YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
130 巻 , 9 号
選択された号の論文の16件中1~16を表示しています
誌上シンポジウム
  • 山本 昌
    2010 年 130 巻 9 号 p. 1113-1114
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
  • 関 俊暢
    2010 年 130 巻 9 号 p. 1115-1121
    発行日: 2010年
    公開日: 2010/09/01
    ジャーナル フリー
      Cationic polymers (e.g., cationated gelatins, cationated pullulans and poly-L-arginines) have potential to promote transmucosal delivery of peptide and protein drugs without producing any toxic effects on epithelial cells. These cationic polymers could interact with the mucosal membranes and increase the number of pathways for water-soluble macromolecules in the tight junctions. In the case of insulin having negative charges in neutral solutions, interaction between the cationic polymers and insulin is also important to promote suitable delivery. An appropriate interaction can help insulin to access to cell surface, but too strong interaction suppresses insulin absorption. When the absorption-enhancing effects of sperminated pullulans and gelatin having different numbers of amino groups on the pulmonary absorption of insulin in rats were evaluated, their enhancing effects correlated with the amino group content. Cationic polymers having suitable charge density will be useful for pulmonary delivery systems of insulin.
  • 山本 昌
    2010 年 130 巻 9 号 p. 1123-1127
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      The intestinal absorption of hydrophilic drugs and macromolecular drugs is generally limited by their poor membrane permeability characteristics in the intestine. Therefore, absorption enhancers were usually adopted for improving the intestinal absorption of these poorly absorbable drugs. However, conventional absorption enhancers were generally more effective in the large intestine rather than the small intestine and absorption enhancers with high effectiveness in the small intestine is highly desirable. Based on the background, we focused on polyamidoamine (PAMAM) dendrimers as novel absorption enhancers and effects of PAMAM dendrimers on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. The absorption of 5(6)-carboxyfluorescein (CF), fluorescein isothiocyanate-dextran with an average molecular weight of 4000 (FD4) and calcitonin from the rat small intestine was significantly enhanced in the presence of PAMAM dendrimers. However, PAMAM dendrimers had almost no absorption enhancing effect on the small intestinal absorption of macromolecular drugs including fluorescein isothiocyanate-dextran with an average molecular weight of 10000 (FD10) and insulin. Furthermore, we evaluated the intestinal membrane damage with or without PAMAM dendrimers. PAMAM dendrimers at concentrations of 0.05% (w/v) and 0.1% (w/v) did not increase the activities of lactate dehydrogenase (LDH) and amounts of protein in the intestine. These findings suggested that PAMAM dendrimers at lower concentrations might be potential and safe absorption enhancers for improving absorption of poorly absorbable drugs from the small intestine.
  • 勝見 英正, 草森 浩輔, 坂根 稔康, 山本 昌
    2010 年 130 巻 9 号 p. 1129-1133
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      Bisphosphonates are carbon-substituted pyrophosphate (PCP) analogues that exhibit high affinity to hydroxylapatite and inhibit bone resorption after their administration. They are widely used as the first-choice drug for the treatment and prevention of bone diseases, including Paget's disease, hypercalcemia of malignancy, and osteoporosis. However, the oral bioavailability of bisphosphonates is quite low (1-2%). In addition, the oral administration of bisphosphonates has been associated with mucosal damage, including gastritis, gastric ulcer, and erosive esophagitis. Therefore, it is highly desirable to develop new delivery systems that improve their bioavailability and safety. In this review, recent challenges in the developments of novel delivery system of bisphosphonates are summarized. Then, future developments of delivery system of bisphosphonates are also discussed in order to improve their therapeutic efficacy and safety in the treatment of bone diseases.
  • 竹内 洋文, 杉原 光
    2010 年 130 巻 9 号 p. 1135-1142
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      We have developed polymer-coated liposomes for effective and non-invasive delivery of peptide drugs. Polymer-coated liposomes, which are liposomal particles coated with functional polymers, were designed in order to have suitable functions required for drug delivery. So far, we have reported prolonged retention in the gastro-intestinal tract owing to the mucoadhesive properties of the polymer-coated liposomes. This review shows outline of effectiveness of polymer-coated liposomes in absorption of calcitonin after oral administration. The main factors for absorption enhancing of calcitonin are mucoadhesion and penetration of polymer-coated liposomes into the mucus layer. Application of polymer-coated liposomes in pulmonal drug delivery and novel strategies for designing mucoadhesive particulate systems are also described.
