title: PCTH: a novel orally active chelator of the aroylhydrazone class that induces iron excretion from mice.
abstract: beta-Thalassaemia major is an inherited blood disorder which is complicated by repeated blood transfusion and excessive gastrointestinal 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-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH), was recently designed and shown to have high Fe chelation efficacy in vitro. 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 (59)Fe from prelabelled cardiomyocytes. Moreover, PCTH prevented the incorporation of (59)Fe into ferritin during Fe uptake from (59)Fe-labelled transferrin. These effects were 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. A dose-dependent increase in faecal (59)Fe 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 (PIH) and deferiprone (L1). Effective Fe chelation in the liver by PCTH was shown via its ability to reduce ferritin-(59)Fe accumulation. Mice treated for 3 weeks with PCTH at doses of 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, PIH and PCTH at 75 mg/kg/bd for 5 days/week increased faecal (59)Fe excretion to 140% and 145% of the vehicle control, respectively. This study showed that PCTH was well tolerated at 100 mg/kg/bd and induced considerable Fe excretion by the oral route, suggesting its potential as a candidate to replace DFO.
authors.affiliation: Iron Metabolism and Chelation Program, Children's Cancer Institute Australia for Medical Research, PO Box 81, High St, Randwick, Sydney, New South Wales 2031, Australia.
authors.forename: C S M
authors.initials: CS
authors.lastname: Wong
authors.forename: J C
authors.initials: JC
authors.lastname: Kwok
authors.forename: D R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D000077543:Deferiprone; D004435:Eating / Q000187:drug effects; D005243:Feces; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D013876:Thiophenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014168:Transferrin / Q000187:drug effects / Q000493:pharmacokinetics
chemical_list: C496154:2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone; D007502:Iron Chelating Agents; D011728:Pyridones; D013876:Thiophenes; D014168:Transferrin; D000077543:Deferiprone; D007501:Iron