Objectives and methods of iron chelation therapy.
Objectives and methods of iron chelation therapy.
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DOI：
10.1155/s1565363303000128
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发表时间：
2003-01-01
影响因子：
3.8
通讯作者：
Link, G
中科院分区：
文献类型：
--
作者：
Hershko, C;Abrahamov, A;Link, G
最近的发展，在理解铁稳态的分子控制提供了新的见解负责正常铁平衡的机制。然而，在与铁过载相关的慢性贫血中，这些机制不再足以提供对铁毒性的保护，铁螯合疗法是唯一可用于预防主要由心肌和肝损伤引起的早期死亡的方法。今天，长期去铁胺（DFO）治疗是地中海贫血和其他输血依赖性贫血管理的一个组成部分，对健康和生存有重大影响。然而，DFO治疗的高成本和严格要求以及去铁酮的显著毒性强调了继续开发新的和改进的口服有效的铁螯合剂的需要。近年来，在动物模型中筛选出了一千多种候选化合物。这些化合物中最突出的包括去铁酮（L1）、吡哆醛异烟酰腙（PIH）和双羟基苯基噻唑。去铁酮已被广泛用作DFO的替代品，在涉及数百名患者的临床试验中。然而，单独L1治疗无法在相当大比例的受试者中实现负铁平衡。去铁酮不如DFO有效，其潜在的肝毒性是目前有争议的问题。一种新的口服有效的铁螯合剂不一定被视为取代目前公认的和高效的肠胃外药物DFO。相反，它可以用于扩展铁螯合策略的范围，其方式类似于在管理其他病症如高血压或糖尿病中联合使用药物。DFO和合适的口服螯合剂的共同给药或交替使用可以允许减少两种药物的剂量，并通过减少对繁琐的胃肠外药物给药的需求来改善依从性。DFO和L1的联合使用已被证明可以成功耗尽以前对单一药物治疗无效的患者的铁储存，并改善治疗依从性。它还可能导致弱细胞内螯合剂和强细胞外螯合剂之间的“穿梭效应”，或利用肠-肝循环促进粪便铁排泄。所有这些螯合剂使用的创新方法现在都在等待实验模型和临床环境的评估。
Recent developments in the understanding of the molecular control of iron homeostasis provided novel insights into the mechanisms responsible for normal iron balance. However in chronic anemias associated with iron overload, such mechanisms are no longer sufficient to offer protection from iron toxicity, and iron chelating therapy is the only method available for preventing early death caused mainly by myocardial and hepatic damage. Today, long-term deferoxamine (DFO) therapy is an integral part of the management of thalassemia and other transfusion-dependent anemias, with a major impact on well-being and survival. However, the high cost and rigorous requirements of DFO therapy, and the significant toxicity of deferiprone underline the need for the continued development of new and improved orally effective iron chelators. Within recent years more than one thousand candidate compounds have been screened in animal models. The most outstanding of these compounds include deferiprone (L1); pyridoxal isonicotinoyl hydrazone (PIH) and; bishydroxy- phenyl thiazole. Deferiprone has been used extensively as a substitute for DFO in clinical trials involving hundreds of patients. However, L1 treatment alone fails to achieve a negative iron balance in a substantial proportion of subjects. Deferiprone is less effective than DFO and its potential hepatotoxicity is an issue of current controversy. A new orally effective iron chelator should not necessarily be regarded as one displacing the presently accepted and highly effective parenteral drug DFO. Rather, it could be employed to extend the scope of iron chelating strategies in a manner analogous with the combined use of medications in the management of other conditions such as hypertension or diabetes. Coadministration or alternating use of DFO and a suitable oral chelator may allow a decrease in dosage of both drugs and improve compliance by decreasing the demand on tedious parenteral drug administration. Combined use of DFO and L1 has already been shown to result in successful depletion of iron stores in patients previously failing to respond to single drug therapy, and to lead to improved compliance with treatment. It may also result in a "shuttle effect" between weak intracellular chelators and powerful extracellular chelators or exploit the entero-hepatic cycle to promote fecal iron excretion. All of these innovative ways of chelator usage are now awaiting evaluation in experimental models and in the clinical setting.