著者

Keiko MORITO Toshiharu HIROSE Junei KINJO Tomoki HIRAKAWA Masafumi OKAWA Toshihiro NOHARA Sumito OGAWA Satoshi INOUE Masami MURAMATSU Yukito MASAMUNE

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.24, no.4, pp.351-356, 2001 (Released:2002-04-26)

参考文献数

37

被引用文献数

391 471

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The human estrogen receptor (hER) exists as two subtypes, hER α and hER β, that differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activities of soy isoflavones after digestion with enteric bacteria in competition binding assays with hER α or hER β protein, and in a gene expression assay using a yeast system. The estrogenic activities of these isoflavones were also investigated by the growth of MCF-7 breast cancer cells. Isoflavone glycoside binds weakly to both receptors and estrogen receptor-dependent transcriptional expression is poor. The aglycones bind more strongly to hER β than to hER α. The binding affinities of genistein, dihydrogenistein and equol are comparable to the binding affinity of 17 β-estradiol. Equol induces transcription most strongly with hER α and hER β. The concentration required for maximal gene expression is much higher than expected from the binding affinities of the compounds, and the maximal activity induced by these compounds is about half the activity of 17 β-estradiol. Although genistin binds more weakly to the receptors and induces transcription less than does genistein, it stimulates the growth of MCF-7 cells more strongly than does genistein.

著者

Yasushi Hori Manami Fujisawa Kenji Shimada Akira Oda Shinichiro Katsuyama Keiji Wada

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.27, no.4, pp.486-491, 2004 (Released:2004-04-01)

参考文献数

17

被引用文献数

11 32

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We have established a new method of HPLC analysis for the rapid separation from human serum and the quantification of 4-O-methylpyridoxine (MPN), which is contained in Ginkgo biloba seeds, and which, when consumed in large amounts, causes vomiting and convulsions. As a result of using IPCC-MS3 (GL Science, Tokyo, Japan), an ion-pair reagent, in the mobile phase, we succeeded in separating MPN in the deproteinized serum sample which was introduced directly onto the reverse-phase HPLC column. For the calibration curve of MPN standard solution, prepared with fluorescence detection at an excitation wavelength of 290 nm and an emission wavelength of 400 nm, a good linear relationship was obtained within the HPLC injection range of 10 ng—10 pg (in terms of the injected sample concentration, range: 1.0 μg/ml—1 ng/ml), allowing the detection of minute amounts, with the limit of detection (concentration of injected sample: 500 pg/ml) being 5 pg. In addition, when MPN solution was added to human reference serum to give a concentration of 0.002 μg/ml, the mean recovery rate was 92.5%, with RSD=7.09% (n=5). The time required for one analysis using this method is approximately 30 min, and thus it offers the advantages of greater speed and superior analytical sensitivity over the conventional methods, which require solid-phase extraction. We employed our new method to determine both the serum levels of MPN in 5 patients with Ginkgo biloba seed poisoning and the levels of free-form MPN in such seeds obtained in 8 regions of Japan.

著者

Tomohito Tsukamoto Eiko Sakai Shunsuke Iizuka Marcos Taracena-Gándara Fuminori Sakurai Hiroyuki Mizuguchi

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.41, no.7, pp.1089-1095, 2018-07-01 (Released:2018-07-01)

参考文献数

37

被引用文献数

15

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The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) 9 system is now widely used as a genome editing tool. CRISPR-associated endonuclease in Prevotella and Francisella 1 (Cpf1) is a recently discovered Cas endonuclease that is designable and highly specific with efficiencies comparable to those of Cas9. Here we generated the adenovirus (Ad) vector carrying an Acidaminococcus sp. Cpf1 (AsCpf1) expression cassette (Ad-AsCpf1) for the first time. Ad-AsCpf1 was applied to primary human hepatocytes prepared from humanized mice with chimeric liver in combination with the Ad vector expressing the guide RNA (gRNA) directed to the Adeno-associated virus integration site 1 (AAVS1) region. The mutation rates were estimated by T7 endonuclease I assay around 12% of insertion/deletion (indel). Furthermore, the transduced human hepatocytes were viable (ca. 60%) at two weeks post transduction. These observations suggest that the Ad vector-mediated delivery of the CRISPR/AsCpf1 system provides a useful tool for genome manipulation of human hepatocytes.

