The proposed Phase II clinical trials are designed to demonstrate the safety and effectiveness of orally administered pyridoxal isonicotinoyl hydrazone (PIH) for the chronic treatment of iron overload. Pyridoxal isonicotinoyl hydrazone (PIH) is easily produced by the Schiff base condensation of two widely used, inexpensive drugs, vitamin B-6 (pyridoxal) and the antituberculous agent isoniazid (INH). PIH was first recognized as an effective iron chelator in vitro in 1979. In the first human trials, our recent Phase I studies of low-dose PIH in healthy controls and volunteers with iron overload have found no evidence of toxicity while producing an amount of iron excretion that would be clinically useful in the treatment of non-transfusion-dependent patients with iron-loading anemias. The accumulated data suggest that PIH may be an almost ideal iron chelator; a highly selective agent that is (i) almost completely absorbed from the gastrointestinal tract, (ii) delivered directly via the portal blood to the liver, where the drug has a high hepatic extraction ratio and intrinsic clearance, (iii) taken up by the hepatocyte, its major site of action, where the drug either chelates iron and is excreted in the bile or is metabolized and eliminated. Excess iron at extra-hepatic sites can then be mobilized and transported by physiologic means to the liver for subsequent chelation and excretion.
The specific aims of the proposed Phase II clinical trials are to demonstrate the safety and effectiveness of PIH in: (1) reducing the body iron burden to near-normal levels in non- transfusion-dependent patients with iron-loading anemias (requires chelate- induced iron excretion of at least 0.10 to 0.20 mg Fe/kg/day); (2) maintaining near-normal body iron stores in transfusion-dependent patients who have previously been well-chelated with chronic subcutaneous or intravenous desferrioxamine (requires chelate-induced iron excretion of at least 0.25 to 0.40 mg Fe/kg/day); (3) reducing the body iron burden to near-normal levels in iron-loaded, transfusion-dependent patients (requires chelate-induced iron excretion greater than 0.40 mg Fe/kg/day). The development of a safe and effective oral dosage regimen for PIH would be a major advance in the treatment of iron overload that could substantially improve both the quality and length of life of affected patients in the United States and provide important public health benefit worldwide.
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