caa a22 4500 477132545 CHVBK 20180405111707.0 cr unu---uuuuu 170330e19971201xx s 000 0 eng 10.1023/A:1018312113969 doi (NATIONALLICENCE)springer-10.1023/A:1018312113969 Liver iron depletion and toxicity of the iron chelator Deferiprone (L, CP20) in the guinea pig [Elektronische Daten] [A. Wong, V. Alder, D. Robertson, J. Papadimitriou, J. Maserei, V. Berdoukas, G. Kontoghiorghes, E. Taylor, E. Baker] The use of the iron chelator deferiprone (L, CP20, 1,2-dimethyl-3-hydroxypyrid-4-one) for the treatment of diseases of iron overload and other disorders is problematic and requires further evaluation. In this study the efficacy, toxicity and mechanism of action of orally administered L were investigated in the guinea pig using the carbonyl iron model of iron overload. In an acute trial, depletion of liver non-heme iron in drug-treated guinea pigs (normal iron status) was maximal (approximately 50% of control) after a single oral dose of L1 of 200 mg kg, suggesting a limited chelatable pool in normal tissue. There was no apparent toxicity up to 600 mg kg. In each of two sub-acute trials, normal and iron-loaded animals were fed L (300 mg kg day) or placebo for six days. Final mortalities were 12/20 (L) and 0/20 (placebo). Symptoms included weakness, weight loss and eye discharge. Iron-loaded as well as normal guinea pigs were affected, indicating that at this drug level iron loading was not protective. In a chronic trial guinea pigs received L (50 mg kg day) or placebo for six days per week over eight months. Liver non-heme iron was reduced in animals iron-loaded prior to the trial. The increase in a wave latency (electroretinogram), the foci of hepatic, myocardial and musculo-skeletal necrosis, and the decrease in white blood cells in the drug-treated/normal diet group even at the low dose of 50 mg kg day suggests that L may be unsuitable for the treatment of diseases which do not involve Fe overload. However, the low level of pathology in animals treated with iron prior to the trial suggests that even a small degree of iron overload (two-fold after eight months) is protective at this drug level. We conclude that the relationship between drug dose and iron status is critical in avoiding toxicity and must be monitored rigorously as cellular iron is depleted. Chapman and Hall, 1997 carbonyl iron nationallicence deferiprone (L) nationallicence guinea pig nationallicence iron nationallicence iron chelators nationallicence iron-overload nationallicence Wong A. Department of Physiology, University of Western Australia, Perth, Western Australia aut Alder V. Prince of Wales Children's Hospital, Sydney, Australia aut Robertson D. Department of Physiology, University of Western Australia, Perth, Western Australia aut Papadimitriou J. Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia aut Maserei J. Department of Pathology, QEII Medical Centre, Perth, Western Australia aut Berdoukas V. Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia aut Kontoghiorghes G. Royal Free Hospital, London, UK aut Taylor E. Department of Physiology, University of Western Australia, Perth, Western Australia aut Baker E. Department of Physiology, University of Western Australia, Perth, Western Australia aut Biometals Kluwer Academic Publishers 10/4(1997-12-01), 247-256 0966-0844 10:4<247 1997 10 10534 https://doi.org/10.1023/A:1018312113969 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1018312113969 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wong A. Department of Physiology, University of Western Australia, Perth, Western Australia aut NATIONALLICENCE 700 1- Alder V. Prince of Wales Children's Hospital, Sydney, Australia aut NATIONALLICENCE 700 1- Robertson D. Department of Physiology, University of Western Australia, Perth, Western Australia aut NATIONALLICENCE 700 1- Papadimitriou J. Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia aut NATIONALLICENCE 700 1- Maserei J. Department of Pathology, QEII Medical Centre, Perth, Western Australia aut NATIONALLICENCE 700 1- Berdoukas V. Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia aut NATIONALLICENCE 700 1- Kontoghiorghes G. Royal Free Hospital, London, UK aut NATIONALLICENCE 700 1- Taylor E. Department of Physiology, University of Western Australia, Perth, Western Australia aut NATIONALLICENCE 700 1- Baker E. Department of Physiology, University of Western Australia, Perth, Western Australia aut NATIONALLICENCE 773 0- Biometals Kluwer Academic Publishers 10/4(1997-12-01), 247-256 0966-0844 10:4<247 1997 10 10534 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer