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Lessons from Preclinical and Clinical Studies with 1,2-Diethyl-3-Hydroxypyridin-4-One, CP94 and Related Compounds

  • John B. Porter
  • Surinder Singh
  • Katherine P. Hoyes
  • Ola Epemolu
  • Raj D. Abeysinghe
  • Robert C. Hider
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 356)

Abstract

In clinical use, the therapeutic safety margin with any iron chelator is likely to be narrow compared with commonly used pharmaceuticals. This is because there is inevitably a fine balance between excess iron and iron depletion within cells. This safety margin may be increased in the presence of iron overload but as not all cells will be equally iron overloaded, some will be more susceptible to iron deprivation than others. It is likely that minor modifications to chelator structure will make important differences to the therapeutic safety margin in clinical practice. The approach of our group has therefore been to identify the principles determining the efficacy and/or toxicity of iron chelators so that compounds which can be effective at lower doses or have less toxicity, than for example L1, can be identified. The hydroxypyridin-4-ones (HPOs) (Hider et al, 1982) are an appropriate group of compounds for such studies as their relatively simple structure allows a systematic investigation of structure-function relationships. The problems in identifying models which will predict the behaviour of chelators in iron overloaded humans has not helped in the development of iron chelators; indeed the preclinical and clinical experience with the HPOs has highlighted these shortcomings.

Keywords

Iron Overload Iron Chelator Intracellular Iron Liver Iron Iron Deprivation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • John B. Porter
    • 1
  • Surinder Singh
    • 2
  • Katherine P. Hoyes
    • 1
  • Ola Epemolu
    • 2
  • Raj D. Abeysinghe
    • 1
  • Robert C. Hider
    • 2
  1. 1.Department of HaematologyUniversity College London Medical SchoolUK
  2. 2.Department of PharmacyKings College LondonUK

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