YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
135 巻, 10 号
選択された号の論文の15件中1~15を表示しています
総説
  • 本島 清人
    2015 年 135 巻 10 号 p. 1083-1089
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      The peroxisome proliferator-activated receptor (PPAR) was discovered a quarter of a century ago. PPAR was soon recognized as a general transcriptional regulator of lipid homeostasis, and several hypolipidemic and antidiabetic agents were shown to be effective ligands for it. Since then, many attempts to develop more potent drugs have been made worldwide, but most were unsuccessful due to serious side effects. It appears that the PPAR boom has ended. This review summarizes the short history of PPAR studies, including our own results, and discusses the lessons learned from the rise and fall of studies in this field for next-generation basic studies and drug development research.
  • 田中 直伸
    2015 年 135 巻 10 号 p. 1091-1097
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      In our continuing search for structurally and biologically interesting metabolites from marine organisms and plants, we investigated the constituents of Okinawan marine sponges and Hypericum plants, resulting in the isolation of several new and unique natural products. Their structures were elucidated on the basis of spectroscopic analyses and chemical conversions. Novel bromopyrrole alkaloids, nagelamides X-Z, were isolated from a sponge Agelas sp. Heteroaromatic alkaloids, hyrtimomines A and B, were isolated from a sponge Hyrtios sp. together with bisindole alkaloids, hyrtimomines C-E. An oxylipin with a trimeric structure, manzamenone O, was obtained from a sponge Plakortis sp. Dimeric eudesmane sesquiterpenes connected through various linker moieties, halichonadins K-L, were isolated from a sponge Halichondria sp., and isomalabaricane triterpenes, stelliferins J-N, were obtained from a sponge Rhabdastrella sp. The investigation for the extracts of Hypericum plants gave new meroterpenes, acylphloroglucinols, and xanthones. Biyoulactones A-E are meroterpenoids from the roots of Hypericum chinense. Acylphloroglucinols, chipericumines A-D, and highly prenylated xanthones, biyouxanthones A-D, were also isolated from the same origin. Tricyclic meroterpenes, yezo'otogirins A-C, and liner meroterpenos, yojironins A and B, were isolated from Hypericum yezoense and Hypericum yojiroanum, respectively.
  • 吉田 将人
    2015 年 135 巻 10 号 p. 1099-1108
    発行日: 2015年
    公開日: 2015/10/01
    ジャーナル フリー
      Total synthesis of biologically active cyclodepsipeptide destruxin E using solid- and solution-phase synthesis is described. The solid-phase synthesis of destruxin E was initially investigated for the efficient synthesis of destruxin analogues. Peptide elongation from polymer-supported β-alanine was efficiently performed using DIC/HOBt or PyBroP/DIEA, and subsequent cleavage from the polymer-support under weakly acidic conditions furnished a cyclization precursor in moderate yield. Macrolactonization of the cyclization precursor was smoothly performed using 2-methyl-6-nitrobenzoic anhydride (MNBA)/4-(dimethylamino)pyridine N-oxide (DMAPO) to afford macrolactone in moderate yield. Finally, formation of the epoxide in the side chain via three steps provided destruxin E, and the stereochemistry of the epoxide was determined to be S. Its diastereomer, epi-destruxin E, was also synthesized in the same manner used to synthesize the natural product. The stereochemistry of the epoxide was critical for the V-ATPase inhibition; natural product destruxin E exhibited 10-fold more potent V-ATPase inhibition than epi-destruxin E. Next, the scalable synthesis of destruxin E for in vivo study was also performed via solution-phase synthesis. The scalable synthesis of a key component, (S)-HA-Pro-OH, was achieved using osmium-catalyzed diastereoselective dihydroxylation with (DHQD)2PHAL as a chiral ligand; peptide synthesis using Cbz-protected amino acid derivatives furnished the cyclization precursor on a gram-scale. Macrolactonization smoothly provided the macrolactone without forming a dimerized product, even at 6 mM, and the synthesis of destruxin E was achieved via three steps on a gram scale in high purity (>98%).
