著者
上野 金太郎
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
no.170, pp.363-373, 1896-04-26
著者
石塚 秀夫 新間 信夫 堀井 郁夫
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.119, no.12, pp.881-897, 1999-12-01 (Released:2008-05-30)
参考文献数
49
被引用文献数
14 20

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three anzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.
著者
高柳 弘明 後藤 元彰 武田 收功 長 由美子
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.124, no.11, pp.751-767, 2004 (Released:2004-11-01)
参考文献数
23
被引用文献数
6 11

Picric acid forms stable picrates with various organic molecules through π- bonding or ionic bonding, and such picrates have been very useful for identification and qualitative analysis. As it seemed desirable to determine the crystal structures and the bonding mode of picrates of basic organic compounds, we have investigated the crystal structures of aromatic hydrocarbons, aromatic amino compounds, heterocyclic compounds and so on. A series of our studies on the crystal structure of basic organic compounds have shown that the complexes of picric acid and aromatic hydrocarbons are formed through π-bonding, and those of aromatic heterocyclic compounds are formed through ionic and hydrogen bonding; in addition, some of them also have π-bonding.

1 0 0 0 OA 附録

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.51, no.4, pp.302-335, 1931-04-26 (Released:2009-11-13)
著者
才川 勇 桃井 海秀 酒井 広志 高下 寛 大橋 俊則 南 尚 山本 芳子 福岡 義和
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.99, no.12, pp.1207-1218, 1979-12-25 (Released:2008-05-30)
参考文献数
16
被引用文献数
3 3

The stability, degradation pattern and structure of degradation products of sodium 7-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamido]-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylate (T-1551) in aqueous solution were investigated. T-1551 was kept in various solutions in pH and μ=0.5 at 35°, its degradation was followed by HPLC. T-1551 was stable at the range of pH 4.0-7.0, slightly unstable at acid and markedly unstable at alkaline. It was confirmed that in alkaline solution, 7-[D (-)-α-[3-[2-(N-ethyl-N-oxaloamino)-ethyl] ureido]-α-(4-hydroxyphenyl) acetamido]-3-(1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (T-1551A) was produced, and that in acidic solution, 7-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamido]-3-hydroxy-methyl-3-cephem-4-carboxylic acid γ-lactone (T-1551B), 7-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (T-1551C), 5-mercapto-1-methyl-1H-tetrazole (T-1551F), 2-[2-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-2-(4-hydroxyphenyl) acetamido]-2-[1, 2, 5, 7-tetrahydro-7-oxo-4H-furo [3, 4-d] [1, 3] thiazin-2-yl] acetic acid (T-1551G), 2-[α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamidomethyl]-2, 3-dihydro-5-hydroxy-methyl-6H-thiazine-4-carboxylic acid γ-lactone (T-1551H) and N-formylmethyl-D-(-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamide (T-1551D) were produced, respectively.
著者
野村 渉
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.137, no.10, pp.1223-1231, 2017 (Released:2017-10-01)
参考文献数
17
被引用文献数
1

Interactions between bio-macromolecules such as proteins, DNA, and polysaccharides play pivotal roles in maintaining homeostasis in living systems. For elucidating the function of biomolecules, peptides are powerful tools, compared to native proteins, because of their lower molecular weights, compatibility with chemical modification, and predictability of interaction with the target molecules. These advantages enabled us to develop peptide-based functional molecules. However, for the purposes of controlling or regulating biomolecule functions, designing artificial proteins is also an effective approach. Not only rational protein design, but also directed molecular evolution, are now regarded as powerful methods for optimizing protein function. The interactions of proteins with bio-macromolecules are usually highly specific and show high affinity because of larger interaction surfaces as compared to small molecules or peptides. Thus, the use of proteins for designing biofunctional molecules is also important for wider applications in the biotechnology field. In this review, four topics will be discussed: 1) the development of fluorescently-labeled ligands for G protein-coupled receptors (GPCR), as well as bivalent ligands for GPCR imaging and function analysis, 2) the design and synthesis of gp41 trimer mimics as HIV-1 inhibitors or vaccines, 3) the development of a ZIP tag-probe system and its application to intracellular protein imaging, and 4) the functional analysis of sequence-specific DNA recombinase for expanding the scope of genome editing. The results of these studies indicate the importance of precision in the design of peptides or proteins for regulating bio-macromolecular interactions.
著者
亀谷 哲治 高野 誠一 寺沢 弘文 武田 裕光
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.7, pp.868-870, 1972-07-25 (Released:2008-05-30)
参考文献数
6
被引用文献数
3 4

