著者

Chung-Yi Lo Hsueh-Ling Cheng Jue-Liang Hsu Ming-Hui Liao Rong-Lang Yen Yo-Chia Chen

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.61, no.6, pp.604-610, 2013-06-01 (Released:2013-06-01)

参考文献数

28

被引用文献数

2 4

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Three phenyl derivatives of butyrate, 2-phenylbutyrate (2-PB), 3-phenylbutyrate (3-PB) and 4-phenylbutyrate (4-PB), were evaluated in terms of their antibacterial and cytotoxic activities. Our results indicated that PBs demonstrated specific inhibitory activity against Helicobacter pylori and Escherichia coli but did not influence the growth of Bifidobacterium bifidium and Lactobacillus reuteri. PBs also exhibited synergistic effects on H. pylori ATCC 43504 especially at pH 5.5. In the protein expression profiles in H. pylori treated by phenylbutyrates, we also found that three protein spots identified as oxidative stress-related proteins were significantly up-regulated, confirming the response of H. pylori when exposed to PBs. Due to their antibacterial activities and low or slight cytotoxicities, PBs are potential candidates for the treatment of H. pylori infection. This is the first study to discover the antibiotic effects of 2-PB, 3-PB and 4-PB (Buphenyl).

著者

Akiko Omori Yuki Fujisawa Shotaro Sasaki Kazumi Shimono Takashi Kikukawa Seiji Miyauchi

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.44, no.5, pp.678-685, 2021-05-01 (Released:2021-05-01)

参考文献数

45

被引用文献数

6

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To clarify the role of an amino acid residue in the pH-dependent efflux process in Chinese hamster ovary (CHO) cells expressing the human oligopeptide transporter hPEPT1 (CHO/hPEPT1), we determined the effect of extracellular pH on the hPEPT1-mediated efflux process. The efflux of glycylsarcosine (Gly-Sar), a typical substrate for hPEPT1, was determined using an infinite dilution method after cells were preloaded with [3H]-Gly-Sar. The efflux of [3H]-Gly-Sar was stimulated by 5 mM unlabeled hPEPT1 substrates in the medium. This trans-stimulation phenomenon showed that hPEPT1 mediated the efflux of [3H]-Gly-Sar from CHO/hPEPT1 and that hPEPT1 is a bi-directional transporter. We then determined the effect of extracellular pH (varying from 8.0 to 3.5) on the efflux activity. The efflux activity by hPEPT1 decreased with the decrease in extracellular pH. The Henderson–Hasselbälch-type equation, which fitted well to the pH-profile of efflux activity, indicated that a single amino acid residue with a pKa value of approximately 5.7 regulates the efflux activity. The pH-profile of the efflux activity remained almost unchanged irrespective of the proton gradient across the plasma membrane. In addition, the chemical modification of the histidine residue with diethylpyrocarbonate completely abolished the efflux activity from cells, which could be prevented by the presence of 10 mM Gly-Sar. These data indicate that the efflux process of hPEPT1 is also regulated in a pH-dependent manner by the protonation state of a histidine residue located at or near the substrate recognition site facing the extracellular space.

著者

Tassadit Belabbas Takaaki Yamada Yuichi Tsuchiya Kimitaka Suetsugu Nobuaki Egashira Ichiro Ieiri

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.69, no.7, pp.646-651, 2021-07-01 (Released:2021-07-01)

参考文献数

17

被引用文献数

2

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With the aim of studying the pharmacokinetics of letermovir, which is a newly developed antiviral agent for human cytomegalovirus, a rapid and simple ultra-performance liquid chromatography coupled with mass spectrometry (UPLC/MS) method was developed and validated for the quantification of letermovir in human plasma. Separation was performed in reverse phase mode using an ACQUITY UPLC BEH C18 column (130 Å, 1.7 µm, 2.1 × 50 mm) at a flow rate of 0.3 mL/min, 10 mM ammonium acetate–0.1% formic acid solution as mobile phase A, and acetonitrile as mobile phase B with a gradient elution. The method was validated over a linear range of 10–1000 ng/mL with a coefficient of determination (R2) >0.99 using weighted linear regression analysis. The intra- and inter-assay accuracy (nominal%) and precision (relative standard deviation%) were within ±15 and ≤15%, respectively. The specificity, recovery, matrix effect, stability, and dilution integrity of this method were also within acceptable limits. This method could be useful in studying the pharmacokinetics and pharmacodynamics, as well as performing the therapeutic drug monitoring of letermovir.

