This review focuses on a new solid-phase synthetic strategy for an anticancer natural product yaku'amide B (1) and its target identification and structure-function relationship study using synthetic analogues and probes. To realize the Fmoc-based solid-phase synthesis of 1, we developed new synthetic methods for enamide formation. Namely, modified traceless Staudinger ligation using alkenyl azides and newly designed phosphinophenol esters enabled stereoselective construction of the (E)- and (Z)-ΔIle moieties. Furthermore, resin-cleavage and C-terminus modification were simultaneously achieved with an ester-amide exchange reaction using C-terminal amine and AlMe3, which successfully afforded 1 via a full solid-phase route. The developed strategy was applied to the construction of seven E/Z isomers of 1. In the target identification of 1, fluorescent imaging study and affinity pull-down assay using the synthetic probes revealed that 1 exerts potent cytostatic activity by binding to subunits α and β of mitochondrial FoF1-ATP synthase. On the basis of the mode of action of 1, we conducted biological evaluation of the seven E/Z-isomers of 1. Assessment of growth inhibition activity and the effect on FoF1-ATP synthase indicates that the E/Z-stereochemistry of the three ΔIle residues controls the magnitude of biological functions of 1.
The number of women in the workforce is increasing because promoting their participation has become part of the country's growth strategy. On the other hand, maintaining the population is also a major issue. It is necessary to consider what kind of education should be provided to trainee pharmacists as people who are personally involved, and what kind of education is necessary for them as future medical professionals. The Basic Law for Child and Maternal Health and Child Development has been enacted, and the concept of preconception care is taking root. Health education for young people is of utmost importance to ensure their health and well-being in the future. We need to provide appropriate education to pharmacists as family pharmacists, as leaders of health support pharmacies, and as medical professionals who support women's health in the community. Because women's health is to be comprehensively supported by society including the community, family, workplace, and school, it seems that education on women's reproductive and general health will become more important in the future, in universities and especially schools of pharmacy.
The Japan Drug Information Institute in Pregnancy (JDIIP) was established in 2005 as a project of the Ministry of Health, Labour and Welfare with the aims of providing information on drug safety to women who are worried about drug use during pregnancy and creating evidence through epidemiological studies based on counseling cases. Since being established, JDIIP has made many contributions to the wellness of mothers and children by promoting the proper use of drugs during pregnancy. However, some studies have shown that this alone is not enough to meet potential needs. From now on, it is hoped that the hub hospitals in the 47 prefectures will take the lead in promoting regional pharmaceutical cooperation and striving for equalization in this field. Pharmacists will play an important role in this effort. In particular, many women consult pharmacists during lactation because they are out of touch with their obstetricians. If the wording of the section on lactating women in the package insert is faithfully explained, breastfeeding and drug therapy become incompatible. However, in most cases, it is possible to achieve both if the benefits of breastfeeding and the amount of drug transfer into milk are taken into consideration. Counseling on drug treatment during lactation is a field where pharmacists who are skilled in reading package inserts and pharmacokinetics should play an active role. The newly established the Japan Drug Information in Pregnancy Society aims to provide a place for pharmacists who do not have many opportunities to learn about this field.
Many lactating women want to breastfeed their baby, but may be overly concerned regarding the drugs present in breast milk; this leads to unnecessary weaning. Moreover, lactating women may stop taking medications at their own discretion and may not receive adequate treatment. Therefore, pharmacists are required to provide appropriate information to lactating women. In 2020, we conducted a questionnaire survey on 1781 pharmacists with the aim of investigating the actual situation of the provision of drug information by pharmacists to lactating women. The results showed that the information source that pharmacists place more importance on is the package itself, rather than databases and books, which are considered to be appropriate sources of information on the use of medicines by lactating women. Besides, more than 90% of pharmacists answered that they would like to participate in the study session. These results indicate that it is important to set up information sources that can effectively be used at workplaces and to organize study sessions for pharmacists with the support of National Center of Child Health and Development and other bodies. By improving the environment, with the aim of further improving the level of pharmacists, pharmacists will be able to provide accurate information more appropriately.
The current adolescent and young adult (AYA) generation represents a unique age group, among whom life changes dramatically due to living environments including school, seeking employment, marriage, and pregnancy, and due to lack of a social support system for cancer during the AYA years. The 3rd term of the Basic Plan for Cancer Control Promotion has stimulated increased momentum toward medical community involvement with AYA generation cancer patients, leading to the establishment of a Department of Cancer in the AYA Generation at our hospital. While promoting provision of highest quality team-based medical care, we have also been working to provide the best daily life/social life support, using our abundance of treatment experience, and taking into consideration various problems peculiar to AYA individuals, including anxiety about the future, a desire to preserve fertility, and a need for reproductive support. Pharmacists are involved in pharmacotherapy as part of medical treatments for AYA patients, aiming to provide optimal pharmacotherapy based on the practice of accurate pharmaceutical management. We foster collaborations between various clinical departments to tackle AYA-specific issues including preservation of fertility. Future challenges to address include long-term follow-up on such issues as late-stage disorders and endocrine disorders after AYA patient cancer treatment. Under current circumstances, our time for face-to-face interaction with patients as members of the hospital's medical staff is limited. Currently, we are involved in the operation of a breast cancer salon that aims to improve breast cancer patients' quality of life by supporting these patients during diagnosis and treatment.
