The history of quinolone antimicrobial agents began when Lesher discovered Nalidixic acid (NA) in 1962. NA showed good antimicrobial activity against members of the family Enterobacteriaceae such as E. coli, and was primarily used for the treatment of urinary tract and gastrointestinal tract infections. Following the discovery and development of NA, numerous studies have been carried out to improve antimicrobial activity and spectrum, and the pharmacokinetic profile of NA derivatives. Further manipulation of the molecule produced new agents such as oxolinic acid, promidic acid and pipemedic acid (PPA) as antimicrobial activity increased and broadened during the period 1965-1975. In 1977, norfloxacin (NFLX), a new quinolone antimicrobial agent, was discovered. It possesses a fluorine atom at position 6 and a piperazinyl group at position 7 on the quinolone ring. NFLX demonstrated a broader spectrum and antimicrobial activity more than 10 times higher than NA and PPA against gram-negative bacteria including Pseudomonas aeruginosa and gram-positive bacteria, thereby providing good in vivo efficacy against animal infection models due to good tissue distribution. Phase 1 clinical studies of NFLX started in 1978 after confirming its safety in various animal toxicological studies, followed by phase 2 and 3 clinical studies. NFLX showed excellent clinical efficacies in urinary tract infections and GI tract infections, as well as upper respiratory tract infections, ear-nose-throat infections, and skin soft tissue infections owing to its potent antimicrobial activity and good tissue distribution. A good safety profile for NFLX was confirmed in these clinical studies. After the development of NFLX, many pharmaceutical companies began the R&D of new quinolone antimicrobial agents. Some of these compounds were successfully developed globally. New quinolones have become an essential antimicrobial agents in clinical settings and have gained an outstanding reputations for their excellent efficacies against various infections. In this review, I provide a retrospect regarding the discovery and development of NFLX, the forefront of new quinolone antimicrobial agents in the world.
Introduction： This study focuses on the reasons for establishing women's pharmacy schools during the preWWII era in Tokyo. Considering that these schools were some of the few science-based educational institutions for women, in this paper, a comparison is made based on the rules of the women’s pharmacy schools in Tokyo and those of private men’s pharmacy schools in Tokyo.
Method： The materials compared in the study were application documents for establishing the women's pharmacy schools in Tokyo, authorization documents for establishing private men's pharmacy schools, and application documents for changing the school rules in the men's pharmacy schools, which were gathered from the Tokyo Metropolitan Archives.
Result： As a result, it was confirmed that the acquisition of pharmacist qualifications and the role of a housewife were organized consistently in the education policy and curriculum of the women's pharmacy schools.
Conclusion： In the prewar society, gender roles were predominantly divided and very few women entered higher education. Hence, there were only a limited number of science-based educational institutions where women could study. The aim of establishing institutes to train women to become professional pharmacists was also considered compatible with Ryosaikenbo, which in Japanese means that the woman can also become a good wife and good mother.
Objective： Although the Sanskrit word amrta was used in ancient India to describe any immortal attribute of a variety of things, The Ayurvedic Pharmacopoeia of India (API) treats this word as a synonym for certain medicinal plants. This paper analyses the usage of amrta in Indian medical literature and discusses the reasons why amrta can be defined as a synonym for certain medicinal plants.
Methods： At first, we pharmacologically examine the efficacies of medicinal plants considered synonymous with amrta in API. Then, the meaning of amrta is interpreted as it appears in the three major ancient Indian medical works-- the Caraka-samhita (CS), the Susruta-samhita (SS), and the Astangahrdaya-samhita (AHS)-- as well as The Bower Manuscript (Bower Ms.), which quotes formulations from these three sources, and the Bhavaprakasa (Bh), which is one of the sources of API.
Results： The description of amrta is then analyzed philologically. This word was used as a synonym for Guduci (Tinospora cordifolia, (Willd.) Miers.), Haritaki (Terminalia chebula Retz.), and Amalaka (Emblica officinalis Gaertn.) in CS, SS, AHS, and Bower Ms. The description of the origin of Guduci as a medicinal plant in the nighantu (meaning vocabulary in Sanskrit) portion of Bh and the resurrection of monkeys described in the Ramayana both mean regaining life and are associated with the concept of immortality.
