著者

山口 知宏

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.136, no.2, pp.197-202, 2016-02-01 (Released:2016-02-01)

参考文献数

17

被引用文献数

1

---

A drug's effectiveness against a disease depends not only on its interaction with receptors but also its pharmacokinetics (absorption, distribution, metabolism, and extrusion; ADME). ATP binding cassette (ABC) multidrug transporters are important proteins that influence the ADME properties of a drug, especially the ABC transporter subfamily B member 1 (ABCB1). Elucidation of the molecular mechanisms of ABCB1 will contribute to our understanding of the molecular basis of ADME. Human ABCB1 is expressed in many organelles, and exports various substrates from cells using energy generated by its ATP hydrolase (ATPase) activity. The ATPase activity depends on the concentration of the transport substrates, and the characteristic behavior of the substrate-dependent ATPase activity can be related to the molecular mechanism of ABCB1. Recently, we have revealed the molecular mechanisms of a eukaryotic ABCB1 homolog, CmABCB1, based on structural and functional studies. In this review, I discuss the relationship between key structural features and the behavior of transport substrate-dependent ATPase activity of CmABCB1, including its role in determining the molecular basis of ADME.

著者

北條 康司 橋本 育子 宮本 陽子 川添 禎浩 水谷 民雄

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.120, no.3, pp.311-314, 2000-03-01 (Released:2008-05-30)

参考文献数

21

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While copper(II) gluconate (CuGL) is generally used as a nutrient supplement for infant foods and as an oral deodorant, little information is available regarding a toxic effect of CuGL on mammals. In this article, we examined in vivo induction of toxicity and change of level of glutathione and ascorbic acid, major biological antioxidants, lipid peroxide and copper (Cu) in liver and kidney 4 h after single intraperitoneal administration of CuGL at 0.05 and 0.10 mmol/kg to mice. Serum glutamic pyruvic transaminase (SGPT) activity, an indicator of hepatotoxicity, significantly increased compared to control in proportion to doses of CuGL. Hepatic level of glutathione measured as nonprotein sulfhydryl was not proportional to CuGL doses, but enhanced after dosing of 0.05 mmol/kg and lowered by 0.10 mmol/kg. Like SGPT activity, serum urea nitrogen (SUN) concentration, an indicator of nephrotoxicity, significantly increased in proportion to doses of CuGL. Renal glutathione level was not different from control after dosing of 0.05 mmol/kg and lowered by 0.10 mmol/kg. In both organs, relative organ weight and lipid peroxide level were not affected by the treatment with CuGL; ascorbic acid level was elevated after dosing of 0.05 mmol/kg and was not different from control after treatment with 0.10 mmol/kg; like SGPT activity and SUN concentration, Cu level significantly increased in proportion to doses of CuGL. These results suggest that in the liver and kidney after the treatment with CuGL Cu accumulated may induce toxicity, leading to level changes of glutathione and ascorbic acid and to no induction of oxidative damage.

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.140, no.4, pp.499-505, 2020-04-01 (Released:2020-04-01)

参考文献数

22

被引用文献数

4

---

Toxicity testing is critical for new drug and chemical development process. A clinical study, experimental animal models, and in vitro study are performed to evaluate the safety of a new drug. The limitations of these methods include extensive time for toxicity testing, an ethical problem, and high costs of experimentation. Therefore computational methods are considered useful for estimating chemical toxicity. In silico toxicity prediction is one of the toxicity assessments that uses computational methods to predict and stimulate the toxicity of chemicals. In silico study aims to contribute to effective development of new drug and chemical design. In this study, quantitative structure-activity relationship (QSAR) models will be used to predict toxicities based on chemical structural parameters. Because toxicities are complicated physiological phenomena, a similar toxicity expression might cause a different pathway. Also, since many drugs with unknown mechanisms of actions are available, the application of artificial intelligence (AI)—which uses sophisticated algorithms— is increasingly used to predict toxicities. Recently, the QSAR model was applied to determine complex relations between chemical structures and toxicities. However, accuracy of QSAR for toxicity prediction remains an important issue. International competitions funded by public institutions can address this issue. Two important toxicity challenges were organized in the past decade; this article presents issues of toxicity based on these challenges.

