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128 巻, 9 号
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橘高 敦史2008 年 128 巻 9 号 p. 1235-1250
発行日: 2008年
公開日: 2008/09/01
ジャーナル フリー1α,25-Dihydroxyvitamin D3 (1) regulates a variety of biological actions through vitamin D receptor (VDR), including calcium and phosphorus homeostasis, bone remodeling, cellular proliferation and differentiation and many other functions. To enhance its potency and to study the structure/function relationship, we synthesized a series of analogs of 1 with a modification at the C-2α position. Introducing 2α-methyl, 2α-(3-hydroxypropyl), or 2α-(3-hydroxypropoxy) group increased its binding affinity for the VDR 2- to 4-fold compared to 1. The crystal structures of the VDR bound to these analogs provide a molecular explanation for the interaction between the 2α-substituents and water molecules exist in the VDR-ligand binding domain. Based on the accumulated knowledge in VDR agonists, we synthesized 2-substituted analogs of ‘double side chain’ (gemini), 19-norvitamin D3 (MART-10), TEI-9647 (VDR antagonist), 1-alkylated vitamin D3, 14-epi-previtamin D3 etc. Gemini analogs showed potent HL-60 cell differentiation activity (13-38 times compared to 1), and MART-10 exhibited remarkable antiproliferative activity on PZ-HPV-7 cells even at 10-10 M. (24S)-2α-(3-Hydroxypropoxy)-24-propyl-TEI-9647 showed potent VDR antagonism, and its IC50 value was 7.4 pM against 10 nM of 1. 1α-Methyl-2α-(3-hydroxypropyl)-25-hydroxyvitamin D3 improved the binding affinity for the mutant VDR(Arg274Leu), which causes hereditary vitamin D resistant rickets. 1α,25-Dihydroxy-2α-methyl-14-epi-previtamin D3 showed moderate osteocalcin transcriptional activity on HOS cells. We theorize that modification at A-ring alone and in combination with functionalization of the other parts of the vitamin D molecule would provide important new information on the mechanism of vitamin D actions that could lead to the development of new therapeutic regimes for the treatment of various diseases.
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池谷 裕二2008 年 128 巻 9 号 p. 1251-1257
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーFunctional multineuron calcium imaging (fMCI) is a large-scale optical technique that records the suprathreshold activity from large neuron populations. fMCI has several advantages, including: i) simultaneous recording from hundreds of neurons, ii) single-cell resolution, iii) identifiable location of neurons, and iv) detection of non-active neurons during the observation period. I review the principle and detailed method of fMCI and also describe the effect of oseltamivir on neuronal network as an example for practical application of fMCI.
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塚本 裕一2008 年 128 巻 9 号 p. 1259-1266
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーWe have developed palladium(0)/monophosphine-catalyzed trans-selective arylative, alkenylative, alkylative, and alkynylative cyclization reactions of alkyne-aldehydes and -ketones with organoboron reagents. These reactions afford six-membered allylic alcohols with endo tri- or tetra-substituted olefin groups and/or five-membered counterparts with exo olefin groups. The ratios of these products are dramatically affected by alkyne substituents as well as the phosphine ligand. The remarkable trans selectivity of the process results from the novel reaction mechanism involving ‘anti-Wacker’-type oxidative addition. Although the cyclization reactions are influenced by the length of the tether between the alkyne and carbonyl group, they can be applied to a multi-component synthesis of biologically important indenes bearing three substituent groups at 1, 2, 3-positions from available o-ethynylbenzaldehyde derivatives. A two-component coupling reaction in methanol provides 1H-indenols, while a three-component reaction involving secondary aliphatic amines as the third component in DMF affords 1H-indenamines. This method allows combinatorial preparation of unsymmetrically substituted 1H-indenes that cannot be prepared via previous synthetic routes. The same catalytic system can also transform allene-carbonyl compounds into 3-cyclohexenols and -cyclopentenols with alkyl, aryl, alkenyl, alkynyl, and boryl groups at C-3. Microwave irradiation efficiently increases not only the reaction rate but also the product yield by suppressing formation of hydroarylation byproducts. Cyclization of optically active 1,3-disubstituted allene-aldehyde reveals that the reaction proceeds through not carbopalladation but ‘anti-Wacker’-type oxidative addition.
