Jarrott Bevyn
Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville 3010, Australia.
Pharmacol Res. 2017 Feb;116:29-31. doi: 10.1016/j.phrs.2016.12.033. Epub 2016 Dec 28.
Tacrine was initially synthesised in 1945 as part of a project seeking antibacterial drugs to treat infected wounds in soldiers. However, it was inactive in vitro against common strains of bacteria. Serendipitously, it was injected in vivo into dogs anaesthetised with chloroform and morphine and noted to immediately counter the respiratory rate depression caused by morphine but not block analgesia. Subsequent studies showed that tacrine was an acetylcholinesterase inhibitor. When combined with morphine in ampoules it was possible to inject larger doses of morphine without causing respiratory depression and it was marketed for 10 years in Australia. Tacrine was also used alone for treating acute anticholinergic syndrome in the 1980s. Shortly after this, it was hypothesised by William Summers that it could be of benefit in treating the early stages of Alzheimer's dementia and an IND was granted by the US Food and Drug Administration and a use patent awarded to Summers. It was the first of four anticholinesterases to be approved for treating this condition although its variable pharmacokinetics was a disadvantage.
他克林最初于1945年合成，是一个旨在寻找治疗士兵感染伤口的抗菌药物项目的一部分。然而，它在体外对常见细菌菌株没有活性。意外的是，它被注射到用氯仿和吗啡麻醉的狗体内，结果发现它能立即对抗吗啡引起的呼吸频率降低，但不会阻断镇痛作用。随后的研究表明，他克林是一种乙酰胆碱酯酶抑制剂。当它与吗啡混合在安瓿中时，可以注射更大剂量的吗啡而不引起呼吸抑制，并且在澳大利亚上市了10年。他克林在20世纪80年代也曾单独用于治疗急性抗胆碱能综合征。此后不久，威廉·萨默斯提出假说，认为它可能对治疗阿尔茨海默病痴呆症的早期阶段有益，美国食品药品监督管理局授予了一项研究性新药申请（IND），萨默斯也获得了一项使用专利。它是四种被批准用于治疗这种疾病的抗胆碱酯酶药物中的第一种，尽管其药代动力学多变是一个缺点。
