I have engaged in medicinal chemical studies based on the theoretical design of bioactive compounds. First, I present a three-dimensional structural diversity-oriented conformational restriction strategy for developing bioactive compounds based on the characteristic steric and stereoelectronic features of cyclopropane. Using this strategy, various biologically active small molecule compounds, such as receptor agonists/antagonists and enzyme inhibitors, were effectively developed. The strategy was also applied to develop versatile peptidomimetics and membrane-permeable cyclic peptides. Next, studies on Ca²⁺-mobilizing second messengers, cyclic ADP-ribose (cADPR) and myo-inositol trisphosphates (IP₃), are described. In these studies, stable equivalents of cADPR were developed, since biological studies of cADPR have been limited due to its instability. Various potent IP₃ receptor ligands, which were designed using the d-glucose structure as a bioisostere of the myo-inositol moiety of IP₃, have been identified. Organic chemistry studies have also been extensively performed, because excellent organic chemistry is essential for promoting high-level medicinal chemical studies. For examples, new methods for the synthesis of chiral cyclopropanes, new radical reactions with silicon tethers, and kinetic anomeric effect-dependent stereoselective glycosidations have been developed.

This study was designed to clarify the intrapulmonary pharmacokinetics and distribution characteristics of drugs in order to develop better therapies for respiratory diseases, including respiratory infections and pulmonary fibrosis. The distribution characteristics of three macrolide antimicrobial agents—clarithromycin, azithromycin, and telithromycin—in plasma, lung epithelial lining fluid (ELF), and alveolar macrophages (AMs), were examined for the optimization of antimicrobial therapy. The time course of the uptake of these agents in ELF and AMs, following oral administration to rats, resulted in markedly higher concentrations than that in plasma. The high concentration of the agents in AMs was due to their sustained distribution to ELF via multidrug resistance protein 1 and to high uptake by AMs themselves via active transport mechanisms and trapping and/or binding in acidic organelles. The intrapulmonary pharmacokinetics of aerosolized model compounds administered to animals with bleomycin-induced pulmonary fibrosis via aerosol formulations of model compounds (MicroSprayer) were then evaluated. The concentrations of these compounds in the plasma of pulmonary fibrotic rats were markedly higher than in that of control rats. The expression of epithelial tight junctions decreased in pulmonary fibrotic lesions. The accumulation of extracellular matrix inhibited the intrapulmonary distribution of aerosolized model compounds, indicating that aerosolized drugs are easily absorbed after leakage through damaged alveolar epithelia, but cannot become widely distributed in the lungs because of interruption by the extracellular matrix. This review provides useful findings for the development of therapies for respiratory infections and pulmonary fibrosis.

In our continuing search for secondary metabolites from plants, we investigated the chemical constituents of various Okinawan plants. From the stems and leaves of Croton cascarilloides (Euphorbiaceae), a great number of rare diterpenoids: crotofolanes; crotocascarins A-Q, and new diterpenoids; rearranged nor-crotofolanes: crotocascarins α-γ; a rearranged crotofolane: neocrotocascarin; and a new skeletal diterpenoid: isocrotofolane glucoside were isolated. Their structures were mainly elucidated from NMR spectroscopic evidence. In addition, absolute configurations of crotocascarins A, B, K and O, crotocascarin α and neocrotocascarin were determined by X-ray crystallographic analyses, chiral HPLC analyses of 2-methylbutyric acid in their molecules, application of the circular dichroism rule for the α,β-unsaturated γ-lactone ring, and the modified Mosher's method. The absolute structures of crotofolanes were reported for the first time, and a biosynthetic mechanism for the formation of crotocascarin α and neocrotocascarin from crotocascarin B was proposed. Other interesting compounds, namely diosmarioside H: a dimeric ent-kaurane glycoside from the leaves of Diospyros maritima, and melionosides A-C: megastigmane glucosides with a spiro-ring structure from the leaves of Meliosma lepidota ssp. squamulata were also isolated.

