Post COVID-19 Reflections and Questions: How Prepared Are We for the Next Pandemic?

While the end of the COVID-19 pandemic was announced earlier in 2023 by WHO, the currently dominating COVID-19 virus variants, such as the omicron sub-lineages XBB [...].

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.

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

Thousands of drugs and nutraceuticals along with their combinations can be used to select candidate therapeutics for targeting the transmission, proliferation and the fatal or severe symptoms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in order to reduce the unacceptably high mortality rate observed in the coronavirus disease 2019 (COVID-19) pandemic and its associated negative effects on daily life worldwide [...].

Phytochelators Intended for Clinical Use in Iron Overload, Other Diseases of Iron Imbalance and Free Radical Pathology.

Iron chelating drugs are primarily and widely used in the treatment of transfusional iron overload in thalassaemia and similar conditions. Recent in vivo and clinical studies have also shown that chelators, and in particular deferiprone, can be used effectively in many conditions involving free radical damage and pathology including neurodegenerative, renal, hepatic, cardiac conditions and cancer. Many classes of phytochelators (Greek: phyto (φυτό)-plant, chele (χηλή)-claw of the crab) with differing chelating properties, including plant polyphenols resembling chelating drugs, can be developed for clinical use. The phytochelators mimosine and tropolone have been identified to be orally active and effective in animal models for the treatment of iron overload and maltol for the treatment of iron deficiency anaemia. Many critical parameters are required for the development of phytochelators for clinical use including the characterization of the therapeutic targets, ADMET, identification of the therapeutic index and risk/benefit assessment by comparison to existing therapies. Phytochelators can be developed and used as main, alternative or adjuvant therapies including combination therapies with synthetic chelators for synergistic and or complimentary therapeutic effects. The development of phytochelators is a challenging area for the introduction of new pharmaceuticals which can be used in many diseases and also in ageing. The commercial and other considerations for such development have great advantages in comparison to synthetic drugs and could also benefit millions of patients in developing countries.

EDTA chelation reappraisal following new clinical trials and regular use in millions of patients: review of preliminary findings and risk/benefit assessment.

EDTA chelation therapy is regularly used in thousands of patients worldwide. An FDA approval of more than 50 years ago for heavy metal detoxification prompted many physicians to use EDTA as an alternative medicine for many categories of patients. Recently, NIH initiated the so-called Trial to Assess Chelation Therapy (TACT), which has been designed to evaluate whether EDTA and high dose oral vitamins and mineral therapy could offer clinical, quality of life, and economic benefits for patients with a previous myocardial infraction. A 50% reduction of urinary Pb and improvement of systolic blood pressure was observed in 33 cardiovascular patients following 20 iv administrations. In another study involving 15 patients of different categories, EDTA also has been shown to be an effective and nontoxic chelator for the removal of xenobiotic metals such as Pb, Cd, Ni and Al. Administration of iv EDTA on weekly basis appears to be a sufficient and nontoxic protocol for treating patients with suspected overload and toxicity of xenobiotic metals especially Pb and Cd. The causative effect of xenobiotic metals in cancer, cardiovascular, neurodegenerative, renal and other diseases needs further investigation. Similarly, the use of EDTA chelation therapy in other conditions, which are not related to xenobiotic metal toxicity needs further investigation and confirmation of therapeutic use from controlled randomized clinical trials. Metal balance and drug interaction studies are required to clarify the risk/benefit assessment for the long term use of EDTA in patients with excess xenobiotic metal toxicity and in other conditions.

The importance of spleen, spleen iron, and splenectomy for determining total body iron load, ferrikinetics, and iron toxicity in thalassemia major patients.

