NEW PROMISE FOR ORAL IRON CHELATION

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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.