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Shyam M, Dev A, Sinha BN, Jayaprakash V. Scaffold Based Search on the Desferithiocin Archetype. Mini Rev Med Chem 2019; 19:1564-1576. [PMID: 30827237 DOI: 10.2174/1389557519666190301151151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 12/17/2018] [Accepted: 01/21/2019] [Indexed: 01/19/2023]
Abstract
Iron overload disorder and diseases where iron mismanagement plays a crucial role require orally available iron chelators with favourable pharmacokinetic and toxicity profile. Desferrithiocin (DFT), a tridentate and orally available iron chelator has a favourable pharmacokinetic profile but its use has been clinically restricted due to its nephrotoxic potential. The chemical architecture of the DFT has been naturally well optimized for better iron chelation and iron clearance from human biological system. Equally they are also responsible for its toxicity. Hence, subsequent research has been devoted to develop a non-nephrotoxic analogue of DFT without losing its iron clearance ability. The review has been designed to classify the compounds reported till date and to discuss the structure activity relationship with reference to modifications attempted at different positions over pyridine and thiazoline ring of DFT. Compounds are clustered under two major classes: (i) Pyridine analogues and (ii) phenyl analogue and further each class has been further subdivided based on the presence or absence and the number of hydroxy functional groups present over pyridine or phenyl ring of the DFT analogues. Finally a summary and few insights into the development of newer analogues are provided.
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Affiliation(s)
- Mousumi Shyam
- Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India
| | - Abhimanyu Dev
- Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India
| | - Barij Nayan Sinha
- Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India
| | - Venkatesan Jayaprakash
- Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India
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Arthur PG, Niu XW, Huang WH, DeBoer B, Lai CT, Rossi E, Joseph J, Jeffrey GP. Desferrioxamine in warm reperfusion media decreases liver injury aggravated by cold storage. World J Gastroenterol 2013; 19:673-681. [PMID: 23429835 PMCID: PMC3574593 DOI: 10.3748/wjg.v19.i5.673] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Revised: 10/25/2012] [Accepted: 12/20/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate whether desferrioxamine decreases ischemia and perfusion injury aggravated by cold storage (CS) in a rat liver perfusion model.
METHODS: Isolated rat livers were kept in CS in University of Wisconsin Solution for 20 h at 4 °C, then exposed to 25 min of warm ischemia (WI) at 37 °C followed by 2 h of warm perfusion (WP) at 37 °C with oxygenated (95% oxygen and 5% carbon dioxide) Krebs-Henseleit buffer. Desferrioxamine (DFO), an iron chelator, was added at different stages of storage, ischemia and perfusion: in CS only, in WI only, in WP only, in WI and perfusion, or in all stages. Effluent samples were collected after CS and after WI. Perfusate samples and bile were collected every 30 min (0, 0.5, 1, 1.5 and 2 h) during liver perfusion. Cellular injury was assessed by the determination of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) in the effluent and perfusate samples. Total iron was analysed in the perfusate samples. After WP, the liver was collected for the determination of liver swelling (wet to dry ratio) and liver morphological examination (hematoxylin and eosin staining).
RESULTS: Increased CS time caused increased liver dysfunction during WP. After 2 h of WP, liver injury was indicated by increased release of AST (0.5 h CS: 9.4 ± 2.2 U/g liver vs 20 h CS: 45.9 ± 10.8 U/g liver, P < 0.05) and LDH (0.5 h CS: 59 ± 14 U/g liver vs 20 h CS: 297 ± 71 U/g liver, P < 0.05). There was an associated increase in iron release into the perfusate (0.5 h CS: 0.11 ± 0.03 μmoL/g liver vs 20 h CS: 0.58 ± 0.10 μmoL/g liver, P < 0.05) and reduction in bile flow (0.5 h CS: 194 ± 12 μL/g vs 20 h CS: 71 ± 8 μL/g liver, P < 0.05). When DFO was added during WI and WP following 20 h of CS, release of iron into the perfusate was decreased (DFO absent 0.58 ± 0.10 μmoL/g liver vs DFO present 0.31 ± 0.06 μmoL/g liver, P < 0.05), and liver function substantially improved with decreased release of AST (DFO absent 45.9 ± 10.8 U/g liver vs DFO present 8.1 ± 0.9 U/g liver, P < 0.05) and LDH (DFO absent 297 ± 71 U/g liver vs DFO present 56 ± 7 U/g liver, P < 0.05), and increased bile flow (DFO absent 71 ± 8 μL/g liver vs DFO present 237 ± 36 μL/g liver, P < 0.05). DFO was also shown to improve liver morphology after WP. Cellular injury (the release of LDH and AST) was significantly reduced with the addition of DFO in CS medium but to a lesser extent compared to the addition of DFO in WP or WI and perfusion. There was no effect on liver swelling or bile flow when DFO was only added to the CS medium.
