a.
Oral
Chelators:
1.
Salicylate
Hydranoxamic acid moiety "SHAM" is a compound composed of salisylate
moiety and hydroxamic acid moiety, the antibacterial activity of the hydroxamic
acid is due to its interaction with bacterial deoxyribonucleic acid (Wang
and Lee, 1977).
Khalifa
et al. (1990) found that increasing
dose of SHAM to 40 mg/kg/day has led to a significant increase in the urinary
iron excretion, but is still lower than that excreted by
the same dose
of subcutaneous desferrioxamine. A combined therapy composed of
subcutaneous desferrio-xamine in a dose of 40 mg/kg/day and oral SHAM in a dose
of 40 mg/kg/day markedly increases the urinary iron excretion.
2. Deferiprone (LI): An orally active iron
chelator. The agent most extensively assessed is 1, 2, dimethyl-3-hydroxypyndin-4-1
(Ferriprox). It is the first orally active chelator studied extensively for the
treatment of transfusion iron overload, introduced into clinical trial 20 years
ago (Kwiatkowski, 2008). Deferiprone has high affinity for iron
and interacts with almost all the iron pools at the molecular, cellular, tissue
and organ levels. 75 mg of deferiprone, per kg body weight induces urinary iron
excretion approximately equivalent to that achieved with 30-40 mg of
desferrioxamine per kg (Olivieri et al., 1995). All the adverse
effects of deferiprone are considered reversible, controllable and manageable.
These include agranulocytosis with a frequency of about 0.6%, neutropenia 6%,
gastrointestinal symptoms including nausea, vomiting, diarrhea, and abdominal
pain, arthropathy with pain and swelling of the knee and other large joints,
low plasma zinc level and elevation of serum alanine aminotransferase.
Discontinuation of the drug is recommended for patients developing
agranulocytosis (Kwiatkowski, 2008).
The lack of reduction of
serum ferritin or liver iron concentration in some patients receiving
deferiprone may be explained by a variety of reasons, including poor
compliance, variability in drug metabolism rate, or higher transfusional iron
burden (Kwiatkowski et al., 2008).
3. Deferasirox: Deferasirox is the first oral
chelator approved to be used in the United States and it is approved in
other countries. Deferasirox is a
triazole compound, two molecules of deferasirox are needed to bind one molecule
of iron fully (tridentate chelator). It has high affinity to iron, with minimal
binding to copper and zinc. The drug is supplied as orally dispersable tablets
that are dissolved in water or juice and administered best on an empty stomach.
The deferasirox-iron complex is execreted almost exclusively in the feces, with
minimal urinary execretion (Piga et al. 2003).
4.
Other oral chelator
in development:
-
Deferritin (GT56-252)
is an orally active tridentate iron chelator. It is a derivative of
desferrithiocin, an oral chelator that showed good iron excretion in animal
studies but had unacceptable renal toxicity, so the structure of deferritin was
modified to limit this toxicity (Barton 2007).
-
Pyridoxal
isonicotinoyl hydraxone (PIH): a tridentate iron chelator, when it is given in
combination with DFX, it has a synergistic effect, suggesting that there may be
a future role of this drug in combination therapy (Kwiatkowski, 2008).
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