Clioquinol was produced as a topical antiseptic and marketed as an oral intestinal amebicide in 1934, being used to treat a wide range of intestinal diseases. In the early 1970s, it was withdrawn from the market as an oral agent because of its association with subacute myelo-optic neuropathy (SMON), a syndrome that involves sensory and motor disturbances in the lower limbs and visual changes. The first methods for determining plasma and tissue clioquinol (5-chloro-7-iodo-8-quinolinol) levels were set up in the 1970s and involved HPLC separation with UV detection, these were followed by a more sensitive GC method with electron capture detection and a gaschromatographic-massspectrometric (GC-MS) method. Finally, an HPLC method using electrochemical detection has proved to be as highly sensitive and specific as the GC-MS. In rats, mice, rabbits, and hamsters, clioquinol is rapidily absorbed and undergoes first-pass metabolization to glucuronate and sulfate conjugates; the concentrations of the metabolites are higher than those of free clioquinol. Bioavailabilty versus intraperitoneal dosing is about 12%. Dogs and monkeys form fewer conjugates. In man, single-dose concentrations are dose related, and the drug's half-life is 11-14 h. There is no accumulation, and the drug is much less metabolized to conjugates. Clioquinol acts as a zinc and copper chelator. Metal chelation is a potential therapeutic strategy for Alzheimer's disease (AD) because zinc and copper are involved in the deposition and stabilization of amyloid plaques, and chelating agents can dissolve amyloid deposits in vitro and in vivo. In general, the ability of clioquinol to chelate and redistribute metals plays an important role in diseases characterised by Zn, Cu, Fe dyshomeostasis, such as AD and Parkinson's disease, as it reduces oxidation and the amyloid burden. Zinc chelators may also act as anticancer agents. Animal toxicity studies have revealed species-specific differences in neurotoxic responses that are related to the serum levels of clioquinol and metabolites. This is also true in humans, who form fewer conjugates. The results of studies of Alzheimer patients are conflicting and need further confirmation. The potential therapeutic role of the two main effects of MPACs (the regulation of the distribution of metals and antioxidants) has not yet been fully explored.

中文翻译：

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氯碘羟喹：回顾其在神经退行性疾病中的作用机制和临床用途。

氯碘羟喹最初是作为一种外用防腐剂生产的，并于 1934 年作为口服肠道阿米巴杀剂上市，用于治疗多种肠道疾病。20 世纪 70 年代初，它作为口服药物从市场上撤出，因为它与亚急性脊髓视神经病 (SMON) 有关，亚急性脊髓视神经病是一种涉及下肢感觉和运动障碍以及视力变化的综合征。第一种测定血浆和组织氯碘羟喹（5-氯-7-碘-8-羟基喹啉）水平的方法建立于 20 世纪 70 年代，涉及采用 UV 检测的 HPLC 分离，随后采用了更灵敏的采用电子捕获检测的 GC 方法以及气相色谱-质谱（GC-MS）方法。最后，使用电化学检测的 HPLC 方法已被证明与 GC-MS 一样具有高灵敏度和特异性。在大鼠、小鼠、兔子和仓鼠中，氯碘羟喹被迅速吸收并首过代谢为葡萄糖醛酸和硫酸盐结合物；代谢物的浓度高于游离氯碘羟喹的浓度。与腹膜内给药相比，生物利用度约为 12%。狗和猴子形成的结合物较少。在人体中，单剂量浓度与剂量相关，药物的半衰期为11-14小时。没有蓄积，药物代谢成结合物的情况也少得多。氯碘羟喹充当锌和铜螯合剂。金属螯合是阿尔茨海默病（AD）的一种潜在治疗策略，因为锌和铜参与淀粉样斑块的沉积和稳定，而螯合剂可以在体外和体内溶解淀粉样沉积物。一般来说，氯碘羟喹螯合和重新分配金属的能力在以 Zn、Cu、Fe 稳态失调为特征的疾病（例如 AD 和帕金森病）中发挥着重要作用，因为它可以减少氧化和淀粉样蛋白负担。锌螯合剂也可用作抗癌剂。动物毒性研究揭示了与氯碘羟喹和代谢物的血清水平相关的神经毒性反应的物种特异性差异。对于人类来说也是如此，因为人类形成的结合物较少。对阿尔茨海默病患者的研究结果相互矛盾，需要进一步证实。MPAC 的两个主要作用（调节金属和抗氧化剂的分布）的潜在治疗作用尚未得到充分探索。