CONCLUSION: DFO added during WI and perfusion decreased liver perfusion injury aggravated by extended CS.
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Bergeron RJ, Xin MG, Weimar WR, Smith RE, Wiegand J. Significance of asymmetric sites in choosing siderophores as deferration agents. J Med Chem 2001; 44:2469-78. [PMID: 11448229 DOI: 10.1021/jm010019s] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The syntheses of the microbial iron chelators L-fluviabactin, its unnatural enantiomer, D-fluviabactin, L-homofluviabactin, and L-agrobactin, are described. The key steps involve the selective bis-acylation of the terminal nitrogens of norspermidine, spermidine, or homospermidine with 2,3-bis(benzyloxy)benzoic acid in the presence of 1,1-carbonyldiimidazole, followed by coupling of the N-hydroxysuccinimide ester of CBZ-protected L- or D-threonine with the central nitrogen. The effectiveness of each of these ligands in supporting the growth of Paracoccus denitrificans in a low-iron environment and the ability of these compounds to promote iron uptake are evaluated. The stereochemical configuration of the oxazoline ring is shown to be the major structural factor controlling both microbial growth stimulation and iron uptake. L-Fluviabactin, L-homofluviabactin, and L-agrobactin all promoted growth and iron uptake; D-fluviabactin was only marginally active. As with the microorganism's native siderophore, L-parabactin, all three ligands in the L-configuration investigated exhibited biphasic, i.e., both high-affinity and low-affinity, kinetics. The high-affinity system (iron concentration < 1 microM) yielded K(m) values between 0.11 and 0.23 microM and V(max) values from 157 to 129 pg-atoms Fe min(-1) (mg of protein)(-1), whereas the low-affinity scheme (iron concentration > 1 microM) gave K(m) values from 0.53 to 3.5 microM and V(max) values between 96 and 413 pg-atoms Fe min(-1) (mg of protein)(-1). Both L- and D-fluviabactin are very effective at clearing iron from the bile duct-cannulated rodent; when given subcutaneously at a dose of 150 micromol/kg, both ligands had iron clearing efficiencies of >13%, which is much greater than that of desferrioxamine in this model. Thus, by altering the stereochemistry of certain microbial siderophores, it is possible to generate deferration agents that are still effective at clearing iron from animals, yet do not promote microbial growth.
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Affiliation(s)
- R J Bergeron
- Department of Medicinal Chemistry, University of Florida, J. Hillis Miller Health Science Center, Gainesville, Florida 32610, USA.
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4
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Martelius T, Scholz M, Krogerus L, Höckerstedt K, Loginov R, Bruggeman C, Cinatl J, Doerr HW, Lautenschlager I. Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection. Transplantation 1999; 68:1753-61. [PMID: 10609953 DOI: 10.1097/00007890-199912150-00020] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model. METHOD One day after liver transplantation, PVG (RT1c) into BN(RT1n), the rats were infected with rat CMV (RCMV, Maastricht strain; 10(5) plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined. RESULTS In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-alpha and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells. CONCLUSIONS Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.
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Affiliation(s)
- T Martelius
- Department of Surgery, Helsinki University Hospital, Finland.
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5
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Kloover JS, Scholz M, Cinatl J, Lautenschlager I, Grauls GE, Bruggeman CA. Effect of desferrioxamine (DFO) and calcium trinatrium diethylenetriaminepentaacetic acid (DTPA) on rat cytomegalovirus replication in vitro and in vivo. Antiviral Res 1999; 44:55-65. [PMID: 10588333 DOI: 10.1016/s0166-3542(99)00054-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Cytomegalovirus (CMV) infection is a major problem in the immunosuppressed patient. It is thought that besides direct CMV induced cell lysis, immunological damage is part of CMV pathogenesis. New antiviral drugs, which combine immunomodulating and antiviral qualities, could be beneficial. Recently, it has been described that desferrioxamine (DFO) and calcium trinatrium diethylenetriaminepentaacetic acid (DTPA) exhibit both properties. In this report the antiviral effects of both compounds against rat CMV (RCMV) are described in vitro and in vivo using a generalised and local infection model. In vitro, both compounds exhibited a significant antiviral effect, DTPA being more potent than DFO. However, in the generalised infection model no effect was seen on mortality, morbidity or presence of virus in internal organs. In rats infected subcutaneously in the hind paw, no effect was seen locally on paw thickness, presence of viral antigens and inflammatory response. In addition, these rats suffered from a generalised infection of low magnitude at 15 days post infection, although both DFO and DTPA were able to lower the level of viral replication. In conclusion, our data indicate that despite in vitro activity, in vivo usage of DFO or DTPA for acute CMV infection is not warranted.