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天滿 敬2008 年 128 巻 9 号 p. 1267-1273
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーThe cerebral metabolic rate for oxygen (CMRO2) and cerebral oxygen extraction fraction (OEF) are two fundamental parameters used to characterize the pathophysiologic status of cerebral tissues. Although the O-15-labeled gas inhalation method is used to measure these parameters in clinical studies, applying this method to small animals requires many intensive procedures. Thus the development of a new method to measure CMRO2 and OEF in small animals is of interest. This study aimed to develop a method to assess CMRO2 and OEF using intravenously injectable oxygen (injectable 15O-O2) and Positron Emission Tomography (PET) for small animals such as rats. Injectable 15O-O2 was obtained after 15O-O2 gas circulation into an artificial lung. The OEF in normal rats was calculated using the same equation as that used for the bolus inhalation in the 15O-O2 gas method. The obtained value of 0.54±0.11 of OEF was similar to the value determined from the arterial-venous difference in the oxygen concentration. Furthermore, we evaluated the usefulness of the injectable 15O-O2 system in rats occluded in the right middle cerebral artery. A decrease in cerebral blood flow (CBF) and compensatory increase in OEF were observed 1 h after occlusion. In contrast, a marked decrease in CBF and CMRO2 and a collapse of the compensatory OEF mechanism were found 24 h after occlusion. Thus injectable 15O-O2 with PET can be used to estimate oxygen metabolism reliably in stroke animal models, and may be useful for accelerating basic research on cerebral diseases.
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一般論文
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奥村 順子, 西田 祥啓, 木村 和子2008 年 128 巻 9 号 p. 1275-1283
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーThe lessons from the Great Hanshin-Awaji Earthquake and Chuuetsu Earthquake showed us how difficult it is to keep chronic disease management for survivors of such large-scale earthquakes, particularly for elderly people. To solve the problem, an ordinance for enforcement on exceptional practices was issued for the Pharmaceutical Affairs Law Article 49 Clause 1. The law allows selling prescription medicines for patients with chronic diseases who have difficulties to continue their medications due to a large-scale disaster. To make it work, the patient should demonstrate that he or she continuosly received the medication by presenting either Medication Notebook or prescription book recorded by the pharmacist. However, the Separation Rate of Prescription and Dispensing in Japan is still low; in particular, that in Ishikawa prefecture, where the Noto Peninsula Earthquake (M 6.9) occurred on March 25, 20007, is very low. It means that few victims hold a Medication Notebook. In consideration of this situation, we conducted a questionnaire survey of elderly victims of the Noto Peninsula Earthquake with a key-informant-interview during the period from July through August, 2007. This study revealed that: 1) Only 16% (18/110) of respondents kept a Medication Notebook; 2) 75% (82/110) had chronic diseases and received medication regularly; 3) Of 81 who had chronic diseases, 42% (34/91) were dispensed at the same pharmacy always, (The rest received from either clinic or changing pharmacy according to clinic location); and 4) Diseases that the respondents had were hypertension, cardiovascular diseases, diabetes, and so on. Based on these results, we discuss the establishment of a pharmaceutical supply system that can effectively distribute appropriate medicines to patients under difficult situations following a large-scale disaster in Japan.
