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.
复制标题
使用口服螯合剂 1,2-二甲基-3-羟基吡啶-4-酮可有效螯合 β 地中海贫血中的铁。
作者：
George I Kontoghiorghes;M. Aldouri;A. Hoffbrand;J. Barr;B. Wonke;Theo Kourouclaris;L. Sheppard
用于输血性铁过载的主要铁螯合剂是去铁胺，其价格昂贵，具有毒副作用，并且必须皮下给予。因此需要口服活性铁螯合剂。口服1，2-二甲基-3-羟基吡啶-4-酮对尿铁排泄的影响进行了研究，在8例接受多次输血的患者中：4例患有骨髓增生异常和4例β地中海贫血。使用了高达100 mg/kg/天的不同每日剂量的药物，单独使用或与抗坏血酸联合使用。在3例地中海贫血患者中，将该药物的效果与相同日剂量的皮下注射去铁胺的效果进行了比较。在所有8名患者中，单剂量口服1，2-二甲基-3-羟基吡啶-4-酮导致大量尿铁排泄，主要在最初12小时内。尿铁排泄量随剂量和患者铁负荷程度的增加而增加。在24小时内分两次或三次给药导致尿铁排泄量高于相同时间内相同剂量的单次给药。在大多数患者共同管理的口服抗坏血酸进一步增加尿铁排泄。1，2-二甲基-3-羟基吡啶-4-酮引起的铁排泄与皮下注射去铁胺在相当剂量下达到的结果相似。在某些情况下，铁排泄量足够高（最高99 mg/天），表明在接受定期输血的患者中，这些方案可以很容易地实现负铁平衡。在任何患者中进行全面临床检查或血液学和生化检测时均未观察到毒性证据。所有患者均未出现可归因于药物的任何症状。这些结果表明，口服螯合剂1，2-二甲基-3-羟基吡啶-4-酮在增加铁负荷患者的尿铁排泄方面与皮下注射去铁胺一样有效。其廉价的合成，口服活性，并在有效剂量下缺乏明显的毒性，这表明它应该迅速开发和彻底测试输血铁过载的管理。
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 beta 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 clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective doses suggest that it should be developed quickly and thoroughly tested for the management of transfusional iron overload.