The importance of spleen, spleen iron and splenectomy has been investigated in 28 male and 19 female ß-thalassemia major (ß-ΤΜ), adult patients. In one study, an increase from about five (615 g; 19.5 × 11.0 × 6.0 cm) to twenty (2030 g; 25.0 × 17.5 × 12.0 cm) times higher than the normal size and weight of spleen has been observed in twenty patients following splenectomy. In a second study, the mean size for the liver (19.4 cm, range 13.5-26.0 cm) and spleen (15.6 cm, range 7.0-21.0 cm) measured by magnetic resonance imaging (MRI) and by ultrasound imaging for spleen (15.1 cm, range 9.0-21.0 cm) of 16 patients indicated that on average the spleen is about 80% of the size of the liver. In the third study, comparison of the iron load using MRI T(2)* and iron grading of stained biopsies indicated that substantial but variable amounts of excess iron are stored in the spleen (0-40%) in addition to that in the liver. Following splenectomy, total body iron storage capacity is reduced, whereas serum ferritin (p = 0.0085) and iron concentration in other organs appears to increase despite the reduction in the rate of transfusions (p = 0.0001) and maintenance of hemoglobin levels (p = 0.1748). Spleen iron seems to be cleared faster than liver iron using effective chelation protocols. Spleen iron is a major constituent of the total body iron load in ß-ΤΜ patients and should be regularly monitored and targeted for chelation. Normalization of the body iron stores at an early age could maintain the spleen in near normal capacity and secondary effects such as cardiac and other complications could be avoided.

Liver iron and serum ferritin levels are misleading for estimating cardiac, pancreatic, splenic and total body iron load in thalassemia patients: factors influencing the heterogenic distribution of excess storage iron in organs as identified by MRI T2*.

A comparative assessment of excess storage iron distribution in the liver, heart, spleen and pancreas of ß-thalassemia major (ß-ΤΜ) patients has been carried out using magnetic resonance imaging (MRI) relaxation times T2*. The ß-ΤΜ patients (8-40 years, 11 males, 9 females) had variable serum ferritin levels (394-5603 µg/L) and were treated with deferoxamine (n = 10), deferiprone (n = 5) and deferoxamine/deferiprone combination (n = 5). MRI T2* assessment revealed that excess iron is not proportionally distributed among the organs but is stored at different concentrations in each organ and the distribution is different for each ß-ΤΜ patient. There is random variation in the distribution of excess storage iron from normal to severe levels in each organ among the ß-ΤΜ patients by comparison to the same organs of ten normal volunteers. The correlation of serum ferritin with T2* was for spleen (r = -0.81), liver (r = -0.63), pancreas (r = -0.33) and none with heart. Similar trend was observed in the correlation of liver T2* with the T2* of spleen (r = 0.62), pancreas (r = 0.61) and none with heart. These studies contradict previous assumptions that serum ferritin and liver iron concentration is proportional to the total body iron stores in ß-ΤΜ and especially cardiac iron load. The random variation in the concentration of iron in the organs of ß-ΤΜ patients appears to be related to the chelation protocol, organ function, genetic, dietary, pharmacological and other factors. Monitoring of the iron load for all the organs is recommended for each ß-ΤΜ patient.

Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease.

Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of effective, personalised iron chelation protocols, in particular the use of oral deferiprone, which is most effective in the removal of excess iron from the heart. This transition in TM has been achieved by the accessibility to combination therapy with the other chelating drugs deferoxamine and deferasirox but also therapeutic advances in the treatment of related co-morbidities. The transition and design of effective personalised chelation protocols was facilitated by the development of new non-invasive diagnostic techniques for monitoring iron removal such as MRI T2*. Despite this progress, the transition in TM is mainly observed in developed countries, but not globally. Similarly, potential cures of TM with haemopoietic stem cell transplantation and gene therapy are available to selected TM patients but potentially carry high risk of toxicity. A global strategy is required for the transition efforts to become available for all TM patients worldwide. The same strategy could also benefit many other categories of transfusional iron loaded patients including other thalassaemias, sickle cell anaemia, myelodysplasia and leukaemia patients.

Efficacy, compliance and toxicity factors are affecting the rate of normalization of body iron stores in thalassemia patients using the deferiprone and deferoxamine combination therapy.

The international committee on chelation (ICOC) of deferiprone (L1) and deferoxamine (DFO) combination therapy was the first protocol reported to have achieved normal range body iron store levels (NRBISL) in ß-thalassemia major (ß-TM) patients. A follow-up study in eight ß-TM patients has been designed to investigate the factors affecting the rate of iron removal leading to NRBISL. The patients had variable serum ferritin [mean ± SE (standard error) =1692 ± 366, range 539-3845 µg/L)] and magnetic resonance imaging (MRI) T2* relaxation times cardiac (mean ± SE =11.1 ± 2.5, range 4.5-24.2 ms) and liver (mean ± SE = 4.3 ± 1.8, range 1.4-14 ms). Organ function, blood and other biochemical parameters were regularly monitored for toxicity. The ICOC L1 (80-100 mg/kg/day) and DFO (40-60 mg/kg, at least 3 days per week) combination therapy caused an increase in cardiac (mean ± SE =30.2 ± 2.3, range 22-41 ms) and liver (mean ± SE =27.6 ± 2.8, range 9.1-35 ms) T2* and reduction in serum ferritin (mean ± SE = 158 ± 49, range 40-421 µg/L) to within the NRBISL. The rate of normalization was variable and in one case was achieved within 9 months, whereas the longest was about 3 years. The initial iron load, the rate of transfusions, the combination dose protocol and the level of compliance were the major factors affecting the rate of normalization of the iron stores. No serious toxicity was observed during the study period, which lasted a total of 24.7 patient years.

