PCTH: a novel orally active chelator of the aroylhydrazone class that induces iron excretion from mice

[摘要] beta-Thalassaemia major is an inherited blood disorder which is complicated by repeated blood transfusion and excessive gastrointestina iron (Fe) absorption, which leads to toxic Fe overload. Current treatment using the chelator, desferrioxamine (DFO), is expensive and cumbersome since the drug requires long subcutaneous infusions and it is not orally active. A novel chelator, 2-pyridylearboxaldehyde 2. thiophenecarboxyl hydrazone (PCTH), was recently designed and shown to have high Fe chelation efficacy in vitro [E.M. Becker, D.R Richardson, J. Lab. Clin. Med. 134 (1999) 510-521; DR. Richardson, et al., Biochim. Biophys. Acta 1536 (2001) 133-140]. The aim of this investigation was to examine the Fe chelation efficacy of PCTH in vitro implementing primary cultures of cardiomyocytes and in vivo using mice. We showed that PCTH was significantly (P<0.005) more effective than DFO at mobilising Fe-59 from prelabelled cardiomyocytes Moreover, PCTH prevented the incorporation of 59Fe into ferritin during Fe uptake from Fe-59-labelled transferrin. These effects wer important to assess as cardiac complications caused by Fe deposition are a major cause of death in beta-thalassaemia major patients. Further studies showed that PCTH was orally active and well tolerated by mice at doses ranging from 50 to 200 mg/kg, twice daily (bd), for 2 days. E dose-dependent increase in faecal 59Fe excretion was observed in the PCTH-treated group. This level of Fe excretion at 200 mg/kg was similar to the same dose of the orally effective chelators, pyridoxal isonicotinoyl hydrazone (PIE) and deferiprone (L1). Effective F chelation in the liver by PCTH was shown via its ability to reduce fenitin-Fe-59 accumulation. Mice treated for 3 weeks with PCTH at doses c 50 and 100 mg/kg/bd showed no overt signs of toxicity as determined by weight loss and a range of biochemical and haematological indices In subchronic Fe excretion studies over 3 weeks, PIE and PCTH at 75 mg/kg/bd for 5 days/week increased faecal Fe-59 excretion to 140% an 145% of the vehicle control, respectively. This study showed that PCTH was well tolerated at 100 mg/kg/bd and induced considerable F excretion by the oral route, suggesting its potential as a candidate to replace DFO. (C) 2004 Elsevier B.V. All rights reserved.

[发布日期] 2004-12-24

[关键词] iron;iron chelator;pyridoxal isonicotinoyl hydrazone