著者

大沢 基保

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.129, no.3, pp.305-319, 2009 (Released:2009-03-01)

参考文献数

58

被引用文献数

17 25

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Immunotoxic effects of heavy metals, as a typical environmental agent, and their mechanisms are reviewed based on our findings on autoimmune response induced by exposure to cadmium (Cd) as CdCl2. Adverse immune effects of chemicals, defined as immunotoxicity, have been used as a sensitive biomarker for assessing health effects of environmental chemicals. My initial research focused on renal toxicity of heavy metals was developed to elucidate characteristics and mechanisms for immune-mediated nephritis induced by heavy metals. In our studies the most interesting finding was autoantibody production enhanced by the oral exposure to Cd at environmental levels. It was observed simultaneously with enhancement of non-specific antibody production and suppression of primed-antigen specific antibody production. Immunostimulation including induction of autoantibodies was found to be the primary immunotoxic effect of Cd, because of the dose-sensitivity, and to be associated with polyclonal B cell activation (PBA). Further mechanism studies on the PBA induced by Cd in vitro showed that it was mediated by T cells, via cytokines, dominantly Type-2 cytokines, and recognition of MHC-II antigens of cell surface. The similarity among PBAs induced by inorganic salts of Cd, mercury and lead suggests that it would be the common effect among the metals to be involved in their pathogenesis of nephritis. Finally possible health significance of chemical-induced PBA is discussed associated with an increasing trend of autoimmune diseases in industrialized countries.

著者

永倉 正彦 岡本 敏彦

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.92, no.2, pp.167-175, 1972-02-25 (Released:2008-05-30)

参考文献数

15

被引用文献数

1 1

---

An addition-elimination reaction, which was reported in the reaction of 3-nitroquinoline with aqueous sodium hypobromite in methanolic KOH, also occurred in the case of other nitroquinolines, i.e., 6-, 5-, 8-, and 4-nitroquinolines. 6-Nitroquinoline (I) gave 6-bromo-5-methoxyquinoline (IIa), 6, 8-dibromo-5-methoxyquinoline (IIb), 6-bromo-5, 7-dimethoxyquinoline (IIIa), 5, 7-dimethoxy-6-nitroquinoline (IIIb), 8-bromo-5, 7-dimethoxy-6-nitroquinoline (IIIc), and 8-bromo-6-oxo-5, 5, 7-trimethoxy-5, 6-dihydroquinoline (IV) on being reacted in the same way as in the reaction of 3-nitroquinoline. Other nitroquinolines and their products from the same reaction were ; 5-nitroquinoline (XI); 5-bromo-6-methoxyquinoline (XIIa), 6-methoxy-5-nitroquinoline (XIIb), 8-methoxy-5-nitroquinoline (XIIIa), 5, 7-dibromo-6, 8-dimethoxyquinoline (XIVa), and 6, 8-dimethoxy-5-nitroquinoline (XIVb). 8-Nitroquinoline (XVIII); 8-bromo-7-methoxyquinoline (XIX), 5-methoxy-8-nitroqninoline (XX), and 6-bromo-5, 7-dimethoxy-8-nitroquinoline (XXI). 4-Nitroquinoline (XXII); 4-bromo-3-methoxyquinoline (XXIIIa), 3-methoxy-4-nitroquinoline (XXIIIb), 2, 3-dimethoxy-4-nitroquinoline (XXIV) and 4-methoxyquinoline (XXV). The reaction of 2-nitroquinoline (XXX) gave only 2-methoxyquinoline (XXXI).