総説
  • 芳生 秀光
    2010 年 130 巻 9 号 p. 1143-1156
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      Mercury and its organic compounds, especially methylmercury are extremely hazardous pollutants that have been released into the environment in substantial quantities by natural events and anthropogenic activities. Due to the acute toxicity of these contaminants, there is an urgent need to develop an effective and affordable technology to remove them from the environments. Recently, attempts have been made to utilize bacterial mer operon-mediated reduction and volatilization of mercurials for environmental remediation of mercury pollution. However, application of this technology to the treatment of mercury-contaminated environments has been limited by social concerns about the release of volatile mercury that will become part of the local mercury cycle and repollute the environment again, into the ambient air. To improve this environmental problem, a new mercury scavenging mechanism that could be expressed in living cells and accumulates mercury from contaminated site without releasing mercury vapor is necessitated. To construct a new biocatalyst that is capable of specifically accumulating mercury from contaminated sites without releasing mercury vapor, we have genetically engineered bacteria and tobacco plant for removal of mercury from wastewater and soils, respectively, to express a mercury transport system and organomercurial lyase enzyme simultaneously, and overexpress polyphosphate, a chelator of divalent metals. The applicability of these new engineered biocatalysts in the environmental remediation of mercurials is evaluated and discussed in this review.
  • 小野寺 祐夫
    2010 年 130 巻 9 号 p. 1157-1174
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      This paper reviews the formation mechanism and chemical safety of nonintentional chemical substances (NICS) present in chlorine-treated water containing organic contaminants. Undesirable compounds, i.e., NICS, may be formed under certain conditions when chlorine reacts with organic matter. The rate and extent of chlorine consumption with organics are strongly dependent on their chemical structures, particularly whether double bonds or sulfur and nitrogen atoms occur in the molecules. Organothiophosphorus pesticides (P=S type) are easily oxidized to their phosphorus compounds (P=O type) in chlorinated water containing HOCl as little as 0.5 mg/l, resulting in an increase in cholinesterase-inhibitory activity. Chlorination of phenols in water also produces a series of highly chlorinated compounds, including chlorophenols, chloroquinones, chlorinated carboxylic acids, and polychlorinated phenoxyphenols (PCPPs). In some of these chloroquinones, 2,6-dichloroalkylsemiquinones exhibit a strong mutagenic response as do positive controls used in the Ames test. 2-Phenoxyphenols in these PCPPs are particularly interesting, as they are present in the chlorine-treated phenol solution and they are also precursors (predioxins) of the highly toxic chlorinated dioxins. Polynuclear aromatic hydrocarbons (PAHs) were found to undergo chemical changes due to hypochlorite reactions to give chloro-substituted PAHs, oxygenated (quinones) and hydroxylated (phenols) compounds, but they exhibit a lower mutagenic response. In addition, field work was performed in river water and drinking water to obtain information on chemical distribution and their safety, and the results are compared with those obtained in the model chlorination experiments.
  • 檜井 栄一
    2010 年 130 巻 9 号 p. 1175-1179
    発行日: 2010年
    公開日: 2010/09/01
    ジャーナル フリー
      L-glutamate (Glu) has been thought to be an excitatory amino acid neurotransmitter in the mammalian central nervous system. Relatively little attention has been paid to the functional expression of Glu signaling machineries in peripheral tissues. In this review, therefore, we summarized the possible signaling by Glu as an extracellular signal mediator in mechanisms underlying maintenance of cellular homeostasis in bone tissues. Constitutive expression of mRNAs for particular Glu receptors (GluR), Glu transporters (GluT) was found in osteoblasts. N-methyl-D-aspartic acid receptor antagonist MK-801 significantly prevented differentiation and maturation of osteoblasts through modulation of expression of Runx2. DL-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid significantly increased the release of endogenous Glu from osteoblasts through its receptor expressed by osteoblasts. In addition, [3H]Glu uptake was also seen in a temperature- and sodium-dependent manner with pharmacological profiles similar to those for brain GluTs in osteoblasts. Although no mRNA expression was found for all GluRs examined in primary cultured mouse osteoclasts, constitutive expression of mRNAs was seen with GluT, such as excitatory amino acid transporters and cystine/Glu antiporter. Glu markedly inhibited osteoclastogenesis in a manner sensitive to the antiporter inhibitor. The systemic administration of Glu significantly prevented the decreased bone mineral density in addition to increased osteoclastic indices in ovariectomized mice in vivo. Taken together, Glu could play a pivotal role in mechanisms underlying the maintenance of cellular homeostasis as an extracellular signal mediator in bone.
