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

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.

Download Full-text

Maturation, iron deficiency, and ligands in enteric radioiron transport in vitro

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1963.204.1.171 ◽

1963 ◽

Vol 204 (1) ◽

pp. 171-175 ◽

Cited By ~ 14

Author(s):

W. S. Ruliffson ◽

J. M. Hopping

Keyword(s):

Ascorbic Acid ◽

Iron Deficiency ◽

Iron Absorption ◽

Deficiency Anemia ◽

Anaerobic Incubation ◽

Reverse Effect ◽

Factors Affecting ◽

Everted Gut Sac

The effects in rats, of age, iron-deficiency anemia, and ascorbic acid, citrate, fluoride, and ethylenediaminetetraacetate (EDTA) on enteric radioiron transport were studied in vitro by an everted gut-sac technique. Sacs from young animals transported more than those from older ones. Proximal jejunal sacs from anemic animals transported more than similar sacs from nonanemic rats, but the reverse effect appeared in sacs formed from proximal duodenum. When added to media containing ascorbic acid or citrate, fluoride depressed transport as did anaerobic incubation in the presence of ascorbic acid. Anaerobic incubation in the presence of EDTA appeared to permit elevated transport. Ascorbic acid, citrate, and EDTA all enhanced the level of Fe59 appearing in serosal media. These results appear to agree with previously established in vivo phenomena and tend to validate the in vitro method as one of promise for further studies of factors affecting iron absorption and of the mechanism of iron absorption.

Download Full-text

Porphyrin synthesis and metabolism in iron deficiency anaemia. I. In-vivo-studies

Blut Zeitschrift für die gesamte Blutforschung ◽

10.1007/bf01632077 ◽

1968 ◽

Vol 16 (6) ◽

pp. 333-341 ◽

Cited By ~ 3

Author(s):

V. Prato ◽

U. Mazza ◽

A. L. Massaro ◽

G. Bianco ◽

V. Battistini

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anaemia ◽

In Vivo Studies ◽

Deficiency Anaemia ◽

Porphyrin Synthesis

Download Full-text

Porphyrin synthesis and metabolism in iron deficiency anaemia: II. in vitro studies

Blut Zeitschrift für die gesamte Blutforschung ◽

10.1007/bf01637286 ◽

1968 ◽

Vol 17 (1) ◽

pp. 14-19 ◽

Cited By ~ 4

Author(s):

V. Prato ◽

U. Mazza ◽

A. L. Massaro ◽

G. Bianco ◽

V. Battistini

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anaemia ◽

In Vitro Studies ◽

Deficiency Anaemia ◽

Porphyrin Synthesis

Download Full-text

Effectiveness of a Nutritional Education Intervention Focussed on Iron among School Children in National Capital Region and Mumbai

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2021/46024.14806 ◽

2021 ◽

Author(s):

Richa Bharti ◽

Ankita Marwaha ◽

Teena Badshah ◽

Rupali Sengupta ◽

Bhavna Barmi ◽

...

Keyword(s):