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Affiliation(s)
- J S Kloover
- Department of Medical Microbiology, University of Maastricht, The Netherlands
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6
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Bergeron RJ, Wiegand J, McManis JS, McCosar BH, Weimar WR, Brittenham GM, Smith RE. Effects of C-4 stereochemistry and C-4' hydroxylation on the iron clearing efficiency and toxicity of desferrithiocin analogues. J Med Chem 1999; 42:2432-40. [PMID: 10395484 DOI: 10.1021/jm990058s] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Additional structure-activity studies of desferrithiocin analogues are carried out. The effects of stereochemistry at C-4 on the ligands' iron clearing efficiency are reviewed and assessed using the enantiomers 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(R)-carboxylic acid and 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid. The utility of 4'-hydroxylation as a method of reducing the toxicity of desazadesferrithiocin analogues is also examined further with the synthesis and in vivo comparison of 4, 5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, which is the natural product 4-methylaeruginoic acid, and 4, 5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid. The stereochemistry at C-4 is shown to have a substantial effect on the iron clearing efficiency of desferrithiocin analogues, as does C-4'-hydroxylation on the toxicity profile. All of the compounds are evaluated in a bile-duct-cannulated rodent model to determine iron clearance efficiency and are carried forward to the iron-overloaded primate for iron clearing measurements. On the basis of the results of the present work, although 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid is still the most promising candidate for clinical evaluation, 4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid (4'-hydroxydesazadesferrithiocin) also merits further preclinical assessment.
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Affiliation(s)
- R J Bergeron
- Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA
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7
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Bergeron RJ, Wiegand J, Ratliff-Thompson K, Weimar WR. The origin of the differences in (R)- and (S)-desmethyldesferrithiocin. Iron-clearing properties. Ann N Y Acad Sci 1998; 850:202-16. [PMID: 9668541 DOI: 10.1111/j.1749-6632.1998.tb10476.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The iron clearance properties, toxicity, and pharmacokinetics of (R)- and (S)-desmethyldesferrithiocin (DMDFT) are described. The studies were performed in rodent and primate models. While both enantiomers were found to be effective iron chelators with minimal toxicity in the rodents, only (S)-DMDFT was able to induce the clearance of any iron in the primates. In addition, two out of nine of the monkeys given (R)-DMDFT died within 24 h of drug administration. The reason for the differences in iron clearance properties and the apparent toxicity of the (R)-enantiomer in the primates is likely related to the disparities in the pharmacokinetics of the two analogues. The pharmacokinetic data suggest enantioselectivity in renal clearance of the desferrithiocins and their iron complexes with (S)-DMDFT clearance 3.5 times greater than that of (R)-DMDFT, and FeIII [(S)-DMDFT]2 clearance 6.8 times greater than that of FeIII [R-DMDFT]2. In all primates studied FeIII [(R)-DMDFT]2 in the plasma exceeded 25 mg/L (50 microM) for several hours and remained above 10 mg/L (20 microM) at 8 h while levels of FeIII [(S)-DMDFT]2 never exceeded 50 microM and were at or below the limits of detection 8 h post-injection.
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Affiliation(s)
- R J Bergeron
- Department of Medicinal Chemistry, University of Florida, Gainesville 32610, USA.
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8
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Fox RC, Taylor PD. Bis(5-hydroxy-2-hydroxymethyl-pyran-4-one-6-yl)methane: a novel ligand for the intracellular mobilisation of ferritin-bound iron. Bioorg Med Chem Lett 1998; 8:443-6. [PMID: 9871595 DOI: 10.1016/s0960-894x(98)00053-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The efficacy of a novel tetradentate iron(III) ligand for the in vitro mobilisation of ferritin-bound iron is measured in direct comparison to the clinically approved agents, 1,2-dimethyl-3-hydroxypyridin-4-one and desferrioxamine.
