YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
127 巻 , 7 号
選択された号の論文の16件中1~16を表示しています
総説
  • 芳本 忠
    2007 年 127 巻 7 号 p. 1035-1045
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      Microbial enzymes were studied from two medicinal viewpoints. First, we examined proline-specific peptidases from pathogenic microorganisms. We found several proline-specific peptidases in pathogenic bacteria. Among them, prolyl tripeptidyl aminopeptidase from Porphylomonas gingivals and prolyl aminopeptidase from Serratia marcescens were crystallized. The complex structures of those enzymes and inhibitors were clarified in X-ray crystallography. Aminopeptidase N, which has wide specificity for amino acids, was distributed in the pathogens. The crystal structure of the aminopeptidase N elucidated the reasons for its wide substrate specificity but inertness to the X-Pro bond. It was also revealed that proline-specific peptidases and aminopeptidase N cooperatively degrade collagen for the uptake of amino acids as nutrition when these bacteria infect cells. Second, we applied enzymes from microorganisms to diagnostic analyses. We found a series of creatinine-metabolizing enzymes in Pseudomonas putida. Creatininase, creatinase, and sarcosine oxidase were coupled and have been developed for a diagnostic analysis kit that examines renal function. The structures of the native and the Mn2+-activated creatininases were determined in X-ray crystallography. Based on the structure, the activated enzyme was used for an improved assay kit. The structure of D-3-hydroxybutyrate dehydrogenase from Pseudomonas fragi was also clarified in crystallography. The enzyme is useful for diagnostic analysis of diabetes mellitus while monitoring ketone bodies.
  • 柏木 良友
    2007 年 127 巻 7 号 p. 1047-1057
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      Thin poly (acrylic acid) (PAA)-coated graphite felt (GF) is a promising electrode material for preparative organic electrosynthesis, because the electrode is not only stable and durable but also can be modified with various mediators and enzymes in the PAA layer. The TEMPO-modified GF electrode for electrocatalytic oxidation of several types of organic compounds were successfully constructed. The modified electrode had many advantageous properties compared with direct electrosynthesis or mediatory reaction synthesis which is still common as an electrochemical system. The use of a chiral nitroxyl radical-modified GF electrode afforded enantioselective oxidation of racemic alcohols or amines (remaining optically pure alcohols or amines) and asymmetric lactonization of methyl-substituted diols. A preparative electrocatalytic radical cyclization of bromo alkyl cyclohexenones was successfully achieved on a nickel (II) tetraazamacrocyclic complex-modified GF electrode. The PAA-coated GF electrode modified with viologen and palladium metal microparticles is effective for the electrocatalytic hydrogenation of olefins. An electrode immobilizing all components of mediator, enzyme, and coenzyme for electroenzymatic reactions was also prepared, and several electroenzymatic reactions were smoothly carried out. Substrate immobilization on GF for the solid-phase acetylene coupling reaction was achieved by electrochemical polymerization of the substrate precursor containing a pyrrole side chain, where the amount of substrate on the electrode surface was easily controlled by the number of repeated cyclic voltammetric scanning. Couplings between terminal acetylenes and the iodobenzene-modified GF electrode or aromatic iodides and the terminal acetylene-modified GF electrode in the presence of palladium catalyst proceeded smoothly with satisfactory yields.
  • 守田 雅志
    2007 年 127 巻 7 号 p. 1059-1064
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      Adrenoleukodystrophy (ALD) is an inherited disorder characterized by progressive demyelination of the central nervous system and adrenal dysfunction. The biochemical characterization is made based on the accumulation of pathgnomonic amounts of saturated very long chain fatty acid (VLCFA, >22) in all tissues, including brain white matter and adrenal glands. The accumulation of VLCFA is linked to a mutation in the ABCD1 gene that encodes ABCD1/ALDP, a peroxisomal ABC protein. ABCD1/ALDP is thought to be involved in the active ATP-driven transport of VLCFA-CoA from the cytoplasm into the peroxisomes. However, the precise function of ABCD1/ALDP is still unclear. The accumulation of VLCFA is caused by reducing peroxisomal VLCFA β-oxidation and/or increasing fatty acid elongation. Since the reduction of accumulated VLCFA in the brain is thought to be crucial for preventing the progression of neurologic symptoms in X-ALD, compounds that can cross the blood-brain barrier and decrease the VLCFA levels in the brain would be a highly attractive candidate for effective treatment of ALD patients. We found that baicalein 5,6,7-trimethyl ether, a flavonoid derivative, decreased the VLCFA level in X-ALD fibroblasts, possibly by activating peroxisomal fatty acid β-oxidation. Continued pharmacologic studies of flavonoids and chemically modified derivatives may lead to major advances in the pharmacologic therapy for X-ALD.
