Deferiprone and Iron–Maltol: Forty Years since Their Discovery and Insights into Their Drug Design, Development, Clinical Use and Future Prospects

Abstract

The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol–iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol–iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world’s population. Detailed insights into different aspects of drug development associated with L1 and the maltol–iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations.

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites

“…Further investigations into the role of aspirin and each of the ACMs are needed in relation to iron deficiency and other diseases of iron metabolism, similar to those used for the development of chelators for the treatment of iron overload and chelator iron complexes for the treatment of iron deficiency [14,51,100,108,222]. The chemical interactions with iron, including the further characterization and stability of the iron complexes, as well as in vitro, in vivo, pharmacological, toxicological, and clinical studies, could provide sufficient information on the overall impact of ACM on iron excretion and the cause of iron deficiency in aspirin users [51,100,108,222]. Many such studies, including clinical trials on iron balance related to increases in iron excretion, which have already been carried out with 2,3-DHB, are also needed for the rest of the ACMs [105][106][107].…”

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

“…Similarly, several other chelators were tested clinically following the first clinical trials of L1, but these were also later abandoned because of similar efficacy or toxicity reasons, as well as a lack of interest from the pharmaceutical industry. These include 1,2-diethyl-3-hydroxypyrid-4-one, 1-ethyl-2-methyl-3-hydroxypyrid-4-one and 1-allyl-2-methyl-3-hydroxypyrid-4-one [111][112][113][114][115].…”

“…The historical aspects of the design, development and use of L1 and DFRA were also recently reviewed [111,112,116,117]. In brief, the design and most of the developmental work including the initial clinical trials of L1 were based on academic initiative and sponsored by the UK Thalassaemia Society, which is a charity organization [117].…”

“…Deferoxamine has been used parenterally for the treatment of iron-overloading conditions for more than 60 years [89][90][91][92][93][94]. Oral L1 was approved by the regulatory authorities of India in 1995, in Europe and in other countries in 1999 and in the USA in 2011 [112,139]. Oral DFRA has been introduced worldwide since 2005 [140,141].…”

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

“…Vitamin C has iron and other metal-binding capacities and is also a reducing agent, forming a complex with iron (III) followed by reduction to iron (II) [ 266 ]. The biological and clinical activities of iron, ascorbate, and the ascorbate–iron complex can also be affected by many other nutrients and pharmaceutical preparations, which may reduce or potentiate iron toxicity [ 274 , 275 , 276 , 277 , 278 ]. Similar effects to those shown in the interactions of vitamin C and iron are expected from other biomolecules with iron-chelating potential such as folic acid, lipoic acid, and catecholamines, as well as metal ions competing with iron [ 59 , 184 , 185 , 279 , 280 , 281 , 282 , 283 ].…”