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Affiliation(s)
- R C Fox
- Department of Chemistry, University College London, U.K
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9
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Affiliation(s)
- Queenie Xianghong Wang
- Center for Diagnostics and Drug Development, Department of Chemistry, University of Central Florida, Orlando, Florida 32816-2366
| | - Otto Phanstiel
- Center for Diagnostics and Drug Development, Department of Chemistry, University of Central Florida, Orlando, Florida 32816-2366
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10
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11
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Cinatl J, Hoffmann F, Cinatl J, Weber B, Scholz M, Rabenau H, Stieneker F, Kabickova H, Blasko M, Doerr HW. In vitro inhibition of human cytomegalovirus replication by calcium trinatrium diethylenetriaminepentaacetic acid. Antiviral Res 1996; 31:23-34. [PMID: 8793006 DOI: 10.1016/0166-3542(95)00833-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Desferrioxamine (DFO) has been shown to inhibit human cytomegalovirus (CMV) replication in vitro. In the present study, we compared antiviral effects of DFO in human foreskin fibroblast (HFF) cells against several CMV strains with those of other chelators that interact with iron and other ions from different pools. DFO, a hydrophilic chelator, that may chelate both intracellular and extracellular ions inhibited production of CMV late antigen at 50% effective concentrations (EC50S) ranging from 6.2 to 8.9 microM. EC50S for calcium trinatrium diethylenetriaminepentaacetic acid (CaDTPA) ranged from 6.1 to 9.9 microM. EC50S for 2,2'-bipyridine (BPD), a hydrophobic chelator, which diffuses into cell membranes ranged from 65 to 72 microM. Concentrations which inhibited BrdU incorporation into cellular DNA by 50% (IC50S) ranged from 8.2 to 12.0 microM (DFO), from 65 to 89 microM (BPD), and from 139 to 249 microM (CaDTPA). CaDTPA was the only chelator which completely inhibited production of infectious virus in HFF and vascular endothelial cells at concentrations which had no significant effects on cellular DNA synthesis and growth. Addition of stoichiometric amounts of Fe3+ in the culture medium of HFF cells completely eliminated antiviral effects of DFO while antiviral effects of CaDTPA and BPD were only moderately affected. Fe2+ and Cu2+ were stronger inhibitors of CaDTPA than Fe3+; however, Mn2+ and Zn2+ completely suppressed antiviral effects of CaDTPA. The results show that CaDTPA is a novel nontoxic inhibitor of CMV replication. The antiviral activity of CaDTPA is suppressed by metal ions with a decreasing potency order of Mn2+/Zn2+ > Fe2+ > Cu2+ > Fe3+.
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Affiliation(s)
- J Cinatl
- Department of Medical Virology, University Hospital, J.W. Goethe-University, Frankfurt/M., Germany
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12
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San Miguel JF, Sanz GF, Vallespí T, del Cañizo MC, Sanz MA. Myelodysplastic syndromes. Crit Rev Oncol Hematol 1996; 23:57-93. [PMID: 8817082 DOI: 10.1016/1040-8428(96)00197-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Affiliation(s)
- J F San Miguel
- Hematology Service, Hospital Clínico Universitario of Salamanca, Spain
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13
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Bergeron RJ, Wiegand J, Wollenweber M, McManis JS, Algee SE, Ratliff-Thompson K. Synthesis and biological evaluation of naphthyldesferrithiocin iron chelators. J Med Chem 1996; 39:1575-81. [PMID: 8648596 DOI: 10.1021/jm9508752] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The synthesis and iron-clearing properties of the naphthyldesferrithiocins 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4R)-carboxylic acid, 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4S)-carboxylic acid, 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4R)-carboxylic acid, and 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4S)-carboxylic acid are described. While the bile duct-cannulated rat model clearly demonstrates that the 3'-hydroxynaphthyl-2'-yl compounds are orally active iron-clearing agents and the corresponding 2'-hydroxynaphthyl-1'-yl compounds are not, in the primate model none of the benz-fused desazadesferrithiocin analogues are active. Oral versus subcutaneous administration of these ligands strongly suggests that metabolism is a key issue in their iron-clearing properties and that these benz-fused desferrithiocins are not good candidates for orally active iron-clearing drugs.