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中川 尚美, 濱邊 和歌子, 徳山 尚吾2008 年 128 巻 9 号 p. 1285-1291
発行日: 2008年
公開日: 2008/09/01
ジャーナル フリーIn times of disaster, it is envisaged that many schools will serve as refuges, and it seems important that school pharmacists play their role as co-medical is in such refuges. Here, we investigated the role of school pharmacists as medical caregivers at the time of the Kobe earthquake and elucidated their future necessity by questionnaire intended for pharmacists and nurse-teachers. Although there was no attendance request for the school pharmacist from either school or pharmacist society at the time of the disaster, about 30% of school pharmacists acted voluntarily. Water investigation was the main subject for their activity. In addition, 58% of pharmacists and 82% of nurse-teachers recognized the necessity of the school pharmacist at the time of the disaster. Many of the activities were related to the normal activity as a conventional school pharmacist, although there was a request for mental healthcare to local inhabitants. Surprisingly, 31% of pharmacists considered that school pharmacists might not be of any assistance at the time of a disaster. It might be useful to prepare a manual so that school pharmacist could be active at the time of disasters in the future.
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Pei LUO, Zheng-Huai TAN, Zhi-Feng ZHANG, Hao ZHANG, Xian-Fu LIU, Zheng ...原稿種別: Regular Article
2008 年 128 巻 9 号 p. 1293-1299
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーErigeron multiradiatus (Lindl.) Benth is a traditional Tibetan medicine herb long used to treat various diseases related to inflammation. Our previous phytochemical studies on E. multiradiatus resulted in the isolation of scutellarin, which is a known flavone glucuronide with comprehensive pharmacological actions. In present study, we investigated the inhibition action of scutellarin on high glucose-induced vascular inflammation in human endothelial cells (ECV304 cells). Consistent with previous reports, exposure of ECV304 cells to high glucose for 24 h caused an increase of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1), and promoted cell adhesion between monocyte and ECV304 cells. However, pretreatment with scutellarin (0.1 and 1 μM) reversed these effects in a concentration-dependent manner. Scutellarin was able to inhibit the activation of NF-κB induced by high glucose in ECV304 cells. Furthermore, although oral administration of scutellarin (10 and 50 mg/kg) did not produce significant antihyperglycemic action, it lowered the serum MCP-1 levels significantly in alloxan-induced diabetic mice. Therefore, our results suggest that scutellarin has anti-inflammation effect that may afford some protection against hyperglycemia-induced vascular inflammatory both in vitro and in vivo.
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佐々木 圭子, 大林 真幸, 神山 紀子, 小林 靖奈, 山元 俊憲原稿種別: Regular Article
2008 年 128 巻 9 号 p. 1301-1309
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーOver-the-counter medications are primarily for self-medication, where the seller, such as a pharmacist, provides the necessary information and the consumer uses the medication at his or her own discretion based on the information provided. A Web survey was conducted from February 8 to 13, 2006, involving 500 men and women, ranging in age from 50 to 69 years, who had purchased over-the-counter medications for the common cold within the past 3 years. Upon consultation with and purchase of a cold medication from a pharmacist, 84.2% of respondents reported “being asked my symptoms,” and less frequently (12.3-21.3%) being asked about contraindications/careful administration. Most respondents (60.8%) when asked whether they confirmed “contraindications/careful administration” responded negatively, stating they “occasionally do not confirm” or “do not confirm.” In addition, among men aged 50-69 years, it became clear that 6.0% had experienced aggravation of prostatic hypertrophy symptoms after taking a cold medication. It is assumed that symptoms are usually confirmed upon the sale of over-the-counter medications, but the rate of confirming whether the consumer may need to consider contraindications/careful administration is low. Urinary retention is a preventable side effect because the confirmation prior to taking the medication can be made. Accordingly, some of those side effects can be avoided by ensuring the environment for confirming whether the individual corresponds to “contraindications/careful administration” before taking the medication.