Conclusion： The description of amrta in API is consistent with the reasoning that originated in ancient mythological legends. Conceivably, this is one of the reasons why API defines the word amrta as a synonym for certain medicinal plants.
Introduction： This article discusses the circumstances of the Shoshisha Foundation and Kyou Shooku, founded and managed by Chobei Takeda the Fifth, in order to clarify the contributions of public services for the growth of the firm. Chobei Takeda the Fifth was an entrepreneur in the Meiji and Taisho eras. In those periods, the Japanese pharmaceutical industry experienced drastic changes in its economical and legal systems.
Method： The paper surveys company history, memoirs, industry history and the annual report of the Central Sanitary Bureau. Chobei Takeda the Fifth showed significant accomplishments in incorporating pharmaceutical manufacturing for growing his company. His company later became Takeda Pharmaceutical Company Limited, which is leading the Japanese pharmaceutical industry.
Result： The surveys reveal the entrepreneurship of Chobei Takeda the Fifth. He grew his pharmaceutical business and modernized his organization in order to sustain the company. This paper also reveals his concern about the reputation of medical merchants. It also describes that he found a problem related to the technical capabilities of his own company, and how he demanded a new type of human resources for improving the abovementioned situations.
Conclusion： The paper concludes that both public services are investments to improve the corporate image and show that pharmaceutical companies are desirable organizations for highly educated, well-established people.
Purpose： This paper reviews the history of Misao Kawai, a proponent of the National Pharmacy modeled after the postal office system had fallen into oblivion.
Method： In this article, the authors shed light on the ideas and life of Misao Kawai by studying his curriculum vitae, petitions for the National Diet and records kept by the local pharmaceutical associations.
Results： Misao Kawai was born in 1867 and entered the predecessor of the Tokyo University of Pharmacy and Life Sciences. He received his pharmacist license in 1887 and opened his pharmacy in Ueda, Nagano Prefecture in 1892. Many people came to his pharmacy, the mottos of which were based on the Christian beliefs of serving the community and treating everyone with kindness. In those days, prescriptions written by physicians and dispensed by pharmacists (i.e., bungyo in Japanese) did not exist. To promote this ideal, as the chairman of the Nagano Pharmaceutical Association, Kawai advocated a National Pharmacy. Despite the rejection of his motion by the board of representatives of the Japan Pharmaceutical Association, he sent petitions to the National Diet. In 1922 and 1924, however, legislators did not approve the introduction of a National Pharmacy, and as the result, Kawai resigned as the chairman of the association. After his resignation, he enjoyed exchanges with prominent figures such as Kanzo Uchimura and the third daughter of Tolstoy. In 1931, at the age of 64, he was re-elected as the chairman of the Nagano Pharmaceutical Association. He promoted bungyo at clinics held by the Ministry of Communications before resigning as the association's chairman in 1933. He studied the Bible in his later years and passed away in 1943 at the age of 78.
Conclusion： Although the idea of National Pharmacy was rejected by the Japan Pharmaceutical Association and the petitions Kawai submitted to the National Diet were also rejected, these efforts may have become emotional support to the Ueda model of regional surface separation (Ueda no men-bungyo in Japanese). He had dedicated his life to Christianity and the promotion of bungyo.
Objective: To study the history of the Division of Biological Chemistry and Biologicals, National Institute of Health Sciences (NIHS) focusing on the 30-year history of developing quality evaluation methods for biopharmaceuticals and their international harmonization.
Methods: Information on Division of Biological Chemistry and Biologicals reported in the Bulletin of the NIHS each year was analyzed. Approval information was obtained from the website of the Division of Biological Chemistry and Biologicals. The guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) were obtained from the website of the Pharmaceuticals and Medical Devices Agency (PMDA).