著者

田邊 思帆里 広瀬 明彦 Maurice Whelan 山田 隆志

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.140, no.4, pp.485-489, 2020-04-01 (Released:2020-04-01)

参考文献数

8

被引用文献数

2

---

The Organisation for Economic Co-operation and Development (OECD) has initiated the adverse outcome pathway (AOP) Development Program in which the concept of AOP is applied to evaluate the safety of molecules such as chemicals. This program aims to assist regulatory needs and construct a knowledge base by accumulating AOP case studies. AOP consists of a molecular initiating event (MIE) as the initiating event of the pathway; key events (KEs) as the events themselves, such as cellular-molecular interactions; and adverse outcome (AO), such as signaling transduction-induced toxicity, as adverse events. KEs are extracted as important events at various levels, such as the molecular, cellular, tissue, organ, individual, and species levels; measurement of KEs and key event relationships (KERs), including mechanisms, plausibility, species differences, and empirical support information, are gathered. The development status of the AOP relating to histone deacetylase inhibition-induced testicular toxicity, currently being reviewed by the OECD, has been introduced. The AOP describing malignancies by Wnt ligand stimulation and Wnt signaling activation using gene expression network analysis-based mechanisms in molecular pathway elucidation has been suggested.

著者

田邊 思帆里 山田 隆志

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.140, no.4, pp.479-480, 2020-04-01 (Released:2020-04-01)

被引用文献数

1

著者

赤堀 有美 山下 京介 石田 和也 齋藤 文代 中井 誠

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.140, no.4, pp.491-498, 2020-04-01 (Released:2020-04-01)

参考文献数

19

被引用文献数

1

---

Because the liver is the primary target organ for chemicals and pharmaceuticals, evaluation of these substances' liver toxicity is of critical importance. New evaluation methods without animal testing (i.e., in vitro and/or in silico) are eagerly anticipated, both for animal welfare and for decreasing cost. Also, the importance of mechanistic interpretation of the output derived from non-animal testing has been increasing. Accordingly, we investigated the potential for evaluating liver toxicity by applying the adverse outcome pathway (AOP) concept using gene set enrichment analysis (GSEA) from gene expression (GEx) data. A case study targeting hepatocellular fatty degeneration (HFD) is reported and discussed. We first identified the events detectable in an in vitro system by comparing the GEx data from the rat primary hepatocyte (in vitro) and rat liver (in vivo) treated with a chemical with the ability to induce HFD as one of the phenotypes in a 28-day repeated-dose toxicity test. Then, the scores based on GSEA were calculated after establishing the gene sets for each event leading to HFD. As a result, the mechanistic information leading to HFD was obtained from the score calculated based on the GSEA and the usefulness of the transcriptome-driven evaluation using AOP was demonstrated.

著者

望月 眞弓

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.140, no.4, pp.543-554, 2020-04-01 (Released:2020-04-01)

参考文献数

36

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I have been exploring methods for education and research on drug information for 43 years. There are various approaches to drug informatics research, which include collecting, evaluating, and analyzing information to solve drug related problems, sometimes producing new information from experiments and clinical research. All are based on information science. Drug informatics is information science from the viewpoint of pharmaceuticals. In addition to basic pharmacology, knowledge and skills such as epidemiology, data science, computer science, mathematical statistics, and communication studies are indispensable for the development of drug informatics.

