YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
139 巻, 11 号
選択された号の論文の15件中1~15を表示しています
受賞総説
  • 櫻井 遊
    2019 年 139 巻 11 号 p. 1357-1363
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    The tumor microenvironment plays a key role in cancer progression, drug resistance, metastasis, etc. To establish a new therapeutic strategy based on control of the tumor microenvironment, I have developed a lipid nanoparticle (LNP)-based in vivo small interfering RNA (siRNA) delivery system equipped with a targeting ligand. First, I established an LNP that induces membrane fusion in response to acidification after internalization by cells using the original pH-sensitive cationic lipid YSK05. A modification of polyethylene glycol to YSK05-containing LNPs allowed significant gene silencing in the human renal cell carcinoma model. Then, I attempted to establish a tumor vasculature-targeting LNP because the vasculature is responsible for the tumor microenvironment. Cyclic RGD peptide is known to be a ligand against integrin αVβ3, which is highly expressed on tumor endothelial cells (TECs). Optimized cyclic RGD peptide-modified LNP (RGD-LNP) suppressed gene expression in TECs to 50%. The inhibition of vascular endothelial cell growth factor receptor 2 (VEGFR2), which is a dominant factor in angiogenesis, by the injection of RGD-LNP significantly delayed tumor growth. Finally, I examined the effect of RGD-LNP on the tumor microenvironment. The suppression of VEGFR2 increased pericyte coverage and endothelial junctions, which indicate maturation of the vasculature. In RGD-LNP-treated mice, systemically administered nanoparticles encapsulating doxorubicin were distributed in a larger area than in untreated mice. Moreover, the therapeutic effect of doxorubicin-loaded liposomes was significantly enhanced by RGD-LNP. In conclusion, I succeeded in developing a new therapy based on regulation of the tumor microenvironment.

  • 佐藤 伸一
    2019 年 139 巻 11 号 p. 1365-1375
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    The chemical labeling of proteins with synthetic small compounds is a key technique in chemical biology, protein-based therapy, and material science. Much of the chemical labeling of native proteins, however, depends on the labeling of lysine and cysteine residues. While those methods have contributed significantly to native protein labeling, alternative methods that can modify different amino acid residues are still required. Here we report the development of a novel methodology of oxidative tyrosine labeling, which was inspired by the single-electron transfer reaction in biological systems. The tyrosine labeling methods were developed using small compounds such as N-methyl luminol derivative, N′-acyl-N,N-phenylenediamine, and 1-methyl-4-aryl-urazole under labeling conditions using a hemin, peroxidase, or ruthenium photocatalyst. These methods were applied to target- and site-selective protein modification.

  • 髙山 健太郎
    2019 年 139 巻 11 号 p. 1377-1384
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Biomolecule-derived peptides are attractive research resources to develop drugs and elucidate the basic mechanisms of life phenomena. This review article focuses on two biomolecules called “neuromedin U (NMU)” and “myostatin” that are deeply involved in obesity and muscle weakness caused by modern lifestyles and aging. A structure-activity relationship (SAR) study based on a biomolecule reveals the structural features required for the biological activity and gives clues leading the drug discovery process. NMU activates two types of receptors (NMUR1 and NMUR2). NMU, which is an attractive candidate for treating obesity, displays a variety of physiological actions in addition to appetite suppression. The discovery of useful receptor-selective agonists helps in elucidating the detailed roles of the respective receptors for each action and in developing therapeutic drugs based on receptor function. Hence, SAR studies focused on the amidated C-terminal heptapeptide of NMU were carried out to obtain selective agonists. Consequently, the respective hexapeptidic NMUR1 and NMUR2 agonists CPN-267 and CPN-116 were discovered. Myostatin, an endogenous negative regulator of skeletal muscle mass, is a promising target for treating muscle atrophy disorders. Focused on the inactivation mechanism of mature myostatin by the myostatin precursor-derived prodomain, a core peptide (23-mer) for effective myostatin inhibition was identified from the mouse myostatin prodomain sequence. The SAR study based on this core peptide afforded a 25-fold more potent derivative (16-mer), which increased skeletal muscle mass and hindlimb grip strength. Therefore, this derivative could be a novel platform for a peptidic drug useful in the treatment of muscle atrophy.

