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128 巻, 4 号
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誌上シンポジウム
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大槻 純男, 崔 吉道2008 年 128 巻 4 号 p. 495-496
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーPDF形式でダウンロード (184K) -
井上 豪, 安達 宏昭, 村上 聡, 高野 和文, 松村 浩由, 森 勇介, 福西 快文, 中村 春木, 木下 誉富, 仲西 功, 奥野 恭 ...2008 年 128 巻 4 号 p. 497-505
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーWe have recently established a Pharamaceutical Innovation Value Chain in collaboration with the SOSHO project (http://www.so-sho.jp) and BioGrid Project (http://www.biogrid.jp/) to accelerate new drug development. The SOSHO project provides novel crystallization technology with laser-irradiation and stirring growth methods, and the BioGrid Project is developing the software necessary for the in silico screening of promising drugs and the simulation of biological responses to proteins. In this paper, we report the recent research work on the crystallization of membrane proteins and the development of a method for in silico drug discovery.
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上家 潤一2008 年 128 巻 4 号 p. 507-512
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーKnowing the amount of membrane transporter expression in human tissue is one of the key issues in the rational and reliable prediction of pharmacokinetic profiles in humans. Recently, we have developed a simultaneous and highly sensitive method for the absolute quantification of multiple membrane transporter proteins in mammalian tissues. To develop quantitative analysis of high molecular-weight membrane proteins, we have solved problems using proteomics technology as follows: 1) The target proteins are detected via tryptic peptides that can be dissolved and analyzed with LC-MS/MS, while membrane protein is difficult to dissolve. 2) LC-MS/MS in multiple reaction monitoring (MRM) mode produce a highly sensitive and selective response for transporter proteins with low expression by separation from highly abundant molecules. 3) Analyte specificity for each peptide was demonstrated in amino acid sequences using multiple MRM detection. Selection of the peptide probe was very important for highly sensitive analysis with LC-MS/MS. We set criteria for peptide selection using an informatics approach. Peptides without unstable residue, double basic residues, and integral membrane domain were selected as useful probes. The developed method will provide an inclusive assay platform for all transporter proteins expressed in both animal/human tissues and will contribute to progress in drug discovery and development.
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根本 知己2008 年 128 巻 4 号 p. 513-520
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーTwo-photon microscopy is a less-invasive cross-sectional imaging technique for long-term visualization of living cells within deeper layers of organs. This microscopy is based on the multi-photon excitation process and has been used widely in medical and biological sciences. An attractive property of two-photon microscopy, multicolor excitation capability has enabled quantification of spatiotemporal patterns of [Ca2+]i, ion transport and single episodes of fusion pore openings during exocytosis. In pancreatic acinar cells, we have successfully demonstrated the existence of “sequential compound exocyotosis” for the first time. Sequential compound exocytosis has subsequently been identified in a wide variety of secretory cells including exocrine, endocrine and blood cells. Further exploration has revealed dynamics and physiological roles of actin cytoskeleton, and soluble NSF attachment receptor (SNARE) proteins. In addition, our newly developed method (TEPIQ method) can be used to determine fusion pores and the diameters of vesicles smaller than the diffraction-limited resolution. Recently, we have successfully observed neurons deeper than 0.9 mm from the brain cortex surface in an anesthetized mouse. We have also improved the spatial resolution needed to visualize fine structures of basal dendrites in layer V in vivo. This microscopy also can be used to visualize dendritic spines, axon terminals and miroglia cells, suggesting that we can follow long-term changes of neural or glial cells in a living mouse. Two-photon microscopy will thus be important in advancing the study of the molecular basis of physiological and pathological events in the human body.
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岩本 和也, 加藤 忠史2008 年 128 巻 4 号 p. 521-525
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーA-to-I RNA editing has mainly been found in various receptors and ion channels in the central nervous system, including the serotonin 2C receptor, glutamate receptor, GABA receptor, and potassium channel. Interestingly, most of them are suggested to be involved in the pathophysiology of major mental disorders such as schizophrenia, bipolar disorder, and major depression. Here we review studies examining the relationship between the serotonin 2C receptor and major mental disorders.
