deferitrin and Iron-Overload

Deferitrin (GT-56-252) is the first drug in a class of desferrithiocin-derived hexadentate iron chelators. Genzyme Corp is developing this compound as an oral drug for the treatment of severe iron overload in people who require repeated erythrocyte transfusion for management of chronic anemia such as beta-thalassemia major. In phase I trials in adults with beta-thalassemia, deferitrin promoted iron excretion in a dose-related manner and was well tolerated as both a liquid and capsule in fed and fasted states. There were no serious adverse events or significant laboratory abnormalities. The author concludes that deferitrin may be useful as chelation monotherapy or as part of combination or doublet chelation therapy for the treatment of severe iron overload in patients with beta-thalassemia major if its favorable pharmacokinetic profile, efficacy, safety and tolerability are confirmed in more extensive clinical trials. A phase I/II trial that began in September 2003 has reportedly completed recruitment.

Topics: Animals; Carboxylic Acids; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Humans; Iron Chelating Agents; Iron Overload; Structure-Activity Relationship; Thiazoles

Deferiprone (L1), and appropriate combinations with deferoxamine (DFO), can be used effectively for the treatment of thalassemia and other transfusional iron loading conditions. A number of experimental iron chelators such as deferasirox or ICL670 or Exjade (4-(3,5-bis (2-hydroxyphenyl)-1,2,4-triazol-1-yl)-benzoic acid), deferitrin (4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4 (S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid-4-one or L1NAll and starch DFO polymers, are under clinical evaluation. ICL670 is the most advanced in development and appears to be effective in reducing liver iron in some patients but is overall ineffective in causing negative iron balance. It is also suspected that it is not effective in cardiac iron removal. Combination therapies using L1, DFO and new iron chelating drugs may cause higher efficacy and lower toxicity by comparison to monotherapies. However, several limitations including the high cost of the new chelating drugs may not facilitate the availability of these new treatments to the vast majority of thalassemia patients, most of whom live in developing countries.

Topics: Benzoates; Carboxylic Acids; Chelation Therapy; Clinical Trials as Topic; Deferasirox; Deferiprone; Deferoxamine; Drug Evaluation; Drug Therapy, Combination; Forecasting; Hemochromatosis; Humans; Hydroxyethyl Starch Derivatives; Iron Chelating Agents; Iron Overload; Molecular Structure; Pyridones; Starch; Thalassemia; Thiazoles; Transfusion Reaction; Triazoles

Effective new therapies and mechanisms have been developed for the targeting and prevention of iron overload and toxicity in thalassaemia and idiopathic haemochromatosis patients. A new era in the development of chelating drugs began with the introduction of deferiprone or L1, which as a monotherapy or in combination with deferoxamine can be used universally for effective chelation treatments, rapid iron removal, maintenance of low iron stores and prevention of heart and other organ damage caused by iron overload. Several experimental iron chelators such as deferasirox (4-[3,5-bis (2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid) or ICL670, deferitrin (4,5-dihydro-2- (2,4-dihydroxyphenyl)-4-methylthiazole-4 (S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid-4-one or L1NAll and starch deferoxamine polymers have reached different stages of clinical development. The lipophilic ICL670, which can only be administered once daily is generally ineffective in causing negative iron balance but is effective in reducing liver iron. It is suspected that it may increase iron absorption and the redistribution of iron from the liver to the heart and other organs. The experimental iron chelators do not appear to have significant advantages in efficacy and toxicity by comparison to deferiprone, deferoxamine or their combination. However, the prospect of combination therapies using deferiprone, deferoxamine and new chelators will provide new mechanisms of chelator interactions, which may lead to higher efficacy and lower toxicity by comparison to monotherapies. A major disadvantage of the experimental chelators is that even if they are approved for clinical use, they are unlikely to be as inexpensive as deferiprone and become available to the vast majority of thalassaemia patients, who live in developing countries.