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廣谷 芳彦, 三河尻 恭子, 池田 賢二, 名徳 倫明, 黒川 信夫2008 年 128 巻 9 号 p. 1311-1316
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーPeptide YY (PYY) is produced by endocrine cells in the lower gastrointestinal tract. The main functions of PYY are antisecretory effects in the colon and inhibition of gastrointestinal motility. We chose PYY as an index of the intrinsic factor in diarrhea and examined the influence of changes induced in a diarrhea rat model by administration of 4 types of laxative and loperamide hydrochloride (loperamide) as an agent for the treatment of diarrhea. A specific radioimmunoassay was performed to determine plasma and intestinal mucosal PYY concentrations. PYY in the rat intestinal tissue extract was distributed at a high density in the lower intestinal mucosa. In the diarrhea rat model, multiple changes in PYY concentrations in the intestinal mucosa and plasma were observed. In rats administered castor oil and sodium picosulfate, the intestinal mucosal PYY levels significantly decreased in a dose-dependent manner. Plasma PYY levels significantly decreased only in rats administered magnesium citrate. Next, we examined the influence of loperamide administration on the intestinal mucosa and plasma PYY concentrations in these rats. Loperamide administration resulted in multiple changes in plasma and intestinal mucosa PYY concentrations, along with an improvement in the diarrhea. Our research showed that the endocrine hormone PYY is involved in the onset of diarrhea, the course of the condition, and the manifestation of medicinal effects in the lower intestine.
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根岸 淳, 白浜 辰弥, 長岡 康夫, 武本 佳樹, 上里 新一原稿種別: Regular Article
2008 年 128 巻 9 号 p. 1317-1323
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーA 2′-succinyltaxol-bovine serum albumin (BSA) conjugate was prepared as an antigen to produce an anti-taxol monoclonal antibody by immunizing mice. Formation of a linkage between hapten and protein is usually confirmed by the UV or fluorescamine method. However, it was difficult to confirm the binding of 2′-succinyltaxol to BSA by these methods owing to the similar UV absorption maxima of 2′-succinyltaxol (273 nm) and BSA (280 nm). In the present study, we therefore conducted a mass spectrometric analysis using the precursor ion scan and MS/MS techniques to confirm the formulation of the 2′-succinyltaxol-BSA conjugate in the following way: The conjugate was subjected to thermal denaturalization, dithiothreitol (DTT)-reduction, iodoacetamide-alkylation and trypsin-digestion, affording a peptide fragment mixture. This was then analyzed by electrospray ionization (ESI)-MS in the positive mode by scanning the peaks containing a mass of 854 corresponding to taxol. The detected peaks were in turn subjected to MS/MS measurements. Among them, a peak at m/z 1247.4 was found to be a peptide fragment containing Lys (ε-2′-succinyltaxol), demonstrating the formulation of the 2′-succinyltaxol-BSA conjugate. In order to confirm the feasibility of this analytical method, the deacetylvinblastine (deacetylVLB)-BSA antigen which produced the anti-VLB monoclonal antibody (MAb-10-A9), was subjected to the same analytical treatment as above, giving a peak at m/z 851.3 originating from a Lys (ε-deacetylVLB). Thus, this new method could serve as an additional tool for confirmation of the formation of hapten-protein conjugates which are difficult to detect by the above spectrophotometric methods.
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ノート
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Dinesh Chandra BHATT, Avinash Sridhar DHAKE, Roop Krishen KHAR, Dina N ...原稿種別: Note
2008 年 128 巻 9 号 p. 1325-1331
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーThe transdermal matrix films of metoprolol tartrate (MT) were prepared by casting on mercury substrate employing different ratios of polymers, ethyl cellulose (EC) and polyvinyl pyrrolidone (PVP), using dibutyl phthalate (DBT) as a plasticizer. Four formulations were prepared. Formulations MF-1, MF-2, MF-3 and MF-4 were composed of EC and PVP in the following ratios: 4.5:0.5, 4:1, 3:2 and 2:3 respectively. The formulations were subjected to various physical characterization studies namely, thickness, weight variation, drug content, moisture uptake, in vitro drug release and in vitro skin permeation. The in vitro permeation studies were carried out across excised porcine ear skin using Franz diffusion cell. Cumulative amounts of the drug released in 24 hours from the four formulations were 69.58%, 96.13%, 98.85% and 99.60%, respectively. Corresponding values for the cumulated amounts of drug permeated across the porcine skin for the above matrix films were 124.38, 153.22, 156.46 and 163.25 μg/cm2 respectively. By fitting the data into zero order, first order and Higuchi model, it was concluded that drug release from matrix films followed Higuchi model (r2=0.9147-0.9823), and the mechanism of release was diffusion mediated. Based on the physical evaluation, in vitro drug release & permeation characteristics, it was concluded that for potential therapeutic use, monolithic drug matrix films MF-3, composed of EC: PVP (3:2), may be suitable for the development of a transdermal drug delivery system of MT.