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総説
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染井 正徳2008 年 128 巻 4 号 p. 527-563
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーWe have had five dreams to challenge through our life. To meet our end, we needed imaginary compounds, 1-hydroxytryptophans. This review describes how we had conceived the 1-hydroxyindole hypothesis, how we created a general synthetic method for 1-hydroxyindoles after 20 years' research, and how we have developed the chemistry of 1-hydroxytryptophans with full of new findings and discoveries. During the period, we defined “the efficient synthesis” and “the ideal synthesis” consisting of originality rate (OR), intellectual property factor (IPF), and application potential factor (APF). For evaluating the originality and the efficiency of the synthetic research, these indexes are more effective than both citation index and impact factor. Taking advantage of our 1-hydroxyindole chemistry, we have achieved three “ideal syntheses” approximately with high OR, IPF, and APF values. The methods employ only conventional reagents and reaction conditions without using any protecting groups. These methods made possible to produce such intellectual properties as leads for an α2-blocker, an inhibitor of platelet aggregation, an anti-osteoporosis agent, and a promising medicine for combating desertification, changing Gobi desert to the tract with full of green plants. These would be suitable for realizing our five dreams. Chemical conversion of enmein to gibberellin A15, four-step total synthesis of optically active ergot alkaloids, and various new reactions for the synthesis of 4-substituted indoles are also involved.
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向後 博司, 吉江 幹浩, 沓掛 真彦, 田村 和広2008 年 128 巻 4 号 p. 565-574
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーSuccessful implantation and placentation require that trophoblasts adhere to the uterine epithelium and penetrate the decidualized endometrium. However, the biochemical mechanisms of the establishment of pregnancy including these phenomena have not yet to be definitively elucidated. We have found that stathmin, a cytosolic phosphoprotein that regulates microtubule dynamics, and insulin-like growth factor-binding protein (IGFBP)-related protein 1 (IGFBP-rP1, now called IGF-binding protein 7) were highly expressed in the endometrium around the time of implantation and decidualization. In this article, we review our recent findings of the research regarding the functions of these implantation-associated proteins in endocrine physiology and pharmacology. Analysis of the expression of both factors in rodent and human uterus has revealed that both factors are crucial for the process of endometrial stromal cell differentiation.
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佐井 君江, 澤田 純一, 南 博信2008 年 128 巻 4 号 p. 575-584
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーRecent progress in pharmacogenetic research has made “personalized medicine” a reality, where a suitable drug at the appropriate dosage is prescribed based on individual genetic factors. Irinotecan, an anticancer drug, is one of the models for personalized medicine, and a number of clinical studies have revealed significant associations between UGT1A1*28 and irinotecan toxicity. Based on the cumulative evidence, clinical tests for the UGT1A1*28 marker have started in the United States since 2005. However, the appropriate criteria for irinotecan dose adjustments have not yet been fully established. Since there are considerable differences in genetic polymorphisms among different ethnic groups and in approved irinotecan-containing regimens between countries, the criteria for the choice of suitable genetic markers and dose adjustments should be standardized in each country. This mini-review outlines our recent studies on irinotecan pharmacogenetics and discusses the clinical significance of UGT1A1*6 and *28 markers for personalized irinotecan therapy in Japanese cancer patients.
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一般論文
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橋口 正行, 山内 暢晃, 内倉 健, 望月 眞弓2008 年 128 巻 4 号 p. 585-594
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーDrug selection for the treatment of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer was analyzed pharmacoeconomically. Two patterns consisting of continuation of an NSAID plus administration of the prostaglandin (PG) preparation misoprostol (PG model) for 8 weeks and continuation of an NSAID plus administration of the proton-pump inhibitors omeprazole and lansoprazole (PPI model) for 8 weeks were examined. Decision analysis models were created on the basis of reports of clinical studies and epidemiologic studies relating to the drugs and gastric ulcer, and cost-comparative analyses were conducted based on the number of persons who had ulcer healing as health outcomes. Costs were estimated with respect to health expenditures from the third-party payer (public) perspective. In the case of continuation of an NSAID plus administration of the proton-pump inhibitor omeprazole for 8 weeks, the health outcomes improved and costs were reduced in comparison with continuation of an NSAID plus administration of misoprostol, thus making the administration of omeprazole the dominant choice. With continuation of an NSAID plus administration of lansoprazole for 8 weeks, the cost-savings of lansoprazole were inferior to those of misoprostol. The generic omeprazole product was the most cost-saving among the four drugs (misoprostol, original omeprazole product, generic omeprazole product, and lansoprazole) examined.
