Preventive medicine and anti-aging medicine have received much attention recently due to an increase in the proportion of elderly people in the population, and to an increase in patients with lifestyle diseases. Oxidative stress is involved in the onset of lifestyle diseases, and various antioxidant supplements and antioxidant-fortified functional foods have recently become available. Many epidemiological studies have shown relationships between the consumption of polyphenol and carotenoid-rich foods and the prevention of lifestyle diseases. We have focused on the absorption mechanism of these food components that show low bioavailability, and have made efforts to improve their poor absorption based on their pharmacokinetic properties. In this report, as examples, we describe the enhancement of the absorption of coenzyme Q10 (CoQ10) and lutein. To improve the absorption of CoQ10, we focused on the component of emulsion. We found that a higher plasma concentration of CoQ10 could be obtained by creating an emulsion containing a surfactant with a higher hydrophile-lipophile balance (HLB) value. For the improvement of lutein absorption, we prepared a solid dispersion and self-emulsifying drug delivery system. It was shown that the plasma concentrations of lutein in these two formulation groups were increased compared with that in the powder group. The absorption of lutein was also evaluated by its cumulative amount in the lymph system. Our data showed that lutein is transferred from the small intestine into the lymph stream, rather than into the blood stream. Further investigations to improve the absorption of these components are in progress.
Second-order nonlinear optical images of aggregates of the ampholytic megamolecular polysaccharide sacran under various stimuli were observed by optical second-harmonic generation (SHG) microscopy. SHG intensity microspots of several tens of micrometers in size are seen for sacran cotton-like lumps and fibers and they have very clear incident polarization dependence. In these microspots, the sacran molecules are oriented in concentric multilayers. We also observed SHG images of sacran prepared in a needle-ring electrode with applied voltage, where SHG was enhanced near the negatively biased needle electrode. We also observed SHG signals near the cast film edges of sacran. The appearance of the SHG image suggested a phase-separation structure in sacran aggregates. These results show that sacran molecules aggregate in several different ways.
Polysaccharides (PS) are one form of biomass occurring in great abundance on earth and are promising organic material alternatives to petroleum-based ones. We have focused on PS produced by cyanobacteria. Aphanothece sacrum, which is a freshwater unicellular cyanobacterium, produces large amounts PS as a main component of the extracellular matrix. We successfully extracted the PS sacran from A. sacrum biomaterials and demonstrated that sacran contains carboxyls and sulfate groups. Furthermore, the constituent sugars of the sacran extracted were determined to be fucose, rhamnose, xylose, arabinose, mannose, glucose, galactose, glucuronic acid, galacturonic acid, and galactosamine. The sequence of sacran is still under investigation. In addition, we confirmed that the sacran was a supergiant with a high absolute molecular weight of 2.35×107 g/mol. Sacran shows a self-orienting behavior in dilute solution at a concentration range over 0.25 wt% to form a liquid crystalline structure. Using this property, it is possible to prepare a sacran cast film with an orientation structure, especially swelling in the thickness direction, to form anisotropic hydrogels. The anisotropy and degree of swelling of the hydrogels could be controlled by varying the heating temperature of the sacran cast file. Furthermore, sacran could be combined successfully with rayon as new fiber materials, and the sacran-rayon complex materials showed increased water absorption compared with the original rayon. This article introduces various applications of sacran in the industrial and medical fields.
Sacran, a large molecular-weight polysaccharide isolated from algae, is composed of 11 types of saccharides, including sulfate and carboxylic acid groups. Because of its unique structure, sacran can form a gel-like sheet in the presence of polyols such as 1,3-butanediol. In addition, those sacran gel-like sheets prevent the evaporation of water and the penetration of chemicals. The results of our previous study suggested that sacran can work as an artificial barrier against external stimuli such as air pollutants which increase the stress on humans. Topically applied sacran was localized at the surface of reconstructed human epidermal equivalents. Those results suggested that sacran inhibits excessive water evaporation from the skin and protects against environmental stimuli by forming an artificial barrier at the skin surface. Then, in a clinical study, we examined the activity of sacran in improving skin problems caused by an impaired epidermal barrier. First, we conducted a use test on a serum formulated with sacran on human volunteers who had impaired skin barrier function. The results showed that sacran provided excellent benefits to improve the maturation of corneocytes. These results suggest that sacran could play an important role in providing optimal skin conditions for keratinocytes to progress through their differentiation.