Results and Discussion: Stage 1 (1989-1998) Twenty biopharmaceuticals were approved. The development of quality evaluation methods was as follows, e.g. the replacement of a recombinant human growth hormone and human insulin in vivo assay with a high-performance liquid chromatography (HPLC) assay. Structural analysis of the oligosaccharide chain of r-hEPO, especially using fluorophore-assisted carbohydrate electrophoresis (FACE) was performed. The ICH guidelines for the quality of biotechnological/biological products, Q5B and Q5C, were implemented. Joined the Inter-pharmacopoeial (EP, JP and USP) open conference on harmonization of biotechnology-derived product standards in 1993. Stage 2 (1999-2008) Thirtyfive biopharmaceuticals were approved. The development of quality evaluation methods such as mass spectrometric glycoform profiling of r-hEPO using LC/ESI-MS were performed. The ICH guidelines for quality, Q5A(R1), Q5D, Q6B and Q5E, were implemented. Stage 3 (2009-2018) Eighty-two biopharmaceuticals were approved. The development of quality evaluation methods, such as rapid evaluation for heterogeneities in monoclonal antibodies using LC/MS with a column-switching system. Harmonization with the ICH guidelines for Pharmaceutical Product Lifecycle Management (Q12) was implemented. Recent topics of research in the characterization and quality control of biopharmaceuticals in Japan, such as monoclonal antibodies, are also discussed.
Objective: Potassium nitrate (KNO3), commonly referred to as saltpeter, was an important ingredient of
gunpowder from 16th to the 18th centuries in Japan. There were three different methods for producing
saltpeter, including Baiyo-hou, Shosekikyu-hou, and Kodo-hou.
Methods: We investigated the differences between the three methods of saltpeter production by comparing
the crystallization of KNO3, conducting ion analyses, and reviewing historical records.
Results: Baiyo-hou was the original method for making saltpeter and was conducted at locations that were
restricted : Gokayama in Kaga and Shirakawa-go in Hida. Shosekikyu-hou was equivalent to western niterbeds, whereas the main source for ammonium-nitrogen for the Baiyo-hou method was silkworm feces. Using wood ashes to boil the soils from both Baiyo-hou and cow manure (i.e., substituted for Shosekikyuhou) afforded KNO3 crystals (i.e., amorphous powders) ; however, recrystallization and purification were required, especially for the cow manure. The yielding of KNO3 crystals from Baiyo-hou was three times higher than that from Kodo-hou. Ion chromatographic analyses of the three different soils revealed that much higher levels of NO3- could be detected in soil using Baiyo-hou. Moreover, the NO3- level in cow manure made within one year was same as the level in soil conserved in an underfloor for 20 years. No detection of K+ was observed in soil using Kodo-hou, while a high level of K+ was detected when using both Baiyo-hou and cow manure. Baiyo-hou and Shosekikyu-hou were biological techniques to hasten NO3- formation due to the abundant availability of ammonium-nitrogen.
Conclusion: Based upon experimental evidence, we conclude that Baiyo-hou had a technological advantage to produce large quantities of high-quality saltpeter among the three different methods in Japan.
Objective: Early in the Meiji era, Zensoku-tabako, the brand name of Asthma Cigarettes, were sold at drug stores in Tokyo. In the product's packaging, there was an Asthma Cigarette [C1] insert on which much important information could be found. In my study, I analyzed the contents of the Asthma Cigarette package insert. The objective of this investigational study on the use of asthma cigarettes in Japan is to examine the transformation of the pharmaceutical system and the Japanese Pharmacopoeia.
Methods: I used the resources of the National Diet Library, the Medical Library at The University of Tokyo, and the Pharmaceutical Sciences Library at The University of Tokyo. The digital archives in these libraries were especially useful. I also examined the biographies and literature of the people involved.
Results: I obtained a package of Asthma Cigarettes made by Koreyoshi Ogata, the second son of Koan Ogata, a famous scholar of rangaku (i.e., Dutch education). The third son of Koan Ogata, Koretaka Ogata, wrote the Asthma Cigarette package insert. Kenzo Kobayashi manufactured and began selling Asthma Cigarettes in November 1881. In 1886, the first Japanese Pharmacopoeia (JP1) was published. Cannabis indica, which was included in Asthma Cigarettes, was listed in the first edition to the fifth edition, published in 1932, of the Japanese Pharmacopoeia. Similarly extractum cannabis indicae and tinctura cannabis indicae were listed starting from the third edition of the Japanese Pharmacopoeia.
