IRON CHELATION--COMBINATION THERAPY, A BETTER APPROACH

铁螯合——联合疗法，更好的方法

• 批准号: 7111573
• 负责人: Robert W. Grady
• 金额: $ 25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111573
• 关键词: chelating agents; chelation therapy; clinical research; combination chemotherapy; deferoxamine; disease /disorder model; drug screening /evaluation; human subject; human therapy evaluation; iron poisoning; laboratory rat; nonhuman therapy evaluation; oral administration; thalassemia

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.

β-地中海贫血（库利贫血）患者继续遭受 输血引起的铁超负荷的后遗症 当前铁螯合疗法的不足之处。遵守使用规定 南卡罗来纳州尽管去铁胺（DFO）仍然是一个主要问题 令人信服的证据表明它可以显着降低发病率并延长寿命 生活。 铁螯合疗法的全部潜力将无法实现 直到出现口服有效的药物。 我们一直在进行 代谢铁平衡研究比较有效性 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) DFO 的。 虽然这两种口服药物都还没有达到其应有的效果 承诺，看来两者都将发挥重要作用 铁螯合疗法。 我们的标准 DFO 方案（皮下注射 60 毫克/公斤） 超过8小时）使所有患者处于净负铁平衡状态，其中 平衡是排出的铁与以铁的形式接收的铁的比率 输注红细胞。 DMHP（75 mg/kg，口服，每日三次）为 60 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，产生相加效应 在 5/6 的患者中观察到，在第六位患者中观察到协同作用。 2,3-二羟基苯甲酸 另一种口服有效的铁螯合剂酸 (2,3-DHB) 也具有 与 DFO 结合使用时有累加效应。 在这两种情况下，总体 对尿铁排泄的影响向我们表明，双齿配体 （去铁酮或 2,3-DHB）正在获取 DFO 无法获得的铁池 （六齿）并将该铁“穿梭”到六齿“水槽”。 HBED（80 mg/kg，口服，每日三次）的效果不如去铁酮， 所有患者均处于正平衡状态（平均 52%）。 什么时候 去铁酮和 HBED 联合使用，2/2 观察到协同作用 患者，现在都达到了负平衡，而两者都没有处于状态 单独去铁酮的负平衡。 这些结果进一步支持 我们的“铁梭”假说。 我们建议结合药物作为新的 铁螯合疗法的方法，既可以减少副作用，又可以 提高功效。 如果这两种药物都可以口服，那就真的有效果了。 找到 DFO 的合适替代品的好机会。我们将进一步 使用铁的过度输血大鼠模型探索这一假设 超负荷和临床研究。