Japan is simultaneously facing both an aging society and low birth rates, causing a continuing population decline. To cope with the declining birthrate, it is urgent to make child health and development medicine a natural accompaniment to all life stages. As pharmacists and pharmacies have a major role to play in this, it is necessary to position child health and development medicine in training for student pharmacists. On the other hand, student pharmacists are young adults who may be directly involved in child health and development, and this is not only an issue for women, but also needs to be understood by men. This symposium provides an opportunity to build a consensus on the role of pharmacists in the increasingly diverse and sophisticated support for child development in terms of pharmaceutical education.
The fight against coronavirus disease 2019 (COVID-19) in Japan began after January 2020. In order for the country to resume an active social life as a society, it is necessary to prevent an increase in the number of newly infected people with severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), and to prevent aggravation and/or death after infection. Although several therapeutic agents have been developed to treat COVID-19 after infection, vaccination with SARS-CoV-2 is the most effective in controlling or even ending the COVID-19 pandemic in Japan. The Ministry of Health, Labour and Welfare has convened a council to publish the collected data on COVID-19 and to proceed with discussions for promoting safe and effective vaccination. However, no matter how we release to the public the scientific basis of our findings and proposed methods of prevention and treatment, there remain cases where false opinions have spread, and vaccinations are refused accordingly. This paper traces the course of the work of this council, and considers current challenges in communicating COVID-19 information to the public based on scientific evidence.
Antibodies play a major role in immune responses against viruses, which inhibit infection by binding to target viral antigen. Antibodies are induced by viral entry to the body and vaccination that artificially induces immune responses; therefore, antibody tests are used in research for infection history and evaluation of vaccine efficacy. Currently, antibody tests against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) by immunochromatography, enzyme-linked immunosorbent assay (ELISA), and electrochemiluminescence immunoassay (ECLIA), or other kits used for automated analyzer are available. However, the test results should be carefully interpreted because requirements for the antibody test to obtain reliable results have not been established. Also, antibodies in human samples are heterogeneous, and their expression level changes over time. This review briefly explains the basic knowledge about antibodies against SARS-CoV-2 and outlines the classification and characteristics of the antibody tests with points to consider in their use. A summary of the collaborative study that evaluated the analytical performance of antibody test kits conducted by the National Institute of Health Sciences is also introduced. Then, the issues in ensuring the reliability of antibody tests results are discussed by considering the usefulness and availability of the World Health Organization international standard for anti-SARS-CoV-2 immunoglobulin.
To tackle the pandemic of the novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2), the international society, including Japan, has been actively promoting vaccination for SARS-CoV-2. To effectively utilize these vaccines, clinical trials have been conducted to evaluate their safety and efficacy. For efficacy evaluation, prevention rate of symptomatic novel coronavirus infections (corona virus disease 2019; COVID-19) between placebo groups and investigational vaccine groups has been the key parameter to evaluate the novel COVID-19 vaccines. This approach is based on a consensus among international regulatory authorities. Compared to several months ago, the public vaccination campaign for COVID-19 has substantially progressed in many countries. This makes it difficult to conduct clinical trials, which have placebo control arms, anywhere in the world because of ethical problems in administering a placebo during a pandemic. Therefore, the new international consensus among regulatory authorities is that immunogenicity bridging studies between the new COVID-19 vaccines that are being developed and approved COVID-19 vaccines may be needed when placebo-controlled studies are no longer feasible. In the future, the number of unvaccinated people worldwide is expected significantly decrease; thus, the issue of how to evaluate additional immunization for those who have completed the initial immunization remains to be addressed. This would require new international convergence. The development of COVID-19 vaccines and their evaluation would have to be updated, considering the social situation and vaccine coverage.
Natural medicines, including crude drugs and Kampo prescriptions, have a long history of clinical uses. An important characteristic of natural medicines is that they are multicomponent medicines. Kampo prescriptions, particularly, usually consist of several crude drugs that contain a large number of constituents. The therapeutic effects of a Kampo prescription result from the total effects of its constituents and not from the effect of a representative constituent with a strong pharmacological effect. In fact, only a few of these constituents with strong biological activity have been listed in the Japanese Pharmacopoeia as therapeutic agents. During my research career, I have observed various synergistic effects and interactions among the constituents of natural medicines. This article reviewed our researches on the biologically active constituents of natural medicines, including the analysis of the anti-inflammatory constituents of orengedokuto (a Kampo prescription). Understanding the role of each constituent with therapeutic effects in Kampo prescriptions forms a scientific basis of Kampo medicine. This will enable the better use and quality control of Kampo prescriptions. Moreover, this will aid the future development of a multicomponent mimic for a specific effect of a Kampo prescription using the appropriate mixture of active constituents in amounts found in the prescription. The above is my dream as a natural product chemist, and I believe that the mixture can do more than we anticipate!
