Deferiprone

Fig. 30. Chemical structures of two siderophore mimic molecules presently in clinical use for treatment of iron overload, Exjade and Deferiprone.

Chelators of iron, which are now widely applied for the treatment of patients with thalassemia and other pathologies associated with iron overload, are the intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI) (Figure 19.23, see also Chapter 31). Desferrioxamine (DFO) belongs to a class of natural compounds called siderophores produced by microorganisms. The antioxidant activity of DFO has been studied and compared with that of synthetic hydroxypyrid-4-nones (LI) and classic antioxidants (vitamin E). It is known that chronic iron overload in humans is associated with hepatocellular damage. Therefore, Morel et al. [370] studied the antioxidant effects of DFO, another siderophore pyoverdin, and hydroxypyrid-4-ones on lipid peroxidation in primary hepatocyte culture. These authors found that the efficacy of chelators to inhibit iron-stimulated lipid peroxidation in hepatocytes decreased in the range of DFO > hydroxypyrid-4-ones > pyoverdin. It seems that other siderophores are also less effective inhibitors of lipid peroxidation than DFO [371],... 

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... 

Other drugs Acetazolamide, acetosulfone, acetylcysteine, acitretin, allopurinol, aminoglutehimide, benzaflbrate, brompheniramine, calcium dobe-silate, chloropheniramine, chlorpropamide, colchicine, deferiprone, dapsone, flutamide, glibenclamide, hydroxychloroquine, mebhydro-lin, meprobamate, metapyrilene, methazolamide, metochlopramide, prednisone, promethazine, retinoic acid, riluzole, ritodrine, tolbutamide, yohimbine... 

Galanello R, Kattamis A, Piga A, Fischer R, Leoni G, Ladis V et al. A prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron... 

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. 

J. Savulescu, Thalassaemia Major The Murky Story of Deferiprone, ... 

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

Hoffbrand AY Al-Refaie F Davis B, et al. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood I 998 91 295-300. 

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. 

Deferiprone is an alpha-ketohydroxypyridine compound with metal-chelating properties (1). It is absorbed within minutes after oral administration and reaches maximum blood concentrations within 1 hour. It has a half-life of 1-2 hours, and is almost completely undetectable in blood within 5-7 hours after a single dose. Deferiprone is mostly metabolized to a glucuronide conjugate that reaches maximum blood concentrations within 1.0-1.5 hours. Deferiprone, its iron complex, and its glucuronide conjugate are detectable in the urine, and in most instances the total amount of all three accounts for almost 100% of the... 

Table 1 Metal stability constants of deferiprone, deferoxamine, and diethylenetriaminepentaacetic acid (DTPA)...

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