著者

横尾 信夫 服部 英三 平田 光輝 渡辺 好一郎 佐藤 文泰 永倉 正彦 藤井 節郎

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.107, no.9, pp.732-737, 1987-09-25 (Released:2008-05-30)

参考文献数

9

被引用文献数

1 1

---

Synthesis of water-soluble chymotrypsin specific inhibitors was attempted to study the roles of chymotrypsin-like enzymes in vivo. Previously we reported that the esters of carboxylic acid containing a condensed ring showed stronger activity than those containing a single ring system. Then we synthesized 4-substituted phenyl esters of carboxylic acid containing a condensed ring, such as tetralin, naphthalene, indole etc., and their inhibitory activities were compared. Among these compounds, esters of tetralin-1-carboxylic acid (FK-448) and 1-naphthylacetic acid showed the strongest activity, and their IC50 values were 8×10-7, 5×10-7 M, respectively. Tetralin-2-carboxylate and 2-naphthylacetate inhibited weaker than 1-analogues. Esters of basic quinoline carboxylic acid and bulky carboxylic acids containing a three-ring system inhibited poorly. Chymotrypsin produced equimolecular 4-substituted phenol rapidly and thereafter the amount of 4-substituded phenol increased slowly, when incubated with FK-448 at 37°C.

著者

津田 恭介

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.69, no.11, pp.486-488, 1949-11-25 (Released:2010-02-19)

参考文献数

15

著者

鈴木 順子 今津 嘉宏

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.138, no.5, pp.599-600, 2018 (Released:2018-05-01)

著者

三塩 晋作 廣瀬 徹 中野 純次 松本 純一

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.107, no.8, pp.634-639, 1987-08-25 (Released:2008-05-30)

参考文献数

6

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A mode of the alkaline and acidic degradation of sodium 6-[D-2-(2-(4-formyl-1-piperazinyl)-5, 8-dihydro-5-oxopyrido [2, 3-d] pyrimidine-6-carboxamido)-p-hydroxyphenylacetamido] penicillanate (1, PL-385) and structures of the degradation products were studied. Treatment of 1 with three equimolar amounts of sodium hydroxide produced a kinetically stable intermediate, (5R)-penicilloic acid (2a), which on kept at 37°C for 65h was converted into a thermodynamically stable product, (5S)-penicilloic acid (2b). Treatment of 1 with an excess of sodium hydroxide gave a deformyl derivative (3) arising from the elimination of formly group via 2. On the acidic treatment of 1, the degradation product, (5R, S)-penilloic acid (4), was yielded.

著者

三塩 晋作 廣瀬 徹 中野 純次 松本 純一

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.107, no.8, pp.607-615, 1987-08-25 (Released:2008-05-30)

参考文献数

11

被引用文献数

1 1

---

A series of N-alkylampicillin (2), N-heteroarylampicillin (5) and N-heteroarylcephalexin (6) were synthesized in order to obtain β-lactam detivatives with a broad and orallypotent antibacterial activity similar to that of the injectable N-acylampicillins. 6-[2-[(Pyrido [2, 3-d] pyrimidin-6-yl) methylamino]-2-phenylacetamido] penicillanic acid derivatives (2) were prepared by the reduction of the Schiff base which was derived from the reaction of pyrido [2, 3-d] pyrimidine-6-carboxaldehyde (1) with ampicillin. 6-N-(4-Pyrimidinyl) ampicillin and -cephalexin derivatives (5 and 6) were obtained by the reaction of 4-chloropyrimidine (4) with ampicillin or cephalexin. Compounds 2, 5 and 6 were tested in vitro antibacterial activity and, however, none of them have a broad and potent activity.

著者

三塩 晋作 廣瀬 徹 中野 純次 松本 純一 南 新作

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.107, no.8, pp.592-606, 1987-08-25 (Released:2008-05-30)