著者

Mitsuyoshi Okita Yuki Yayoshi Kousuke Ohara Akio Negishi Hayato Akimoto Naoko Inoue Sachihiko Numajiri Shigeru Ohshima Seiichi Honma Shinji Oshima Daisuke Kobayashi

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.40, no.10, pp.1730-1738, 2017-10-01 (Released:2017-10-01)

参考文献数

21

被引用文献数

3

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Kakkonto (KK), a traditional Japanese Kampo formulation for cold and flu, is generally sold as an OTC pharmaceuticals used for self-medication. Kampo formulations should be used according to the Sho-symptoms of Kampo medicine. These symptoms refer to the subjective symptoms themselves. Although with OTC pharmaceuticals, this is often not the case. We surveyed the relationship of agreement of Sho with the benefit feeling rate (BFR) of patients who took KK (n=555), cold remedies with KK (CK, n=315), and general cold remedies (GC, n=539) using internet research. BFR of a faster recovery was greater in participants who took the medication early and who had confidence in their physical strength in all treatment groups. BFR was significantly higher in the GC group than in the KK group for patients with headache, runny nose, blocked nose, sneezing, and cough. BFR was also significantly higher in the GC group than in the CK group for headache (males) and cough (females). BFR was the highest in the KK group for stiff shoulders. All cold remedies were more effective when taken early, and the larger the number of Sho that a patient had, the greater the BFR increased. Therefore, a cold remedy is expected to be most effective when there are many cold symptoms and when it is taken at an early stage of the common cold.

著者

Mahitab Elsayed Daisuke Kobayashi Toshio Kubota Naoya Matsunaga Ryusei Murata Yuko Yoshizawa Natsuki Watanabe Tohru Matsuura Yuya Tsurudome Takashi Ogino Shigehiro Ohdo Takao Shimazoe

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.39, no.8, pp.1238-1246, 2016-08-01 (Released:2016-08-01)

参考文献数

64

被引用文献数

2 22

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Bisphosphonates and statins are known to have antitumor activities against different types of cancer cell lines. In the present study, we investigated the antiproliferative effects of the combination of zoledronic acid (ZOL), a bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer cell lines were treated with ZOL and FLU both individually and in combination to evaluate their antiproliferative effects using WST-8 cell proliferation assay. In this study, we demonstrated a potent synergistic antiproliferative effect of both drugs when used in combination in both cell lines. Moreover, we studied the molecular mechanism behind this synergistic effect, which was inhibited by the addition of the mevalonate pathway products, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Furthermore, we aimed to determine the effect of ZOL and FLU combination on RhoA and Ras guanosine 5′-triphosphate (GTP)-proteins. The combination induced a marked accumulation in RhoA and unprenylated Ras. GGPP and FPP reversed the increase in the amount of both proteins. These results indicated that the combination treatment impaired RhoA and Ras signaling pathway by the inhibition of geranylgeranylation and/or farnesylation. This study provides a potentially effective approach for the treatment of pancreatic cancer using a combination treatment of ZOL and FLU.

著者

Takuya Izawa Koji Nakayama Noritaka Uchida Kazuhiro Nojima

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

pp.c17-00938, (Released:2018-02-22)

参考文献数

30

被引用文献数

13

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Dehydroacetic acid (1) was found to induce photoisomerization, converting aldrin (3) and dieldrin (4) into photoaldrin (5) and photodieldrin (6), respectively, not only when irradiated with artificial light at wavelengths longer than 290 nm in air but also when exposed to sunlight in air. By contrast, sodium dehydroacetate (2) induced both photoisomerization, primarily converting 3 to 5 and photoepoxidation, partially forming 6. Thus, because 2 is usually used as a water-soluble antiseptic, photo-erethism might occur due to the isomerization and epoxidation properties of this compound. The difference between the photoreactivity of 1 and that of 2 might be attributed to the spin density of the odd electron on the carbon atom in the respective radicals that were formed after photo-excited 1 and 2 caused H-abstraction.

