IRON CHELATION--COMBINATION THERAPY, A BETTER APPROACH

β-地中海贫血（库利氏贫血）患者继续遭受 输血引起的铁过载的后遗症， 当前铁螯合疗法的不足之处。遵守使用 关于S.C.去铁胺（DFO）仍然是一个主要问题， 令人信服的证据表明，它显着降低发病率和死亡率， 生活 铁螯合疗法的全部潜力将无法实现 直到有口服有效的药物。 我们一直在进行 代谢铁平衡研究比较的有效性 去铁酮（1，2-二甲基-3-羟基吡啶-4-酮，DMHP，L1）和N，N '- 双（邻羟基苄基）乙二胺-N，N '-二乙酸（HBED）， 的DFO。 虽然这两种口服药物都没有达到其 这两个方面似乎都将发挥重要作用， 铁螯合疗法 我们的标准DFO方案（60 mg/kg s.c. 超过8小时）使所有患者处于净负铁平衡，其中 平衡是排泄的铁与以铁的形式接受的铁的比率。 输了红细胞 DMHP（75 mg/kg p.o.分开的t.i.d.）为60 13例患者中有7例为净负铁 平衡 当去铁酮和DFO联合使用时， 5/6例观察到，第6例出现协同作用。 2，3-二羟基苯甲酸 酸（2，3-DHB），另一种口服有效的铁螯合剂，也有 当与DFO组合时的累加效应。 在这两种情况下， 对尿铁排泄的影响表明， （去铁酮或2，3-DHB）正在进入DFO不可用的铁池 （六齿）并将该铁“穿梭”到六齿“槽”。" HBED（80 mg/kg p.o.分开的t.i.d.）不如去铁酮有效， 所有患者均处于正平衡状态（平均52%）。 当 去铁酮和HBED联合使用，2/2例观察到协同作用， 病人，现在都实现了负平衡， 去铁酮单药的负平衡。 这些结果进一步支持 我们的“铁穿梭机”假说 我们建议联合用药作为一种新的 铁螯合疗法的方法，既减少副作用， 提高功效。 如果这两种药物都可以口服， 一个很好的机会找到一个合适的替代DFO。我们将进一步 使用高输血大鼠模型和铁 超负荷和临床研究。

Patients with beta-thalassemia (Cooley's Anemia) continue to suffer from the sequelae of transfusion-induced iron overload due to the inadequacies of current iron-chelation therapy. Compliance with the use of s.c. desferrioxamine (DFO) continues to be a major problem despite convincing evidence that it markedly reduces morbidity and prolongs life. The full potential of iron-chelation therapy will not be realized until an orally-effective drug is available. We have been conducting metabolic iron balance studies comparing the effectiveness of deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, DMHP, L1) and N,N'- bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) with that of DFO. While neither of these oral agents has yet fulfilled its promise, it appears likely that both will play a significant role in iron chelation therapy. Our standard DFO regimen (60 mg/kg infused s.c. over 8 hours) placed all patients in net negative iron balance, where balance is the ratio of iron excreted to that received in the form of transfused red cells. DMHP (75 mg/kg p.o. divided t.i.d.) was 60 percent as effective as DFO, 7/13 patients being in net negative iron balance. When deferiprone and DFO were combined, an additive effect was observed in 5/6 patients, synergy in the sixth. 2,3-Dihydroxybenzoic acid (2,3-DHB), another orally effective iron chelator, also had an additive effect when combined with DFO. In both cases, an overall towards urinary iron excretion suggested to us that the bidentate ligand (deferiprone or 2,3-DHB) was accessing pools of iron unavailable to DFO (hexadentate) and was "shuttling" this iron to the hexadentate "sink." HBED (80 mg/kg p.o. divided t.i.d.) was less effective than deferiprone, all patients being in positive balance (mean 52 percent). When deferiprone and HBED were combined, synergy was observed in 2/2 patients, both now achieving negative balance where neither was in negative balance on deferiprone alone. These results further support our "iron shuttle" hypothesis. We suggest combining drugs as a new approach to iron chelation therapy, both to reduce side effects and increase efficacy. If both drugs can be given orally, there is truly a good chance of finding a suitable alternative to DFO. We will further explore this hypothesis using both the hypertransfused rat model of iron overload and clinical studies.