巻号一覧
131 巻, 11 号
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総説
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南雲 清二2011 年 131 巻 11 号 p. 1527-1543
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーCinchona is one of the most important medicinal plants as it contains quinine, a potent medicine for malaria. In this review, I reveal the history of cinchona introduction and cultivation in Japan. Cinchona was first introduced to Japan in 1876 from Java based on the proposal submitted by Takeaki Enomoto to the Meiji government. However, the cultivation attempt ended in failure. Later in 1922, Hoshi Pharmaceutical Co. succeeded for the first time in cultivating cinchona in Taiwan, which was then under Japanese colonial rule, and in manufacturing quinine from the cinchona tree in 1934. This was a historic feat in Japan, completing an entire process from cinchona cultivation to quinine manufacture all within the confines of the country. To commemorate this undertaking, the company dedicated a cinchona log harvested for the first time to the Imperial court. It was revealed that a log of unknown origin, which had been left untouched for years at Hoshi University, was the cinchona log from the time of commemoration. Yasusada Tashiro (1856-1928), who has made a great contribution to cinchona cultivation in Japan for over 50 years, led Hoshi Pharmaceutical Co. to success in cultivation.
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秋田 英万2011 年 131 巻 11 号 p. 1545-1556
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーIn the 21st century the category of biomedicine is now expanding from low-molecular drugs to recombinant proteins, antibodies, and nucleic acids (e.q., siRNA and plasmid DNA). In this era also, development of a novel nanotechnology to control intracellular trafficking is highly desired. For a promising gene therapy, an efficient nuclear delivery vector is a minimum requirement. Quantitative and mechanism-based information on differences in transfection efficiency between viral and non-viral vectors would be highly useful to improve the effectiveness of non-viral vectors. In this review, we will summarize our recent progress in quantitative comparison and underlying mechanisms of the intracellular trafficking between adenovirus vectors and plasmid DNA (pDNA) transfected by non-viral vectors. Our analysis has revealed that poor post-nuclear delivery events, as well as the nuclear delivery process itself are key processes to focus on. Especially, less effective transcription and translation are most likely due to poor nuclear decondensation and excess electrostatic interaction between mRNA and the gene carrier, respectively. Meanwhile, we have developed a multi-functional envelope-type nano device (MEND), in which the pDNA/polycation core is encapsulated in the lipid bilayers. Based on feedback information concerning the rate-limiting processes of gene carriers, we controlled the number of lipid envelopes to enhance the decoating of encapsulated pDNA from the envelope structure. As an expanded application of this concept, we have developed a tetra-lamellar MEND (T-MEND), which is designed to overcome the endosome and nuclear membranes by step-wise membrane fusion.
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細井 徹2011 年 131 巻 11 号 p. 1557-1562
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーObesity is associated with metabolic syndrome, a cluster of symptoms including diabetes, hyperlipidemia, hypertension and arteriosclerosis, which can cause serious health problems. Accumulating evidence suggests that endoplasmic reticulum stress (ER stress) is associated with metabolic syndrome. Leptin is an anti-obesity hormone, which is secreted from adipose tissue. Circulating leptin acts at the brain hypothalamus and reduces food intake. As most forms of obesity indicate a state of leptin resistance, elucidation of the mechanisms of leptin resistance would be an important subject. We and other groups have recently suggested that leptin resistance may be derived from ER stress. These results raised the possibility that attenuating ER stress would be effective treatment for the disease. In the present review article, recent understanding of the mechanisms of the development of obesity and the potential novel therapeutic approaches targeting ER stress are discussed.