  • 山下 沢
    2010 年 130 巻 9 号 p. 1181-1187
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      Heme-containing proteins, the heme proteins, are known to have physiologic functions in humans, mammalians, fish, plants, and bacteria. For example, hemoglobin and myoglobin, which belong to the globin family, have been studied in terms of their structures and functions with spectroscopic and mutagenic methods. Recently, a new class of heme proteins has been discovered, referred to as gas sensors. These are heme-based sensor proteins that play important roles in transcriptional activation, histidinekinase activities, phosphodiesterase activities, etc. CooA is a CO-sensing transcriptional activator derived from the photosynthetic bacterium Rhodospirillum rubrum. FixL is a rhizobial oxygen sensor protein, and we have targeted Bj FixL derived from Bradyrhizobium japonicum. Dos from Escherichia coli is an oxygen sensor protein, which senses oxygen in the heme-containing domain and induces phosphodiesterase activity in other domains. In previous work, we studied the axial ligands and C-helix of CooA to clarify the activation mechanism. Moreover, FixL and Dos were investigated using time-resolved spectroscopic methods. Whereas FixL has a pentacoordinate heme in the ferrous deoxy form, there are a proximal histidine (His 77) and a distal methionine (Met 95) as axial ligands to coordinate to the heme iron in EcDos. However almost all gas sensors show mono-exponential rebinding (6-7 ps), while EcDosH and full-length Dos show biexponential rebinding (7 ps and 35 ps) on the internal ligand. The results were also supported by molecular dynamic simulation. Here we discuss recent work on gas sensors with implications provided by our research.
  • 芳原 成美, 合田 光寛, 吉田 菜三夏, 橋川 直也, 川﨑 博己
    2010 年 130 巻 9 号 p. 1189-1195
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      The present study was designed to investigate involvement of angiotensin (Ang) II type 2 receptors (AT2R) in restoration of perivascular nerve innervation injured by topical phenol treatment. Male Wistar rats underwent in vivo topical application of 10% phenol around the superior mesenteric artery to induce nerve injure. Phenol treatment markedly reduced densities of both calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI)- and neuropeptide Y (NPY)-LI-containing fibers. NGF restored densities of both nerve fibers to the Sham control level. Coadministration of Ang II and losartan (AT1R antagonist) significantly increased the density of CGRP-LI-fibers but not NPY-LI-fibers compared with saline control. The increase of the density of CGRP-LI-fibers by coadministration of Ang II and losartan was suppressed by adding PD123319 (AT2R antagonist). Furthermore, NGF-induced CGRP-LI nerve regeneration was inhibited by PD123319 treatment. NGF-induced increase of AT2R mRNA level was siginificantly suppressed by AT1R antagonist treatment in phenol treated rats dorsal root ganglia. These results suggest that selective stimulation of AT2R by Ang II facilitates reinnervation of mesenteric perivascular CGRP-containing nerves injured by topical phenol application in the rat.
