Skip to main content
SpringerLink
Log in

Iron Chelation Therapy for Malaria

  • Chapter
Progress in Iron Research

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 356))

Abstract

Malaria is one of the most devastating and geographically widespread infections in man. Of the four protozoan species that cause malaria in humans, Plasmodium falciparum is responsible for the most severe clinical consequences including coma, profound anemia, renal failure and death. It is estimated that in 1986 there were 234 million clinical cases of falciparum malaria worldwide and that 2.2 million individuals died (Sturchler, 1989). Earlier in the century, the widespread application of effective insecticides and antimalarial drugs led to a decline in the incidence of malaria and the disease was eradicated from some countries. Over the past two decades, global resistance to both insecticides and antimalarials has emerged, the incidence of malaria has increased rapidly, and the geographic occurrence has become more widespread (Clyde, 1987). Efforts to develop a malaria vaccine are underway but face formidable obstacles, such as the observations that immunity resulting from natural infection is partial and of limited duration (Hoffman et al, 1987) and that the antigens of P. falciparum are highly polymorphic (Anders and Smythe, 1989). Although early tests of malaria vaccines in human volunteers have been conducted (Cox, 1993), clinically applicable vaccines will not be available for a number of years and their importance in controlling malaria is uncertain. In this setting, antimalarial chemotherapy remains the principal means available for reducing the morbidity and mortality of malaria, and the task of developing new antimalarial drugs with new mechanisms of action is of critical importance (WHO Scientific Group, {1984).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Aikawa, M., 1988a, Fine structure of malaria parasites in the various stages of development, in: “Principles and Practice of Malariology,”} W.H. Wernsdorfer, I. McGregor, eds., Churchill Livingstone, Edinburgh.

    Google Scholar 

  • Aikawa, M., 1988b, Human cerebral malaria, American Journal of Tropical Medicine and Hygiene 39: 3.

    PubMed  CAS  Google Scholar 

  • Anders, R.F., and Smythe, J.A., 1989, Polymorphic antigens in Plasmodium falciparum, Blood 74: 1865.

    PubMed  CAS  Google Scholar 

  • Atkinson, C.T., Bayne, M.T., Gordeuk, V.R., Brittenham, G.M., and Aikawa, M., 1991, Stage-specific ultrastructural effects of desferrioxamine on Plasmodium falciparum in vitro, Am. J. Trop. Med. Hyg. 45: 593.

    PubMed  CAS  Google Scholar 

  • Bailey-Wood, R., Blayney, L.M., Muir, J.R., and Jacobs, A., 1975, The effects of iron deficiency on rat liver enzymes, Brit. J. Exp. Pathol. 56, 193.

    CAS  Google Scholar 

  • Bergeron, R.J., Iron: a controlling nutrient in proliferative processes, Trends in Biochem. Sci. 11: 133.

    Google Scholar 

  • Bezkorovainy, A., 1980, “Biochemistry of Nonheme Iron”, Plenum Press, New York and London.

    Google Scholar 

  • Brittenham, G.M., 1987, Iron chelating agents, in: “Current Therapy in Hematology Oncology 3,” Mosby, St.Louis.

    Google Scholar 

  • Cavanaugh, P.F., Porter, C.W., Tukalo, D., Frankfurt, D.S., Pavelic, Z.P., and Bergeron, R.J., 1985, Characterization of L1210 cell growth inhibition by the bacterial iron chelators parabactin and compound II, Cancer Res. 45: 4754.

    PubMed  CAS  Google Scholar 

  • Cazzola, M., Arioso, P., Barosi, G., Bergamaschi, G., Dezza, L., and Ascari, E., 1983, Ferritin in the red cells of normal subjects and patients with iron deficiency and iron overload, Brit J Haematol 53: 659.

    Article  CAS  Google Scholar 

  • Clarke, C.J., and Eaton, J.M., 1990, Hydrophobic iron chelators as new antimalarial drugs, Clin. Res. 38: 300A.

