Iron overload is a major life-threatening complication of
thalassemia major and other
iron-loading
anemias treated by regular
blood transfusions. Although the clinical manifestations of
iron overload may be prevented by
desferrioxamine, the only
iron-chelating
drug in routine clinical use, this treatment requires
subcutaneous infusion of
desferrioxamine for 12 hours each day. New orally effective
iron chelators are urgently needed, and
pyridoxal isonicotinoyl hydrazone (PIH), which was first recognized as an effective
iron chelator in vitro and subsequently in vivo, shows promise for the treatment of
iron overload. More recently, over 40 analogs of PIH were synthesized, and some of them proved to be very potent in mobilizing 59Fe in vitro from 59Fe-labeled cells. In this study, we show that PIH analogs such as
pyridoxal benzoyl hydrazone,
pyridoxal p-methoxybenzoyl
hydrazone (PMBH),
pyridoxal m-fluorobenzoyl
hydrazone (PFBH), and pyridoxal-2-thiophenecarboxyl
hydrazone, compounds previously shown to mobilize
iron from cells in vitro, are also effective in vivo. All of these
chelators significantly enhanced biliary excretion of
iron (measured by atomic absorption spectrophotometry) following their intraperitoneal (IP) and/or
oral administration to rats. The most effective was PFBH, which increased
iron concentration in the bile about 150-fold, as compared with basal biliary
iron concentration, within 1 hour following a single IP dose of 0.2 mmol/kg
body weight. In contrast,
desferrioxamine increased the biliary
iron concentration only 20-fold to 30-fold under the same conditions. Moreover, while control rats excreted approximately 0.8 microg Fe in 2 hours, treatment with PFBH, PMBH, and
desferrioxamine resulted in cumulative excretions of 87, 59, and 22 microg Fe, respectively, in the same period of time. Interestingly, PMBH was also quite effective following gastric administration, resulting in a 6-hour cumulative value of 34 microg Fe. These compounds are nontoxic and are inexpensive and easy to make. Their further evaluation as candidate drugs for the treatment of
iron overload is warranted.