IRON CHELATION--COMBINATION THERAPY, A BETTER APPROACH

患有β-地中海贫血(库利氏贫血)的患者继续遭受 输血引起的铁超载的后遗症 目前铁络合疗法的不足之处。遵守使用规定 南卡罗来纳州。去铁胺(DFO)仍然是一个主要问题，尽管 令人信服的证据表明，它显著降低了发病率并延长了 生活。铁螯合疗法的全部潜力将不会被实现 直到有口服有效的药物可用。我们一直在进行 代谢性铁平衡研究比较 脱铁酮(1，2-二甲基-3-羟基吡啶-4-酮，DMHP，L1)和N，N‘- 双(邻羟基苯基)乙二胺-N，N‘-二醋酸(HBED) DFO。虽然这两种口服制剂都没有履行其 承诺，这两个似乎都将在 铁络合疗法。我们的标准DFO方案(60 mg/kg皮下注射) 超过8小时)将所有患者置于净负铁平衡，其中 平衡是排出的铁与以铁形式接收的铁的比率。 输注的红细胞。DMHP(75 mg/kg P.O.分开的T.I.D.)是60岁 与DFO一样有效的百分比，7/13的患者处于净负铁状态 平衡。当去铁酮和DFO联合使用时，相加效应是 观察5/6例，协同作用6例。2，3-二羟基苯甲酸 酸(2，3-DHB)，另一种口服有效的铁络合剂，也有 当与DFO结合时会产生相加效应。在这两种情况下，总体上 向我们提示尿铁排泄的双齿配基 (去铁酮或2，3-DHB)正在访问DFO无法获得的铁池 (六齿)，并将这块铁“穿梭”到六齿“洗涤槽”。 HBED(80 mg/kg P.O.分开的T.I.D.)不如去铁酮有效， 所有患者都处于正平衡状态(平均52%)。什么时候 去铁酮联合HBED，2/2观察到协同作用 患者，现在都达到了负平衡，两人都没有 单用去铁酮的负值平衡。这些结果进一步支持了 我们的“铁质穿梭”假说。我们建议将药物作为一种新的 铁络合疗法的方法，既可减少副作用，又可 提高药效。如果这两种药物都可以口服，那么真正的 找到合适的DFO替代品的好机会。我们将进一步 用铁过量输注的大鼠模型探索这一假说 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.