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Review Article

Corresponding author: [email protected]

(-thalassemia major) (cardiac arrhythmia) ion channel Ryanodine receptor cardiac fibrosis (heart failure) : , , , 2553;5(4):363-371§

(Iron) (oxygen transport) (cofactor) 3 - 5 60 - 70 20 - 30 reticuloendothelial macrophages (myoglobin) cytochrome ( 1 2 )1,2

§

2 (free iron inorganic iron) (heme iron) duodenum (Ferric Fe3+ oxidized iron) (pH = 7.4)

§

(reduced) (ferrous Fe2+) duodenal cytochrome b (Dcytb) Ferrireductase (ascorbic acid) Fe3+ Fe2+ Fe2+ Fe2+ (transporter) brush border membrane divalent metal transporter 1 (DMT1) divalent cation transporter 1 (DCT1) 2+ ( 1) heme carrier protein 1 (HCP1) (metabolize) heme oxygenase 1 protoporphyrin1-5 Fe2+ (enterocyte) (ferritin) basolateral membrane ferroportin-1 ferroportin-1 Fe2+ (oxidize) Fe3+ hephaestin ( Ferroxidase) Fe3+ (transferrin) 1-5

15th year of Srinakharinwirot Journal of Pharmaceutical Science

Thai Pharmaceutical and Health Science Journal, Vol. 5 No. 4, Oct. ­ Dec. 2010

363

1 Metal ion transporter

Name

DCT1/Nramp2 Nramp1 SFT Frataxin/FRDA

Metal transported

Fe ,Zn , Mn ,Cu , Co2+,Cd2+, Pb2+ Fe2+ ,Mn2+ Fe2+/ Fe3+ Fe2+/Fe3+

2+ 2+ 2+ 2+

Function

Uptake/ endosomal exit Phagosomal/ lysosomal exit Uptake Mitochondrial export

TM

12 12 6 n.d.

Tissue distribution

Widespread (intestine, kidney, liver, neurons, ect.) Macrophages Ubiquitous Neuronal

Disease

Haemochromatosis Microcytic anaemia Infectious susceptibility Friedreich's ataxia

: TM = Transmembrane domain, FRDA= Friedreich's ataxia, n.d = not determined; Nramp = Natural resistance-associated macrophage protein

: Rolfs A, Hediger MA. J Physiol 1999;518(1):1-12.5

(Fe3+) (iron transport protein) transferrin (Tf) Tf Fe3+ 2 diferric Tf diferric Tf 2 transferrin receptor 1 (TfR1) Tf-TfR1 complex Tf-TfR1 complex endocytosis endosome endosome Tf pH proton (H+) pump endosome Fe3+ Fe2+ DMT1 endosome cytosol ( 1)1-5

4,500 ( 1) ferritin (upregulation) (iron homeostasis) ferritin (reactive oxygen species; ROS) 1,2

hepcidin

hepcidin hepcidin ferroportin ferroportin (internalization) (degradation) hepcidin macrophage hepcidin 2,3 hepcidin (iron overload) (inflammation) IL-6 hepcidin gene (HAMP) hepcidin (hypoxia) (anemia) ( 2)2,3

1

: Kalinowski DS, Richardson DR. Pharmacol Rev 2005;57:547-583.1

endosome Fe2+ labile iron pool (LIP) mitochondria (erythroid cells) heme ferritin

364

2 / hepcidin

: Papanikolaou G, Pantopoulos K. Toxicol Appl Pharmacol 2005;202:199211.2

Thai Pharmaceutical and Health Science Journal, Vol. 5 No. 4, Oct. ­ Dec. 2010

(Iron overload in -Thalassemia patients)

(hemoglobin) -globin chain 6 reticuloendothelial macrophage (bone marrow) (organ failure) 6

3

A) hydroxyl radical catalyze

Fenton reaction Haber-Weiss reaction

B) organic radical catalyze C) oxygen radical heme catalyze D)

: Papanikolaou G, Pantopoulos K. Toxicol Appl Pharmacol 2005;202: 199-211.2

(aerobic condition) (catalyze) Fenton reaction HaberWeiss reaction Fe2+ (electron donor) Fe3+ (electron acceptor) ( 3) hydroxyl radicals (OH) superoxide (O2-) hydrogen peroxide (H2O2) peroxidation (membrane lipid) (antioxidant) 1,2 transferrin transferrin (non-transferrin bound iron; NTBI) (tissue injury) 2

10 insulin-like growth factor 1 (IGF1) growth hormone 2 10 - 20 interstitial cell collagen insulin hypoparathyroidism (pituitary gland) gonadotropin (hypogonadism)2 30 - 40 (osteoporosis) 2 coagulation cascade (venous thrombo365

Thai Pharmaceutical and Health Science Journal, Vol. 5 No. 4, Oct. ­ Dec. 2010

embolism) pulmonary embolism venous thrombosis6

Phase 3

NTBI cardiac fibrosis, heart failure cardiac arrhythmia 7

repolarization K+ Delayed-rectifier potassium channel (IKr, IKs) resting membrane potential Na+ K+ Na+ K+

