YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
Volume 138 , Issue 2
Showing 1-14 articles out of 14 articles from the selected issue
Review for award
  • Masashi Tachibana
    2018 Volume 138 Issue 2 Pages 143-148
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     Myeloid-derived suppressor cells (MDSCs) accumulate under pathological conditions, including cancer and chronic inflammation, and they suppress various immune responses such as T cell proliferation. Although several inflammatory signals enhance the differentiation and/or function of MDSCs, it is not clear which factors regulate their differentiation and immunosuppressive function. It has been highlighted that damage-associated molecular patterns (DAMPs) play important roles in the induction of inflammation. One of the DAMPs, the high mobility group box 1 (HMGB1), is released from necrotic cells and secreted by macrophages. It has been shown that HMGB1 level is elevated in tumors and tumor-bearing hosts. It has also been reported that HMGB1 transduces intracellular signaling via several receptors, including the receptor for advanced glycation end-products (RAGE) and the toll-like receptor (TLR)4, both of which enhance the differentiation and/or function of MDSCs. However, the effects of HMGB1 on MDSCs remain unclear. In the present study, we examined the effect of HMGB1 on in vitro MDSC differentiation and immunosuppressive functions. Since murine bone marrow (BM) cells can differentiate into MDSCs upon granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation for 4 d in vitro, we cultured murine BM cells in the presence of HMGB1 and GM-CSF. The results demonstrated that HMGB1 enhanced the suppressive activity of in vitro MDSCs, depending on TLR4, whereas lipopolysaccharide (LPS), one of the TLR4 ligands, interfered with this differentiation and immunosuppressive activity of in vitro MDSCs, depending on TLR4. Our findings thus suggest that the HMGB1-TLR4 axis enhances the immunosuppressive function of MDSCs.
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Symposium Reviews
  • Mitsutoshi Satoh
    2018 Volume 138 Issue 2 Pages 149-150
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
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  • Katsuji Uno
    2018 Volume 138 Issue 2 Pages 151-167
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     Three stages of the pathogenic mechanism of drug allergies can be considered: antigen formation, immune reaction and inflammation/disorder reaction. Drugs are thought to form 4 types of antigens: drug only, polymers, drug-carrier conjugates, and metabolite-carrier complexes. Antigens are recognized by B cell receptors and T cell receptors. Helper T cells (Th) are differentiated into four subsets, namely, Th1, Th2, Th17 and regulatory T cells (Treg). Th1 produces interleukin (IL)-2 and interferon (IFN)-γ, and activates macrophages and cytotoxic T cells (Tc). Macrophages induce type IV allergies, and Tc lead to serious type IV allergies. On the other hand, Th2 produces IL-4, IL-5, and IL-6, etc., and activates B cells. B cells produce IgE antibodies, and the IgE antibody affects mast cells and induces type I allergies. Activated eosinophil leads to the chronic state of type I allergy. Diagnostic testing for allergenic drugs is necessary for patients with drug allergies. Because in vivo diagnostic tests for allergenic drugs are associated with a risk and burden to the patient, in vitro allergy tests are recommended to identify allergenic drugs. In allergy tests performed in vitro, cytological tests are more effective than serological tests, and the leukocyte migration test (LMT) presently has the highest efficacy. An LMT-chamber is better than LMT-agarose in terms of usability and sensitivity, and it can detect about 80% of allergenic drugs.
