The Status of New Iron Chelators*

Cerami, Anthony; Grady, Robert W.; Bhargava, Kuldeep K.

doi:10.1111/j.1749-6632.1980.tb33682.x

Cited by 30 publications

(9 citation statements)

References 42 publications

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“…Single doses ranged from 1 g to 3 g a day. White cell ascorbate concentration was measured before the studies and was low in six patients (cases [3][4][5][6][7][8]. Repeated doses up to 2 g three times during the day and combinations with ascorbic acid (200 mg, single daily dose) were also used.…”

Section: Methodsmentioning

confidence: 99%

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

Kontoghiorghes

Aldouri

Hoffbrand

et al. 1987

BMJ

186

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The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four P thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough

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Section: Methodsmentioning

confidence: 99%

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

Kontoghiorghes

Aldouri

Hoffbrand

et al. 1987

BMJ

186

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“…Chemical measurements of fecal iron excretion in hypertransfused rats showed an oral efficiency equal to that of parenteral DF,*"O whereas in hypertransfused rats labeled with selective RE and parenchymal probes, no evidence of oral effectiveness could be A compounding factor in these studies might have been the fecal excretion of iron chelated in situ, within the intestinal tract. Although no serious toxicity has been found in animal studies, preliminary trials in humans were complicated by diarrhea at the therapeutic dose of 25 rng/kg 4 times daily 2oo, 206 and clinical studies were apparently not pursued any further.…”

Section: A Hydroxamic Acidsmentioning

confidence: 98%

Iron-Chelating Therapy

Hershko

Weatherall

Finch

1988

CRC Critical Reviews in Clinical Laboratory Sciences

128

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Because of the catalytic action of iron in one-electron redox reactions, it has a key role in the formation of harmful oxygen derivatives and production of peroxidative damage to vital cellular structures. The clinical manifestations of iron overload may be prevented and even reversed by the effective administration of the iron-chelating drug deferoxamine (DF). Recent experimental evidence suggests that DF may also be useful in modifying disease conditions unrelated to iron overload by preventing the formation of free radicals, the powerful final effectors of tissue damage resulting from the respiratory burst of granulocytes and macrophages participating in the inflammatory response. Although much experimental work is still needed, this novel approach in iron-chelating therapy may have far-reaching implications in the management of autoimmune disease, adult respiratory distress syndrome, and organ transplantation. The poor intestinal absorption of DF, its almost prohibitive price, and short duration of action underline the need for new, orally effective iron chelators. A number of very promising orally effective drugs have been identified in recent years, such as the polyanionic amines, aryl hydrazones, and hydroxypyridones. Further development for clinical use of this new generation of iron-chelating drugs is a major challenge for future research.

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“…DF's safety is buttressed by more than two decades of use in the treatment of siderosis in Cooley's anemia ( 15). It is possible that other iron-chelating compounds also have antimalarial activity and that the ongoing effort to develop agents which remove iron with greater efficiency and which can be given orally may prove to have a double benefit (16).…”

Section: F-fmentioning

confidence: 99%

Desferrioxamine Suppresses Plasmodium falciparum in Aotus Monkeys

Pollack

Rossan²,

Davidson

et al. 1987

Experimental Biology and Medicine

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Clinical observation has suggested that iron deficiency may be protective in malaria, and we have found that desfemoxamine (DF), an iron-specific chelating agent, inhibited Plasmodium falciparum growth in vitro. It was difficult to be confident that DF would be effective in an intact animal, however, because continuous exposure to DF was required in vitro and, in vivo, DF is rapidly excreted. Also, the in vitro effect of DF was overcome by addition of iron to the culture and in vivo there are potentially high local iron concentrations when iron is absorbed from the diet or released from reticuloendothelial cells. We now show that DF given by constant subcutaneous infusion does suppress parasitemia in P. fakiparum-infected Aotus monkeys.

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The Status of New Iron Chelators*

Cited by 30 publications

References 42 publications

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

Iron-Chelating Therapy

Desferrioxamine Suppresses Plasmodium falciparum in Aotus Monkeys

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