参考文献数

11

被引用文献数

1 1

---

A series of N-(pyrido [2, 3-d] pyrimidine-6-carbonyl) ampicillin and -amoxicillin derivatives (1-3) were synthesized and tested for antibacterial activity and acute toxicity in mice. 5, 8-Dihydro-2-(1-piperazinyl)-5-oxopyrido [2, 3-d] pyrimidine-6-carboxylic acid (7) was converted to N-acyl- and -alkylpiperazinyl derivatives (8 and 9) by acylation and alkylation, respectively ; a part of 9 was alternatively prepared by the reactions involving the displacement of N-alkylpiperazines with sulfoxide 11 which was derived from ethyl 5, 8-dihydro-2-methylthio-5-oxopyrido [2, 3-d] pyrimidine-6-carboxylate (10). Treatment of 4, 5, 8 and 9 with ethyl chloroformate followed by the reaction with ampicillin and amoxicillin gave the desired N-acylampicillin (2) and -amoxicillins (1 and 3), respectively. Among compounds 1-3, sodium 6-[D-(-)-2-(2-(4-formyl-1-piperazinyl)-5, 8-dihydro-5-oxopyrido [2, 3-d] pyrimidine-6-carboxamido)-p-hydroxyphenylacetamido] penicillanate (3l, PL-385) was found to be the most excellent in antibacterial activity and to be the less potent in acute toxicity in mice. An alternative route for the synthesis of PL-385 was accomplished, consisting of the reaction of an active ester 13 with amoxicillin. Structure-activity relationships of 1-3 were discussed.

著者

尾崎 幸紘 菅 忠三 吉岡 利紘 森本 悌次郎 原田 正敏

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.4, pp.268-272, 1990-04-25 (Released:2008-05-30)

参考文献数

12

被引用文献数

1 4

---

The present study was carried out to evaluate an equivalence of pharmacological properties between natural crude drugs and their cultured cells. The effects of ether extract of Lithospermi Radix and cultured cells of Lithospermum erythrorhizon SIEB. et ZUCC. and aqueous extract of Coptidis Rizoma and cultured cells of Coptis japonica MAKINO var. dissecta NAKAI on proliferation of granulation tissue in rats were compared. The ether extracts of Lithospermi Radix and the cultured cells enhanced proliferation of granulation tissue by the cotton pellet method. The potency of both extract was about the same, if results were compared with the corresponding doses which contained the same quantity of shikonin derivatives. On the other hand, the aqueous extracts of Coptidis Rhizoma and the cultured cells inhibited it. The potency of both extract was about the same, if results were compared with the corresponding doses which contained the same quantity of berberine-type alkaloids. From these results, to evaluate an equivalence of pharmacological properties between natural crude drugs and their cultured cells, it is concluded that their qualities and quantities are not so different each other and the almost same pharmacological effect expected on the basis of their uses is required.

著者

長野 一也 東阪 和馬 角田 慎一 堤 康央

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.138, no.7, pp.903-909, 2018 (Released:2018-07-01)

参考文献数

15

---

Human epidermal growth factor receptor 2 (Her2)-targeting antibodies and anti-hormone therapy are effective for most breast cancer patients. However, such approaches are not viable with resistant cases or in triple-negative breast cancer (TNBC) patients, given the lack of Her2 and estrogen and progesterone receptors in these patients. Thus, new drug targets are urgently required. From this perspective, we searched for novel drug targets using proteomic analysis, and identified Eph receptor A10 (EphA10), which is elevated in breast cancer cells as compared to normal breast tissue. Here, we evaluated the potential of EphA10 as a drug target by analyzing its protein expression profile/function in cancer cells, and then by using an anti-EphA10 antibody to treat EphA10-expressing tumor-bearing mice. Protein expression profile analysis showed that EphA10 was expressed in various breast cancer subtypes, including TNBCs, with no expression observed in normal tissues, apart from the testes. Moreover, functional analysis of the cancer cells revealed that ligand-dependent proliferation was observed in EphA10-expressed cancer cells. Thus, we developed our novel anti-EphA10 antibody, which binds to EphA10 with high specificity and affinity at the nanomolar level. Finally, therapeutic analysis indicated that tumor growth was significantly suppressed in the mAb-treated mice in a dose-dependent manner. These results suggest that the EphA10-targeting therapy may be a novel therapeutic option for the management of breast cancer, including in TNBCs which aren't currently treated with molecular-targeted agents. Consequently, we hope that these findings will contribute to the development of a new targeting therapy for refractory breast cancer patients.

