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Page 1: Taro Pharmaceuticals, Ltd. 1 of 30...A Division of Harcourt Brace & Company PHILADELPHIA LONOON TORONTO MONTREAL SYDNEY TOKYO 2 of 30 Taro Pharmaceuticals, Ltd. ... Authorization to

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THE PEDIATRIC CLINICS OF NORTH AMERICA

New Frontiers in Pediatric Drug Therapy

BENOIT BAILEY, MD, MSc, FRCPC, and GIDEON KOREN, MD, ABMT, FRCPC, GUEST EDITORS

VOLUME 44 • NUMBER 1 • FEBRUARY 1997

W.B. SAUNDERS COMPANY A Division of Harcourt Brace & Company PHILADELPHIA LONOON TORONTO MONTREAL SYDNEY TOKYO

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W.B. SAU DERS COMPA Y I\ Vn•isio11 of Hnrco11rl Brace & Co111pn11y

The Curtis Center • Independence Square West • Ph1ladl'lphi.i, Penn.'>yhama 19106

T HE PEDIATRIC CLINICS OF O RTH AMERICA February 1997 Edi tor: Carin Baniewicz

Volume 44, umber 1 ISSN 0031- 3955

Production Editor: Carrie Schaller

Copyright © 1997 by W. B. Saunders Company. All rights reserved No part or this public,1tion may be reproduced or tran.,mitted in any form or by any me,111s, e lectronic or m<.'Chanical, including photocopy, recording, or any information retrievnl system, without written permission from the publisher.

The ideas and opinions expressed in The Pedintric Clinics of Nortli l\1111•ricn do not necessarily n.•Oect those or the Publisher. The Publisher doe!> not assume any responsibility for any injury and/or damage to persons or property ari-.ing out or or related to any use of the material contained in this periodical. The reader is advised to cht'Ck the appropriate medic,11 literature and the product information currently prov1dl'<l by the manufacturer or each drug to be administered to \•erif} the dosage, the method and duration of administra­tion, or contraindications. It is the responsibility of the tre,1ting physician or o ther health care profos.,1onal, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Mention or any product in thlS ,.,sue should not be construed as endol"S('ment by the contributors, editor;, or the Publisher or the product OT manufacturers' claims.

Authorization to photocopy items for internal or per.onal use, or the internal or personal use of SJX'Cific clients, is granted by w. B. S.1unders Comp.1ny. providl>d that the base rec of S0.00 per copy plus S0.20 per page i., paid directly to Copyright Clearance Center (CCC), Transactional Reporting Service, 222 Ro:.ewood Drive, Danvers, MA 01923. Identify this public.1tion by including with your payment the rec code 0031-3955/ 97 $0.00 + $0.20. for those organizations that have been granted a photocopy license by CCC, a separate system or payment has been arranged All fees are sub1ect to change without nohce.

T/11• l't'dinlric Clinics if North America (ISSN 0031-3955) i' published bi-monthly by W. ll Saunders Company, Corporate and Editorial Offices: Thl• Curtis Center, Independence Square We:,t, Philadelphia, PA 19106-3399. Accounting and Circulation Orfices: 6277 Sea Harbor Drive, Orlando, FL 32887-4800. Periodicals postage paid a t Orlando, FL 32862, and additional mailing offices. Subscription price per year is $88.00 (US individuals), $122.00 (US institutions), $125.00 (foreign individuals), and $1 49.00 (foreign ins titutions), $ 121.00 (Cnnadian individuals), $149.00 (Canadian ins titutions). To receive s tudent / resident rate, orders mu~t be accompanied by name of affiliated institution, date or term, and the signature or program/residency coordinator on institu tion le tterhead Ordl•rs will be billed at individual ra te until proof of status is recl•ived. Foreign air speed delivery for all Climes 1s $6.00 per issue. All prices are subject to change without nobce. POSTMASTER: Send address changl'!> to W. B. Saunders Company, Periodicals Fulfillment, Orlando, fL 32887-4800. Customer Service: 1-800-654-2452 (US). From ou tside the US, ca ll 1-407-345-4000.

T/11• l'l'dilltric Clmics of North America is also publi~hed in Spanish b) '-EISA (McGraw­! hll lnteramericana de Mexico), Cedro 512, ()6.t50, Mexico, D.F .• Me'.l.1co, m Portugul>se by lnterhnos Edicoes Lida., Rua Comandante Coelho 1085, err 21250, Rio de Janeiro, Brazil; and in Greek by Althayia SA, Athens, Greece.

The Ped111/ric Cl1111Cs of North l\mericn is covered in Index M1·diC11>, Lrcerpln Mr.11c11, Current Conte11ts, C11rrmt Contents/Cl1111cnl Medicine, Sci1·nc. Citation lnde.\, A5CA, 151/BlOMEO, ,ind 810515.

Printed in the United States of America

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l NEW FRONTIERS IN PEDIATRIC DRUG THERAPY

GUEST EDITORS

BENOIT BAILEY, MD, MSc, FRCPC, Fellow, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

GIDEON KOREN, MD, ABMT, FRCPC, Professor, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, and Research Institute, The Hospital for Sick Child ren; and the Departments of Pediatrics, Pharmacology, and Medicine, University of Toronto, Toronto, Ontario, Canada

CONTRIBUTORS

MICHAEL R. ANDERSON, MD, Fellow, Division of Pediatric Critical Care, Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Childrens Hospital, Cleveland, Ohio

BENOIT BAILEY, MD, MSc, FRCPC, Fellow, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

JEFFREY L. BLUMER, PhD, MD, Professor, Departments of Pediatrics and Pharmacology, Case Western Reserve University School of Medicine; and Chief, Division of Pediatric Pharmacology and Critical Care, Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, Ohio

SYLVAIN CH EMTOB, MD, PhD, Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hopital Sainte-Justine, University of Montreal, Montreal, Quebec, Canada

ORNA DIAV-CITRIN, MD, Fellow, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

THO MAS W. FERKOL, MD, Assistant Professor, Division of Pediatric Pulmonology, Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Childrens Hospital, Cleveland, Ohio

TERENCE R. FLOTTE, MD, Assistant Professor, Department of Pediatrics, and Assistant Professor, Department of Molecular Genetics and Microbiology, and Co-Director, Gene Therapy Center, University of Florida School of Medicine, Gainesville, Florida

iii

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NEW FROt\TIERS IN PEDIATRIC DRUG THERAPY 0031-3955/97 $0.00 + .20

ORAL IRON CHELATION WITH DEFERIPRONE

Oma Diav-Citrin, MD, and Gideon Koren, MD, ABMT, FRCPC

Patients with refractory anemias, such as tha lassemia major, who require regular red blood cell transfusions progressively accumulate iron. Each unit of red blood cells contains 200 to 250 mg of elemental iron and thus, patients on chronic transfusion programs accumulate approximately 0.5 mg/ kg/day of iron. Tissue iron accumulation results in progressive organ dysfunction, leading to death if no iron-chelating therapy is initiated. Although transfusions sustain normal growth and development and improve the life expectancy of patients, they are complicated by the harmful consequences of iron overload because humans lack a physiologic mechanism for excreting excess iron.

Lron-chelating therapy for the management of transfus iona l iron overload was first introduced in the early 1960s.'"· ~1 • 63• 7• It is only since 1974, after the demonstration that it was possible to reduce the concentration of hepatic iron and arrest the progression of hepatic fibrosis in thalassemic patients with its long-term use,1• that desferrioxamine gained acceptance as the standard form of therapy. Unfortunately, desferrioxamine is only effective when administered parenterally. Subcutaneous doses of 20 to 40 mg/kg/day for 8 to 12 hours resulted in iron excretion sufficient to produce a negative iron balance.37· ' 111

Over the pilst two decades, several studies have demonstrated that regular desferrioxamine therapy ameliorntes hepatic, cardiac, and endocrine dysfunc­tion, improves growth and sexual maturation, and prolongs survival in iron­loaded patients.1u 1

Because of its high cost (approximately $40 US/2 g vial), desferrioxamine is not available in many countries where it is most needed. Even where it is available, many patients fail to comply with a regimen of prolonged subcutane­ous infusions, especially during adolescence. Other problems with desferrioxa­rnine therapy include its serious adverse effects. Intensive therapy in young

This work was s upported by an MRC-lndustry grant and by Apotex, Inc, Toronto.

From the Division of Clinical Pharmacology and Toxicology, Department of Pediatrics (ODC, GK), and Research Institute (GK), The Hospital for Sick Children; and the Departments of Pediatrics, Pharmacology, and Medicine, University of Toronto, To­ronto, Ontario, Canada

PEDIATRIC CLINICS OF NORTH AMERICA

VOLUME 44 • NUMBFR 1 • FEBRUARY 1997 235

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236 OIAV-CITRIN & KOREN

Figure 1. Chemical structure of desferrioxamine.

patients with low body-iron stores may result in serious neurotoxicity (audi­tory and visual), abnormali ties of cartilage formation, and stunted linear growth.5s-5!o. M

ln the last decade we have witnessed the emergence of interest in oral iron chelation for transfusional iron-loaded patients in thalassemia and other refractory anemias. Currently, the orally active iron chelator with the broadest cUnical experience is deferiprone (l,2-dimethyl-3-hyd roxypyrid-4-one, or L1).

The agent is a member of the hydroxypyridones of bidentate (two binding sites) iron chelators patented by Hider et al33 in 1982 as an alternative to desferrioxa­mine in the treatment of chronic iron overload.

This article summarizes the experience with this new, orally active iron chelator, deferiprone. In addition, it reviews novel uses of iron chelation and potential new applications in acute iron poisoning.

