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。 重型β地中海贫血（库利氏贫血）患者继续 患有输血引起的铁过载的后遗症， 当前铁螯合疗法的不足之处 合规 使用皮下去铁胺（DFO）是主要的 尽管人们通过改善其效用的认识有所提高， 患者之间的沟通。 因此，充分发挥潜力 铁螯合疗法的应用将无法实现，直到口服- 有效的药物是可用的。 两种化合物，N，N '-双（o- 羟苄基）乙二胺-N，N '-糖尿病酸（HBED）和1，2- 二甲基-3-羟基吡啶-4-酮（DMHP），在 这方面。 对高输血大鼠的研究表明， 口服HBED的有效性是等效剂量的70%， DFO的剂量。 没有毒性的证据， 在将该化合物给药至动物达3 个月 一旦动物药代动力学研究完成， 完成后，将获得IND，以便I期临床 可以进行拟议的试验。 HBED的疗效将是 与DFO治疗的标准方案相比，代谢 在临床研究中心进行的铁平衡研究。 DMHP已在多种动物研究中证明有效 以及初步的临床试验，包括一些在 地中海贫血患者 事实上，其预计成本是 DFO的十分之一是最令人鼓舞的。 但进一步 这种潜在药物的开发受到缺乏 对其毒性进行适当评估。 慢性毒性 将在三种动物中进行DMHP的研究 根据获得IND，这将允许I期临床 将进行审判。 同样，比较代谢铁平衡 将进行研究。 迄今为止的证据表明， 口服DMHP诱导的铁排泄水平相当 相当于皮下注射同等剂量的DFO 超过8小时。 因此，甚至可以维持 最年轻的患者在净负铁平衡与DMHP。 如果安全 有效，然后将对该化合物进行评估， 门诊基础，而住院研究侧重于优化其 使用. HBED或DMHP的成功开发应导致 在生命的长度和质量上都有显著的提高， 地中海贫血和其他疾病的患者 也

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.