  • 横須賀 章人
    2015 年 135 巻 10 号 p. 1109-1114
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      Numerous clinically valuable medicines, including anticancer drugs, have been developed from biologically active natural compounds and their structurally related derivatives. This review discusses novel natural compounds with promising biological activities and those with novel chemical structures. Glaziovianin A, an isoflavone isolated from the leaves of Ateleia glazioviana (Legminosae), inhibited cell cycle progression at the M-phase with an abnormal spindle structure. AU-1 and YG-1, 5β-steroidal glycosides isolated from the whole plants of Agave utahensis and the underground parts of Yucca glauca (Agavaceae), induced apoptosis of HL-60 cells via caspase-3 activation. Lycolicidinol, an alkaloid isolated from the bulbs of Lycoris albiflora (Amaryllidaceae), induced transient autophagy and morphological changes in mitochondria in the early stage of the apoptotic cell death process in HSC-2 cells. Taccasterosides isolated from the rhizomes of Tacca chantrieri (Taccaceae) and stryphnosides isolated from the pericarps of Stryphnodendron fissuratum (Legminosae) are steroidal and triterpene glycosides with unique chemical structures having novel sugar sequences.
  • 加藤 美紀
    2015 年 135 巻 10 号 p. 1115-1122
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      The use of nanotechnology has increased over the past 10 years, and various nanomaterials with a wide range of applications have been developed. Carbon nanotubes (CNTs), which are cylindrical molecules consisting of hexagonally arranged carbon atoms, are nanomaterials with high utility. Recently, applications of single-walled CNT (SWCNT) in the medical field for drug-delivery and as gene-delivery agents have been proposed. Due to its structural characteristics and physicochemical properties, the inhalation of SWCNT could be considered as one route for targeted drug delivery into the lungs. Therefore, it is necessary to investigate the effects of SWCNT on the physiological state and response of the cells upon delivery into the lung. We clarified the different response of two carcinoma cell lines to SWCNT exposure, and determined these differences may be due to different cell functions. Furthermore, SWCNT exposure resulted in a global downregulation of stress-responsive genes in normal human bronchial epithelial cells, thereby indicating that the factors involved in the stress responses were not activated by SWCNT. We then tried to ascertain the possible effect of SWCNT on the fate of drugs delivered with SWCNT. Exposure to SWCNT down-regulated the mRNA expression and enzymatic activity of CYP1A1 and CYP1B1 by preventing the binding of activated aryl hydrocarbon receptors to the enhancer region of these genes. This review provides basic information for the prediction of human responses to SWCNT exposure by inhalation, and in its use as a drug delivery carrier.
  • 見野 靖晃
    2015 年 135 巻 10 号 p. 1123-1127
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      Mycophenolate mofetil (MMF) has recently been reported to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG), and factors affecting their pharmacokinetics, remain to be clarified. The influence of the pharmacokinetics of MPA and MPAG on the activity of inosine 5′-monophosphate dehydrogenase (IMPDH), a target of the MPA, also remains to be revealed. The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole frequently co-administered with immunosuppressants in immunocompromised patients, is not fully known. The aim of this study was to establish the optimal dosage and administration of immunosuppressants and antifungal agents. MMF improved clinical laboratory markers and reduced prednisolone dosage in 31 SLE patients, with a pre-dose plasma concentration of MPA and MPAG in the interquartile ranges of 0.94-2.96 and 18.6-53.7 μg/mL, respectively. Renal function and co-administered metal influenced the pharmacokinetics of MPA and MPAG in 31 SLE patients in the remission maintenance phase. IMPDH activity was induced in 29 SLE patients receiving the MMF therapy. This induction was dependent on the plasma concentration of MPAG, but not MPA. In addition, IMPDH activity was negatively correlated with complement fraction C3. MPA exposure and disease activity in SLE patients may determine IMPDH activity. The pharmacokinetic variability of OH-ITZ was associated with saturated metabolism to keto-itraconazole, serum concentration of albumin, and renal function in 46 immunocompromised patients. Prevention of fungal infections and drug-drug interactions in immunocompromised patients can be obtained by considering these identified confounding factors.