Conclusion: The Ogata brothers and Kenzo Kobayashi are credited with the propagation of Asthma Cigarettes. After World War II, traditional politics, institutions, and society changed dramatically. One change can be seen in the sixth edition of the Japanese Pharmacopoeia (JP6), which adopted an American format. Cannabis indicae, which had been used in cigarettes and listed for 66 years in the Japanese Pharmacopoeia, was deleted. With the enforcement of the Cannabis Control Act of 1948, the medical use of Cannabis became prohibited. Though this act still remains in force today, thereby making the use of medicinal cannabis illegal, it is noteworthy that cannabis was used as a patent medicine in Japan 150 years ago.
Objective： The incense, zhan tang xiang, first appeared in shen nong ben cao jing ji zhu (502-536) and xin xiu ben cao (659). The description of the incense in the former literature indicates the origin to be an oilcontaining resin that exudes from the wound part of tree, and that in the latter literature indicates the origin to be a decoction of the branches and leaves of a tree resembling a citrus tree. But, investigation of the original plant(s) was not performed until the Ching dynasty. The author investigated zhan tang xiang to clarify the plant from which it originated.
Methods： The investigation mainly consisted of reviewing Chinese herbal books. From the plants considered to be the origin of zhan tang xiang, concentrated water extracts were made by the method of xin xiu ben cao. The odors of the extracts were evaluated by fragrance experts.
Results： The high priest of the Tang dynasty, Jian Zhen saw the trees of zhan tang xiang on Hainan Island. The characteristics of this tree, written in tang da he shang dong zheng chuan (779), suggests that the tree is Murraya paniculata (L.) Jack (Rutaceae), and the characteristics are in accordance with the descriptions of xin xiu ben cao and ben cao gang mu. Therefore, the original plant of zhan tang xiang during the Tang dynasty (i.e., Heian period of Japan) was M. paniculata. During the Ching dynasty, zhi wu ming shi tu kao (1848) wrote that Lindera erythrocarpa Makino (Lauraceae) is the original plant of zhan tang xiang. Modern China supports this opinion. However, this plant does not resemble a citrus tree. Accordingly, an experiment was carried out to determine whether or not the extracts of M. paniculata and L. erythrocarpa are usable as fragrances. The extracts were made using the method of xin xiu ben cao. Both of the extracts have a sweet scent and their five fragrances are very similar. They can be used well for incense.
Conclusions： The original plant of zhan tang xiang during the Tang dynasty was M. paniculata and during the Ching dynasty it was L. erythrocarpa. The extracts of both plants have similar fragrances and are usable as incense. It seems that L. erythrocarpa was used as substitution for M. paniculata in areas where M. paniculata did not grow.
Objective： The Town Hall Pharmacy in Tallinn (Estonia) has existed in the same premises for 598 years. We studied the history of pharmacy, and clarified the reasons why the pharmacy has such a long history.
Methods： In 2018, Aarn Ruber wrote a book in English entitled The Story of Town Hall Pharmacy. The authors of this report (K.K. and M.O.) visited the pharmacy in June 2019, and obtained the book. J.O. translated the book, and prepared this report with our photos.
Results and Discussion：The reasons include the following 4 items. 1. At various periods in history, the right of possession for the pharmacy has been decided after negotiation between the city office of Tallinn and the pharmacist. 2. The semiofficial pharmacy is located in the north-eastern corner of the central plaza of Tallinn city. The pharmacy has been frequented by many customers through the years. 3. The pharmacy operated in business for 328 years from 1583 until 1911 by ten generations of the Burchart family (German family line). 4. The successive pharmacists of the pharmacy had strong ties with town's people during 598 years, and worked even when the city was infected with the plague. The pharmacist, therefore, has been respected by the people.