Topics: Benzoates; Carboxylic Acids; Deferasirox; Deferiprone; Deferoxamine; Drug Therapy, Combination; Hemochromatosis; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Siderophores; Thalassemia; Thiazoles; Triazoles

Deferitrin, a novel, orally available iron chelator, is in the early stage of clinical development for the treatment of chronic iron overload due to transfusional therapy. Preclinical pharmacology studies demonstrate iron excretion largely by the fecal route. Initial clinical studies have shown deferitrin to be well absorbed. Further clinical studies are ongoing to determine the efficiency and safety of deferitrin.

Topics: Administration, Oral; Animals; beta-Thalassemia; Carboxylic Acids; Chelation Therapy; Clinical Trials, Phase I as Topic; Dogs; Drug Evaluation, Preclinical; Feces; Humans; Iron; Iron Chelating Agents; Iron Overload; Macaca fascicularis; Molecular Structure; Rats; Thiazoles

Deferitrin (GT-56-252) is the first drug in a class of desferrithiocin-derived hexadentate iron chelators. Genzyme Corp is developing this compound as an oral drug for the treatment of severe iron overload in people who require repeated erythrocyte transfusion for management of chronic anemia such as beta-thalassemia major. In phase I clinical trials in adults with beta-thalassemia, deferitrin promoted iron excretion in a dose-related manner and was well tolerated as both a liquid and capsule in fed and fasted states. There were no serious adverse events or significant laboratory abnormalities. The author concludes that deferitrin may be useful as chelation monotherapy or as part of combination or doublet chelation therapy for the treatment of severe iron overload in patients with beta-thalassemia major if its favorable pharmacokinetic profile, efficacy, safety and tolerability are confirmed in more extensive clinical trials. A phase I/II clinical trial that began in September 2003 has reportedly completed recruitment.

Topics: Animals; Carboxylic Acids; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Iron Chelating Agents; Iron Overload; Molecular Structure; Structure-Activity Relationship; Thiazoles

Iron chelation therapy using deferoxamine or deferiprone (L1) is effective for the treatment of most transfused iron-loaded patients. The combination administration of deferiprone in the daytime and deferoxamine in the night appears to be universally effective in rapidly achieving negative iron balance. The cardiac iron removal effect of deferiprone increases the prospects of longer survival in beta-thalassaemia patients. New chelators have reached the stage of clinical development such as deferitrin, 1-allyl-2-methyl-3-hydroxypyrid-4-one (L1NAll) and the starch deferoxamine polymers. Deferasirox has received a conditional approval in the US under the FDA-accelerated approval regulations, but needs further verification of its efficacy and safety. Future iron chelation therapies are likely to be based on combinations of chelating drugs.

Topics: beta-Thalassemia; Carboxylic Acids; Clinical Trials as Topic; Deferiprone; Deferoxamine; Drug Design; Drug Therapy, Combination; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Thiazoles; Transfusion Reaction

The impact of altering the octanol-water partition properties (log P) of analogues of desazadesferrithiocin, (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid, on the ligands' iron clearing properties is described. Increasing chelator lipophilicity can both substantially augment iron clearing efficiency in Cebus apella primates as well as alter the mode of iron excretion, favoring fecal over urinary output. The complications of iron overload are often associated with the metal's interaction with hydrogen peroxide, generating hydroxyl radicals (Fenton chemistry) and, ultimately, other related deleterious species. In fact, some iron chelators actually promote this chemistry. All of the compounds synthesized and tested in the current study are shown to be both inhibitors of the iron-mediated oxidation of ascorbate, thus removing the metal from the Fenton cycle, and effective radical scavengers.

Topics: 1-Octanol; Animals; Ascorbic Acid; Cebus; Feces; Free Radical Scavengers; Iron; Iron Chelating Agents; Iron Overload; Ligands; Oxidation-Reduction; Pyridines; Solubility; Solvents; Structure-Activity Relationship; Thiazoles; Urine; Water