著者

Naofumi Seira Naoki Yanagisawa Akiko Suganami Takuya Honda Makiko Wasai John W. Regan Keijo Fukushima Naoto Yamaguchi Yutaka Tamura Takayoshi Arai Toshihiko Murayama Hiromichi Fujino

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.40, no.10, pp.1806-1812, 2017-10-01 (Released:2017-10-01)

参考文献数

31

被引用文献数

3

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Increases in the expression of prostaglandin E2 (PGE2) are widely known to be involved in aberrant growth in the early stage of colon cancer development. We herein demonstrated that the novel indole compound MW-03 reduced PGE2-induced cAMP formation by catalization to an inactive metabolite by inducing 15-hydroxyprostaglandin dehydrogenase through the activation of peroxisome proliferator-activated receptor-γ. MW-03 also inhibited colon cancer cell growth by arresting the cell cycle at the S phase. Although the target of MW-03 for cell cycle inhibition has not yet been identified, these dual anti-cancer effects of MW-03 itself and/or its leading compound(s) on colon cancer cells may reduce colon cancer development and, thus, have potential as a novel treatment for the early stage of this disease.

著者

Hiroki Sasaki Yoichi Sunagawa Kenji Takahashi Atsushi Imaizumi Hiroyuki Fukuda Tadashi Hashimoto Hiromichi Wada Yasufumi Katanasaka Hideaki Kakeya Masatoshi Fujita Koji Hasegawa Tatsuya Morimoto

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.34, no.5, pp.660-665, 2011-05-01 (Released:2011-05-01)

参考文献数

26

被引用文献数

68 326

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Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. We have successfully developed a highly absorptive curcumin dispersed with colloidal nano-particles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concentration–time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addition, THERACURMIN exhibited an inhibitory action against alcohol intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concentration of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available preparations. Thus, THERACURMIN may be useful to exert clinical benefits in humans at a lower dosage.

著者

Takeo Yasu Kenji Momo Shunsuke Kobayashi Seiichirou Kuroda Arinobu Tojo

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

pp.b17-00806, (Released:2017-12-06)

参考文献数

16

被引用文献数

16

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Ponatinib, a novel tyrosine kinase inhibitor marketed in 2016, is a key drug used for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. This study aimed to develop a simple method for determining plasma ponatinib concentration. The analysis required extraction of a 400-μL sample of plasma and precipitation of proteins using an Oasis HLB cartridge. Ponatinib and bosutinib, which is used as an internal standard, were separated by HPLC using a mobile phase of acetonitrile: 0.037 mol/L KH2PO4 (pH 4.5) (39:61, v/v) on a Capcell Pack C18 MG II (250 mm × 4.6 mm) monitored at 250 nm, with a flow rate of 1.0 mL/min. This assay method was then used for determining plasma ponatinib concentration in a 42-year-old man treated with ponatinib at 15 mg/day. The calibration curve was found to be linear for the plasma concentration range of 5–250 ng/mL with a regression coefficient (r2) of 0.9999. The coefficients of intra-day and inter-day validation under these concentrations were 2.1–6.0% and 4.5–8.0%, respectively. The assay accuracy was -1.5–9.0%, and the recovery was greater than 86%. The plasma concentration of the patient at 2.5 and 3 h after 15 mg ponatinib administration was 43.6 ng/mL and 49.3 ng/mL, respectively. This method of HPLC equipped with UV detection for determining plasma ponatinib concentration has several advantages, such as simplicity and applicability to routine therapeutic drug monitoring at hospital laboratories.

著者

Hideyuki Konishi

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.66, no.1, pp.1-19, 2018-01-01 (Released:2018-01-01)

参考文献数

110

被引用文献数

15

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The use of toxic gas surrogates in organic reactions instead of the gas itself contributes to enhancing the safety, practicality, and efficiency of the reactions involved. Our efforts toward the creation of toxic gas surrogates and the development of a series of catalytic reactions using these surrogates are described. Improvements in substrate scope during the hydroesterification of alkenes using formates facilitated by the Ru–imidazole catalyst system provided the opportunity to discover that phenyl formate is a useful carbon monoxide (CO) surrogate for the generation of CO and phenol under weakly basic conditions. This discovery triggered the development of highly reactive but stable CO surrogates and a variety of Pd-catalyzed carbonylative transformations. N-Formylsaccharin facilitated the use of additional nucleophiles in carbonylation reactions that provided access to a variety of carbonyl compounds. Detailed experimental and theoretical mechanistic studies into the generation of CO from phenyl formate suggest that CO generation proceeds via a concerted E2 α-elimination. Furthermore, a known surrogate of sulfur dioxide was applied for the first time to the selective syntheses of cyclic sulfonamides and sulfinamides, confirming that the surrogate operates as an “S=O” source. Notably, the reactions described herein are scalable and can be performed without the use of external toxic gases and specialized reaction vessels; they are easy and simple to perform and demonstrate enormous potential for industrial application.

