Yokel R A, Ackrill P, Burgess E, Day J P, Domingo J L, Flaten T P, Savory J
College of Pharmacy, University of Kentucky Medical Center, Lexington 40536-0082, USA.
J Toxicol Environ Health. 1996 Aug 30;48(6):667-83.
The prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al-induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders.
本文综述了铝（Al）蓄积和毒性的防治方法。文中提供了一些建议，以增进我们对去铁胺（去铁敏，DFO）治疗的理解，并开发更有效的螯合方法。减少铝的蓄积和毒性可能会使终末期肾病（ESRD）患者受益，或许对患有特定神经退行性疾病的患者以及患有铝诱导神经认知障碍的工人也有益处。体外螯合、肾移植、或许与简单配体如硅（Si）络合以及全身螯合疗法都可能增加铝的清除。体外螯合和硅减少铝蓄积的能力需要进一步评估。尽管可能无法设计出针对铝的特异性螯合剂，但仍需要具有更高铝选择性的螯合剂。铝选择性螯合可通过靶向螯合剂分布或使用与螯合剂结合的佐剂来实现。在特定条件下，羧酸促进铝排泄的能力值得进一步研究。去铁胺不会使铝通过胆汁大量排泄。具有这种特性的螯合剂可能对ESRD患者有用。铝螯合剂有效分布于血管外的必要性尚不清楚，应该确定这一点以指导选择DFO的替代物。DFO缺乏口服疗效且偶尔有副作用，这促使人们寻找口服有效、更安全的铝螯合剂。双齿3 - 羟基吡啶 - 4 - 酮目前是DFO最有前景的替代物。它们已被证明可增加大鼠和兔子的尿铝排泄，但毒性与DFO相当或更大。它们的毒性可能与金属络合不完全有关。口服有效螯合剂增加胃肠道（Gl）中螯合金属吸收的能力需要评估。如果需要进行铝螯合治疗，口服有效、安全的铝螯合剂将对腹膜透析患者和患有神经退行性疾病的患者有益。DFO可减缓阿尔茨海默病（AD）的进展，并逆转铝诱导的行为缺陷和神经原纤维缠结，这鼓励进一步研究针对特定神经退行性疾病的铝螯合疗法。