STRUCTURAL COMPARISON BETWEEN DESFERRIOXAMINE AND DEFERIPRONE

Desferrioxamine (Fig. 1), a trihydroxamate siderophore derived from Strep­tomyces pilosus, is a hexadentate chelator.30 It is capable of combining with ferric iron at a 1:1 molar ratio because of its six binding sites with a high stability constant (Hl31). The desferrioxamine molecule is wrapped around the iron nu­cleus, encasing it in an envelope of organic material. Because of its high molecu­lar weight, desferrioxamine is poorly absorbed from the gastrointestinal tract, and is therefore administered parenterally.

Deferiprone (Fig. 2) is a bidentate ligand. Therefore, three chelator molecules are required to form a neutral complex with a single iron a tom.

The hexadentate chelators are inherently more stable kinetically than biden­tate chelators. The greater stability of the hexadentate molecules minimizes the risk of iron redistribution or the participation of unstable iron-chelate complexes

Figure 2. Chemical structure of deferiprone.

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ORAL IROl\ CHELATION WITH DEFERlPRONE 237

in the generation of harmful free radicals; they also have the ability to scavenge iron at low concentrations. On the other hand, bidentate compounds have a lower molecular weight and are usually easily absorbed from the gut. Because of this, however, they are able to penetrate other cells more quickly with the potential risk of cellular toxicity resulting from their interaction with iron­requiring enzymes.65

ORAL IRON CHELATION WITH DEFERIPRONE

Chemistry and Pharmacology of Deferiprone

Deferiprone is a white solid compound with a molecular weight of 139 kD.44 It is water-soluble with a partition coefficient (K part, the ratio of the concentrations of the compound between an organic phase and water at a pH of 7.4) close to one.67 Deferiprone is highly stable at pH values ranging from 1 to 1244 and it is resistant to cleavage by digestive enzymes.67 It generally forms a 1:3 complex with iron with a stability constant of 36.4° At low concentrations of chelator, however, partially dissociated deferiprone-iron complexes (2:1, 1:1) can form and may, in turn, generate hydroxyl radicals.67 Deferiprone binds ferric iron with a high affinity (binding constant log J3 = 37).

Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Jt is excreted in the urine mostly as a glucuronide or unchanged, bound to iron or bound to trace metals such as zinc and aluminum.<• Glucuronidation abolishes the ability of deferiprone to chelate iron, because the hydroxyl group of deferiprone needed for iron binding is involved in the conjugation. The excretion of deferiprone-glucuronide is slower than that of free deferiprone. In patients with impaired renal function, the glucuronide derivative may accumu­late in the plasma.q The pharmacokinetic characteristics of deferiprone are sum­marized in Table 1.

The efficacy of the drug in heavily iron-loaded patients, assessed by the amount of the drug excreted in urine bound to iron in 24 hours compared with the size of a single oral dose, has been estimated to be approximately 4%.9 The urinary iron excretion in heavily iron-loaded patients following a single dose is related to the area under the concentration-time curve for plasma deferiprone.

Whether deferiprone is excreted in the stools and whether or not it increases fecal iron excretion in humans remain controversial. There are reports of iron excretion in the stool of iron-loaded patients following oral administration of deferiprone amounting to up to 30% of the total iron excreted.23•57 Another study9

indirectly suggested that approximately 20% of an oral dose of deferiprone may be excreted in the stools. Kontoghiorghes et al,44 however, reported no increase

Table 1. A SUMMARY OF DEFERIPRONE PHARMACOKINETICS

No. of t'h.. Cmax t'h,, AUC Study Dose Patients (minutes) (11g/ml ) (minutes) (11g•minute/ml)

Kontoghiorghes 3000 mg 7 7.1 :!: 11.3 NA 74.3 :!: 28.7 NA et al"

Matsui et a1•• 25 mgll<g 14 NA 17.49 :!: 2.08 159.6 :!: 20.5 1635 :!: 174.97 AJ-Refaie et al• 50 mgll<g 24 22.2 :t 17.7 20.1 :!: 11 .5 91 .1 :t 33.1 3020 :t 1199

t'h e half·lite. " s absorption: II e elimination: Cmax - maximum concentration: AUG = area under the plasma serum concentrabon·bme CtJrve lrom time zero to inlinity; NA - not available

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238 DIAV-CITRll'\ & KORF.>'J

in iron excretion and no evidence of deferiprone in the stools of two patients with iron overload given deferiprone.

Several factors may influence deferiprone pharrnacokinetics and efficacy. Food prolongs the ra te of absorption of deieriprone but it does not signifi­

cantly affect the extent of absorption measured by the area under the plasma concentration-time curve. Thus, food docs not change the chelation capacity of the drug.~q

Vitamin C was found to have no effect on urinary iron excretion in two small trials.72 The exact effect of vitamin C therapy, however, both in vitamin C replete and deficient patients is yet to be determined.

No increase in the urinary iron excretion was found in two normal volun­teers when deferiprone complexed to iron was administered oral ly.' 7

There has been some evidence tha t long-term treatment with defcriprone may be associated with a fall in the defcriprone trough concentrations.'" The findings suggest self-induction of deferiprone metabolism or decreased absorp­tion during long-term therapy. The former is supported by the results of an in vi tro study that has shown that deferiprone induces its own metabolism by human hepa tocytes in culture.5i

The sites from which defcriprone chelates iron are not fully established. Anima l studies have shown that deferiprone concentrates main ly in the liver.'-' Because free deferiprone readily enters cells, it is likely that both parenchymal and reticuloendolhelial cells are sources of chelated iron. Unlike desferrioxa­mine, deferiprone can also chelate iron from transferrin•· 27 and, based on studies of iron-loaded patients, it is estimated that up to 20% of iron excreted in the uri ne following a single oral dose may be derived from iron bound to trans­ferrin.q Deferiprone also chelates iron from intact red cells that may be important in the therapeutic response to dcfcripronc in thalassernia intermcdia.71

Clinical Trials of Deferiprone

The results of the fi rst clinical studies on the efficacy of deferiprone in patients with myelodysplasia and thalassernia major were reported in 1987. 11

• 12

They showed tha t deferiprone could induce urinary iron excretion comparable to that achieved with desferrioxamine. Iron excretion correlated to the iron burden. Subsequent short-term clinical trials have confirmed those preliminary findings.~· n Dose-response studies have shown that 75 mg/kg body weight was the minimal daily dose required to achieve a negative iron balance (> 0.5 mg/ kg/ day) in most patients with thalassemia major.57 These findings, confirmed in a later comparison study between deferipronc and desferrioxamine~' in sickle­cell d isease, provide evidence that short-term efficacy of defcriprone is inferior to that of desfcr rioxamine. Long-term trials of deferiprone have shown long­term effectiveness of deferiprone in the majority of patients with transfusional iron overload.'· 17 43• ><. n These studies have a lso provided information on a number of adverse effects that were not apparent in the initial short-term trials.

Changes in Serum Ferritin Concentrations

Significant decreases in serum fcrritin were reported in most of the long­term clinical studies~· 51160 but not in all of them.2u 3.n Those trials were d ifferent in their design in many aspects: the duration of deferiprone treatment before repeated scrum ferritin assays were conducted; different adm inistered doses of

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ORAL IRON Cl IF.LA TlON WIT!-! DF.FF.Rll'RONE 239

deferiprone; the number of patients entering the studies after being poorly compliant with desferrioxamine and, thus, starting with high serum ferritin levels; and the degree of compliance with deferiprone therapy. One prospective trial>i showed a reduction in the mean serum ferritin level from approximately 4000 µ.g/L to approximately 2500 µ.g/L, whereas in all patients with initial ferritin levels below 2500 µ.g/L there was no change. This may suggest that deferiprone can reduce serum ferritin to the range associated with cardiac disease-free survival in desferrioxamine-treated patients or maintain it in that range.22

Reduction in serum ferritin concentration suggests a decline in body iron burden during long-term oral chelation with deferiprone. Serum ferritin levels may be misleading in the assessment of iron burden in individua l patients,21

however, because serum ferritin is a lso influenced by other factors such as hemolysis, ineffective erythropoiesis, vitamin C deficiency, inflammation, and liver disease, all of which are common in iron-loaded patients.

Changes in Hepatic Iron Concentration

Initial evidence that therapy with deferiprone may reduce tissue iron stores was provided by a study of an iron-loaded patient with thalassernia intermedia in whom stores were reduced to normal over a period of 9 months.-w

This was subsequently followed by a report of a significant decrease in hepatic iron concentrations in heavily iron-loaded, previously poorly chelated patients.~ The patients in that cohort were given deferiprone therapy at a dose of 75 mg/kg/day for a mean of 3.1 ± 0.3 years. in 10 patients in whom previous chelation therapy with desferrioxamine had been ineffective, initial hepatic iron concentrations decreased from a mean of 125.3 :!: 11.5 to 60.3 :!: 9.6 µ.mol/g wet weight (P < 0.005). Jn the remaining 11 patients, previously effectively chelated and with initial liver iron less than 80 µ.mol/g wet weight, the liver iron remained below this level. Hepatic iron concentrations below 80 µ.mol/g wet weight are associated with prolonged survival free of clinical complications from iron overload in thalassemia patients treated with desferrioxamine.22

Improvement in Organ Function

Lightening of skin color occurring within a few months of initiating chela­tion with deferiprone was observed in heavily pigmented, previously inade­quately chelated patients.J. 1~

Improvement in cardiac function assessed by radionuclide angiography was observed in one patient with an established iron-related cardiomyopathy. This was associated over a 1-year period of study with a decrease in cardiac iron measured by MR imaging.;.i Jn the prospective study of deferiprone in 21 patients with thalassemia,si a reduction in card iac stores has been observed53 by cardiac MR imaging eva luation. ln other studiesJ~ no overall change in cardiac function assessed by multiple gated acquisition (MUGA) scanning occurred among 31 patients treated for a year (Al-Refaie et al, unpublished data). Because the leading cause of death in iron-loaded patients2' is cardiac iron loading, the ability to prevent and reverse cardiac iron loading is crucial for any iron chelator.

In two patients with thalassemia treated with deferiprone, changes consis­tent with the reduction of anterior pituitary iron were demonstrated by MR imaging.53

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240 DIA V-CITRL'J & KOREN

Progressive decline in serum aspartate aminotransferase level has been reported in some patients during long-term deferiprone treatment.1·•.n

Changes in Non-Transferrin Bound Iron

Non-transferrin bound iron (NTBI) is a form of iron present in the serum of heavily iron-loaded patients.30 It is believed to be involved in free-radical formation and hence tissue toxicity.31 The concentration of NTBI has been found to correlate with the degree of organ damage in thalassemia major. Serum NTBI dropped significantly after 6 months of deferiprone therapy. TB! was sug­gested as an independent parameter to measure the effectiveness of chelation.'°

Adverse Effects

Deferiprone is generally well tolerated with no significant acute toxic effects at doses up to 150 mg/kg daily. Excellent compliance with the treatment has been reported in most patients.54

• 62 There have been several reports of side

effects, however, the most important of which are agranu locytosis and arthropa­thy.

Neutropenia and Agranulocytosis

The first reported toxic effect of deferiprone was agranulocytosis in a woman with Blackfan-Diamond anemia.36 To date, there have been 13 patients in whom neutropenia or agranulocytosis has been reported (11 of whom had neutrophil counts of 0.5 x 10• /Lor less at the time of diagnosis).2· 11 n 2'1." The overall incidence of agranulocytosis has been estimated at approximately 2% of long-term treated patients.13 Agranulocytosis has been observed as early as 6 weeks, and up to 21 months, after initiating therapy with deferiprone. The periods of neutropenia and of total agranulocytosis have ranged from 7 to 124 days and up to 7 weeks, respectively. Three patients have received at least one course of granulocyte colony-stimulating factor during their course of neutro­penia:i.; in an attempt to accelerate recovery. The dose of deferiprone in these patients has ranged from 50 to 105 mg/kg. The patients suffered from thalas­semia major, Blackfan-Diamond anemia, and myelodysplasia. Females tended to predominate (9/13) and, in general, the patients have been heavily iron­loaded. Rechallenge has invariably led to a second episode of neutropcnia and should be avoided.

The mechanism for the neutropenia or agranulocytosis associa ted with deferiprone administration remains obscure.12- 13 It seems most likely that the patients affected have an idiosyncratic sensitivity to a toxic effect of deferiprone or one of its metabolites. Deferiprone-associated neutropenia or agranulocytosis appears to be fully reversible to date.

Arthropathy

The second most important adverse effect and the most common clinical problem associated with deferiprone treatment is joint toxicity, first described by Bartlett et al.1' Studies have reported an incidence in up to 38°0 of patients.' 3• 14•

14 The reported incidence of arthropathy from the International Collaborative

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ORAL IRON CHELATION WITH OEFl:.RIPRONE 241

Study Group, however, was 21 %.• The arthropathy or lesser degree of joint pain may occur within a few weeks after initiation of therapy with deferiprone. The syndrome consists of musculoskeletal stiffness, joint pain, and, in severe cases, joint effusions. The large joints are primarily affected. In the Indian trial, the incidence was greatest in the most iron-loaded patients receiving the largest dose of the drug (100 mg/kg/day).1' In most patients, the symptoms and signs resolved spontaneously on discontinuation of the drug or following dose reduction. In a minority of patients who developed severe arthropathy the drug had to be permanently discontinued. Arthroscopy in seven affected patients in Bombay revealed excess iron in the synovium, cartilage, and joint fluid but no deferiprone, implying that iron may be involved in the cause of the problem.• In the Canadian study, aspiration of synoviaJ fluid in three patients revealed a sterile transudate without inflammatory celJs; arthroscopy showed mild synovial hypertrophy and hyperplasia with iron staining; and synovial biopsy revealed lining-cell proliferation and extensive iron deposition without evidence of an inflammatory or allergic reac t1on.1q In two patients, symptoms resolved during continued drug administration whereas the third has continued therapy without worsening of the symptoms.'~

The cause of the deferiprone-associated arthropathy is still not fully known. The arthri tis seems to be due to a toxic effect of deferiprone, possibly mediated by free radicals, caused by formation of 1:1 or 1:2 deferiprone-iron complexes rather than the usual inert 1:3 complexes. It has been hypothesized that as iron is shifted into the synovium and incompletely complexed with deferiprone, increased production of free radicals may result in the peroxidation of synovial membranes. No relation to the presence of antinuclear factor antibody, rheuma­toid factor, antihistone antibody, or antiDNA antibody in the patient's plasma before or during deferiprone treatment has been consistently detected. The overall incidence of a positive rheumatoid factor test in patients with deferiprone long-term treatment has been estimated to increase from 13.9% to 16.2% and the incidence of antinuclear factor from 9.8% to 11.9%; minor fluctuations in the titer of these antibodies were observed.7· ~

Other Adverse Effects Reported with Deferiprone

A decrease in the concentration of zinc in plasma and increased urinary zinc excretion in patients receiving long-term deferiprone therapy were first reported by Al-Refaie et al. 14 In 8 of 10 patients on deferiprone treatment, increased urinary zinc excretion was found associated with a decrease in the serum zinc concentration to subnormal levels in four patients. One patient developed dry, scaling skin lesions tha t were ascribed to zinc deficiency and responded to zinc therapy. A few cases with zinc depletion have been reported by others.•· ici. 33 Al-Refaie et all~ have shown that deferiprone causes increased urinary zinc excretion, particularly in patients with diabetes meUitus and to a lesser extent in patients with glucose intolerance. Decreased serum zinc levels were found in 7 of 39 patients treated with deferiprone for at least 6 months. In other studies no changes in serum zinc status have been reported. The observed difference may be partly due to the absence of diabetic patients from some trial groups. Serum zinc estimation has limited value in assessing zinc deficiency. Patients with normal zinc concentrations may be z inc deficient and subnormal serum zinc is only suggestive of zinc deficiency.1

"' The reported incidence of zinc deficiency from the International Collaborative Study Group was 14'Yo.1'

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242 DIAV-CrrRIN & KOREN

Zinc deficiency is not a major adverse effect of deferiprone therapy. It can be readily detected and easily treated.

Gastrointestinal symptoms have been reported with deferiprone therapy. Symptoms include anorexia, nausea, and vomiting.1

· " · 14 '~ In some patients the gastrointestinal symptoms were a cause of discontinuing therapy. The reported incidence of nausea from the International Collaborative Study Group on oral iron chelation was 8% of patients.•

Fluctuations in liver function during dcferiprone treatment were first re­ported by Barllctt.17 Elevated liver function tests <1ppeared to be more frequent in patients infected with hepatitis C. In all cases the ra ised serum transaminase levels gradually settled to pretreatment levels or lower after 3 months of therapy. More recently, the incidence of abnormal liver er1zymes, defined as an increase of more than twice the upper limit of normal serum alanine aminotransferase (ALT) at any time during the observation period, was SO of 84 patients (60%) in combined data from four centers.0 Nine of the SO had hepatitis C and three had raised scrum ALr before initiating defcriprone therapy. ln 37 of the remaining 38, liver abnormalities were mild and transient, resolving spontaneously without reducing or discontinuing defcriprone therapy. In one patient abnormal liver enzymes were considered to be related to defcriprone and they fell to pre­dcfcriprone levels on cessation of deferiprone therapy.

ACUTE IRON POISONING

iron intoxication remains a common and serious form of accidental poison­ing, especially in children. Recently, there has been an increased number of reported iron intoxications;~ as well as increa!>ed mortality related to acute iron poisoning.~'

Dcsfcrrioxamine has been used as a potent chclator in the context of acute iron poisoning . ..,· 71 It is currently the most effective agent in eliminating excess iron after its absorption.~• Dcsfcrrioxaminc, however, is limited to use in coun­tries that can afford it. For use in the treatment of acute iron poisoning, it is further limited to use in a hospital setting. Defcriprone may have a potential use in the treatment of acute iron intoxication in remote areas, far away from a medical center, as well as in countries where dcsfcrrioxamine is unavailable. Deferiprone was shown to be efficacious in the treatment of acute iron intoxica­tion in an animal model.28

Desfcrrioxamine has been reported to have adverse effects, such as hypoten­sion in the context of acute iron intoxication. Desfcrrioxamine covillcntly attached to high- molecular weight carbohydrates s uch as dcxtran and hydroxy­ethyl starch prevented the decrease in blood pressure that may occur with large desferrioxamine doses in experimental animals.•1 It was generally less toxic than the free desferrioxamine when given intravenously.

NOVEL USES OF IRON CHELATION

Protection from acute and chronic iron toxicity is only one aspect of the clinical potential of iron chelation therapy. 1 here are three categories of diseases unrelated to iron toxicity in which chelation therapy may be considered poten­tially useful by interfering with iron dependent reactions.

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ORAL IRON Cl IELA rlOI\ WITH DEfERIPRO'JE 243

Diseases in Which Iron May Be Essential for the Production of Free Radicals Involved in Tissue Damage

The number of diseases known to be associated with oxygen radical damage in which treatment with iron chelators may be beneficial is increasing each year. The diseases include rheumatoid arthritis,1>1 adult respiratory distress syn­drome,""' anthracycline cardiotoxicity,'\2 postischemic reperfusion injury,'~ and others. Tron-chelation therapy might be of benefit if given in these conditions; clinica l trials are underway.

Diseases in Which Iron Depletion May Interfere with Cell Division

Several studies have suggested that available iron may have a role in promoting cell growth. Another study demonstrated the antitumor activity of desferrioxamine, especially in patients with neuroblastoma in whom ferritin is in part tumor-derived and high concentrations correlate with poor outcome.2r,

Malaria continues to represent a serious global health hazard. New stra ins of l?lns111odi11111 fnlcipnrnm have emerged, resistant to conventional antima larial drugs. It is estimated that 300 million patients worldwide suffer from malaria yearly.7'

The pathogenicity of P. Jnlciparnm is related to its abi lity to reproduce rapid ly. ln the asexual erythrocytic stage of its life cycle, which is responsible for the clinical manifestations, a single merozoite invades the red blood cell, matures into a trophozoite, and undergoes DNA replication to give rise to up to 32 daughter cells in just 48 hours. Iron is req uired for a number of the parasite enzyme systems necessary for this explosive growth and proliferation. In addi­tion, the iron-dependent enzyme ribonucleotide reductase, a rate-limiting en­zyme in DNA synthesis, has been considered a potential site of action for an iron-chelating agent. Withholding iron from the parasite by iron chelators could be expected to inhibit parasitic growth, and studies in vitro and in animal models have shown that this is the case. Evidence now exists that iron chelation therapy has clinical activity in both uncomplicated and severe malaria.46

Porphyria: Iron Depletion May Promote Porphyrin Breakdown

Porphyria cutanea tarda is an inherited disease characterized by a deficiency of uroporphyrinogen decarboxylase. Desferrioxamine may be a reasonable alter­native to phlebotomy in the treatment of the disease.ro

SUMMARY

Deferiprone is the most widely studied oral iron chelator and, at present, the only one shown to be effective in achieving negative iron balance in long­term clinical trials for chronic iron overload. Because of its adverse effects (e.g., agranulocytosis and arthropathy) its use is presently restricted to clinical trials and to countries where desferrioxamine is unavailable. Deferiprone was licensed for clinical use in India in 1995. Clinical trials are in progress in many centers worldwide that will provide further information on the long-term effectiveness

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244 OlAV-CITRIN & KOREl\

of deforiprone as well as on the incidence of -.criou ... adn·r~· cfft'Ct ... m p.1tu:nt ... \\ ith iron overload. Trials of combined use of deferiprone and dcsforriox.1min..: are also in progress. In the meantime, deferipmne ..... m acceptable .1llL'm.11" l' for patient.., who cannot use desferrioxamine bt-c.1use of ... eriou .... 1d\ t'rse effect ... , lad. of compliance, or unavailability. Elucidation of tht• mt>chanbms imolved in the agranulocytosis and arthropathy associatt>d \\ ith defcriprone 1s still nt-eded, as are methods to predict indh idual su!><:eptibility to these ,1Jvt?r::.e effects and ways of preventing them. In addition, new indications for iron­chelating therapy are continuously being explored.

References

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2. Agarwal MB, Gupte SS, Viswanathan C, c t ell. Clinic.1llv si~mficant l1l't1lropcni.1 !>Ccondnry to L, therapy in iron-loadLoJ thalas:.cmic-. i'> a r.1rc .ind rcvcrMblc C\Cnl Abstract of the Fourth lntemahonal Conference on O r.11 Chcl.1 tion, Bomb.1y. lndi.1, 1993, p 62

3. Agarwal MH, Guptc SS, Vbwan,1lhan C, ct JI· Long tcrm il''l"''>ml•nt of cHic:.1cy .mJ snfctv o( L,, an o ra l iron cheleltor in triln:>fu,ion·de~ndent th.1l.1sscm1.1 lndi,1n tri.11. Br J I lilematol 82:-160-166, 1992

-I Agarwal MB, Cupte SS, Viswanelthiln C. ct .11: Long-term dfic.1C\ .rnd to,icity nf L · o ra l iron c:hcla tor in transfusion-dependent th.1la~"4!m1<' OH'r thl• la<,t thn-e }'•'M' Abstract o( the Fifth International Confcrcncc on Th.1la~mia~ and I lacm1~lobinop.1-thics, icosia, Crete, 1993, p 192

5. Agan"al "'18, Viswanathan C, Ramanilthan J, ct al: Oral iron lhclahon with L Lmcct 335:601, 1990

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12. Al-Rcfaie F , Wilkes S, Wonke B. ct al: The dfoct of ddcripronc (L,) elnd de;.fl•rrio,a· mine on myclopoicsis using a liquid culture ")"•tcm. Br I HacmJtol 87·19~ 198, 1994

13. Al-Rcfoic FN, Wonke B, Hoffbrand AV· Dcfcripronc-.1.,.,ociatcJ m}cloto\icity. fur J liaematol 53:298-301, 199-1

14. Al-Rcfoic F 1, Wonke B, Hoifbrilnd AV, ct .11: Efficacv and po-.sibk• .1d\ l'™-' cffoct:. of the oral iron chelator l,2-dimclhyl-3-hydro'YP> ml -I-one (L,) in th.11.l'>~cmi.1 m.11or Blood 80:593-599, 1992

15. Al-Refaie F , Wonkc B, Wickens DC, et .11: Linc con,cntrahon in pahcnb \\1th mm O\Crload rccci1 ing oral iron chelato r, l,2-dimcthyl-3 hydro,yp~ rid--1-(>nL' o r dl":>fcrri· o'aminc. J Clin Pathol -17:657-660, 199-1

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ORAL IRON CHELATlON WITH DFFFRIPRONE 245

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17. Bartlcll AN, Hoffbrand AV, Kontoghiorghcs GJ: Long-term tria l with the oral iron chclator l,2-dimethyl-3-hydroxypyrid-4-onc (L,). II. Clinical observations. Br J Haema­tol 76:301-3().t, 1990

18. Bel A, Martinod E, Menasche P: Cardioprotective effect of dcsforrioxamine. Acta Haematol 95:~5, 1996

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21. Bri ttenham GM, Cohen AR, McLaren CE, et al: Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Haematol 42:81-85, 1993

22. Brittenham GM, Griffith PM, Nienhuis AW, et al: Efficacy of deferoxamine in pre­venting complications of iron overload in patients with thalassemia major. N Engl J Med 331:567-573, 1994

23. Collin!> AF, Fassos F, Stobie S, et al: Iron balance and dose response !>tudies of the o ral iron chelator l,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with s icl-.le cell disease. Blood 83:2329-2333, 1994

24. Cunningham JM, Al-Refaie FN, Hunter A, et a l: Differential toxicity of a-ketohydroxy­pyridine iron chclators and desferrioxamine to human hemopoietic precursors in vitro. Eur J Haematol 52:176--179, 1994

25. Donfrancesco A, Deb G, DeSio L: Role of deferoxamine in tumor therapy. Acta Haematol 95:66-69, 1996

26. Engle MA, Erlandson M, Smith CH: Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis. Circulation 30:698-705, 1964

27. Evans RW, Sharma M, Ogwang W, et al: The effect of a-ketohydroxypyridine chela­tors on transferrin saturation in vi tro and in vivo. Drugs of Today 28(suppl): l 9-23, 1992

28. Fassos FF, Berkovitch M, Daneman N, et al: Efficacy of deferiprone in the treatment of acute iron intoxication in rats. Clin Toxicol 34:279-287, 1996

29. Goudsmit R, Kersten MJ: Long-term treatment of transfusion hemosiderosis with the oral iron chelator L1• Drugs of Today 28(supp1):133-135, 1992

30. Gutteridge JMC, Rowley DA, Griffiths E, et al: Low-molecular weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis. Clin Sci 68:463-467, 1985

31. Halliwell B, Gulleridge JMC: Oxygen, free radicals, and iron in relation to biology and medicine: Some problems and concepts. Arch Biochem Biophys 246:501-514, 1986

32. Hcrshko C, Pinson A, Link G: Prevention of anthracycline cardiotoxicity by iron chelation. Acta Haematol 95:87- 92, 1996

33. Hider RC, Kontoghiorghes GJ, Silver J: UK Patent: GB-2118176, 1982 34. Hileti D, l'anayiotidis P, Hoffbrand AV: Iron chelators induce apoptosis in proliferat­

ing cells. Br J Haematol 89:181-187, 1995 35. Hoffbrand AV: Oral iron chelation. Semin Hematol 33:1-8, 1996 36. Hoffbrand AV, Bartlett AN, Veys PA, et al: Agranulocytosis and thrombocytopenia in

patient with Bh1ckfan-Diamond anaemia during ora l chelator trial. Lancet 2:457, 1989 37. Hussain MAM, Flynn DM, Green N, ct al: Subcutaneous infusion and intramuscular

injection of desferrioxamine in patients with transfusiona l iron overload. Lancet 1:977-979, 1976

38. Jaeger M, Aul C, Sohngen D, et al: Iron overload in polytransfused patients with MDS: Use of L, for oral iron chelation. Drugs of Today 28(suppl):l43-147, 1992

39. Keberle H: The biochemistry of desferrioxamine and its relation to iron metabolism. Ann N Y Acad Sci 119:758-768, 1964

40. Kline MA, Orvig C: Complexation of iron with the orally active decorporation drug L, (3-hydroxy-1,2-dimethyl-4-pyridinone). Clin Chem 38:562-565, 1992

41. Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, et al: Effective chelation of iron in

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246 DIA V-CITKIN & KOREN

13-thalasscmia wilh the oral chclator 1.2-dimclhyl-3-hydroxypyrid-4·one. BM) 295:1509-1512, 1987

42. Kontoghiorghcs CJ, Aldouri MA, Sheppard LN, ct al: l,2-dimethyl-3-hydroxypyrid· 4-one, an orally active chelator for the treatment of transfusional iron overload. Lancet 1: 1294-1295, 1987

43. Kontoghiorghcs GJ, Bartlett AN, Hoffbrand AV, cl al: Long·tcrm trial with th~ oral iron chelalor 1.2-dimethyl-3-hydroxypyrid-4-onc (L,). I. Iron chelation and metabolic studies. Br) Haematol 76:295-300, 1990

44. Kontoghiorghes CJ, Goddard G, Bartlett AN, ct al: Pharmacokinetic studiel> in hu­mans with the oral iron chelator l.2-dimethyl-3-hydroxypyrid-4-one. Clin Pharmacol Ther 48:255-261, 1990

45. Litovitz TL, Holm KC, Clancy C, et al: 1992 Annual Report of the American Associa­tion of Poison Control Centers Toxic Exposure Surveillance System. Am) Emerg Med 11:494-555, 1993

46. Mabeza CF, Biemba G, Gordeuk VR: Clinical studies of iron chelators in malari;i. Acta Haematol 95:78-86, 1996

47. Mahoney JR, Hallaway PE, Hed land BE, et al: Acute iron poisoning: Rescue with macromolecular chclators. J Clin Invest 84:1362- 1366, 1989

48. Marx )JM, Van-Asbeck BS: Use of iron chelators in preventing hydroxyl radical damage: Adult respiratory distress syndrome as a model for the pathophysiology and treatment of free radical-mediated tissue damage. Acta Haematol 95:49-62, 1996

49. Matsui D, Klein J, Hermann C, et al: Relationship between the pharmacokinetics and iron excretion pharmacodynamics of the new oral iron chelator l,2-dimcthyl-3-hydroxypyrid-4-one in patients with thalassemia. Clin Pharmacol Tuer 50:294-298, 1991

SO. McEncry JT, Greengard J: Treatment of acule iron ingestion with defcrox.imine in 20 children. J Pcdiatr 68:773-779, 1966

51. Meyer-Brunot HG, Keberle H: The metabolism of desferrioxamine B. Biochem Phar­macol 16:527-537, 1967

52. Neuman MC, Klein J, Koren G, et al: Oral iron chclator L, induces its metabolism in vitro in human hepatocyte Jines. /11 Proceedings of lhc Sixteenth World C(mgrcss of Ana tomic and Clinical Pathology, Vancouver, 1991, p 15

53. O livieri NF, Beluzzo N, Muraca M. et a l: Evidence of reduction in hep;itic, cardiac, and pituitary iron stores in patients wilh thalassemia major during long-term lhNapy with the orally active iron chelating agent L1• Blood 84(suppl):l09, 1994

54. Olivieri NF, Brittenham GM. Matsui D, ct al: Iron chelation therapy with oral dcfori · prone m patients with thalassemia major. N Engl J Med 14:918-922, 1995

55. Olivieri NF, Buncic JR, Chew E, et al: Vi~ual and auditory neurotoxicity in patients receiving subcutaneous defcroxamine infusions. N Engl J Med 314:869-873, 1986

56. Olivieri NF, Harris J, Koren G, et al: Growth failure and bony changt'S induced by defcroxaminc. Am J Pediatr Hematol Oncol 14:48-56, 1992

57. Olivieri NF, Koren G, Hermann C, et al: Comparison of oral iron chelator L ,md desfcrrioxamine in iron-loaded patients. Lance! 336:1275-1279, 1990

58. Olivieri NF, Koren G, Matsui l), el al: Oral iron chelation with 1,2-dimethyl-J­hydroxypyrid-4-one (L1) in thalassemia major: One-year com parison with subcutant~ ous desfcrrioxamine. Blood 78(suppl):369, 1991

59. Olivieri NF, Koren C, Matsui D, et al: Reduction of tissue iron stores and normaliza­tion of serum ferritin during treatment with the oral iron chclator L, in th;ila~scmia intermedia. Blood 79:2741-2748, 1992

60. Olivieri NF, Matsui D, Berkovitch M, et al: Superior effectiveness of the oral chclator versus subcutaneous desferrioxamine in patients with homoqgous beta tha l.w,cmia (1 IBT): The impact of patient compliance during 2 years of therapy. Blood 80(suppl):344, 1992

61. Olivieri NF, Nathan DC, MacMillan JI I, ct al: Survival in medically treated patients with homozygous 13-thalassemia. N Engl J Med 331:574-578, 1994

62. Olivieri NF, Sher GD, MacKinnon )A, ct al: The first prospective randomized I rial of subcutaneous deferoxamine and the orally active iron chelating agenl L,. Blood 84(suppl):363, 1994

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ORAL IRON Cl !ELATION WITH L>EFERIPRONE 247

63. Peters C, Keberle H, Schmid K, et al: Distribution and renal excretion of desferrioxa­mine and ferrioxamine in the dog and in the rat. Biochem Pharmacol 15:93-109, 1966

64. Polson RJ, Jawad ASM, Bomford A, el al: Treatment of rheumatoid arthritis with desferrioxamine. QJM 61:1153-1158, 1986

65. Porter JB: Evaluation of new iron chelators for clinical use. Acta Haematol 95:13-25, 1996

66. Porter JB, Huehns ER: The toxic effecls of desferrioxamine. Clin l laematol 2:459-.J74, 1989

67. Porter JB, Huens ER, Hider R: The development of iron chelating drugs. Baillieres C lin Hnematol 2:257-292, 1989

68. Propper RD, Cooper B, Rufo R, e t al: Contiirnous subcutaneous adminis tration of desferrioxamine in patients with iron overload. N Engl J Med 297:418-423, 1977

69. Proudfoot AT, Simpson D, Dyson EH: Management of acute iron poisoning. Med Toxicol 1:83-100, 1986

70. Rocchi E, Cilberlini P, Cassanelli M, et al: Iron removal therapy in porphyria cutanea tarda: Phlebotomy versus slow subcutaneous desferrioxarnine infusion. Br J Dermatol 114:621-629, 1986

71. Shalev 0, Repka T, Goldfarb L, et al: Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells both in vitro and in vivo. Blood 86:2008-2013, 1995

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73. Weslin WF: Deferoxamine in the treatment of acute iron poisoning. Clinical experi­ence wilh 172 ch ildren. C lin Pediatr 5:531- 535, 1966

74. Wohler F: The treatment of haemochromatosis with desferrioxamine. Acta Haemalol 30:65-87, 1963

75. Wyler DJ: Bark, weeds, and iron chelators-drugs for malaria. N Engl J Med 327:1519-1521, 1992

Address reprint requests to Gideon Koren, MD, ABMT, FRCPC

Division of Clinical Pharmacology/Toxicology The Hospital for Sick Children

555 University Avenue Toronto, Ontario

MSC 1X8 Canada

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NEW FRONTIERS IN PEDIATRIC DRUG THERAPY 0031-3955/97 $0.00 + .20

ORAL IRON CHELATION WITH DEFERIPRONE

Oma Diav-Citrin, MD, and Gideon Koren, MD, ABMT, FRCPC

Patients with refractory anemias, such as thaJassemia major, who require regular red blood cell transfusions progressively accumulate iron. Each unit of red blood cells contains 200 to 250 mg of elemental iron and thus, patients on chronic transfusion programs accumulate approximately 0.5 mg/kg/day of iron. Tissue iron accumulation results in progressive organ dysfunction, leading to death if no iron-chelating therapy is initiated. Although transfusions sustain normal growth and development and improve the life expectancy of patients, they are complicated by the harmful consequences of iron overload because humans lack a physiologic mechanism for excreting excess iron.

Iron-chelating therapy for the management of transfusional iron overload was first introduced in the early 1960s.39•

5•, 63• 74 It is only since 1974, after the

demonstration that it was possible to reduce the concentration of hepatic iron and arrest the progression of hepatic fibrosis in thalasseniic patients with its long-term use,16 that desferrioxamine gained acceptance as the standard form of therapy. Unfortunately, desferrioxamine is only effective when administered parenterally. Subcutaneous doses of 20 to 40 mg/kg/day for 8 to 12 hours resulted in iron excretion sufficient to produce a negative iron balance.37• 68

Over the past two decades, several studies have demonstrated that regular desferrioxamine therapy ameliorates hepatic, cardiac, and endocrine dysfunc­tion, improves growth and sexual maturation, and prolongs survival in iron-loaded patients.22• 61 .

Because of its high cost (approximately $40 US/2 g vial), desferrioxamine is not available in many countries where it is most needed. Even where it is available, many patients faiJ to comply with a regimen of prolonged subcutane­ous infusions, especially during adolescence. Other problems with desferrioxa­mine therapy include its serious adverse effects. Intensive therapy in young

This work was supported by an MRC-Industry grant and by Apotex, Inc, Toronto.

From the Division of Clinical Pharmacology and Toxicology, Department of Pediatrics (ODC, GK), and Research Institute (GK), The Hospital for Sick Children; and the Departments of Pediatrics, Pharmacology, and Medicine, University of Toronto, To­ronto, Ontario, Canada

PEDIATRIC CLINICS OF NORTH AMERICA

VOLUME 44 • NUMBER 1 • FEBRUARY 1997 235

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236 DIA V-CITRIN & KOREN

H\N /CONH\ /CONH\

(C\Hvs /

(CH2h (C\H.Js (CH.J2

(CHvs CH3

I \ I N- C N- C N-C

I II I II I 11 OH 0 OH 0 OH 0

Figure 1. Chemical structure of desferrioxamine.

patients with low body-iron stores may result in serious neurotoxicity (audi­tory and visual), abnormalities of cartilage formation, and stunted linear growth.sS-56. 66

In the last decade we have witnessed the emergence of ·interest in oral iron chelation for transfusional iron-loaded patients in thalassemia and other refractory anemias. Currently, the orally active iron chelator with the broadest clinical experience is deferiprone (l,2-dimethyl-3-hydroxypyrid-4-one, or L1)· The agent is a member of the hydroxypyridones of bidentate (two binding sites) iron chelators patented by Hider et al33 in 1982 as an alternative to desferrioxa­mine in the treatment of chronic iron overload.

11lis article summarizes the experience with this new, orally active iron chelator, deferiprone. In addition, it reviews novel uses of iron chelation and potential new applications in acute iron poisoning.

STRUCTURAL COMPARISON BETWEEN DESFERRIOXAMINE AND DEFERIPRONE

Desferrioxamine (Fig. 1), a trihydroxamate siderophore derived from Strep­tomyces pilosus, is a hexadentate chelator.39 It is capable of combining with ferric iron at a 1:1 molar ratio because of its six binding sites with a high stability constant (1031

). The desferrioxamine molecule is wrapped around the iron nu­cleus, encasing it in an envelope of organic material. Because of its high molecu­lar weight, desferrioxamine is poorly absorbed from the gastrointestinal tract, and is therefore administered parenterally.

Deferiprone (Fig. 2) is a bidentate ligand. Therefore, three chelator molecules are required to form a neutral complex with a single iron atom.

The hexadentate chelators are inherently more stable kinetically than biden­tate chelators. The greater stability of the hexadentate molecules minimizes the risk of iron redistribution or the participation of unstable iron-chelate complexes

0

CH3

Figure 2. Chemical structure of deferiprone.

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ORAL IRON CHELATION WITH DEFERIPRONE 237

~ the generation of hai:mful free radicals; they also have the ability to scavenge iron at low concentrations. On the other hand, bidentate compounds have a lowe~ molecular weight and are usually easily absorbed from the gut. Because of this: ho~ever, they are able to penetrate other cells more quickly with the potential nsk of cellular toxicity resulting from their interaction with iron­requiring enzymes.65

ORAL IRON CHELATION WITH DEFERIPRONE

Chemistry and Pharmacology of Deferiprone

Deferiprone is a white solid compound with a molecular weight of 139 kD.44 It is water-soluble with a partition coefficient (K part, the ratio of the concentrations of the compound between an organic phase and water at a pH of 7.4) dose to one.67 Deferiprone is highly stable at pH values ranging from 1 to 1244 and it is resistant to cleavage by digestive enzymes.67 It generally forms a 1:3 complex with iron with a stability constant of 36.4-0 At low concentrations of chelator, however, partially dissociated deferiprone-iron complexes (2:1, 1:1) can form and may, in turn, generate hydroxyl radicals.67 Deferiprone binds ferric iron with a high affinity (binding constant log J3 = 37).

Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. It is excreted in the urine mostly as a glucuronide or unchanged, bound to iron or bound to trace metals such as zinc and aluminum.44 Glucuronidation abolishes the ability of deferiprone to chelate iron, because the hydroxyl group of deferiprone needed for iron binding is involved in the conjugation. The excretion of deferiprone-glucuronide is slower than that of free deferiprone. In patients with impaired renal function, the glucuronide derivative may accumu­late in the plasma.9 The pharrnacokinetic characteristics of deferiprone are sum­marized in Table 1.

The efficacy of the drug in heavily iron-loaded patients, assessed by the amount of the drug excreted in urine bound to iron in 24 hours compared with the size of a single oral dose, has been estimated to be approximately 4%.9 The urinary iron excretion in heavily iron-loaded patients following a single dose is related to the area under the concentration-time curve for plasma deferiprone.

Whether deferiprone is excreted in the stools and whether or not it increases fecal iron excretion in humans remain controversial. There are reports of iron excretion in the stool of iron-loaded patients following oral administration of deferiprone amounting to up to 30% of the total iron excreted.23

•57 An~ther study9

indirectly suggested that approximately 20% of an oral dose of defenpr~ne may be excreted in the stools. Kontoghiorghes et al, 44 however, reported no increase

Table 1. A SUMMARY OF DEFERIPRONE PHARMACOKINETICS

No.of t1/.a0 Cmax t1h. AUC Study Dose Patients (minutes) (JA.g/mL) (minutes) (j.1.~lnute/mL)

Kontoghiorghes 3000 mg 7 7.1 ± 11.3 NA 74.3 ± 28.7 NA et al44

1635 ± 174.97 Matsui et af49 25 mg/kg 14 NA 17.49 ± 2.08 159.6 ± 20.5 AJ-Aefaie et al9 50 mg/kg 24 22.2 :t 17.7 20.1 ± 11.5 91.1 ± 33.1 3020 ± 1199

t1h = half-life; a == absorption; p = elimination; Cmax = maximui:n concentration; AUC = area under the plasma serum concentration-time curve from time zero to infinity; NA = not available

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238 DIA V-CITRIN & KOREN

in iron excretion and no evidence of deferiprone in the stools of two patients with iron overload given deferiprone.

Several factors may influence deferiprone pharmacokinetics and efficacy. Food prolongs the rate of absorption of deferiprone but it does not signifi­

cantly affect the extent of absorption measured by the area under the plasma concentration-time curve. Thus, food does not change the chelation capacity of the drug.49

Vitamin C was found to have no effect on urinary iron excretion in two small trials.72 The exact effect of vitamin C therapy, however, both in vitamin C replete and deficient patients is yet to be determined.

No increase in the urinary iron excretion was found in two normal vo]un­teers when deferiprone complexed to iron was administered orally.57

There has been some evidence that long-term treatment with deferiprone may be associated with a fall in the deferiprone trough concentrations.49 The findings suggest self-induction of deferiprone metabolism or decreased absorp­tion during long-term therapy. The former is supported by the results of an in vitro study that has shown that deferiprone induces its own metabolism by human hepatocytes in culture.52

The sites from which deferiprone chelates iron are not fully established. Animal studies have shown that deferiprone concentrates mainJy in the liver.34

Because free deferiprone readily enters cells, it is likely that both parenchymal and reticuloendothelial cells are sources of chelated iron. Unlike desferrioxa­mine, deferiprone can also chelate iron from transferrin9· v and, based on studies of iron-loaded patients, it is estimated that up to 20% of iron excreted in the urine following a single oral dose may be derived from iron bound to trans­ferrin.9 Deferiprone also chelates iron from intact red cells that may be important in the therapeutic response to deferiprone in thalassemia intermedia.71

Clinical Trials of Deferiprone

The results of the first clinical studies on the efficacy of deferiprone in patients with myelodysplasia and thalassemia major were reported in 1987.41

' 42

They showed that deferiprone could induce urinary iron excretion comparable to that achieved with desferrioxamine. Iron excretion correlated to the iron burden. Subsequent short-term clinical trials have confirmed those preliminary findings.5

• n Dose-response studies have shown that 75 mg/kg body weight was the minimal daily dose required to achieve a negative iron balance (>0.5 mg/ kg/ day) in most patients with thalassemia major.57 These findings, confirmed in a later comparison study between deferiprone and desferrioxamine23 in sickle­cell disease, provide evidence that short-term efficacy of deferiprone is inferior to that of desferrioxamine. Long-term trials of deferiprone have shown long­term effectiveness of deferiprone in the majority of patients with transfusional iron overload.3•

17•

43• 54• n These studies have also provided information on a

number of adverse effects that were not apparent in the initial short-term trials.

Changes In Serum Ferritin Concentrations

Significant decreases in serum ferritin were reported in most of the long­term clinical sludies3' 58• 60 but not in all of them.29• 43• 72 Those trials were different in their design in many aspects: the duration of deferiprone treatment before repeated serum ferritin assays were conducted; different administered doses of

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ORAL IRON CHELATION WITH DEFERIPRONE 239

deferii;>rone; _the numb7r of patients entering the studies after being poorly compliant with desfernoxamme and, thus, starting with high serum ferritin le~e~; and the degree ~f c~rnpliance with deferiprone therapy. One prospective trial showed a reduc~1on 111 the mean serum ferri~ level from approximately 400? . µg/L to approxnnate1y 2500 µg/L, whereas m all patients with initial fernt~ levels below 2500 µ.g/L there was no change. This may suggest that defenprone can reduce serum ferritin to the range associated with cardiac disease-free survival in desferrioxamine-treated patients or maintain it in that range.22

Reduction in serum ferritin concentration suggests a decline in body iron burden during long-term oral chelation with deferiprone. Serum ferritin levels may be misleading in the assessment of iron burden in individual patients,21

however, because serum ferri tin is also influenced by other factors such as hemolysis, ineffective erythropoiesis, vitamin C deficiency, inflammation, and liver disease, all of which are common in iron-loaded patients.

Changes in Hepatic Iron Concentration

Initial evidence that therapy with deferiprone may reduce tissue iron stores was provided by a study of an iron-loaded patient with thalassemia intermedia in whom stores were reduced to normal over a period of 9 months.59

This was subsequently followed by a report of a significant decrease in hepatic iron concentrations in heavily iron~loaded, previously poorly chelated patients.54 The patients in that cohort were given deferiprone therapy at a dose of 75 mg/kg/ day for a mean of 3.1 ± 0.3 years. In 10 patients in whom previous chelation therapy with desferrioxamine had been ineffective, initial hepatic iron concentrations decreased from a mean of 125.3 ± 11.5 to 60.3 ± 9.6 µmoll g wet weight (P < 0.005). In the remaining 11 patients, previously effectively chelated and with initial liver iron less than 80 µmoll g wet weight, the liver iron remained below this level. Hepatic iron concentrations below 80 µmoll g wet weight are associated with prolonged survival free of clinical complications from iron overload in thalassemia patients treated with desferrioxamine.22

Improvement in Organ Function

Lightening of skin color occurring within a few months of initiating chela­tion with deferiprone was observed in heavily pigmented, previously inade­quately chelated patients.3•

14

Improvement in cardiac function assessed by radionuclide angiography was observed in one patient with an established iron:related cardio~yopat~y. !his was associated over a 1-year period of study with a decrease m cardiac iron measured by MR imaging.59 In the prospective study of deferiprone ii; 21 patients with thalassemia,54 a reduction in car~iac stores has been obs:rved~3 ~y cardiac MR imaging evaluation. In other s~~1~s35 no overall chan?e m cardiac function assessed by multiple gated acqws1tion (MUGA) scanning occurred among 31 patients treated for a year (Al-Refai: et al, ~publ.ish~d data). ~ecause the leading cause of death in iron-loaded patients26 is cardiac rron loading, the ability to prevent and reverse cardiac iron loading is cruci~l for any iron chelat~r.

In two patients with thalassemia treated with defenprone, changes consis­tent with the reduction of anterior pituitary iron were demonstrated by MR imaging.53

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240 DIA V-CITRIN & KOREN

Progressive decline in serum aspartate aminotransferase level has been reported in some patients during long-term deferiprone treatment.1

., 72

Changes In Non·Transferrin Bound Iron

Non-transferrin bound iron (NTBI) is a form of iron present in the serum of heavily iron-loaded patients.30 It is believed to be involved in free-radical formation and hence tissue toxicity.31 The concentration of NTBI has been found to correlate with the degree of organ damage in thalassemia major. Serum NTBI dropped significantly after 6 months of deferiprone therapy. NTBI was sug­gested as an independent parameter to measure the effectiveness of chelation.10

Adverse Effects

Deferiprone is generally well tolerated with no significant acute toxic effects at doses up to 150 mg/kg daily. Excellent compliance with the treatment has been reported in most patients.54•

62 There have been several reports of side effects, however, the most important of which are agranulocytosis and arthropa­thy.

Neutropenfa and Agranulocytosfs

The first reported toxic effect of deferiprone was agranulocytosis in a woman with Blackfan-Diamond anemia.36 To date, there have been 13 patients in whom neutropenia or agranulocytosis has been reported (11 of whom had neutrophil counts of 0.5 x 109 /Lor less at the time of diagnosis).2• 1

1• 13• 29• 3

5 The overall incidence of agranulocytosis has been estimated at approximately 2% of long-term treated patients.13 Agranulocytosis has been observed as early as 6 weeks, and up to 21 months, after initiating therapy with deferiprone. The periods of neutropenia and of total agranulocytosis have ranged from 7 to 124 days and up to 7 weeks, respectively. Three patients have received at least one course of granulocyte colony-stimulating factor during their course of neutro­penia35 in an attempt to accelerate recovery. The dose of deferiprone in these patients has ranged from 50 to 105 mg/kg. The patients suffered from thalas­semia major, Blackfan-Diamond anemia, and myelodysplasia. Females tended to predominate (9 /13) and, in general, the patients have been heavily iron­loaded. RechaJlenge has invariably led to a second episode of neutropenia and should be avoided.

The mechanism for the neutropenia or agranulocytosis associated with deferiprone administration remains obscure.12- 13 It seems most likely that the patients affected have an idiosyncratic sensitivity to a toxic effect of deferiprone or one of its metabolites. Deferiprone-assodated neutropenia or agranulocytosis appears to be fully reversible to date.

Arthropathy

The second most important adverse effect and the most common clinical problem associated with deferiprone treatment is joint toxicity, first described by Bartlett et al.11 Studies have reported an incidence in up to 38% of patients.1

3• 14•

19 The reported incidence of arthropathy from the International Collaborative 23 of 30

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ORAL IRON CHELATION WITH DEFERIPRONE 241

Study Group, however, was 21%.6 The arthropathy or lesser degree of joint pain may occur wit~in a few weeks after initiation of therapy with deferiprone. The ~~ndrome .consists of musculoskeletal stiffness, joint pain, and, in severe cases, ~o~t effusions. The large joints are primarily affected. In the Indian trial, the modence was greatest in the most iron-loaded patients receiving the largest ~ose of the drug (100 mg/kg/ day).14 In most patients, the symptoms and signs resolved spontaneously on discontinuation of the drug or following dose reduction. In a minority of patients who developed severe arthropathy the drug had to be permanently discontinued. Arthroscopy in seven affected patients in Bombay revealed excess iron in the synovium, cartilage, and joint fluid but no deferiprone, implying that iron may be involved in the cause of the problem.1

In the Canadian study, aspiration of synovial fluid in three patients revealed a sterile transudate without inflammatory cells; arthroscopy showed mild synovial hypertrophy and hyperplasia with iron staining; and synovial biopsy revealed lining-cell proliferation and extensive iron deposition without evidence of an inflammatory or allergic reaction.19 In two patients, symptoms resolved during continued drug administration whereas the third has continued therapy without worsening of the symptoms.19

The cause of the deferiprone-associated arthropathy is still not fully known. The arthritis seems to be due to a toxic effect of deferiprone, possibly mediated by free radicals, caused by formation of 1:1 or 1:2 deferiprone-iron complexes rather than the usual inert 1:3 complexes. It has been hypothesized that as iron is shifted into the synovium and incompletely complexed with deferiprone, increased production of free radicals may result in the peroxidation of synovial membranes. No relation to the presence of antinuclear factor antibody, rheuma­toid factor, antihistone antibody, or antiDNA antibody in the patient's plasma before or during deferiprone treatment has been consistently detected. The overall incidence of a positive rheumatoid factor test in patients with deferiprone long-term treatment has been estimated to increase from 13.9% to 16.2% and the

..,_ incidence of anti.nuclear factor from 9.8% to 11.9%; minor fluctuations in the titer of these antibodies were observed.7· 8

Other Adverse Effects Reported with Deferiprone

A decrease in the concentration of zinc in plasma and increased urinary zinc excretion in patients receiving long-term deferiprone therapy were first reported by Al-Refaie et al.14 In 8 of 10 patients on deferiprone trea~ent, increased urinary zinc excretion was found associated with a decrease m the serum zinc concentration to subnormal levels in four patients. One patient developed dry, scaling skin lesions that were ascribed to zinc deficiency and responded to zinc therapy. A few cases with zinc deple~ion have been_ reported by others.4, 29• 38 Al-Refaie et al15 have shown that defenprone causes mcreased urinary zinc excretion, particularly in patients with diabetes mellitus. and to a lesser extent in patients with glucose intolerance. Decreased serum zmc Jevels were found in 7 of 39 patients treated with deferiprone for at least 6 months. In other studies no changes in serum zinc status have been reported. The observed difference may be partly due to the a?s~nce of dia~etic pati~nts ~om sor_n~ trial groups. Serum zinc estimation has ~nuted value 1!1 ass~s~g zinc deficiency. Patients with norma] zinc concentrations may be zmc deficient and subnormal serum zinc is only suggestive of zinc deficiency.153 The reported incidence of zinc deficiency from the International Collaborative Study Group was 14%.6

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242 DIA V-CITRIN & KOREN

Zinc deficiency is not a major adverse effect of deferiprone therapy. It can be readily detected and easily treated.

Gastrointestinal symptoms have been reported with deferiprone therapy. Symptoms include anorexia, nausea, and vomiting.3'

9,

14•

32 In some patients the gastrointestinal symptoms were a cause of discontinuing therapy. The reported incidence of nausea from the International Collaborative Study Group on oral iron chelation was 8% of patients.6

Flu.ctuations in liver function during deferiprone treatment were first re­ported by Bartlett.17 Elevated liver function tests appeared to be ~ore frequent in patients infected with hepatitis C. In all cases the raised serum transaminase levels gradually settled to pretreatment levels or lower after 3 months of therapy. More recently, the incidence of abnormal liver enzymes, defined as an increase of more than nvice the upper limit of normal serum alanine aminotransferase (ALT) at any time during the observation period, was 50 of 84 patients (60%) in combined data from four centers.6 Nine of the 50 had hepatitis C and three had raised serum ALT before initiating deferiprone therapy. In 37 of the remaining 38, liver abnormalities were mild and transient, resolving spontaneously without reducing or discontinuing deferiprone therapy. In one patient abnormal liver enzymes were considered to be related to deferiprone and they fell to pre­deferiprone levels on cessation of deferiprone therapy.

ACUTE IRON POISONING

Iron intoxication remains a common and serious form of accidental poison­ing, especially in children. Recently, there has been an increased number of reported iron intoxications,45 as well as increased mortality related to acute iron poisoning.20

Desferrioxamine has been used as a potent chelator in the context of acute iron poisoning.50• 73 It is currently the most effective agent in eliminatirtg excess iron after its absorption.69 Desferrioxamine, however, is limited to use in coun­tries that can afford it. For use in the treatment of acute iron poisoning, it is further limited to use in a hospital setting. Deferiprone may have a potential use in the treatment of acute iron intoxication in remote areas, far away from a medical center, as well as in countries where desferrioxamine is unavailable. Deferiprone was shown to be efficacious in the treatment of acute iron intoxica­tion in an animal model. 28

Desferrioxamine has been reported to have adverse effects, such as hypoten­sion in the context of acute iron intoxication. Desferrioxamine covalently attached to high-molecular weight carbohydrates such as dextran and hydroxy­ethyl starch prevented the decrease in blood pressure that may occur with large desferrioxamine doses in experimental animals.47 It was generally less toxic than the free desferrioxamine when given intravenously.

NOVEL USES OF IRON CHELATION

Protection from acute and chronic iron toxicity is only one aspect of the clinical potential of iron chelation therapy. There are three categories of diseases unrelated to iron toxicity in which chelation therapy may be considered poten­tially useful by interfering with iron dependent reactions.

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ORAL IRON CHELATION WITH DEFERIPRONE 243

Diseases in Which f ron May Be Essential for the Production of Free Radicals Involved in Tissue Damage

. ~e number of di:5ea~es known to be associated with oxygen radical damage m wh~~h treatment with rron chelators may be beneficial is increasing each year. The diseases include rheumatoid arthritis,64 adult respiratory distress syn­drome,48 anthracycline cardiotoxicity,32 postischemic reperfusion injury,18 and others. Iron-chelation therapy might be of benefit if given in these conditions; clinical trials are underway.

