Can Pre-Emptive Iron Chelation Lower Transfusion Requirements?

This is a very interesting approach to treating thalassemia and may lead to a re-examining of the correct time to begin iron chelation in thalassemics. The idea behind this approach is that much of the reason red blood cells degenerate prematurely is the oxidation that iron causes to red blood cells. By preventing iron levels from ever getting high, it is hoped that blood will last longer, leading to a reduced transfusion requirement. This makes sense and also makes me think that adding antioxidants to a child's treatment regimen as early as possible could also be a factor that would lead to longer life for RBC's. One has to ask if we are waiting too long to begin chelation and if we should consider starting chelation as early as possible to prevent any abnormal iron load from building. This could also lead to a change in what is thought to be acceptable iron levels in thalassemia. More research is needed to see if patients can reduce their transfusion requirements by lowering their iron load to as close to normal as possible. This is a good example of how continuing research will improve and lengthen the lives of thalassemics. One thing is certain. We need to learn more about the hydrazone compounds and their role in iron chelation. I think that in one respect, Exjade has been a curse, as there has been so much focus on developing an imperfect oral chelator, while other chelators like the hydrazones and starch desferal have been left on the back burner and not given the emphasis they deserve.

These three links refer to recent findings concerning the early use of chelators. It was found that the iron chelator, pyridoxal ortho-chlorobenzoyl hydrazone, was the most successful for this purpose.

http://www.ncbi.nlm.nih.gov/pubmed/18456387

Alternative treatment paradigm for thalassemia using iron chelators.
Szuber N, Buss JL, Soe-Lin S, Felfly H, Trudel M, Ponka P.

Department of Physiology, Medicine, and Experimental Medicine, McGill University, Montreal, Quebec, Canada.

OBJECTIVE: beta-thalassemia major, or Cooley's anemia, is a red blood cell disorder requiring lifelong blood transfusions for survival. Erythrocytes accumulate toxic iron at their membranes, triggering an oxidative cascade that leads to their premature destruction in high numbers. We hypothesized that removing this proximate iron compartment as a primary treatment, using standard and alternative orally active iron chelators, could prevent hastened red cell removal and, clinically, perhaps alleviate the need for transfusion. MATERIALS AND METHODS: Iron chelators of the pyridoxal isonicotinoyl hydrazone family (pyridoxal isonicotinoyl hydrazone and its analog pyridoxal ortho-chlorobenzoyl hydrazone) were evaluated in addition to the present mainstay, desferrioxamine and deferiprone, in vitro and in vivo. RESULTS: Treatment of human beta-thalassemic erythrocytes with chelators resulted in significant depletion of membrane-associated iron and reduction of oxidative stress, as evaluated by methemoglobin levels. When administered to beta-thalassemic mice, iron chelators mobilized erythrocyte membrane iron, reduced cellular oxidation, and prolonged erythrocyte half-life. The treated thalassemic mice also showed improved hematological abnormalities. Remarkably, a beneficial effect as early as the erythroid precursor stage was manifested by normalized proportions of mature vs immature reticulocytes. All four compounds were also found to mitigate iron accumulation in target organs, a critical determinant for patient survival. In this respect, pyridoxal ortho-chlorobenzoyl hydrazone displayed higher activity relative to other chelators tested, further diminishing iron in liver and spleen by up to approximately fivefold and twofold, respectively. CONCLUSION: Our study demonstrates the ability of iron chelators to improve several of the fundamental pathological disturbances of thalassemia, and reveals their potential for clinical use in diminishing requirement for transfusion when administered early in disease development.

http://www.sabm.org/professionals/reference/detail.php?newsid=780

Alternative Treatment Paradigm for Thalassemia Using Iron Chelators
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Date Posted: Tuesday, October 7th, 2008