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杉本 健士2011 年 131 巻 11 号 p. 1563-1573
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーDomino reactions, which enable formations of several chemical bonds and multi-step transformation in one-pot process, have received much attention as an efficient synthetic methodology to preserve chemists from time-consuming purification protocols and protection-deprotection procedures. Furthermore, the domino processes containing skeletal rearrangement have been utilized for constructions of complex molecules because of their potential that they could afford entirely different valuable structures from readily available simple substrates. We recently developed novel domino reactions including ring enlargement process, which could afford biologically important cyclopentanones and nitrogen heterocycles. In this review, we will describe 1) a novel type of palladium-catalyzed domino insertion-ring expansion reaction of dienylcyclobutanols, which could enable a stereospecific synthesis of (Z)-2-(3-aryl-1-propenyl)cyclopentanones, 2) ruthenium-catalyzed domino ring expansion-insertion reaction of 1-acetylenylcyclobutanols for a construction of 2-alkylidenecyclopentanones, and 3) DIBALH-mediated reductive ring expansion reaction of oximes and studies on the reaction mechanisms. The rationales for the observed stereoselectivities in each reaction are also discussed.
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島本 茂, 吉田 卓也, 大久保 忠恭2011 年 131 巻 11 号 p. 1575-1581
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーLipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a multi functional protein acting as a PGD2 synthesizing enzyme, a transporter or scavenger of various lipophilic ligands, and an amyloid β chaperon in the brain. L-PGDS is a member of the lipocalin superfamily and has the ability to bind various lipophilic molecules such as prostanoid, retinoid, bile pigment, and amyloid β peptide. However, the molecular mechanism for a wide variety of ligand binding has not been well understood. In this study, we determined by NMR the structure of recombinant mouse L-PGDS and L-PGDS/PGH2 analog complex. L-PGDS has the typical lipocalin fold, consisting of an eight-stranded β-barrel and a long α-helix. The interior of the barrel formed a hydrophobic cavity opening to the upper end of the barrel, the size of which was larger than those of other lipocalins and the cavity contained two pockets. Kinetic studies and molecular docking studies based on the result of NMR titration experiments provide the direct evidence for two binding sites for PGH2 and retinoic acid in the large cavity of L-PGDS. Structural comparison of L-PGDS/U-46619 complex with apo-L-PGDS showed that the H2-helix, CD-loop, and EF-loop located at the upper end of the β-barrel change the conformation to cover the entry of the cavity upon U-46619 binding. These results indicated that the two binding sites in the large cavity and induced fit mechanism were responsible for the broad ligand specificity of L-PGDS.
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髙橋 梓, 近藤 昌夫, 八木 清仁2011 年 131 巻 11 号 p. 1583-1587
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーThe intercellular spaces between adjacent epithelial cells are sealed by tight junctions (TJs). Modulation of TJ-seal is a potent strategy for drug absorption. Claudin is a key structural and functional component of TJ-seal. Claudin comprises a tetra-transmembrane protein family consisting of more than 20 members, whose expression profiles and barrier-function differ among tissues. For instance, claudin-1 plays roles in the epidermal and mucosal barriers, and claudin-4 regulates the mucosal barrier. Claudin forms homo- and hetero-type TJ strands. Properties of TJ-seal are determined by combination of the claudin family members. Some claudin strands work as size-selective or charge-selective paracellular routes for solutes. Thus, claudin modulators will make it possible to deliver drugs in a solute- and tissue-specific manner. The C-terminal fragment of the Clostridium perfringens enterotoxin (C-CPE) is the most characterized claudin modulator. In this review, we describe potency of claudin-targeting mucosal absorption, and we mentioned development of a novel claudin modulator using C-CPE as a prototype.
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高根 浩2011 年 131 巻 11 号 p. 1589-1594
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーVarious drug transporters are selectively expressed in single or multiple tissues, such as the intestine, liver and kidney, where these transporters play various roles in drug absorption, distribution and excretion. Genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy and toxicity. Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). Some single nucleotide polymorphisms or haplotypes of the SLCO1B1 gene have been identified and demonstrated to have functional significance for transporter activity. For examples, the SLCO1B1*15 haplotype (or 521T>C genotype) results in decreased uptake activity of SN-38 from systemic circulation, leading to increased plasma concentration of SN-38 and an enhanced risk of neutropenia. This review focuses on the impact of genetic polymorphisms of the SLCO1B1 gene on transport activity, and implications for the clinical efficacy and toxicity of clinically useful drugs.