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Affiliation(s)
- R J Bergeron
- Department of Medicinal Chemistry, University of Florida, Gainesville, 32610, USA
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14
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Cinatl J, Scholz M, Weber B, Cinatl J, Rabenau H, Markus BH, Encke A, Doerr HW. Effects of desferrioxamine on human cytomegalovirus replication and expression of HLA antigens and adhesion molecules in human vascular endothelial cells. Transpl Immunol 1995; 3:313-20. [PMID: 8665150 DOI: 10.1016/0966-3274(95)80017-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Desferrioxamine (DFO), commonly used in therapy as a chelator of ferric ion in disorders of iron overload, is a potent inhibitor of human cytomegalovirus (HCMV) replication in cultured fibroblast cells. Moreover, DFO has immunomodulatory activity both in vitro and in vivo. We studied DFO effects on HCMV replication in cultured human endothelial cells and on the expression of several cell surface molecules, which mediate interactions of endothelial cells with other cell types in the immune system. The concentrations of DFO required for 50% reduction in the number of endothelial cells expressing HCMV late antigen, ranged for several HCMV strains from 5.2 to 8.8 microM. DFO concentrations ranging from 5 to 40 microM inhibited cellular DNA synthesis in a dose-dependent manner without any significant effects on the cell viability. DFO at 10 microM concentration suppressed expression of intercellular adhesion molecule-1 (ICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1), while it had no significant effect on the expression of vascular cell adhesion molecule-1 (VCAM-1). Expression of HLA class I and class II was not influenced by DFO treatment. The results showed that DFO is both effective in inhibition of HCMV replication and expression of ICAM-1 and ELAM-1 in endothelial cells, a combination that warrants attention to its potential use to prevent HCMV-induced allograft rejection in transplant recipients.
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Affiliation(s)
- J Cinatl
- Institut für Medizinische Virologie, Zentrum der Hygiene, Frankfurt, Germany
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15
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Di Palma A, Moratelli S, Tolomelli P, Giuberti M, Tenan R, Fagioli F, Landi L, Toffoli C, Atti G, Vullo C. Pattern of iron excretion in relation to haemoglobin level and iron load in 8 haematological patients following the administration of subcutaneous deferrioxamine. Eur J Haematol 1994; 53:197-200. [PMID: 7957802 DOI: 10.1111/j.1600-0609.1994.tb00188.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Iron excretion following subcutaneous administration of deferrioxamine (DFO) was measured between two transfusions of packed red cells in 6 patients with beta-thalassaemia major on the high level Hb transfusion regime; and in a single 3-day period in 2 other patients, 1 with transfused beta-thalassaemia major and the other with haemolytic anaemia due to PK deficiency. The pattern of iron excretion did not change significantly during the period between the two transfusions and was found to be related to serum ferritin levels. The proportion of iron excreted in the stools was inversely related to the serum ferritin level. These observations on iron excretion are of practical importance in relation to DFO administration, especially when evaluated in thalassaemics with normal haemoglobin levels and low iron stores.
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Affiliation(s)
- A Di Palma
- Department of Paediatrics, S. Anna Hospital of Ferrara, Italy
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16
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Cinatl J, Cinatl J, Rabenau H, Gümbel HO, Kornhuber B, Doerr HW. In vitro inhibition of human cytomegalovirus replication by desferrioxamine. Antiviral Res 1994; 25:73-7. [PMID: 7811060 DOI: 10.1016/0166-3542(94)90095-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Desferrioxamine (DFO) is commonly used in therapy as a chelator of ferric ion in disorders of iron overload. We found that DFO inhibits human cytomegalovirus (HCMV) replication in infected cultures of human foreskin fibroblasts (HFF) at concentrations that have been achieved in humans with no significant adverse effects. The concentrations of DFO required for 50 and 90% reduction in the production of a HCMV-late antigen ranged for several HCMV strains from 3.1 to 4.9 microM and from 14.2 to 17.3 microM, respectively. DFO concentration of 60 microM had no significant effect on the viability of HFF cells. Inhibitory effects of DFO on HCMV replication were completely prevented by co-incubation with stoichiometric amounts of Fe3+.
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Affiliation(s)
- J Cinatl
- Department of Medical Virology, Universitätsklinikum, J.W. Goethe-Universität, Frankfurt a. M., Germany
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17
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Jaulmes D, Quarre MC, Audat F, Gaonach MJ. [Post-transfusion hemochromatosis. Results of a study carried out in Blood Transfusion Centers. Analysis of 15 cases treated with subcutaneous perfusion of Desferal. Working group "Transfusion Techniques and Therapeutics"]. Transfus Clin Biol 1994; 1:55-64. [PMID: 8186855 DOI: 10.1016/s1246-7820(05)80061-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Post-transfusional iron overload is a real problem for doctors in charge of transfusions, as shown by the survey we led in twenty French blood banks. Deferoxamine remains the most efficient chelator, but can be prescribed only in a parenteral way. It is now proved that continuous infusions, intravenous or subcutaneous, are preferable to intermittent injections as far as iron excretion is concerned. In our study, we selected 15 polytransfused patients for dysmyelopoiesis. 13 cases were analysed by measuring the serum ferritin level. A clear decrease was noted, as well as a relative normalization of serum alanine amino transferases. However, if this treatment is effective and well tolerated, the problem is that it obviously requires the patient's compliance. It seems important to us to optimize prevention and treatment of post-transfusional iron overload through a consensus.