著者

Mitsuo Miyazawa Hirotoshi Utsunomiya Ken-ichi Inada Tomoki Yamada Yoshiharu Okuno Harunari Tanaka Masae Tatematsu

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.29, no.1, pp.172-173, 2006 (Released:2006-01-01)

参考文献数

16

被引用文献数

24 56

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A methanol extract from unripe Japanese apricot showed inhibitory activity of Helicobacter pylori motility. Inhibitory compound 1 was isolated and identified as (+)-syringaresinol (1) by spectoroscopic means. (+)-Syringaresinol (1) inhibited >90% of the H. pylori motility at a concentration of 500 μg/ml and the IC50 value was 50 μg/ml.

著者

Chihiro Tsukano Satoshi Suetsugu Nobusuke Muto Yoshiji Takemoto

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.65, no.12, pp.1167-1174, 2017-12-01 (Released:2017-12-01)

参考文献数

43

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Tetrahydrobiphenylene consists of cyclobutene fused with benzene and cyclohexene rings. In this paper, a direct method for synthesizing tetrahydrobiphenylenes based on a palladium (Pd)(0)-catalyzed C(sp2)–H functionalization was investigated. The developed method was applied to the synthesis of several tetrahydrobiphenylenes having an oxygen functionality at the ring juncture. The derivatization of a tetrahydrobiphenylene is also reported.

著者

Takuma Yamashita Haruka Shinotsuka Yuki Takahashi Kana Kato Makiya Nishikawa Yoshinobu Takakura

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.40, no.12, pp.2140-2145, 2017-12-01 (Released:2017-12-01)

参考文献数

23

被引用文献数

9

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Cell-derived nanosized vesicles or exosomes are expected to become delivery carriers for functional RNAs, such as small interfering RNA (siRNA). A method to efficiently load functional RNAs into exosomes is required for the development of exosome-based delivery carriers of functional RNAs. However, there is no method to find exosome-tropic exogenous RNA sequences. In this study, we used a systematic evolution of ligands by exponential enrichment (SELEX) method to screen exosome-tropic RNAs that can be used to load functional RNAs into exosomes by conjugation. Pooled single stranded 80-base RNAs, each of which contains a randomized 40-base sequence, were transfected into B16-BL6 murine melanoma cells and exosomes were collected from the cells. RNAs extracted from the exosomes were subjected to next round of SELEX. Cloning and sequencing of RNAs in SELEX-screened RNA pools showed that 29 of 56 clones had a typical RNA sequence. The sequence found by SELEX was enriched in exosomes after transfection to B16-BL6 cells. The results show that the SELEX-based method can be used for screening of exosome-tropic RNAs.

著者

Amit Roy Shailendra Saraf

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.29, no.2, pp.191-201, 2006 (Released:2006-02-01)

参考文献数

121

被引用文献数

333 407

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The search for limonoids started long back when scientists started looking for the factor responsible for bitterness in citrus which has negative impact on citrus fruit and juice industry worldwide. The term limonoids was derived from limonin, the first tetranortriterpenoid obtained from citrus bitter principles. Compounds belonging to this group have exhibited a range of biological activities like insecticidal, insect antifeedant and growth regulating activity on insects as well as antibacterial, antifungal, antimalarial, anticancer, antiviral and a number of other pharmacological activities on humans. Although hundreds of limonoids have been isolated from various plants but, their occurrence in the plant kingdom is confined to only plant families of order Rutales and that too more abundantly in Meliaceae and Rutaceae, and less frequently in Cneoraceae and Harrisonia sp. of Simaroubaceae. Limonoids are highly oxygenated, modified terpenoids with a prototypical structure either containing or derived from a precursor with a 4,4,8-trimethyl-17-furanylsteroid skeleton. All naturally occurring citrus limonoids contain a furan ring attached to the D-ring, at C-17, as well as oxygen containing functional groups at C-3, C-4, C-7, C-16 and C-17. The structural variations of limonoids found in Rutaceae are less than in Meliaceae and are generally limited to the modification of A and B rings, the limonoids of Meliaceae are more complex with very high degree of oxidation and rearrangement exhibited in the parent limonoid structure. To counter the problem of bitterness in citrus juice and products genetic engineering of citrus to maximize the formation of limonoid glucosides for reducing limonoid bitterness is the focus of recent and future research. Regarding the biological activities of limonoids the investigations are to be directed towards detailed characterization, quantification, and designing a simple as well as versatile synthetic route of apparently important limonoids. Extraction methods too should be optimized; evaluation and establishment of pharmaco-dynamic and kinetic principles, and structure activity relationships should be a key goal associated with limonoids so that they can be safely introduced in our arsenal of pharmaceuticals to safeguard the humanity from the wrath of disease and its discomfort.