著者

中村 光浩

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.136, no.4, pp.549-556, 2016 (Released:2016-04-01)

参考文献数

25

被引用文献数

5 9

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Observational study is necessary for the evaluation of drug effectiveness in clinical practice. In recent years, the use of spontaneous reporting systems (SRS) for adverse drug reactions has increased and they have become an important resource for regulatory science. SRS, being the largest and most well-known databases worldwide, are one of the primary tools used for postmarketing surveillance and pharmacovigilance. To analyze SRS, the US Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report Database (JADER) are reviewed. Authorized pharmacovigilance algorithms were used for signal detection, including the reporting odds ratio. An SRS is a passive reporting database and is therefore subject to numerous sources of selection bias, including overreporting, underreporting, and a lack of a denominator. Despite the inherent limitations of spontaneous reporting, SRS databases are a rich resource and data mining index that provide powerful means of identifying potential associations between drugs and their adverse effects. Our results, which are based on the evaluation of SRS databases, provide essential knowledge that could improve our understanding of clinical issues.

著者

宮本 理人 土屋 浩一郎

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.138, no.7, pp.933-938, 2018-07-01 (Released:2018-07-01)

参考文献数

11

被引用文献数

3 3

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Sodium-glucose transporter (SGLT)-2 inhibitors, which are currently in clinical use in most of the world, are unique as their hypoglycemic effects are completely independent of insulin action. Potential benefits and indications for the treatment of other diseases like circulatory and renal disorders are attracting attention. SGLT2 inhibitors not only reduce blood glucose levels but also alter the whole-body energy balance to lower body weight, which should result in the amelioration of multiple metabolic disorders like metabolic syndrome. In the symposium, we briefly introduced the physiological as well as biological functions of SGLTs and discussed strategies for drug design by looking back at the history of drug discovery for SGLT2 inhibitors. We also shared our recent data on their combined usage with other hypoglycemic agents and effects on glucagon secretion, which are current clinical topics relevant to SGLT2 inhibitors. Among those topics, strategies for drug discovery of SGLT2 inhibitors are discussed in this review.

著者

高橋 酉蔵 堀 幹夫 浜島 好男

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.78, no.1, pp.6-10, 1958-01-25 (Released:2010-02-19)

参考文献数

18

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For the purpose of elucidating the relationship between effective partial structure of morphine skeleton and analgesic action, several compounds possessing the A-C rings in the morphine skeleton as the basic structure were synthesized. The compounds prepared were 1-dimethylaminoalkyl-1-phenylcyclohexanes (XIII, XVIII, XXV, and XXXII) and 2-dimethylaminoalkyl-2-phenylcyclohexanols (XIV, XXI, XXIX, and XXXV).

著者

近藤 昌夫 藤井 まき子 八木 清仁 渡辺 善照

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.127, no.4, pp.601-609, 2007 (Released:2007-04-01)

参考文献数

47

被引用文献数

1 1

---

Passing of drugs across epithelial cell sheets and endothelial cell sheets is an obligatory step in the absorption of a drug. The passing routes of drugs are classified into transcellular and paracellular pathways. The transcellular route has been widely investigated and is used in clinical therapy. In contrast, drug delivery using the paracellular route has never been fully developed. Sodium caprate is the only absorption-enhancer of drugs that uses the paracellular route. Tight junctions (TJs) exist between adjacent cells in epithelial and endothelial cell sheets, and they play a role in sealing the cell sheets. Therefore, we must modulate the TJ barrier for drug delivery using paracellular route. In this review, we describe barriology, including very recent topics, and overview absorption-enhancers from the perspective of barriology.