一般論文
  • 築地 茉莉子, 古山 光, 長谷川 毅, 石田 恵子, 松田 公子, 福田 恵子, 清水 秀行
    2010 年 130 巻 9 号 p. 1197-1205
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      Recently, certification systems for Board-Certified Psychiatric Pharmacy Specialists (BCPPS) and Board-Certified Pharmacists in Psychiatric Pharmacy (BCPPP) were established by the Japanese Society of Hospital Pharmacists (JSHP) in 2008, to meet the increasing needs for specialists in psychiatric pharmacy. However, there was no report on the background and opinion of pharmacists who have intention to take the BCPPS or BCPPP and/or seminar programs for BCPPS or BCPPP. The Chiba Society of Hospital Pharmacists has started to provide a seminar program certified by the JSHP to study psychiatry for pharmacists and also investigated the participants' background, demand for the program, and issues in taking the BCPPS or BCPPP using questionnaires. We found that many participants wanted lectures to obtain information on issues they face in routine work as well as for certification testing. For many participants, satisfying the requirements for applying for the BCPPS or BCPPP was one of the most important issues in receiving the qualifications. We found that over 40% of participants working at community pharmacies intended to take the BCPPS or BCPPP, although working experience at a community pharmacy does not entitle them to apply for the BCPPS or BCPPP. The intention of community pharmacists indicates that discussion of the requirements for BCPPS or BCPPP certification systems is necessary to improve psychiatric community care. We will plan a practical seminar program with feedback from this investigation.
  • Xingsheng WANG, Jianmin LIAO, Dengke YIN, Fan ZHAN, Sufei DAI, Guangya ...
    原稿種別: Regular Article
    2010 年 130 巻 9 号 p. 1207-1214
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      Human steroid 5α-reductase type II (hSRD5A2) and dihydrotestosterone (DHT) play important roles in benign prostatic hyperplasia (BPH). The aim of our study was to establish a novel model to investigate the inhibitory effects of extracts and compounds of Chinese herb medicine on hSRD5A2. The gene, hSRD5A2, was artificially synthesized and cloned into pcDNA3.1(+) vector, which was transfected into CHO cells by liposome. Transfected cells were screened through G418 and MTX. The expressed protein of hSRD5A2 by cells was purified and detected by western blotting. A minim reactive system comprising hSRD5A2 and testosterone (T) as substrate together with NADPH as hydrogen donor was established for screening inhibitors of hSRD5A2. The reaction system was optimized in the concentrations of T, NADPH, and hSRD5A2 and reaction temperature, time, and activity of hSRD5A2 were determined by the production of DHT. Furthermore, we screened some extracts and compounds of Chinese herb medicine using this model. The concentrations of T, NADPH, and hSRD5A2 were 0.02 μM, 0.8 mM, and 0.05 U/μl, respectively, in the model; maximum activity of hSRD5A2 was achieved at 37°C and 60 min reaction, and mangiferin had significant inhibitory effect on the activity of hSRD5A2. The model in this study is convenient and reliable for screening and evaluation of inhibitors of hSRD5A2; mangiferin may be a potential medicine for the treatment of BPH.
  • 飯嶋 久志, 大澄 朋香, 小清水 敏昌
    2010 年 130 巻 9 号 p. 1215-1223
    発行日: 2010年
    公開日: 2010/09/01
    ジャーナル フリー
      In recent years, Evidence-based Medicine is practiced in medical care, and meta-analysis is positioned as the highest quality research paper. However, there are no unified criteria to evaluate meta-analysis. Thus, we developed and evaluated objective criteria of meta-analysis paper. Meta-analysis was evaluated from the standpoint of format and quality. Format score was developed based on QUOROM statement. Quality scores were evaluated in each step of meta-analysis. We evaluated meta-analysis for advantageous or adverse effect in the relationship between Renin-angiotensin system (RAS) inhibitor and diabetes mellitus. Research articles either in English or Japanese were searched in PubMed and the Cochrane Library in July 2009. Fifty-five studies were evaluated for format and quality score. Format score was 64.5±25.3% (Mean±S.D.), and quality score was 57.1±21.6%. After plotting each score along the X-Y coordinate, format score was correlated with quality score (R2=0.702, p<0.001). In studies with quality score of 70% or higher, RAS inhibitor prevented new-onset diabetes mellitus. Angiotensin converting enzyme (ACE) inhibitor reduced risk of myocardial infarction, however, angiotensin receptor blockers (ARB) increased the incidence in odds ratio 1.21 (95%CI: 1.04-1.40). We evaluated meta-analysis by format and quality score, and these factors showed correlation. Therefore, assessment of quality score leads to prompt and reliable evaluation of meta-analysis. According to articles evaluated by quality score, RAS inhibitor showed effectiveness on diabetes mellitus. However, careful attention must be given in ARB therapy on patients with myocardial infarction risk.