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Noël P, Solberg LA. Myelodysplastic syndromes. Pathogenesis, diagnosis and treatment. Crit Rev Oncol Hematol 1992; 12:193-215. [PMID: 1379818 DOI: 10.1016/1040-8428(92)90054-t] [Citation(s) in RCA: 28] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Our understanding of the biology of leukemia and myelodysplasia is still only partial. The diagnosis of myelodysplasia is often based on quantitative and qualitative findings in the peripheral blood and bone marrow. These findings are often shared by other disorders. There is a need for sensitive and inexpensive laboratory tests to determine clonality and karyotypic abnormalities in this disorder. Future classifications of these syndromes will need to be based on morphologic and biologic markers that are closely linked to disease progression, response to treatment, and survival. Our limited understanding of the pathogenesis of MDS decreases the specificity and effectiveness of our therapeutic interventions. Agents that are minimally toxic such as CRA, danazol, 1,25-dihydroxyvitamin D3, androgens, and pyridoxine are seldom useful. Antileukemic therapy and allogeneic bone marrow transplantation have a major role to play in patients younger than 45 years of age; in older patients these treatment modalities remain controversial because of their toxicity. Hematopoietic growth factors, used alone or in combination, may improve the quality of life and improve survival of patients with MDS. Growth factors may also decrease treatment-related mortality associated with chemotherapy and bone marrow transplantation and render these treatment modalities available for a higher percentage of patients. The development of more specific differentiating agents may permit hematopoietic differentiation while minimizing side effects.
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Affiliation(s)
- P Noël
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN 55905
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Lucarelli G, Weatherall DJ. For debate: bone marrow transplantation for severe thalassaemia (1). The view from Pesaro (2). To be or not to be. Br J Haematol 1991; 78:300-3. [PMID: 1873216 DOI: 10.1111/j.1365-2141.1991.tb04440.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Abstract
The myelodysplastic syndromes are composed of a group of clonal hematologic neoplasms, the course of which is complicated by ineffective hematopoiesis or leukemic transformation (or both). Therapeutic results may have been misleading in the past. Most patients have been managed with supportive measures, such as transfusions of erythrocytes, administration of antibiotics, and transfusions of platelets during active bleeding episodes. These supportive measures have prolonged and improved the quality of life of patients with myelodysplastic syndromes. Vitamin supplementation (folate, vitamin B12, and pyridoxine) has seldom been rewarding. Differentiation agents such as cis-retinoic acid and 1,25-dihydroxyvitamin D3 have been of benefit in only a limited number of patients. Androgens have not been useful, although danazol, which is an attenuated androgen, has been effective in a subset of patients with the presence of cell-bound platelet antibodies. Low-dose cytarabine, which has been studied extensively because of its differentiating activity in vitro, is associated with a generally low rate of complete remission and substantial toxicity. Antileukemic therapy is generally useful in young patients with rapidly progressive disease. Several hematopoietic growth factors are currently being evaluated in clinical trials; their use in combination or in conjunction with chemotherapy may be opening new horizons for these patients. With improvements in the prevention and treatment of graft-versus-host disease, allogeneic transplantation is a viable option for patients younger than 55 years of age who have severe cytopenias.
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Affiliation(s)
- P Noël
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN 55905
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Domingo JL. The use of chelating agents in the treatment of aluminum overload. JOURNAL OF TOXICOLOGY. CLINICAL TOXICOLOGY 1989; 27:355-67. [PMID: 2697761 DOI: 10.3109/15563658909000356] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Desferrioxamine (DFO), traditionally used as an iron chelator has been shown to increase urinary aluminum output in humans and aluminum-loaded mice, rats and rabbits. However, major side-effects of DFO treatment have been observed and the drug may accumulate in dialysis patients receiving repeated doses. In recent years, it has been reported that some dicarboxylic or tricarboxylic acids such as succinic, malic or citric may be considered as possible alternatives to DFO in the management of aluminum accumulation. Ethylene-di-(o-hydroxyphenylacetic acid)-like compounds may also have potential as alternatives to DFO in the treatment of aluminum accumulation and aluminum-induced toxicity. Investigation of new therapeutic agents with lower toxicity than DFO and clinical advantages in administration and cost is clearly encouraged.
