[Frontiers in Bioscience E1, 161-178, June 1, 2009]

Prospects for introducing deferiprone as potent pharmaceutical antioxidant

George J Kontoghiorghes

Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Metabolic imbalance of free radical production leading to toxicity and biological damage
4. Iron and copper metabolic pathways and associated diseases of metal metabolic imbalance
5. Mechanisms of iron and copper binding by chelating drugs: Molecular aspects of chelation therapy
6. The effect of naturally occurring low molecular weight iron chelators on iron metabolism
7. General properties of deferiprone
8. Toxic side effects of deferiprone therapy and safety levels of its use
9. Mode of action of deferiprone and other chelators against free radical damage and other chelator interactions affecting this process
10. Free radical inhibitory effects of deferiprone in in vitro models of free radical damage
11. Free radical inhibitory effects of deferiprone in in vivo models of free radical damage
12. The antioxidant effects of deferiprone and other chelating drugs in clinical conditions involving free radical toxicity and tissue damage
13. Future prospects of the use of deferiprone and other chelators as antioxidant pharmaceuticals
14. Conclusion
15. References

1. ABSTRACT

Free radical formation is primarily initiated from metal catalytic centers involving iron and copper. Under certain conditions, free radical reactions can lead to free radical cascades and oxidative stress, which can cause biomolecular, cellular and tissue damage (FRD). The use of natural antioxidants to prevent FRD is in most cases not effective. Many chelators have been shown to inhibit free radical reactions and toxicity in experimental models of both in vitro and in vivo. Deferiprone (L1) has been shown to be effective and safe in the reversal of accelerating oxidative stress related tissue damage in iron loading and non iron loading conditions such as cardiomyopathy in thalassaemia, acute kidney disease and Friedreich ataxia. The selection of chelating drugs and their combinations could be used as new strategies for antioxidant therapies. In vitro, in vivo and clinical data suggest that L1 is the most potent drug antioxidant because of its high therapeutic index, ability to reach extracellular and intracellular compartments of many tissues and ability to inhibit both iron and copper catalysed free radical reactions.