I have developed novel ternary complexes of various vaccines with cationic materials and anionic polymers. Plasmid DNA (pDNA) encoding firefly luciferase was used as a model drug to form adequate ternary complexes. Cationic binary complexes were constructed using pDNA and polyethylenimine, and these binary complexes were coated with various anionic polymers to form ternary complexes. These ternary complexes significantly improved cytotoxicity and aggregation with erythrocytes in comparison to the binary complexes. On the other hand, most of those ternary complexes showed little in vitro transgene efficiency because of their anionic surface charge. γ-Polyglutamic acid (γ-PGA)-ternary complexes, however, demonstrated high in vitro transgene efficiency. After the intravenous administration of γ-PGA-ternary complexes to mice, extremely high gene expression was detected in the marginal zone of the spleen, which is rich in antigen-presenting cells. This spleen-specific phenomenon of γ-PGA-ternary complexes appeared to be suited to DNA vaccines against cancer. I therefore examined the preventive effect of γ-PGA-ternary complexes containing pUb-M, a pDNA encoding melanoma surface antigen, against melanoma-bearing mice. Vaccinations of γ-PGA-ternary complexes into mice significantly suppressed the tumor growth of B16-F10 melanoma cells subcutaneously injected into the mice. In the same manner, vaccinations of γ-PGA-ternary complexes containing ovalbumin (OVA) completely suppressed the growth of E.G7-OVA cells expressing OVA. These results strongly suggest that γ-PGA-ternary complexes are useful in the manufacture of specific tumor vaccines.

The first-pass hydrolysis of oral ester-type prodrugs in the liver and intestine is mediated mainly by hCE1 and hCE2 of the respective predominant carboxylesterase (CES) isozymes. In order to provide high blood concentrations of the parent drugs, it is preferable that prodrugs are absorbed as an intact ester in the intestine, then rapidly converted to active parent drugs by hCE1 in the liver. In the present study, we designed a prodrug of fexofenadine (FXD) as a model parent drug that is resistant to hCE2 but hydrolyzed by hCE1, utilizing the differences in catalytic characteristics of hCE1 and hCE2. In order to precisely predict the intestinal absorption of an FXD prodrug candidate, we developed a novel high-throughput system by modifying Caco-2 cells. Further, we evaluated species differences and aging effects in the intestinal and hepatic hydrolysis of prodrugs to improve the estimation of in vivo first-pass hydrolysis of ester-type prodrugs. Consequently, it was possible to design a hepatotropic prodrug utilizing the differences in tissue distribution and substrate specificity of CESs. In addition, we successfully established three useful in vitro systems for predicting the intestinal absorption of hCE1 substrate using Caco-2 cells. However, some factors involved in estimating the bioavailability of prodrugs in human, such as changes in recognition of drug transporters by esterification, and species differences of the first-pass hydrolysis, should be comprehensively considered in prodrug development.

Age-related decreases of various physiological functions have significant influence on activities of daily living (ADL) and QOL in elderly populations. Mechanisms of aging are currently the focus of many researchers in a wide range of studies. Researchers are trying to find novel ways to attenuate or delay aging in humans as well as to develop interventions for age-associated diseases. In this review, we briefly discuss the need for a multidisciplinary approach in aging research.

Caloric restriction (CR) improves whole-body metabolism, suppresses various age-related pathophysiological changes, and extends lifespan. The beneficial actions of CR are regulated in growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signal-dependent and -independent manners. To clarify the GH/IGF-1-independent mechanism, we compared gene expression profiles in white adipose tissue (WAT) between CR and GH/IGF-1 suppression, and found that CR upregulated sterol regulatory element-binding protein 1c (SREBP-1c) regulatory gene expression. To validate the impact of SREBP-1c as a beneficial mediator of CR, we compared the responses to CR between wild-type and SREBP-1c knockout (KO) mice. CR extended lifespan, upregulated gene expression involved in FA biosynthesis, activated mitochondrial biogenesis, and suppressed oxidative stress predominantly in WAT. In contrast, most of these findings were not observed in KO mice. Furthermore, SREBP-1c was implicated in CR-associated mitochondrial activation through upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Sirtuin-3 (SIRT3) regulates mitochondrial quality and is also involved in the beneficial actions of CR. We observed that CR upregulated the mature form of SIRT3 protein and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in WAT. MIPEP cleaved precursor form of SIRT3 to mature form, and activated certain mitochondrial matrix proteins, suggesting that MIPEP might contribute to maintenance of mitochondrial quality during CR via SIRT3 activation. Taken together, CR induces SREBP-1c-dependent metabolic remodeling, including enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α, and improvement of mitochondria quality via Mipep in WAT, resulting in beneficial actions.

Recently, aging is becoming an important social problem in many developed countries including Japan. It is socially and universally important to unveil the impact of aging and extend healthy life expectancy. Here we show our recent finding that dedicator of cytokinesis 11 (DOCK11, also known as Zizimin2) may be involved in immunosenescence of B cells. DOCK11 was identified as a guanine nucleotide exchange factor for a small GTPase called cell division cycle 42. Expression of DOCK11 is restricted to lymphoid tissues, and becomes downregulated with age. Thus we examined the involvement of DOCK11 in immunosenescence of B-1a B cells as an example. B-1a cells are the main source of antibodies at steady state, and function as the first line of defense against infection. Although DOCK11 was expressed by B-1a cells, the expression levels declined with age. Furthermore, production of anti-pneumococcal immunoglobulin M antibodies was suppressed in aged mice, and was recovered by adoptive transfer with B-1a cells in a DOCK11-dependent manner. Thus DOCK11 may be involved in immunosenescence of B-1a cells.