    Google Scholar 

  • Clyde, D.F., 1987, Recent trends in the epidemiology and control of malaria, Epidemiol. Rev. 9: 219.

    PubMed  CAS  Google Scholar 

  • Cook, L., Grant, P.T., and Kermack, W.O., 1961, Proteolytic enzymes of the erythrocytic forms of rodent and simian species of malarial plasmodia, Exp. Parasitol. 11, 372.

    Article  PubMed  CAS  Google Scholar 

  • Cox, F.E.G., 1993, That vaccine passes a trial, Nature 362: 410.

    Article  PubMed  CAS  Google Scholar 

  • Fritsch, G., Sawatzki, G., Treumer, J., Jung, A., and Spira, D. T., 1987, Plasmodium falciparum: inhibition in vitro with lactoferrin, desferrithiocin and desferricrocin, Exp. Parasitol. 63: 1.

    Article  PubMed  CAS  Google Scholar 

  • Garnham, P.C.C., 1988, Malaria parasites in man: life-cycles and morphology (excluding ultrastructure), In I. McGregor, eds., Principles and Practice of Malariology. Churchill Livingstone, Edinburgh

    Google Scholar 

  • Gordeuk, V.R., Thuma, P.E., Brittenham, G.M., Biemba, G., Zulu, S., Simwanza, G., Kalense, P., M’hango, A., Parry, D., Poltera, A.A., and Aikawa, M., 1993, Iron chelation as a chemotherapeutic strategy for falciparum malaria, Am. J. Trop. Med. Hyg. 48: 193.

    PubMed  CAS  Google Scholar 

  • Gordeuk, V.R., Thuma, P.E., Brittenham, G.M., McLaren, C., Parry, D., Backenstose, A.R., Biemba, G., Msiska, R., Holmes, L., McKinley, E., Vargas, L., Gilkeson, R.C., and Poltera, A.A., 1992b, Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria, New Engl. J. Med. 327: 1473.

    Article  PubMed  CAS  Google Scholar 

  • Gordeuk, V.R., Thuma, P.E., Brittenham, G.M., Zulu, S., Simwanza, G., Mhangu, A., Flesch, G., and Parry, D., 1992a, Iron chelation with deferoxamine B in adults with asymptomatic Plasmodium falciparum parasitemia, Blood 79: 308.

    PubMed  CAS  Google Scholar 

  • Haldar, K., Henderson, C. L., and Cross, G. A. M., 1986, Identification of the parasite transferrin receptor of Plasmodium falciparum infected erythrocytes and its acylation via 1,2-diacyl-Sn-glycerol, Proc. Natl. Acad. Sci. USA 83: 8565.

    Article  PubMed  CAS  Google Scholar 

  • Harvey, P.W J., Heywood, P.F., Nesheim, M.C., Galme, K., Zegans, M., Habicht, J.-P., Stephenson, L S., Radimer, K.L., Brabin, B., Forsyth, K., and Alpers, M.P., 1989, The effect of iron therapy on malarial infection in Papua New Guinean schoolchildren, Am. J. Trop. Med. Hyg. 40: 12.

    PubMed  CAS  Google Scholar 

  • Heppner, D.G., Hallaway, P.E., Kontoghiorghes, G.J., and Eaton, J.W., 1988, Antimalarial properties of orally active iron chelators, Blood 72: 358.

    PubMed  CAS  Google Scholar 

  • Hershko, C., and Peto, T.E.A., 1988, Deferoxamine inhibition of malaria is independent of host iron status, J. Exp. Med. 168: 375.

    Article  PubMed  CAS  Google Scholar 

  • Hershko, C., Theanacho, E.N., Spira, D.T., Peter, H.H., Dobbin, P., and Hider, R.C., 1991, The effect of N-alkyl modification on the antimalarial activity of 3-hydroxyppyridin-4-one oral iron chelators, Blood 77: 637.

    PubMed  CAS  Google Scholar 

  • Hoffman, S.L., Oster, C.N., Plowe, C.V., Woollett, G.R., Beier, J.C., Chulay, J.D., Wirtz, F.A., Hollingdale, M.R., and Mugambi, M., 1987, Naturally acquired antibodies to sporozoites do not prevent malaria: vaccine development implications, Science 237: 639.