  • 羽田 紀康
    2007 年 127 巻 7 号 p. 1065-1076
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      This review describes the oligosaccharide syntheses and biological activities of glycosphingolipids, focusing especially on those found in invertebrates like millipedes, nematoda parasites, and cestoda parasites, and model compounds related to a major antigenic epitope against antibupleurum 2IIc/PG-1-IgG from antiulcer pectic polysaccharides. A novel and simple approach for the rational design of glycoclusters and glycodendrimers by coupling with a sugar unit and a cluster unit, was developed with β-alanine derivatives used to construct the latter compounds.
  • 岩本 卓也
    2007 年 127 巻 7 号 p. 1077-1080
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      To prevent medical errors, especially drug-related ones, clinical pharmacists have to play an important role in multidisciplinary team care. We have investigated the pharmacokinetics, pharmacodynamics, and molecular biology of several drugs and have applied the findings obtained in our studies to therapeutic drug monitoring. The first finding is that achieving vancomycin (VCM) concentrations at an appropriate concentration contributes to a decreased incidence of VCM-induced nephrotoxicity and a decreased duration of VCM therapy. From this result, we have constructed a system to provided recommendations for VCM doses to attending medical staff as soon as possible. The second finding is that we clarified the risk factors for steroid-induced diabetes in patients with neurologic diseases, indicating a close relationship among postprandial hyperglycemia, advanced age, and hypercholesterolemia in these patients. We also determined that monitoring plasma glucose concentrations 2 hours after lunch could be useful to detect diabetes in these patients. Finally, we identified the mechanism of 3′-azido-3′-deoxythymidine and dacarbazine photogenotoxicity, including the specific site of DNA damage. These findings may provide useful information to prevent phototoxicity of drugs and to develop new photodynamic therapies.
  • 福土 将秀
    2007 年 127 巻 7 号 p. 1081-1089
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      The calcineurin inhibitors cyclosporine and tacrolimus are widely used to prevent allograft rejection after transplantation. Since these drugs have narrow therapeutic windows and show considerable pharmacokinetic variability, therapeutic drug monitoring (TDM) is essential to avoid adverse effects such as nephrotoxicity while maximizing immunosuppressive efficacy. On the other hand, some patients experience acute rejection episodes or postoperative complications despite achieving therapeutic blood drug levels. Therefore, pharmacokinetic and pharmacodynamic factors by which to establish individualized dosage adjustment for these drugs should be identified. Recently, it was recognized that pharmacogenomics has the potential to facilitate personalized medicine by translating knowledge of human genome variability into rational therapeutics. In this paper, we review the population pharmacokinetic and pharmacogenomic analysis of tacrolimus, focusing on an efflux transporter P-glycoprotein (multidrug resistance 1 [MDR1/ABCB1]) and drug-metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5, and describe Bayesian forecasting to individualize the tacrolimus dose in de novo living-donor liver transplant recipients. Furthermore, the pharmacodynamic properties of tacrolimus and cyclosporine, which were evaluated by measuring calcineurin phosphatase activity in peripheral blood mononuclear cells, are reviewed in relation to an optimal monitoring strategy as well as a rational dosage regimen for these drugs.