Exp Hematol. 2008 Jul;36(7):773-85. Epub 2008 May 5.
Szuber N, Buss JL, Soe-Lin S, Felfly H, Trudel M, Ponka P.
Department of Physiology, Medicine, and Experimental Medicine, McGill University, Montreal, Quebec, Canada
Abstract Here
Summary
β-Thalassemia major (Cooley’s disease) is a major cause of morbidity and mortality with no available cure. Patients need lifelong blood transfusion to survive and, as a result, they are in a state of continuous iron overload caused by the toxic iron that accumulates at the RBC membrane, within major organs due to dysregulated iron absorption, and potentially fatally, throughout tissues due to the transfusion therapy. Although the iron chelator, desferrioxamine, is combined with the transfusion, it must be administered by long, painful subcutaneous infusions, leading to a high noncompliance rate among patients. Less well studied iron chelators of the pyridoxal isonicotinoyl hydrazone family (pyridoxal isonicotinoyl hydrazone and its analog pyridoxal ortho-chlorobenzoyl hydrazone) have high cell permeability and low toxicity and can be given orally. Szuber and colleagues characterized these two compounds as potential pharmacologic agents compared with desferrioxamine and deferiprone, in vitro in a model of human β-thalassemic RBCs and in vivo in a mouse model of β-thalassemia. Using blood samples from healthy human volunteers, normal human RBCs with isolated α-chains generated model β-thalassemic RBCs that were treated to create the abnormalities present in actual β-thalassemic cells. Inbred mice were identified as having intermediate to severe β-thalassemia. Because a large population of hemi-βthal mice (β-major and β-minor globin genes deleted) could not be obtained due to poor breeding efficiency, bone marrow transplants from hemi-βthal mice were thus performed, conferring the entire range of hematologic defects from thalassemic donors to marrow recipients. Pumps were implanted subcutaneously and chelator delivered continuously at a rate of 50 mg/kg/d; this is a conservative, nontoxic dose within or below the range of pharmacologic concentrations given to humans (30-100 mg/kg/d) and animals (100-500 mg/kg/d). The regime was started 12 weeks after transplantation and lasted 4 weeks. RBC membrane iron, oxidative stress, RBC survival, hematologic parameters, tissue iron, and organ pathology were assessed. Treatment of human β-thalassemic RBCs with 50 mM chelators over 20 h significantly depleted membrane-associated iron and reduced oxidative stress, as evaluated by methemoglobin (metHb) levels. In mice, treatment for 28 d reduced membrane-bound iron by 30-50% compared with untreated hemi-βthal RBCs. In untreated mice, metHb increased by 25% during the study period. All chelator-treated mice generated 25-35% less metHb by the end of the 4-week period. Iron chelators reduced RBC metHb levels to less than those before treatment, which indicates a partial reversal of oxidative damage. All four chelators prolonged RBC survival and significantly improved the hematologic parameters along with reducing tissue iron and improving organ pathology. Pyridoxal ortho-chlorobenzoyl hydrazone displayed higher activity relative to other chelators tested. These iron chelators improved several pathologies associated with thalassemia and may be ultimately useful clinically to decrease the requirements for transfusion.

http://pubs.acs.org/doi/abs/10.1021/tx800331j

In summary, this investigation has shown that both DFO and PCTH were able to afford significant cytoprotection of cardiac cells against ISO toxicity in vitro. In contrast, in vivo, DFO at the highest clinically relevant dose (equimolar to 20 mg/kg PCTH) showed no positive influence. On the other hand, the novel lipophilic Fe chelator, PCTH (20 mg/kg), was able to completely prevent ISO-mediated mortality in vivo and significantly attenuate some markers of cardiac injury caused by a necrogenic dose of ISO. This study demonstrates that further investigation of lipophilic Fe chelators such as PCTH is warranted for protection against catecholamine-induced cardiotoxicity.

These last findings could be critical. Iron damage to the heart is the main cause of death in thalassemics. A chelator that has a superior ability to protect the heart from damage caused by iron oxidation would be of tremendous value in keeping thals alive.

Thanks Andy,

For the info,what you are saying makes complete sense,i also thought that beginning chelation early would stop iron levels from being elevated,i recently met a mother whose daughter started chelating very late,and even after starting she was only on ferriprox,she told me very proudly that she has never poked her daughter for desferal,and her ferritin was 8000,i was really unable to understand what was there to be proud of,a few pokes earlier in life are way better then loosing your child due to heart failure.

Zaini.

Thanx Andy , for sharing a useful piece of information .  i also believe in this approach , to controle iron before it become like a probeleme . its easy to controle iron over-load than reducing iron .
thanx again for very usefull informtaion for the beginners  ....

Best Regards
TAke Care
Umair

Hi Andy,

It sounds like the hydrazones can alleviate so many problems in thalassemia - reduce iron in liver and the spleen, protect heart tissue and reduce tranfusion requirement (which ultimately further reduces iron).  What more could we want?  I hope research advances for this chelator soon.  I will ask Dr. Vichinsky about this as well.
Thanks Andy,

Sharmin

Thanks Sharmin. I was hoping you'd say you'd ask Dr V. I spent quite a bit of time reading about the hydrazones last night and learned that they've been studied since the 1980's. I would like to know why more research hasn't been done with hydrazones and why no one has been trying to advance it towards the market.