著者

Sunhee Shin Seongho Yeon Dongsun Park Jiyoung Oh Hyomin Kang Sunghyun Kim Seong Soo Joo Woo-Taek Lim Jeong-Yong Lee Kyung-Chul Choi Ki Yon Kim Seung Up Kim Jong-Choon Kim Yun-Bae Kim

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.33, no.2, pp.273-278, 2010-02-01 (Released:2010-02-01)

参考文献数

56

被引用文献数

22 25 10

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The effects of a silk amino acid (SAA) preparation on the physical stamina and male reproductive function of mice were investigated. Eight-week-old male ICR mice (29—31 g) were orally administered SAA (50, 160 or 500 mg/kg) for 44 d during 30-min daily swimming exercise. The mice were subjected to a weight-loaded (5% of body weight) forced swimming on the 14th, 28th and 42nd day to determine maximum swimming time, and after a 2-d recovery period (treated with SAA without swimming exercise), parameters related to fatigue and reproductive function were analyzed from blood, muscles and reproductive organs. Repeated swimming exercise increased the maximum swimming time to some extent, in spite of a marked reduction in body weight gain, and SAA further enhanced the stamina in a dose-dependent manner. Forced swimming exercises increased blood parameters of tissue injury, but depleted blood glucose and tissue glycogen, which were substantially prevented by SAA treatment. In addition, SAA significantly reduced the muscular thiobarbituric acid-reactive substances and blood corticosterone content increased by forced swimming. Swimming exercise decreased the blood testosterone level, which was recovered by SAA, leading to enhanced sperm counts. These combined results indicate that SAA not only enhances physical stamina by minimizing damage to tissues, including muscles, as well as preventing energy depletion caused by swimming stress, but also improves male reproductive function by increasing testosterone and sperm counts.

著者

Seisho Tobinaga Michio Hashimoto Iku Utsunomiya Kyoji Taguchi Morihiko Nakamura Tokugoro Tsunematsu

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.35, no.1, pp.127-129, 2012-01-01 (Released:2012-01-05)

参考文献数

20

被引用文献数

3 7

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Cardanol (ginkgol) extracted from Ginkgo biloba leaves and cashew nutshell liquid enhances the growth of NSC-34 immortalized motor neuron-like cells and, when chronically administered to young rats, improves working memory-related learning ability as assessed by eight-arm radial maze tasks. These findings suggest that cardanol is one of the components in Ginkgo biloba leaves that improves cognitive learning ability.

著者

横澤 隆子 金井 久美子 岳藤 美知子 大浦 彦吉

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.24, no.12, pp.3202-3204, 1976-12-25 (Released:2008-03-31)

被引用文献数

1 2

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Investigations were carried out to determine whether or not a decreasing action of hepatic glycogen content in rats by ginseng extract is due to its main constituent, saponin. The experimental results suggested that ginseng saponin decreases the glycogen stores, but the degree of its effect is regulated by the nutritional status of rats.

著者

Akihiro Ito Lei Wang Ryotaro Notomi Shigeki Sasaki Yosuke Taniguchi

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.72, no.1, pp.16-20, 2024-01-01 (Released:2024-01-01)

参考文献数

24

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Triplex DNA formation has generated much interest as a genomic targeting tool that directly targets duplex DNA. However, fundamental limitations in the base pairs of target duplex DNA sequences that can form stable triplex DNA have limited the application. Recently, we have reported on the recognition of CG and 5mCG base pairs by artificial nucleic acid derivatives with a 2′-deoxynebularine skeleton. Therefore, we attempted to explore the basic skeleton that is important for the development of new artificial nucleic acids allowing for the recognition of TA base pairs. In this study, we focused on a benzimidazole skeleton and introduced a hydroxyl group to enable one-point hydrogen bonding. We have synthesized artificial nucleoside analogues with hydroxyl group on the benzimidazole and incorporated their amidite derivatives into triplex forming oligonucleotides (TFOs). The gel shift assay was performed to evaluate the triplex DNA formation ability of synthesized TFOs, and TFOs containing hydroxybenzimidazole were successfully recognized TA base pairs for all four different sequences. Moreover, compared to the results for the TFOs containing benzimidazole, which suggested hydrogen bonding formation at the hydroxyl group. Therefore, hydroxybenzimidazole would be an important artificial nucleic acid skeleton for TA base pair recognition.