  • 川端 健二
    2007 年 127 巻 7 号 p. 1091-1096
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      Coxsackievirus and adenovirus receptor (CAR) is a member of the immunoglobulin superfamily and a component of epithelial tight junction. CAR also functions as a primary receptor for coxsackievirus B and adenovirus (Ad) infection. Recently, we have identified a novel protein, CAR-like soluble protein (CLSP), which is closely related to CAR. Mouse CLSP (mCLSP) was composed of 390 amino acids, including three Ig domains, and showed strong homology to the IgV domain of CAR. Interestingly, mCLSP lacks a transmembrane domain, indicating that this is a soluble protein. When mCLSP cDNA was introduced into CAR-positive cells, the infection with Ad vector was severely inhibited. On the other hand, mCLSP promoted the infection with Ad vector in CAR-negative cells. Furthermore, recombinant CLSP directly bound to Ad and inhibited the Ad vector-mediated transduction in CAR-positive cells. Computational analysis for a genome database showed that the CLSP gene is rodent-specific, and that human and bovine lack this gene. Here, I discuss the function of CLSP for Ad infection.
  • 池田 龍二
    2007 年 127 巻 7 号 p. 1097-1102
    発行日: 2007年
    公開日: 2007/07/01
    ジャーナル フリー
      An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity, partially prevented hypoxia-induced apoptosis. TP was expressed at higher levels in tumor tissues compared to the adjacent non-neoplastic tissues in a variety of human carcinomas. High expression of TP is associated with an unfavorable prognosis. To investigate the effect of TP on cisplatin-induced apoptosis, human leukemia Jurkat cells were transfected with wild-type or mutant (L148R) TP cDNA. Jurkat cells transfected with TP cDNA (Jurkat/TP) and mutant TP cDNA (Jurkat/TPMu) expressed high levels of TP, while Jurkat/CV cells which were transfected with a control vector did not express TP. A high TP enzyme activity was detected in Jurkat/TP cells, but not in Jurkat/CV and Jurkat/TPMu cells. Sensitivities to cisplatin of these cells were determined by MTT assay. IC50 values for cisplatin of Jurkat/CV, Jurkat/TP, and Jurkat/TPMu cells were 4.50, 14.08, 13.40 μM, respectively. Jurkat/TP and Jurkat/TPMu cells were about three times more resistant to cisplatin than Jurkat/CV cells. TP inhibited activation of caspase 3, 9 and mitochondrial cytochrome c release induced by cisplatin. These findings suggest a mechanism by which TP confers the resistance to cisplatin-induced apoptosis. Moreover, mutant TP that has no enzymatic activity also suppressed the cisplatin-induced apoptosis. These suggest that TP molecules have cytoprotective functions against cytotoxic agents.
  • 古閑 健二郎, 河島 進, 芝田 信人, 高田 寛治
    2007 年 127 巻 7 号 p. 1103-1114
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      In Japan, glycyrrhizin injections have been used as a therapeutic drug for allergy inflammation since 1948 and for chronic hepatitis since 1979. A 20 ml injection of glycyrrhizin contains 53 mg of monoammonium glycyrrhizinate (40 mg as glycyrrhizin acid), 400 mg of glycine, and 20 mg of L-cysteine. Patients receiving glycyrrhizin injections two or three times per week are forced to accept a decline in quality of life. Because administering glycyrrhizin by injection has some disadvantages, many researchers have systematically searched for novel glycyrrhizin formulations that can be administered through oral, rectal, intranasal, and subcutaneous routes. There are two problems, however, in developing new formulations: (1) glycyrrhizin has low membrane permeability and is thus poorly absorbed, and (2) highly concentrated glycyrrhizin readily forms gels in aqueous solutions. Here, we describe the utility of glycyrrhizin formulations prepared in safe solubility agents and absorption-enhancing agents, as assessed in animal experiments. We also discuss pharmaceutical issues in developing various glycyrrhizin formulations. In the near future, convenient pharmaceutical preparations of glycyrrhizin will be developed for chronic hepatitis patients who require glycyrrhizin therapy.