    Article  PubMed  CAS  Google Scholar 

  • Jairam, K.T., Havlik, I., and Monteagudo, F.S.E., 1991, Possible mechanism of action of desferrioxamine and 2,2’-bipyridyl on inhibiting the in vitro growth of Plasmodium falciparum (3 strain), Biochem Pharmacol 8: 1633.

    Article  Google Scholar 

  • Jambou, R., Ghogomu, N.A., Kouka-Bemba, K., and Hengy, C., 1992, Activity of chloroquine and desferrioxamine in vitro against newly isolated Plasmodium falciparum and their antagonism in combination, Trans Roy Soc Trop Med Hyg 86: 11.

    Article  PubMed  CAS  Google Scholar 

  • Loyevsky, M., Lytton, S.D., Mester, B., Libman, J., Shanzer, A., and Cabantchik, Z.I., 1993, The antimalarial action of Desferal involves a direct access route to erythrocytic Plasmodium falciparum) parasites, J. Clin. Invest. 91: 218

    Article  PubMed  CAS  Google Scholar 

  • Lytton, S.D., Cabantchik, I., Libman, J., and Shanzer, A., 1991, Reversed siderophores as antimalarial agents. II. Selective scavenging of Fe (III) from parasitized erythrocytes by a fluorescent derivative of Desferal, Molecular Pharmacol. 40: 584.

    CAS  Google Scholar 

  • Lytton, S.D., Mester B., Dayan, I., Glickstein, H., Libman, J., Shanzer, A., and Cabantchik, Z.I., 1993, Mode of action of iron (III) chelators as antimalarials: I. Membrane permeation properties and cytotoxic activity, Blood, 81: 214.

    PubMed  CAS  Google Scholar 

  • MacPherson, G.G., Warrell, M.J., White, N.J., Looareesuwan, S., Warrell, D.A., 1985, Human cerebral malaria: a quantitative ultrastructural analysis of parasitized erythrocyte sequestration, Am. J. Pathol. 119: 385.

    PubMed  CAS  Google Scholar 

  • McCord, J.M., 1985, Oxygen-derived free radicals in postischemic tissue injury, New Engl. J. Med. 312: 159.

    Article  PubMed  CAS  Google Scholar 

  • Modell, B. and Berdoukas, V., 1984, Desferrioxamine, in: “The Clinical Approach to Thalassemia”, Grune and Stratton, London.

    Google Scholar 

  • Molyneux, M.E., Taylor, T.E., Wirima, J.J., and Borgstein, A., 1989, Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children, Q. J. Med., New Series 71: 441.

    PubMed  CAS  Google Scholar 

  • Murray, M.J., Murray, A.B., Murray, M.B., and Murray, C.J., 1978, The adverse effect of iron repletion on the course of certain infections, Brit. Med. J. 2: 1113.

    Article  PubMed  CAS  Google Scholar 

  • Oppenheimer, S. J., Gibson, F. D., MacFarlane, S. B., Moody, J. B., Harrison, C., Spencer, A., and Bunari, O., 1986, Iron supplementation increases prevalence and effects of malaria: report on clinical studies in Papua New Guinea, Trans. Roy. Soc. Trop. Med. Hyg. 80: 603.

    Article  PubMed  CAS  Google Scholar 

  • Peto, T. E. A, and Thompson, J. L., 1986, A reappraisal of the effects of iron and desferrioxamine on the growth of Plasmodium falciparum in vitro’: the unimportance of serum iron, Brit. J. Haematol. 63: 273

    Article  CAS  Google Scholar 

  • Pollack, S., and Hemming, J., 1984, P. falciparum takes up iron from transferrin, Brit. J. Haematol. 58: 289.

    Article  CAS  Google Scholar 

  • Pollack, S., Rossan, R.N., Davidson, D.E., and Escajadillo, A., 1987, Desferrioxamine suppresses Plasmodium falciparum in Aotus Monkeys, Proc. Soc. Experiment. Biol. Med. 184: 162.

