ISSN:0001-5792    

DOI:10.1159/000203848

出版商:S. Karger AG    

年代:1996

数据来源: Karger

ISSN:0001-5792    

DOI:10.1159/000203849

出版商:S. Karger AG    

年代:1996

数据来源: Karger

ISSN:0001-5792    

DOI:10.1159/000203850

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Three parameters which are critical for the development of non-toxic orally active iron chelators are identified: bioavailability, selectivity for iron (III) and distribution and toxicity. Each is discussed in detail. Arguments are presented for the use of bi- and tridentate ligands as opposed to hexadentate ligands. The discussion leads to the identification of 3-hydroxypyridin-4-ones as compounds with a unique potential for iron chelation under clinical conditions. The prodrug concept utilising efficient liver first-pass kinetics is introduced.

ISSN:0001-5792    

DOI:10.1159/000203851

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Evaluation of new chelators for clinical use is limited by the availability of models which will predict the therapeutic safety margin of chelators in iron-overloaded humans such as those with thalassaemia major. Animal models show significant differences with respect to the relative toxicity of different chelators compared with humans. These differences can be ascribed to several factors: differences in iron metabolism between different species, human metabolims being significantly more conservative than in rodents or non-human primates; differences in drug metabolism between different species which are often difficult to predict from first principles, and difficulties in obtaining iron-overloaded models that are truly representative of transfusional iron overload clinically. These differences have been highlighted by clinical studies on hydroxypyridinone iron chelators such as 1, 2-dimethyl-3-hydroxypyridin-4-one (L1, CP20, deferiprone) and l,2-diethyl-3-hydroxypyridin-4-one (CP94). New tissue culture approaches towards understanding the mechanisms of neutropenia, cytostasis and apoptosis induced by chelators as well as the relative rates of inhibition of non-haem-iron-containing enzymes such as ribonucleotide reductase are predicted to identify chelators with a higher therapeutic safety margin.

ISSN:0001-5792    

DOI:10.1159/000203852

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The improvement in survival and quality of life of iron-overloaded patients achieved by regular subcutaneous chelation has been extensively documented over the years. A review of the long-term results allows one to establish the following points: (1) with regular subcutaneous chelation, a negative iron balance can be obtained in most patients, except very young ones; (2) severe deferoxamine (DFO) toxicity may be prevented by skipping high doses and by carefully monitoring and modulating chelation, especially in patients with a low iron overload; (3) the maintenance of compliance with DFO over 0.6 and of ferritin levels below 2,000 prevents iron overload complications, at least for the first 20 years of life; (4) long-term chelation can reverse functional complications such as liver fibrosis, arrhythmia and echocardiographic abnormalities, but not complications due to extensive tissue alterations, such as frank diabetes, hypothyroidism and myocardiosclerosis; (5) intensive intravenous protocols can be successfully applied in heavily overloaded patients and represent the only possibility to reverse their dangerous iron burden in a relatively short period of time; (6) survival and quality of life in well-chelated patients are approaching a normal pattern, and (7) clinical outcome and prognosis are better evaluated by parameters that consider iron overload and chelation trends.

ISSN:0001-5792    

DOI:10.1159/000203853

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Data from several trials have provided direct and supportive evidence for the efficacy of deferiprone in the treatment of iron overload in thalassemia major. Deferiprone has been shown to induce sustained decreases in body iron to concentrations associated with survival free from the complications of iron overload in deferoxamine (DFO)-treated patients. Despite this evidence of efficacy, the risk of agranulocytosis mandates a careful evaluation in patients willing and able to use DFO. The incidence of agranulocytosis associated with deferiprone is under study in a prospective multicenter trial in Canada, Italy and the United States, under corporate sponsorship (Apotex Research, Canada). The results of this study should determine the risk associated with the use of this agent, and may provide the data required for an FDA decision regarding licensing of this agent for the treatment of iron overload, a goal supported by investigators worldwide.

ISSN:0001-5792    

DOI:10.1159/000203854

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Tissue damage in many diseases is caused by hydroxyl radicals, generated during single electron reduction of oxygen. The first step is usually the formation of the superoxide radical. This radical is constantly formed in all living cells, and in particular during activation of phagocytes or during reoxygenation following ischaemia. Damage, however, only occurs in the presence of catalytic transition metals of which iron is the most important in human pathology. Oxygen-radical-mediated damage can be prevented by iron chelators, as has been demonstrated in numerous in vitro and in vivo experiments. A description is given as to how toxic oxygen products are formed in biological systems, and how organisms succeed in preventing autodestruction by scavenger molecules. The use of iron chelators to prevent oxygen radical damage is reviewed with emphasis on possible clinical applications. The adult respiratory distress syndrome is described in more detail as a model for oxygen-radical-mediated damage that can be successfully prevented with iron chelators.

ISSN:0001-5792    

DOI:10.1159/000203949

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Cardiopulmonary bypass and the superimposed period of ischemia-reperfusion are situations in cardiac surgery that promote free radical generation. In these conditions, most animal and clinical studies have demonstrated the role of desferrioxamine, an iron chelator, in reducing generation of these highly cytotoxic radical species. However, this biological demonstration has not been translated into improved postoperative patient outcome.

ISSN:0001-5792    

DOI:10.1159/000203950

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Several studies are consistent with the hypothesis that available iron may have some role in promoting tumor cell growth with different biological mechanisms. For this reason, several studies have been carried out to demonstrate the antitumor activity of deferoxamine (DFO), an iron chelator with a high affinity for ferritin-bound iron. In particular, the effects of DFO have been studied in patients with neuroblastoma, where ferritin is in part tumor derived and high concentrations correlate with poor outcome. To date, in vitro and in vivo studies demonstrating the antitumor effects of DFO are very promising, but further investigations are required to establish an exact role for DFO in the treatment of cancer.

ISSN:0001-5792    

DOI:10.1159/000203951

出版商:S. Karger AG    

年代:1996

数据来源: Karger