著者

Shigeru Ishida Ken Masuguchi Takehiro Kawashiri Toshikazu Tsuji Hiroyuki Watanabe Sayuri Akiyoshi Makoto Kubo Satohiro Masuda Nobuaki Egashira

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.43, no.4, pp.663-668, 2020-04-01 (Released:2020-04-01)

参考文献数

38

被引用文献数

1 2

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Hypersensitivity reactions, including anaphylaxis, are common side effects associated with docetaxel treatment in breast cancer patients. However, preventive measures have not yet been established. In this study, we retrospectively analyzed the risk factors for developing anaphylaxis in 182 female breast cancer patients treated with docetaxel. We found that 6.6% of all patients (n = 12) experienced anaphylaxis. Multivariate analyses indicated that concentration of docetaxel higher than 0.275 mg/m2/mL, docetaxel dose rate higher than 1.15 mg/m2/min, and white blood cell count less than 4290 cells/mL are risk factors for developing docetaxel-related anaphylaxis. In particular, concentrations of docetaxel or doses per administration time were associated with a high odds ratio (11.88 or 11.60) for docetaxel-related anaphylaxis. Moreover, patients receiving doses in 250 mL volume experienced anaphylaxis more frequently than those receiving doses in 500 mL (7.0 vs. 0.9%, p = 0.0236). Additionally, patients receiving treatments over 60 min tended to experience anaphylaxis more frequently than those who were treated over 90 min (6.7 vs. 1.1%, p = 0.0637). The present results indicate that high docetaxel concentrations, high dose rates, and low white blood cell counts are risk factors for developing docetaxel-related anaphylaxis, and administering docetaxel diluted in 500 mL over 90 min may limit docetaxel-induced hypersensitivity reactions.

著者

Katsunori Yamaura Kohei Ogawa Taeko Yonekawa Tomonori Nakamura Shingo Yano Koichi Ueno

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.25, no.2, pp.201-205, 2002 (Released:2002-04-27)

参考文献数

44

被引用文献数

10 18

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The causal relationship between the inhibition of antibody production and liver injury induced by single doses of acetaminophen (APAP) was investigated in mice. The liver injury and antibody production were evaluated using the serum transaminase activity and the number of antibody forming cells against sheep red blood cells (SRBC), respectively. The relevance of APAP hepatotoxicity with inhibiting antibody production was elucidated in fasted and fed mice treated with a single oral administration of APAP. In fasted mice, the oral administration of APAP produced serious liver injury, while it was not the case in the fed mice. As the antibody production was measured under these conditions, APAP significantly depressed the antibody production in fed mice as well as in fasted mice. The rate of B220 positive cells in the splenocytes was significantly decreased by APAP administration in both the fasted and fed mice. Splenocytes proliferative responses following mitogenic stimulation with concanavalin A or lipopolysaccharide were inhibited by APAP. Moreover, APAP added directly to the splenocyte culture also inhibited the in vitro antibody-producing response to SRBC. These findings indicate that the APAP-induced depression of antibody production may not be a secondary response to APAP-hepatitis, but may be a primary response to APAP.

著者

Midori A. Arai

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.69, no.6, pp.503-515, 2021-06-01 (Released:2021-06-01)

参考文献数

29

被引用文献数

2

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Natural products are very attractive for development of medicine. Their structure and bioactivities are often beyond human knowledge and imagination. We have developed isolation methods for target protein-oriented natural products so as quickly to discover bioactive compounds from natural resources. This review summarizes our recent results including protein beads methods for neural stem cells differentiation activators and new cancer drug candidates. Syntheses of isolated compounds are described. We also developed protein plate method for identification of protein–protein interaction inhibitors. Because protein binding ability is tightly related to bioactivity, protein-based natural products isolation is a powerful means to find new candidate medicines.

著者

Ryo Yazaki

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.69, no.6, pp.516-525, 2021-06-01 (Released:2021-06-01)

参考文献数

88

被引用文献数

5

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Catalytic chemoselective reactions of innately less reactive functionalities over more reactive functionalities are described. A cooperative catalyst comprising a soft Lewis acid/hard Brønsted base enabled chemoselective activation of a hydroxyl group over an amino group, allowing for nucleophilic addition to electron-deficient olefins. The reaction could be applicable for a variety of amino alcohols, including pharmaceuticals, without requiring a tedious protection–deprotection process. Chemoselective enolization and subsequent α-functionalization of carboxylic acid derivatives were also achieved by a redox active catalyst through the radical process, providing unnatural α-amino/hydroxy acid derivatives bearing a complex carbon framework and a diverse set of functionalities. The present chemoselective catalysis described herein offers new opportunities to expand the chemical space for innovative drug discovery research.

