NEW PROMISE FOR ORAL IRON CHELATION

我们的目标是开发一种口服有效的铁螯合药物。 患有重型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 目前的铁络合疗法的不足之处。合规性 皮下注射去铁胺(DFO)是一种主要的 尽管通过改进提高了对其效用的认识，但仍存在问题 患者之间的沟通。因此，充分发挥潜力 在口服之前，铁络合疗法不会实现。 有有效的药物可用。两个化合物，N，N‘-双(o- 羟基苄基乙二胺-N，N‘-糖尿病酸(HBED) 二甲基-3-羟基-4-酮(DMHP)，在 这方面。对过度输血的大鼠的研究表明 口服HBED的有效率是同等剂量的70% 非肠道给药的DFO。目前还没有毒性的证据 给动物服用该化合物最多3次后观察 月份。一旦在动物身上进行的药代动力学研究 完成后，将获得IND，以便I期临床 建议的试验可以进行。HBED的功效将是 与DFO治疗的标准方案相比，代谢 铁平衡研究正在临床研究中心进行。 DMHP已被证明在各种动物研究中是有效的 以及初步的临床试验，包括一些在 地中海贫血患者。它的预计成本是 DFO的十分之一是最令人鼓舞的。然而，进一步 这种潜在药物的开发因缺乏药物而受到阻碍 对其毒性进行适当的评估。慢性毒性 DMHP的研究将在三种动物身上进行 根据获得的IND将允许I期临床 有待进行的试验。再说一次，相对代谢铁平衡 我们会进行研究。迄今为止的证据表明， 口服DMHP引起的铁排泄水平相似 相当于皮下注射DFO的等量剂量 超过8个小时。因此，甚至有可能保持 DMHP净铁负平衡的最年轻患者。如果安全 这种化合物是有效的，然后将在 门诊为基础，住院研究重点为优化ITS 使用。HBED或DMHP的成功开发应该会导致 在生活长度和质量方面都有显著的提高 地中海贫血或其他疾病患者的经历 也是。

Our goal is to develop an orally-effective iron-chelating drug. Patients with beta-thalassemia major (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 subcutaneous desferrioxamine (DFO) is a major problem despite increased awareness of its utility through improved communication among the patients. Accordingly, the full potential of iron-chelation therapy will not be realized until an orally- effective drug is available. Two compounds, N,N'-bis(o- hydroxybenzyl)ethylenediamine-N,N'-diabetic acid (HBED) and 1,2- dimethyl-3-hydroxypyrid-4-one (DMHP), show particular promise in this regard. Studies in hypertransfused rats have demonstrated that HBED given orally is 70% as effective as an equivalent dose of DFO given parenterally. No evidence of toxicity has been observed upon administering this compound to animals for up to 3 months. Once pharmacokinetic studies in animals have been completed, an IND will be obtained so that the Phase I clinical trials proposed can undertaken. The efficacy of HBED will be compared with that of a standard regimen of DFO therapy, metabolic iron balance studies being conducted in a Clinical Research Center. DMHP has proven to be efficacious in a variety of animal studies as well as in preliminary clinical trials, including some in patients with thalassemia. The fact that its projected cost is one-tenth that of DFO is most encouraging. However, further development of this potential drug is hampered by the absence of an appropriate assessment of its toxicity. Chronic toxicity studies of DMHP will be undertaken in three species of animals pursuant to obtaining an IND which will allow Phase I clinical trials to be conducted. Again, comparative metabolic iron balance studies will be carried out. Evidence to date suggests that the level of iron excretion induced by DMHP given orally is comparable to that of an equivalent dose of DFO administered subcutaneously over 8 hours. Thus, it may be possible to maintain even the youngest patients in net negative iron balance with DMHP. If safe and effective, this compound will then be evaluated on an outpatient basis while inpatient studies focus on optomizing its use. Successful development of either HBED or DMHP should result in a significant increase in both the length and quality of life experienced by patients with thalassemia and perhaps other diseases as well.