YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
Volume 138 , Issue 7
Showing 1-19 articles out of 19 articles from the selected issue
Symposium Reviews
  • Kazuhisa Sekimizu, Kohji Itoh
    2018 Volume 138 Issue 7 Pages 861-862
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
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  • Hideki Sezutsu, Megumi Sumitani, Mari Kondo, Isao Kobayashi, Yoko Taka ...
    2018 Volume 138 Issue 7 Pages 863-874
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     We have been constructing a platform for the development of pharmaceutical and medical applications using the domesticated silkworm, Bombyx mori, as a new animal model for drug development and evaluation. Because silkworm larvae originally have the capacity to synthesize up to 0.5 g of silk proteins, genetically modified silkworms (transgenic silkworms) are expected to have high potential in the production of recombinant silks/proteins. An innovative method for generating transgenic silkworms was established in 2000, and ever since this epoch-defining technological development, longstanding efforts have succeeded in developing novel silks that enable the manufacture of new textile materials for regenerative medical uses. Furthermore, we have succeeded in developing a new system of recombinant protein production. This recombinant protein production system is currently capable of producing a maximum of approximately 15 mg recombinant protein per silkworm larva. Transgenic silkworms have also been shown to produce a wide variety of useful proteins, including antibodies and membrane proteins. Some of these recombinant proteins have been in commercial use since 2011. In addition, we have been developing transgenic silkworms as a novel animal model for testing medicines based on metabolic similarities between silkworms and mammals. These applications show the suitability and potential of transgenic silkworms for medical use. Here, we will describe the challenges faced in creating a transgenic silkworm-based platform for pharmaceutical and medical applications.
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  • Masahiro Tomita
    2018 Volume 138 Issue 7 Pages 875-884
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     There exists an increasing need to produce useful proteins in recombinant technologies. In particular, most biologics for medical purposes are produced as recombinant proteins. Various host cell/vector systems have been developed, but it remains difficult to efficiently produce large molecular weight proteins with complex structures. As a result of breeding for several thousand years, the silkworm has acquired the ability to synthesize bulk amounts of silk proteins. To utilize this capacity for the mass production of useful proteins, transgenic silkworms have been generated that synthesize recombinant proteins in the silk gland and secrete them into the silk cocoon. Using this transgenic silkworm system, various proteins, including antibodies, collagen, and fibrinogen, have been successfully produced and are being developed as materials for diagnostic or research-use reagents, as well as for cosmetics. Moreover, several silkworm-produced proteins are being developed as biologics for therapeutic use. Transgenic silkworms need to be reared under good manufacturing practices (GMP)-compliant conditions to produce biologics. Therefore, we have constructed a GMP-compliant pilot plant for producing biologics using transgenic silkworm, and are now developing silkworm-rearing technology under GMP-compliant conditions.
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  • Kohji Itoh, So-ichiro Nishioka, Tomo Hidaka, Daisuke Tsuji, Nobuo Mait ...
    2018 Volume 138 Issue 7 Pages 885-893
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Lysosomal storage diseases (LSDs) are inborn errors caused by genetic defects of lysosomal enzymes associated with the excessive accumulation of natural substrates and neurovisceral manifestations. Until now, enzyme replacement therapy (ERT) with human lysosomal enzymes produced by genetically engineered mammalian cell lines has been applied clinically to treat several LSDs. ERT is based on the incorporation of N-glycosylated lysosomal enzymes through binding to glycan receptors on the surface of target cells and delivery to lysosomes. However, ERT has several disadvantages, including difficulty in mass producing human enzymes, dangers of pathogen contamination, and high cost. Recently, we have succeeded in producing transgenic silkworms which overexpress human lysosomal enzymes in silk glands, and have purified active and functional enzymes from middle silk glands and cocoons. Silk gland- and cocoon-derived human enzymes carrying high-mannose and pauci-mannose N-glycans are endocytosed by monocytes via the mannose receptor pathway; these were then delivered to lysosomes. Human cathepsin A (Ctsa) precursor proteins purified from the cocoons have been found to suppress microglial activation in the brains of Ctsa-deficient mice; this deficiency is caused by a splicing defect, and serves as a galactosialidosis model associated with the combination of a deficiency of lysosomal neuraminidase 1 (NEU1) and the accumulation of sialyloligosaccharides. Transgenic silkworms overexpressing human lysosomal enzymes in silk glands could serve as a future bioresource to provide safe therapeutic enzymes for the treatment of LSDs. The combination of recent developments in transglycosylation technology with microbial endoglycosidases will aid in the development of therapeutic glycoproteins as bio-medicines.