    CAS  Google Scholar 

  • Pollack, S., and Schnelle, V., 1986, Inability to detect transferrin receptors on P. falciparum parasitized red cells, Brit. J. Haematol. 68: 125.

    Article  Google Scholar 

  • Raventos-Suarez, C., Pollack, S., and Nagel, R.L., 1982, Plasmodium falciparum: inhibition of in vitro growth by desferrioxamine, Am. J. Trop. Med. Hyg. 31: 919.

    PubMed  CAS  Google Scholar 

  • Reichard, P. and Ehrenburg, A., 1983, Ribonucleotide reductase-a radical enzyme, Science 221: 514.

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez, M.H., and Jungery, M.H., 1986, A protein of Plasmodium falciparum-infected erythrocytes functions as a transferrin receptor, Nature 324: 388.

    Article  PubMed  CAS  Google Scholar 

  • Rosenthal, P.J., McKerrow, J.H., Aikawa, M., Nagasawa, H., and Leech, J.H., 1988, A malarial cysteine protease is necessary for hemoglobin degradation by Plasmodium falciparum, J. Clin. Invest. 82; 1560.

    Article  PubMed  CAS  Google Scholar 

  • Sadrzadeh, S.M.H., Anderson, D.K., Panter, S.S., Hallaway, P.E., and Eaton, J.W., 1987, Hemoglobin potentiates central nervous system damage, J. Clin. Invest. 79: 662.

    Article  PubMed  CAS  Google Scholar 

  • Sadrzadeh, S.M.H., Graf, E., Panter, S.S., Hallaway, P.E., and Eaton, J.W., 1984, Hemoglobin: a biologic Fenton reagent, J. Biol. Chem. 259: 14354.

    PubMed  CAS  Google Scholar 

  • Shanzer, A., Libman, J., Lytton, S.D., Glickstein, H., and Cabantchik, Z.I., Reversed siderophores act as antimalarial agents. Proc. Natl. Acad. Sci. USA 88: 6585.

    Google Scholar 

  • Scheibel, L.W., 1988, Plasmodial parasite biology: carbohydrate metabolism and related organeller function during various stages of the life-cycle, in: “Malaria,” Wernsdorfer, W., McGregor, I., Eds, Churchill, Livingstone, Edinburgh.

    Google Scholar 

  • Scheibel, L.W., and Adler, A., 1980, Antimalarial activity of selected aromatic chelators, Molecular. Pharmacol. 18, 320.

    CAS  Google Scholar 

  • Scheibel, L., and Adler, A., 1981, Antimalarial activity of selected aromatic chelators. II. Substituted quinolines and quinoline-N-oxides, Molecular Pharmacol 20: 218.

    CAS  Google Scholar 

  • Scheibel, L., and Rodriguez, S., 1989, Antimalarial activity of selected aromatic chelators v. localization of 59Fe in Plasmodium falciparum in the presence of oxines, in: “Malaria and the Red Cell,” Alan R. Liss, Inc., New York.

    Google Scholar 

  • Scheibel, L. W., and Sherman, I. W., 1988, Metabolism and organeller functions during various stages of the life-cycle: proteins, lipids, nucleic acids and vitamins, in: “Malaria,” Wernsdorfer, W., McGregor, I., Eds, Churchill, Livingstone, Edinburgh.

    Google Scholar 

  • Scheibel, L.W., and Stanton, G.G., 1986, Antimalarial activity of selected aromatic chelators. IV. Cation uptake of Plasmodium falciparum in the presence of oxines and siderochromes, Molecular Pharmacol. 30: 364.

    CAS  Google Scholar 

  • Scott, M.D., Ranz, A., Kuypers, F.A., Lubin, B.H., and Meshnick, S.R., 1990, Parasite uptake of desferrioxamine: a prerequisite for antimalarial activity, Brit. J. Haematol. 75: 598.