Approximately 20% of diabetic patients develop diabetic cataracts. As lens proteins are known to be only slightly metabolized during the lifetime, cataracts are difficult to recover from once they have progressed. Therefore, the daily intake of natural compounds would be an important strategy for the prevention of diabetic cataracts. Aphanothece sacrum Okada (Asa) is a freshwater blue-green algae endemic to Japan. It has been eaten since the Edo period in Kyushu. In this study, the inhibitory effects of Asa on the pathogenesis of diabetic cataracts were evaluated. Furthermore, the inhibitory effects of Asa on the formation of Nε-(carboxymethyl) lysine (CML), an oxidation-dependent advanced glycation end-product, were also measured. After 3-month administration, the CML contents in the lens were measured by liquid chromatography tandem mass spectrometry using an internal standard of CML or lysine. Asa significantly inhibited the progression of cataractogenesis and accumulation of CML in diabetic lens compared with the normal diet group. These results suggested that daily intake of Asa reduces oxidative stress and prevents the pathogenesis of cataracts.
Sacran, a new polysaccharide isolated from cyanobacterium Aphanothece sacrum (Sur.) Okada, is known to have potential as an active pharmaceutical ingredient (API) for the treatment of atopic dermatitis, various types of dermatitis, skin wound, hemorrhoids and corneal epithelium disorder. In the present studies, the effects of sacran on skin injury and skin pain induced by stratum corneum tape-stripping and gastric ulcer induced by indomethacin, a non-steroidal anti-inflammatory drug (NSAID), and hydrochloride/ethanol (HCl/EtOH) in mice were investigated. Sacran solution 0.05% (w/v) showed greater reduction of skin injury and skin pain induced by stratum corneum tape-stripping, compared to that of 0.01% (w/v) and 0.1% (w/v) sacran solutions. In addition, the inhibitory effects of 0.05% (w/v) sacran on skin injury and skin pain induced by tape-stripping were significantly superior to 0.05% (w/v) hyaluronic acid solution. On the other hand, 1.0% (w/v) sacran solution significantly inhibited gastric ulcer formation induced by indomethacin, compared with 1% (w/v) dextran solution and the inhibitory effect of sacran was comparable to that of the positive control omeprazole. In addition, 1% (w/v) and 2% (w/v) sacran solution reduced HCl/EtOH-induced gastric ulcer in mice, with the alleviative effect of sacran was comparable to or greater than that of the positive control sodium alginate. These results suggest that sacran has potential as API to treat skin injury and pain induced by tape-stripping and gastric ulcer induced by NSAIDs and EtOH.
The Science Council of Japan issued “The report: Promotion of Social Contributions of Research on Clinical Pharmacy and Pharmaceutical Sciences” on September 29, 2017. This report was prepared based on the analysis of current situation of the four-year doctoral course in the graduate school of pharmacy and the contents of the symposium of 137th annual meeting of the Pharmaceutical Society of Japan (PSJ), “Pharmaceutical Sciences in the Future: The Bridge Linking between Basic and Clinical Research”. The goal of the 4-year doctoral program is to nurture the pharmacist-scientist who has both researcher mind and professionalism as a clinical pharmacist. Research on clinical pharmacy and pharmaceutical sciences is a core research area of the 4-year doctoral course, therefore its promotion is an important issue for the faculty of pharmacy. “Research on clinical pharmacy and pharmaceutical sciences” has to be based on various subjects and needs of the clinical site and be conducted not only at the clinical setting but also in universities, industries, research institutions and so on. Finally, the results have to be fed back to medical care and contribute to society. In this symposium, several representatives from various academic societies and one research institution which have important functions for academic interchanges, will give presentations on issues and initiatives for promoting research on clinical pharmacy and pharmaceutical sciences.
