Deferoxamine

Deferoxamine is isolated as the iron chelate from Streptomyces pilosus and is treated chemically to obtain the metal-free ligand. Deferoxamine has the desirable properties of a remarkably high affinity for ferric iron (K = 1031 M-1) coupled with a very low affinity for calcium (Ka = 102 M-1). Studies in vitro have shown that it removes iron from hemosiderin and ferritin and, to a lesser extent, from transferrin. Iron in hemoglobin or cytochromes is not removed by deferoxamine.

Deferoxamine (deferoxamine mesylate, desferal mesylate) is poorly absorbed after oral administration, and parenteral administration is required in most cases. For severe iron toxicity (serum iron levels >500 mg/dL), the intravenous route is preferred. The drug is administered at 10-15 mg/kg/h by constant infusion. Faster rates of infusion (45 mg/kg/h) have been used in a few cases; rapid boluses usually are associated with hypotension. Deferoxamine may be given intramuscularly in moderately toxic cases (serum iron 350-500 mg/dL) at a dose of 50 mg/kg with a maximum dose of 1 g. Hypotension also can occur with the intramuscular route.

For chronic iron intoxication (e.g., thalassemia), an intramuscular dose of 0.5-1.0 g/day is recommended, although continuous subcutaneous administration (1-2 g/day) is almost as effective as intravenous administration. When blood is being transfused to patients with thalassemia, 2 g deferoxamine (per unit of blood) should be given by slow intravenous infusion (rate not to exceed 15 mg/kg/h) during the transfusion but not by the same intravenous line. Deferoxamine is not recommended in primary hemochromatosis; phlebotomy is the treatment of choice. Deferoxamine also has been used for the chelation of aluminum in dialysis patients. Deferoxamine is metabolized principally by plasma enzymes, but the pathways have not been defined. The drug also is excreted readily in the urine.

Deferoxamine causes a number of allergic reactions, including pruritus, wheals, rash, and anaphylaxis. Other adverse effects include dysuria, abdominal discomfort, diarrhea, fever, leg cramps, and tachycardia. Occasional cases of cataract formation have been reported. Deferox-amine may cause neurotoxicity during long-term, high-dose therapy for transfusion-dependent thalassemia major; both visual and auditory changes have been described. A "pulmonary syndrome" has been associated with high-dose (10-25 mg/kg/h) deferoxamine therapy; tachypnea, hypoxemia, fever, and eosinophilia are prominent manifestations. Contraindications to the use of defer-oxamine include renal insufficiency and anuria; during pregnancy, the drug should be used only if clearly indicated.

An orally effective iron chelator now under clinical investigation, deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one), may be of value in patients with thalassemia major who are unable or unwilling to receive deferoxamine. Combination therapy with deferoxamine also is under investigation.

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