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  • Takehisa Hanawa, Yayoi Kawano, Mitsutoshi Satoh
    2018 Volume 138 Issue 2 Pages 169-175
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     Anticancer drug-induced stomatitis develops in 30% to 40% of cancer patients undergoing chemotherapy. However, medications for this condition are not commercially available in Japan. The “hospital formulation” is a customized medicine which hospital pharmacists prepare when doctors cannot carry out the medical therapy most suitable for a patient using commercial medicines. However, as the duties of pharmacists increase, use of the “hospital fomulation” decreases. Therefore, development of “hospital fomulations” based on individual evidence has a limit. Irsogladine maleate (IM) is a drug with gastric mucosal protective properties. IM increases intracellular cAMP levels in the gastric mucosa and activates communication between cells. It has been reported that the oral administration of IM reduces the incidence of 5-FU-based chemotherapy-induced stomatitis. However, there have been no reports on the effect of the direct use of IM in treating stomatitis. Therefore, we studied the development of an IM oral spray for stomatitis treatment, and obtained evidence of a direct effect in an animal experiment using a stomatitis model. Next, rebamipide mouthwash was administered to patients who had stomatitis caused by cancer chemotherapy. The total scores were classified into Grades 0 to 4 and evaluated as a stomatitis evaluation score (SES). When comparing SES and changes in the stomatitis area in patients, gradual reductions in the extent of stomatitis were observed, even during the period when SES did not change. Having patients fill in an observation chart was effective for grasping changes in symptoms in outpatients.
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  • Yoshiaki Ohashi
    2018 Volume 138 Issue 2 Pages 177-183
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     In Japan and overseas, Chugai Pharmaceutical Company handles numerous biopharmaceuticals, molecular targeted therapies and other pharmaceuticals with innovative modes of action. Expert safety evaluation is essential for promoting the appropriate use of these pharmaceuticals around the world and in gaining acceptance from patients and healthcare professionals (HCPs), while speedy decision-making is crucial for the timely collection and provision of safety information and thus ensuring safety. In 2015, we collected safety information on more than 180000 cases and evaluated it from a medical standpoint. We have established a system for recording the collected information in a global database, and are conducting signal detection of adverse drug reactions using this database. With this system, we promptly disclose information to regulatory authorities in Japan, the US, Europe and Asia. We have in-house medical doctors with abundant clinical experience who conduct expert safety evaluations. Many innovative drugs, such as anticancer drugs or biopharmaceuticals, require wider-ranging, more rigorous management, including the provision of appropriate safety information to HCPs, management of distribution through wholesalers and dispensing pharmacies, and confirmation of conditions of use, in addition to all-case registration surveillance. With progress in the development of individualized medicine and drugs with new modes of action, in order for HCPs to understand the characteristics of these new drugs and use them appropriately, pharmacists and pharmaceutical companies should cooperate in promoting their appropriate use in the spirit of ‘All Pharmacists for Patients’.
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  • Yoshihiro Uesawa
    2018 Volume 138 Issue 2 Pages 185-190
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.
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Reviews
  • Susumi Hatakeyama
    2018 Volume 138 Issue 2 Pages 191-209
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     This review article describes the total syntheses of englerin A, ophiodilactones A and B, marinomycin A, N-methylwelwitindolinone C isothiocyanate, tirandamycins A-D, and tirandalydigin, which possess intriguing biological activities and challenging structures with characteristic ring systems. The focus is on the synthetic methodologies that lead to the highly stereocontrolled assembly of these natural products.
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  • Kenichi Watanabe
    2018 Volume 138 Issue 2 Pages 211-219
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     Posey et al. have reported multiple molecular diagnoses in 4.5% of cases (101/2076) in which whole-exome sequencing was informative. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. My research projects at the Niigata University of Pharmacy have investigated underlying mechanisms involved in human disease, including fatty acid metabolism, diabetic cardiomyopathy, atopic dermatitis, colitis, hepatitis, etc. Three students from abroad graduated this year from the Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences. These students reported on treatments for heart disease, non-alcoholic steatohepatitis and atopic dermatitis, as well as the underlying mechanisms involved in each. The titles of these reports are “Study of the role of cardiac 14-3-3η protein in cardiac inflammation and adverse cardiac remodeling during heart failure in mice”, “Non-alcoholic steatohepatitis: onset of mechanisms under diabetic background and treatment strategies” and “The role of HMGB1 and its cascade signaling pathway in atopic dermatitis”. It can be concluded from these three theses that oxidative stress and inflammation are among the principal mechanisms underlying these diseases.
