Risk/Benefit Assessment, Advantages Over Other Drugs and Targeting Methods in the Use of Deferiprone as a Pharmaceutical Antioxidant in Iron Loading and Non Iron Loading Conditions

Abstract

Tissue damage caused by oxidative stress is a common characteristic of many conditions involving different major organs such as the brain, heart, liver and kidneys. The treatment of such conditions using classical antioxidants is not in most cases sufficient or effective because it lacks specificity and has a low therapeutic index. Increased evidence from in vitro, in vivo and clinical studies suggest that deferiprone (L1) can be used as a potent pharmaceutical antioxidant by mobilizing labile iron and copper and/or inhibiting their catalytic activity in the formation of free radicals and oxidative stress in tissue damage. The high therapeutic index, tissue penetration, rapid iron binding and clearance of the iron complex, and the low toxicity of L1, support its application as an antioxidant pharmaceutical for adjuvant, alternative or main therapy, especially in conditions where other treatments have failed. Substantial clinical improvement and reversal in most cases of the tissue damage has been observed in cardiomyopathy in thalassemia, diabetic nephropathy and glomerulonephritis in kidney disease, Friedreich's Ataxia and Fanconi Anemia patients. In contrast to L1, both deferoxamine (DFO) and deferasirox (DFRA) have major disadvantages in their use in non iron loading conditions due to toxicity implications. Further studies in the above and other conditions and optimization of the L1 therapy in each individual will increase the prospects of the application and role of L1 as a universal antioxidant pharmaceutical.

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

“…The proposed mechanism for the mode of action of L1 was removal of localised excess deposited iron and inhibition of the iron induced catalytic activity and free radical cascades which caused increase in oxidative stress and cellular damage. This proposal was based on in vitro findings, animal studies and clinical results suggesting that L1 had access to all major organs and tissues including the heart and the brain [5,69,70] . The ability of L1 to remove excess deposited iron from the hearts of FA patients similar to TM patients, was also suggested since focal or gross iron overload appears to be the main cause of mortality in both diseases [5,69,70] .…”

“…This proposal was based on in vitro findings, animal studies and clinical results suggesting that L1 had access to all major organs and tissues including the heart and the brain [5,69,70] . The ability of L1 to remove excess deposited iron from the hearts of FA patients similar to TM patients, was also suggested since focal or gross iron overload appears to be the main cause of mortality in both diseases [5,69,70] . Similarly, it was also suggested that the application of L1 was a more appropriate therapy than the use of antioxidants for the toxicity arising from focal or localised excess deposited iron and also that the therapeutic options included drug combinations [5,69,70] .…”

“…Free radicals and other nitrogen and oxygen activated products such as the nitrogen oxide, superoxide, hydroxyl radical, lipid peroxides and hydrogen peroxide are constantly and continuously generated in aerobic organisms during normal metabolism and physiological functions and also in response to both internal and external stimuli. However, if free radical reactions and related by-products are continuously overproduced and are not regulated or controlled by the antioxidant pathways and molecules, this can cause free radical toxicity and damage from the molecular level to the organ level as shown in many diseases including TM and FA [69][70][71] . The catalytic effects of iron can cause free radical toxicity cascades and biomolecular damage including damage to sugars, lipids, proteins, DNA and also widespread subcellular, cellular, tissue and organ damage (Figure 2).…”

“…The catalytic effects of iron can cause free radical toxicity cascades and biomolecular damage including damage to sugars, lipids, proteins, DNA and also widespread subcellular, cellular, tissue and organ damage (Figure 2). Such free radical cascades are not sufficiently neutralized by antioxidants but can usually be prevented by iron binding or chelation [69,70] .…”

“…The damaging effects of iron overload and the rupture of iron-laden lysosomes into the cell sap can also cause the release of hydrolytic enzymes and potentially toxic forms of labile iron. The latter can catalyse the production of free radical cascades and cause further free radical damage which can progressively lead to a vicious cycle of further cellular, tissue and organ damage (Figure 2) [69,70] . Iron overload and toxicity causes organ damage, which is generally detectable when approximately 50-100 units of red blood cells have been transfused.…”