Interactions of hydroxycarbamide (hydroxyurea) with iron and copper: implications on toxicity and therapeutic strategies.

Presented at the 19th International Conference on Chelation, London, UK, 13-16 November 2009 Preliminary spectrophotometric and potentiometric studies have shown that hydroxycarbamide or hydroxyurea (HU) can interact with copper(II) [Cu(II)], iron(II) [Fe(II)] and Fe(III) ions and form complexes, for example, a ratio of 1 HU:1 metal at pH 5. The affinity for Cu (log ß1 = 3.1) and Fe (log ß1 = 5) by HU is much lower than that of the Fe and Cu chelating drug deferiprone (L1), which is used for the treatment of iron overload. It is anticipated that under certain conditions of high concentrations of these metal ions such as in transfusional iron overload, the therapeutic, pharmacological and toxicological properties of HU could be affected. It is also suggested that excess chelatable and labile forms of Fe or Cu ions, such as non transferrin-bound iron (NTBI) or intracellular low molecular weight labile iron, are among the main factors that may cause variations in the therapeutic response to HU in cancer, sickle cell anemia, thalassemia intermedia and other groups of patients. Further studies are needed to clarify the interaction mechanisms of HU with metal ions in vitro, in vivo and in clinical conditions.

Reduction of body iron stores to normal range levels in thalassaemia by using a deferiprone/deferoxamine combination and their maintenance thereafter by deferiprone monotherapy.

BACKGROUND: Iron overload and toxicity is the major cause of morbidity and mortality in thalassaemia patients. New chelating drug protocols are necessary to treat completely transfusional iron overload and eliminate associated toxicity. Appropriate deferiprone/deferoxamine combinations could achieve this goal. METHODS: A single-centre, single-armed, proof-of-concept study of the combination of deferiprone (75-100 mg/kg/d) and deferoxamine (40-60 mg/kg, at least 3 d per week) was carried out in eight patients with thalassaemia major (four men and four women) for 21-68 months. The patients were previously treated with deferoxamine and had variable serum ferritin [geometric (G) mean ± SD = 1446 ± 1035 µg/L] and magnetic resonance imaging relaxation times T2* cardiac (Gmean ± SD = 10.32 ± 6.72 ms) and liver (G mean ± SD = 3.77 ± 4.69 ms). The use of deferiprone (80-100 mg/kg/d) continued for 7-26 months in seven of the eight patients following the combination therapy. Organ function, blood and other biochemical parameters were monitored for toxicity. RESULTS: The deferiprone/deferoxamine combination caused an absolute value increase in cardiac (G mean ± SD = 29.6 ± 6.6 ms, P < 0.00076) and liver (G mean ± SD = 25.9 ± 8.07 ms, P < 0.00075) T2* and reduction in serum ferritin (G mean ± SD = 114.7 ± 139.8 µg/L, P < 0.0052) to within the normal body iron store range levels. In two cases, normalisation was achieved within a year. Deferiprone monotherapy was sufficient thereafter in maintaining normal range cardiac (G mean ± SD = 31.4 ± 5.25 ms, P < 0.79) and liver (G mean ± SD = 26.2 ± 12.4 ms, P < 0.58) T2* and normal serum ferritin (G mean ± SD = 150.7 ± 159.1, µg/L, P < 0.17) in five of the seven patients. No serious toxicity was observed. CONCLUSION: Transfusional iron overload in patients with thalassaemia could be reduced to normal body iron range levels using effective deferiprone/deferoxamine combinations. These levels could be maintained using deferiprone monotherapy.

Maintenance of normal range body iron store levels for up to 4.5 years in thalassemia major patients using deferiprone monotherapy.