  • 岩尾 康範
    2015 年 135 巻 10 号 p. 1129-1134
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      With the aim of directly predicting the functionality and mechanism of pharmaceutical excipients, we investigated an analysis method based on available surface area (S(t)), which is the surface area of a drug in direct contact with the external solvent during dissolution. First, to study the effect of lubricant concentration on the dissolution rate of acetaminophen (APAP), the dissolution behaviors as well as the change over time in S(t) of APAP tablets were examined. In the dissolution tests, a retarded dissolution of APAP was not observed with new lubricant triglycerin full behenate (TR-FB), whereas magnesium stearate (Mg-St) retarded the dissolution. The S(t) profiles for APAP with Mg-St at>0.5% showed downward curvature indicating a gradual decrease in surface area over time. Conversely, with TR-FB, even when its concentration was increased, the S(t) profile for APAP had a maximum value. The differences between Mg-St and TR-FB could be explained by the differences in extensibility deriving from their morphology. Next, we evaluated the effect of disintegtant concentration using five disintegrants. When disintegrant was added to ethenzamide tablet formulation, an increase in the dissolution rate and S(t) dependent on disintegrant concentration was observed, according to the type of disintegrant. It was found that the water absorption ability of disintegrants had strong correlations with the parameters of S(t). Taken together, this study demonstrates that analysis of S(t) can directly provide useful information, especially about the functionality of pharmaceutical excipients.
  • 久保 義行
    2015 年 135 巻 10 号 p. 1135-1140
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      Studies of neurological dysfunction have revealed the neuroprotective effect of several cationic drugs, suggesting their usefulness in the treatment of neurological diseases. In the brain and retina, blood-tissue barriers such as blood-brain barrier (BBB) and blood-retinal barrier (BRB) are formed to restrict nonspecific solute transport between the circulating blood and neural tissues. Therefore study of cationic drug transport at these barriers is essential to achieve systemic delivery of neuroprotective agents into the neural tissues. In the retina, severe diseases such as diabetic retinopathy and macular degeneration can cause neurological dysfunction that dramatically affects patients' QOL. The BRB is formed by retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB). Blood-to-retina transport of cationic drugs was investigated at the inner BRB, which is known to nourish two thirds of the retina. Blood-to-retinal transport of verapamil suggested that the barrier function of the BRB differs from that of the BBB. Moreover, carrier-mediated transport of verapamil and pyrilamine revealed the involvement of novel organic cation transporters at the inner BRB. The identified transport systems for cationic drugs are sensitive to several cationic neuroprotective and anti-angiogenic agents such as clonidine and propranolol, and the involvement of novel transporters was also suggested in their blood-to-retina transport across the inner BRB.
  • 高山 和雄
    2015 年 135 巻 10 号 p. 1141-1146
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      Hepatocyte-like cells differentiated from human pluripotent stem cells (such as human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells) are expected to be utilized in drug screening. However, the hepatocyte differentiation efficiency and hepatic functions of hepatocyte-like cells were not sufficient to perform ES/iPS cell-based drug discovery. Therefore, we decided to improve the method of hepatocyte differentiation from human ES/iPS cells. To enhance this hepatocyte differentiation efficiency, hepatocyte-related transcription factors, such as forkhead box protein A2 (FOXA2) and hepatocyte nuclear factor 1 alpha (HNF1α), were overexpressed during the hepatocyte differentiation process. In addition, to enhance the functions of hepatocyte-like cells, these cells were cultured in three dimensional (3D) conditions using a Nanopillar plate. By FOXA2 and HNF1α overexpression, human ES/iPS cells could efficiently (more than 80%) differentiate into albumin-positive hepatocyte-like cells. Various hepatic functions, including albumin secretion and drug metabolism capacities, of the hepatocyte-like cells were significantly enhanced by performing 3D cell culture. These results suggest that the method of hepatocyte differentiation could be improved by using gene transfer and 3D cell culture technologies. We believe that these new hepatocyte-like cells would be useful tools in drug development.
