I here present the results of our studies on the synthesis and functional analysis of tautomeric dihydropyrimidines (DPs) and related compounds in two sections. In the first section, we describe our experimental and theoretical studies on the thermodynamics and properties of 2-substituted 1,4- and 1,6-dihydropyrimidine-5-carboxylates by ¹H NMR measurements and density functional theory (DFT) calculations, respectively. The concentration ratios of tautomers a/b of DPs 1, 2, and 3 were determined under various conditions to determine the effects of temperature, solvent, and concentration on thermodynamics data. The obtained free energy differences (ΔG), enthalpy differences (ΔH), and entropy differences (ΔS) are discussed in terms of the molecular structures, dipole moments (DM), and electrostatic potential maps obtained by DFT calculations to clarify the nature of DPs 4-8. In the second section, an efficient synthetic method developed for 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-thiones 9 and 2-ones 10 is described. The novelties of the synthesis protocol are as follows: 1) the use of Lewis acid-mediated reaction, 2) good to high yields, and 3) its broad scope of applicability to aldehydes and ureas. Hitherto unavailable 6-unsubstituted 2-amino DP 11 and 2-aryl DP 12 were obtained from 9 by a substitution reaction with the amine and the Liebeskind-Srogl reaction, respectively. The compounds 9, 10, and related 6-methyl derivatives 19-21 were assessed for their antiproliferative effect on the human promyelocytic leukemia cell line HL-60. 4,4-Dipropyl derivative 20 showed relatively strong activity with an IC₅₀ value of 341 nM.

In recent years, a variety of medical information has been digitized, and hence, various medical big data have become available. Spontaneous reporting databases are a part of the medical big data. In Japan, the Pharmaceuticals and Medical Devices Agency has developed the “Japanese Adverse Drug Event Report (JADER) database” which has been available since 2012. Thus, everyone can publish safety signal information based on the results of disproportionality analysis using the spontaneous reporting database. Since the release of JADER, many researchers and healthcare professionals are interested in it, and many reports have been prepared using JADER. Although we tend to focus on the fact that it is a publicly available database with many cases, it also has various limitations such as lack of the denominator information, under-reporting, and reporting biases. Detected signals do not necessarily imply a causal relationship between the drug and adverse event. In the “Guideline on good pharmacovigilance practices (GVP) Module IX by European Medicines Agency”, signal detection is the first step in the signal management process. Signal detection alone does not complete pharmacovigilance activities. It is important to understand that spontaneous reporting databases are not only for researchers but also for those who are considering to apply them to clinical work by referring to research using these databases. In this symposium review, I will discuss the role and applicability of spontaneous reporting databases in medical big data.

Medical big data, also referred to as ‘real-world data’ (RWD) is defined as “data related to patient health status and/or health care delivery collected routinely from a variety of sources”. This includes data from disease and drug registries, electronic health records, claims and billing data and census data collected from clinicians, hospitals, and payers. Observational studies using RWD collected during general clinical practice are considered complementary to randomized control trials. However, since this design does not allow the random assignment of patients, causal inference analyses are required. Researchers should study the protocol properly before considering the combination of study design, the characteristics of data source, calculation of the appropriate sample size and the validity of outcomes. Data definition using data code should also be considered. Furthermore, the reliability of the source studies must be considered and discussed when the article is written. This review aims to outline the methods for performing reliable observational studies using RWD.

Recent years, evidences for medical safety and efficacy are accelerated-developing using medical big data. Medical big data were adequate for analyzing 1) rare events that difficult for finding in each hospital, 2) for comparison of bench marks obtained routine work between average data in large number of hospitals and specific hospital data and 3) prescription surveys etc. As so far, these analyses using medical big data were conducted by academia and/or researcher. However, in these days, evidences using medical big data were focused on hospital pharmacists little by little. In this review, we show 3 researches using large claims data such as 1) risk factors assessing for failed low-density lipoprotein level achievement in members of the working-age population, 2) prevalence of drug-drug interaction in atrial fibrillation patients and 3) assessment of “look-alike” packaging designs related to medication errors using information technology and large claims data. Medical big data such as large claims data analysis is useful and suitable for building evidences according to medical staffs-needs.

Industrial reforms utilizing artificial intelligence (AI) have advanced remarkably in recent years. The application of AI to big data analysis in the medical information field has also been advancing and is expected to be used to find drug adverse effects that cannot be predicted by conventional methods. We have developed an adverse drug reactions analysis system that uses machine learning and data from the Japanese Adverse Drug Event Report (JADER) database. The system was developed using the C# programming language and incorporates the open source machine learning library Accord.Net. Potential analytical capabilities of the system include discovering unknown drug adverse effects and evaluating drug-induced adverse events in pharmaceutical management. However, to apply the system to pharmaceutical management, it is important to examine the characteristics and suitability of the level of AI used in the system and to select statistical methods or machine learning when appropriate. If these points are addressed, there is potential for pharmaceutical management to be individualized and optimized in the clinical setting by using the developed system to analyze big data. The system also has the potential to allow individual healthcare facilities such as hospitals and pharmacies to contribute to drug repositioning, including the discovery of new efficacies, interactions, and drug adverse events.

In September 2015, “the Act on the Protection of Personal Information” was amended. Accordingly, “the Ethical Guidelines for Medical Research Involving Human Subjects” were also amended. “The Act on Anonymized Medical Data That Are Meant to Contribute to Research and Development in the Medical Field,” which came into effect in May 2018, aims to collect and utilize medical information of each patient from medical institutions for the purpose of research and development in the medical field. Thus, the rules of personal information that need to be followed are changing considerably in the balance between importance of protection and utilization for medical development. Therefore, health care professionals and researchers are required to fully understand the current situation and the future.

There have been a number of reports of medical device materials becoming denatured or damaged by interactions with pharmaceutical products. For example, the polycarbonate (PC) resin that is widely used in medical devices has the shortcoming of weak chemical resistance, and in more than one case, three-way stopcocks made of PC resin have been damaged when drugs like propofol are used. There have also been reports where concomitant use of pharmaceutical products prevented medical devices from exerting their effect properly. For example, owing to the heart-slowing action of amiodarone hydrochloride, a dose increase in a patient with an implantable cardioverter-defibrillator caused the device to fail to detect a sustained tachycardia attack, as a consequence of which defibrillation therapy was not administered. These are but a few of the numerous and varied interactions between pharmaceutical products and medical devices. We introduce the drug-medical device interactions that have been reported to Pharmaceuticals and Medical Devices Agency (PMDA) thus far.

Pharmaceuticals reportedly cause damage to some polymeric medical devices that administer them. Because this phenomenon and its causes still remain unclear, in this study, all the possible combinations of polymeric materials and pharmaceutical ingredients that could cause failures were identified by conducting a comprehensive analysis on a wide variety of such combinations and through verification tests using the products. The results of the simple immersion tests and the reports of clinical failures indicated that the failures were not caused by the lack of chemical resistance of the polymers but by the environmental stress cracking (ESC) induced by a combination of the stress generated in the material and the interaction with a specific chemical. Therefore, we evaluated all combinations that could cause ESC by developing and applying a simple method for testing ESC. Polycarbonate and polyethylene terephthalate were found to be damaged by alkaline solutions and oils and fats, and surfactants solutions. These failures were also confirmed by the verification tests. Results from the stress state verification, fractographic analysis, and other studies confirmed that these failures were caused by ESC. Cytotoxicity owing to the induction of ESC was not detected in any combination. These results indicated that the residual stress generated during the manufacturing process was one of the reasons for the failure of the medical devices. This residual stress can be eliminated by employing additional processes such as annealing, thereby preventing medical device failures induced through interactions with pharmaceutical ingredients.

Contact between plastic medical devices and medicine causes damage to the medical device and liquid medicine leakage because of physicochemical reactions. These phenomena are listed as contraindications and precautions on individual package inserts of medical devices and drugs; medical device package inserts draw attention to such as interactions. We carried out a questionnaire survey of medical-, drug-, and device-safety managers in hospitals that examined the management system for medical device package inserts, responsibility for dealing with the occurrence of drug and medical device interactions, and at desirable system to avoid such occurrence. Drug package inserts are managed by pharmacists. The medical device package inserts are managed mainly by the device safety managers, as well as by other personnel, including the clinical engineer, doctor, nurse, and clinical radiographer. The survey confirmed that interactions occurred at many phenomena; the procedure involved detailing such occurrences by various medical staff to a medical-safety manager in an incident report. Our study revealed that there were many problems with the package inserts management system for medical devices. Cooperation between safety managers within hospitals is necessary to avoid such incidents.

