著者

森口 郁生

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.114, no.3, pp.135-146, 1994-03-25 (Released:2008-05-30)

参考文献数

39

被引用文献数

3 3

---

Recent development of quantitative structure-activity relationships (QSARs) and computer-aided drug design contributed by the author and his coworkers was briefly reviewed. Fuzzy adaptive least-squares (FALS), a pattern recognition method for analysing structure-activity rating data to generate QSAR models was developed. A novel feature of FALS is that the degree to which each sample belongs to its activity class is given by a fuzzy membership function. Using FALS, non-congeneric QSAR analyses of carcinogenicity, mutagenicity, and six kinds of pharmacokinetic properties of miscellaneous organic chemicals were performed to construct predictive models for drug design. In these QSAR analyses, the values of log P (partition coefficient in octanol/water) calculated by the simple method of Moriguchi et al. were used as the descriptor for hydrophobicity. The method of Moriguchi et al. is not only simple and convenient but also reliable in the application to 22 drugs selected by Rekker et al. compared to the Rekker method and the Hansch-Leo method. Lastly, a heulistic search method for active conformers using molecular mechanical confor-mational analysis and principal component analysis was proposed.

著者

上野 勝次郎 岡田 清三郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.82, no.4, pp.532-535, 1962-04-25 (Released:2010-02-19)

参考文献数

10

---

Dornow and others synthesized 2-aminonicotinic acid derivatives by the condensation of β-diketone and amidine or imino ethers. Pyridine cyclization by the condensation of β-diketones with non-symmetrical structure and malonamideamidine or ethyl 3-amino-3-ethoxyacrylate was examined and a new derivative of 2-aminonicotinic acid derivatives, which may serve as intermediate for synthesis of pyridoxine, were obtained. The compounds synthesized were ethyl 2-amino-4-ethoxymethyl-6-methylnicotinate, diethyl 2-amino-6-methyl-3, 4-pyridinedicarboxylate, and ethyl 2-amino-4-carbamoyl-6-methylnicotinate, and their structures were determined.

著者

首藤 紘一

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.120, no.10, pp.987-995, 2000-10-01 (Released:2008-05-30)

参考文献数

30

被引用文献数

2 3

---

Cancer is a common life-threatening disease. Prevention and therapy of the disease are the desire of everybody. This paper summarizes our attempt to the tough challenge. Chronologically we began the study of carcinogenesis, and then turned to the research of anticancer agents. Identification of food mutagens was extensively studied. Once they were identified, the mechanism of nucleic acid modifications by these mutagens had been studied. The modification study gave information on the nucleic acid modification by mitomycin and bleomycin. The structure-activity relationship study of phorbol esters and teleocidines whose tumor promotion is epigenetic, was extensively studied. On the other hand, retinoic acid, a vitamin A metabolite, suppresses the epigenetic tumor promotion. This suggests that an epigenetically active compound rather than a cytotoxic anticancer agent can be used for tumor suppression. In the retinoid research, we found a number of characteristic new active substances which may be of therapeutic use : some of them are in the clinical trial stages in the field of dermatology and cancer. During the chemical study of retinoids, we encountered the retinoic acid receptor, coded by the retinoic acid receptor (RAR) gene which had just reported. Further retinoid research yielded retinoids antagonists, and then RXR(retinoic acid-X-receptor)-agonists and RXR-antagonists. These ligands have a big potential in the therapy of diabetes and obesity.

著者

川島 嘉明

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.106, no.6, pp.433-445, 1986-06-25 (Released:2011-01-31)

参考文献数

34

被引用文献数

1

---

A novel agglomerated crystallization technique, termed spherical crystallization technique, which can transform fine crystals precipitated into spherical agglomerates in one step during the crystallization process, has been developed by using new agglomeration phenomena of particles in liquid system. In this technique, a binary or a ternary mixture of partially miscible solvents was used as a crystallization solvent. It was found that by choosing the proper proportion of the mixture, a small amount of immiscible liquid was liberated from the system, which could preferentially wet the crystals, forming spherical agglomerates. By using this technique, needle like crystals of salicylic acid were agglomerated into spheres being directly compressible into tablet. Spherically agglomerated crystals of aminophylline were prepared directly by reacting theophylline with ethylenediamine in an alcohol-organic solvent-water mixture. The spherically agglomerated crystals of new complex of indomethacin and epirizole with increased solubilities were prepared. Controlled release microspheres of ibuprofen with acrylic polymer were prepared to improve bioavailability.