New gold standard protocols are tested for the complete removal of iron overload in thalassemia using the International Committee on Chelation (ICOC) Maintaining Normal Body Iron combination protocol therapy of deferiprone (L1)/deferoxamine (DFO) and maintenance of normal range body iron store levels (NRBISL) using L1 monotherapy. Deferiprone (80-100 mg/kg/day) was administered for a mean of 21.3 months (range 7-91, total 171) in eight thalassemia major patients (four males and four females, 29-47 years) who have achieved serum ferritin (mean 108.5 microg/L, range 25-408), cardiac T2* (mean 31.5 ms, range 24-41) and liver T2* (30.1 ms, range 9.1-41) magnetic resonance imaging (MRI) relaxation times. At the end of the study normal range MRI T2* relaxation time was maintained in all eight patients with a cardiac mean of T2* 30.3 ms (range 23-37), liver T2* 28.8 ms (range 9.8-43) and serum ferritin with a mean of 173.7 microg/L (range 86-406). In one patient, this NRBISL was maintained for more than 4.5 years. No toxic side effects have been observed during the L1 monotherapy period.

Iron chelation therapy in hereditary hemochromatosis and thalassemia intermedia: regulatory and non regulatory mechanisms of increased iron absorption.

Millions of people are affected by hereditary hemochromatosis (HH) and thalassemia intermedia (TI), the iron overloading disorders caused by chronic increases in iron absorption. Genetic factors, regulatory pathways involving proteins of iron metabolism, non regulatory molecules, dietary constituents and iron binding drugs could affect iron absorption and could lead to iron overload or iron deficiency. Chelators and chelating drugs can affect both iron absorption and excretion. Deferoxamine (DFO), deferiprone (L1) and the DFO/L1 combination therapies have been used effectively for reversing the toxic side effects of iron overload including cardiac and liver damage in TI and HH patients where venesection is contraindicated. Selected protocols using DFO, L1 and their combination could be designed for optimizing chelation therapy in TI and HH. The use of deferasirox (DFRA) in HH and TI could cause an increase in iron and other toxic metal absorption. Future treatments of HH and TI could involve the use of iron chelating and other drugs not only for increasing iron excretion but also for preventing iron absorption.

The role of iron and chelators on infections in iron overload and non iron loaded conditions: prospects for the design of new antimicrobial therapies.

Iron overload is known to exacerbate many infectious diseases. Infectious complications are considered to be the second main cause of morbidity and mortality in iron loaded thalassemia patients. Effective chelation therapy leading to the normalization of the iron stores could reduce the incidence of related infections. Microbial pathogens could obtain growth-essential iron from healthy hosts. Conversely, iron withholding and/or removal is an important defense strategy for mammalian hosts, which is primarily accomplished by the iron chelating proteins transferrin and lactoferrin. Chelating drugs could prevent microbial growth and play an essential role in antimicrobial therapeutic strategies. Specific mechanisms and interactions apply in the transfer or withholding of iron between the chelating drugs deferoxamine (DFO), deferiprone (L1) and deferasirox (DFRA) with microbial pathogens such as bacteria, fungi and protozoa. In some cases, chelators and in particular DFO, could act as a siderophore for the microbe and exacerbate infections such as yersiniasis and mucormycosis. Deferiprone appears to have the highest therapeutic index for long-term antimicrobial activity and the highest tissue penetration, including access to the brain. Selection of specific chelation therapy protocols could be considered in conditions where other antimicrobial therapies have failed or where resistance has developed to existing therapies.

Trying to Solve the Puzzle of the Interaction of Ascorbic Acid and Iron: Redox, Chelation and Therapeutic Implications.

Iron and ascorbic acid (vitamin C) are essential nutrients for the normal growth and development of humans, and their deficiency can result in serious diseases. Their interaction is of nutritional, physiological, pharmacological and toxicological interest, with major implications in health and disease. Millions of people are using pharmaceutical and nutraceutical preparations of these two nutrients, including ferrous ascorbate for the treatment of iron deficiency anaemia and ascorbate combination with deferoxamine for increasing iron excretion in iron overload. The main function and use of vitamin C is its antioxidant activity against reactive oxygen species, which are implicated in many diseases of free radical pathology, including biomolecular-, cellular- and tissue damage-related diseases, as well as cancer and ageing. Ascorbic acid and its metabolites, including the ascorbate anion and oxalate, have metal binding capacity and bind iron, copper and other metals. The biological roles of ascorbate as a vitamin are affected by metal complexation, in particular following binding with iron and copper. Ascorbate forms a complex with Fe3+ followed by reduction to Fe2+, which may potentiate free radical production. The biological and clinical activities of iron, ascorbate and the ascorbate-iron complex can also be affected by many nutrients and pharmaceutical preparations. Optimal therapeutic strategies of improved efficacy and lower toxicity could be designed for the use of ascorbate, iron and the iron-ascorbate complex in different clinical conditions based on their absorption, distribution, metabolism, excretion, toxicity (ADMET), pharmacokinetic, redox and other properties. Similar strategies could also be designed in relation to their interactions with food components and pharmaceuticals, as well as in relation to other aspects concerning personalized medicine.