Studies on functional molecules starting from syntheses of cysteine-containing peptides and protein are described. Starting from evaluation of a cysteine specific side-reaction, a specific reaction for disulfide-bond formation was developed. The reaction made it possible to independently construct a disulfide bridge without effecting the existing disulfide bonds, which resulted in a unique approach for the synthesis of human insulin by site-specific disulfide bond formation. In a series of studies on sulfur-containing amino acids, another cysteine related un-natural amino acid, α-methyl cysteine, was used for the total syntheses of natural products containing a unique thiazorine/thiazole ring system. Chloroimidazolidium coupling reagent developed by us was effective for the successive couplings of the α-methyl cysteine residues. Based on these synthetic studies, design and evaluation of protease inhibitors were then studied, since a stereo-specific synthesis of the key structure is crucial to make the inhibitor an effective functional molecule in the interactions with its target protease. As the target proteases, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and chymotrypsin-like protease of severe acute respiratory syndrome (SARS 3CL protease) were selected: the former is a crucial enzyme for amyloid β production and the latter is an essential enzyme for the re-construction of SARS corona virus in host cells. Structure optimization procedure of the respective inhibitors are described based on X-ray crystal structure analyses of the inhibitor-protease complex.

Antimicrobial resistance (AMR) is a serious problem worldwide. We searched for the AMR determinants of various bacteria isolated from clinical settings and studied their resistance mechanisms and molecular epidemiology. This review focuses on the AMR of Staphylococcus aureus, a major gram-positive pathogen, which has the ability to acquire resistance to antimicrobials. The resistance factors of S. aureus are frequently found on mobile elements, including plasmids and transposons. We determined the complete DNA sequence of the tetracycline-resistance plasmid and found that the inducible expression of tetK in S. aureus was regulated by a post-transcriptional attenuation mechanism. Furthermore, outbreaks of methicillin-resistant S. aureus (MRSA) in hospitals and communities have led us to study infection controls, including the antiseptic susceptibility evaluation and molecular epidemiology of MRSA. Various antiseptic resistance determinants, such as qacA/B and smr, were identified on plasmids and characterized. We demonstrated that the plasmid-mediated efflux pump QacB variant QacIII confers fluoroquinolone efflux ability to S. aureus. Studies on MRSA epidemiology had shown that community-acquired MRSA (CA-MRSA) was disseminated into hospitals and that an increased use of alcohol-based rubs could reduce the incidence of MRSA infections in such institutions. Additionally, the study of CA-MRSA collected from communities and hospitals showed an increase in Panton-Valentine leucocidin (PVL)-positive CA-MRSA, causing severe skin and soft tissue infections. Moreover, various PVL-positive CA-MRSA clones have disseminated in Japan, whereas the USA300 LV/J clone evolved in that country. Our study provides important information regarding MRSA infection control.

Distigmine bromide (distigmine) is a carbamate cholinesterase (ChE) inhibitor, which is mainly used for the treatment of myasthenia gravis. Distigmine is also used in Japan for the treatment for underactive bladder and glaucoma. The effectiveness of distigmine for underactive bladder treatment has been confirmed by many clinical reports, and this effect is thought to be caused by potentiating urinary bladder smooth muscle contraction due to inhibition of acetylcholine degradation during micturition. However, the pharmacological effects of distigmine on urinary bladder smooth muscle have not been well studied. The most distinctive pharmacological feature of distigmine is that it shows long-lasting effects than other ChE inhibitors; however, few studies have investigated the persistence of the enhancing effect of distigmine on the contractile function of urinary bladder smooth muscle. Moreover, this mechanism remains unclear. In this review, we present our findings on the mechanism of the potentiating effect of distigmine on isolated guinea pig urinary bladder smooth muscle contraction. We also discuss the long-lasting potentiating effect of distigmine on urinary bladder motility and the mechanism of these effects using guinea pig urinary bladder smooth muscle in vivo and in vitro. In addition, we present our investigations on the long-lasting mechanism of distigmine using recombinant human acetylcholinesterase.

The efficacy and safety of linaclotide in elderly patients are poorly understood. Herein, we aimed to assess the efficacy and safety of linaclotide in elderly patients in real-world setting. We retrospectively enrolled consecutive patients who started linaclotide therapy at Sapporo Medical University Hospital from October 1, 2017 to December 31, 2019. The efficacy and safety of linaclotide were examined in relation to various factors, including age (<65 or ≥65 years) and dose (0.25 or 0.5 mg/d). Fifty-two patients were enrolled, 60% of whom were over 65 years old and 40% were female. Thirty-six patients received a linaclotide dose of 0.25 mg/d. The most common side effect was diarrhea, but there was no difference in the incidence of diarrhea between the elderly (64.5%) and non-elderly patients (42.9%, p=0.130). No significant difference was observed with respect to improvement in constipation in the elderly (83.9%) and non-elderly patients (71.4%, p=0.318). Additionally, the difference in efficacy of linaclotide in patients who received a reduced dose (80.6%) vs. those who received the recommended dose (75.0%) was not statistically significant (p=0.719). Multivariate analysis revealed that age, gender, and dose were not associated with diarrhea induced by linaclotide treatment. However, concurrent treatment with constipation-inducing medications [odds ratio (OR) 5.79, p=0.047] and linaclotide monotherapy (OR 11.1, p=0.040) were both risk factors contributing to diarrhea. Linaclotide is effective and safe for use in elderly patients. The incidence of diarrhea may increase when linaclotide is administered alone or concurrently used with medications that cause constipation.

