In humans and other primates iron is stored in the body in the form of ferritin and hemosiderin, which are protein complexes, and is transported in the plasma via another protein complex, namely transferrin. The manner in which iron is utilized is very efficient, but there is no specific mechanism that exists for the elimination of excess iron. Under conditions of iron overload the protein complexes become saturated with iron, resulting in excess iron being deposited in tissues which induces iron toxicity, and ultimately leads to peroxidative tissue damage. An iron overload condition may occur for example through a genetically determined error that results in increased absorption of iron from a normal diet or may occur through repeated blood transfusions to treat a condition, e.g., sickle-cell anemia or Cooley's anemia.
One way of treating iron overload is by administering an iron chelator. In principle, the chelator transforms the deposited iron back into a soluble form that is then capable of excretion. However, none of the available iron chelators employed for this purpose is ideal; the chelators have poor gastrointestinal absorption, or have low efficacy and/or undesirable side effects.
One iron chelator that overcomes some of these disadvantages, and is widely used in therapy, is deferoxamine B (DFO) as the methanesulfonate salt, also known as desferrioxamine B mesylate (DFOM). This is available commercially as Desferal from Novartis (previously Ciba-Giegy). In general DFOM is capable of controlling excess body iron and can prolong survival and prevent or ameliorate organ dysfunction in a person suffering from iron overload. However, DFOM is far from an ideal treatment for iron overload. It is cumbersome, inefficient, expensive, and unpleasant to the patient. Because DFOM is poorly absorbed from the gastrointestinal tract and rapidly eliminated from circulation, prolonged parenteral infusion is required for treatment; it is generally administered by a portable infusion pump for 9-12 hours daily. Not surprisingly, very few patients are capable of complying with such a demanding regimen. Additionally, DFOM is very inefficient as an iron chelator, in that typically 5% or less of the compound administered binds iron.
Yet another disadvantage is the cost of DFO, which is commercially produced by large scale fermentation of a strain of Streptomyces pilosus, a method of manufacture that is very expensive. In addition, almost all patients experience an allergic reaction to DFOM, which is uncomfortable and sometimes very painful. The allergic reaction is thought to be caused by cytokines and/or other fermentation products formed during the fermentation process that are not completely removed during purification of the crude product mixture.
It would therefore be desirable to provide a method for treating iron overload that employs a safe and inexpensive alternative to DFOM. Ideally, the iron chelator would not be associated with an allergic reaction in patients, and would be a more efficient chelator of iron than DFOM.
HBED is a compound known to be an iron chelator. U.S. Pat. No. 3,758,540 discloses that iron chelates of HBED and other compounds are useful as a source of iron in plant nutrition. See also U.S. Pat. No. 4,116,991. U.S. Pat. No. 4,528,196 discloses, on the basis of testing in rat and mouse screens, that HBED and its alkyl esters are orally active in the treatment of iron overload, and more active given orally than DFO given intraperitoneally. However, the rodent findings were not substantiated in higher animals. Testing in the Cebus apella monkey screen, which is known to be an excellent predictor of the behavior of chelators in humans, showed that DFOM administered subcutaneously has significantly higher activity than HBED or its dimethyl ester given orally (Bergeron et al., Blood, 81:2166 (1993), Peter et al., "A Comparative Evaluation of Iron Chelators in a Primate Model", pp 373, Development of Iron Chelators for Clinical Use, Boca Raton, CRC Press (1994)). It has also been demonstrated that HBED, when given orally to human patients, provides iron excretion at a level that is ineffective for the treatment of iron overload (Grady et al., "Preliminary Results from a Phase I Clinical Trial of HBED", in the Development of Iron Chelators for Clinical Use, Boca Raton, CRC Press (I 994), pp 395).
It was therefore totally unexpected, based upon the above findings, that mono-cationic salts of HBED would prove to be highly efficient compounds for treating iron overload when administered subcutaneously. These HBED salts upon subcutaneous administration do not require prolonged parenteral infusion for effective iron chelation and excretion, are not associated with an allergic reaction in primates, and are a more efficient chelators of iron than DFOM.
USPTO Backgrounds
USPTO Backgrounds