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  • Hiroshi Hamamoto, Kazuhisa Sekimizu
    2018 Volume 138 Issue 7 Pages 895-899
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     The emergence of antimicrobial resistant (AMR) bacteria has become a serious threat to public health. It is important that we find a mechanistically novel antibiotic to combat AMR. However, finding compounds which are both therapeutically effective and safe is difficult in the development of antibiotics. To solve these problems, we have focused on the silkworm model, which is economical and poses fewer ethical issues, as a means to evaluate the therapeutic effectiveness of test compounds in early stages of antibiotic development. Actually, the silkworm has pharmacokinetic parameters similar to mammals, and we revealed that antibiotics showed ED50s consistent with mammalian models. Thus, we screened therapeutically effective samples from natural products using the silkworm model, and found 23 candidates out of 15000 samples. We ultimately identified a novel antibiotic, lysocin E, and found that it demonstrates a potent therapeutic effect in the mouse systemic infection model. Furthermore, since the target of lysocin E is menaquinone on the bacterial membrane, it belongs to a novel class of antibiotics. In addition, we found a novel antibacterial agent named nosokomycin, GPI0363, and an antifungal agent, VL-2397 (ASP2397), using the silkworm model. In this report, we introduce the usefulness of the silkworm model in the development of antibiotics.
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  • Naoki Utoguchi, Yuichiro Taira
    2018 Volume 138 Issue 7 Pages 901-902
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
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  • Kazuya Nagano, Kazuma Higashisaka, Shin-ichi Tsunoda, Yasuo Tsutsumi
    2018 Volume 138 Issue 7 Pages 903-909
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Human epidermal growth factor receptor 2 (Her2)-targeting antibodies and anti-hormone therapy are effective for most breast cancer patients. However, such approaches are not viable with resistant cases or in triple-negative breast cancer (TNBC) patients, given the lack of Her2 and estrogen and progesterone receptors in these patients. Thus, new drug targets are urgently required. From this perspective, we searched for novel drug targets using proteomic analysis, and identified Eph receptor A10 (EphA10), which is elevated in breast cancer cells as compared to normal breast tissue. Here, we evaluated the potential of EphA10 as a drug target by analyzing its protein expression profile/function in cancer cells, and then by using an anti-EphA10 antibody to treat EphA10-expressing tumor-bearing mice. Protein expression profile analysis showed that EphA10 was expressed in various breast cancer subtypes, including TNBCs, with no expression observed in normal tissues, apart from the testes. Moreover, functional analysis of the cancer cells revealed that ligand-dependent proliferation was observed in EphA10-expressed cancer cells. Thus, we developed our novel anti-EphA10 antibody, which binds to EphA10 with high specificity and affinity at the nanomolar level. Finally, therapeutic analysis indicated that tumor growth was significantly suppressed in the mAb-treated mice in a dose-dependent manner. These results suggest that the EphA10-targeting therapy may be a novel therapeutic option for the management of breast cancer, including in TNBCs which aren't currently treated with molecular-targeted agents. Consequently, we hope that these findings will contribute to the development of a new targeting therapy for refractory breast cancer patients.
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  • Yukio Nagasaki
    2018 Volume 138 Issue 7 Pages 911-918
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Reactive oxygen species (ROS) are known to play a variety of roles in many important events in vivo. However, the overproduction of ROS causes serious adverse effects to living beings. Numerous drugs have been developed and applied to reduce overproduced ROS, but these have failed to be clinically approved. Since most of these antioxidants are low molecular weight (LMW) compounds, they not only eliminate ROS related to diseases, but also destroy the essential redox reactions necessary for basic energy production in living bodies. In the mitochondria of normal cells, ATP production by electron transport chain is carried out, and a large amount of ROS is thus generated; however, LMW antioxidants also nonspecifically enter normal cells and affect essential oxidation. To improve selective antioxidant properties without damage to these normal redox reactions, we designed new polymer antioxidants. These polymers have self-assembling properties and form nanoparticles (RNPs) in which nitroxide radicals covalently attach as a side chain of the hydrophobic segment in the amphiphilic block copolymers, which are then compartmentalized into the solid core of the nanoparticles. Unlike LMW antioxidants, RNPs have extremely poor in vivo toxicity, as they are less likely to be taken up by healthy cells. Since one of RNPs, RNPN has pH-sensitive disintegration properties, it disintegrates at pH lower than 7.0 such as solid tumors and inflammation. It can therefore be used in pH responsive bioimaging and therapy. We have used RNPs experimentally in the treatment of several diseases and confirmed their effectiveness.
