Iron chelators clinically useful

Desferrioxamine (DFO-B), the natural siderophore initially isolated from Streptomyces pilosus, is the only iron chelator currently used for clinical treatment of iron-overload disease such as thalassemia, sickle cell anemia and hemochromatosis ° . ... 

Desferrioxamine (108) is the only clinically approved iron chelator. As well as being used for the treatment of iron overload diseases it is... 

There have been many reviews on the use of hydroxypyridinones, particularly LI, as iron chelators. Many deal with LI and other hydroxypyridinones in the overall context of chelation therapy for iron overload, some concentrating on the more chemical aspects, others on clinical practice. We cite a selection here, in chronological order from 1989 through 2002 so that interested readers may follow the development of this subject. The citations have been chosen to range from short articles to lengthy and fully referenced reviews, and to feature contributions from a range of the groups active in this area (373). 

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 photosensitisers in clinical or pre-clinical trials include zinc phthalocya-nine, aluminium sulphonated phthalocyanines, benzoporphyrins, benzochlorins and purpurin-lS-iV-alkylamides, all of which absorb strongly in the 675-700 nm region. An alternative approach to the photosensitisation in PDT involves the use of 5-aminolaevulinic acid (ALA). This compound itself is not a sensitiser but in human cells it is the key metabolic precursor in the biosynthesis of protoporphyrin IX, which can act as a photosensitiser. Normally the biosynthetic process would continue beyond protoporphyrin IX to the iron containing haem. However, by adding extra ALA and iron chelators, the ferrochelatase action is inhibited and the normal feedback mechanism by-passed resulting in a build up of protoporphyrin IX in the cell. The mechanism is illustrated in Figure 4.24. ... 

Neiland JB (1981) Microbial iron transport compounds (siderophores) as chelating agents. In Martell AE, Anderson WF, Badman DG (eds) Development of Iron Chelators for Clinical Use. Elsevier/North Holland, New York p 13-31... 

Desferrioxamine (DFO) is a trihydroaminic acid obtained from isolates of Streptomyces pilosus. Since 1963 it has been clinically used as an iron-chelating agent in patients with iron overload [261], DFO effectively chelates trivalent ions such as iron and Al, producing respectively ferrioxamine and aluminox-amine [12, 30, 260-269]. DFO displays rather complicated physicochemical characteristics. Unchelated DFO is a straight chained lipophilic molecule that can penetrate plasma membranes and undergo metabolic breakdown. In contact with Al, it twines itself around the metal to form stable hydrophilic... 

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. 

The structures of the three iron chelators which are currently approved for clinical use are presented in Figure 22.4. It is now well established that iron chelation therapy reduces the risk of death and improves patient survival during more than four decades of clinical experience with the current reference standard chelator, des-ferrioxamine (DFO). DFO is a hexadentate chelator (as we saw in Chapter 2). However, it is not active by oral... 

Penicillamine (D-(3,(3-dimethylcysteine) is an effective chelator of copper, mercury, zinc and lead which promotes the excretion of these metals in the urine. It is clinically used in patients with Wilson s disease, with rheumatoid arthritis and with heavy-metal intoxications. Ziram and ferbam are the zinc and the iron salts respectively of dimethyl-dithiocarbamic acid (Figure 20.44). They are widely used as selective fungicides in agriculture. Pyrithione (1 -hydroxy-2(l//)-pyridinethione), as its zinc salt is used in dermatology as antiseborrheic. 

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