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Regular Articles
  • Masahiro Murakami, Kenichi Toraishi, Masayoshi Koinuma, Manabu Amano
    2018 Volume 138 Issue 2 Pages 221-228
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     In this study, we prepared 4 assistive devices (A-D) for Miriopen® to improve the “ease of holding” and “ease of pushing” and compared their usability with that of a device provided by the pharmaceutical company (S). Fifty-five healthy volunteers in their 20s performed the self-injection maneuver using all 5 assistive devices and ranked them regarding 3 items, i.e., the “ease of holding”, “ease of pushing”, and “overall ease of administration”. In all evaluation items, C was ranked first by the largest number of subjects, and the ranking by the subjects was shown by Kendall's coefficient of concordance to be consistent. In addition, comparison of the distance scale calculated from the ordinal scale showed significantly higher ranks of C and D compared with A, B, and S in all evaluation items. No significant difference was noted between C and D. Since C and D had shapes with concavities and convexities that fit the index, middle, and ring fingers (2nd-4th fingers), the fingers are considered to be better stabilized during the injection maneuver with consequent high ratings. Moreover, the 4 assistive devices prepared in this study were rated to be equal to or higher than S.
    Editor’s picks

    In this study, we prepared 4 assistive devices (A-D) for Insulin Pen to improve the “ease of holding” and “ease of pushing” and compared their usability with that of a device provided by the pharmaceutical company (S). Fifty-five healthy volunteers in their 20s performed the self-injection maneuver using all 5 assistive devices and ranked them regarding above 3 items. In all evaluation items, C was ranked first by the largest number of subjects. Moreover, the 4 assistive devices prepared in this study were rated to be equal to or higher than S.

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  • Fusao Komada
    2018 Volume 138 Issue 2 Pages 229-235
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis. The median onset times of DILD for afatinib, bortezomib, crizotinib, erlotinib, gefitinib, and nilotinib were within one month. The median onset times of DILD for dasatinib, everolimus, lapatinib, osimertinib, and temsirolimus ranged from 1 to 2 months. The median onset times of the DILD for alectinib, imatinib, and tofacitinib ranged from 2 to 3 months. The median onset times of the DILD for sunitinib and sorafenib ranged from 8 to 9 months. Weibull distributions for these drugs when using the cluster analysis showed that there were 4 clusters. Cluster 1 described a subgroup with early to later onset DILD and early failure type profiles or a random failure type profile. Cluster 2 exhibited early failure type profiles or a random failure type profile with early onset DILD. Cluster 3 exhibited a random failure type profile or wear out failure type profiles with later onset DILD. Cluster 4 exhibited an early failure type profile or a random failure type profile with the latest onset DILD.
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Notes
  • Akane Nagasato, Masatoshi Nakamura, Hidetoshi Kamimura
    2018 Volume 138 Issue 2 Pages 237-242
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     Methylxanthine is widely administered for the treatment of apnea of prematurity in many countries, and previous reports have clearly established that caffeine is effective for the treatment of apnea of prematurity. In Japan, caffeine has been available since December 2014. Thus, we compared the efficacy and safety of caffeine with that of aminophylline in our hospital. There was no significant difference between the caffeine group and aminophylline group regarding the characteristics of the study patients. The mean efficacy rate from day 1 to day 10 was 89.5% in the caffeine group, and 81.9% in the aminophylline group, although the rate of improvement in apnea episodes each day from day 1 to day 10 was not significantly different between the two groups. On the other hand, the adverse event rates in the caffeine group and the aminophylline group were 70.6% and 75.0%, respectively. No significant difference was observed in the adverse event rates between the two groups. Moreover, suspected abdominal distension due to the drug administration was more frequently observed with the aminophylline group. Our findings indicate that caffeine is as effective as aminophylline, while it is superior to aminophylline regarding its overall safety.