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  • Ryo Suzuki, Kazuo Maruyama
    2018 Volume 138 Issue 7 Pages 919-922
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Theranostics is a term used to describe the combination of diagnostic and therapeutic functions in a single agent. Ultrasound, for example, is a good tool for theranostics due to its multi-potency as both a diagnostic tool using sonography, and as a therapeutic, i.e., by high intensity focused ultrasound (HIFU). Likewise, microbubbles and nanobubbles are not only used as contrast imaging agents, but also as enhancers of drug delivery. Recently, the combination of these bubbles with low intensity ultrasound has been utilized as an effective drug delivery system. We have implemented a similar technique by combining bubbles and ultrasound to study cancer gene therapy and chemotherapy. In addition, we have used high intensity ultrasound as a method for directly damaging tumor cells, thus serving as a cancer therapy. For effective cancer treatment, however, the properties of the bubbles are of utmost importance. Currently, we are applying these bubbles to various therapeutic strategies in cancer treatment. In this session, we would like to introduce the feasibility study of our use of these bubbles in cancer treatment.
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  • Yuichiro Taira, Ikuko Taira, Takeshi Nisikawa, Isao Ishida
    2018 Volume 138 Issue 7 Pages 923-930
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Intravenously administered obligate anaerobic bacteria, such as bifidobacteria, grow specifically in tumor tissues. This specificity is attributed to the following: (1) Vascular walls in tumor tissues have nanometer- to micrometer-wide cracks, which allow the bacteria to pass through; (2) the intratumoral environment is hypoxic, due to poor vascularization, and therefore bifidobacteria can survive and proliferate in this anaerobic environment; (3) bifidobacteria cannot survive in well-oxygenated normal tissues. Moreover, unlike gram-negative bacteria, the gram-positive bifidobacteria do not produce endotoxins; therefore, there is no risk of endotoxin shock associated with their intravenous administration. Recently, the utility of bifidobacteria for specific drug delivery to tumor tissues has been highlighted. We have established a novel anti-cancer drug-delivery system using Bifidobacterium longum for the specific release of anti-tumor antibodies (e.g., antibody-drug complexes or single-chain antibodies) to targeted tumor tissues. Here, we introduce the results of our investigation.
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  • Shogo Tokuyama, Tetsuya Yamada
    2018 Volume 138 Issue 7 Pages 931-932
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
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  • Licht Miyamoto, Koichiro Tsuchiya
    2018 Volume 138 Issue 7 Pages 933-938
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Sodium-glucose transporter (SGLT)-2 inhibitors, which are currently in clinical use in most of the world, are unique as their hypoglycemic effects are completely independent of insulin action. Potential benefits and indications for the treatment of other diseases like circulatory and renal disorders are attracting attention. SGLT2 inhibitors not only reduce blood glucose levels but also alter the whole-body energy balance to lower body weight, which should result in the amelioration of multiple metabolic disorders like metabolic syndrome. In the symposium, we briefly introduced the physiological as well as biological functions of SGLTs and discussed strategies for drug design by looking back at the history of drug discovery for SGLT2 inhibitors. We also shared our recent data on their combined usage with other hypoglycemic agents and effects on glucagon secretion, which are current clinical topics relevant to SGLT2 inhibitors. Among those topics, strategies for drug discovery of SGLT2 inhibitors are discussed in this review.
