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Kontoghiorghes G.J.,Postgraduate Research Institute of Science
Expert Opinion on Drug Safety | Year: 2010

Importance of the field: Thousands of iron loaded patients are using deferasirox, who are not aware of the new, fatal and irreversible serious toxic side effects, the need for prophylaxis and the availability of more effective and less toxic chelation therapies. Areas covered in this review: Updating on efficacy issues in relation to the introduction of higher deferasirox doses and comparison to existing chelation therapies. A new maximum dose of 40 mg/kg/day has been introduced for deferasirox in an attempt to achieve negative iron balance in thalassemia and other transfused iron loaded patients. A marginal increase in cardiac iron removal using doses of 30 40 mg/kg/day suggests that the rate of iron removal by deferasirox is insufficient by comparison to the deferiprone/deferoxamine combination, where total and rapid clearance of excess cardiac iron and normalization of the body iron stores could be achieved. What the reader will gain: Identification of drug interactions and new fatal and permanent toxic side effects of deferasirox and implications on efficacy, toxicity and cost of using higher doses. Deferasirox has been identified to cause fatal gastrointestinal hemorrhages, renal tubulopathy, hepatic and renal failure, alopecia and anaphylactic reactions in addition to previously reported fatal or serious toxic side effects such as agranulocytosis, renal and hepatic toxicity, skin rash and gastric intolerance. Interactions with UDP-glucuronosyl transferase inducers, CYP2C8 and CYP3A4 substrates and drugs affecting enterohepatic recycling are likely to affect deferasirox's efficacy and toxicity. Increased toxicity is expected from the use of higher doses of deferasirox and regular prophylactic monitoring is required to avoid fatal and permanent toxicity incidences. The increased costs from higher doses of deferasirox will mostly affect patients living in the developing countries. Take home message: Only few patients may benefit from the introduction of higher doses of deferasirox. There is a need for introducing more effective prophylactic measures. Safer, more effective and less costly chelation treatments are available using deferiprone, deferoxamine and their combination. © 2010 Informa UK Ltd. Source

Flaten T.P.,Norwegian University of Science and Technology | Aaseth J.,Innlandet Hospital Trust | Andersen O.,Roskilde University | Kontoghiorghes G.J.,Postgraduate Research Institute of Science
Journal of Trace Elements in Medicine and Biology | Year: 2012

Knowledge of the basic mechanisms involved in iron metabolism has increased greatly in recent years, improving our ability to deal with the huge global public health problems of iron deficiency and overload. Several million people worldwide suffer iron overload with serious clinical implications. Iron overload has many different causes, both genetic and environmental. The two most common iron overload disorders are hereditary haemochromatosis and transfusional siderosis, which occurs in thalassaemias and other refractory anaemias. The two most important treatment options for iron overload are phlebotomy and chelation. Phlebotomy is the initial treatment of choice in haemochromatosis, while chelation is a mainstay in the treatment of transfusional siderosis. The classical iron chelator is deferoxamine (Desferal), but due to poor gastrointestinal absorption it has to be administered intravenously or subcutaneously, mostly on a daily basis. Thus, there is an obvious need to find and develop new effective iron chelators for oral use. In later years, particularly two such oral iron chelators have shown promise and have been approved for clinical use, namely deferiprone (Ferriprox) and deferasirox (Exjade). Combined subcutaneous (deferoxamine) and oral (deferiprone) treatment seems to hold particular promise. © 2012 Elsevier GmbH. Source

Timoshnikov V.A.,Novosibirsk State University | Kobzeva T.V.,RAS Institute of Chemical Kinetics and Combustion | Polyakov N.E.,RAS Institute of Chemical Kinetics and Combustion | Kontoghiorghes G.J.,Postgraduate Research Institute of Science
Free Radical Biology and Medicine | Year: 2015

Deferiprone (L1) is an effective iron-chelating drug that is widely used for the treatment of iron-overload diseases. It is known that in aqueous solutions Fe2+ and Fe3+ ions can produce hydroxyl radicals via Fenton and photo-Fenton reactions. Although previous studies with Fe2+ have reported ferroxidase activity by L1 followed by the formation of Fe3+ chelate complexes and potential inhibition of Fenton reaction, no detailed data are available on the molecular antioxidant mechanisms involved. Similarly, in vitro studies have also shown that L1-Fe3+ complexes exhibit intense absorption bands up to 800 nm and might be potential sources of phototoxicity. In this study we have applied an EPR spin trapping technique to answer two questions: (1) does L1 inhibit the Fenton reaction catalyzed by Fe2+ and Fe3+ ions and (2) does UV-Vis irradiation of the L1-Fe3+ complex result in the formation of reactive oxygen species. PBN and TMIO spin traps were used for detection of oxygen free radicals, and TEMP was used to trap singlet oxygen if it was formed via energy transfer from L1 in the triplet excited state. It was demonstrated that irradiation of Fe3+ aqua complexes by UV and visible light in the presence of spin traps results in the appearance of an EPR signal of the OH spin adduct (TMIO-OH, a(N)=14.15 G, a(H)=16.25 G; PBN-OH, a(N)=16.0 G, a(H)=2.7 G). The presence of L1 completely inhibited the OH radical production. The mechanism of OH spin adduct formation was confirmed by the detection of methyl radicals in the presence of dimethyl sulfoxide. No formation of singlet oxygen was detected under irradiation of L1 or its iron complexes. Furthermore, the interaction of L1 with Fe2+ ions completely inhibited hydroxyl radical production in the presence of hydrogen peroxide. These findings confirm an antioxidant targeting potential of L1 in diseases related to oxidative damage. © 2014 Elsevier Inc. All rights reserved. Source

Kolnagou A.,Postgraduate Research Institute of Science | Kontoghiorghes G.J.,Postgraduate Research Institute of Science
Hemoglobin | Year: 2010

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 (80100 mgkgday) was administered for a mean of 21.3 months (range 791, total 171) in eight thalassemia major patients (four males and four females, 2947 years) who have achieved serum ferritin (mean 108.5 μgL, range 25408), cardiac T2* (mean 31.5 ms, range 2441) and liver T2* (30.1 ms, range 9.141) 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 2337), liver T2* 28.8 ms (range 9.843) and serum ferritin with a mean of 173.7 μgL (range 86406). 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. © 2010 Informa UK, Ltd. Source

Kontoghiorghes G.J.,Postgraduate Research Institute of Science | Spyrou A.,Postgraduate Research Institute of Science | Kolnagou A.,Postgraduate Research Institute of Science
Hemoglobin | Year: 2010

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 DFOL1 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. © 2010 Informa UK, Ltd. Source

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