The Science Council of Japan issued “The report: Promotion of social contributions of Research on Clinical Pharmacy and Pharmaceutical Sciences” on September 29, 2017. Research on clinical pharmacy and pharmaceutical sciences is a core research area of the 4-year doctoral course. In this symposium, several representatives from various academic societies and one research institution which have important functions for academic interchanges, will give presentations on issues and initiatives for promoting research on clinical pharmacy and pharmaceutical sciences.
The Subcommittee of Clinical Pharmacy and Pharmaceutical Sciences, Committee of Pharmaceutical Sciences, Science Council of Japan, released the report “Promotion of Social Contributions of Research on Clinical Pharmacy and Pharmaceutical Sciences” in September 2017, after analyzing the current status of the doctoral course in the 4-year system and extensive discussion. The analysis demonstrated that most of the themes of the doctoral course were related to research. However, most of the students in the general selection were involved in basic research, while the students in the adult selection were undertaking research on clinical pharmacy and pharmaceutical sciences. This situation should be improved because the number of students in the adult selection is limited at present. On the other hand, most of the research on clinical practice includes only survey studies and their generalization will be difficult. It will therefore be important to promote collaboration between clinical practice and universities in the future. Based on this condition, the subcommittee proposed that “reverse-translational research” should be the core of research on clinical pharmacy and pharmaceutical sciences in the near future. In addition, 1) collaboration among different research fields, 2) collaboration with clinical practice, 3) maintenance of research funding, and 4) development of human resources should be addressed.
Since the start of the 6-year program in pharmacy education, outcome-based education has progressed, and students' experience of onsite pharmacy practice has increased their awareness of their roles as pharmacists. This progress has been confirmed by student reports submitted at the end of onsite practice. In addition, the results of undergraduate students' graduation research as well as those of clinical research carried out in graduate schools are presented at the annual meetings of the Pharmaceutical Society of Japan (PSJ) and its local branches. Research activity is also promoted by the various divisions of the PSJ that represent a wide range of pharmacy-related fields, including the Division of Clinical Pharmaceutical Sciences. In this way, the PSJ effectively connects researchers in basic and clinical fields, promoting the development of both translational research and reverse-translational research based on needs and ideas brought from the clinic to the basic sciences. Following their presentation at academic meetings, clinical research outcomes are often published in academic journals, including in the three academic journals published by the PSJ: Yakugaku Zasshi, Biological and Pharmaceutical Bulletin, and Chemical and Pharmaceutical Bulletin. Yakugaku Zasshi accepts submissions of case studies, case reports, and survey reports related to clinical pharmacy, which can be submitted in either English or Japanese. As the foundational society for pharmacy and pharmaceutical sciences in Japan, the PSJ is committed to continuing advances in basic and clinical pharmacy research. In the last part of this review, I discuss graduate schools of pharmacy and pharmaceutical sciences.
The 6-year education system for pharmacists was introduced in Japanese schools of pharmacy in 2006, after which a 4-year doctoral course system was established for advancing clinical pharmaceutical research. The roles of hospital pharmacists and community pharmacists have been expanded from drug dispensing to patient care. Clinical pharmacists practice patient care daily using evidence-based medicine and shared decision making. Clinical pharmacists also carry out research proactively for resolving clinical questions encountered in practice. The Japanese Society of Pharmaceutical Health Care and Sciences (JSPHCS) was established in June 1990, and its membership has expanded significantly. The society has over 12000 members including clinical pharmacists and those in pharmacies who participate in practice, research, and education. The JSPHCS functions as the main platform for pharmacy professionals. It holds annual meetings, publishes an academic journal, supports overseas study, and confers awards on exceptional individuals. It also authorizes JSPHCS-Certified Clinical Pharmacists, Board-Certified Oncology Pharmacists, and Board-Certified Pharmacotherapy Specialists. Recently, clinical pharmacy educational seminars and conferences for newly qualified pharmacists have been held to improve the quality of clinical research performed. Several subcommittees under the JSPHCS were newly established for promoting clinical pharmacy research. The mission of the JSPHCS is to promote clinical pharmacy research and systematize the evidence and information, thereby contributing to the healthcare of all.