    Article  CAS  Google Scholar 

  • Slater, A.F.G., and Cerami, A., 1992, Inhibition by chloroquine of a novel heme polymerase enzyme activity in malaria trophozoites, Nature 355: 167.

    Article  PubMed  CAS  Google Scholar 

  • Stahel, B., Mazier, D., Guillouzo, A., Miltgen, P., Landau, I., Mellouk, S., Beaudoin, R.L., Langlois, P., and Gentilini, M., 1988, Iron chelators: in vitro inhibitory effect on the liver stage of rodent and human malaria, Am. J. Trop. Med. Hyg. 39: 236.

    PubMed  CAS  Google Scholar 

  • Sturchler, D, 1989, How much malaria is there worldwide? Parasitol. Today 5: 39.

    Article  Google Scholar 

  • Summers, M., Jacobs, A., Tudway, D., Perera, P., and Ricketts, C., 1979, Studies in desferrioxamine and ferrioxamine in normal and iron-loaded subjects, Brit. J. Haematol. 42: 547.

    Article  CAS  Google Scholar 

  • Traore, O., Carnevale, P., Kaptue-Noche, L., M’Bede, J., Desfontaine, M., Elion, J., Labie, D., and Nagel, R.L., 1991, Preliminary report on the use of desferrioxamine in the treatment of Plasmodium falciparum malaria, Am. J. Hematol. 37: 206.

    Article  PubMed  CAS  Google Scholar 

  • vanZyl, R.L., Havlik, I., and Monteagudo F.S.E., 1992, The combined effect of iron chelators and classical antimalarials on the in-vitro growth of Plasmodium falciparum, J. Antimicrob. Chemotherapy 30: 273.

    Article  Google Scholar 

  • Yinnon, A.M., Theanacho, E.N., Grady, R.W., Spira, D.T., and Hershko, C., 1989, Antimalarial effect of HBED and other phenolic and catecholic iron chelators, Blood 74: 2166.

    PubMed  CAS  Google Scholar 

  • White, N.J., Warrell, D.A., Looareesuwan, S., Chanthavanich, P., Phillips, R.E., Pongpew, P., 1985, Pathophysiological and prognostic significance of cerebrospinal fluid lactate in cerebral malaria, Lancet i: 776.

    Article  Google Scholar 

  • Whitehead, S., and Peto, T.E.A., 1990, Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro, Blood 76: 1250.

    PubMed  CAS  Google Scholar 

  • WHO Scientific Group, 1984, Advances in malaria chemotherapy, WHO Tech. Rep. Series 711:1.

    Google Scholar 

  • Wrigglesworth, J.M., and Baum, H., 1980, The biochemical functions of iron, in: “Iron in Biochemistry and Medicine II,” A. Jacobs, M. Worwood, eds., Academic Press, New York.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, MetroHealth Medical Center Case Western Reserve University, Cleveland, OH, 44109, USA

    Victor R. Gordeuk & Gary M. Brittenham

  2. Department of Pediatrics, Hershey Medical Center Pennsylvania State University, Hershey, PA, USA

    Philip E. Thuma

Authors
  1. Victor R. Gordeuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip E. Thuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary M. Brittenham
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Shaare Zedek Medical Center and Hebrew University of Jerusalem, Jerusalem, Israel

    Chaim Hershko

  2. The Hebrew University Hadassah Medical School, Jerusalem, Israel

    Abraham M. Konijn

  3. Albert Einstein College of Medicine, Bronx, New York, USA

    Philip Aisen

Rights and permissions

Reprints and permissions

Copyright information

© 1994 Springer Science+Business Media New York

About this chapter

Cite this chapter

Gordeuk, V.R., Thuma, P.E., Brittenham, G.M. (1994). Iron Chelation Therapy for Malaria. In: Hershko, C., Konijn, A.M., Aisen, P. (eds) Progress in Iron Research. Advances in Experimental Medicine and Biology, vol 356. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2554-7_39

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-2554-7_39

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6090-2

  • Online ISBN: 978-1-4615-2554-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation