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`http://exz.excerptamedica.coni/QSesh/abstracts/absz184.html
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`Abstract #2184 - Monday, December 7, 1998 - Hall C, 5:00-6:30 pm
`Posterboard 4l-IV, THALASSEMIA AND GLOBIN GENE REGULATION II
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`CARDIAC FAILURE AND MYOCARDEAL FiBROSlS IN A PATIENT WiTH
`THALASSEMIA MAJOR (TM) TREATED WETH LONG-TERM DEFERIPRONE
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`NF. Olivieri, J. Butany*, DM. Templeton*, GM. Brittenham
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`University ofToronto, CanadaColumbia UniversityNew York, USA
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`We report the development ofaczite congestive cardiacfailure in a 23-year-old man with TM after
`prolonged treatment with deferiprone, an orally active iron chelator. This patient had complied with
`defleroxamine (DFO) for 15 years until 1993 when he was randomized to deferiprone treatment in a
`prospective trial comparing defiriprone and DFO. Deferiprone, 75 mg/kg/day, was givenfor 3. 6 years
`hepatic iron varied betweeni9and 13 milligrams per gram liver, dry weight (mg/g) and cardiac ejection
`fraction between 50 and 70% (normal >50%) Because ofconcerns about the safety ofdeferzprone the
`patient was advised to discontinue deferiprone and resume DFO. Six months later, he presented with
`severe acute congestive cardiacfailure. Transthoraczc echocardiogram and Doppler showed an ejection
`fraction of<20% and markedly impaired diastolic relaxation. Myocardial and hepatic biopsies were
`performed: biochemical results are shown in the Table and compared with findings in the explantea'
`heart and liver ofa 20year-old TMpatient who had been non—compliant with DF0for several years
`and had required combined heart and liver transplantationfor end--stage iron-~induced disease (N Engl
`M Med 1994;330 1125- 7). Note that patients with TMin whom the bodymm butden as assessed by
`hepatic iron is maintained below 15 mg/g have a low risk ofcardiac complications (N Engl J Med
`1994;331 567 73). Although the cardiaciron concentration in the patient treated with deferiprone was
`lower, both myocardial biopsies showed similar widespread endocardial and interstitialfibrosis with
`extensive muscle fiber degeneration. No other riskfactorsfor cardiac fibrosis were present.
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`Patient
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`Hepatic iron
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`Myocardial iron
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`(mg/g, dry weight) (mg/g, div weight)
`13.2
`3.7
`Deferiprone therapy
`No iron-chelating therapy 28.1
`5.8
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`In cultured cardiomyocytes, deferiprone fails to mobilize iron andpromotes iron-induced cardiotoxicity
`(Blood 1997;90 (Suppl. I):11a). Studies in an animal model ofhuman iron overload have found that the
`combination of iron overload and treatment with a hydroxypyridinone structurally similar to
`deferiprone was associated with redistribution ofiron leading to increased cardiac1;on deposition and
`fibrosis (BioMetals 1994; 7.26 7- 71) Long-term clinical studies suggest that defieriprone may accelerate
`hepaticfibrosis (N Engl J Med I998339g61 7-23) Deathsfiom cardiac causes have been reported1n
`patients treated with deferipronefbr up to 2 years (Blood 1998, 91. 295-300) but ascribed solely to the
`underlying'1ron overload; no autopsy results have been reported. Overall these observations raise
`concerns that deferiprone treatment in patients with TM may be associated with (i) redistribution of
`bodyiron leading to increased cardiac iron deposition at lower bodyiron burdens, and (ii) an
`exacerbation or acceleratmn ofcardiac f'broszs We conclude that the risk ofcardiac disease associated
`with deferiprone therapy needsfurther evaluation.
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`Iron 21ansport and kinetics
`Iron overload and hemochromatosis
`Thalassemias
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`Apotex Tech.
`Ex. 2012
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`Apotex Tech.
`Ex. 2012
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