  • 久保 美和
    2015 年 135 巻 10 号 p. 1147-1152
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      As part of our continuing studies on neurotrophin-mimic active compounds in natural products, we investigated the chemical constituents of the pericarps of Illicium jiadifengpi and the roots of Indonesian ginger Zingiber purpureum, resulting in the isolation of new seco-prezizaane-type sesquiterpenoid 1 and phenylbutenoid dimer 3-4 and two new curcuminoids 5-6. The MeOH extract of I. jiadifengpi was fractionated, leading to the isolation of compound 1. Compound 1 significantly enhanced neurite outgrowth in primary cell cultures of fetal rat cortical neurons. It is noteworthy that compound 1 has potential significantly to promote differentiation of multipotent neural stem cell line (MEB5 cells) into neurons. Additionally, we investigated the MeOH extract of the root of Bangle (Z. purpureum) that exhibited neuritogenesis activity in PC12 cells at 25 μg/mL, resulting in the isolation of neurotrophic phenylbutenoid dimers 3-4 and new compounds 5-6. Compounds 3 and 4 were found not only significantly to induce neurite sprouting of PC12 cells but also to increase the neurite length and number of neurites in primary cultured rat cortical neurons, and also showed protective activity against cell death caused by deprivation of serum. Furthermore, chronic treatment with these compounds enhanced hippocampal neurogenesis in dementia model olfactory bulbectomized (OBX) mice. Compounds 5 and 6 had significant NGF-potentiating effects on PC12 cells whereas compound 5 enhanced prevention of amyloid β (Aβ) 42 aggregation.
  • 奥山 聡
    2015 年 135 巻 10 号 p. 1153-1159
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      We have recently shown that 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF) and auraptene (AUR) have neuroprotective effects on the central nervous system. HMF, a citrus flavonoid, altered NMDA-type glutamate receptor antagonist MK-801-induced memory dysfunction and schizophrenia-positive symptom-like behavior. HMF also showed a protective effect against ischemia-induced short-term memory dysfunction. In the ischemic brain, HMF induced the following protective effects against brain dysfunction: 1) rescue of neuronal cell death in the hippocampus; 2) increased production of brain-derived neurotrophic factor; 3) stimulation of neurogenesis in the dentate gyrus subgranular zone; 4) activation of the autophosphorylation of calcium—calmodulin-dependent protein kinase II; and 5) suppression of microglial activation. On the other hand, AUR, a citrus coumarin, ameliorated lipopolysaccharide-induced inflammation in the brain as shown by inhibition of microglial activation and inhibition of cyclooxygenase (COX)-2 expression in the hippocampus. AUR also showed antiinflammatory effects on the ischemic brain by inhibiting microglial activation, COX-2 expression, and neuronal cell death in the hippocampus. The peel of kawachibankan (Citrus kawachiensis), a noted citrus product of Ehime prefecture, Japan, contains AUR, HMF, naringin, and narirutin. The dried powder of both the peel and juice had antiinflammatory effects in the mouse hippocampus, suggesting that citrus compounds may be beneficial as neuroprotective agents in the treatment of neurological disorders.
  • 高木 達也, Carla van Bennekom, Steffen Amann, 服部 千鶴子, 白國 優子, 佐藤 嗣道, 那須 正夫
    2015 年 135 巻 10 号 p. 1161-1168
    発行日: 2015/10/01
    公開日: 2015/10/01
    [早期公開] 公開日: 2015/08/03
    ジャーナル フリー
      Thalidomide was approved for the treatment of multiple myeloma in Japan under a risk management program, named TERMS, in 2008. Since then, we have been conducting a survey of the stakeholders to assess the effectiveness of TERMS. These surveys showed patients had enough knowledge of the risks of thalidomide. In the USA, legislation in 2007 granted its U.S. Food and Drug Administration (FDA) the authority to require Risk Evaluation and Mitigation Strategies (REMS) when necessary to ensure that a drug's benefits outweigh its risks. As of 2015, more than 70 drugs, including thalidomide, have REMS programs. In Germany, in the early 1960s, over 5000 children were born with deformities. Therefore, the safety regulations in Germany go far beyond the European Medicines Agency (EMA) safety regulations at the time of thalidomide re-approval; thalidomide can be prescribed by a special prescribing form, including both proof of the patients' awareness of information about the risks, and participation in a pregnancy prevention program. While Japan has taken similar safety measures, a portion of thalidomide is still privately imported there. By March 2013, 594 patients have been registered to Japan's Safety Management System for Unapproved Drugs (SMUD), which was introduced by the Ministry of Health, Labour and Welfare (MHLW) in 2009. The number of females of child bearing potential (FCBPs) was 33 and the fraction (33/594=5.6%) was higher than that (48/7370=0.7%) in the case of TERMS. Risk management of thalidomide is described in this review.
