pyridoxal-isonicotinoyl-hydrazone and Chemical-and-Drug-Induced-Liver-Injury

Topics: Animals; Apoptosis; Behavior, Animal; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Fatty Liver; Gene Expression Regulation; Hepatocytes; Humans; Isoniazid; Male; Models, Molecular; Necrosis; Protein Conformation; Pyridoxal; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; RNA, Messenger

Although iron chelation therapy with deferoxamine (DFO) has changed life expectancy in thalassemic patients, compliance with the rigorous requirements of long-term subcutaneous DFO infusions is unsatisfactory. This problem underlines the current efforts for developing alternative, orally effective chelators to improve compliance and treatment results. For the patient with transfusional iron overload in whom results of DFO treatment are unsatisfactory, several orally effective agents are now available. The most important of the new generation of oral chelators are deferiprone and ICL670. Total iron excretion with deferiprone is less than with DFO, but deferiprone has a better ability to penetrate cell membranes and may have a better cardioprotective effect than DFO. Current studies of the clinical efficacy and tolerability of ICL670 indicate that at a single oral dose of 20 mg/kg daily, it may be as effective as parenteral DFO used at the standard dose of 40 mg/kg daily. Combined chelation treatment, employing a weak chelator that penetrates cells better, and a stronger chelator with efficient urinary excretion, may result in improved therapeutic effect through iron shuttling between the two compounds. The efficacy of combined chelation treatment is additive and offers an increased likelihood of success in patients previously failing DFO or deferiprone monotherapy.

Topics: Administration, Oral; Benzoates; beta-Thalassemia; Chelation Therapy; Chemical and Drug Induced Liver Injury; Deferasirox; Deferiprone; Deferoxamine; Drug Therapy, Combination; Humans; Infusions, Intravenous; Iron Chelating Agents; Iron Overload; Isoniazid; Pyridones; Pyridoxal; Survival; Triazoles