Providing plausible strategies for brain aging protection should be a critical concern for countries with large elderly populations including Japan. Age-related cognitive impairments and movement disorders, such as Alzheimer's and Parkinson's diseases, are caused by neurodegeneration that primarily initiates in the hippocampus and the midbrain substantia nigra, respectively. Neurons are postmitotic, and therefore, the accuracy of cellular metabolism should be crucial for maintaining neural functions throughout their life. Thus accuracy of protein synthesis is a critical concern in discussing mechanisms of aging. The essence of the so-called “error catastrophe theory” of aging was on the fidelity of ribosomal translation and/or aminoacylation of tRNA. There is evidence that reduced protein synthesis accuracy results in neurodegeneration. Similarly, reduced proteostasis via autophagy and proteasomes in aging is crucial for protein quality control and well documented as a risk for aging. In both neurodegeneration and protein quality controls, various proteins are involved in their regulation, but recent evidence suggests that repressor element-1 silencing transcription factor (REST) could be a master regulatory protein that is crucial for orchestrating the neural protecting events in human brain aging. REST is induced in the aged brain, and protects neurons against oxidative stress and protein toxicity. Interestingly, REST is identical with neuron-restrictive silencer factor (NRSF), the master regulator of neural development. Thus NRSF/REST play important roles in both neurogenesis and neurodegeneration. In this review, I summarize the interesting scientific crossover, and discuss the potential use of NRSF/REST as a pharmaceutical target for controlling aging, particularly in relation to brain aging.

As a teacher of biochemistry in a school of pharmacy, a basic subject in pharmacist education, I try to include applied topics such as the biochemical mechanisms of diseases and side effects of medicines in relation to basic knowledge of biochemistry for advanced subjects that students will learn in later years. In aging societies, many people visiting community pharmacies are elderly who tend to have health concerns other than diseases diagnosed by physicians. If asked, community pharmacists should be able to give advice on potential problems patients might have, in addition to giving explanations of medicines prescribed. Basic subjects covered in university pharmacy courses should be the most useful in such community settings.

Over the past few decades, pharmacists' work has changed from product-centered tasks to patient-centered care. In response to such social changes and needs, the pharmacy education course was also extended from 4 to 6 years, and the importance of the humanities in the curriculum (e.g., medical psychology, medical ethics, and communication) is now recognized. The Model Core Curriculum for Pharmacy Education, 2013 version, described 10 professional competencies for pharmacists (professionalism, patient-oriented attitude, communication skills, interprofessional team care, basic sciences, medication therapy management, community health and medical care, research, lifelong learning, and education and training) and stated that the humanities are a foundation of pharmaceutical education. However, a report by the Pharmaceutical Society of Japan (2014) expressed concern that clinical practice was not connected with knowledge of the humanities. It is educationally meaningful when pharmacists who studied the humanities can then offer the best medical care to patients. In order to utilize knowledge of the humanities in the clinical setting, educators need to provide opportunities for active learning. Furthermore, the humanities are useful to help pharmacists acquire meta-cognition.

Drug-related work is one of the most difficult tasks for nurses. This may stem from the lack of knowledge of pharmacology as the minimum duration of the pharmacology course in basic nursing education is only 30 h (2 units). According to the Project to Collect Medical Near-miss/Adverse Event Information 2018 Annual Report of the Japan Council for Quality Health Care, 9.2% of incidents were related to medication and the majority involved nurses. Several medication management tasks in hospitals are currently managed by nurses, while at the same time many nurses have high expectations of pharmacists as experts in pharmacology. Nurses recognize that pharmacists working in hospital wards have great responsibilities. Furthermore, in hospitals that promote advanced treatments, the expertise of pharmacists is demonstrated in the fields of chemotherapy and palliative care in cancer treatment, infection control, and nutrition support team (NST). In many hospitals, however, nurses are responsible for several medication management tasks. Therefore, nurses believe that it would be beneficial for pharmacists to participate more in medical management tasks.

Pharmacists at National Cancer Center Hospital East play important roles in designing, conducting new protocol for clinical trials for developing new regimens and even new drugs. They are also key staffs in treating cancer patients in both in- and out-patient clinics by conducting chemotherapy and monitoring adverse effects. In addition, they educate patients and families before and during treatment by operating independent pharmacists' out-patient clinics. Pharmacists are in front-line of cancer chemotherapy. I was in National Cancer Center but am now in a small city hospital where most of the patients are age over 70 or 80 and frequently live alone. They are suffered from cancer, cardiovascular diseases, and mental diseases. Because most of the patients are elderly, their renal function is more or less disturbed. In this area, medical social workers, nurses, care workers and medical doctors together with visiting nurse system, care worker station try to let the patients enjoy life out of hospital. Japan is a leading country to overcome many problems in an elderly society and try to establish comprehensive community system. The position of pharmacists in this system is not fully clear in our city and probably in other city. Here is another frontier for pharmacists.