著者

坂上 吉一 住谷 保治 米虫 節夫

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.130, no.11, pp.1445-1451, 2010-11-01 (Released:2010-11-01)

参考文献数

8

被引用文献数

2 3

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Carotenoids are liposoluble pigments widely distributed in nature. More than 750 carotenoids are isolated from natural sources, but only a few kinds are used industrially. The production of carotenoid by microorganisms is to be expected, but few carotenoids originate from living things on land. And there is little knowledge about carotenoid-producing microorganisms in the oceans. The possibility still exists of discovering new carotenoid-producing microorganisms. Sunlight is very strong in subtropical regions. The surface of the sea and coral reefs in these regions is a severe environment for growth of microorganisms. While such conditions produce reactive oxygen species, the continuing strong irradiation can also lead to damaging and lethal photo-oxidative reactions. Many undiscovered microorganisms may possess protective mechanisms such as anti-oxidative activities for survival in this environment. This study focused on marine microorganisms inhabiting coral reefs in the Okinawa area, especially carotenoid-producing bacteria possessing anti-oxidative activities. Many carotenoid-producing microorganisms were collected from subtropical ocean areas (a total of 334 strains of pigmented microorganisms), and the chemical composition, some culture conditions and genetic characteristics of the carotenoids from these microorganisms were examined. Furthermore, similar research was performed using some creatures from the ocean surrounding Kochi Prefecture.

著者

星川 典子 小野 恭司 塩田 寛子 鈴木 俊也 猪又 明子 守安 貴子

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.139, no.1, pp.135-140, 2019-01-01 (Released:2019-01-01)

参考文献数

14

---

Nail tips are nail art materials that can be attached to the nail with adhesives. Recently, nail/finger injuries related to nail tips have been reported and one of the causes is considered to be the adhesives used for attaching nail tips. The components of nail adhesives are mostly cyanoacrylate, which is also used as an industrial instant adhesive. During curing, cyanoacrylate adhesives release formaldehyde through hydrolysis. When it is marketed as a nail adhesive, there is no regulation regarding its formaldehyde amount nor obligation to indicate its ingredients in Japan. Additionally, a biological safety test is not required for nail adhesives. Thus, because the safety of nail adhesives is inadequately confirmed, it is necessary to investigate their biological safety. Therefore, we purchased 5 commercially available nail adhesives and 1 medical adhesive and examined their formaldehyde content and cytotoxicity. We examined the cytotoxicity of the adhesives in V79 cells by a colony forming assay. In this test, 5 nail adhesives showed higher toxicity than 1 medical adhesive. Formaldehyde concentrations in the extract of adhesives were as follows: 17.5 to 24.2 μg/mL for nail adhesives and 7.4 μg/mL for medical adhesives. Cyanoacetate did not elicit cytotoxicity at the final concentration up to 1000 μM. However, formaldehyde showed cytotoxicity, with an IC50 of 79 μM (2.4 μg/mL). Taken together, the cytotoxicity of nail adhesives could be due to the formaldehyde generated by the hydrolysis of cyanoacrylate. It seems important that nail adhesives will be regulated by obligation and enhanced safety in the future.

著者

林 京子 林 利光 李 貞範

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.130, no.2, pp.171-176, 2010-02-01 (Released:2010-02-01)

参考文献数

23

被引用文献数

1 1

---

The limited efficacy and significant clinical toxicity of combination interferone and ribavirin therapy have generated strong interest in developing novel inhibitors of hepatitis C virus (HCV) replication. Recently, a growing understanding of the structure and function of critical viral enzymes and the development of HCV replicons have accelerated the development of highly specific candidate antiviral agents. In the life cycle of HCV, enveloped virions bind and penetrate into host cell using viral envelope glycoproteins. In the cytoplasm, the viral RNA genome serves as mRNA, and produces viral protein as a long polyprotein that is cleaved by both host and viral proteases. Progeny virions assemble by budding into ER/Golgi apparatus, where the glycoproteins maturate, and are released at the cell surface. All stages of replication cycle from the attachment of virus to the release of progeny should be antiviral targets. We have searched for antiviral candidates from natural resources for about 20 years. So far, we have found several classes of compounds with unique antiviral action. Among them, anionic substances interfere with virus attachment and/or entry, several substances inhibit the maturation of virus-specific glycoproteins, low molecules can inhibit the virus release from infected cells, glycerol derivatives reduce the pathogenicity of virus, and some compounds exert virucidal action that impairs the ability of virus to infect host cells. These substances might be worthy to be evaluated as novel anti-HCV agents by using HCV replication systems in cultured cell lines.