One of the important characteristics of natural medicines, including crude drugs and Kampo prescriptions, is that they contain many constituents, and their therapeutic effects result from the total effects of the constituents. The author reviewed various synergistic effects and interactions among the constituents of natural medicines experienced in his researches. This review will provide an opportunity to have a glimpse into the scientific basis of the effectiveness of natural medicines as multicomponent medicines.
Bevacizumab (BV) is a recombinant and humanized monoclonal antibody that inhibits vascular endothelial growth factor. BV is used to treat various types of cancer. Proteinuria is a characteristic adverse event that occurs as a result of treatment with BV. However, the onset timing of proteinuria after BV administration remains unclear. In the present study, we examined the risk factors affecting the timing of proteinuria onset upon BV administration. Medical records of 135 patients (62 males and 73 females; mean age: 67.8±10.7 years) treated with BV were reviewed at the Kindai University Nara Hospital from April 2011 to December 2019. Proteinuria was identified in 44.4% (60/135) of the studied patients. The time to the first onset of proteinuria was significantly shorter in the administration of doses of BV (≥10) and history of diabetes mellitus. The median cumulative dose associated with the onset of proteinuria was 30.0 (16.1-58.8) mg/kg. When this cumulative dose was compared with 10 mg/kg, no significant difference was observed (p=0.319). The present study demonstrated that the administration of doses of BV (≥10) and history of diabetes mellitus are one of the main risk factors for early-onset proteinuria. These findings may be useful for the future treatment of early-onset proteinuria in patients treated with BV.
Many healthcare workers who handle anticancer drugs are at risk for occupational exposure. However, there are no established permissible limits for occupational exposure to anticancer drugs; thus, in this study, we aimed to search for and improve procedures that have a greater impact on the amount of spatter for handling anticancer drugs in vials, which are frequently used, based on the quantitative evaluation of the amount of exposure. We used sodium riboflavin phosphate (FMN) as a simulated anticancer drug and measured the amount of FMN dispersed to the handling area by the wiping method and the amount of FMN dispersed in both gloves using high-performance liquid chromatography with fluorescence detection (HPLC-FL). In this study, it was suggested that the overall amount of dispersal in the preparation process was affected by the different methods of injecting the drug solution into the infusion bottles and whether recapping. It was also found that the variation in the amount of dispersal differed depending on the selected preparation technique. It was suggested that the amount of dispersal could be reduced by selecting an appropriate dissolution method for multiple vials, recapping, an appropriate method for injecting the drug into the infusion bottle, and properly preparing the internal pressure of the infusion bottle. The results of this study suggest that there are some techniques and procedures in the preparation process of vials that have a significant effect on the amount of dispersal, and that proper implementation of these techniques can contribute to the reduction of dispersal.
With the coronavirus disease 2019 pandemic, businesses are rapidly expanding their online practices, and the online medical care system has been established and is growing. The field of pharmacy education is also looking for ways to conduct practical online training. Hence, we developed an online role-play-based medical interview training method for fourth-year pharmacy students. The purpose of this study was to describe in detail this method and to clarify the effect of online on medical interviewing practice. The training sessions were conducted using video teleconferencing software. Two settings were used for the role-play scenarios: the pharmacy and hospital. To evaluate the effectiveness of the sessions, a questionnaire was sent to the students, and the results were analyzed using text mining. The most important requirement for successfully conducting the interviews was a stable voice connection, and we reduced audio interruptions and delays by connecting the host personal computer to a wired local area network. We also solved the problem of howling when multiple terminals were installed in the same room by muting all devices in the room. Results of the analysis of the questionnaires suggested that students were more tense online. We also found that students perceived a difference between online and face-to-face interviews in terms of eye contact and the presentation of documents. In this way, we succeeded in conducting smooth online role-playing sessions while taking countermeasures against infection. In the future, it will be necessary to devise nonverbal communication methods and digital methods of presenting the training material.
Arylcyclohexylamines are a category of substances to which the anesthetic ketamine belongs. The arylcyclohexylamines have been reported to act as antagonists of the N-methyl-d-aspartate (NMDA) receptor. An analog of ketamine, 2-(ethylamino)-2-(3-methoxyphenyl)-cyclohexanone (methoxetamine; MXE), has been controlled as a narcotic in Japan and overdoses of MXE have been reported to cause health problems. In recent years, MXE derivatives have beendetected in illegal products in Japan. In this study, we describe the identification of three MXE derivatives, 2-(3-methoxyphenyl)-2-(propylamino)cyclohexan-1-one (methoxpropamine; MXPr), 2-(isopropylamino)-2-(3-methoxyphenyl)cyclohexan-1-one (methoxisopropamine; MXiPr) and 2-(3-methoxyphenyl)-2-(propylamino)cyclohexan-1-one (deoxymethoxetamine; DMXE), from illegal products.