RESUMO
Iron chelation therapy with desferrioxamine (DFO) has dramatically improved the outlook in beta-thalassemia. Parenteral DFO reduces tissue iron stores, prevents iron-induced organ damage, and reduces morbidity and mortality, with little serious toxicity. However, the burden of prolonged subcutaneous portable pump infusions, high cost, and patient noncompliance have prompted the development of new methods of administration and new formulations of DFO as well as oral iron chelators. Deferiprone (L1), the only oral iron chelator studied in large long-term clinical trials, is less effective and more toxic than DFO and may not adequately control iron overload; however, compliance and quality of life are improved. Combinations of two iron chelators (such as parenteral DFO plus oral L1, or 2,3-DHB; or oral L1 plus HBED) have been shown to produce additive and synergistic effects, explained by the shuttle hypothesis. Iron bound to a "shuttle"--an oral agent that mobilizes tissue iron--is exchanged in the bloodstream with a "sink"--such as parenteral DFO--and excreted via the kidneys, while the shuttle is reutilized. Combination therapy may produce enhanced iron excretion, target specific iron compartments, minimize side effects, increase treatment options, improve compliance, and facilitate individualization of therapy. Better understanding of the kinetics of iron metabolism, iron overload, and chelation should improve therapeutic strategies.
Assuntos
Quelantes de Ferro/uso terapêutico , Talassemia beta/tratamento farmacológico , Desferroxamina/administração & dosagem , Quimioterapia Combinada , Humanos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Talassemia beta/sangueRESUMO
In summary, long-term studies of DFO therapy in multiply-transfused patients with beta-thalassemia major have clearly shown it to be generally safe and effective. Appropriate use of DFO can remove excess iron, prevent iron-induced organ damage, and improve survival in thalassemia patients. Patients who begin treatment at a young age can be protected from the lethal complications of iron overload for at least two decades, but chelation therapy may not always prevent or ameliorate late growth failure and/or delayed or absent puberty. Those with iron damage to the heart and possibly other organs may experience stability or improvement in function with intense chelation. High-dose intravenous DFO produces a rapid decrease in hepatic iron content and improved cardiac function but can also cause severe toxicity, as can normal doses in patients with a low iron burden. Continuing studies of DFO are necessary to help further define its long-term efficacy and toxicity. In particular, significant attention should be paid to new strategies aimed at fostering improved compliance with its use.
Assuntos
Quelantes/uso terapêutico , Terapia por Quelação , Desferroxamina/uso terapêutico , Hemocromatose/terapia , Ferro , Talassemia/terapia , Reação Transfusional , Adolescente , Adulto , Quelantes/efeitos adversos , Terapia por Quelação/efeitos adversos , Criança , Desferroxamina/efeitos adversos , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/prevenção & controle , Perda Auditiva/induzido quimicamente , Cardiopatias/etiologia , Cardiopatias/mortalidade , Cardiopatias/prevenção & controle , Hemocromatose/etiologia , Hemossiderose/etiologia , Hemossiderose/terapia , Humanos , Nefropatias/induzido quimicamente , Pneumopatias/induzido quimicamente , Talassemia/complicações , Transtornos da Visão/induzido quimicamenteRESUMO
In summary, it has been shown that orally administered HBED causes enhanced excretion of iron in all of the thalassemia major patients studied and that both urinary and stool iron are increased in the process. Increasing the dose from 40 to 80 mg/kg divided t.i.d. caused iron balance to increase from 38% to 50%. While this is significantly less than that expected based on our preclinical studies in animals, the potential usefulness of this chelator has been demonstrated. Efforts to increase its oral bioavailability are now in progress. Lending further support to the effort is the fact that no evidence of toxicity has been observed in the studies performed to date and that negative iron balance was achieved in the one thalassemia intermedia patient studied. The results also reinforce the conclusion that DFO causes the excretion of substantially more iron than would be predicted by an assessment of serum ferritin levels or past compliance with chelation therapy. In patients with thalassemia major, serum ferritin levels relate more to tissue damage than to body iron load. Effective chelation therapy can diminish the former much faster than it can remove storage iron. Hence, in cases of iron overload, aggressive chelation therapy should not be tapered off until a significant reduction in iron excretion can be demonstrated. Routine measurements of urinary iron excretion should now be considered essential in the management of beta-thalassemia. Finally, two more patients with thalassemia intermedia will be studied in an effort to substantiate that net negative iron balance can be achieved in this subgroup of patients. We also plan to study several transfused patients in whom the dose of HBED will be increased to 120 mg/kg divided t.i.d. While the chances of achieving net negative iron balance in these patients seems remote, we hope to further demonstrate the safety of this drug with an eye toward the development of an effective prodrug.
