New Era in the Treatment of Iron Deficiency Anaemia Using Trimaltol Iron and Other Lipophilic Iron Chelator Complexes: Historical Perspectives of Discovery and Future Applications

Abstract

The trimaltol iron complex (International Non-proprietary Name: ferric maltol) was originally designed, synthesised, and screened in vitro and in vivo in 1980–1981 by Kontoghiorghes G.J. following his discovery of the novel alpha-ketohydroxyheteroaromatic (KHP) class of iron chelators (1978–1981), which were intended for clinical use, including the treatment of iron deficiency anaemia (IDA). Iron deficiency anaemia is a global health problem affecting about one-third of the world’s population. Many (and different) ferrous and ferric iron complex formulations are widely available and sold worldwide over the counter for the treatment of IDA. Almost all such complexes suffer from instability in the acidic environment of the stomach and competition from other dietary molecules or drugs. Natural and synthetic lipophilic KHP chelators, including maltol, have been shown in in vitro and in vivo studies to form stable iron complexes, to transfer iron across cell membranes, and to increase iron absorption in animals. Trimaltol iron, sold as Feraccru or Accrufer, was recently approved for clinical use in IDA patients in many countries, including the USA and in EU countries, and was shown to be effective and safe, with a better therapeutic index in comparison to other iron formulations. Similar properties of increased iron absorption were also shown by lipophilic iron complexes of 8-hydroxyquinoline, tropolone, 2-hydroxy-4-methoxypyridine-1-oxide, and related analogues. The interactions of the KHP iron complexes with natural chelators, drugs, metal ions, proteins, and other molecules appear to affect the pharmacological and metabolic effects of both iron and the KHP chelators. A new era in the treatment of IDA and other possible clinical applications, such as theranostic and anticancer formulations and metal radiotracers in diagnostic medicine, are envisaged from the introduction of maltol, KHP, and similar lipophilic chelators.

Iron Replacement Therapy with Oral Ferric Maltol: Review of the Evidence and Expert Opinion

“…Ferric maltol was rationally designed to optimize the absorption and tolerability of oral iron [ 48 ]. It has been approved by the European Medicines Agency, SwissMedic, and the US Food and Drug Administration and is commercially available in Europe and the United States for the treatment of adults with iron deficiency, with or without anemia.…”

Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients

“…In general, natural or synthetic lipophilic metal chelator complexes can increase cellular metal ion intake and increase metal ion absorption, whereas hydrophilic chelators can remove intracellular metal ion and increase metal ion excretion [4,5,44,49]. In particular, the increase of iron absorption by lipophilic iron chelator complexes is important for all those affected by iron deficiency and mostly vegetarian populations [53].…”

“…The diagnosis and treatment of different conditions related to iron and other metal metabolic abnormalities are among the major areas of conflict and controversy involving marketing tactics for the promotion of different medical diagnostics and drugs by pharmaceutical and other companies. In general, the marketing activities of private companies affect academic research and the reporting of clinical findings and also, most importantly, the morbidity and mortality rate of billions of patients [4,5,25,53,[71][72][73]. For example, in the case of iron deficiency anaemia, hundreds of different chelator and other iron complexes are promoted, especially of new and expensive formulations claiming effective treatments and superiority over other inexpensive, generic formulations [53,74,75].…”

“…In general, the marketing activities of private companies affect academic research and the reporting of clinical findings and also, most importantly, the morbidity and mortality rate of billions of patients [4,5,25,53,[71][72][73]. For example, in the case of iron deficiency anaemia, hundreds of different chelator and other iron complexes are promoted, especially of new and expensive formulations claiming effective treatments and superiority over other inexpensive, generic formulations [53,74,75].…”

Conventional and Unconventional Approaches for Innovative Drug Treatments in COVID-19: Looking Outside of Plato’s Cave

“…The strategy for drug selection could be based on different methods as previously shown in other drug development cases, including the identification of one drug for one target, or of a multi-potent drug for many targets and drug combinations for one or more targets [4][5][6][7][8]. Furthermore, the investigations for drug selection could be based amongst others on personalized medicine parameters including absorption, distribution, metabolism, elimination, toxicity (ADMET) characteristics, drug interactions especially for drugs taken concurrently by patients with co-morbidities, which may have positive or negative effects against SARS-CoV-2 (COVID-19), and also drug interactions with vaccines [3][4][5][6][7][8].…”