  • 久保山 友晴
    2019 年 139 巻 11 号 p. 1385-1390
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    In neurodegenerative diseases, such as Alzheimer's disease (AD) and spinal cord injury (SCI), inhibited axonal regeneration lead to irreversible functional impairment. Although many agents that eliminate axonal growth impediments have been clinically investigated, none induced functional recovery. I hypothesized that the removal of impediments alone was not enough and that promoting axonal growth and neuronal network reconstruction were needed for recovery from neurodegenerative diseases. To promote axonal growth, I have focused on neurons and microglia. In vitro models of AD and SCI were developed by culturing neurons in the presence of amyloid β (Aβ) and chondroitin sulfate proteoglycan, respectively. These were then used to identify several extracts of herbal medicines and their constituents that promoted axonal growth. Oral administration of these extracts and their constituents improved memory and motor function in in vivo mouse models of AD and SCI, respectively. The bioactive compounds in these extracts were identified by analyzing brain and spinal cord samples from the mice. Their protein targets were identified using the drug affinity responsive target stability method. Analysis of early events in the axons after culture with Aβ revealed that the inhibition of endocytosis was sufficient to prevent the axonal atrophy and memory deficits caused by Aβ. The compounds that increased M2 microglia were observed to promote axonal normalization and growth; they were also found to recover memory and motor function in mice models of AD and SCI, respectively. The above results indicate that axonal growth plays important roles in the recovery from AD and SCI.

  • 原 雄大
    2019 年 139 巻 11 号 p. 1391-1396
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Over the last decade there has been an increase in the prevalence of autism spectrum disorder (ASD); however, its pathogenic mechanisms remain unclear. To date, no effective drug has been developed to treat the core symptoms of ASD, especially social interaction deficits. Previous studies have mainly focused on the glutamatergic, GABAergic, and serotonergic signaling pathways; however, a growing number of studies have reported abnormalities in the dopaminergic pathway, such as mutations and functional alterations of dopamine-related molecules, in ASD patients. Furthermore, atypical antipsychotic drugs risperidone and aripiprazole are prescribed for the treatment of non-core symptoms, such as irritability, in patients with ASD. These observations suggest that the dopaminergic pathway is involved in the pathogenesis of ASD. Previously, we have established a mouse model of ASD based on clinical research, which shows that exposure to valproic acid, an antiepileptic drug, during pregnancy causes an increase in the risk of developing ASD in children. This review summarizes our recent studies, which have assessed alterations in the prefrontal dopaminergic pathway. In addition, we discuss the effects of treatment with attention deficit/hyperactivity disorder drugs and atypical antipsychotic drugs, which activate the prefrontal dopaminergic pathway, on ASD-like behavioral abnormalities in the valproic acid exposure mouse model of ASD.

  • 武智 研志
    2019 年 139 巻 11 号 p. 1397-1402
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Patients with epilepsy are often affected by not only seizures but also a variety of cognitive and psychiatric comorbidities that further impair their quality of life. However, it is unclear whether epilepsy is associated with psychic function. The aim of the present study was to clarify the effects of kindling-induced epileptic seizures on psychic functioning, using behavioral pharmacological tests. Pentylenetetrazol (PTZ)-kindled mice displayed impaired motor coordination (in the rotarod test), and social approach impairment (in the three-chamber social test) compared with vehicle mice. Intraperitoneal ABT-418 treatment (0.05 mg/kg) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the α4 subunit of the α4β2 nicotinic acetylcholine receptor in the piriform cortex was significantly decreased in PTZ-kindled mice. In contrast, expression of the synaptic adhesion molecule neuroligin 3 (NLG3) was significantly higher in the piriform cortex of PTZ-kindled mice compared with vehicle mice. Collectively, our findings suggest that attention deficit/hyperactivity disorder (ADHD)-like or autistic-like behavioral abnormalities associated with epilepsy are closely linked to downregulation of the α4 subunit of the α4β2 receptor and upregulation of NLG3 in the mouse piriform cortex. In summary, this study indicates that ABT-418 is a good candidate for the treatment of patients with epilepsy complicated by psychiatric symptoms such as autism and ADHD.