著者

山田 安彦 伊藤 清美 中村 幸一 澤田 康文 伊賀 立二

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.16, no.12, pp.1251-1259, 1993-12-15 (Released:2008-04-10)

参考文献数

29

被引用文献数

22 21

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The usual therapeutic doses for the treatment of both angina pectoris and cardiac arrhythmia vary widely among beta-blocking agents, with a maximum of about a 200-fold difference, despite subjects' same clinical improvement at the varying doses. In order to clarify the mechanism of this difference, we analyzed retrospectively the cardiac pharmacological activities of beta-blocking agents based on the receptor occupancy theory by using both their unbound concentrations in plasma at steady state (Cssf), as well as dissociation constants (KB and KI, which were determined by in vitro binding experiments and by in vitro pharmacological experiments, respectively) for a beta 1 receptor. A significant log-linear relationship between Cssf and the KB values was obtained with a slope of regression line of 0.91 (r=0.83, p<0.01). On the other hand, the correlation coefficient of the relationship between Cssf and the KI values was low, with a slope of about 0.5 (r=0.80, p<0.01). The beta 1 receptor occupancies calculated from KB values at the steady state condition after the oral administration of usual doses were almost constant (80.5±16.8%), regardless of the wide variation of usual doses of the drugs. This result indicated that the receptor occupancy may be an appropriate indicator for the pharmacological activity of the drug. Furtheremore, there were significant relationships between the primary pharmacokinetic parameters : Cb/Cf, CLtot/F, and Vdssf, and the octanol/water partition coefficient (PC), with correlation coefficients of 0.80, 0.50 and 0.85, respectively. Accordingly, it is suggested that the prediction of a ususal dose of a new beta-blocking agent can be carried out by using the KB and PC values based on quantitative structure-Pharmacokinetic/pharmacodynamic relationships. This methodology should be very useful for estimating the rational usual dose of a new beta-blocking agent from the animal experimental and physicochemical data in the preclinical study.

著者

Takashi Hasegawa Kenji Tsukigawa Kindness Commey Mina Sakuragi Shuhei Imoto Kazuaki Taguchi Koji Nishi Masaki Otagiri Keishi Yamasaki

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.72, no.1, pp.21-27, 2024-01-01 (Released:2024-01-01)

参考文献数

28

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Pirarubicin (THP) shows more rapid intracellular uptake, more effective antitumor activity, and less cardiac toxicity, compared to doxorubicin. However, THP is distributed to both tumor and normal tissues indiscriminately. This study aimed to develop a nanosuspension to deliver THP to tumor tissues more efficiently. Fatty-acid-modified THPs (FA-THPs; octanoic acid, dodecanoic acid, palmitic acid-THPs) were synthesized to increase the hydrophobicity of THP. Nanosuspensions of these FA-THPs were then prepared using an antisolvent precipitation technique. Among the FA-THPs, the most efficiently drug-loaded nanosuspension was obtained from palmitic acid-THP (pal-THP) using an aqueous antisolvent containing bovine serum albumin as a stabilizer. The pal-THP nanoparticles in the nanosuspension were confirmed to be of optimal size (100–125 nm) for delivery to tumor tissues using dynamic light scattering and transmission electron microscopy. The pal-THP nanosuspension showed cytotoxicity in colon 26 cells. The nanosuspension was shown to disintegrate in the presence of surfactants such as lecithin, liberating pal-THP, which was converted to free THP in acidic media. It is therefore proposed that pal-THP nanoparticles that reach tumor cells after intravenous administration would exert antitumor effect by liberating pal-THP (i.e., disintegration of nanoparticles by the interaction with cell membrane), followed by the release of free THP in the acidic milieu of tumor cells. These findings indicate that FA-THP nanosuspensions, particularly pal-THP nanosuspension, hold promise as a candidate for cancer treatment. However, further in vivo studies are necessary.