著者

梁井 光二

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.70, no.4, pp.181-184, 1950-04-25 (Released:2010-02-19)

著者

三木 卓一 松尾 泰介

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.87, no.3, pp.323-325, 1967-03-25 (Released:2008-05-30)

参考文献数

17

被引用文献数

2 12

著者

芦澤 一英 内川 清彦 服部 禎一 石橋 泰雄 三宅 康夫 里 忠

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.110, no.3, pp.191-201, 1990-03-25 (Released:2008-05-30)

参考文献数

45

被引用文献数

1 2

---

In designing the dosage form, one major factor controling their physicochemical properties is solid forms of the drug powder. The method for improving the physicochemical stability of unstable β-lactam antibiotics is very important. E1040 is a novel parenteral 3-betaine type cephalosporin which has a broad antibacterial spectrum and potent activities against Citrobacter, freundii, Enterobacter cloacase, and glucose-nonfermentative bacteria, including P. aeruginosa. The present study was intended to provide the solid-state chemical stability of perenteral steril dry dosage form of E1040. The chemical stability differences among the various solid forms, dry amorphous, additive freeze dried amorphous solid and crystalline powder, were evaluated as a function of temperature by thermo stress tests. Freeze dried anhydrous amorphous form was the first steril dry dosage form investigated during the preformulation study. However, this compound is chemically unstable, in the titer of them, reduction are observed in the freeze dried amorphous solid. In order to select the most suitable solid form of E1040, two methods were used. One was crystalline solid and the other was NaCl additive freezedried formulation. Through our experiments, the solid-state chemical stabilization can be achieved by these two methods (effect of crystal structure and effect of NaCl additive).

著者

三井 幸雄

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.100, no.6, pp.585-601, 1980-06-25 (Released:2008-05-30)

参考文献数

72

---

There are two different techniques for the X-ray structure analyses of materials ; that for small molecules and that for macromolecules. The latter technique, is called"protein crystallography."The characteristics of protein crystallography as opposed to ordinary crystallography for small molecules are described. Some of the achievements of protein crystallography and their impact on other scientific fields are discussed, and perspectives for the possible contribution of protein crystallography to molecular pharmacology are given.

著者

大村 貞文 森本 繁夫 長手 尊俊 安達 孝 河野 喜郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.112, no.9, pp.593-614, 1992-09-25 (Released:2008-05-30)

参考文献数

60

被引用文献数

7 18

---

A series of O-alkylated derivatives of erythromycin (EM) has been prepared and their biological properties were evaluated. Among them, clarithromycin (CAM, 6-O-methylerythromycin) exhibits most potent in vitro and in vivo antibacterial activities, higher acid-stability than EM and favorable pharmacokinetic properties as an antibiotic. CAM was originally synthesized via methylation of 2'-O, 3'-N-bis (benzyloxycarbonyl)-N-demethylerythromycin in low yield, because of the less selectivity of 6-O-methylation. The selective 6-O-methylation was achieved using the erythromycin 9-oxime derivative as a key intermediate. By the further investigation on the protective groups of 9-oxime and desosamine moiety, the production process of CAM on an industrial scale has been established via methylation of 2', 4"-O-bis (trimethylsilyl) erythromycin 9-[O-(1-isopropoxycyclohexyl) oxime] in more than 45% overall yield. CAM has the same antibacterial spectra as EM and is active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, Mycoplasma and Chlamydia. The activity of CAM against clinical isolates was 1 to 16 times higher than that of EM. The efficacies of CAM were 6 to 15 times superior to those of EM against systemic infections due to Gram-positive bacteria in mice. CAM also showed more potent therapeutic efficacies than EM against respiratory tract infections caused by S. pneumoniae and H. influenzae. CAM was well absorbed after oral administration, and its distribution to various tissues was significantly higher than that of EM in animals. The level of CAM in the lung was extremely high, which accounted 69 times that of EM. CAM was found to be distributed predominantly in the alveolar wall, especially in the alveolar epithelial cells, by microautoradiography. After oral administration in human, the serum level and urinary excretion of CAM were 5 and 20 times higher than those of EM, respectively. The major and active metabolite of CAM in human, (14R)-14-hydroxyclarithromycin, existed in significant quantity in the serum and urine, suggesting that the metabolite contributes to the excellent clinical efficacy of CAM. This paper describes the synthesis, structure-activity relationships, antibacterial activities, metabolism and clinical efficacies of CAM, a new macrolide antibiotic.