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一般論文
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齋藤 勲, 向後 麻里, 小林 文, 渡邊 徹, 阿部 誠治, 冨家 俊弥, 若林 仁美, 宮野 正弘, 唐沢 浩二, 大戸 祐治, 岡崎 ...2011 年 131 巻 11 号 p. 1595-1604
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーWe have previously reported the efficacy of the Patient Oriented Clerkship (POC) in the clinical clerkship in Showa University Hospitals, by a trial with old four-year pharmacy program students. In the unique clerkship, each student has a patient in charge, and follows his/her clinical conditions throughout the rotation. The aim of the POC is that having the students learn spontaneously (Active Learning) and actively (Adult Learning) promoted by student's commitment and responsibility by communicating with patients and health professionals in a team. As the POC requires students both Active Learning and Adult Learning, we define the POC as Active Adult Learning (AAL). Having a patient in charge for each student gives them many opportunities to participate in the medical team and foster their problem solving skills. Our previous study eventually showed positive results of the POC in the one-month short clerkship in the four-year program. On the other hand, the effect of the unique hospital clerkship in the new six-year program is not known. We conducted a student survey to clarify the learning effect in the new six-year education system which was revised and 2.5 month clinical clerkship was scheduled according to the model core clerkship curriculum. This report is the first report to show a challenge of the AAL/POC clerkship in the new six-year pharmacy education program.
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廣澤 伊織, 荻野 未央, 真野 泰成, 田島 正教, 大内 かおり, 加藤 芳徳, 小瀧 一, 旭 満里子, 山田 治美2011 年 131 巻 11 号 p. 1605-1611
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーWe investigated the use of multiple antipsychotics and the manifestation of side effects in outpatients with schizophrenia and compared the results of patients who received 1 antipsychotic (monotherapy) with those of patients who received more than 1 antipsychotic (multidrug therapy). To achieve this, we visited 8 community life-support centers and conducted a face-to-face questionnaire survey with 47 outpatients. Sixteen (34%) of these patients had received monotherapy and 31 (66%), multidrug therapy. Complaints involving the central nervous system, anticholinergic symptoms, metabolic symptoms (weight gain, increase in blood glucose, etc.), and extrapyramidal symptoms were seen across the patients. The average incidence of side effects was 2.2 per person in the monotherapy group and 4.8 in the multidrug-therapy group. The number of nonantipsychotic drugs used concomitantly in the monotherapy group was also smaller than that used in the multidrug-therapy group (2.3 and 5.0 per person, respectively). Further, we analyzed the 47 patients as described above; 20 patients received typical antipsychotics (TA group), 10 patients received atypical antipsychotics (AA group), and 17 patients received both typical and atypical antipsychotics (MIX group). The average incidence of side effects in the TA, AA, and MIX groups was 2.8, 3.2, and 5.5 per person, respectively, and the number of nonantipsychotic drugs used concomitantly was 2.2, 3.2, and 6.1, respectively. On the basis of our results, it can be suggested that monotherapy with an atypical antipsychotic can reduce both the number of nonantipsychotic drugs used concomitantly and the average incidence of side effects.