Diseases in Which Iron Depletion May Interfere with Cell Division

Several studies have suggested that available iron may have a role in promoting cell growth. Another study demonstrated the antitumor activity of desferrioxam.ine, especially in patients with neuroblastoma in whom ferritin is in part tumor-derived and high concentrations correlate with poor outcome.25

Malaria continues to represent a serious global health hazard. New strains of Plasmodium falciparum have emerged, resistant to conventional antimalarial drugs. It is estimated that 300 million patients worldwide suffer from malaria yearly.75

The pathogenicity of P. falciparum is related to its ability to reproduce rapidly. In the asexual erythrocytic stage of its life cycle, which is responsible for the clinical manifestations~ a single merozoite invades the red blood cell, matures into a trophozoite, and undergoes DNA replication to give rise to up to 32 daughter cells in just 48 hours. Iron is required for a number of the parasite enzyme systems necessary for this explosive growth and proliferation. In addi­tion, the iron-dependent enzyme ribonucleotide reductase, a rate-limiting en­zyme in DNA synthesis, has been considered a potential site of action for an iron-chelating agent. Withholding iron from the parasite by iron chelators could be expected to inhibit parasitic growth, and studies in vitro and in animal models have shown that this is the case. Evidence now exists that iron chelation therapy has clinical activity in both uncomplicated and severe malaria.46

Porphyria: Iron Depletion May Promote Porphyrin Breakdown

Porphyria cutanea tarda is an inherited disease characterized by a deficiency of uroporphyrinogen decarboxylase. Desferrioxamine may be a reasonable alter· native to phlebotomy in the treatment of the disease.70

SUMMARY

Deferiprone is the most widely studied oral iron chelator and, at present, the only one shown to be effective in achieving negativ~ iron balance in long­term dinical trials for chronic iron overload. Because of its adverse effects (e.g., agranulocytosis and arthropathy) its use is presently restricted to clinical trials and to countries where desferrioxamine is unavailable. Deferiprone was licensed for clinical use in India in 1995. Clinical trials are in progress in many centers worldwide that will provide further information on the long-term effectiveness

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244 DIA V-CITRIN & KOREN

of deferiprone as well as on the incidence of serious adverse effects in patients with iron overload. Trials of combined use of deferiprone and desferrioxamine are also in progress. In the meantime, deferiprone is an acceptable alternative for patients who cannot use desferrioxami.ne because of serious adverse effects, lack of compliance, or unavailability. Elucidation of the mechanisms involved in the agranulocytosis and arthropathy associated with deferiprone is still needed, as are methods to predict individual susceptibility to these adverse effects and ways of preventing them. In addition, new indications for iron­chelating therapy are continuously being explored.

References

1. Agarwal MB: Oral iron chelation: A review with special emphasis on Indian work on deferiprone (L1). Indian J Pediatr 60:509-516, 1993

2. Agarwal MB, Gupte SS, Viswanathan C, et al: Clinically significant neutropertia secondary to L1 therapy in iron-loaded thalassemics is a rare and reversible event. Abstract of the Fourth International Conference on Oral Chelation, Bombay, India, 1993, p 62

3. Agarwal MB, Gupte SS, Viswanathan C, et al: Long-term assessment of efficacy and safety of Li, an oral iron chelator in transfusion-dependent thalassemia: Indian trial. Br J Haemato) 82:460--466, 1992

4. Agarwal MB, Gupte SS, Viswanathan C, et a): Long-term efficacy and toxicity of L,­oral iron chelator in transfusion-dependent thalassemics over the last three years. Abstract of the Fifth International Conference on Thalassemias and Haemoglobinopa­thies, Nicosia, Crete, 1993, p 192

5. Agarwal MB, Viswanathan C, Ramanathan J, et al: Oral iron chelation with L1• Lancet 335:601, 1990

6. Al-Refaie FN, Hershko C, Hoffbrand AV, et al: Results of long-term deferiprone (L1) therapy: A report by the International Study Group on Oral Iron Chelators. Br J Haematol 91:224-229, 1995

7. Al-Refaie FN, Hoffbrand AV: Oral iron-<:helating therapy: The L1 experience. Bailliere's Cl.in Haernatol 7:941- 961, 1994

8. Al-Refaie FN, Hoffbrand AV: Oral iron chelation therapy. Recent Advances in Haem­atology 7:185-216, 1993

9. Al-Refaie FN, Sheppard LN, Nortey P, et al: Pharmacokinetics of the oral iron chelator deferiprone (Li) in patients with iron overload. Br J Haematol 89:403--408, 1995

10. Al-Refaie FN, Wickens DG, Wonke 6, et al: Serum non- transferrin-bound iron in beta-thalassemia major patients treated with desferrioxamine and l 1• Br J Haematol 82:431-436, 1992

11. Al-Refaie FN, Wilkes S, Veys PA, et al: Agranulocytosis in a patient with thalassemia major during treatment with oral iron chelator l,2-dimethyl-3-hydroxypyrid-4-one. Acta Haematol 89:86-90, 1993

12. Al-Refaie FN, Wilkes S, Wonke B, et al: The effect of deferiprone (L1) and desferrioxa­rnine on myelopoiesis using a liquid culture sys tem. Br J Haematol 87:196-198, 1994

13. Al-Refaie FN, Wonke B, Hoffbrand AV: Deferiprone-associated myelotoxicity. Eur J Haematol 53:298-301, 1994

14. Al-Refaie FN, Wonke B, Hoffbrand AV, et al: Efficacy and possible adverse effects of the oral iron chelator l,2-dimethyl-3-hydroxypyrid-4-one (Li) in thalassemia major. Blood 80:593-599, 1992

15. Al-Refaie FN, Wonke B, Wickens DG, et al: Zinc concentration in patients with iron overload receiving oral iron chelator, l,2-dimethyl-3-hydroxypyrid-4-one or desferri­oxamine. J Clin Pathol 47:657-660, 1994

15a. American Academy of Pediatrics, Committee on Nutrition: Zinc. Pediatrics 62:408-412, 1978

16. Barry M, Flynn OM, Letsky EA, et al: Long-term chelation therapy in thalassemia

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ORAL IRON CHELATION WITH DEFERIPRONE 245

major: Effect on liver iron concentration, liver histology, and clinical progress. BMJ 2:16-20, 1974

17. Bartlett AN, ~offbrand AV, Kontoghiorghes GJ: Long-term trial with the oral iron chelator l,2-dimethyl-3-hydroxypyrid-4-one (L1). II. Clinical observations. Br J Haema­tol 76:301-304, 1990

18. Bel A, Martinod E, Menasche P: Cardioprotective effect of desferrioxamine. Acta Haematol 95:63-65, 1996

19. Berkovitch M, Laxer RM, Inman R, et al: Arthropathy in thalassemia patients receiv­ing deferiprone. Lancet 343:1471-1472, 1994

20. Berkovitch M, Matsui D, Lamm SH, et al: Recent increases in numbers and risk of fatalities in young children ingesting iron preparations. Vet Hum Toxicol 36:53-55, 1994

21. Brittenham GM, Cohen AR, McLaren CE, et al: Hepatic iron stores and plasma ferritin concentration in patients with sickle ceU anemia and thalassemia major. Am J Haematol 42:81-85, 1993

22. Brittenham GM, Griffith PM, Nienhuis AW, et al: Efficacy of deferoxamine in pre­venting complications of iron overload in patients with thalassemia major. N Engl J Med 331:567-573, 1994

23. Collins AF, Fassos F, Stobie S, et al: Iron balance and dose response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease. Blood 83:2329-2333, 1994

24. Cunningham JM, Al-Refaie FN, Hunter A, et al: Differential toxicity of a-ketohydroxy­pyridine iron chelators and desferrioxamine to human hemopoietic precursors in vitro. Eur J Haematol 52:176-179, 1994

25. Donfrancesco A, Deb G, DeSio L: Role of deferoxamine in tumor therapy. Acta Haematol 95:66-69, 1996

26. Engle MA, Erlandson M, Smith CH: Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis. Circulation 30:698-705, 1964

27. Evans RW, Sharma M, Ogwang W, et al: The effect of a-ketohydroxypyridine chela· tors on transferrin saturation in vitro and in vivo. Drugs of Today 28(suppl):19-23, 1992

28. Fassos FF, Berkovitch M, Daneman N, et al: Efficacy of deferiprone in the treatment of acute iron intoxication in rats. Clin Toxicol 34:279-287, 1996

29. Goudsmit R, Kersten MJ: Long-term treatment of transfusion hemosiderosis with the oral iron chelator L 1• Drugs of Today 28(suppl):133-135, 1992

30. Gutteridge JMC, Rowley DA, Griffiths E, et a l: Low-molecular weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis. Clin Sci 68:463-467, 1985

31. Halliwell B, Gutteridge JMC: Oxygen, free radicals, and iron in relation to biology and medicine: Some problems and concepts. Arch Biochem Biophys 246:501-514, 1986

32. Hershko C, Pinson A, Link G: Prevention of anthracycline cardiotoxicity by iron chelation. Acta Haematol 95:87-92, 1996

33. Hider RC, Kontoghiorghes GJ, Silver J: UK Patent: GB-2118176, 1982 34. Hileti D, Panayiotidis P, Hoffbrand AV: Lron chelators induce apoptosis in proliferat­

ing cells. Br J Haematol 89:181- 187, 1995 35. Hoffbrand AV: Oral iron chelation. Semin Hematol 33:1-8, 1996 36. Hoffbrand AV, Bartlett AN, Veys PA, et al: Agranulocytosis and thrombocytopenia in

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Address reprint requests to

Gideon Koren, MD, ABMT, FRCPC Division of Clinical Pharmacology /Toxicology

The Hospital for Sick Children 555 University A venue

Toronto, Ontario MSG 1X8

Canada

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