総説
  • 植田 弘師
    2019 年 139 巻 11 号 p. 1403-1415
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    For my Ph.D. research topic, I isolated endogenous morphine-like analgesic dipeptide, kyotorphin, which mediates Met-enkephalin release, and discovered kyotorphin synthetase, a putative receptor and antagonist. Furthermore, I succeeded in purifying μ-opioid receptor and functional reconstitution with purified G proteins. After receiving my full professor position at Nagasaki University in 1996, I worked on two topics of research, molecular mechanisms of chronic pain through lysophosphatidic acid (LPA) and identification and characterization of neuroprotective protein, prothymosin α. In a series of studies, we have shown that LPA signaling defines the molecular mechanisms of neuropathic pain and fibromyalgia in terms of development and maintenance. Above all, the discovery of feed-forward system in LPA production and pain memory may contribute to better understanding of chronic pain and future analgesic drug discovery. Regarding prothymosin α, we first discovered it as neuronal necrosis-inhibitory molecule through two independent mechanisms, such as toll-like receptor and F0/F1 ATPase, both which protect neurons through indirect mechanisms. Prothymosin α is released by non-classical and non-vesicular mechanisms on various stresses, such as ischemia, starvation, and heat-shock. Thus it may be called a new type of neuroprotective damage-associated molecular patterns (DAMPs)/Alarmins. Heterozygotic mice showed a defect in memory-learning and neurogenesis as well as anxiogenic behaviors. Small peptide, P6Q derived from prothymosin α retains neuroprotective actions, which include blockade of cerebral hemorrhage caused by late treatment with tissue plasminogen activator in the stroke model in mice.

  • 小田口 浩, 日向 須美子, 関根 麻理子, 中森 俊輔, 竹元 裕明, 黄 雪丹, 大嶋 直浩, 嶋田 典基, 楊 金緯, 天倉 吉章, ...
    2019 年 139 巻 11 号 p. 1417-1425
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Ephedra Herb is defined in the 17th edition of the Japanese Pharmacopoeia (JP) as the terrestrial stem of Ephedra sinica Stapf., Ephedra intermedia Schrenk et C.A. Meyer, or Ephedra equisetina Bunge (Ephedraceae). The stems of Ephedra Herb contain greater than 0.7% ephedrine alkaloids (ephedrine and pseudoephedrine). Despite its high effectiveness, Ephedra Herb exert several adverse effects, including palpitation, excitation, insomnia, and dysuria. Both the primary and adverse effects of Ephedra Herb have been traditionally believed to be mediated by these ephedrine alkaloids. However, our study found that several pharmacological actions of Ephedra Herb were not associated with ephedrine alkaloids. We prepared an ephedrine alkaloid-free Ephedra Herb extract (EFE) by eliminating ephedrine alkaloids from Ephedra Herb extract (EHE) using ion-exchange column chromatography. EFE exerted analgesic, anti-influenza, and anticancer activities in the same manner as EHE. Moreover, EFE did not induce adverse effects due to ephedrine alkaloids, such as excitation, insomnia, and arrhythmias, and showed no toxicity. Furthermore, we evaluated the safety of EFE in healthy volunteers. The number of adverse event cases was higher in the EHE-treated group than in the EFE-treated group, although the difference was not significant. Our evidence suggested that EFE was safer than EHE.

一般論文
  • 四十物 由香, 神山 紀子, 鴨志田 敏郎, 山元 俊憲, 向後 麻里
    2019 年 139 巻 11 号 p. 1427-1434
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Recently, a clinical study using a Chronic Liver Disease Questionnaire (CLDQ) showed that ledipasvir/sofosbuvir (LDV/SOF)-treated patients' QOL was more favorable than that of IFN/ribavirin (RBV)-treated patients. However, no study has reported QOL assessment in clinical practice. In this study, we compared the QOL between patients treated with LDV/SOF and those treated with simeprevir (SMV)/peginterferon (Peg-IFN)/RBV to provide QOL information in clinical practice. The subjects were 169 patients with type I chronic hepatitis C or compensated cirrhosis C (Child-Pugh Grade A) who were treated with SMV/Peg-IFN/RBV or LDV/SOF in Hitachi General Hospital. The QOL was assessed ≥2 weeks after the start of administration using the Japanese version of the CLDQ (Kida et al., 2008 version). The total CLDQ score in the LDV/SOF group was significantly higher than in the SMV/Peg-IFN/RBV group (6.59 vs. 6.38, respectively, p=0.007). In particular, the scores for 4 domains (abdominal symptoms, systemic symptoms, activity, and emotional function) in the former were significantly higher than in the latter (p<0.05). Furthermore, the rates of patients scoring 7 (no symptom) on 8 items in the former were significantly higher than in the latter (p<0.05). In clinical practice, LDV/SOF-treated patients' QOL was more favorable than that of those receiving conventional treatment with IFN and RBV. This study may make it possible for health care professionals to provide clinical QOL information on LDV/SOF therapy to patients. Furthermore, QOL information may promote decision-making for treatment, leading to effective treatment.

