HPLC determination of 1,2-diethyl-3-hydroxypyridin-4-one (CP94), its iron complex [Fe(III) (CP94)3] and glucuronide conjugate [CP94-GLUC] in serum and urine of thalassaemic patients

Epemolu, R.O.; Ackerman, Rubén; Porter, John B.; Hider, Robert C.; Damani, L. A.; Singh, Surinder

doi:10.1016/0731-7085(94)e0027-x

Cited by 12 publications

(8 citation statements)

References 8 publications

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“…It should be noted that efficacy would have been much improved if normal lesion pre-treatment had been conducted but it was decided not to do this in these initial clinical studies, so that histological measurements could be employed as endpoints. CP94 [57] and its close relation relation, CP20 (1,2-dimethyl-3-hydroxypyridin-4-one; L1; Deferiprone; DFP) have also been investigated as iron chelating agents in humans not undergoing PDT, with the latter being studied in detail in long term investigations of daily oral administration [58,59]. There is rapid first pass metabolism by the liver following oral administration of CP20 in humans [60] which limits the clinical effectiveness of these particular hydroxypyridinone iron chelators for the treatment of conditions of iron overload [61,62], resulting in Deferasirox administration being utilised, either on its own or in combination with the established Deferoxamine long infusion treatment regime [63].…”

Section: Introductionmentioning

confidence: 99%

Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug

Curnow

Perry

Wood

2019

Photodiagnosis and Photodynamic Therapy

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Section: Introductionmentioning

confidence: 99%

Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug

Curnow

Perry

Wood

2019

Photodiagnosis and Photodynamic Therapy

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“…Four additional synthetic ligands are depicted in Figure 11 . These include three hydroxypyridones, deferiprone (L1, CP20), 121 − 123 1,2-diethyl-3-hydroxy-4-pyridinone (CP94), 124 tris[(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl]amine [TREN-(Me-3,2-HOPO)], 125 − 127 and the triazole 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox, Exjade). 128 − 130 The hydroxypyridones represent a well-articulated structure–activity relationship (SAR) study.…”

Section: Chelator Design Conceptsmentioning

confidence: 99%

“… 128 − 130 The hydroxypyridones represent a well-articulated structure–activity relationship (SAR) study. 121 − 124 , 131 , 132 L1 is a bidentate ligand 133 , 134 that forms a 3:1 complex with Fe(III) at millimolar concentrations at neutral pH. 133 However, a dilution effect seen in speciation studies suggests that a substantial fraction of a 2:1 Fe(III) complex (40%) exists at micromolar ligand concentrations at pH 7.…”

Section: Chelator Design Conceptsmentioning

confidence: 99%

Desferrithiocin: A Search for Clinically Effective Iron Chelators

et al. 2014

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The successful search for orally active iron chelators to treat transfusional iron-overload diseases, e.g., thalassemia, is overviewed. The critical role of iron in nature as a redox engine is first described, as well as how primitive life forms and humans manage the metal. The problems that derive when iron homeostasis in humans is disrupted and the mechanism of the ensuing damage, uncontrolled Fenton chemistry, are discussed. The solution to the problem, chelator-mediated iron removal, is clear. Design options for the assembly of ligands that sequester and decorporate iron are reviewed, along with the shortcomings of the currently available therapeutics. The rationale for choosing desferrithiocin, a natural product iron chelator (a siderophore), as a platform for structure–activity relationship studies in the search for an orally active iron chelator is thoroughly developed. The study provides an excellent example of how to systematically reengineer a pharmacophore in order to overcome toxicological problems while maintaining iron clearing efficacy and has led to three ligands being evaluated in human clinical trials.

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“…[31][32][33][34][35] However, based on further studies and clinical trials in thalassaemia patients, EL1NEt was later abandoned. [36][37][38][39] Similarly, Ciba Geigy (now Novartis) the then manufacturers of DF have also carried out animal toxicity studies with L1 and reached the conclusion that L1 was toxic. 40 However, the evaluation methods used for L1, as well as the comparative toxicity data obtained previously with DF questioned Ciba Geigy's conclusions.…”

mentioning

confidence: 99%

The History of Deferiprone (L1) and the Complete Treatment of Iron Overload in Thalassaemia

Kontoghiorghes¹,

Kleanthous²,

Kontoghiorghe³

2020

Mediterr J Hematol Infect Dis

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Deferiprone (L1) was originally designed, synthesised and screened in vitro and in vivo in 1981 by Kontoghiorghes G J following his discovery of the novel alpha-ketohydroxypyridine class of iron chelators (1978-1981), which were intended for clinical use. The journey through the years for the treatment of thalassaemia with L1 has been a very difficult one with intriguing turn of events, which continue until today. Despite many complications, such as the wide use of L1 suboptimal dose protocols, the aim of chelation therapy- namely the complete removal of excess iron in thalassaemia major patients, has been achieved following the introduction of specific L1 and L1/deferoxamine combinations. Many such patients continue to maintain normal iron stores. As a result of the introduction of L1, thalassaemia has changed from a fatal to a chronic disease and thalassaemia patients are active professional members in all sectors of society, have their own families with children and grandchildren and their lifespan is approaching that of normal individuals. No changes in the low toxicity profile of L1 have been observed in more than 30 years of clinical use. Thousands of thalassaemia patients are still denied the cardioprotective and other beneficial effects of L1 therapy. The safety of L1 in thalassaemia and other non-iron loaded diseases resulted in its selection as one of the leading therapeutics for the treatment of Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration and other similar cases. There are also increasing prospects for the application of L1 as a main, alternative or adjuvant therapy in many pathological conditions including cancer, infectious diseases and as a general antioxidant for diseases related to free radical pathology.

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HPLC determination of 1,2-diethyl-3-hydroxypyridin-4-one (CP94), its iron complex [Fe(III) (CP94)3] and glucuronide conjugate [CP94-GLUC] in serum and urine of thalassaemic patients

Cited by 12 publications

References 8 publications

Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug

Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug

Desferrithiocin: A Search for Clinically Effective Iron Chelators

The History of Deferiprone (L1) and the Complete Treatment of Iron Overload in Thalassaemia

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