Phase 4

arrhythmia)

(Cardiac

ion channels action potential action potential atrium ventricle ( 4)8

4 action potential

: Morrow JP, et al. Am Heart J 2007;154:824-829.8

Phase 0

depolarization sodium ion fast sodium channel (INa)

Phase 1

repolarization potassium ion (K ) potassium channel (IKur, Ito)

+

Phase 2

plateau phase depolarization calcium ion L-type Ca2+ channel K+

NTBI (uptake) fastsodium channel (INa) delayed-rectifier potassium channel (IKr, IKs) INa current (slow cardiac conduction) IKr repolarization repolarization QTc prolongation Torsade de pointes ( 5) ventricular arrhythmia 7,9

5 QT prolongation Torsade de pointes (TdP); : EAD = Early after depolarization

: Zünkler BJ. Pharmacol Ther 2006;112:12-37.9

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Thai Pharmaceutical and Health Science Journal, Vol. 5 No. 4, Oct. ­ Dec. 2010

calcium ion (Ca2+) voltage-dependent calcium channel phase 2 action potential calcium sarcoplasmic reticulum Ryanodine receptor (RyR2) Ca2+ actin myosin (contraction) ( 6)10 Ryanodine-sensitive calcium channel sarcoplasmic reticulum Ryanodine channel (myocardial dysfunction) (left ventricular dysfunction) 7

MRI) ferritometer (superconducting quantum interference device; SQUID) () 6 4 deferoxamine 4 - 6 8 - 10 deferoxamine 17 11

(iron chelators)

3 deferoxamine, deferiprone (L1) deferasirox ( 7) 2

6

: Mohamed U, et al. J Cardiovasc Electrophysiol 2007;18(7):791-797.10

Deferoxamine (Hexadentate (1:1) High MW)

(Iron chelation therapy)

NTBI (heart failure) 11

= x x Deferiprone (Bidentate (3:1) Low MW)

Deferasirox (Tridentate (2:1) Low MW)

7 Iron chelators

: MW = molecular weight

: Sharma RN, Pancholi SS. J Curr Pharm Res 2010;1:1-7.14

(magnetic resonance imaging;

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367

ferritin

ferritin cytoplasm mitochondria lysosome hemosiderin ferritin, ferrintin (denatured ferritin) hemosiderin 17 ferritin (ferric-ferritin) (mineral) hydrous ferric oxide phosphate Fe3+ ferritin Fe2+ (pore) ferritin ( 8) ferritin 16,17

30 - 60 mg/kg infusion 8 15 5 - 7 15 mg/kg/hr ( 6 )11,14,15

Deferiprone (L1)

deferoxamine deferoxamine 75 mg/kg/day 3 100 mg/kg/day11,14,15

Deferasirox

(dispersible tablet) 30 20 mg/kg/day 5 - 10 mg/kg/day 3 - 6 30 mg/kg/day 40 mg/kg/day11,14,15

(Iron chelators)

.. 2008 The Society for the Study of Thalassemia and Hemoglobinopathies (SoSTE) 12 12 1) 20 ferritin 1,000 g/dl ( 2 3 ) 3.2 ­ 7 1 (mg Fe per g dry weight) 2) (tolerance), (compliance) (side effect) 3) deferoxamine deferiprone 4)

8 ferritin ferritin

: Harrison PM, et al. Biochem J 1974;143:445-451.16

ferritin 3 deferoxamine mesylate ferritin lysosome endocytosis lysosome ferritin lysosome (autophagy) deferiprone (L1) deferasirox ferritin cytosol Fe3+ ferritin active site, labile iron pool carrier protein Fe2+ 17

Deferoxamine (Desferrioxamine)

( NTBI) (cardiac arrhythmia) left-ventricular dysfunction

368

Thai Pharmaceutical and Health Science Journal, Vol. 5 No. 4, Oct. ­ Dec. 2010

2 (Iron chelators)

Properties

Ideal chelator

,

Deferoxamine

( 20 )

Deferiprone

( 2 ) 3 50 - 100 mg/kg/day 3 (bidentate); Agranulocytosis ( ) Mild neutropenia () ( ) CBC ALT 3 - 6 6 serum ferritin 3 10

Deferasirox

( 8 - 16 ) 24 20 - 30 mg/kg/day (tridentate); creatinine ( ) serum creatinine ALT serum ferritin 10

(molar iron chelating efficiency)

20 - 60 mg/kg/day (hexadentate); deferiprone deferasirox serum ferritin 3 10

-

: Neufeld EJ. Blood 2006;107:3436-3441.13; Sharma RN & Pancholi SS. J Curr Pharm Res 2010;1:1-7. 14

