Postgraduate Research Institute of Science Technology

Limassol, Cyprus

Postgraduate Research Institute of Science Technology

Limassol, Cyprus

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Kontoghiorghes G.J.,Postgraduate Research Institute of Science Technology | Kolnagou A.,Paphos General Hospital | Peng C.-T.,China Medical University at Taichung | Shah S.V.,University of Arkansas for Medical Sciences | Aessopos A.,National and Kapodistrian University of Athens
Expert Opinion on Drug Safety | Year: 2010

An increased number of thalassaemia patients treated with effective chelation therapy protocols are achieving body iron levels similar to those of normal individuals. Iron chelation therapy has also been recently used in a number of other categories of patients with no excess body iron load such as neurodegenerative, renal and infectious diseases. Chelation therapy in the absence of iron overload in the latter conditions raises many safety issues including chelator overdose toxicity and toxicity related to iron and other essential metal deficiencies. Preliminary preclinical and clinical toxicity evidence suggest that deferoxamine and deferasirox can only be safely used for these non-iron loaded conditions for short-term treatments of a few weeks, whereas deferiprone can be used for longer term treatments of many months. The selection of the chelating drug and appropriate dose protocols for targeting specific organs and conditions is critical for the safety of patients with normal iron stores. Chelation therapy is likely to play a major role as adjuvant, alternative or main therapy in many non-iron loading conditions in the forthcoming years. © 2010 Informa UK Ltd.


Konstantinou E.,University of Cyprus | Pashalidis I.,University of Cyprus | Kolnagou A.,Postgraduate Research Institute of Science Technology | Kontoghiorghes G.J.,Postgraduate Research Institute of Science Technology
Hemoglobin | Year: 2011

Presented at the 19th International Conference on Chelation, London, UK, 13-16 November 2009Preliminary 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 β1 = 3.1) and Fe (log β1 = 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. Copyright © Informa Healthcare USA, Inc.


Major advances were presented at the 19th International Conference on Chelation (ICOC) in London, UK including changes in iron chelation therapy that led to the complete treatment of transfusional iron overload. The first oral iron chelation results in animals using deferiprone (L1) were published in 1985, and effective iron removal in thalassemia and myelodysplasia patients were reported 2 years later. The results of multicenter clinical trials of L1 were presented at the 1st ICOC in London, UK in 1989. Long-term use of L1 resulted in the reduction of the mortality rate in thalassemia patients due to the effective removal of all excess iron from the heart. In 2008, specific combinations of L1 and deferoxamine (DFO) were reported to cause the complete removal of excess iron load and the achievement of normal range body iron store levels (NRBISL) in thalassemia patients. Patients with NRBISL were identified to require lower doses of L1 for the maintenance of negative iron balance. The introduction of deferasirox (DFRA) may benefit patients not tolerating L1, DFO or their combination. A simple, inexpensive synthesis of L1 has encouraged its manufacture in developing countries for the benefit of patients who could not afford the expensive imported chelating drugs or formulations. Copyright © Informa Healthcare USA, Inc.


Born T.,Michigan State University | Kontoghiorghe C.N.,Postgraduate Research Institute of Science Technology | Spyrou A.,Postgraduate Research Institute of Science Technology | Kolnagou A.,Postgraduate Research Institute of Science Technology | Kontoghiorghes G.J.,Postgraduate Research Institute of Science Technology
Toxicology Mechanisms and Methods | Year: 2013

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. © 2013 Informa Healthcare USA, Inc.


Kolnagou A.,Postgraduate Research Institute of Science Technology | Natsiopoulos K.,Postgraduate Research Institute of Science Technology | Kleanthous M.,Postgraduate Research Institute of Science Technology | Ioannou A.,Postgraduate Research Institute of Science Technology | Kontoghiorghes G.J.,Postgraduate Research Institute of Science Technology
Toxicology Mechanisms and Methods | Year: 2013

A comparative assessment of excess storage iron distribution in the liver, heart, spleen and pancreas of β-thalassemia major (β-TM) patients has been carried out using magnetic resonance imaging (MRI) relaxation times T2. The β-TM 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 β-TM patient. There is random variation in the distribution of excess storage iron from normal to severe levels in each organ among the β-TM 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 β-TM and especially cardiac iron load. The random variation in the concentration of iron in the organs of β-TM 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 β-TM patient. © 2013 Informa Healthcare USA, Inc.


A new era in thalassemia and other transfusional iron loading conditions was highlighted during the 18th International Conference on Chelation (ICOC) with reports that all excess iron accumulated from transfusions could be removed using the ICOC combination protocol of deferiprone (L1) (80100 mgkgday) and subcutaneous deferoxamine (DFO) (4060 mgkgday, at least 3 days per week), and that normal range body iron store levels (NRBISL) could be maintained using L1 monotherapy. Hundreds of patients in Cyprus, Greece, Italy, UK and elsewhere, maintain NRBISL, some for more than 9 years, and without complications. This gold standard of complete iron overload treatment is likely to change current practices, aims and protocols because it could prevent and also reverse cardiac, liver, endocrine and other organ complications as well as the incidence of infections and hepatocellular carcinomas. The overall morbidity and mortality in thalassemia and other transfusional iron loading conditions is expected to be substantially reduced. New applications of chelating drugs include renal, neurodegenerative, infectious diseases and ischemia reperfusion injury patients. Ethical questions have been raised on the role of pharmaceutical companies, the clinicians and the Hippocratic oath in relation to chelation therapy. © 2010 Informa UK, Ltd.


Kontoghiorghes G.J.,Postgraduate Research Institute of Science Technology
Toxicology Mechanisms and Methods | Year: 2013

New developments on chelation have been discussed during the 20th International Conference on Chelation in Grand Rapids, MI, USA, which could affect the treatments of millions of patients worldwide. The complete treatment of transfusional iron overload in thalassaemia using the deferiprone (L1) and deferoxamine combination is a paradigm to be followed in the treatment of many other metal toxicity conditions. Encouraging results from clinical testing increased the prospects of the application of L1 as a pharmaceutical chelator antioxidant in renal, neurodegenerative and other conditions. The development of new chelators for the detoxification of heavy and radioactive metals is in the final stages of approval for clinical use. EDTA chelation for heavy metal detoxification has been used in millions of patients worldwide in the last 50 years and continues to attract many categories of patients because of low toxicity and therapeutic benefits. Major changes on chelation therapy policy have been introduced by the FDA in the USA in the last few years, including the approval of L1 in 2011, the release of reports with 2474 fatalities which include thalassaemia and sickle cell anaemia patients in the period 2007-2011 in the case of deferasirox and the reappraisal of EDTA chelation therapy by NIH for patients who have suffered myocardial infraction. Major controversies in the use of chelating drugs worldwide include the risk/benefit assessment of different chelation protocols for different conditions and the commercial conflicts between generic and patented drugs. © 2013 Informa Healthcare USA, Inc.

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