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  • Kazuyuki Niki, Miho Takemura, Kyosuke Kitagawa, Ruka Shimizu, Yuri Tak ...
    2018 Volume 138 Issue 2 Pages 243-250
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     While the community-based integrated care systems are in the process of being structured currently, more and more community pharmacists want to learn physical assessment skills. However, no large-scale survey focusing on present implementation status and problems of physical assessment by community pharmacists has been conducted yet. Osaka has the 2nd highest number of community pharmacies in Japan now, and the population aged ≥65 years will be expected to become the 3rd highest in 2025. Thus, Osaka can become a national leading model case for community pharmacists' activity in future home medical care. Therefore, this study aimed to reveal the present implementation status and problems of physical assessment by community pharmacists in Osaka, especially focusing on vital-signs. The questionnaires were sent to all the 3571 insurance pharmacies belonging to the Osaka Pharmaceutical Association and 871 pharmacies responded. Many pharmacists recognized the necessity for vital-signs measurement by pharmacists in home medical care (81.5% of pharmacies that offered home medical care and 75.4% of pharmacies that did not offer one). However, the proportion of pharmacies that conduct vital-signs measurement in home medical care was 18.7%, therefore, it was suggested that the present problem is “many pharmacists cannot conduct vital-signs measurement, although they think it should be conducted”. Moreover, the most common reason for not measuring vital-signs was the lack of instruments, such as stethoscopes and sphygmomanometer (43.2%). This is the latest report with a large-scale sample, thus, it can serve as valuable knowledge in considering what pharmacists do for the future.
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  • Takashi Majima, Hiroshi Ohara
    2018 Volume 138 Issue 2 Pages 251-258
    Published: February 01, 2018
    Released: February 01, 2018
    [Advance publication] Released: November 09, 2017
    JOURNALS FREE ACCESS
     The scope of pharmaceutical education in Japan has been expanding, and with it an awareness of the importance of team medical care. However, pharmaceutical education still gives little attention to the psychosocial aspects of care, instead focusing on the structures and functions of drugs. In contrast, nursing education emphasizes the fact that medical care involves patients' family and significant others as much as the patients themselves, and thus nursing students are taught the basic needs and developmental stages of those people requiring care alongside their practical nursing skills. In this study, we examined the effect of incorporating certain aspects of introductory nursing education into pharmaceutical education on the self-efficacy of pharmaceutical students. We thus ran an introduction to nursing education course for fourth-year pharmaceutical students (n=86). After the course had finished, we surveyed students about the course. Approximately 94.2% of the students became more interested in team medical care and nearly all (98.8%) thought that what they had learned in the course would be useful in their career. The results indicated that the introduction to nursing education course offered students an opportunity to acquire different viewpoints on clinical situations because the lectures were given by a pharmacist with a nurse license and they were based on his clinical experiences. We therefore propose that more facets of introductory nursing education be incorporated into pharmaceutical education to help students develop their ability to consider patients' psychosocial backgrounds.
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  • Akari Shimauchi, Misa Naganuma, Sayaka Sasaoka, Haruna Hatahira, Yumi ...
    2018 Volume 138 Issue 2 Pages 259-267
    Published: February 01, 2018
    Released: February 01, 2018
    JOURNALS FREE ACCESS
     The “self-medication tax deduction” system began in Japan in January 2017, allowing people to encourage the use of OTC drugs. Package inserts contain important information for consumers regarding their use. In this study, we first checked whether the items, as required in the notifications of the Japanese Ministry of Health, Labour and Welfare, are described in the package inserts of cold remedies and analgesic antipyretics in OTC drugs. The descriptions of almost all packages checked in this study were based on the notifications, but those of a small number of them were not. Next, we examined the description of the items, unrequired in the notification, but worthy for proper use of drugs; e.g., the description of prohibition for use by “patients with severe hypertension” in case of ibuprofen-containing products, and the description was found in only seven of 180 products. Manufactures should make package inserts along with notifications, including the description for proper use of drugs.
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