Advances in the prevention and treatment are changing thalassemia from a fatal to a chronic disease. experience from a Cyprus model and its use as a paradigm for future applications.

Thalassemia is endemic in Cyprus with a frequency of 1 in 6 persons being a heterozygote and about 1 in 1,000 a homozygous thalassemia major patient. Cyprus has been a pioneer nation in reducing and almost eliminating the number of births of thalassemia major patients by introducing prenatal and antenatal diagnosis. The risks associated with bone marrow transplantation (BMT) make transfusion and chelation therapy the major form of treatment for the vast majority of thalassemia patients. Improved transfusion techniques, diagnostic methods, iron chelation and supportive therapy have increased the quality of life and survival of patients, some of whom are exceeding 50 years of age. The introduction of effective chelation therapy protocols using primarily deferiprone (L1) in combination with deferoxamine (DFO) resulted in the reduction of iron overload induced cardiac failures, which is the main cause of death in thalassemia major. Despite their chronic condition and tedious clinical management many patients are successful professionals, married and have children. The advancement in treatment is transforming thalassemia from a fatal to a chronic condition and some families are opting for giving birth to a thalassemic child rather than abortion.

Uses and limitations of serum ferritin, magnetic resonance imaging T2 and T2* in the diagnosis of iron overload and in the ferrikinetics of normalization of the iron stores in thalassemia using the International Committee on Chelation deferiprone/deferoxamine combination protocol.

Excess cardiac iron deposition leads to congestive cardiac failure and accounts for more than 70% of deaths in thalassemia major patients. In three separate studies involving 145 thalassemia patients, serum ferritin and magnetic resonance imaging (MRI) relaxation times T2 and T2* have been compared for assessing iron load levels during chelation treatment. In two studies, variable levels of cardiac iron load have been detected by T2 and T2* in patients treated with deferoxamine (DFO), which, however, were unrelated to serum ferritin. In most cases, similar range levels from normal to severe cardiac iron load could be identified by both the T2 and T2* methods. However, in a few cases there were substantial differences in the levels detected between the two methods. In the third study, the ferrikinetics of the normalization of the iron stores during the International Committee on Chelation (ICOC) deferiprone (L1)/DFO combination protocol was followed up using T2 and T2* and serum ferritin. Iron deposits were found not to be proportionally distributed between the liver and the heart or uniformly distributed within each organ. Iron mobilization in each patient varied and iron deposits in each organ were cleared at different rates. Despite some limitations, the application of the MRI relaxation times T2 and T2* offers the best diagnostic methods for iron overload estimations in most organs and especially the heart. These MRI methods and serum ferritin could also be used for the ferrikinetics of iron mobilization and removal during chelation therapy and the normalization of the iron stores during the ICOC L1/DFO combination protocol. There is a need to standardize the two MRI relaxation times T2 and T2* methods and identify the factors causing the differences between them.

Risk/benefit assessment, advantages over other drugs and targeting methods in the use of deferiprone as a pharmaceutical antioxidant in iron loading and non iron loading conditions.

Tissue damage caused by oxidative stress is a common characteristic of many conditions involving different major organs such as the brain, heart, liver and kidneys. The treatment of such conditions using classical antioxidants is not in most cases sufficient or effective because it lacks specificity and has a low therapeutic index. Increased evidence from in vitro, in vivo and clinical studies suggest that deferiprone (L1) can be used as a potent pharmaceutical antioxidant by mobilizing labile iron and copper and/or inhibiting their catalytic activity in the formation of free radicals and oxidative stress in tissue damage. The high therapeutic index, tissue penetration, rapid iron binding and clearance of the iron complex, and the low toxicity of L1, support its application as an antioxidant pharmaceutical for adjuvant, alternative or main therapy, especially in conditions where other treatments have failed. Substantial clinical improvement and reversal in most cases of the tissue damage has been observed in cardiomyopathy in thalassemia, diabetic nephropathy and glomerulonephritis in kidney disease, Friedreich's Ataxia and Fanconi Anemia patients. In contrast to L1, both deferoxamine (DFO) and deferasirox (DFRA) have major disadvantages in their use in non iron loading conditions due to toxicity implications. Further studies in the above and other conditions and optimization of the L1 therapy in each individual will increase the prospects of the application and role of L1 as a universal antioxidant pharmaceutical.