  • 岡部 知之, 加藤 正巳, 狩野 真由美, 岡﨑 梨紗, 田中 祥之, 豊田 弘, 上野 眞義
    2019 年 139 巻 11 号 p. 1435-1448
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Animal models of chronic kidney failure (CKF) have been developed for the pharmacodynamic evaluation of various phosphate binders that are used clinically to treat hyperphosphatemia in patients with chronic kidney disease. However, these models represent different disease states and severities, depending on the experimental conditions and are not clearly defined for pharmacological evaluation. In addition, experimental models have not yet been established for artificial dialysis. The purpose of this study was to confirm the utility of the various rat models of CKF and the mini-pig model of hemodialysis as models of hyperphosphatemia for pharmacodynamic evaluation. Various rat models of pre-dialysis CKF (oral adenine dosing, 5/6 resection, and ligation nephrectomy model) were evaluated through determinations of serum and urinary parameters (osmolality, creatinine, and phosphorus), pathological observations of kidney, and the phosphorus-absorbing properties of lanthanum carbonate (La) formulations. The rat and mini-pig models were compared based on each evaluation index. In the oral adenine dosing model, serum phosphorus increased markedly and the area under the serum phosphorus concentration-time curve (phosphorus AUC) decreased in a dose-dependent manner with the administration of La formulations. In contrast, a significant decrease in serum phosphorus AUC, a prolongation of the dialysis interval, and an improvement in dialysis efficiency were observed after administration of La formulations to the mini-pig hemodialysis model. Furthermore, the results of bioequivalence studies between two La formulations (Fosrenol and SW670, a generic formulation) suggested that the rat and mini-pig models are useful and precise as pre-dialysis and dialysis models, respectively.

  • 進 健司, 小林 大介, 川尻 雄大, 猪狩 圭介, 光安 博志, 村上 智哉, 堤 一樹, 金澤 康範, 神村 英利, 島添 隆雄
    2019 年 139 巻 11 号 p. 1449-1456
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Benzodiazepine receptor agonists (BZDs) should be appropriately used owing to the associated risks of delirium and falls. Since January 2018, the liaison team pharmacist at Iizuka Hospital has been applying digital labels with recommendations for the reduction of use and changes in the medication orders and prescriptions of BZDs on electronic medical records of patients in the surgical ward. This study aimed to verify the effectiveness of reducing the use of BZDs via the implementation of digital labels. Patients in the surgical ward were retrospectively assessed for changes in medication orders and prescription ratios of BZDs before and after the implementation of digital labels. The ratio of the number of digital labels implemented to the number of confirmations of medication orders and prescriptions of BZDs was 15.0% at the start of implementation; however, the ratio gradually and significantly decreased to 3.6%. The medication order ratio of BZDs was 52.2% before the implementation of digital labels; however, this ratio decreased to 2.7% and 5.6% immediately and 4 months after the implementation of digital labels, respectively. The present study showed that medication orders for BZDs were reduced after the implementation of digital labels and that the reduction effect was maintained for a certain period of time. Thus, the liaison team pharmacist-led approach can contribute to the proper use of BZDs.

    Editor's pick

    The authors on the liaison team have been applying digital labels with recommendations for the reduction of use and changes in the medication orders and prescriptions of BZDs on electronic medical records. This study showed that the medication orders for BZDs were reduced after the implementation of digital labels and that the reduction effect was maintained for a certain period of time, and suggest that the liaison team pharmacist-led approach can contribute to the proper use of BZDs.