著者

大坪 健児

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.120, no.11, pp.1135-1147, 2000-11-01 (Released:2008-05-30)

参考文献数

41

被引用文献数

1 2

---

This review summarizes our recent findings in the syntheses of drug metabolites. The metabolites of Grepafloxacin (1) and OPC-14117 (10) were prepared from the common intermediates (5) and (21), respectively. Moreover, treatment of 10 with a model P450 system led to a benzyl alcohol derivative (11) in one step. OPC-31260 (22) was efficiently N-dealkylated using several metalloporphyrins with oxidants to afford three metabolites (23-25). In addition, I succeeded in obtaining the metabolite (23) in high yield from N-oxide (26) not only as an oxygen donor but also as a substrate, there after, in the model P450 system. Optically active metabolites of OPC-29030 (27) were prepared by enzyme-catalyzed enantioselective transesterification of racemic sulfinyl metabolites. On the other hand, a chiral 1, 1'-bi-2-naphthol derivative (38a) was found to be an efficient asymmetric acylating agent for a secondary alcohol (36) which is a valuable intermediate for preparing optically active metabolites of 22. Furthermore, metabolites (45) and (47) of OPC-21268 (44) were prepared using SmI2-induced cyclization and oxidative decarboxylation with Pb(OAc)4 as key steps, respectively.

著者

黒田 宏紀 藤田 俊郎 宮寺 彰彦 金内 徹

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.110, no.8, pp.547-554, 1990-08-25 (Released:2008-05-30)

参考文献数

10

被引用文献数

2 1

---

Cetraxate hydrochloride (1) (antiulcer agent) can be produced by the enzymatic debenzylation of cetraxate benzyl ester hydrochloride (2). In order to use the enzymatic method as an industrial procedure, it is essential to obtain the crystal of cetraxate (3, free compound of 1) as an intermediate from the enzymatic reaction solution. Cetraxate (3) was found to have four polymorphic forms, two anhydrides (A, B) and two hydrates (dihydrate I, II). It is very important for the practical procedure that cetraxate (3) crystal forms transform from the light crystal form (dihydrate I) to the heavy one (dihydrate II) in the enzymatic reaction solution. The transformation was strongly prevented by the cetraxate related substance, tranexamic acid-cetraxate hydrochloride condonsate (TS-1). The heavy crystal forms (dihydrate II, anhydride B) are thermodynamically more stable than the light one (dihydrate I). Crystal forms of 3 are stabilized as dihydrate II in water below 29°C and as anhydride B over 29°C.

著者

木内 祐二 増田 豊 亀井 大輔 向後 麻里 中村 明弘

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.133, no.2, pp.231-241, 2013-02-01 (Released:2013-02-01)

参考文献数

4

被引用文献数

3 4

---

In Showa University School of pharmacy, 7 competencies for outcome-based education were set up in 2011. We are now creating sequential curriculum in order to achieve these competencies. As a member of team medical treatment, pharmacist must share a patient's information with other members, assess each patient's condition, propose the best medication with evidence, and also check the effect of medication. Therefore, many active practices in a hospital and community and problem-based learning (PBL) tutorials are carried out in curriculum in School of Pharmacy. As a training for the future pharmacists who positively perform primary care with responsibility in community pharmacy, students study the method of clinical assessment (assessment of condition of disease from the patient's complain, and choice of appropriate proposal). Furthermore, the exercise and training of parenteral medication, physical assessment, and first aid, etc. are also taken in the curriculums as new clinical skill. The systematic and gradual interprofessional education curriculum for the team medical education has been carried out aiming at training of active members in medical team in a hospital and community. At this symposium, I will introduce these systematic advanced curriculums for the pharmacist of a new age, and to show the usefulness and learning effect.

著者

佐藤 英治

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.135, no.3, pp.345-347, 2015-03-01 (Released:2015-03-01)

参考文献数

2

被引用文献数

1 2

---

The third advanced workshop of the Pharmaceutical Society of Japan for pharmaceutical teachers was held from October 12th to 14th, 2013, and participants discussed an outcome-based approach to curriculum development in pharmacy education. In this article, I report the outcome-based spiral curriculum model of group 2A, which was designed to enable pharmacy students to understand a patient's condition, and to provide a basic practical ability in medical therapy. In the curriculum, pharmacy students will learn biochemistry and functional morphology in the first and second years, skills to interview patients in the third year, pathophysiology and pharmacotherapeutics in the third and fourth years, skills to estimate patient disease from physical examination in the fourth year, and practice in understanding real patient conditions in a clinical clerkship in the fifth year. The curriculum also included learning and evaluation methods.