( 3)11,12 1) deferoxamine 40 - 60 mg/kg continuous subcutaneous infusion 2) deferoxamine (peripheral vein central catheter) 50 - 100 mg/kg/day 60 mg/kg central catheter 3) deferoxamine ( 40 - 50 mg/kg) deferiprone ( 70 - 80 mg/kg)

3

Cardiac conditions Recommended chelation Monitoring

Non-transferrin bound iron NTBI fast

ferritin Intensive chelation deferoxamine 12 2-3 7 6 cardiac dysfunction; deferasirox T2* < 20 ms 6 Maximum chelation deferoxamine , T2* < 20 24 ms deferiprone T2* < 10 ms

: T2* T2* > 20 ms cardiac dysfunction, T2* = 10 - 20 ms cardiac dysfunction T2* < 10 ms cardiac dysfunction

: Bhatia S, et al. Standard of care guidelines for thalassemi-2009. (http://www. thalassemia.com/documents/thalhandbook2009.pdf)11

Thai Pharmaceutical and Health Science Journal, Vol. 5 No. 4, Oct. ­ Dec. 2010

369

sodium channel (INa) delayed-rectifier potassium channel (IKr) Ryanodine receptor

9.

10.

11.

1. Kalinowski DS, Richardson DR. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev 2005;57:547-583. Papanikolaou G, Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol 2005;202:199-211. DonovanA, Roy CN, Andrews NC. The ins and outs of iron homeostasis. Physiology 2006;21:115-123. Ezquer F, NÚÑEZ MT, Rojas A, et al. Hereditary hemochromatosis: An opportunity for gene therapy. Biol Res 2006; 39:113-124. Rolfs A, Hediger MA. Metal ion transporters in mammals: structure, function and pathological implications. J Physiol 1999;518(1):1-12. Rund D, Rachmilewitz E. -Thalassemia. N Engl J Med 2005; 353:1135-1146. Wood JC, Enriquez C, Ghugre N, et al. Physiology and pathophysiology of iron cardiomyopathy in thalassemia. Ann N Y Acad Sci 2005;1054:386­395. Morrow JP, Cannon CP, Reiffel JA, et al. New antiarrhythmic drugs for establishing sinus rhythm in atrial fibrillation: What 12.

2. 3. 4.

13.

14.

5.

15. 16.

6. 7.

17.

are our therapies likely to be by 2010 and beyond? Am Heart J 2007;154:824-829. Zünkler BJ. Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects. Pharmacol Ther 2006;112:12-37. Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol 2007;18 (7):791-797. Bhatia S, Bojanowski J, Coates T, et al. Standard of care guidelines for thalassemi-2009. (Accessed on Sep. 25, 2010, at http://www.thalassemia.com/documents/thalhandbook2009. pdf). Cogliandro T, Derchi G, Mancuso L, et al. Guideline recommendations for heart complications in thalassemia major: the Society for the Study of Thalassemia and Hemoglobinopathies (SoSTE). J Cardiovasc Med 2008;9:515­525. Neufeld EJ. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood 2006;107:3436-3441. Sharma RN, Pancholi SS. Oral iron chelators: a new avenue for the management of thalassemia major. J Curr Pharm Res 2010;1:1-7. Cochen AR. New advances in iron chelation therapy. Hematol Am Soc Hematol Educ Prog 2006:42-7. Harrison PM, Hoy TG, Macara IG. Ferritin iron uptake and release: structure-function relationships. Biochem J 1974;143: 445-451. Theil EC. Mining ferritin iron: 2 pathways. Blood 2009;114(20): 4325-4326.

8.

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Thai Pharmaceutical and Health Science Journal, Vol. 5 No. 4, Oct. ­ Dec. 2010

Review Article

Molecular Basis of Cardiotoxicity from Iron Overload and Role of Iron Chelators in -Thalassemia Patients

Surasak Wichaiyo

Department of Consumer Protection and Public Health Pharmacy, Chaiyaphum Provincial Public Health Office Corresponding author: [email protected]

ABSTRACT

Iron is a mineral critical for physiological function. Iron overload is a condition in patients with -Thalassemia major which requires constant blood transfusion. In these patients, absorption of iron from gastrointestinal tract is increased and more free radicals are generated. Such excessive free radicals cause more damages to proteins, and subsequently various organ functions especially cardiac function. Cardiotoxicity is the major cause of death in these patients. Regarding cardiac arrhythmia , free radicals interfere with functions of ion channels regulating cardiac rhythm. In terms of cardiac abnormal contractions, free radicals cause malfunction of Ryanodine receptor. In addition, free radicals also cause cardiotoxicity by means of cardiac fibrosis. These cardiac abnormalities lead to heart failure. Iron chelators play a major role in eliminating excessive iron both by preventing and resolving cardiotoxicity in patients with -Thalassemia major. Keywords: iron overload, cardiotoxicity, thalassemia, iron chelator Thai Pharm Health Sci J 2010;5(4):363-371

Thai Pharmaceutical and Health Science Journal, Vol. 5 No. 4, Oct. ­ Dec. 2010

371

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