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The Crisis of Iron in Transfusion Medicine: Improved Iron Chelation Therapy and Its Implications for Clinical Practice in the Maldives

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The Crisis of Iron in Transfusion Medicine: Improved Iron Chelation Therapy and Its Implications for Clinical Practice in the Maldives THE CRISIS OF IRON IN TRANSFUSION MEDICINE: IMPROVED IRON CHELATION THERAPY AND ITS IMPLICATIONS FOR CLINICAL PRACTICE IN THE MALDIVES by Ibrahim Mustafa BSc., Baqai Medical University, 1999 MSc., Baqai Medical University, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2011 © Ibrahim Mustafa, 2011 Abstract The Maldives has one of the highest incidences of ß thalassemia in the world. Treatment of ß thalassemia is characterized by two distinct phases: treatment of nature’s disease (anemia) and the secondary treatment of transfusional iron overload, a side effect of our cure. Interestingly, excess iron may also exert a negative effect on immune competence thus explaining the recurrent bacterial infections in these patients. Current iron chelation therapy using Desferal! (DFO) is challenging due to its short vascular half-life, frequency of injections, toxicity and expense. To address this problem, we have tested novel, low toxicity, high molecular weight (HMW) iron chelators. The utility of these chelators was tested in vitro using iron loaded (0-500 µM ferric (Fe3+) ammonium citrate, FAC; 0- 48 hours) HepG2 and dendritic cells (DC). Iron chelation studies utilized either single or combinational treatment with deferiprone (L1) or DFO (both low molecular weight chelators) and S-DFO (a HMW derivative of DFO) for 0-48 hrs. The efficacy of treatment was assessed by cellular ferritin, Perl's iron stain, transmission electron microscopy (TEM), antigen presentation assays and cell viability assays. Iron treatment alone resulted in a significant increase in intracellular ferritin, histochemical iron staining and also resulted in a ~65.2% reduction in PBMC proliferation in response to the tetanus toxoid following 14 days of incubation. Treatment with either L1 or S-DFO alone demonstrated modestly decreased ferritin levels and iron staining. Importantly, combination therapy (L1+S-DFO) resulted in an additive effect resulting in a 79% decrease in FAC-driven ferritin levels after 48 hours and TEM studies of FAC treated, but not control, cells. FAC treated cells also demonstrated organellular and structural changes with electron dense iron deposits. As hypothesized, iron chelators (e.g., 200 µM DFO or L1) restored the PBMC proliferation in a concentration ii dependent manner and reversed the ultra structural changes in organelles. The development of HMW chelators may provide better therapeutic value (reduced toxicity and less frequent administration) in developing nations. Consequent to this, iron mediated pathology in patients would be diminished, resulting in less cost to already strained public health budgets such as in the Maldives. iii Preface Following informed consent, human blood samples were collected from normal volunteer donors for this research as approved by the UBC Office of Research Services certificate number H0270215-A005. iv Table of Contents Abstract.................................................................................................................................... ii! Preface..................................................................................................................................... iv! Table of Contents .................................................................................................................... v! List of Tables ........................................................................................................................... x! List of Figures......................................................................................................................... xi! List of Acronyms and Abbreviations .................................................................................. xv! Acknowledgements ............................................................................................................. xvii! Dedication ...........................................................................................................................xviii! Chapter 1: Background......................................................................................................... 1! 1.1 Overview...................................................................................................................... 1 1.2! Transfusion Medicine in the Third World – The Maldives Experience ...................... 2! 1.2.1! Saga of Thalassemia: Maldives Outlook and the At-Risk Population.................. 3! 1.2.2! Geographical Challenges ...................................................................................... 7! 1.2.3! Financial Challenges............................................................................................. 9! 1.2.4! Current Transfusion Medicine Practice in the Maldives .................................... 10! 1.2.5! What Can be Done in Light of These Challenges?............................................. 12! 1.3 Where! is “Misplaced” Iron in Transfusion Medicine? .............................................. 13! 1.3.1! “Primary” Iron Overload-Misplaced Iron Within the RBC................................ 13! 1.3.1.1! Thalassemia Pathophysiology...................................................................... 14! 1.3.1.2! Secondary Iron Overload ............................................................................. 18! 1.3.1.3! Other Disorders Characterized by Iron Accumulation ................................ 20! 1.4 Iron Metabolism! in Normal Cells .............................................................................. 21! 1.4.1! Iron Absorption From the Gut and Up Take in Cells ......................................... 21! 1.4.2! Distribution of Bodily Stores of Iron.................................................................. 22! 1.4.3! Biological “Detoxification”/Buffering of Misplaced/Excess Iron...................... 24! 1.4.3.1! Transferrin.................................................................................................... 24! 1.4.3.2! Ferritin.......................................................................................................... 25! 1.4.3.3! Hemosiderin................................................................................................. 26! 1.5 Why is! “Misplaced” Iron Dangerous? ....................................................................... 26! ! ! v 1.5.1 Iron Chemistry and Biochemistry....................................................................... 26 1.5.2! Redox Chemistry and Toxicity of Iron ............................................................... 29! 1.5.2.1! Consequences of Misplaced/Excess Iron in Transfusion Medicine ............ 30! 1.5.2.2! Iron and the Immunological Status of Thalassemia..................................... 31! 1.6 Iron Chelation! in Transfusion Medicine.................................................................... 33! 1.6.1! History of Iron Chelation.................................................................................... 33! 1.6.2! Current and Potential Iron Chelators .................................................................. 35! 1.6.2.1! Deferoxamine (DFO)................................................................................... 36! 1.6.2.2! Deferiprone (L1) .......................................................................................... 38! 1.6.2.3! Deferasirox (ICL670)................................................................................... 39! 1.6.2.4! N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED) .... 40! 1.6.3 High! Molecular Weight Iron Chelators .............................................................. 40! 1.6.3.1! Novel High Molecular Weight Iron Chelators: New Class ......................... 44! 1.6.4 Iron! Shuttle Chelation Therapy........................................................................... 47! 1.7 Summary! .................................................................................................................... 50! ! Chapter! 2: Hypothesis and Specific Aims ......................................................................... 51! 2.1 Overview.................................................................................................................... 51 2.2! Global Hypothesis...................................................................................................... 52! 2.2.1! Experimental Hypothesis.................................................................................... 52! 2.3 Specific! Aims............................................................................................................. 54! 2.3.1! Primary RBC Iron Overload ............................................................................... 54! 2.3.2! Secondary Iron Overload, Tissue Damage ......................................................... 55! 2.3.3! Immune Dysfunction .......................................................................................... 56! 2.4 The! Significance of Improved Iron Chelation Therapy............................................. 57! ! Chapter! 3: Materials and Methods .................................................................................... 59! 3.1 Overview.................................................................................................................... 59 3.2! Common Methods and Materials..............................................................................
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