著者

髙橋 良哉 大寺 恵子

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.140, no.3, pp.379-382, 2020-03-01 (Released:2020-03-01)

参考文献数

30

被引用文献数

3

---

Age-related decreases of various physiological functions have significant influence on activities of daily living (ADL) and QOL in elderly populations. Mechanisms of aging are currently the focus of many researchers in a wide range of studies. Researchers are trying to find novel ways to attenuate or delay aging in humans as well as to develop interventions for age-associated diseases. In this review, we briefly discuss the need for a multidisciplinary approach in aging research.

著者

大寺 恵子 竹平 理恵子 川田 桂子

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.140, no.3, pp.405-406, 2020-03-01 (Released:2020-03-01)

著者

橘高 敦史

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.128, no.9, pp.1235-1250, 2008 (Released:2008-09-01)

参考文献数

76

被引用文献数

7 7

---

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.

著者

小林 英一

出版者

公益社団法人 日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

vol.1922, no.488, pp.958-964, 1922-10-26 (Released:2008-04-11)

著者

石黒 淳三 多田 俊人 荻原 琢男 井田 圭一 大澤 伸雄 小雀 浩司 相澤 登

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.108, no.3, pp.239-245, 1988-03-25 (Released:2008-05-30)

参考文献数

48

被引用文献数

1 2

---

The effects of ethyl eicosapentaenoate (EPA-E) and docosahexaenoic acid (DHA) on the rat hepatic drug and fatty acid metabolizing enzyme systems were studied after single or repeated oral administration for 14 d. The ratio of liver to body weight and protein concentration in each fraction of microsomes, mitochondria and peroxisomes were not affected after single or repeated administration of EPA-E or DHA. Neither induction nor inhibition of hepatic drug metabolizing enzymes was not observed in EPA-E group. A single administration of DHA decreased aniline p-hydroxylase activity. This decrease in activity, however, was neither enhanced nor reduced after repeated administration of DHA. Other hepatic drug metabolizing enzymes were not affected by DHA. No effects on fatty acid oxidizing enzyme systems of mitochondria and peroxisomes were observed after administration of EPA-E or DHA. No effects on fatty acid elongation and desaturation on microsomes were observed after administration of EPA-E or DHA.

著者

田中 信忠 梅田 知伸 日下部 吉男 中西 雅之 北出 幸夫 中村 和郎

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.133, no.5, pp.527-537, 2013 (Released:2013-05-01)

参考文献数

30

被引用文献数

4 4

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The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of this malaria parasite resistant to conventional drug therapy has stimulated the search for antimalarial compounds with novel modes of action. Here the structure-function relationship studies for two Plasmodium proteins are presented. One example is the structural studies for S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum (PfSAHH) and the other example is those for 1-deoxy-D-xylulose reductoisomerase from Plasmodium falciparum (PfDXR). In the former study, the clue for design of species specific PfSAHH inhibitors was obtained by the structural comparison of the active site of PfSAHH with that of human SAHH (HsSAHH). Our study revealed that the inhibitor selectivity depends on the difference of only one amino acid residue in the active site; Cys59 in PfSAHH vs. Thr60 in HsSAHH. In the latter study, the inhibition of PfDXR enzyme by fosmidomycin has proved to be efficient in the treatment of uncomplicated malaria in recent clinical trials conducted in Gabon and Thailand. Our crystal structure analyses of PfDXR/inhibitor complexes revealed the molecular basis of fosmidomycin's action in P. falciparum. We expect that the structure-function relationship studies on Plasmodium proteins are useful for developing the more effective antimalarial compounds.