The Academy of Pharmaceutical Science and Technology, Japan (APSTJ) has contributed to advances in pharmaceutical sciences and progress in formulation technologies. The APSTJ has some 2000 individual members including pharmacists, researchers, technologists, and representatives of regulatory authorities. Remarkably, more than 800 individual members are from the industry. The APSTJ holds an annual meeting and several conferences or seminars on pharmaceutical technologies and skills. It has also set up 13 focus groups (FGs), including some working energetically on medical pharmacy research. For example, the FG on “personalized formulations” aims to develop a suitable dosage form for each individual patient to confirm the concept of personalized medication. To provide opportunities to hear the voices of patients and understand their medical needs, another FG has started a hospital-based internship program for industrial researchers. Furthermore, as an activity of the Japan Agency for Medical Research and Development, an industry-university joint consortium for “pediatric drug formulations” was organized within an FG to develop suitable formulations for pediatric use. The mission of the APSTJ is to provide safe, effective, user-friendly drug products based on pharmaceutical science and technology and cooperation with clinical researchers and medical staff.
The Japanese Society for the Study of Xenobiotics has focused on drug development and clinical pharmacotherapy by applying cutting-edge technology and reviewing drugs. One specific area of focus has been the reverse-translational approach. This approach uses data from the investigation of clinical problems and from the detailed revisiting of preclinical studies to discover new pharmacotherapies and new methods to prevent drug-induced side effects. In 2017, the U.S. Food and Drug Administration restricted the use of prescription codeine cough-and-cold medicines in children. This decision was based on concerns about the effects of the extensive metabolite morphine in cytochrome P450 2D6 ultra-rapid metabolizers. However, there are few reports on the side effects of dihydrocodeine in Japanese children. Our laboratory measured serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression who was given dihydrocodeine phosphate in a suspected case of overdosing. Levels of dihydrocodeine and its primary metabolite, dihydromorphine, were high in this infant. However, the molar ratios of glucuronide conjugates of dihydrocodeine and dihydromorphine were lower than those found in a 3-year-old and a 6-year-old child used as references. To support and facilitate reverse-translational research, the elimination of regional differences in the methodologies used for liquid chromatography to measure drug concentrations and for the genotyping of drug-metabolizing enzymes should become the focus in hospitals, laboratories, and doctoral programs.
After 32 years as a researcher in a pharmaceutical company, the author has served as a professor in the Development of Pharmaceutical Engineering and Drug Delivery Science at University of Shizuoka for the past 11 years. The research I was involved in can be categorized into four main items. First, the crystal transformation of clarithromycin (CAM) was focused on to develop the CAM high-loaded sustained release and gastro-floating formulations. Furthermore, the stabilization mechanism of CAM in the gastro-intestinal tract was clarified to elucidate gel formation under conditions of low pH. Second, the development of novel dosage regimens and optimization of formulation design were carried out using powder technology. In this category, a wax matrix formulation for taste masking, highly drug-loaded fine globular granules using a multi-functional rotor processor, and orally disintegrating tablets treated with microwave or high-pressure carbon dioxide were our targets. The third category was the manufacture of dispersion systems including lipid nanoparticles and cubosomes in order to improve the bioavailability and stability of poorly water-soluble drugs. The fourth category was the development and application of novel physical testing methods including investigation of the internal structure of fine granules using microtomography with synchrotron X-ray radiation, dissolution of spherical granules under non-sink conditions, mathematical models to analyze the dissolution behavior of metastable crystals or amorphous drugs and prediction of the available surface area of tablets during dissolution process.
