The toxic effects of desferrioxamine.
The toxic effects of desferrioxamine.
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DOI：
10.1016/s0950-3536(89)80027-7
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发表时间：
1989-04-01
期刊：
影响因子：
--
通讯作者：
Huehns, E R
中科院分区：
文献类型：
--
作者：
Porter, J B;Huehns, E R
DF一般毒性低，可能是因为其脂溶性低，Kpart 0.01 （Porter et al ., 1988b）。这种分子的特性可能会阻止它穿透身体的大多数细胞。似乎肝细胞对药物的摄取可能有一个特定的机制（Porter et al ., 1987），使这些细胞中的铁可通过胆汁排泄，而尿液中排泄的铁可能全部来自细胞外螯合，特别是当铁离开网状内皮细胞时（Hershko et al ., 1978）。根据这一假设，只有当DF以足够的数量穿透敏感细胞，使得在这些细胞中的所有可用铁被螯合后，一些自由DF仍然存在时，才会发生细胞毒性。这样的假设解释了铁超载对细胞的保护，因此对未超载的病人更敏感。视网膜和中枢神经系统进一步受到血-视网膜或血-脑屏障的保护，并且由于DF的峰值水平，药物或其他疾病介导该屏障的渗透性增加，将导致所见的视网膜或神经毒性作用。在耳中，一段时间内高水平的无配体DF可能是导致耳聋所必需的。因此，阻止其口服活性的特性可能是DF毒性低的部分原因。高剂量的DF更有可能对视力、听力和生长产生严重的毒性影响，铁超载似乎可以部分保护它们。在决定每个病人的适当剂量时，必须考虑到这两个结论。小心地，可以调整剂量，以去除足够的铁，以防止铁的积累，从而防止其毒性作用，同时保持剂量足够低，以防止DF本身有毒。似乎即使在铁负荷严重的患者中，剂量高于125 mg kg-1 day-1也可能引起视力障碍，应避免使用。在有铝毒性的肾透析患者中，即使剂量低至50mg kg-1 day-1，也需要非常小心避免视网膜毒性，尽管在临床指征时不应停药。Pogglitsch等人（1981,1983）、Pacitti等人（1983）、Ihle等人（1986）和Molitoris等人（1987）描述了对肾透析患者给予DF的情况。除非有明确确定的临床指征，否则不应给予患者DF。（摘要删节为400字）
DF has a low general toxicity, perhaps because of its low lipid solubility, Kpart 0.01 (Porter et al, 1988b). This feature of the molecule may prevent it from penetrating most cells of the body. It appears that there may be a specific mechanism of uptake of the drug by hepatocytes (Porter et al, 1987), making the iron in these cells available for excretion via the bile, while the iron excreted in the urine may all come from extracellular chelation, particularly when iron leaves the reticuloendothelial cells (Hershko et al, 1978). On this hypothesis, cellular toxicity occurs only when DF penetrates sensitive cells in sufficient amounts so that some free DF remains after all the available iron in such cells has been chelated. Such a hypothesis accounts for the protection of cells by iron overload and therefore the greater sensitivity of unloaded patients. The retina and central nervous system are further protected by the blood-retinal or blood-brain barrier, and increased penetration of this barrier, mediated by high peak levels of DF, by drugs or other diseases would lead to the retinal or neurotoxic effects seen. In the ear, high levels of unliganded DF for a period of time may be necessary to cause deafness. Thus the very property that prevents its oral activity may be part of the reason for the low toxicity of DF. The severe toxic effects on vision, hearing and growth are all more likely at higher doses of DF and there appears to be partial protection against them by iron overload. These two conclusions have to be taken into account when deciding on the appropriate dosage for each patient. With care, the dosage can be adjusted to remove enough iron to prevent iron accumulation and therefore its toxic effects, whilst keeping doses low enough to prevent DF from being toxic itself. It appears that even in very iron-overloaded patients dosages higher than 125 mg kg-1 day-1 may cause visual disturbances and should be avoided. In patients on renal dialysis with aluminium toxicity great care is needed to avoid retinal toxicity even with dosages as low as 50 mg kg-1 day-1, although the drug should not be withheld if clinically indicated. The administration of DF to renal dialysis patients is described by Pogglitsch et al (1981, 1983), Pacitti et al (1983), Ihle et al (1986) and Molitoris et al (1987). DF should not be given to patients unless there is a clearly established clinical indication.(ABSTRACT TRUNCATED AT 400 WORDS)