著者

西山 成

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.4, pp.455-459, 2012-04-01 (Released:2012-04-01)

参考文献数

29

被引用文献数

3 3

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In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. It has also been revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of chronic kidney disease (CKD). Indeed, most national guideline groups now recommend the use of RAS inhibitors in preference to other antihypertensive agents for hypertensive patients with CKD. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS. We will also discuss the impact of RAS inhibitors in preventing the progressive increases in the intrarenal RAS during the development of CKD.

著者

三輪 芳弘 山路 昭 中浜 肇 折田 義正 福原 吉典 鎌田 武信 石橋 道男 市川 靖二 高原 史郎 園田 孝夫

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.108, no.11, pp.1087-1092, 1988-11-25 (Released:2008-05-30)

参考文献数

15

被引用文献数

1 1

---

A method of high performance liquid chromatography for the determination of unchanged furosemide and its metabolites in the plasma and urine of human subjects is reported. A reversed phase Hibar Lichrosorb RP-8 column was applied to the present method. Furosemide from samples was extracted with diethylether. Beta-glucronidate of furosemide was determined after the addition of beta-glucronidase. 4-Chloro-5-sulfamoyl-anthranilic acid (CSA) was determined by the supernatant obtained from ten minutes centrifugation of the urine with ethanol. In the plasma and urine concentrations of unchanged furosemide of healthy volunteers, there were recognized differences among individuals. In patients with chronic renal failure, urine concentration of beta-glucronidate of furosemide increased in response to impairment of creatinine clearance. CSA could be detected only in the urine of patients receiving renal transplantation under a large dose administration of furosemide (above 200mg/d during rejection). And CSA does not seem to be an artifact product by the procedures of extraction. No interference could be observed by the drugs co-administered with furosemide. The present method can be utilized for a routine drug monitoring system of furosemide. Mechanism of formation of metabolites of furosemide should be further studied.

著者

北川 勲 石津 隆 大橋 一慶 澁谷 博孝

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.1017-1023, 2000-10-01 (Released:2008-05-30)

参考文献数

20

被引用文献数

6 9

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Monthly changes of the content-ratio between S-(-)-and R-(+)-hyoscyamine as well as those between S-(-)-and R-(+)-scopolamine in the leaves of Datura metel L. cultivated in the field, were quantitatively analyzed by the use of HPLC with a chiral adsorbent. It was found that S-(-)-isomer was predominant for hyoscyamine and the ratio of R-(+)-isomer gradually increased during the growth, whereas in the case of scopolamine, S-(-)-isomer was the sole one found throughout the cultivation period. The 1H-NMR study in the CD3OD solution has suggested that S-(-)-hyoscyamine (1) and S-(-)-scopolamine (2) take a "face-to-face"conformation between their tropane skeletons and the benzene rings of the tropic acid moieties. In the presence of an equimolar NaOD in the CD3OD solution, the racemization at C-2' of 1 and 2 proceeded more rapidly than the hydrolysis at the tropic acid ester bond, presumably due to the steric hindrance caused by their"face-to-face"conformations. In the D2O and H2O solutions, on the other hand, the racemization and the hydrolysis of 1 proceeded smoothly, while those of 2 did not occur. It has been supposed that these individual reaction manners are ascribable in considerable extent to the different basicity of N atom in each tropane skeleton of 1 and 2 and to stronger intramolecular hydrogen bond occurring between the carbonyl oxygen at C-1' and the hydroxyl group at C-3' in the tropic acid moiety of 1.

著者

佐々木 順一 北澤 京子 中山 健夫

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.138, no.5, pp.631-635, 2018-05-01 (Released:2018-05-01)

参考文献数

18

被引用文献数

1 3

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This research aimed to clarify the present status and challenges of evidence-based medicine (EBM) education in schools of pharmacy. We sent a questionnaire to 268 faculty members in August 2015, and a total of 192 were completed. The educational contents by respondents differed considerably. Only about 30% of respondents self-assessed the current EBM courses they taught as “fulfilling”. Challenges such as “time deficits”, “lack of exercise lessons and practical training”, “limited awareness and skills of teachers”, “lack of appropriate educational tools”, and “insufficient academic ability of students” were mentioned.