The Scope for Thalassemia Gene Therapy by Disruption of Aberrant Regulatory Elements.

The common IVSI-110 (G>A) ß-thalassemia mutation is a paradigm for intronic disease-causing mutations and their functional repair by non-homologous end joining-mediated disruption. Such mutation-specific repair by disruption of aberrant regulatory elements (DARE) is highly efficient, but to date, no systematic analysis has been performed to evaluate disease-causing mutations as therapeutic targets. Here, DARE was performed in highly characterized erythroid IVSI-110(G>A) transgenic cells and the disruption events were compared with published observations in primary CD34+ cells. DARE achieved the functional correction of ß-globin expression equally through the removal of causative mutations and through the removal of context sequences, with disruption events and the restriction of indel events close to the cut site closely resembling those seen in primary cells. Correlation of DNA-, RNA-, and protein-level findings then allowed the extrapolation of findings to other mutations by in silico analyses for potential repair based on the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9, Cas12a, and transcription activator-like effector nuclease (TALEN) platforms. The high efficiency of DARE and unexpected freedom of target design render the approach potentially suitable for 14 known thalassemia mutations besides IVSI-110(G>A) and put it forward for several prominent mutations causing other inherited diseases. The application of DARE, therefore, has a wide scope for sustainable personalized advanced therapy medicinal product development for thalassemia and beyond.

Chelation protocols for the elimination and prevention of iron overload in thalassaemia.

Iron overload toxicity is the main cause of mortality and morbidity in thalassaemia patients. The complete elimination and prevention of iron overload is the main aim of chelation therapy, which can be achieved by chelation protocols that can effectively remove excess iron load and maintain body iron at normal levels. Deferiprone and selected combinations with deferoxamine can be designed, adjusted and used effectively for removing all excess stored iron and for maintaining normal iron stores (NIS) in different categories of thalassaemia patients. High doses of deferiprone (75-100 mg/kg/day) and deferoxamine (50-60 mg/kg, 1-7 days/week) combinations can be used for achieving and maintaining NIS in heavily iron loaded transfused patients. In contrast, deferiprone (75-100 mg/kg/day) can be used effectively and sometimes intermittently for maintaining NIS in non heavily transfused patients. Deferasirox can in particular be used in patients not tolerating deferoxamine and deferiprone. The design of tailored made personalised protocols using deferiprone and selected combinations with deferoxamine should be considered as optimum chelation therapies for the complete treatment and the prevention of iron overload in thalassaemia.

New targeted therapies and diagnostic methods for iron overload diseases.

Millions of people worldwide suffer from iron overload toxicity diseases such as transfusional iron overload in thalassaemia and hereditary haemochromatosis. The accumulation and presence of toxic focal iron deposits causing tissue damage can also be identified in Friedreich's ataxia, Alzheimer's, Parkinson's, renal and other diseases. Different diagnostic criteria of toxicity and therapeutic interventions apply to each disease of excess or misplaced iron. Magnetic resonance imaging relaxation times T2 and T2* for monitoring iron deposits in organs and iron biomarkers such as serum ferritin and transferrin iron saturation have contributed in the elucidation of iron toxicity mechanisms and pathways, and also the evaluation of the efficacy and mode of action of chelating drugs in the treatment of diseases related to iron overload, toxicity and metabolism. Similarly, histopathological and electron microscopy diagnostic methods have revealed mechanisms of iron overload toxicity at cellular and sub-cellular levels. These new diagnostic criteria and chelator dose adjustments could apply in different or special patient categories e.g. thalassaemia patients with normal iron stores, where iron deficiency and over-chelation toxicity should be avoided.