著者

Takashi Tsujimoto Ryoko Arai Taichi Yoshitomi Yutaka Yamamoto Yoshihiro Ozeki Takashi Hakamatsuka Nahoko Uchiyama

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

pp.c21-00180, (Released:2021-05-21)

参考文献数

19

被引用文献数

9

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Citrus-type crude drugs (CCDs) are commonly used to formulate decoctions in Kampo formula (traditional Japanese medicine). Our previous study reported metabolomic analyses for differentiation of the methanol extracts of Citrus-type crude drugs (CCDs) using UHPLC/MS, and 13C- and 1H-NMR. The present study expanded the scope of its application by analyzing four CCD water extracts (Kijitsu, Tohi, Chimpi, and Kippi); these CCDs are usually used as decoction ingredients in the Kampo formula. A principal component analysis score plot of processed UPLC/MS and NMR analysis data indicated that the CCD water extracts could be classified into three groups. The loading plots showed that naringin and neohesperidin were the distinguishing components. Three primary metabolites, α-glucose, β-glucose, and sucrose were identified as distinguishing compounds by NMR spectroscopy. During the preparation of CCD dry extracts, some compounds volatilized or decomposed. Consequently, fewer compounds were detected than in our previous studies using methanol extract. However, these results suggested that the combined NMR- and LC/MS-based metabolomics can discriminate crude drugs in dried water extracts of CCDs.

著者

柏田 良樹 森田 益史 野中 源一郎 西岡 五夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.38, no.4, pp.856-860, 1990-04-25 (Released:2008-03-31)

参考文献数

13

被引用文献数

11 15

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A chemical examination of the polyphenolic constituents of the fern, Dicranopteris pedata HOUTT., has led to the isolation of eight new proanthocyanidins possessing a doubly-linked (A-type) unit, together with known flavan-3-ols and proanthocyanidins. On the basis of chemical and spectroscopic evidence, they are characterized as epiafzelechin-(4β→8, 2β→O→7)-eniafzelechin-(4α→8)-epiafzelechin(8), epicatechin-(4β→8, 2β→O→7)-epiafzelechin-(4α→8)-epiafzelechin(9), epiafzelechin-(4β→8, 2β→O→7)-epizfzelechin-(4α→8)-epicatechin(10), epiafzelechin-(4β→8, 2β→O→7)-epicatechin-(4α→8)-epicatechin (11), epicatechin-(4β→8, 2β→O→7)-epiafzelechin-(4α→8)-epicatechin (12), epicatechin-(4β→8, 2β→O→7)-epicatechin-(4α→8)-epiafzelechin (13), epicatechin-(4β→8, 2β→O→7)-epicatechin-(4α→8)-epigallocatechin (14) and epiafzelechin-(4β→8)epicatechin-(4β→8, 2β→O→β→7)-epicatechin-(4α→8)-epicatechin (15).

著者

Shadi Sedghi Masoud Kazuo Nagasawa

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.12, pp.1091-1103, 2018-12-01 (Released:2018-12-01)

参考文献数

112

被引用文献数

14 43

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The i-motif is a high-order DNA structure formed by hemiprotonated cytosine–cytosine base pairs under acidic conditions. It is less well studied than other high-order DNA structures, such as G-quadruplexes. However, increasing numbers of i-motif-binding ligands are being reported, and they are being used as tools to investigate the i-motif’s structure and biological functions. It has become clear that the i-motif has a functional role in the regulation of gene expression. In this review, we provide an overview of i-motif ligands so far reported, and we summarize their effects on the structure and their use as tools to investigate its biological functions.

