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 In the early 1970s, it was withdrawn from the market as an oral agent because of its association with subacute myelo-optic neuropathy (SMON), a syndrome that involves sensory and motor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：

---

氯喹醇：其在神经退行性疾病中的作用机制和临床用途综述。


Clioquinol 作为局部防腐剂生产，并于 1934 年作为口服肠道杀虫剂上市，用于治疗多种肠道疾病。在 1970 年代初期，由于它与亚急性髓视神经病变 （SMON） 有关，它作为口服剂退出市场，SMON 是一种涉及下肢感觉和运动障碍以及视觉变化的综合征。测定血浆和组织氯喹醇（5-氯-7-碘-8-喹啉醇）水平的第一种方法是在 1970 年代建立的，涉及 HPLC 分离和紫外线检测，然后是更灵敏的 GC 方法和电子捕获检测和气相色谱-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 一样具有高度的灵敏度和特异性。在大鼠、小鼠、兔子和仓鼠中，氯喹醇被迅速吸收并经历第一道代谢为葡萄糖醛酸和硫酸盐偶联物;代谢物的浓度高于游离氯喹醇的浓度。与腹膜内给药相比，生物利用度约为 12%。狗和猴子形成的偶联物较少。在人中，单剂量浓度与剂量相关，药物的半衰期为 11-14 小时。没有积累，并且药物对偶联物的代谢要小得多。Clioquinol 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蛋白斑块的沉积和稳定，而螯合剂可以在体外和体内溶解淀粉样蛋白沉积物。 一般来说，氯喹醇螯合和重新分布金属的能力在以 Zn、Cu、Fe 稳态障碍为特征的疾病（如 AD 和帕金森病）中起着重要作用，因为它可以减少氧化和淀粉样蛋白负荷。锌螯合剂也可以用作抗癌剂。动物毒性研究揭示了神经毒性反应的物种特异性差异，这些差异与血清氯喹醇和代谢物水平有关。在人类中也是如此，他们形成的偶联物较少。阿尔茨海默病患者的研究结果相互矛盾，需要进一步证实。MPACs 的两种主要作用 （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。