著者

真野 高司

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.133, no.1, pp.67-72, 2013-01-01 (Released:2013-01-01)

参考文献数

6

---

In order to successfully apply drug delivery systems (DDS) to new chemical entities (NCEs), collaboration between medicinal chemists and formulation scientists is critical for efficient drug discovery. Formulation scientists have to use ‘language’ that medicinal chemists understand to help promote mutual understanding, and medicinal chemists and formulation scientists have to set up strategies to use suitable DDS technologies at the discovery phase of the programmes to ensure successful transfer into the development phase. In this review, strategies of solubilisation formulation for oral delivery, inhalation delivery, nasal delivery and bioconjugation are all discussed. For example, for oral drug delivery, multiple initiatives can be proposed to improve the process to select an optimal delivery option for an NCE. From a technical perspective, formulation scientists have to explain the scope and limitations of formulations as some DDS technologies might be applicable only to limited chemical spaces. Other limitations could be the administered dose and, cost, time and resources for formulation development and manufacturing. Since DDS selection is best placed as part of lead-optimisation, formulation scientists need to be involved in discovery projects at lead selection and optimisation stages. The key to success in their collaboration is to facilitate communication between these two areas of expertise at both a strategic and scientific level. Also, it would be beneficial for medicinal chemists and formulation scientists to set common goals to improve the process of collaboration and build long term partnerships to improve DDS.

著者

糸川 秀治 竹谷 孝一 一柳 幸生 森田 博史

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.119, no.8, pp.529-583, 1999-08-01 (Released:2008-05-30)

参考文献数

149

被引用文献数

2 10

---

A lot of anticancer agents have been isolated from natural sources, especially from microorganisms and plants. However, there is no special type of compounds for cancer therapy. Various types of substances are effective for various types of cancers and tumors : for instance, alka1oids, lignans, terpenes and steroids, etc. In this report, the authors will describe especially about higher plants.

著者

平川 善行 原田 清

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.103, no.6, pp.690-695, 1983-06-25 (Released:2008-05-30)

参考文献数

5

被引用文献数

2 2

---

In the previous paper, a new technique for particle size reduction of oxolinic acid (OA), a slightly soluble model drug having an acidic group in a molecule, by the crystallization through the neutralization of its alkaline solution in the presence of certain surfactant or polymer was described. The wet sieving method by the use of polycarbonate membrane filter for the evaluation of size reduction effect was also described. Various factors affecting the size reduction of OA were investigated in this paper. The results obtained were as follows ; manners of participation in various factors affecting the size reduction varied with OA concentration at crystallization, and in the case of 5 w/v% OA concentration, the influences of addition rate of hydrochloric acid solution, stirring rate, reaction temperature and concentration of hydrochloric acid were relatively low. Size reduction effects of various surfactants and polymers were investigated. All of them were effective, though differences were recognized in the extent of size reduction. It has been found that the establishment of optimal conditions to obtain the finest particles is enabled and moreover, there is a possibility to prepare the particle that have an optional particle size by regulating the various factors.

著者

平川 善行 原田 清

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.102, no.10, pp.951-959, 1982-10-25 (Released:2008-05-30)

参考文献数

26

---

When slightly soluble medicinal crystals are administered orally, their particle size is one of the important factors affecting the bioavailability. Therefore, it was attempted to develop a new technique of particle size reduction, in which the addition of surfactants or polymers at crystallization was examined. In order to evaluate the size reduction effect for oxolinic acid (OA), the wet sieving method was studied by the use of the polycarbonate memblane filter. This method consists of the following procedures : 1) sonication of suspension more than 10 min, 2) suction filtration of suspension after dilution, 3) measurement of the weight of the residue on each filter by the determination of OA, 4) plots of the cumulative weight of residues on a log-probability paper, followed by calculation of apparent geometric mean diameter on weight basis, 5) regulation of the volume of filtrate according to the particle size of microcrystallines. It was found that the new method studied enabled to evaluate the size reduction effect easily and accurately.