著者

Wei Peng Yan-Yan Ma Kun Zhang Ai-Yu Zhou Yu Zhang Huaqian Wang Zhiyun Du Deng-Gao Zhao

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.64, no.6, pp.609-615, 2016-06-01 (Released:2016-06-01)

参考文献数

18

被引用文献数

9 14

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Long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) may cause serious side effects such as gastric mucosal damage. Resveratrol, a naturally dietary polyphenol, exhibited anti-inflammatory activity and a protective effect against gastric mucosa damage induced by NSAIDs. In this regard, we synthesized a series of resveratrol-based NSAIDs derivatives and evaluated their anti-inflammatory activity against nitric oxide (NO) overproduction in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We identified mono-substituted resveratrol–ibuprofen combination 21 as the most potent anti-inflammatory agent, which is more active than a physical mixture of ibuprofen and resveratrol, individual ibuprofen, or individual resveratrol. In addition, compound 21 exerted potent inhibitory effects on the LPS-induced expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Furthermore, compound 21 significantly increased the survival rate in an LPS-induced acute inflammatory model and produced markedly less gastric damage than ibuprofen. It was found that compound 21 may be a potent anti-inflammatory agent for the treatment of inflammation-related diseases.

著者

Kazumasa Kotake Takashi Hongo Akihiro Tahira Nana Niimi Ikue Haisa Yasuhiro Kawakami

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.44, no.5, pp.605-610, 2021-05-01 (Released:2021-05-01)

参考文献数

36

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Recombinant human thrombomodulin (rhTM) is an anti-coagulant used to treat disseminated intravascular coagulation (DIC). The efficacy of rhTM in patients with sepsis-induced DIC has been proved in some clinical trials, but the determining factors are not known. The aim of this study was to identify patients for whom rhTM will be effective and the factors that determine rhTM efficacy in alleviating DIC. A single-center, retrospective, observational study was conducted in patients with sepsis-induced DIC who were treated with rhTM in Okayama Saiseikai General Hospital (Okayama, Japan) between January 2010 and December 2019. Among 67 patients who were treated with rhTM, DIC was resolved in 24 patients. The multivariate logistic regression analysis revealed that age (odds ratio (OR) 1.05; 95% confidence interval (CI) 1.00–1.10; p < 0.05) and acute physiology and chronic health evaluation II scores (OR 0.88; 95% CI 0.78–0.98; p < 0.05) were factors that determined rhTM efficacy in alleviating DIC. Overall, our study provides valuable information on factors that should be considered before rhTM administration to patients with sepsis-induced DIC for a better management of healthcare costs.

著者

Masato Maruyama Yousuke Nakano Takuya Nishimura Ryoichi Iwata Satoshi Matsuda Mikio Hayashi Yuki Nakai Masahiro Nonaka Tetsuo Sugimoto

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

pp.b20-00868, (Released:2021-04-23)

参考文献数

42

被引用文献数

4

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Glioblastoma multiforme (GBM) is the most prevalent malignant primary brain tumor with a high recurrence rate. Despite multimodal therapy including surgical resection, chemotherapy, and radiotherapy, the median survival time after the initial diagnosis of GBM is approximately 14 months. Since cancer stem cells (CSCs) are considered the leading cause of cancer recurrence, glioblastoma stem cell-targeted therapy is a promising strategy for the treatment of GBM. However, because CSC heterogeneity has been implicated in the difficulties of CSC-target therapy, more in-depth knowledge of CSC biology is still required to develop novel therapies.In this study, we established single cell-derived tumorspheres from human glioblastoma U87MG cells. One of these tumorspheres, P4E8 clone, showed CSC-like phenotypes, such as self-renewal capacity, expression of CSC markers, resistance to anti-cancer agents, and in vivo tumorigenicity. Therefore, we used P4E8 cells as a cell-based model of glioblastoma stem cells (GSCs). Gene expression analysis using microarray indicated that the most highly expressed genes in P4E8 cells compared to the parental U87MG were PC3-secreted microprotein (MSMP). Furthermore, MSMP was expressed in patient-derived GSCs and human glioma tissues at the protein level, implying that MSMP might contribute to glioma development and progression.

著者

Shinya Suzuki Mayako Uchida Yukio Suga Hideki Sugawara Hideya Kokubun Yoshihiro Uesawa Takayuki Nakagawa Hisamitsu Takase

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.42, no.7, pp.1164-1171, 2019-07-01 (Released:2019-07-01)