In order to obtain 2, 6-dicyano-7-ethoxycarbonyl-1, 5-dioxo-1, 2, 3, 5-tetrahydroindolizine as an intermediate for the synthesis of camptothecin, Michael condensation of methyl 3-cyano-4-ethoxycarbonyl-1, 2-dihydro-2-oxopyridine-6-carboxylate (V) with acrylonitrile was carried out but failed to afford the objective substance. A similar condensation of V with t-butyl acrylate also resulted in failure. Ethyl 5-cyano-4-ethoxycarbonyl-5-oxo1, 6-dihydro-2-pyridine glyoxylate (VIII) was synthesized by the reaction of 3-cyano-4-ethoxycarbonyl-1, 2-dihydro-2-oxopyridine-6-carboxylic acid chloride with ethyl t-butylmalonate. Although cyclization of VIII to ethyl 6-cyano-1, 2, 3, 5-tetrahydro-1, 3, 5-trioxo-7-indolizine carboxylate (IX) was unsuccessful, Friedlander reaction of VIII with 2-aminobenzaldehyde gave the expected 8-cyano-7-ethoxycarbonyl-9, 11-dihydro-9, 11-dioxoindolizino[1, 2-b]quinoline (X) in one step.
著者
丹羽 弘司 引地 登 桜井 栄一 植田 公孝 福勢 元
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.11, pp.1118-1126, 1980-11-25 (Released:2008-05-30)
参考文献数
30
被引用文献数
2

Effects of maltitol and mannitol on the gastrointestinal absorption of acetaminophen, sulfisoxazole and riboflavine in mice were investigated. When drugs were orally administered with maltitol or mannitol, and 2 hr after maltitol or mannitol was orally given in mice (in diarrhea), the blood levels of drugs became lower than that in the control, and drug absorption was inhibited. It was suggested that these results were not caused by molecular interaction between drugs and sugar alcohols, but by the action of maltitol and mannitol which accelerated small intestinal motility, secretion and vascular permeability in the intestinal membrane. These changes may be mediated by biogenic amine, serotonin, histamine and polyamines in the small intestine.
著者
福原 潔 大野 彰子 花尻(木倉) 瑠理
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.137, no.9, pp.1147-1154, 2017 (Released:2017-09-01)
参考文献数
14

Considering the pharmacological effects of chiral drugs, enantiopure drugs may differ from their racemic mixture formulation in efficacy, potency, or adverse effects. Levomethorphan (LVM) and Dextromethorphan (DXM) act on the central nervous system and exhibit different pharmacological features. LVM, the l-stereoisomer of methorphan, shows many similarities to opiates such as heroin, morphine and codeine, including the potential for addiction, while the d-stereoisomer, DXM, does not have the same opioid effect. In the present study, NMR-based metabolomics were performed on the urine of rats treated with these stereoisomers, and showed significant differences in metabolic profiles. In urine within 24 h after treatment of these samples, levels of citrate, 2-oxoglutarate, creatine, and dimethylglycine were higher in LVM-treated rats than in DXM-treated rats. While urinary levels of hippurate and creatinine gradually increased over 72 h in DXM-treated rats, these metabolites were decreased in the urine by 48-72 h after treatment with LVM. The levels of these changed metabolites may provide the first evidence for different cellular responses to the metabolism of stereoisomers.
著者
小村 弘 茂本 友貴枝 河原 亥一郎 松田 健一 阿野 理恵子 村山 洋子 森脇 俊哉 吉田 長弘
出版者
公益社団法人日本薬学会
雑誌
藥學雜誌 = Journal of the Pharmaceutical Society of Japan (ISSN:00316903)
巻号頁・発行日
vol.125, no.1, pp.141-147, 2005-01-01
参考文献数
27
被引用文献数
1 2