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範本 文哲, 与茂田 敏, 藤田 日奈, 遠野（小菅） 弘美, 道原 成和, 神成 真代, 大窪 敏樹原稿種別: Regular Article
2011 年 131 巻 11 号 p. 1613-1619
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーThe production of melanin is not only activated by external factors such as sunlight or UV-exposure, but is also considered to be triggered by hormonal factors, particularly sex hormones such as ovarian hormones. Previously, keishibukuryoganryokayokuinin (KBY) was reported to increase the pigmentation and moisture content of dermis in women during the luteal phase of the menstrual cycle, thus suggesting that progesterone could play a critical role in the development of skin pigmentation. In the present study, female DBA/2 mice, a dilute brown strain, were used to examine the effects of KBY on the increase in epidermal pigment cells in mice exposed to ultraviolet B (UVB) radiation or progesterone in an attempt to elucidate its mechanism. An increase in epidermal pigment cells was observed in mice exposed to progesterone. To the best of our knowledge, this is the first study to demonstrate that progesterone causes pigmentation in vivo. Furthermore, administration of KBY to progesterone-exposed mice significantly reduced the number of epidermal pigment cells. However, KBY had no such effects on UVB-induced pigmentation. Another important finding was the gain in body weight in progesterone-exposed mice, while body weight gain was reduced by KBY. The body weight gain was believed to be due to sodium and fluid retention, a kind of adverse effect of progesterone, which may further affect the intracellular pH of melanosomes, which synthesize melanin, in turn, leading to melanin production because tyrosinase activity is linked to the intracellular pH environment. This may help explain the mechanism of the role of KBY in pigmentation.
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山本 知佳, 湯田 朋子, 有元 明恵, 勢島 英, 川原 義弘, 鷲山 厚司, 二神 幸次郎原稿種別: Regular Article
2011 年 131 巻 11 号 p. 1621-1628
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーDrug information (DI) services is an essential resource for pharmacists to provide counseling to patients and guide appropriate medication use. We devised a DI practical training course that incorporated an inquiry-based practical training program and evaluated its effectiveness. A total of 91 fifth-year students in Pharmaceutical Sciences at Fukuoka University took part in the following DI sessions based on specific behavioral objectives (SBOs) for DI in the Model Core Curriculum for Practical Training: inquiry practice, simulated pharmacy and therapeutics committee, DI newsletter, use of emergency and safety information, off-label use in clinical trials, PRE-AVOID (Be prepared to avoid the adverse drug reactions), adverse drug reactions, and small group discussions about drug poisoning. The level of understanding of the SBOs for DI training was >4.2 for each item assessed, and the level of satisfaction for each practice was >3.9. This DI practical training successfully facilitated students' ability to provide DI. The number of students interested in DI services significantly increased (p<0.01). After the DI practical training, many students made statements such as “I realized that DI services is a very important job” and “I feel that pharmacists have much to contribute to DI services by evaluating the most appropriate information from a pharmacist's standpoint.” It appears that students recognized the pharmacist's role and importance of DI services in clinical practice through the DI training. These results suggest that this DI practical training program was effective.
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山田 真之亮, 桑原 宏貴, 浅井 玲名, 小谷 悠, 岸 里奈, 平林 彩, 水野 智博, 長谷川 雅哉, 毛利 彰宏, 久米 裕昭, 伊 ...2011 年 131 巻 11 号 p. 1629-1638
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーIn the present study, we investigated whether counseling at an outpatient asthma clinic improved asthma symptoms, adherence and patient satisfaction: The asthma control test (ACT) and asthma control questionnaire (ACQ) were used to assess subjective symptoms, 10-item version of the drug attitude inventory (DAI-10) was used to determine medication adherence, and 8-item Japanese version of the client satisfaction questionnaire (CSQ-8J) was used to ascertain patient satisfaction. All scores of inhalation technique, PEF (peak expiratory flow) value/predicted PEF value (%), ACT, ACQ and DAI-10 in 26 patients with asthma increased after counseling at the outpatient asthma clinic compared to those before counseling. The average CSQ-8J score of 28 points (highest possible score: 32 points) indicated that the patients were satisfied with services provided by this clinic. These results indicate that counseling provided by pharmacists at the outpatient clinic is a valuable way improving subjective symptoms, lung function and medication adherence. These results also indicate that counseling at the asthma clinic by pharmacists improves the quality of life of patients with asthma.
