Suehiro M
Japanese Society for History of Pharmacy.
Yakushigaku Zasshi. 1994;29(3):428-34.
"Fugu," a species of globefish has eaten by Japanese people for a long time, so globefish poisoning in Japan has been prevalent. Figures are shown in the Annual Food Poisoning Report collected and issued by health service authorities of Japanese Government since 1879. These reports prompted Dr. Yoshizumi Tahara, National Institute of Hygienic Sciences to conduct a chemical investigation of the toxic substance of globefish in 1884. However, the analysis was very difficult and his report of investigation was delayed. Before publication of the report of Dr. Tahara, pharmacological and toxicological studies of globefish poisoning were reported by three research groups from the Facultly of Medicine, University of Tokyo in 1889. These reports concluded that globefish poison has curare-like activity and its distribution was limited to specific organs such as the ovaries and the liver. Dr. Tahara successfully isolated the poison from aqueaous extract of ovaries of globefish by precipitation with lead acetate in the presence of ammonia. He presented the results at the monthly meeting of the Pharmaceutical Society of Japan in July 1894. He continued the studies and established an improved method for extraction and purification suitable for large-scale production. Finally, he confirmed that globefish contains only one toxic substance and named it Tetrodotoxin (TTX) in 1909. He elucidated the chemical nature of TTX as follows: 1) TTX is an amorphous hygroscopic powder and its character is neither alkaloid nor protein. 2) The possibility of TTX being a protamine was excluded by chemical analysis. Before the discovery ot TTX, according to folklore, globefish was regarded as medicine for leprosy because flesh of globefish contaminated with a sublethal dose of toxic substance alleviated the neuralgia of patients affected with leprosy. The clinical effect of TTX prepared by Tahara's method to suppress severe neuralgia due to leprosy and to reduce muscle spasms due to tetanus were reported by dermatologists in 1911. TTX was also given to patients with rheumatoid arthritis due to its analgesic effect. Thus, injectable TTX was manufactured and distributed by Sankyo Co., Ltd. from 1913. In terms of purity, the TTX preparation manufactured by Tahara's method seemed to be much more crude than the crystalline TTX obtained by Professor Tsuda and Dr. Kawamura in 1952. According to their report, the LD50 of the preparation for clinical use manufactured by Tahara's method was 4-5 mg/kg mouse compared to 4-6 microg/kg mouse of crystalline TTX.
“河豚”，作为一种鲀科鱼类，长期以来一直被日本人食用，因此河豚中毒在日本很普遍。相关数据在日本政府卫生服务部门自1879年起收集并发布的《年度食物中毒报告》中有显示。这些报告促使国立卫生科学研究所的田原义泉博士于1884年对河豚的有毒物质进行化学研究。然而，分析工作非常困难，他的调查报告延迟发布。在田原博士的报告发表之前，东京大学医学部的三个研究小组于1889年报告了关于河豚中毒的药理学和毒理学研究。这些报告得出结论，河豚毒素具有箭毒样活性，其分布仅限于卵巢和肝脏等特定器官。田原博士在氨存在的情况下，通过用醋酸铅沉淀，成功地从河豚卵巢的水提取物中分离出了这种毒素。他于1894年7月在日本药学会的月度会议上公布了研究结果。他继续进行研究，并建立了一种适合大规模生产的提取和纯化改进方法。最终，他确认河豚只含有一种有毒物质，并于1909年将其命名为河豚毒素（TTX）。他阐明了TTX的化学性质如下：1）TTX是一种无定形的吸湿粉末，其性质既不是生物碱也不是蛋白质。2）通过化学分析排除了TTX是鱼精蛋白的可能性。在发现TTX之前，根据民间传说，河豚被视为治疗麻风病的药物，因为含有亚致死剂量有毒物质的河豚肉能缓解麻风病患者的神经痛。1911年，皮肤科医生报告了田原方法制备的TTX对抑制麻风病引起的严重神经痛和减轻破伤风引起的肌肉痉挛的临床效果。由于其镇痛作用，TTX也被用于治疗类风湿性关节炎患者。因此，自制药公司于1913年开始生产并销售注射用TTX。就纯度而言，田原方法制备的TTX制剂似乎比津田教授和川村博士于1952年获得的结晶TTX粗糙得多。根据他们的报告, 田原方法制备的临床用制剂的半数致死量为4 - 5毫克/千克（小鼠），而结晶TTX为4 - 6微克/千克（小鼠）。