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Nita MONDAL, Arnab SAMANTA, Tapan Kumar PAL, Saroj Kumar GHOSAL原稿種別: Regular Article
2008 年 128 巻 4 号 p. 595-601
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーThis study investigates the effect of some formulation variables on particulate characteristics of poly (DL-lactide-co-glycolide) (PLGA) copolymer nanoparticles by applying 23 factorial design and response surface methodology (RSM). Nanoparticles were prepared by solvent displacement technique. Initially, appropriate formulation factors for elaboration of polymeric particles were selected by screening. A 23 full factorial design was employed to evaluate the influence of three formulation variables, polymer concentration (X1), dispersant concentration (X2) and phase volume ratio (X3) on the percentage of total particles at submicron range (Y1), mean diameter (Y2) and specific surface area (Y3) as particle characteristics. The results showed that all the three variables had significant influence on mean diameter of particles and amount of particles at submicron range. Simultaneous change of polymer concentration and dispersant concentration had significant effect on specific surface area of particles. Span value as an index of polydispersity indicated uniformity in particle size distribution.
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Pulak Kumar METIA, Amal Kumar BANDYOPADHYAY原稿種別: Regular Article
2008 年 128 巻 4 号 p. 603-609
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーNovel mucoadhesive buccal tablets (NMBTs) of oxytocin were prepared as cores in cup fashion to release and permeate the drug unidirectionally toward the buccal mucosa to reach the systemic circulation directly. Adhesive cups for NMBTs were prepared with mucilage (DPM) isolated from edible Diospyros peregrina fruit. Mucoadhesive properties like shear and tensile and peel strengths of the adhesive cups were estimated on freshly excised bovine buccal mucosa. Core tablets were formulated with oxytocin using two penetration enhancers, sodium taurocholate and sodium thioglycollate. In vitro permeability studies of NMBTs were conducted in a Franz diffusion cell containing 50 ml of phosphate buffer, pH 6.6, at 37±0.2°C through excised bovine buccal mucosa, and the amount of drug permeated was estimated at 220 nm on reverse-phase HPLC using a BDS Hypersil C8 column with acetonitrile and potassium dihydrogen orthophosphate buffer 0.05 M, pH 6.6, (20 : 80 v/v) as the mobile phase, at flow rate of 1.25 ml/m. The NMBTs containing 0.75% w/w sodium taurocholate showed 26% permeability without damaging the histology of the buccal mucosa. The results suggest that this formulation may be a suitable alternative to oxytocin injections.
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大関 圭一, 北原 雅樹, 鈴木 憲子, 田口 恭次, 山崎 勇樹, 秋山 真二, 高橋 健太郎, 神崎 愷原稿種別: Regular Article
2008 年 128 巻 4 号 p. 611-616
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーLocal anesthetic creams for the clinical treatment of conditions such as postherpetic neuralgia were prepared as an in-house formulation from the eutectic mixture of lidocaine-tetracaine (LT cream) using two eutectic mixtures of local anesthetic (EMLA) type bases. The LT formulation was compared with a lidocaine-prilocaine (LP cream) eutectic mixture formulated using the same base as EMLA. The chemical stability of lidocaine was examined in advance and was found to be stable for more than 3 months either in LT cream or in LP cream. The release rate of lidocaine from the formulated creams was examined using a cellulose ester membrane. The release rate of lidocaine from LT cream was similar to that from LP cream. The release rate of tetracaine was slightly slower than that of lidocaine in LT cream reflecting the larger molecular size of tetracaine. The penetration rate was examined in vitro using a Yucatan micropig skin. The penetration rate of lidocaine was similar between LT and LP creams. Infiltration anesthesia action examined in guinea pigs indicated that the difference between the two creams was statistically insignificant. The present study suggests the equivalence of the LT and LP creams as a local anesthetic and the potential of LT cream for clinical use either in the easy formulation or in the low-cost formulation.
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Bing LIN, Xian-Cheng ZHAN, Lin-Li LI, Cheng-Rong LI, Hai-Jun QI, Jian- ...原稿種別: Regular Article
2008 年 128 巻 4 号 p. 617-624
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーA step nonisothermal experiment under high oxygen pressure and a computation with optimization for a step nonisothermal experiment on a stability study of drugs are introduced. The kinetics parameters of captopril oxidation in aqueous solution were determined with this method. It is reported that the reaction of captopril solution occurs under either aerobic or anaerobic conditions, giving different products. Then the total rate constant ktotal can be expressed as: ktotal=kanaerobic+kaerobic=Aanaerobic exp (−Ea, anaerobic/RT)+Aaerobic exp (−Ea, aerobic/RT)pO2, where kanaerobic and kaerobic are the rate constants of anaerobic and aerobic degradation, respectively. The results indicate that the parameters obtained in the step nonisothermal experiment are comparable to those obtained in isothermal-isobaric experiments.