In this review, 9 compounds with insufficient absorption characteristics, safety or efficacy were selected from among the compounds for which the author was in charge of development between 2000 and 2005, in order to evaluate the pharmacokinetic (PK) approaches used to develop these compounds. Optimization of the PK characteristics of a compound at the early stage of chemical design was found to be the most important factor for successful development. For example, (i) selecting class I or II drugs in the biopharmaceutical classification system, while avoiding efflux transporters, and introducing an appropriate dissociation moiety into a compound to make it soluble lead to sufficient drug absorption; (ii) designing compounds whose production of reactive metabolites, such as acyl glucuronide, does not largely affect total metabolism, yet helps to prevent abnormal PK caused by reactive metabolites. Other factors include (i) selection of a drug efficacy evaluation system based on the correct understanding of the relationship between PK and pharmacodynamics (PD) helps to solve species differences in PD; (ii) the establishment of a nonclinical study based on the identification of the involvement of specific cytochrome P450 molecules in the total metabolic clearance of a drug (fm,CYPs) helps to solve species differences in PK; and (iii) PK analysis using the tube model for hepatic extraction kinetics, and knowledge of the fm,CYPs of the victim drug, lead to successful drug-drug interaction (DDI) prediction. I hope that this review aids in future drug discovery or development.
Direct oral anticoagulants (DOACs) are safe and efficacious when compared to warfarin for patients with venous thromboembolism (VTE). However, bleeding is a major side effect of anticoagulant therapy in VTE patients. Discontinuation of the DOACs associated to adverse events such as bleeding. The HAS-BLED score predicts warfarin-associated hemorrhage. However, little is known about risk factors for DOAC-associated minor bleeding in VTE patients. We aimed to identify risk factors for minor bleeding in VTE patients that were treated with edoxaban, rivaroxaban, or apixaban. We retrospectively evaluated the data of 212 VTE patients who received treatment with a DOAC. The study endpoint was defined as the occurrence of minor bleeding. Logistic regression analysis was used to determine risk factors that were significantly associated with minor bleeding. A total of 36 (17.0%) patients experienced minor bleeding, with rates of 15.7%, 0%, and 21.3% for edoxaban, rivaroxaban, and apixaban, respectively. In the multivariate analysis, bleeding history or predisposition [odds ratio (OR) 6.083, 95% confidence interval (CI) 2.131-17.364, p=0.001] and cancer (OR 6.397, 95% CI 2.858-14.317, p<0.001) were significantly associated with minor bleeding. Bleeding history or predisposition and cancer were the most important risk factors for DOAC-induced minor bleeding in VTE patients in this study. To continue anticoagulant therapy of the DOACs, further management systems by minor bleeding risk factors for patients with VTE will be required.
Inactivated quadrivalent influenza vaccine (IIV4) has been used as seasonal influenza vaccine since 2016 in Japan. This study examined the safety of IIV4 in comparison with the AH1pdm monovalent vaccine used for novel influenza in 2009. Questionnaire surveillance associated with adverse events (AEs) was conducted at Chiba University Hospital, Japan. After being vaccinated, all health care workers (HCWs) were given a daily AEs check sheet on which they recorded solicited events, the same surveillance program used after AH1pdm vaccination in 2009. The frequency of injection site AEs with IIV4 was significantly higher than with the monovalent vaccine, but there was no significant difference with systemic AEs. Injection site and systemic AEs were reported as 83.7% and 25.5%, respectively, with IIV4. The grades of AE, mild, moderate and severe, were 67.2%, 16.4% and 0.1% with IIV4, respectively, indicating that almost all of the AEs reported with IIV4 were mild or moderate. Systemic AEs with IIV4 and monovalent vaccine were reported to be 25.5% and 23.1%, respectively, with the difference not being significant. The grade of AEs with IIV4, mild, moderate and severe, was 19.1%, 5.6% and 0.9%, respectively. The ratio of HCWs reporting AEs peaked at around 80% on day 1, then decreasing to less than 5% by day 7. AEs with IIV4 were reported more frequently compared with the AH1pdm monovalent vaccine. However, in consideration of the grade and duration of AEs, IIV4 was a well-tolerated, safe vaccine.