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Affiliation(s)
- J L Domingo
- Laboratory of Toxicology and Biochemistry, School of Medicine, University of Barcelona, Reus, Spain
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Levine DS, Huebers HA, Rubin CE, Finch CA. Blocking action of parenteral desferrioxamine on iron absorption in rodents and men. Gastroenterology 1988; 95:1242-8. [PMID: 3169492 DOI: 10.1016/0016-5085(88)90357-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Desferrioxamine (DFO) is an iron chelating agent that, when administered orally, interferes with gut absorption of inorganic iron and, when administered parenterally, binds body iron and is excreted as ferrioxamine in bile and urine. Studies were carried out in normal and iron-deficient male rats and in normal, iron-replete male volunteers to investigate the blocking action of parenteral DFO on the absorption of radioiron. Radiolabeled ferrous ammonium sulfate, transferrin iron, or hemoglobin iron was injected directly into the jejunum of rats with or without intramuscular injections of DFO. Radioiron administered as ferrous sulfate or as transferrin iron was given to the volunteers by mouth or by direct duodenal infusion, respectively, with or without intravenous infusions of DFO. In iron-deficient rats, intramuscular DFO injections commencing 1 h before direct jejunal injection of radioiron significantly blocked absorption of inorganic iron (26% with DFO, 64% without DFO), transferrin iron (4% with DFO, 69% without DFO), and hemoglobin iron (3% with DFO, 19% without DFO). In normal rats, DFO injections also significantly blocked absorption of inorganic iron and transferrin iron. In normal volunteers, intravenous DFO infusions commencing 1 h before administration of radioiron significantly blocked absorption of physiologic doses of inorganic iron (3% with DFO, 21% without DFO) and transferrin iron (1% with DFO, 20% without DFO). The quantity of radioiron excreted in urine by both rats and humans with administration of DFO did not account for the observed decrement in absorption of radioiron. Biochemical analysis of rat intestinal mucosal scrapings after injection of DFO and administration of radioiron demonstrated the accumulation of a small molecular weight fraction containing iron that was ferrioxamine (iron-chelate) complex. We conclude that parenterally administered DFO can enter the small intestinal mucosa, bind intracellular iron, and block iron absorption. Parenteral DFO blocks the absorption of inorganic iron, transferrin iron, and hemoglobin iron, suggesting that all three iron species enter a common chelatable pool within the small intestinal mucosa and may share a common pathway of absorption.
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Affiliation(s)
- D S Levine
- Department of Medicine, University of Washington, Seattle
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Affiliation(s)
- H A Huebers
- University of Washington, Division of Hematology, Seattle 98195
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Domingo JL, Gómez M, Llobet JM, Corbella J. Citric, malic and succinic acids as possible alternatives to deferoxamine in aluminum toxicity. JOURNAL OF TOXICOLOGY. CLINICAL TOXICOLOGY 1988; 26:67-79. [PMID: 3385849 DOI: 10.3109/15563658808995398] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The effect of repeated intraperitoneal administration of deferoxamine, citric, malic and succinic acids on the distribution and excretion of aluminum was determined in male Swiss mice which had previously received aluminum nitrate intraperitoneally at a daily dose of 0.27 mmol/kg for five weeks. Chelating agents were administered for two weeks at doses approximately equal to one-fourth of their respective LD50. Treatment with DFOA, citric, malic or succinic acids significantly increased the fecal and urinary excretion of aluminum and reduced the concentration of aluminum found in various organs and tissues, with citric acid being the most effective. In sight of these results, citric, malic or succinic acids may be considered as alternatives to deferoxamine in aluminum toxicity. However, further investigations are required previous to the possible use of these compounds in human aluminum poisoning.
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Affiliation(s)
- J L Domingo
- Laboratory of Toxicology & Biochemistry, School of Medicine, University of Barcelona, Reus, Spain
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Abstract
Because of the catalytic action of iron in one-electron redox reactions, it has a key role in the formation of harmful oxygen derivatives and production of peroxidative damage to vital cellular structures. The clinical manifestations of iron overload may be prevented and even reversed by the effective administration of the iron-chelating drug deferoxamine (DF). Recent experimental evidence suggests that DF may also be useful in modifying disease conditions unrelated to iron overload by preventing the formation of free radicals, the powerful final effectors of tissue damage resulting from the respiratory burst of granulocytes and macrophages participating in the inflammatory response. Although much experimental work is still needed, this novel approach in iron-chelating therapy may have far-reaching implications in the management of autoimmune disease, adult respiratory distress syndrome, and organ transplantation. The poor intestinal absorption of DF, its almost prohibitive price, and short duration of action underline the need for new, orally effective iron chelators. A number of very promising orally effective drugs have been identified in recent years, such as the polyanionic amines, aryl hydrazones, and hydroxypyridones. Further development for clinical use of this new generation of iron-chelating drugs is a major challenge for future research.