著者

須藤 雄気

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.136, no.2, pp.185-189, 2016

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Retinal proteins possess vitamin A aldehyde (retinal) as a chromophore within seven transmembrane α-helices. Visible light absorption of them triggers <i>trans-cis</i> photoisomerization of the retinal chromophore and induces structural changes in the protein moiety, resulting in a variety of biological functions such as vision, ion transportation, and photosensing. Environmental genomics revealed that retinal proteins are widely distributed through all three biological kingdoms, eukarya, bacteria, and archaea, indicating the biological significance of their light energy conversion. In addition to their biological aspect, retinal proteins have become a focus of interest in part because of applications for optogenetics. On the basis of our results and other findings, we highlight the recent progress in structural and functional studies on retinal proteins.<br>

著者

安本 三治 山下 純一 橋本 貞夫

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.98, no.11, pp.1551-1553, 1978-11-25 (Released:2008-05-30)

参考文献数

10

被引用文献数

6 5

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Synthesis of 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-Thf-FU) (III), which has been found to be a metabolic intermediate of 1, 3-bis (tetrahydro-2-furanyl)-5-fluorouracil (Thf2-FU) and an effective antitumor agent, is reported. 1-Alkane- or 1-arene-sulfonyl-5-fluorouracil (I) was trimethylsilylated by treatment with N, O-bis (trimethylsilyl) acetamide and treated with 2-acetoxytetrahydrofuran in the presence of stannic chloride to give 1-alkane- or 1-arene-sulfonyl-3-(tetrahydro-2-furanyl)-5-fluorouracil (II). III was obtained by deblocking of II with methanolic ammonia.

著者

佐藤 大作

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.134, no.2, pp.213-222, 2014

被引用文献数

5

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Circulating counterfeit medicines in the market is a public health threat. Counterfeit medicines become common problem, not only in developing countries, but also in industrialised countries, as internet has made them more accessible. In Japan, the recent survey on the medicines purchased through on-line pharmacy (targeting Japanese consumers) showed that the majority of erectile dysfunction (ED) medicines imported by individuals in Japan were counterfeit version. The survey of Japanese consumers, who privately imported medicines through on-line pharmacy, indicated that 16% of these consumers experienced adverse events associated with these products. Not only that it is just fake brand, but fake medicines may even cause health hazard. The counterfeit version of Avastin recently detected in the United States became a serious threat for those who desperately need these medicines for life-threatening disease. The Japanese regulatory authorities have provided risk information of counterfeit medicines to general public, as well as monitored on-line pharmacies and conducted enforcement action where necessary. However, more resources of compliance activity should be allocated to respond to the situation of growing threats of counterfeit medicines. Purchasing medicines from abroad through unauthorised channel is the major source of counterfeit medicines. It is essential to prevent circulation of counterfeit medicines through international collaboration of various regulatory authorities. To address these problems, the World Health Organization (WHO) has launched a new Member States Mechanism (MSM) to build network of the authorities. Also, INTERPOL (ICPO) initiated globally concerted enforcement actions (Operation Pangea) against pharmaceutical crime as well as built partnership with pharmaceutical industry to create Pharmaceutical Crime Programme. It is also necessary to prevent consumers encountering counterfeit medicines and to prevent health hazard. The Ministry of Health, Labour and Welfare (MHLW) has been actively involved in prevention and educational activities such as public awareness campaign. MHLW started anti-counterfeit medicines and new psychoactive substance project from February 2013, which centrally collects information about counterfeit medicines, in particular, and provides the risk information more effectively to the public. Japanese Government will work together with international community and contribute to combating counterfeiting through public and private partnership.<br>

著者

中尾 英雄 福島 正美 清水 総明 荒川 順生

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.94, no.8, pp.1032-1037, 1974-08-25 (Released:2008-05-30)

参考文献数

6

被引用文献数

12 14

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Water-soluble derivatives of N-(2-chloroethyl)-N-nitrosourea were synthesized and their antitumor activity was tested against leukemia L-1210. Most of these compounds showed a high activity.

著者

中尾 英雄 福島 正美 菅原 眞一

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.93, no.11, pp.1526-1529, 1973-11-25 (Released:2008-05-30)

参考文献数

5

被引用文献数

2 2

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5-Cyano-2-furaldehyde and its derivatives were synthesized and their antimicrobial activities were tested. Neither series of compound possessed significant antimicrobial activity.

著者

植沢 芳広

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.138, no.2, pp.185-190, 2018-02-01 (Released:2018-02-01)

参考文献数

14

被引用文献数

4

---

Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.