Recently, because the marked rise in medical expenses in Japan has become a major social problem, self-medication using OTC drugs in cases of minor health problems has attracted increasing attention. When people use OTC drugs for self-medication, they need support and/or advice from pharmacists on their proper use. This paper outlines recent revisions in the legal sales system of OTC drugs, the social background of self-medication, characteristics of OTC drugs and role of the pharmacists in providing consultation on OTC preparations. Next, consumers' views of self-medication and the OTC drug sales system are described based on the results of surveys performed after they attended an educational event on the proper use of OTC drugs. The survey of consumer views on the legal sales system of OTC drugs revealed that they were the most concerned about safety and convenience. From the survey of consumer views on self-medication, a significant percentage of the group who understood the meaning of the term “self-medication” practiced it in cases of minor health problems. Although no significant difference was seen between the groups who understood the term “self-medication” and those who did not in regard to the reading the drug package label and/or insert, a significant difference was found in their understanding of “The System for Sufferers from Adverse Drug Reactions”. Therefore, it was clear that the consumers familiar with “self-medication” not only practiced it, but also understood the contents of drug package labels and/or inserts.

Hydrophobically-modified hydroxypropylmethylcellulose (HM-HPMC) is a thickener with a long hydrophobic alkyl side chain. In this study, we investigated the gelation ability and rheological properties of a liposome/HM-HPMC mixed solution. The liposome suspension and the HM-HPMC aqueous solution each had low viscosities, but the viscosity increased rapidly when they were mixed. This is thought to be due to the formation of a 3D network structure caused by the hydrophobic group of HM-HPMC penetrating into the liposomal bilayer membrane, crosslinking the liposomes together. This hypothesis was supported by the fact that gelation did not occur when hydroxypropylmethylcellulose without a hydrophobic group was used. The viscosity of the liposome/HM-HPMC mixed solution decreased rapidly when a shear was applied, but immediately returned to the original gel state when the shear was removed, indicating a reversible reaction. When a strong shear is applied, the hydrophobic group of HM-HPMC detaches from the liposome. When the shear is removed, the liposome is again cross-linked by HM-HPMC. From these results, it was revealed that liposome cross-linked gels can be prepared when HM-HPMC is used.

The consumption of health food products, such as Foods with Function Claims, has grown in Japan. Significant information, such as possible side effects or drug interactions, are expected to be described on the packaging to help consumers to make an informed choice about products. In this study, we checked the items described on the packaging of Foods with Function Claims containing eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), Salacinol/Fagomine/Neokotalanol, or Varyl-Tyrosine/Lactotripeptide. We found that the label information on the package have issues that need to be addressed; for example, the description about a warning for concomitant use with antithrombotic drugs was found in only 29.7% of EPA and/or DHA containing products (44 out of 148). Providing information for safe usage of products to consumers is pivotal. Therefore, improving product labeling, and further pharmaceutical support in case of taking health foods, should be considered.

Herein, we investigated the pharmacokinetic (PK) profile of nedaplatin (cis-diamine-glycolateplatinum; CDGP) in a hemodialysis (HD) patient with advanced esophageal squamous cell carcinoma (ESCC) by administering the CDGP immediately prior to HD. Our patient was treated with CDGP (45 mg/m² for a total dose of 60.2 mg) and 5-fluorouracil (560 mg/m² for a total dose of 750 mg) before initiating HD. The total platinum (Pt) concentration (Pt_{_total}) and free Pt concentration (Pt_{_free}) 2 h after completion of HD were 0.4 μg/mL and 0.3 μg/mL, respectively. The removal rates of Pt_{_total} and Pt_{_free} by the dialyzer were 76.5% and 84.6%, respectively. Twenty-four hours after CDGP administration, the Pt_{_free} was below the detection limit of the method of analysis. Pt_{_free} within the range of the recommended CDGP target AUC_0-24 was 8-10 μg/mL•h, the AUC_0-24 of Pt_{_total} and Pt_{_free} were 16.5 μg/mL•h and 8.8 μg/mL•h, respectively. We conclude that HD should be performed after the end of CDGP infusion as part of the CDGP chemotherapy regimen for HD patients with ESCC, and suggest that HD is effective for obtaining a PK profile of CDGP similar to patients with normal renal function.