The History of Deferiprone (L1) and the Paradigm of the Complete Treatment of Iron Overload in Thalassaemia.

Deferiprone (L1) was originally designed, synthesised and screened in vitro and in vivo in 1981 by Kontoghiorghes G. J. following his discovery of the novel alpha-ketohydroxypyridine class of iron chelators (1978-1981), which were intended for clinical use. The journey through the years for the treatment of thalassaemia with L1 has been a very difficult one with an intriguing turn of events, which continue until today. Despite many complications, such as the extensive use of L1 suboptimal dose protocols, the aim of chelation therapy-namely, the complete removal of excess iron in thalassaemia major patients, has been achieved in most cases following the introduction of specific L1 and L1/deferoxamine combinations. Many such patients continue to maintain normal iron stores. Thalassemia has changed from a fatal to chronic disease; also thanks to L1 therapy and thalassaemia patients are active professional members in all sectors of society, have their own families with children and grandchildren and their lifespan is approaching that of normal individuals. No changes in the low toxicity profile of L1 have been observed in more than 30 years of clinical use and prophylaxis against the low incidence of agranulocytosis is maintained using mandatory monitoring of weekly white blood cells' count. Thousands of thalassaemia patients are still denied the cardioprotective and other beneficial effects of L1 therapy. The safety of L1 in thalassaemia and other non-iron loaded diseases resulted in its selection as one of the leading therapeutics for the treatment of Friedreich's ataxia, pantothenate kinase-associated neurodegeneration and other similar cases. There are also increasing prospects for the application of L1 as a main, alternative or adjuvant therapy in many pathological conditions including cancer, infectious diseases and as a general antioxidant for diseases related to free radical pathology.

New developments and controversies in iron metabolism and iron chelation therapy.

Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies.

Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes.

The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30-40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO-L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption.

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.

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases.

Thalassaemia major (TM) and Friedreich's ataxia (FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients. Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in the prevention and treatment of TM can be used for application worldwide.

Antioxidant targeting by deferiprone in diseases related to oxidative damage.

The design of antioxidant pharmaceuticals is a major challenge for the treatment of many clinical conditions and in aging. Free radical damage (FRD) is primarily catalysed by iron catalytic centers. Most of the natural and synthetic antioxidants are ineffective in inhibiting FRD because of the achievement of low concentrations at the affected tissues. Despite that many chelators inhibit FRD in vitro and in vivo, only Deferiprone (L1) has been shown to be effective and safe in the reversal of oxidative stress related tissue damage in iron overload and other conditions such as cardiomyopathy, acute kidney disease, Friedreich ataxia etc. Deferiprone, other chelators and their combinations could be used as main, adjuvant and alternative therapies in untreated conditions eg forms of cancer, Alzheimer's and Parkinson's diseases. Therapeutic targeting in each case requires specific chelator selection based on structure/activity correlation and consideration of other parameters eg ADMET. The ability of L1 to reach extracellular and intracellular compartments of almost all tissues including the brain is a major advantage for further development and use in many clinical conditions.

Potential clinical applications of chelating drugs in diseases targeting transferrin-bound iron and other metals.

INTRODUCTION: Iron is essential for normal, neoplasmic and microbial cells. Transferrin (Tf) is responsible for iron transport and its interactions with chelators are of physiological and toxicological importance and could lead to new therapeutic applications. AREAS COVERED: Differential interactions of Tf with chelators such as deferiprone (L1) could be used to modify toxicity and disease pathways in relation to iron and other metal metabolism. Iron mobilization by L1 could achieve normal body iron stores in thalassemia patients. Iron mobilization from the reticuloendothelial system by L1 and exchange with Tf could be used to increase the production of hemoglobin in the anemia of chronic disease. Iron accumulation is pathogenic in neurodegenerative, acute kidney and other diseases and could be removed by L1 with therapeutic implications. Deprivation of iron from neoplasmic and microbial cells by chelators could increase the prospect of improved treatments in cancer and infectious diseases. Other applications include metal detoxification and inhibition of oxidative stress-related conditions. EXPERT OPINION: Specific mechanisms apply in the interactions of chelators with Tf, which could be used in the design of targeted therapeutic strategies in many conditions. In each case specific chelator protocols have to be designed for achieving optimum therapeutic activity.

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.

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.