  • 國津 侑貴, 磯野 哲一郎, 平 大樹, 寺田 智祐
    2019 年 139 巻 11 号 p. 1457-1462
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Recently, there have been reports that the combination of renin angiotensin inhibitors, diuretics, and non-steroidal anti-inflammatory drugs increases the risk of acute kidney injury (AKI). This combination has been dubbed the “Triple Whammy”. However, there have been no reports about its chronic effects on the kidney. In this study, we investigated the chronic effects of the “Triple Whammy” on kidney function. There were 203 outpatients who were prescribed this combination in our hospital for 5 years. We excluded patients who could also confirm the combination in the previous year and patients for whom laboratory data were unavailable, thus, leaving a target patient group of 95 patients. The average estimated glomerular filtration rate (eGFR) decreased significantly from 62.6 to 58.9 mL/min/1.73 m2 immediately after administering the combination (p<0.01). Although no patients were diagnosed with AKI within 90 days after being administered the combination, 7.4% of patients exhibited a ≥25% reduction in eGFR compared with that before commencing the combination. Correlation analysis of gender, age, past renal function, and renal function change demonstrated that eGFR before administration of the combination negatively correlated with changes in eGFR (p<0.01). Considering the effects of individual differences, eGFR changes before and after administering the combination were compared using a case-crossover design and eGFR after administering the combination was found to be significantly reduced (p<0.01). Therefore, it appears that the “Triple Whammy” may cause not only AKI but also chronic renal degeneration.

  • 生田 智樹, 三浦 健, 篠塚 和正
    2019 年 139 巻 11 号 p. 1463-1470
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Since “Foods with Function Claims” system was established in 2015, the percentage of people taking health foods and supplements is gradually increasing. The number of people taking both dietary supplements and medicines is also increasing. Therefore, providing information on interaction between dietary supplements and medicines has become increasingly important. We have conducted a study for understanding the awareness of the consumers on the interaction of health foods and supplements with medicines. The ratio of those who do not consult with an informed opinion on the interaction between health foods and supplements with medicines was 76% and 55.2% admitted that they did not experience any side effects as a result of this interaction. In conclusion, the understanding of the interaction between health foods and medication among consumers is still limited and most of them do not consult with specialized physicians. It has been revealed that efforts to expanding the consumers understanding on the risk of interaction between supplements and medicines are necessary. It was suggested that the “Database for guiding the interaction between medicines and health foods” could be a useful tool for providing this type of information.

ノート
ケースレポート
  • 山本 麻里子, 井出 直仁, 北島 信三, 大林 正和, 淺田 馨, 松島 暁, 伊藤 政治
    2019 年 139 巻 11 号 p. 1479-1483
    発行日: 2019/11/01
    公開日: 2019/11/01
    ジャーナル フリー

    Empagliflozin reduces blood glucose levels independently of insulin secretion by reducing glucose reabsorption in the proximal renal tubules through inhibition of sodium-glucose cotransporter 2 (SGLT2). Because SGLT2 inhibitors have a different mechanism of action to conventional antidiabetic drugs, recommendations have been issued about the management of specific side effect such as ketoacidosis, urinary tract infection, and genital infection. There have been some reports of SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis (euDKA), but there have been few reports about euDKA in patients with type 2 diabetes using SGLT2 inhibitors while on a low-carbohydrate diet. Here we report a patient who developed euDKA after starting a very low-carbohydrate diet while taking empagliflozin. A 51-year-old man was hospitalized with nausea and vomiting, and investigations revealed metabolic acidosis. euDKA was diagnosed from the information about medications in his drug notebook and a history of eating a low-carbohydrate diet (1900 kcal, consisting of 5.7% carbohydrate, 21.1% protein, 47.3% fat and 25.9% alcohol) for 4 d. The patient improved after infusion of acetated Ringer's solution with 5% glucose and administration of regular insulin. It is necessary for physicians and pharmacists to thoroughly inform patients about the side effects of SGLT2 inhibitors such as ketoacidosis, urinary tract infection, and genital infection. Patients should also be advised about the higher risk of euDKA associated with a low-carbohydrate diet while taking SGLT2 inhibitors.

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