As one of the strategies for the early detection and treatment of osteoporosis, we have recommended visiting a hospital, based on the Fracture Risk Assessment Tool (FRAX^®) and evaluation questionnaire for osteoporotic fracture risk. In this study, we evaluated the impact of intervention by community pharmacists by integrating our data for the FRAX^® and questionnaire. The measurement of FRAX^® and the questionnaire survey were conducted through participation in health seminars organized by a community general support center from June 2018 to December 2019. Participants with a FRAX^® score more than 15% and at least one item in the questionnaire were considered to have “suspected osteoporosis” were recommended medical consultation. The medical treatment status for the participants considered to have “suspected osteoporosis” aged 40-90 years were analyzed. Of the 84 participants, 54 had a FRAX^® score more than 15%, and 44 participants fulfilled at least one item in the questionnaire. Medical consultation was recommended to 26 of these 44 participants, excluding 18 under treatment. Of the 25 participants, six (excluding one who disagreed) received consultation, and medical treatment was started for four of them (66.7%). However, consultation with the attending physician was recommended to five of the 18 participants who were initially on treatment but discontinued it at the time of the survey. Consequently, two participants resumed their osteoporosis treatment. Our data suggest advantages of community pharmacists' intervention using FRAX^® and a questionnaire for osteoporotic fracture risk measurement for early detection and medical treatment.

In Japan, the aging of the population is serious problem. The Ministry of Health, Labour and Welfare is constructing a new support system for elderly people called “Community-based integrated care system”. In this system, community pharmacists are expected to play an important role as healthcare professionals for the whole community, including elderly people. Since pharmacists will be needed to manage community health in addition to their daily tasks, it is required to reassess the distribution of community pharmacies and pharmacists. In this study, we surveyed their distribution in Miyagi prefecture by using statistical data from public institutions and reevaluated the distribution to raise problems. Based on the numbers of community pharmacies and pharmacists per 1000 population in the whole Miyagi prefecture, each area was ranked to 2 categories and analyzed regarding population, aging rate and inhabitable land area. It was disclosed that the higher aging rate areas had the higher rate of category below the average of whole Miyagi prefecture, especially in the number of pharmacists. When the numbers of pharmacies and pharmacists per the inhabitable land area were used, the uneven distribution became clearer than when those per population were used. These findings suggested that it was important to characterize the areas by not only the ratios of community pharmacies and pharmacists to population numbers but also by the aging rates and inhabitable land area, which were related to the work efficiency of pharmacists and accessibility for resident to pharmacies.

Tolvaptan (TLV) carries the risk of serious side effects, and its introduction requires hospitalization. Therefore, it is important from the viewpoints of safety and medical economics to predict in advance, the patients for whom it will be effective and introduce it. The purpose of this study was to investigate the noninvasive and simple predictors for identifying TLV responders. We conducted a retrospective observational study of patients with heart failure who had TLV introduced at our hospital from January 1, 2017, to December 31, 2018. By using the body weight and BNP reduction as the effect indices, predictors of body weight and BNP reduction were extracted by logistic analysis. The sensitivity and specificity at the cutoff value obtained by ROC analysis were also examined. Among 85 subjects, urine sodium concentration >63 mEq/L [odds ratio (OR): 6.11, 95% confidence interval (CI): 1.36-27.4] was detected as a predictor of body weight reduction. The sensitivity at this cutoff value was 81%, and the specificity was 70%. Serum osmolarity>291 mOsm/L (OR: 3.76, 95% CI: 1.00-14.2), urine potassium concentration<21 mEq/L (OR: 4.45, 95% CI: 1.09-18.2), and urine sodium concentration>71 mEq/L (OR: 7.38, 95% CI: 2.05-26.6) were detected as predictors of BNP reduction. The sensitivities were 62%, 53%, and 73%, and the specificities were 58%, 68%, and 68%, respectively. Therefore, it was suggested that urine sodium concentration may be useful as a predictor of body weight and BNP decrease after TLV induction.