Abstract
Evaluation of new chelators for clinical use is limited by the availability of models which will predict the therapeutic safety margin of chelators in iron-overloaded humans such as those with thalassaemia major. Animal models show significant differences with respect to the relative toxicity of different chelators compared with human. These differences can be ascribed to several factors: differences in iron metabolism between different species, human metabolism being significantly more conservative than in rodents or nonhuman primates; differences in drug metabolism between different species which are often difficult to predict from first principles, and difficulties in obtaining iron-overloaded models that are truly representative of transfusional iron overload clinically. These differences have been highlighted by clinical studies on hydroxypyridinone iron chelators such as 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20, deferiprone) and 1,2-diethyl-3-hydroxypyridin-4-one (CP94). New tissue culture approaches towards understanding the mechanisms of neutropenia, cytostasis and apoptosis induced by chelators as well as the relative rates of inhibition of non-haem-iron-containing enzymes such as ribonucleotide reductase are pred...Continue Reading
Citations
Dec 1, 2009·Future Medicinal Chemistry·Heather C HatcherSuzy V Torti
Dec 5, 1998·Free Radical Biology & Medicine·J B GaleyO Cantoni
Oct 3, 2003·Expert Opinion on Pharmacotherapy·Adriana CeciDomenico De Mattia
Jul 23, 2008·Molecular Nutrition & Food Research·István PócsiGyörgy Balla
Oct 8, 1998·Biochemical Pharmacology·N ChenoufiG Lescoat
Feb 1, 1997·Pediatric Clinics of North America·O Diav-Citrin, G Koren
Jul 20, 2002·Blood Reviews·L Merson, N Olivier
Nov 13, 2001·British Journal of Haematology·J B Porter
Oct 29, 2000·British Journal of Haematology·T SergejewH P Schnebli
Mar 2, 1999·Therapeutic Drug Monitoring·O Diav-CitrinG Koren
Dec 13, 2005·The Biochemical Journal·Yongmin MaFrank Petrat
Apr 4, 2002·Blood·Raymond J BergeronGary M Brittenham
Jan 5, 2002·Environmental and Molecular Mutagenesis·P WhittakerV C Dunkel
Nov 11, 1999·British Journal of Haematology·O ShalevV A Hoffbrand
Jun 8, 2000·Physics in Medicine and Biology·M J FarquharsonR D Abeysinghe
Apr 20, 1999·Chemical Research in Toxicology·S BergaminiA Iannone