Conclusion： The semiofficial pharmacy operation, the contribution by ten generations of the Burchart family line, and the heartful sense of responsibility of successive pharmacists made it possible for the pharmacy to continue to operate for 598 years, the longest such operation in Europe.
Introduction: The first rescue actions by pharmacists was witnessed at the time of the Nobi Great Earthquake in 1891. In this study, the author investigated the medical rescue actions of pharmacists after the Kanto Great Flood in August 1910.
Methods: The author researched materials of the Tokyo Metropolitan Archives, the library of the Tokyo University of Pharmacy and Life Sciences, the National Diet Library Digital Collection and the author's own studies.
Results and Discussion: Pharmacists took two actions at the time of this disaster : (1) supplying medicines and (2) conducting hygienic activities by inspecting the drinking water and supplying disinfectants. The Tokyo Pharmaceutical Association set up a tent from which drugs were dispensed to the disaster areas. Prefectural field clinics issued prescriptions and members of the Tokyo Pharmaceutical Association dispensed them without charging a fee. Prefectural inspectors and pharmacists jointly inspected the drinking water. After the disaster, the pharmacists were recognized for their service and received awards from each
of the prefectural governments. Among them, the Kanagawa Pharmaceutical Association received a commendation from the Minister of Home Affairs.
Objective: In the biopharmaceutical book in which Asafetida has been reported, farnesiferol was newly listed as a component. Farnesiferol is a compound belonging to sesquiterpen coumarins. The author conducted a literature survey on the chemical structures and the active effects of various sesquiterpen coumarins newly discovered in Asafetida, including farnesiferol.
Method: The author searched the literature information of sesquiterpen coumarins on J-GLOBAL using a comprehensive academic database. From the search results, the author extracted the literature on sesquiterpen coumarins isolated from Asafetida.
Results: From the 1950s to recent years, many sesquiterpen coumarins found in Asafetida have been isolated and identified by researchers overseas due to the progress of analytical chemistry technology. As a starting point, farnesiferol A, B and C were isolated by Caglioti et al. in the latter half of the 1950s. The chemical structure of sesquiterpen coumarins newly discovered and isolated from Asafetida is consistent with the inclusion of the coumarins umbelliferone skeleton and 24 carbon atoms (C24). Since umbelliferone has been reported to have an anti-inflammatory effect, some of the sesquiterpen coumarins contained in Asafetida may also have an anti-inflammatory effect. The same component, ferulic acid, has an A beta neurotoxicity inhibitory action. If the inflammatory action of specific coumarins is added to this, improvement of the cognitive function of Alzheimer-type dementia and suppression of its progression can be expected.
Furthermore, in recent years, new activity effects such as anticancer activity and antiviral activity have been reported for sesquiterpen coumarins.
Conclusion: The author believes that these findings will contribute to reassessing the value of Asafetida as a crude drug.
Objective： We found a letter written by Munenori Yagyu, a warlord and government bureaucrat early in the Edo era. In it, he mentions a medicinal herb garden. The objective of this report is to identify the medicinal herb garden and elucidate the relationship between the garden and Munenori Yagyu through identifying people appearing in the letter.
Methods： The letter, written in cursive by Munenori Yagyu, was first transcribed into text. Based on the contents of the transcribed letter, the people and medicinal herb garden were identified and the relationships between the garden and the people, including Munenori Yagyu, were analyzed.
Results： The contents of the letter suggest that Gen'ya Okamoto, a physician who treated Tokugawa shoguns, played a leading role in planting the Takagamine Medicinal Herb Garden, a government medicinal herb garden located in Kyoto, together with Doju Fujibayashi, who was later assigned as the first administrator of the medicinal herb garden. Munenori Yagyu may also have had an advisory role in the planting of the medicinal herb garden.
Conclusion： Munenori Yagyu's letter was found to suggest his involvement with the few other people identified for planting the Takagamine Medicinal Herb Garden. The letter will be important for elucidating the unclear circumstances of the Tokugawa Shogunate's project of establishing government medicinal herb gardens.