コンビナトリアルケミストリーの発展により化合物ライブラリーの数は百万を越え, 週に何十万もの化合物が多くの生物学的ターゲットに対してスクリーニングされている. これに伴い多くのリード化合物が見出されている. さらに開発候補品のディベロッパビリティにおいて動態代謝特性が重要な要因の1つであるとの認識が深まり,優れた薬物動態プロファイルを伴った開発候補品を見出すため探索動態グループに対する要求が年々高まってきている.このような状況下において, 溶解性, Caco-2膜透過性及び代謝安定性試験などについてハイスループットスクリーニング(HTS)への取り組みが行われてきた. しかしながら, 探索動態試験におけるHTSは時間と労力を必要とし, 評価できる化合物の数は最大でも生物学的ターゲットに対するHTSの1/100から1/10000と限られている. 近年, 合成化合物の体内動態特性を予測するためのin silicoモデルが検討されている.特にpolar surface area(PSA), molecular weight(MW), 脂溶性(logP)及びhydrogen bonding(HB)の数などの種々のパラメータが用いられ, 薬物の膜透過性又は経口吸収性の予測が試みられている.
著者
小村 弘 松田 健一 茂本 友貴枝 河原 亥一郎 阿野 理恵子 村山 洋子 森脇 俊哉 吉田 長弘
出版者
公益社団法人日本薬学会
雑誌
藥學雜誌 = Journal of the Pharmaceutical Society of Japan (ISSN:00316903)
巻号頁・発行日
vol.125, no.1, pp.131-139, 2005-01-01
参考文献数
25
被引用文献数
1 3

肝臓での代謝安定性は経口吸収性とともに生体内利用率に影響する重要な因子であり, その最適化は多くのプロジェクトにおける最重要課題の1つである. 一般に代謝試験には肝ミクロソーム系又は単離肝細胞系が用いられている. 肝細胞系はphaseI及びII代謝活性, さらに肝取り込みや胆汁排泄に関与する膜輸送系を有しており, 開発候補品を初め薬物の詳細な代謝検討に使用されている.しかし非凍結及び凍結ヒト肝細胞の場合コストが高く付くこと, またロット間の代謝活性の個体差が大きいこと, そしてロボットへの適応が難しいことから, 創薬の初期スクリーニングには適していないものと考えられる. 一方, 肝ミクロソーム系では細胞質の酵素によるphaseI及び硫酸抱合活性などのphaseII代謝を測定することができないが, 主代謝酵素であるcytochromeP450(CYP)活性が存在し,いずれの種についてもミクロソームを容易に入手できる. 特にヒトではハイスループットスクリーニング用として多くのドナーから調製されたミクロソームが市販されている.
著者
小村 弘 河原 亥一郎 茂本 友貴枝 松田 健一 阿野 理恵子 村山 洋子 森脇 俊哉 吉田 長弘
出版者
公益社団法人日本薬学会
雑誌
藥學雜誌 = Journal of the Pharmaceutical Society of Japan (ISSN:00316903)
巻号頁・発行日
vol.125, no.1, pp.121-130, 2005-01-01
参考文献数
27
被引用文献数
2 5