一般論文
  • 櫻井 秀彦, 川原 昇平, 多田 裕一郎, 中島 史雄, 猪狩 富夫, 百瀬 晴彦, 近藤 弘之, 小森 雄太, 早瀬 幸俊
    2007 年 127 巻 7 号 p. 1115-1123
    発行日: 2007年
    公開日: 2007/07/01
    ジャーナル フリー
      Separation of the dispensing function and the prescribing function, Iyaku Bungyo, has been progressing in Japan. We are now witnessing the advent of a new society where patients select pharmacists and their satisfaction is recognized as one of the healthcare outcome indicators. It is necessary to clarify which factors affect patients' satisfaction with the services provided at community pharmacies and how they do so. A survey was conducted among 104 community pharmacies and their patients around the Tokyo metropolitan area in Japan. The questionnaire comprised 11 items (observed variables), each with a five-grade scale. With the transformed data-oriented pharmacy, the percentage of being not unsatisfactory was examined in two multivariate analyses of the relation and structure of patient satisfaction with a community pharmacy. Structural equation modeling (SEM) with factor analysis (FA) was performed using the observed variables and latent factors. Multiple regression analysis was performed with comprehensive satisfaction as an independent variable, examining the factors that affect comprehensive satisfaction with the pharmacy. The result of the FA indicated three latent factors of instruction on the use of drugs, quality of staff, and environment, based on which SEM model was constructed with a relatively high goodness of fit index. The result of multiple regression analyses indicated almost all variables such as satisfaction with reception by the pharmacist affected the comprehensive satisfaction, but privacy did not show a significant effect. These results, notably the relationship between each variables and latent factors, suggested the importance of higher skills of pharmacists, service qualities at pharmacies, and their functions adjusted to the community.
  • Milind PARLE, Nirmal SINGH
    2007 年 127 巻 7 号 p. 1125-1137
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      The present study was undertaken to investigate the beneficial effects of Atorvastatin and Simvastatin in cognitive dysfunctions of rats. Alprazolam, Scopolamine and high fat diet (HFD) induced amnesia served as interoceptive memory models where as, Water-maze and Elevated plus-maze served as exteroceptive models. A total of 38 groups of rats were used in this investigation. Escape latency time (ELT) recorded during acquisition trials conducted from day 1 to day 4, in water maze was taken as an index of acquisition, where as mean time spent in target quadrant during retrieval trial on day 5, was taken as the index of retrieval (memory). On elevated plus-maze, transfer latency (TL) measured on 1st d served as the index of acquisition and TL recorded on 2nd d was taken as the index of retrieval (memory). Alprazolam (0.5 mg kg-1 intraperitoneally), Scopolamine (0.4 mg kg-1 intraperitoneally) and HFD treated (for 90 days) rats exhibited amnesia as reflected by impairment in learning ability as well as memory, when tested on both, water maze and elevated plus maze. Atorvastatin (5 mg kg-1 orally) as well as Simvastatin (5 mg kg-1 orally) significantly attenuated Alprazolam, Scopolamine and HFD induced amnesia. These results highlight the ameliorative role of statins in experimental amnesia with possible involvement of their cholesterol dependent as well as cholesterol independent actions.
  • 渡部 俊彦, 上野 将明, 小笠原 綾子, 三上 健, 松本 達二
    2007 年 127 巻 7 号 p. 1139-1144
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      When Cladosporium cladosporioides was cultured with cysteine, its growth was completely inhibited statically. The growth of C. cladosporioides cultured on potato-dextrose agar plates was also inhibited by the addition of cysteine. The production of ATP in C. cladosporioides was inhibited by cysteine. When a silicone block was incubated with C. cladosporioides, the surface of the block was coated with the biofilm of C. cladosporioides. However, the block containing cysteine was not covered with biofilm. These results indicate that cysteine is useful as a material to prevent the growth of C. cladosporioides.
  • Kun LI, Qingwang LI, Jian LI, Tao ZHANG, Zhengsheng HAN, Dawei GAO, Fu ...
    2007 年 127 巻 7 号 p. 1145-1151
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      Pinus koraiensis Bark Procyanidins Extract (PKBPE) has been used in traditional Chinese medicine for thousands of years. In this study, we determined PKBPE effect on tumor weight, SOD (superoxidate dismutase) activity, the content of MDA (malondialdehyde) through colorimetric analysis antigenic, and expression of Ki-67, p53 and Bcl-2 on mice bearing U14 cervical cancer. Treatment with PKBPE (158 and 250 mg/kg body weight, p.o.) could inhibit U14 cervical carcinoma growth up to 47.68 and 58.94%. In addition, PKBPE enhance the activity of SOD (p<0.01) and decrease MDA content. Furthermore, we also observed that PKBPE treatment significantly inhibited the expression of Ki-67, mutant p53 and Bcl-2 protein (p<0.01). The results suggested that PKBPE showed antitumor activities on U14 cervical carcinoma mice. The mechanism of PKBPE antitumor activity might be associated with free radical production inhibition and regulation of the expression of Ki-67, mutant p53 and Bcl-2 protein.