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櫻井 秀彦, 恩田 光子, 今野 広崇, 荒川 行生, 早瀬 幸俊2008 年 128 巻 4 号 p. 625-633
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーWe investigated consciousness of the prevention of dispensing errors with the pharmacists and clerical staffs which work in community pharmacies and analyzed the structure of those subconscious to examine preventive measures of dispensing errors. Questionnaire survey was performed for all pharmacists and clerical staffs working in community pharmacies where each is affiliated with four pharmacy groups. The questionnaire consisted of 38 questions about “atmospheres for the prevention of dispensing errors” in the pharmacy along their attributions. And data were analyzed by occupation to confirm the difference. As a result of factor analysis, five factors such as “the posture of the boss”, “information exchange”, “the order of the pharmacy” were extracted from the pharmacists. Moreover, in the case of the clerical staffs, five similar factors have been extracted besides “a sense of responsibility to duties” replaced “the order of the pharmacy”. As a result of structural equation modeling, the pass model with high goodness of fit to which “measures for dispensing error prevention” and “consciousness to the dispensing error of a pharmacy” were assumed to be a subordinate concept respectively by each occupational category. It became clear that a suggestion of the concrete preventive measures drafting was provided even from the investigation of the consciousness level.
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須田 恭代, 花田 和彦, 土綿 慎一, 齋藤 誠, 中村 知夫, 伊藤 裕司, 石川 洋一, 櫛田 賢次, 緒方 宏泰2008 年 128 巻 4 号 p. 635-640
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーA study was conducted to clarify differences in the theophylline pharmacokinetics of two orally available products, theophylline alcohol and Apnecut, in premature neonates and infants using population pharmacokinetic analysis. Fifty-two patients with apnea hospitalized at the National Center for Child Health and Development were enrolled (total number of plasma concentration points=90). Population pharmacokinetic analysis under steady-state conditions was performed using NONMEM ver. V. The mean oral clearance was 0.0249 (l/h), and the inter- and intraindividual variation was 30.3% and 28.3%, respectively, in the basic model. The oral clearance was significantly affected by body weight, sex, and age. The final model obtained was expressed by the following equation: oral clearance (l/h)=0.0201×(body weight (g)/1000)1.08×(1−0.282×drug product), where theophylline alcohol is 0 and Apnecut is 1. The inter- and intraindividual variations in the final model were 15.0% and 15.3%, respectively. The oral clearance of the two oral formulations differed significantly, and this difference should be considered when adjusting the theophylline dose.
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辰見 明俊, 織田 祥子, 中元 智子, 村岡 玲子, 高橋 佳子, 田中 邦佳, 志方 敏幸, 辰己 純代, 多河 典子, 小林 吉晴, ...2008 年 128 巻 4 号 p. 641-648
発行日: 2008/01/11
公開日: 2008/04/01
ジャーナル フリーPrednisolone suppositories have been used successfully for the treatment of ulcerative colitis in hospital settings. However, the raw material of prednisolone suppository, JP prednisolone powder (JP Powder), was recently removed from the market. Therefore we studied the effects of raw material and suppository base on the release of prednisolone suppository for the purpose of designing a new suppository with similar effects to those of suppository prepared using JP powder (old suppository). New suppositories consisting of the powder of pulverized tablet as raw material and Witepsol H-15 and Witepsol E-75 as suppository base were prepared according to the fusion method. Suppository release test was performed by reciprocating dialysis tube method with tapping (RDT method) and dialysis tubing method (DT method). Both RDT method and DT method were performed using a suppository dissolution apparatus (modified JP disintegration apparatus) and a JP15 paddle apparatus, respectively. The test fluid was 50 mM phosphate buffer solution (pH 7.4) maintained at 37±0.5°C. The results of release test by RDT method were similar to those of DT method. Release rate of prednisolone from the new suppository was much faster than that of old suppository. The addition of Witepsol E-75 to new suppository base markedly delayed the release of prednisolone from the new suppository. Release rate of prednisolone from the new suppository, consisting of pulverized tablet and Witepsol H-15 and Witepsol E-75 (76:24), corresponded well with that of the old suppository. It was suggested that this suppository could be used as incoming preparation of suppository prepared using JP powder.