経口吸収性は生体内利用率に影響する重要なファクターの1つであり, ヒトでの低い吸収率さらにはその個体間の大きなバラツキは, 開発候補品のディベロッパビリティーを大きく低下させる. 近年コンビナトリアルケミストリー及びハイスループットスクリーニング(HTS)の導入は幅広い生物学的ターゲットに対して効率的にリード化合物の創出を可能にしてきたが, リード化合物の経口吸収性を初め体内動態に関わる物性を悪化させた. したがって, 創薬において吸収性に優れた開発候補品を創製するためにはリード化合物の最適化が必要となる. 吸収性は主に水に対する溶解性と膜透過性が大きく関わっており, これらのスクリーニング系が開発されてきた.近年その処理能力を上げるため, より簡便な比濁分析法や溶液沈殿法を用いた溶解性試験, さらにはCaco-2細胞の短期間培養法, N in one 及び96 well formatを用いた透過性試験系が採用されている.
著者
市川 創作 黒岩 崇
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.5, pp.681-686, 2008 (Released:2008-05-01)
参考文献数
18
被引用文献数
2 3

A vesicle is a compartment composed of lipid bilayer of amphiphilic molecules. The vesicle is applied to carriers of drugs, cosmetics and functional food ingredients in industries. Vesicles are also applied as a model for artificial cell membrane and expected as micro- and nano-reactors. They are generally prepared by the hydration of dry lipid film, but there is no method to prepare vesicles of a controlled size and high entrapment yield of hydrophilic materials inside them. In this article, a microchannel (MC) emulsification method was applied to prepare vesicles aimed at controlling the size and improving the entrapment yield. Firstly, monodisperse water-in-oil (W/O) emulsions were prepared by the MC emulsification method. In this process, hydrophilic materials to be entrapped were contained inside the water droplets of the emulsions. Keeping the water droplets frozen, the emulsifier was replaced by a bilayer-forming lipid mixture, and then the oil phase was evaporated. After hydration of lipid layers surrounding the water droplets, vesicles were formed. We call this preparation “lipid-coated ice droplet hydration method”. The final sizes of the prepared vesicles were comparable to the original emulsion droplet sizes. This means that the size of vesicles can be controlled by controlling the size of original water droplets of the W/O emulsions. Furthermore, calcein as a hydrophilic fluorescent marker and biopolymers, such as enzyme and polysaccharide, were entrapped into the internal water phases of vesicles. The method proposed in this study enables the formation of vesicles with a controlled size and high entrapment yields, potentially useful for expanding the application fields of vesicles as biocompatible carriers and micro- and nano-reactors for biochemical reactions.
著者
藤田 直希 鍋谷 伸子 梅村 紀匡 菊池 千草 鈴木 匡
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.10, pp.1445-1448, 2016 (Released:2016-10-01)
参考文献数
7
被引用文献数
3

In this study, we took continuous measurements of hemoglobin A1c (HbA1c) levels and conducted lifestyle checks in three cases to determine if these parameters were effective in improving overall wellness. We selected three young men with relatively high HbA1c levels. During the 12-weeks study periods, we regularly measured each participant's HbA1c levels and monitored their lifestyle habits every two weeks at the community pharmacy once every 2 weeks using specific guidelines. The first participant, a 23-year-old man, had a HbA1c level of 5.7% at his first measurement. His HbA1c level decreased to 5.2% at the last measurement. The second participant, a 19-year-old man, had an initial HbA1c level of 5.7% and a final HbA1c level of 5.4%. The third participant was a 22-year-old man with an initial HbA1c level of 5.4%. His HbA1c level had decreased to 5.1% by the last measurement. The lifestyles of all three men improved with respect to exercise and diet. Based on these results, we surmise that continuous measurements of HbA1c and regular lifestyle checks may contribute to reducing the risk of lifestyle-related disease.
著者
朝比 奈泰彦 上野 周
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
no.408, pp.146-159, 1916-02-26

著者等は甘茶の甘味成分たる結晶性物質の化學的研究を行ひ之をフヰロヅルチンと命名し各種誘導體及分解成績物の檢査によりて一種の構造式を提出せり
著者
異島 優 丸山 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.136, no.1, pp.39-47, 2016 (Released:2016-01-01)
参考文献数
43
被引用文献数
1 18