ノート
  • 瀬沼 香代子, 畝崎 榮, 竹内 裕紀, 林 正弘
    2007 年 127 巻 7 号 p. 1153-1157
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      The six-year curriculum has been introduced into all pharmacy schools in Japan since April 2006. Those schools are currently preparing for an additional two years of pharmacy education and are in the process of readying the necessary educational infrastructure. However, students' expectations of the new curriculum and understanding of the professional roles of a pharmacist have yet to be investigated. Therefore we surveyed the first group of students on their expectations of the new curriculum and on their understandings of the newly emerging roles of pharmacists in general. Our questionnaire consisted of six questions, and we further had the students conduct self-evaluations using the admission interview items of a pharmacy school from the USA. Of the 440 first-year students, 89.1% responded. Based on the results of the survey, we found that the majority of students did not believe that pharmacists will have a respected role in multidisciplinary teams or in public. Approximately half of the students also said that they had no confidence in taking leadership roles or thinking logically when compared with the average person. We therefore believe that schools and pharmacy educators need to teach students pharmaceutical care and the various roles pharmacists can play in the future. Schools and pharmacy educators should also support students by providing training and introducing new methods of learning to develop their professional attitude and leadership skills.
  • 恩田 光子, 兼松 美和, 北村 朋子, 酒井 隆浩, 阪上 久美子, 田中 景子, 濱畑 有記美, 廣岡 輝子, 藤井 貴和子, 松田 雅 ...
    2007 年 127 巻 7 号 p. 1159-1166
    発行日: 2007年
    公開日: 2007/07/01
    ジャーナル フリー
      Access to drug information (DI) needed to evaluate generic product bioequivalence was studied to identify problems with the current status of DI availability and encourage proper use of DI. Ten items were chosen from among the stock of branded products at the University Pharmacy, and five corresponding generics were selected for each item. Conditions of access to information on pharmacokinetic tests and dissolution tests were rated and the assigned ratings compared. In the case of pharmacokinetic parameters obtainable from makers of generic drugs, we also performed Welch's t-test to compare the difference between values reported for branded and generic products. From the standpoint of individual tests, the pharmacokinetic tests yielded higher scores on the whole than did the dissolution tests, and low scores were obtained for the half-life of blood drug concentration (T1/2). We observed a tendency for the adequacy of information to depend more upon the drug item itself than upon the nature of the test. The percentage of tests allowing for comparison with branded products varied from 0%-75% (average 49%). Parameter by parameter, the range of variation was from 35% of Tmax to 63% of Cmax. Factors precluding comparison included insufficient data on branded products, mismatch in assayed chemical species between branded and generic, mismatch between final sampling time in AUCt measurement, dosage inconsistency, and insufficient data on generic products. DI should be provided in a manner that facilitates comparison of information supplied by generic drug makers with data released by makers of branded products.
  • 田上 貴臣, 梶村 計志, 高木 総吉, 皐月 由香, 中村 暁彦, 起橋 雅浩, 阿久津 和彦, 尾花 裕孝, 北川 幹也
    2007 年 127 巻 7 号 p. 1167-1171
    発行日: 2007/07/01
    公開日: 2007/07/01
    ジャーナル フリー
      Many methods for the determination of pesticide residues in food have been reported. Although natural medicines should be confirmed to be as safe as food, few methods for the determination of pesticide residues in natural medicines have been reported. In this study, 17 organochlorine pesticides were detected in natural medicines using GC/MS with negative chemical ionization (NCI). GC/MS with NCI can detect halogenated pesticides selectively and thus is suitable for the detection of organochlorine pesticides. This study indicates that GC/MS with NCI is useful for analyzing organochlorine pesticides in natural medicines.
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