Iron Deficiency ◽

School Children ◽

Iron Deficiency Anaemia ◽

Iron Absorption ◽

Age Group ◽

Nutritional Education ◽

Post Intervention ◽

Deficiency Anaemia ◽

Alternate Hypothesis

Introduction: Anaemia is a major health problem in India. Various studies mention poor nutrition knowledge and education as main factors of malnutrition. Aim: This study aims at assessing the effect of nutritional education on iron among school children. Materials and Methods: A cross-sectional interventional study to improve nutrition literacy in schools was undertaken from April 2018 to February 2019. The outreach platform used was Eat Right School program by Food Safety and Standards Authority of India (FSSAI). A study tool employed was data collection using self-developed questionnaire for pre and post-intervention knowledge assessment. School children from Delhi NCR and Mumbai participated in this study. Knowledge intervention was done on 5 key elements related to iron including role, sources, iron deficiency anaemia, iron absorption and knowledge of fortification. Chi-squared test (α=0.05) was applied for comparison. Results: It was found that 54% (n=18,626) of school children studied were in the age group 11-14 years. From 27355 participants who reported the gender, 58.1% (n=15899) were boys and 41.9% (n=11456) girls. Comparison of pre and post-intervention assessment revealed that percentage of students knowing importance/role of iron increased from 27.30% to 59.50%, iron deficiency anaemia from 34.03% to 59.85%, sources of iron from 25.20% to 51.70%, iron absorption from 36.00% to 61.2% and knowledge of fortification from 55.4% to 76.9%. Thus, significant shift (p≤0.001) in all the parameters was observed; improvement in scores ranged from 21.5% to 32.20% with highest increase seen in understanding the role of iron. Conclusion: Results of the study reject the null hypothesis leading to acceptance of alternate hypothesis. The alternate hypothesis highlights the role of nutrition education in improving the nutritional literacy of school children in the area of iron and iron deficiency anaemia. Results of the current study increased the knowledge of children on all parameters related to iron education module. Thus, nutritional literacy is imperative in improving nutritional status and adolescent age-group is the window of opportunity to correct it.

Download Full-text

A Preliminary Study of Iron Absorption by Whole Body Counting and Correlation with DFO Excretion

Nuklearmedizin ◽

10.1055/s-0038-1624888 ◽

1975 ◽

Vol 14 (01) ◽

pp. 74-80

Author(s):

M. M. Gupta ◽

R. Manchanda ◽

L. Bhattacharyya ◽

M. Bhargva ◽

S. Kumar ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anaemia ◽

Iron Absorption ◽

Whole Body ◽

Healthy Controls ◽

Deficiency Anaemia ◽

Iron Deficient ◽

Body Counting ◽

Preliminary Study ◽

Whole Body Counting

SummaryA preliminary study of iron absorption by whole body counting was carried on a group of 16 women. The cases included 8 patients suffering from iron deficiency anaemia and various infections as well as 8 healthy controls. High iron absorption is associated with iron dificiency, these changes being more marked in iron deficient controls than in those with infection or malignancy. In iron deficient controls results of whole body counting correlate very well with other haematological investigations.

Download Full-text

Sources and Forms of Iron in Nigerian Foods and Effects of Processing on Availability

Food and Nutrition Bulletin ◽

10.1177/156482659701800107 ◽

1997 ◽

Vol 18 (1) ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

G. Oluyemisi Latunde-Dada ◽

Suresh Chandra Babu ◽

Evance Chapasuka

Keyword(s):

Iron Deficiency Anaemia ◽

Iron Availability ◽

Deficiency Anaemia ◽

Advantages And Disadvantages ◽

Food Items ◽

High Incidence ◽

Traditional Processing ◽

Forms Of Iron

The average diet in most developing countries, including Nigeria, is predominantly plant based. Cereals, legumes, tubers, and vegetables are the main food types. Although most of these food items have considerable iron, its low bioavailability is one of the factors accounting for the high incidence of iron-deficiency anaemia. The traditional processing procedures, fermentation and germination, improved the chemical and bioavailable iron in the foods studied. Techniques of measuring iron availability in vitro and in vivo were applied to a variety of foods. The advantages and disadvantages of the methods employed are discussed.

Download Full-text

Efficacy of oral iron therapy in geophagic women with iron deficiency anaemia residing in Botshabelo, South Africa

Journal of Medical Laboratory Science & Technology of South Africa ◽

10.36303/jmlstsa.2020.2.1.38 ◽

2020 ◽

pp. 13-21 ◽

Cited By ~ 1

Author(s):