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  • Masamichi Hirose, Naoko Matsushita, Nanae Ishida, Miho Ibi, Maki Saito
    2018 Volume 138 Issue 7 Pages 939-943
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     It is well-known that metabolic remodeling occurs in the presence of cardiomyopathy induced by cardiac ischemia and hypertrophy, and diabetes mellitus. It is also known that a novel cardiac glucose transporter, sodium-glucose co-transporter 1 (SGLT1), is expressed in the human heart. However, the role of SGLT1 in the development of cardiac metabolic remodeling is still unclear. Recent studies demonstrated that SGLT1 activation improves ischemia-reperfusion-induced cardiac injury, and increased SGLT1 gene expression is observed in hypertrophic, ischemic, and diabetic cardiomyopathy in human hearts. Moreover, increases in SGLT1 protein expression cause cardiac remodeling such as hypertrophy and increased interstitial fibrosis in mice. We demonstrated that ischemia-reperfusion-induced cardiac injury was potentiated in SGLT1-deficient mice. In contrast, chronic pressure overload induced by transverse aortic constriction (TAC) caused cardiac hypertrophy and reduced left ventricular fractional shortening in C57BL/6J wild-type mice. Moreover, the TAC-induced hypertrophied heart showed increased SGLT1 and AMPKαprotein expressions. These results suggest the different effects of SGLT1 activation on cardiac diseases such as acute ischemia-reperfusion-induced cardiac injury and chronically-induced cardiac hypertrophy. Thus, SGLT1 may be a novel therapeutic target for the treatment of patients with cardiac diseases such as ischemic and hypertrophic cardiomyopathy.
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  • Yumiko Chiba, Tetsuya Yamada, Hideki Katagiri
    2018 Volume 138 Issue 7 Pages 945-954
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Selective sodium glucose transporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i administration. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i on systemic energy expenditure have not been fully elucidated. We investigated the acute effects of dapagliflozin, an SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin administration, oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared with those after vehicle administration. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa), which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression, NE contents in BAT, and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, occurred prior to the suppression of BAT thermogenesis, e.g., 6 h after dapagliflozin treatment. Collectively, these results suggest that SGLT2i acutely suppresses energy expenditure in BAT via regulation of an interorgan neural network consisting of the common hepatic vagal branch and sympathetic nerves.
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  • Yui Yamazaki, Shinichi Harada, Shogo Tokuyama
    2018 Volume 138 Issue 7 Pages 955-962
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Cerebral ischemic stress often induces a hyperglycemic condition. This postischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage, although the mechanism of this exacerbation remains to be clarified. We previously discovered that the cerebral sodium-glucose transporter (SGLT) was closely involved in the development of cerebral ischemic neuronal damage. SGLT is a member of the glucose transporter family and moves glucose together with sodium ions. SGLT-1, -3, -4, and -6 are distributed in the brain. We conducted further experiments to elucidate the detailed mechanism of the exacerbation of cerebral ischemia by cerebral SGLT. The results clarified: 1) the relationship between cerebral SGLT and postischemic hyperglycemia; 2) the involvement of cerebral SGLT-1 (a cerebral SGLT isoform) in cerebral ischemic neuronal damage; and 3) the effects of sodium influx through cerebral SGLT on the development of cerebral ischemic neuronal damage. This paper presents our data on the involvement of cerebral SGLT in the exacerbation of cerebral ischemic neuronal damage.
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Regular Articles
  • Aya Goto, Kana Yanamoto, Akira Yoshimi, Toshitaka Nabeshima, Yukihiro ...
    2018 Volume 138 Issue 7 Pages 963-971
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     The early intake of alcohol and/or nicotine in childhood or adolescence is one of risk factors for alcohol and/or nicotine dependence in adult. Recently, non-alcoholic beverages with less than 0.00% alcohol are on sale for adults as substitutes for alcoholic beverages without strict legal limitations. However, it is unclear whether non-alcoholic beverages could be a risk factor in drinking and smoking in childhood or adolescence. The purpose of the present survey is to clarify the effect of non-alcoholic beverage intake in children on alcoholic beverage drinking and smoking. We examined as follows: the experience of alcoholic or non-alcoholic beverage intake, and of smoking in elementary school pupils and/or their family members, and interest in or motivation for drinking and smoking in the pupils. As a result, the percentage of alcoholic or non-alcoholic beverage intake, and of smoking in the pupils were 16.8% or 21.9%, and 0.3%, respectively. The number of family members took the alcoholic or non-alcoholic beverage was larger in the pupils took it compared to the pupils did not take it. In the pupils who experienced the non-alcoholic beverage intake, interest in or motivation for drinking alcoholic beverages and/or smoking is higher than in those who did not. These findings indicate that non-alcoholic beverage intake is related to drinking and smoking. We will introduce drug abuse prevention education on the risk of drug dependence among childhood or adolescents based on the findings of this survey.