著者

桑田 一夫

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.132, no.8, pp.873-879, 2012 (Released:2012-08-01)

参考文献数

17

被引用文献数

1

---

We developed a theoretical framework for the regulation of biological macromolecules using the logically designed compounds. According to the cohomology theory, algebraic objects can be translated into geometrical ones. Successfully established quantum theory at 20th century, which essentially deals with the non-commutative nature of the space, also suggests the non-commutative topology of biological space. Arithmetic geometrical representation of the molecules as well as the macroscopic membranous structures would uncover their structural groups in Hilbert space. In order to construct the concrete image of biological space, here we combined quantum chemical (QC) model, all-atom (AA) model and coarse grained (CG) model, into one program designated ‘NAGARA’. These three models can be arranged in an arbitrary manner to yield the desired statistical ensemble. For example, QC model was applied to the optimization of the chemical structure of anti-prion lead compound GN8. Arithmetic geometrical representation of these algebraic models is in progress.

著者

濵田 芳男

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.133, no.10, pp.1113-1120, 2013-10-01 (Released:2013-10-01)

参考文献数

23

被引用文献数

1 1

---

This review discusses the importance of quantum chemical interactions in biomolecules for medicinal science and their relevance to the author's β-secretase (BACE1) inhibitor drug discovery research. Although molecular mechanics/dynamics (MM/MD) methods are available in many in silico design tools used for drug discovery, they cannot accurately evaluate quantum effects between biomolecules and drugs. The key roles of biomolecular quantum chemical interactions in drug discovery are discussed using the arginine side chain as an example. Arginine is recognized as a charged amino acid in commonly used drug design software, unlike other amino acids with π-electron orbitals, such as phenylalanine, tyrosine, and tryptophan. Quantum chemical interactions via the arginine side chain are crucial for molecular recognition, and are found in many X-ray crystal structures, such as protein-protein, protein homodimer, RNA aptamer-protein, and enzyme-inhibitor complexes. This review describes the essential role of quantum chemical interactions via the arginine side chain in the mechanism of BACE1 inhibition, and proposes an “electron donor/acceptor bioisostere” concept for medicinal science based on quantum chemical interactions. Several potent BACE1 inhibitors, as well as the first peptides with BACE1 inhibiting activity were designed and synthesized based on studies of quantum chemical interactions via arginine side chain and the “electron donor bioisostere” concept.

著者

中村 和則 城村 綾子 織田 実 猪 好孝 内山 浩之 大谷 尚也 宮崎 裕行 来海 正輝 秋澤 有四郎 岡 俊範

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.115, no.3, pp.201-212, 1995-03-25 (Released:2008-05-30)

参考文献数

28

被引用文献数

3 7

---

Inhibitory activities of FUT-187 on trypsin-like serine proteases were compared using camostat mesilate (camostat), and 4-(4-guanidino benzoyloxy)-phenyl acetic acid methanesulfonate (GBPA) known as an active metabolite of camostat in the blood. Ki values of FUT-187 on the competitive inhibition mechanism were 0.097 μM for trypsin, 0.029 μM for pancreatic kallikrein, 0.61 μM for plasma kallikrein, 0.57 μM for plasmin, 2.5 μM for thrombin, 20.4 μM for factor Xa and 6.4 μM for Clr. However, FUT-187 acted as a noncompetitive inhibitor for factor XIIa and an uncompetitive inhibitor for Cls, and Ki values for these proteases were 0.021 and 0.18 μM, respectively. Ki values of camostat for these proteases were in the range of 0.037 to 96.4 μM, and those of GBPA for the above proteases except trypsin and plasma kallikrein were higher than those of FUT-187. The inhibitory activity of FUT-187 on trypsin was not reduced by the addition of the serum at 10%, whereas, that of GBPA was reduced (4.3 fold) in terms of IC50 values. The concentration of FUT-187 required to double APTT (activated partial thromboplastin time) was 1.09 μM, while GBPA, by concentrations up to 1 mM failed to double APTT. The kinin formation by glandular kallikrein in the rat plasma was inhibited by FUT-187 with IC50 value of 0.024 μM, while camostat revealed no inhibition by concentrations up to 1 μM. The complement-mediated hemolyses in the classical and alternative pathways were also inhibited by FUT-187 with IC50 values of 0.17 and 3.5 μM, respectively, the corresponding values for camostat being 350 and 150 μM, respectively. It is concluded that FUT-187 is a potent and selective inhibitor of trypsin-like serine proteases, and its inhibitory activities are stronger than those of camostat on glandular kallikrein, factor XIIa and Cls in complement pathway.