LF Mogongoa

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anaemia ◽

Iron Absorption ◽

Binding Capacity ◽

Transferrin Saturation ◽

Oral Iron ◽

Iron Therapy ◽

Deficiency Anaemia ◽

Oral Iron Therapy ◽

Soil Consumption

Background: Iron deficiency anaemia is the most commonly encountered form of anaemia in females worldwide. This form of anaemia is, amongst others, associated with geophagia that is defined as the consumption of soil. The two main reasons for the association of geophagia with anaemia are that soil is thought to supplement mineral deficiency and geophagia is seen as a symptom of the anaemia. However, it is hypothesised that soil consumption interferes with iron absorption instead of supplementing it. The first line of therapy for iron deficiency anaemia is oral iron. Therefore, if soil consumption interferes with iron absorption it could interfere with oral iron therapy leading to patients being burdened with symptoms of anaemia as treatment is not effective. The aim of the study was to evaluate the efficacy of oral iron therapy in female participants afflicted with iron deficiency anaemia associated with geophagia. Methods: In this prospective randomised intervention study, 84 geophagic women with iron deficiency anaemia were divided into two groups. One group continued with soil consumption while the other stopped consumption. Oral iron therapy was administered for ten weeks at increasing therapy doses for both groups. Red cell and iron study parameters were evaluated at different time intervals to ascertain the efficacy of iron replacement therapy. Results: The group that stopped soil consumption showed a statistically significant change in haemoglobin (9.4 to 10.0 g/dL, p = 0.029), mean corpuscular volume (73.6 to 75.7 fl), mean corpuscular haemoglobin (23.7 to 24.6 pg), serum iron (22.5 to 28 μg/dL, p < 0.001, transferrin saturation (4.8 to 6.9%, p < 0.001) and total iron-binding capacity (467 to 441 μg/L, p = 0.001). These findings were contrary to the group that continued with consumption, where the statistical changes were only observed for the iron study parameters (serum iron: 21 to 28 μg/dL, p = 0.038; transferrin saturation: 4.3 to 6.9%, p = 0.011; total iron-binding capacity: 496 to 421 μg/L, p = 0.002). Nevertheless, the changes for both groups were clinically insignificant. Oral iron therapy did not correct the anaemia in geophagic females of both groups, this could be explained by two hypotheses where soil affected the gastrointestinal lining and soil directly interfered with therapy iron absorption. This is evidenced by the group that continued with consumption showing fewer changes than the group that abstained from soil consumption. These results were consistent with a case study where oral iron therapy was implemented. Conclusion: Oral iron therapy was not effective in geophagia cases of iron deficiency anaemia.

Download Full-text

Organometallic iron complexes as potential cancer therapeutics.

Acta Biochimica Polonica ◽

10.18388/abp.2014_1826 ◽

2014 ◽

Vol 61 (4) ◽

Cited By ~ 3

Author(s):

Gabriela Mojžišová ◽

Ján Mojžiš ◽

Janka Vašková

Keyword(s):

Anticancer Agents ◽

Acquired Resistance ◽

Cancer Therapeutics ◽

Iron Complexes ◽

Cytotoxic Agents ◽

In Vitro Tests ◽

Clinical Use ◽

In Vivo Experiments

Metal-containing drugs have long been used for medicinal purposes in more or less empirical way. The potential of these anticancer agents has only been fully realised and explored since the discovery of the biological activity of cisplatin. Cisplatin and carboplatin have been two of the most successful anti-cancer agents ever developed, and are currently used to treat ovarian, lung and testicular cancers. They share certain side effects, so their clinical use is severely limited by dose-limiting toxicity. Inherent or acquired resistance is a second problem often associated with platinum-based drugs, with further limits of their clinical use. These problems have prompted chemists to employ different strategies in development of the new metal-based anticancer agents with different mechanisms of action. There are various metal complexes still under development and investigation for the future cancer treatment use. In the search for novel bio-organometallic molecules, iron containing anti-tumoral agents are enjoying an increasing interest and appear very promising as the potential drug candidates. Iron, as an essential cofactor in a number of enzymes and physiological processes, may be less toxic than non essential metals, such as platinum. Up to now, some of iron complexes have been tested as cytotoxic agents and found to be endowed with an antitumor activity in several in vitro tests (on cultured cancer cell lines) and few in vivo experiments (e. g. on Ehrlich's ascites carcinoma). Although the precise molecular mechanism is yet to be defined, a number of observations suggest that the reactive oxygen species can play important role in iron-induced cytotoxicty. This review covers some relevant examples of research on the novel iron complexes.

Download Full-text