  • Inderbir SINGH, Pradeep KUMAR, Sanjeev KUMAR, Vikas RANA
    原稿種別: Regular Article
    2010 年 130 巻 9 号 p. 1225-1231
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      The present study was aimed to study the drug release retardant property of katira gum in matrix tablets containing tramadol as a model drug. Katira gum was characterized in terms of pH, viscosity and swelling index. The tablets were evaluated for various physical tests viz. hardness, friability, tensile strength and drug content. In vitro dissolution studies were performed and different empirical models were applied to drug release data for evaluating the drug release mechanisms and kinetics. Owing to good swelling properties (swelling index 340% and 480% after 6 and 24 h hydration) of the gum, the n values (as computed from Korsmeyer-Peppas model) were found to be ranging between 0.453 to 0.710 indicating involvement of both polymeric hydration and relaxation in the diffusion of drug from the matrix tablet.
ノート
  • 土屋 寛典, 白神 誠
    2010 年 130 巻 9 号 p. 1233-1237
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      In order to detect adverse events in patients at pharmacies, a questionnaire was developed to evaluate adverse drug reactions that may come from the use of pharmaceuticals. The questionnaire enabled pharmacists to assume possible adverse drug reactions while they dispense a prescription but was designed not to make patients sensitive. An investigation method was developed to detect adverse drug reactions that may be attributable to drug treatment by leading patient natural complaints while pharmacists provide drug treatment guidance to patients. This investigation was conducted at six pharmacies. As a result, 26.6% of the adverse drug reactions that can be associated with the question items ticked by at least five patients who had received the same drug were not indicated in the precautionary statements of the drugs. This suggests that this investigation may possibly contribute to detection of unknown adverse drug reactions. Furthermore, some of the patients who ticked question items related to prodromal symptoms of serious adverse drug reactions had received drug therapies that were known to be associated with those adverse drug reactions. This also suggests that the investigation may possibly contribute to detection of serious adverse drug reactions. It was considered to be more effective to focus on detection of serious adverse drug reactions with the use of the questionnaire in the future, which is more important than safety precautions. The accuracy in judging adverse drug reactions can be enhanced by asking patients with chronic diseases to respond to the questionnaire every time a prescription is dispensed.
資料
  • Wenchang ZHAO, Lijun SONG, Deng HONGZHU
    原稿種別: Article
    2010 年 130 巻 9 号 p. 1239-1249
    発行日: 2010/09/01
    公開日: 2010/09/01
    ジャーナル フリー
      Sulfasalazine salicylazosulfapyridine (SASP), consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, is an effective drug in the treatment of inflammatory bowel diseases (IBD). Howerer, its mechanism of action remains a matter of debate. The objective of our work was to investigate SASP's effect on NF-κB signal transduction pathway in transcriptional regulation level. Repeated colitis was induced by administration of 4 cycles of 4% dextran sulfate sodium (DSS); The severity of colitis was assessed on the basis of clinical signs, colon length, and histology scores. Moreover, sIgA and haptoglobin (HP) were analyzed by enzyme linked immunosorbent assay, and ICAM-1 gene expression was analyzed by quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR) using SYBA green I. NF-κB signal transduction proteins and transcriptional factor p65 interaction with promoter of ICAM-1 were assessed by western blotting and chromatin immunoprecipitation assay. SASP administration significantly attenuated the colitis signs and caused substantial reductions of HP expression, and maintained the level of cecum sIgA. SASP inhibited ICAM-1 gene expression and had no effect on MIF gene expression. Also, SASP was able to reduce p-IkBα protein expression; however, no change in the activation of IKKα, IKKβ, p65, and IKBα was noted. SASP inhibited p65 recruitment to the gene ICAM-1 promoter. In conclusion, inhibition of NF-κB pathway signal proteins and blockade of p65 binding to gene ICAM-1 promoter might explain the effect and mechanisms of SASP at alleviating DSS-induced colitis in mice.
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