Assuntos
Quelantes/toxicidade , Desferroxamina/uso terapêutico , Ácido Edético/análogos & derivados , Ferro/sangue , Talassemia beta/terapia , Adolescente , Adulto , Quelantes/farmacocinética , Desferroxamina/farmacocinética , Ácido Edético/farmacocinética , Ácido Edético/uso terapêutico , Ácido Edético/toxicidade , Feminino , Humanos , Ferro/toxicidade , Masculino , Reação TransfusionalAssuntos
Hemocromatose/fisiopatologia , Ferro/fisiologia , Subpopulações de Linfócitos T/fisiologia , Animais , Sangria , Relação CD4-CD8/efeitos dos fármacos , Terapia por Quelação , Desferroxamina/farmacologia , Compostos Férricos/toxicidade , Hemocromatose/induzido quimicamente , Hemocromatose/genética , Hemocromatose/terapia , Ferro/toxicidade , Camundongos , Modelos Biológicos , Ratos , Ratos Endogâmicos , Ratos Endogâmicos WF , Subpopulações de Linfócitos T/efeitos dos fármacos , Talassemia/tratamento farmacológico , Talassemia/fisiopatologiaRESUMO
Previous studies showed that deferoxamine inhibits malaria by interacting with a labile iron pool within parasitized erythrocytes. Consequently, we studied the antimalarial properties of other iron-chelating drugs such as 2,3-dihydroxybenzoic acid (2,3-DHB) and its methyl ester as well as two polyanionic amines, N.N'-bis (o-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED) and N,N'-ethylenebis(o-hydroxyphenylglycine) (EHPG) in rats infected with Plasmodium berghei. All drugs were delivered by subcutaneous injection at 8-hour intervals, 40 mg per animal per day. All animals receiving N,N'-ethylenebis(o-hydroxyphenylglycine) died of drug toxicity between days 6 and 11. Peak parasitemia on day 11 of infection was 32.8% in control animals; 25.3% with methyl 2,3-DHB, 15.5% with 2,3-DHB, 8.0% with deferoxamine, and 0.9% with HBED. Subsequent studies of HBED and deferoxamine in P falciparum cultures in human erythrocytes showed a marked suppression of parasite counts by both drugs at concentrations of greater than 5 mumol/L. At all concentrations tested, HBED was four to five times more effective than deferoxamine in suppressing parasite counts. The superior antimalarial activity of HBED is attributed to its increased lipophilicity and higher affinity to ferric iron. These findings indicate that selective iron deprivation by interaction with an intracellular chelator may represent a novel approach to antimalarial drug development, and that systematic screening of available iron-chelating drugs may result in identification of potentially useful antimalarial compounds.
Assuntos
Quelantes/uso terapêutico , Malária/tratamento farmacológico , Animais , Catecóis , Ácido Edético/uso terapêutico , Eritrócitos/parasitologia , Feminino , Fenóis , Plasmodium berghei , Ratos , Ratos EndogâmicosRESUMO
The phenolic EDTA analogues ethylenediamine-N,N'-bis-(2- hydroxyphenylglycine ) ( EHPG ), N,N'-bis(2-hydroxybenzyl)-ethylenediamine diacetic acid ( HBED ), and their respective dimethyl esters ( dimethylEHPG and dimethylHBED ) were studied in hypertransfused rats. Radioiron bound to these compounds was cleared mainly by the liver and excreted in the bile. After a single 40 mg i.m. injection, the percentage of radioiron removed from 59Fe-ferritin-labelled hepatocytes and excreted in the bile was 4% in untreated controls, 24% for desferral , 42% for dimethylEHPG , 58% for EHPG , 63% for HBED , and 80% for dimethylHBED . DimethylHBED combines oral effectiveness with superior chelating ability, selective hepatocellular action, and low apparent toxicity. It may represent a significant advance in the development of new iron chelating drugs.