    Editor’s picks

    Non-alcoholic beverages with < 0.00% alcohol are on sale for adults as substitutes for alcoholic beverages, but it is unclear whether they could be a risk factor in drinking and smoking in childhood/adolescence. The authors indicated that 21.9 % of pupils in elementary school have drunk non-alcoholic beverages related with family drinking, and that non-alcoholic beverage intake is related to drinking and smoking. They also will introduce drug abuse prevention education among childhood/adolescents based on this survey.

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  • Chiaki Ogawa, Megumi Yatabe, Motoki Inoue, Shoko Hirose, Yasukata Ohas ...
    2018 Volume 138 Issue 7 Pages 973-984
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     Although generic anti-tumor agents are in wide clinical use, they have not in all cases been shown to be equivalent to the original agents after preparation. In the present study, original and generic docetaxel formulations were compared with respect to stability when prepared as a non-alcoholic solution for use. When the original formulation was diluted with physiological saline solution to make a non-alcoholic preparation, the concentration decreased with time, whereas no such decrease occurred when a preparation of the generic formulation was made in a similar manner. With both the original and generic formulations, no decrease in docetaxel concentration with time was found after dilution with 5% glucose solution. On the basis of these results, it is concluded that the behaviors of original and generic docetaxel formulations are not equivalent when prepared, but that the original and generic formulations can be taken to be equivalent if they are diluted with 5% glucose solution at preparation.
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Notes
  • Norikazu Kikuchi, Katsuyuki Hazama, Toru Imai, Shinichiro Suzuki, Yosh ...
    2018 Volume 138 Issue 7 Pages 985-990
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     The Japanese Adverse Drug Event Report (JADER) database was used to examine the risk of delirium and the time of its onset with various hypnotics, including 10 benzodiazepines (BZDs), 3 non-benzodiazepines (non-BZDs), 1 melatonin receptor agonist (MRTA), and 1 orexin receptor inhibitor (OXRI). Data entered in the JADER database between April 1, 2004 and February 1, 2016 were analyzed. The index for safety signal detection, the reporting odds ratio (ROR), was the odds ratio for adverse drug reaction reporting. The ROR for each drug was calculated; a signal was considered present if the lower bound of the 95% confidence interval of the ROR was greater than 1. The time to onset of delirium was calculated for drugs for which the number of days from the start of drug administration to delirium onset was reported. During the period examined in the analysis, a total of 621114 adverse drug reaction reports were seen, and the total number of delirium reports was 1417 after redundant cases were excluded. A signal was detected for 5 of the 10 BZDs and all 3 non-BZDs, with no signal for the MRTA and the OXRI. The time of delirium onset varied widely even for drugs classified as being in the same action duration group, and no correlation was seen for delirium onset time. The results of this study suggested that delirium risk varies depending on the hypnotic. Thus, hypnotics can be selected according to their delirium risk.
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  • Satoko Yajima, Akari Shimauchi, Chihiro Sakai, Satoshi Yokoyama, Yoko ...
    2018 Volume 138 Issue 7 Pages 991-1000
    Published: July 01, 2018
    Released: July 01, 2018
    JOURNALS FREE ACCESS
     In Japan, within the background of a progressively aging society, a community general support system is gradually being established. Under this system, community pharmacists are expected to expand their activities in local communities. Here, we surveyed the distribution of community pharmacists in Japan by using government statistics. We found that there are 153 towns/villages without community pharmacists, which is about six times the number of towns without physicians (26 towns/villages). The number of community pharmacists per 100000 population was correlated with the population of the municipality. There was a significant difference in the number of community pharmacists per 100000 population between depopulated and non-depopulated areas. A multiple regression analysis revealed that population, financial capability index, and number of physicians per 100000 population were positively associated with the number of community pharmacists per 100000 population in a given municipality. We hope that the survey provides useful information about future issues facing community pharmacy in a community general support system.
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