一般論文
  • 田中 龍一郎, 宮田 侑磨, 水口 直紀, 村上 綾子, 坂崎 文俊
    2015 年 135 巻 10 号 p. 1169-1176
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      This study evaluated the effects of crude drugs obtained from the silkworm in mice with oxonic acid-induced hyperuricemia using xanthine oxidase inhibitory activity and plasma uric acid levels. The plasma uric acid level was analyzed using an improved HPLC with UV detection (HPLC-UV) method, which enabled high-sensitivity analysis of a microliter of plasma. Using this method, we evaluated natural products administered orally to the hypouricemic mice. The plasma uric acid level of mice administered a water-soluble extract from silkworm larvae with botrytis (used in traditional Chinese medicine to reduce wind, lower blood pressure, and change platelet coagulation) was significantly lower than in the control group 1, 2, and 3 h after treatment. In addition, water soluble extracts from a fungus (NBRC 31161) metabolite and silkworm pupae and larvae reduced the plasma uric acid levels in mice compared with the control group.
  • 元井 玲子, 矢野 育子, 尾崎 淳子, 鋒山 香苗, 山本 崇, 深津 祥央, 石塚 良子, 松村 由美, 谷口 正洋, 東村 享治, 松 ...
    2015 年 135 巻 10 号 p. 1177-1184
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      The use of iodine contrast agents occasionally causes serious allergic symptoms including anaphylaxis. At Kyoto University Hospital to prevent nephropathy we began recommending water intake before and after administration of iodine contrast agents in September 2012. In the present study we investigated the effect of water intake on the incidence of allergy-like events after the use of non-ionic iodine contrast agents. We extracted the occurrence of allergy-like events from the incident report system in our hospital from January 2011 to September 2014, and classified these events into the following 3 grades: 1+ (follow-up); 2+ (medication treatment); and 3+ (hospitalization). The allergy-like incidence rate was calculated for subsequent evaluation according to season and water intake. Allergy-like events significantly decreased from 0.49% before the recommendation of water intake to 0.26% at 1 year and 0.20% at 2 years after implementing the recommendation. The incidence of allergy-like events was significantly higher in summer than in winter before water intake was recommended. After implementing the recommendation, the value for summer significantly decreased to an incidence similar to that of winter. Respiratory and gastrointestinal allergy-like symptoms were dramatically decreased after implementing the recommendation. Water intake may be useful for preventing allergy-like events associated with non-ionic iodine contrast agents, especially during the summer.
  • 原田 亜紀子, 杉原 数美, 渡部 容子, 山路 誠一, 北村 繁幸, 太田 茂
    2015 年 135 巻 10 号 p. 1185-1196
    発行日: 2015/10/01
    公開日: 2015/10/01
    ジャーナル フリー
      Aryl hydrocarbon receptor (AhR) ligand activity of the extracts of 62 herbal medicines was examined using yeast reporter assay. Fifty-eight herbal extracts exhibited AhR ligand activity. The highest activity was observed with Ogon (Scutellariae Radix), followed by Oren (Coptidis Rhizoma), Kujin (Sophorae Radix) and Shoma (Cimicifiigae Rhizoma). When these extracts were treated with hesperinase, a hydrolase for sugar conjugates, the aglycones showed higher activity than the parent extracts. Among the constituents of Ogon extract, baicalein and wogonin showed AhR ligand activity, while the sugar conjugate of baicalein, baicalin, was inactive. Among the flavonoid components of these herbal medicines, flavone and chrysin exhibited high ligand activity for AhR. Ethoxyresorufin O-dealkylase (EROD) activity due to CYP1A1 in HepG2 cells was enhanced by the addition of baicalein. Baicalein also decreased the 3-methylcholanthrene-induced increase of EROD activity, but this effect was not statistically significant. When wogonin or baicalein was orally administered at the dose of 100 mg/kg to mice, EROD activity in liver was only slightly changed. Furthermore, when Ogon extract was co-administered with 3-methylcholanthrene, the EROD and methoxyresorufin O-dealkylase activities were not significantly changed. These results indicate that many herbal extracts have AhR ligand activity, and their inducing effect on CYP1A1/2 can be evaluated in HepG2 cells.
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