We investigated the possibility that having pharmacists give asthma patients informational sheets on climate and environmental changes at insurance pharmacies during patient counseling might prevent the worsening of asthma symptoms. Patients with hyperlipidemia were comparative subjects. We created informational sheets about climate and environmental changes and their influence on asthma. During patient counseling, pharmacists gave them to all asthma patients who visited insurance pharmacies over a period of 2 months, between November and December 2017. Based on previous studies, we called days which showed certain climate or environmental changes as compared to the previous day “change days”. We compared the number of visiting patients on change days after preventative information was provided (between January and March 2018) with the number before information was provided (between January and March 2017). In addition, we compared those numbers with the number of patients who visited the target pharmacies between January and March 2016 in order to examine the influence of yearly climate change. The same procedure was used with hyperlipidemic patients. The number of visiting asthma patients after information was provided significantly decreased (5.1±2.1, p=0.03) compared with the number before information was provided, between January and March 2017 (6.1±2.8). The number of aforementioned visits compared to those between January and March 2016 also significantly decreased (p=0.01). Our results suggest that preventative information about climate and environmental changes provided by pharmacists during patient counseling might influence the number of asthma patient visits and prevent the exacerbation of their symptoms.
This study aimed to clarify the situation of use of health foods by patients and the level of satisfaction of patients in order to make use of information on cases where patients undergoing cancer medication therapy use health foods. Between May 7, 2018 and June 29, 2018, we conducted a questionnaire survey of patients with progressive cancer who were undergoing cancer chemotherapy at Ogaki Municipal Hospital. In addition, we conducted a multivariate analysis of patients who were using health foods and those who were not. The questionnaire items included the objectives of use, product effectiveness and satisfaction, and QOL. The rate of health food use was 81/281 (29.5%). The primary objectives of use were, “to maintain health” (29.8%) and “to alleviate symptoms” (24.0%). The primary sources of information about health foods were “a friend” (50.6%) and “TV” (13.5%). The satisfaction level was 0-3 points in 8.3% of patients, 4-6 points in 38.1% of patients, and 7-10 points in 53.6% of patients. For “stage of illness (recurrence),” the odds ratio was 1.810 (95% CI, 1.040-3.150; p=0.035), and for “QOL value,” the odds ratio was 2.210 (95% CI, 1.220-4.020; p=0.009), indicating that these factors had a significant influence on health food use. Health foods tended to be used in patients who had recurring cancer with low QOL and various symptoms, and friends and other people close to the patient had a large influence on the patient's decision. It was clear that the patients' satisfaction level was high.
Nivolumab, an anti-programmed cell death 1 antibody, has been approved for the treatment of unresectable advanced non-small-cell lung cancer (NSCLC). Although immune-related adverse events (irAEs) such as dermatologic, digestive, endocrine, hepatic, and pulmonary toxicities are known to occur upon administration of immune checkpoint inhibitors, case reports of polymyalgia rheumatica (PMR) associated with nivolumab use are rare. We report a case of an NSCLC patient who developed PMR during treatment with nivolumab and received corticosteroids. A 74-year-old man without a history of autoimmune diseases received nivolumab at a dosage of 3 mg/kg once every 2 weeks for the treatment of stage IIIB squamous cell carcinoma. After 12 cycles of nivolumab treatment, he developed grade 3 muscle pain and arthralgia, requiring hospitalization and discontinuation of nivolumab. A bone scintigraphy revealed no bone metastasis. Serological tests showed that although creatine phosphokinase did not increase, C-reactive protein and the erythrocyte sedimentation rate were both high. Tests for the rheumatoid factor, anti-cyclic citrullinated peptide antibody, and anti-nuclear antibody were negative. In addition to the serological findings, joint ultrasonography data and clinical symptoms were evaluated, leading to the diagnosis of PMR. Oral prednisolone 20 mg/d was started to treat the PMR without giant-cell arteritis. The patient's symptoms improved within 5 d of the initiation of treatment. Prednisolone was tapered to 5 mg/d without recurrence of PMR. Although grade 3 or 4 irAEs (except in type 1 diabetes) are generally treated with high-dose corticosteroids, grade 3 PMR associated with nivolumab use may be treatable with low-dose corticosteroids.