in the community, on the Kenyan coast it is estimated that more than 40% die in a hospital (Marsh K, unpublished data) and one-third of pediatric hospital admissions and one-third of pediatric hospital deaths in Malawi can be attributed to malaria. 4

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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%

An extended-release formulation of desferrioxamine for subcutaneous administration

2009

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Effect of Iron Chelation Therapy on Recovery from Deep Coma in Children with Cerebral Malaria

Abstract: Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.

Cited by 192 publications

References 18 publications

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

Pathophysiology of fatal falciparum malaria in African children.

An extended-release formulation of desferrioxamine for subcutaneous administration

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