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Affiliation(s)
- C Hershko
- Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel
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Kontoghiorghes GJ. The effect of 2,4-dihydroxypyridine-N-oxide, a new orally active iron chelator, on iron excretion in mice. Clin Chim Acta 1987; 163:137-41. [PMID: 3568416 DOI: 10.1016/0009-8981(87)90015-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A comparative study of the iron chelating properties of 2,4-dihydroxypyridine-N-oxide with heteroaromatic chelators containing an alpha-ketohydroxy binding site has been performed in iron loaded mice labelled with 59Fe lactoferrin. All the chelators were administered at a dose of 300 mg/kg either intraperitoneally or intragastrically. The pyridine derivatives were the only chelators which caused increased 59Fe excretion following their intragastric administration to mice. 1,2-Dimethyl-3-hydroxypyrid-4-one was the most effective oral chelator of all, followed by 2,4-dihydroxypyridine-N-oxide which caused further increase in 59Fe excretion when it was administered twice a day at a 200 mg/kg dose.
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Abstract
A 4-hour in vivo test for iron chelator activity in the rat is described. The amount of radioiron in the gut and urine that results from chelator-induced excretion of previously injected radioiron labelled ferritin is measured. Hepatocyte localization and desferrioxamine-induced radioiron mobilization from in vitro tagged homologous ferritin is shown to be similar to that from in vivo tagged ferritin. Non-homologous ferritin preparations labelled in vitro proved unsatisfactory. Radioiron mobilization by chelator occurred regardless of the iron status of the animal. Employing this measurement, the effectiveness of three iron chelators, pyridoxal isonicotinoyl hydrazone, the dimethyl ester of ethylene diamine-N, N'-dis (3-hydroxyphenyl acetic acid), and the dimethyl ester N, N'-di (3-hydroxybenzyl) ethylene-1, ethylene-1, 2-diamine-N, N'-diacetic acid, given orally was determined. All three chelators, when given in comparable dosage, induced iron excretion similar in amount to that observed with parenteral desferrioxamine. In addition, pyridoxal isonicotinoyl hydrazone administered in the diet over a period of 4 weeks was shown to reduce hepatic and splenic iron of normal animals by about one third, providing further validation of this method of evaluating chelator effectiveness.
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Baker E, Vitolo ML, Webb J. Iron chelation by pyridoxal isonicotinoyl hydrazone and analogues in hepatocytes in culture. Biochem Pharmacol 1985; 34:3011-7. [PMID: 4038321 DOI: 10.1016/0006-2952(85)90142-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Pyridoxal isonicotinoyl hydrazone (PIH) and several analogues were synthesized and assessed in the rat hepatocyte culture for their potential in iron chelation therapy. Pyridoxal isonicotinoyl hydrazone and pyridoxal benzoyl hydrazone were as effective as desferrioxamine (DFO) in reducing both net uptake of rat transferrin-59Fe and incorporation into ferritin by hepatocytes. Dialysis studies showed that this was due to a cellular action and not to the extracellular chelation of transferrin-bound 59Fe. The analogues of PIH were more effective in mobilization studies than PIH and DFO, releasing more 59Fe from ferritin as well as from the stroma-mitochondrial membranes in hepatocytes prelabelled using transferrin-59Fe. Chelator action was dependent on incubation time, concentration, temperature and lipophilicity. Pyridoxal benzoyl hydrazone, the most effective iron chelator, was also the most lipophilic, suggesting that access to cellular iron compartments as well as iron-binding affinity is important in effective iron chelation.
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Abstract
To determine the therapeutic effect of long-term, intensive iron chelation therapy, we studied liver iron content and histology in four children with thalassaemia major during 52-83 months of intensive therapy with desferrioxamine. The initial biopsies obtained prior to or within 21 months after beginning chelation therapy had Grade IV iron staining, with heavy iron deposition present in parenchymal and reticuloendothelial cells. Subsequent biopsies, obtained when serum ferritin levels had fallen to 71-246 micrograms/l, contained Grade 0 or Grade I stainable iron. Little or no iron was present in parenchymal or reticuloendothelial cells. The liver iron concentration, measured by magnetic susceptibility, returned to normal or nearly normal levels. Hepatic fibrosis did not progress during treatment with desferrioxamine. These findings demonstrate that intensive and sustained chelation therapy with desferrioxamine will remove excessive liver iron and preserve hepatocellular structure.
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