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ノート
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奥山 清, 吉元 公一, 岩瀬 理, 大関 健志, 山田 安彦2008 年 128 巻 4 号 p. 649-655
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーTo evaluate the antiemetic effects of 5-HT3 receptor antagonists, we investigated the relationship between condition of food intake and occurrence of nausea and vomiting. We collected data such as sex, age, disease, combination of steroids and central antiemetic agents, eating condition, and vomiting condition from medical records in 33 hematologic cancer patients receiving chemotherapy; combination with 5-HT3 receptor antagonists. The conditions of food intake and nausea/vomiting were checked at 4 mealtime points (lunch, supper, breakfast, and next lunch) after chemotherapy, and were recorded as 1, 3, or 5 as each condition score. To calculate eating scores and nausea/vomiting scores, the sum of scores from 4 mealtime points was used. We found a significant negative correlation between eating scores and nausea/ vomiting scores (n=62, p<0.01). At eating points in which combination therapy with steroids and central antiemetic agents was not given, antiemetic effects of granisetron, azasetron and ramosetron were compared and revealed that azaseton was the most effective antiemetic agent. This result is inagreement with our previous study predicting antiemetic effects of 5-HT3 receptor antagonists based on the receptor occupancy theory. This study suggests that eithes receptor occupancy or eating score is a useful indicator for assessment of the efficacy of 5-HT3 receptor antagonists.
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河添 仁, 滝口 祥令, 井上 達也, 山口 佳津騎, 田中 裕章, 加地 雅人, 辻 繁子, 二宮 昌樹, 福岡 憲泰, 大西 宏明, 石 ...2008 年 128 巻 4 号 p. 657-661
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーInfections caused by multiple-drug-resistant Pseudomonas aeruginosa (MDRP) are a clinically significant problem. We reported here the effective use of combination therapy in a patient with infection caused by MDRP according to an interventional treatment strategy suggested by a pharmacist. The patient was a 70-year-old male who underwent allogeneic hematopoietic stem cell transplantation. On day 45 after transplant, MDRP was newly isolated from urine, but the diagnosis at that time was colonization. On day 61, the patient developed a fever (≥38.0°C). In addition, laboratory data showed that C-reactive protein (CRP) was also increased. At the medical team conference, the pharmacist proposed the following treatment strategy for this infection. Aztreonam and amikacin were intravenously administered at doses of 2 g/day and 800 mg/day, respectively. The subsequent clinical course was well controlled, but the infection recurred and was aggravated. Aztreonam and ciprofloxacin were then intravenously administered at doses of 4 g/day and 600 mg/day, respectively, resulting in the alleviation of fever in the patient as well as a decrease in CRP and disappearance of MDRP isolates from urine on day 67; that is, MDRP infection was consequently well controlled. In conclusion, the combination therapy between aztreonam and amikacin, or ciprofloxacin may be clinically useful for severe infections of MDRP in compromised hosts.
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Yue HOU, Tao GUO, Chunfu WU, Xiang HE原稿種別: Note
2008 年 128 巻 4 号 p. 663-666
発行日: 2008/04/01
公開日: 2008/04/01
ジャーナル フリーMultidrug resistance presents a serious problem in cancer chemotherapy. Recent studies have shown that the multidrug resistance of tumor cells can be reversed by tetrandrine by potentiating the cytotoxicity of chemotherapeutic agents. However, whether tetrandrine has such potentiating effect on epirubicin has not been reported. Thus, the combined effect of tetrandrine and epirubicin on the growth of human breast carcinoma multidrug-resistant MCF-7/ADM cells was studied in the present study. It was shown that tetrandrine significantly potentiated the cytotoxicity of epirubicin. To examine the mechanism of the combined effect of tetrandrine and epirubicin on MCF-7/ADM cell growth, cell cycle progression was evaluated by using flow cytometry. The combined use of tetrandrine and epirubicin caused an accumulation of cells at G2/M phase, accompanied with a concomitant decrement of cell number at G0/G1 phase. The present study demonstrated for the first time that tetrandrine potentiated the cytotoxcity of epirubicin on MCF-7/ADM cells. Cell cycle arrest at G2/M phase may contribute to the combined effect of tetrandrine and epirubicin.
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