Deferiprone iron chelator

The most successful up-to-date treatment of thalassemic patients is chelating therapy, which is based on patient s lifetime application of iron chelators. Removal of excess iron is supposed to be effective route for suppressing free radical-mediated damage. There is a great number of studies showing successful treatment of thalassemic patients with intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI). Biochemical studies show the efficacy of both chelators in removal of excess iron. For example, the incubation of thalassemic erythrocytes with 0.5 mmol 1 1 LI during 6h resulted in 96% removal of membrane-free iron [392], It was demonstrated that LI is able to remove pathologic deposits of... 

The choice of iron chelators on the basis of both molecular and cellular criteria was discussed in 2003 (374). One 2005 review is concerned with the design of orally active iron chelators (375), another considers the prospects for effective clinical use of several hydro-x5rpyridinones, dealing with novel species such as the 1-allyl compound as well as with the established deferiprone (LI) and desferrioxamine (Desferal, DFO) (376). A review dated 2006 deals with relevance of iron mobilization from both transferrin and other iron-containing proteins by LI to the treatment of various anemias and other iron-overload conditions (377). Two 2007 reviews concentrate on LI, as the only hydroxypyridinone in general clinical use. One author concludes that, on balance, LI is to be preferred to DFO. This conclusion is on the grounds that, despite the not infrequent occurrence of minor side effects, the incidence of serious side effects... 

Desferrioxamine is expensive and must be taken by continuous injection. It is not absorbed through the intestine. Many potent iron chelators have been tested to find an effective one that can be taken orally, but only the drug deferiprone is currently used orally.In the long term, bone marrow transplants or gene therapy10 might cure the disease. 

Matthews AJ, Vercellotti GM, Menchaca HJ, et al. Iron and Atherosclerosis inhibition by the iron chelator deferiprone. J Surg Res 1997 73 35-40. 

The treatment of thalassemia, as in other metal overload disorder, is chelation therapy. The chelating agent most widely nsed is deferoxamine administered subcutaneously. The search for an orally administered iron chelator has intensified in recent years, leading to cUnical trials of many potential new iron chelators snch as deferiprone(Ll). However, many issues regarding the nse of these drugs, such as dose-related toxicity and recommended age of initiation, remain unresolved. " ... 

A safe, effective, inexpensive, orally-absorbed iron chelating agent would improve compliance and the quality of life of affected patients. Deferiprone, which is the best of many agents examined, is less effective than desferrioxamine, carries a risk of agranulocytosis and may itself cause tissue fibrosis. It remains under clinical trial but may be too toxic for general use. 

Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, McQelland RA, Burt AD, Fleming KA. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med 1998 339(7) 417-23. 

Cohen A, Galanello R, Piga A, Vullo C, Tricta F. A multicenter safety trial of the oral iron chelator deferiprone. Ann NY Acad Sci 1998 850 223-6. 

Mazza P, Amurri B, Lazzari G, Masi C, Palazzo G, Spartera MA, Gina R, Sebastio AM, Suma V, De Marco S, Semeraro F, Moscogiuri R. Oral iron chelating therapy. A single center interim report on deferiprone (LI) in thalassemia. Haematologica 1998 83(6) 496-501. 

Al-Refaie FN, Hershko C, Hoffbrand AV, Kosaryan M, Olivieri NF, Tondury P, Wonke B. Results of long-term deferiprone (LI) therapy a report by the International Study Group on Oral Iron Chelators. Br J Haematol 1995 91(l) 224-9. 

Kersten MJ, Lange R, Smeets ME, Vreugdenhil G, Roozendaal KJ, Lameijer W, Goudsmit R. Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (LI) a Dutch multicenter trial. Ann Hematol 1996 73(5) 247-52. 

Adhikari D, Roy TB, Biswas A, Chakraborty ML, Bhattacharya B, Maitra TK, Basu AK, Chandra S. Efficacy and safety of oral iron chelating agent deferiprone in beta-thalassemia and hemoglobin E-beta thalassemia. Indian Pediatr 1995 32(8) 855-61. 

Castriota-Scanderbeg A, Sacco M. Agranulocytosis, arthritis and systemic vasculitis in a patient receiving the oral iron chelator LI (deferiprone). Br J Haematol 1997 96(2) 254-5. 

Berdoukas V, Bohane T, Eagle C, Lindeman R, DeSUva K, Tobias V, Painter D, Fraser I. The Sydney Children s Hospital experience with the oral iron chelator deferiprone (LI). Transfus Sci 2000 23(3) 239. ... 

Olivieri. N.F. et al. (1995) Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N. Engl. J. Med.. 332,918-922. 

An orally effective iron chelator now under clinical investigation, deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one), may be of value in patients with thalassemia major who are unable or unwilling to receive deferoxamine. Combination therapy with deferoxamine also is under investigation. 

Infection risk Iron is an essential nutrient in many species, and iron overload increases the risk of infections. Deferoxamine is a natural siderophore, and its use is a susceptibility factor for infections with a variety of microbes, notably Yersinia enterocolitica and Mucorales infections, and increases their infectivity. On the other hand, iron chelators, by extracting iron, may also have cm anti-infectious action, which may be therapeutically beneficial, in particular in the treatment of malaria (deferiprone) [4 ] or mucormycosis (deferasirox) [5 ]. While the use of iron-chelating drugs is currently being further investigated, for the... 

Fig.2. Some synthetic iron chelators. Structures are numbered for reference in the text. Ill, deferiprone IV, MECAM V, DTPA VII, 2,3-DHB X, EHPG XI, cholylhydroxamic acid XII, HBED XIII, PIH...

A comparison of values for bi- (n = 3) and hexadentate (n = 1) chelators can be misleading. For example, log P of deferiprone is 35.9 but the log of the third stepwise formation constant given by log(P /p2) is only 9.7 (Motekaitis and Martell 1991). Also, this definition of stability constant does not take into account the different acidities of the ligands and the ability of iron to compete for them with proton. Protonation of the ligand and hydrolysis of the metal, as well as competition with other metals and ligands in biological systems, complicate the interpretation of stability constants. Therefore, in comparing the stability of iron chelates it is useful to introduce the additional terms iTeff and pM. Martell has defined an effective stability constant for Fe complexes based on competition for the... 

Kontoghiorghes GJ, Agarwal MB, Tondury P, Kersten MJ, Jaeger M, Vreugdenhil G, Vania A, Rahman YE (1993) Future of oral iron chelator deferiprone (LI). Lancet 341 1479-1480... 

Porter JB, Taher AT, Cappellini MD, Vichinsky EP. Ethical issues and risk/benefit assessment of iron chelation therapy advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox [Kontoghiorghes GJ, Hemoglobin 2008 32 (1-2) 1-15]. Hemoglobin 2008 32(6) 601-7. 

Deferoxamine is the oldest of the chelation therapies, and is administered typically at 40mg/kg body weight, for 8-12 h, 4 days per week. However, some patients do not receive sufficient benefit from deferoxamine and develop cardiac iron overload and failure [S ]. More recently, orally bioavailable chelators, such as deferiprone and deferasirox, have become popular. However, the oral iron chelators have shown side effects that differ from those of deferoxamine. Deferiprone has proven to be more efficacious than deferasirox in several clinical trials, and is now routinely administered when deferoxamine treatment has failed. However, it is associated with agranulocytosis in about 1% of patients through an as yet undetermined mechanism and neutropenia more rarely. Deferiprone has been in use in Europe since 1999 but was not approved in the United States until 2011, due in part to a controversy over its safety [4 ]. 

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