Recently, human serum albumin (HSA) has emerged as a versatile carrier for therapeutic agents against diabetes, cancer, and infectious diseases. Market-approved products include fatty acid derivatives of human insulin for diabetes and the paclitaxel-HSA nanoparticle for various cancers such as metastatic breast cancer and advanced pancreatic cancer. In this review, we focus on the next-generation approach including HSA-binding bioactive gas such as nitric oxide (NO) for treating ischemic/reperfusion injury, cancer, and bacterial infection. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated HSA (SNO-HSA), which is why we are investigating whether this albumin form can be therapeutically useful. Recently, we have developed SNO-HSA analogues such as SNO-HSA with many conjugated SNO groups (poly-SNO-HSA) prepared using chemical modification. Unexpectedly, we found striking inverse effects between poly-SNO-HSA and SNO-HSA. Despite the fact that SNO-HSA inhibits apoptosis, poly-SNO-HSA possesses very strong pro-apoptotic effects against tumor cells. Furthermore, poly-SNO-HSA can reduce or even completely eliminate the multidrug resistance often developed by cancer cells. In this review, we put forward the possibility that poly-SNO-HSA can be used as a safe, effective multifunctional antitumor agent.
著者
浅井 将 川久保 昂 森 亮太郎 岩田 修永
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.137, no.7, pp.801-805, 2017 (Released:2017-07-01)
参考文献数
18
被引用文献数
12

Down syndrome (DS) patients demonstrate the neuropathology of Alzheimer's disease (AD) characterized by the formation of senile plaques and neurofibrillary tangles by age 40-50 years. It has been considered for a number of years that 1.5-fold expression of the gene for the amyloid precursor protein (APP) located on chromosome 21 leading to overproduction of amyloid-β peptide (Aβ) results in the early onset of AD in adults with DS. However, the mean age of onset of familial AD with the Swedish mutation on APP which has high affinity for β-secretase associated with a dramatic increase in Aβ production is about 55 years. This paradox indicates that there is a poor correlation between average ages of AD onset and the theoretical amount of Aβ production and that there are factors exacerbating AD on chromosome 21. We therefore focused on dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), since overexpressing transgenic mice show AD-like brain pathology. The overexpression of DYRK1A caused suppression of the activity of neprilysin (NEP), which is a major Aβ-degrading enzyme in the brain, and phosphorylation at the NEP cytoplasmic domain. NEP activity was markedly reduced in fibroblasts derived from DS patients compared with that in fibroblasts derived from healthy controls. This impaired activity of NEP was rescued by DYRK1A inhibition. These results show that DYRK1A overexpression causes suppression of NEP activity through its phosphorylation in DS patients. Our results suggest that DYRK1A inhibitors could be effective against AD not only in adults with DS but also in sporadic AD patients.
著者
漆崎 文男 山口 洋 水町 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.106, no.6, pp.491-497, 1986-06-25 (Released:2011-01-31)
参考文献数
9
被引用文献数
1 7

Polyvinyl alcohol (PVA) aqueous solutions with high water content were repeatedly frozen and defrosted to obtain PVA hydrogels with high elasticity.Tack and viscoelasticities such as storage modulus and loss tangent of the PVA hydrogels were determined as a function of molecular weight, saponification value of PVA, number of cycles of freezing-defrosting procedure or temperature of defrosting, in order to obtain an information on utilities of the materials as prepared poultices and transdermal therapeutic system.Correlation matrix method of multiregression analysis was applied to our data on tack and viscoelasticities of gels, and it was found that there was a significant correlation between tack and storage modulus as well as loss tangent of the materials.Tack, which is one of the most essential properties of pressure sensitive adhesives as prepared poultices and drug delivery system, can easily be predicted, if we measure viscoelasticities of the materials.