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神山 尚子, 小川 竜一, 浜田 寛子, 大野 哲郎, 浅野 竜太, 梅村 純, 吉田 久博2008 年 128 巻 9 号 p. 1333-1339
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーContrast-induced nephropathy (CIN) is one of the serious side effects of contrast media. A few studies have suggested that N-acetylcysteine (NAC) is effective to prevent CIN, but the efficacy remains unclear in Japanese. Therefore, we retrospectively studied the preventive effect of NAC on CIN in Sakakibara Heart Institute. Patients who had been administered NAC for the purpose of preventing CIN before coronary intervention between February 2005 and November 2006 were included in the NAC group. In addition, age- and rate of diabetes mellitus-matched controls were randomly extracted. We retrieved and analyzed patient data including demographics, NAC dosage, and serum creatinine concentrations (Scr). NAC group (n=16) showed significantly higher baseline Scr (p<0.01) and a tendency toward a lower dose of contrast media (p=0.068) compared with controls (n=48). Since the occurrence of CIN was low, there was no significant difference in the proportion of CIN between the groups (NAC: 6%, controls: 4%). NAC group trended toward a decrease in Scr after the use of contrast media, while controls increased (−0.04±0.25 versus +0.03±0.36 mg/dl, p=0.096). The multivariate analysis showed that the dosage of NAC is inversely correlated with Scr independent of baseline Scr and dosage of contrast media. Despite higher baseline Scr (i.e., high-risk with CIN) in the NAC group, the real Scr value reflected a lower trend on average. In addition, this finding suggests that a larger dose of NAC results in a lower Scr value, we consider that the NAC dosage more likely prevented CIN.
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岩尾 一生, 川合 トキエ・ルシアナ, 小田 雅子, 小林 道也, 齊藤 浩司原稿種別: Note
2008 年 128 巻 9 号 p. 1341-1345
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーIn this study, as an approach to possible pharmacokinetic interactions between antidiabetic agents and health foods, we investigated the binding of metformin and glibenclamide to aojiru, kurosu, and blueberry extract using a dialysis method. The permeation of metformin from the inner to the outer side of the dialysis tube during 90 min was not altered in the presence of aojiru or kurosu, and slightly decreased by 20% compared with the control in the presence of blueberry extract, indicating that the interactions between metformin and these three health foods are limited. On the other hand, when these three health foods were added to inner medium together with glibenclamide, they significantly lowered the outer glibenclamide concentrations. The magnitude of the decrease in the outer glibenclamide concentrations was the most extensive in the presence of kurosu (60%), followed by aojiru (36%) and blueberry extract (45%). The present results suggest that metformin and glibenclamide interact differently with aojiru, kurosu, and blueberry extract and that these three health foods might modulate the absorption of glibenclamide in vivo.
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廣谷 芳彦, 三河尻 恭子, 池田 賢二, 名徳 倫明, 黒川 信夫原稿種別: Note
2008 年 128 巻 9 号 p. 1347-1353
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーFew studies have reported the changes in the peptide YY (PYY) levels in the intestinal tissue of rats with ulcerative colitis (UC) following oral administration of mesalazine and prednisolone. We investigated the effects of these drugs on the intestinal mucosal PYY levels in a rat model of UC. We confirmed that the PYY levels in the rat intestinal mucosal tissue were high in the lower intestinal tract. The leukocyte count and hemoglobin levels approached the normal values after administering mesalazine or prednisolone to rats treated with 3% dextran sulfate sodium (DSS). The PYY levels in the caecum and colon decreased significantly after administering DSS but increased when mesalazine was administered in a tissue-specific manner. Unlike mesalazine, the PYY levels increased in the ileum in addition to the colon and rectum after administering prednisolone. However, neither of the drugs induced any changes in the plasma PYY levels. These findings indicate that changes in the intestinal tissue PYY levels may be partially involved in the improvement of DSS-induced UC in rats following the administration of these drugs.