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佐竹 清, 中島 孝則, 岩田 政則, 藤掛 佳男, 木村 正幸2011 年 131 巻 11 号 p. 1639-1644
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーWe studied a locally applied vaginal preparation (vaginal suppositories) of ulinastatin (urinary trypsin inhibitor, UTI), designed to threatened premature delivery and maintain pregnancy. Witepsol S55 was chosen as the basic component of the vaginal suppositories based on the physical pharmaceutical characteristics of three kinds of hard fats. The average particle size of the UTI aqueous injection was approximately 70% as compared with that of the UTI lyophilized product, used as the base material for the preparation of UTI vaginal suppositories. We compared the physical pharmaceutical properties of UTI vaginal suppositories with water contents of 2.5%, 5.0%, and 7.5%, respectively. Preparation strength negatively correlated with the water content. The coefficient of viscosity positively correlated with the water content of the preparation. UTI vaginal suppositories with a water content of 5.0% had the highest average drug release rate on moment analysis. A comprehensive evaluation of the properties of UTI vaginal suppositories, including high strength due to disintegration resistance, the coefficient of viscosity and its influence on local retention, and drug release and its influence on the duration of effect, indicated that a 5.0% UTI aqueous solution for injection combined with Witepsol S55 as the base was the optimal formulation for the hospital preparation of vaginal suppositories.
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鈴木 一衛, 宮嵜 靖則, 内野 智信, 賀川 義之2011 年 131 巻 11 号 p. 1645-1651
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーMarketing authorization holders do not disclose any information on the pharmaceutical properties of over-the-counter drugs (OTC). When a drug is switched from a prescription drug to OTC, pharmacists can acquire that information from the corresponding ethical drug (ED) through the package insert, interview form, and so on. However, the pharmaceutical equivalence between ED and OTC is unclear. In this study, we examined the drug dissolution behavior of both ED and OTCs containing scopolamine butylbromide. Dissolution tests were performed by the paddle method using Japanese Pharmacopeia (JP) XV test fluids at pH 1.2, 4.0 and 6.8 and water based on the guidelines for bioequivalence studies of generic products. The dissolution profiles of OTCs differed significantly from ED showing a similarity factor (f2) value ranging from 8.9 to 42.9. Time until 85% dissolution ranged from 23 to 95 min and from 17 to 174 min at pH 1.2 and pH 6.8, respectively. Then JP XV disintegration tests were conducted to investigate differences in the disintegration process. The disintegration time of preparations showing delayed dissolution was prolonged compared to that of others, suggesting that the disintegration of the tablet or capsule is one of the important factors affecting the drug dissolution. These differences in the disintegration and drug dissolution might cause differences in the bioavailability of the drug. For patient safety, more detailed product information of OTCs should be supplied by the manufacturer, and not be assumed from that of corresponding ED.
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岩木 真生, 野口 雅久, 中南 秀将, 笹津 備規, 伊藤 正俊2011 年 131 巻 11 号 p. 1653-1659
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーGentamicin is used in an ointment form for the treatment of skin infections. To investigate the effect of gentamicin used as an ointment, the antimicrobial susceptibilities against Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pyogenes, and Pseudomonas aeruginosa isolated from community and medical settings were studied and compared with other antibacterial agents such as fradiomycin, chloramphenicol, and bacitracin used as active ingredient for each ointment. Gentamicin showed antibacterial activities for all standard bacteria tested, but fradiomycin and chloramphenicol showed no such activities for St. pyogenes and P. aeruginosa, respectively. Bacitracin showed activity for St. pyogenes only. The strains of staphylococci isolated from healthy people were highly susceptible to gentamicin, while 49.3% of the isolates from the patients with skin infections were resistant to gentamicin and 96.4% of the gentamicin-resistant staphylococci carried the aminoglycoside-resistance gene aacA-aphD. The growths of all strains tested, except for two strains of P. aeruginosa, were inhibited by close below 128 μg/ml of gentamicin. Furthermore, the frequencies of spontaneous mutants resistant to gentamicin, fradiomycin, and chloramphenicol were each investigated using S. aureus, S. epidermidis, St. pyogenes, and P. aeruginosa. At doses of more than 32 μg/ml of gentamicin, no resistant mutants in any of bacteria strains tested were obtained. The concentration of gentamicin on the skin was calculated at approximately 895 μg/ml at least when the commercially used 0.1% gentamicin ointment was applied to the skin. Therefore, our study strongly indicates that the gentamicin ointment used has a potency of sufficiently inhibiting the growth of bacteria, including gentamicin-resistant strains, which cause skin infections in the community.