Assuntos
Quelantes de Ferro/farmacologia , Administração Oral , Animais , Desferroxamina/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Ácido Edético/análogos & derivados , Ácido Edético/uso terapêutico , Etilenodiaminas/uso terapêutico , Feminino , Infusões Parenterais , Radioisótopos de Ferro , Ratos , Ratos Endogâmicos , Reação TransfusionalRESUMO
Salicylhydroxamic acid (SHAM) and glycerol, when administered together, cause destruction of bloodstream forms of Trypanosoma brucei brucei, both in vitro and in vivo, but the dose required is exceedingly high. In an attempt to improve the efficacy of this drug combination, we examined the ability of various polyols and hydroxamic acids to substitute for glycerol and SHAM, respectively. No satisfactory substitute for glycerol was found. The inhibition of the trypanosomal alpha-glycerophosphate oxidase system (GPO) by SHAM (Ki 21 microM) was uncompetitive. Only primary and secondary aromatic hydroxamates were inhibitory. Among a series of 19 benzhydroxamates, no correlation existed between their acidity or their affinity for iron and their inhibition of the GPO in a cell free preparation. The Ki's of most of the primary hydroxamates ranged from 10 to 24 microM, with the more lipophilic derivatives being slightly more active. The Ki's of secondary hydroxamates were more variable, the best having Ki's of about 10 microM. Several other classes of iron chelators were also evaluated. Tropolones were active with 3-bromo-4,5-benzotropolone being as active as SHAM. 3,4-Dihydroxybenzaldehyde (Ki 15 microM) also inhibited the GPO. On the other hand, diphenylamine and 8-hydroxyquinoline, known inhibitors of the GPO, were 30 to 50 times less active. The results suggest that a lipophilic aromatic iron-chelating agent may be useful as a substitute for SHAM in combination therapy.
Assuntos
Glicerol/farmacologia , Glicerolfosfato Desidrogenase/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Salicilamidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Fenômenos Químicos , Química , Avaliação Pré-Clínica de Medicamentos , Quelantes de Ferro/farmacologia , Relação Estrutura-Atividade , Tropolona/farmacologia , Trypanosoma brucei brucei/enzimologiaAssuntos
Quelantes , Animais , Quelantes/metabolismo , Quelantes/farmacologia , Fenômenos Químicos , Química , Ácidos Cólicos/farmacologia , Desferroxamina/farmacologia , Avaliação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Enterobactina/análogos & derivados , Enterobactina/farmacologia , Etilenodiaminas/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Hidroxibenzoatos/farmacologia , Ferro/metabolismo , Ácido Pentético/farmacologia , Piperazinas/farmacologia , Talassemia/tratamento farmacológicoRESUMO
A year-long double-blind study of 2,3-dihydroxybenzoic acid (2,3-DHB) given orally at a dose of 25 mg/kg four times per day was undertaken in 15 patients with beta-thalassemia major. 2,3-DHB and placebo (mannitol) were tolerated to an equal degree and there were no signs of drug toxicity at the end of 1 year. Efficacy in terms of retardation of iron accumulation could be documented using serial liver biopsies, serum ferritin determinations, or clinical laboratory assessment. Serum iron values increased, as did the iron binding capacity, in the group receiving 2,3-DHB. The increase in iron binding capacity was due to drug interference with the method of determination. Because of the greater efficacy of slow infusions of desferrioxamine in chelating iron when administered slowly, the clinic has shifted its emphasis toward further evaluation of that compound. Nevertheless, in view of the minimal toxicity of 2,3-DHB, further work appears warranted to define its role in the treatment of iron-overload.