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田中 守, 末丸 克矢, 池川 嘉郎, 田淵 典子, 荒木 博陽原稿種別: Note
2008 年 128 巻 9 号 p. 1355-1361
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーThe purpose of this study was to investigate the frequency of inpatient falls and to evaluate the risk factors of drugs in an academic hospital. The study population consisted of inpatients at Ehime University Hospital in Japan and the study was conducted from April 1st to October 31st, 2006. Children and teenagers (<18 years old) were excluded. Inpatient falls were registered regularly with incident reports submitted by nurses and other hospital employees discovering the fall. Logistic regression techniques were used to estimate the odds ratios (OR) of the association of falls and drug use. Of the 4084 adult patients, 65 (1.6%) fell. An OR (unadjusted) for risk of falling were observed for various drug classes; hypnotics (OR 2.12; 95% CI, 1.25 to 3.52), anxiolytic (OR 3.35; 95% CI, 1.83 to 5.82), anti-Parkinson's (OR 5.79; 95% CI, 1.71 to 14.80), narcotics (OR 3.08; 95% CI, 1.06 to 7.11), hypotensives, diuretics (OR 2.39; 95% CI, 1.42 to 3.95). A multivariate logistic regression analysis showed that inpatient falls were significantly associated with patients older than 70 years (OR, 2.25; 95% CI, 1.35 to 3.77), with patients taking anxiolytic drugs (OR 2.36; 95% CI, 1.24 to 4.25), and with patients taking anti-Parkinson's medication (OR 5.04; 95% CI, 1.44 to 13.43). In conclusion, this study provides information regarding the relationship between fall-related accidents and drugs. Therefore, pharmacists should provide appropriate drug information related to the risk of falling to both patients and medical staff members.
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廣谷 芳彦, 池田 賢二, 加藤 隆児, 名徳 倫明, 楳田 高士, 井尻 好雄, 田中 一彦原稿種別: Note
2008 年 128 巻 9 号 p. 1363-1368
発行日: 2008/09/01
公開日: 2008/09/01
ジャーナル フリーIndirect evidence suggests that lactoferrin (Lf), a major iron-binding protein in human milk, induces enterocyte growth and proliferation, depending on its concentration and affects the function and permeability of the intestinal mucosa. The bacterial endotoxin (lipopolysaccharide, LPS) is known to cause mucosal hyperpermeability in vivo. However, protective effects of Lf against LPS-mediated intestinal mucosal damage and barrier function in epithelial cells are not yet fully clarified. The aim of this study was to investigate whether Lf can reduce the cellular injury and alter epithelial hyperpermeability caused by LPS in human intestinal Caco-2 cells. When cell viability was measured by a WST-1 assay (tetrazolium salt-based assay), the protective effects against LPS-induced damage to Caco-2 cells were observed at doses of 800 and 1000 μg/ml Lf. The barrier function of Caco-2 monolayer tight junctions was assessed by measuring transepithelial electrical resistance (TEER) and permeability of FITC-labeled dextran 4000 (FD-4). The treatment of Caco-2 cells with Lf at doses of 400 and 1000 μg/ml significantly increased TEER as compared to treatment with LPS alone for 2 h (p<0.05). Further, at doses of 400 and 1000 μg/ml, Lf inhibited the enhancement of LPS-mediated permeability in Caco-2 cell monolayer. The results of this study suggest that Lf may have protective effects against LPS-mediated intestinal mucosal damage and impairment of barrier function in intestinal epithelial cells.
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