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ノート
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佐藤 由美子, 立松 三千子, 石川 和宏, 岡本 浩一, 室 圭, 野間 秀一2011 年 131 巻 11 号 p. 1661-1666
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーControlling of chemotherapy-induced nausea and vomiting (CINV) is very important for the continuation of chemotherapy, especially for outpatients. CINV can significantly affect a patient's quality of life, leading to poor compliance with further chemotherapy treatment. In this retrospective study, we investigated the incidence of CINV induced by mFOLFOX6 and FOLFIRI in 59 outpatients (32 males and 27 females) with advanced colorectal cancer to evaluate CINV severity using the Common Terminology Criteria for Adverse Events v.3.0. The incidence of nausea in the female group receiving FOLFIRI (grade 1: 66.7% and grade 2: 20.0%) was significantly higher than that in the male group (grade 1: 23.1% and grade 2: 7.7%, p=0.0066). The incidence of nausea in the younger (<63 years old) group receiving FOLFIRI (grade 1: 57.1% and grade 2: 28.6%) was significantly higher than that in the older (≧63 years old) group (grade 1: 35.7%, p=0.0031). Multivariable logistic regression analysis indicated that patients who were female or younger had a significantly higher incidence of nausea or vomiting than patients who were male or older, respectively, when treated with FOLFIRI. This suggests that gender (female) and age (younger) are factors predicting poor antiemetic control in outpatients receiving FOLFIRI, but not those treated with mFOLFOX6. Information on such predictive factors should be useful to promote the effectiveness of cancer chemotherapy.
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國方 敏夫, 河野 恵三, 牛尾 慎平, 福田 恵温2011 年 131 巻 11 号 p. 1667-1674
発行日: 2011/11/01
公開日: 2011/11/01
ジャーナル フリーWe previously reported that oral administration of NK-4, a criptocyanine dye, enhances interleukin (IL)-12-depend- ent interferon (IFN)-γ production by lipopolysaccharide (LPS)-stimulated mouse splenocytes. These findings raised a possibility that NK-4 potentiated IFN-γ production by T cells, natural killer (NK) cells or natural killer T (NKT) cells in response to IL-12 produced by macrophage and dendritic cells. To explore this possibility, we first analyzed percentages of T, NK or NKT cells in splenocytes of mice that were administered NK-4 orally for three days. The percentage of NKT cells in splenocytes from NK-4-treated mice was significantly (p<0.05) increased compared to vehicle-treated mice. When splenocytes were stimulated with α-galactosylceramide (α-GalCer), an NKT cell ligand, IFN-γ production by splenocytes from NK-4-treated mice tended to increase, while no difference in the IL-4 production and proliferation were observed between the vehicle- and NK-4-treated mice. When IFN-γ/IL-4 ratios were calculated in individual mice, the ratios were significantly (p<0.05) elevated in NK-4-treated mice. Furthermore, IL-12 production by α-GalCer-stimulated splenocytes from NK-4-treated mice was also significantly (p<0.05) increased. These results suggest that oral administration of NK-4 increases the population of type I NKT cells with potent IFN-γ-producing activities. Since IL-12 and IFN-γ have been shown to play important roles in anti-tumor immunity as well as in the defence against bacterial infection, our results further imply that NK-4 may provide a potential therapeutic tool in cancer immunotherapy.
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