参考文献数

40

被引用文献数

2 12

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No nationwide study on polypharmacy in palliative care among Japanese community pharmacies has yet been conducted. We conducted an online questionnaire survey for community pharmacist members of The Japanese Society for Pharmaceutical Palliative Care and Sciences regarding their contributions to cancer patients who regularly used six or more drugs, including opioids, in service during the two-month period from October to November 2017. Of 579 community pharmacists, 83 responded to the survey (14.3%). Among them, 47.0 and 27.7% of respondents replied that more than 40% of opioid-using and non-using cancer patients were prescribed six or more regular medications, respectively. The proportion of patients with polypharmacy was marginally higher among opioid-using than non-using patients. Additionally, 31.3 and 22.9% of respondents replied that a low or moderate rate of opioid-using and non-using patients with polypharmacy received inappropriate prescriptions, respectively, including “unnecessary medications,” “adverse drug reactions” and “duplication of pharmacological effect.” The proportion of patients who received inappropriate prescriptions was significantly higher among opioid-using than non-using patients. Furthermore, 37.3 and 19.3% of respondents replied that pharmacist’s recommendations contributed to drug reduction in opioid-using and non-using patients with polypharmacy who received inappropriate prescriptions, respectively. The responders with higher confidence in palliative care showed more success rate for reducing inappropriate medications. Our findings suggest that opioid use can be associated with an increased risk of polypharmacy in cancer patients, and that recommendations by a population of community pharmacists can reduce inappropriate medications and improve adverse drug reactions in both opioid-using and non-using cancer patients with polypharmacy.

著者

Yasuo Uchida

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.44, no.4, pp.465-473, 2021-04-01 (Released:2021-04-01)

参考文献数

41

被引用文献数

6

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From the viewpoint of drug discovery, it is an important issue to elucidate the drug permeability at the human central nervous system (CNS) barriers and the molecular mechanisms in the cells forming CNS barriers especially during CNS diseases. I introduced quantitative proteomics techniques into the blood–brain barrier (BBB) study, then quantitatively investigated the transport system at the human BBB and clarified the quantitative differences in protein expression levels and functions of transporters and receptors between animals and humans, or in vitro and in vivo. Based on the difference in the absolute expression level of transporters between in vitro and in vivo, I demonstrated that the drug efflux activity of P-glycoprotein (P-gp) at in vivo BBB can be accurately reconstructed from the in vitro system, not only in mouse models but also monkeys similar to humans and pathological conditions. Furthermore, I discovered Claudin-11 as another tight junction molecule expressed at the CNS barriers, and clarified that it contributes to the disruption of the CNS barriers in multiple sclerosis. Furthermore, it was also elucidated that the P-gp dysfunction causes excessive brain entry of glucocorticoid which causes a nerve damage in cerebral infarct, and it can be suppressed by targeting Abl/Src kinases. These suggest that targeting the tight junctions and transporters, which are important molecules at the CNS barriers, would potentially lead to the treatment of CNS diseases. In this review, I would like to introduce a new CNS barrier study opened by quantitative proteomics research.

著者

Yoshihiro Kobashigawa Mana Namikawa Mitsuhiro Sekiguchi Yuki Inada Soichiro Yamauchi Yuu Kimoto Kyo Okazaki Yuya Toyota Takashi Sato Hiroshi Morioka

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.44, no.1, pp.125-130, 2021-01-01 (Released:2021-01-01)

参考文献数

35

被引用文献数

7

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The constitutive active/androstane receptor (CAR) is a nuclear receptor that functions as a xenobiotic sensor, which regulates the expression of enzymes involved in drug metabolism and of efflux transporters. Evaluation of the binding properties between CAR and a drug was assumed to facilitate the prediction of drug–drug interaction, thereby contributing to drug discovery. The purpose of this study is to construct a system for the rapid evaluation of interactions between CAR and drugs. We prepared recombinant CAR protein using the Escherichia coli expression system. Since isolated CAR protein is known to be unstable, we designed a fusion protein with the CAR binding sequence of the nuclear receptor coactivator 1 (NCOA1), which was expressed as a fusion protein with maltose binding protein (MBP), and purified it by several chromatography steps. The thus-obtained CAR/NCOA1 tethered protein (CAR-NCOA1) was used to evaluate the interactions of CAR with agonists and inverse agonists by a thermal denaturation experiment using differential scanning fluorometry (DSF) in the presence and absence of drugs. An increase in the melting temperature was observed with the addition of the drugs, confirming the direct interaction between them and CAR. DSF is easy to set up and compatible with multiwell plate devices (such as 96-well plates). The use of DSF and the CAR-NCOA1 fusion protein together allows for the rapid evaluation of the interaction between a drug and CAR, and is thereby considered to be useful in drug discovery.

著者

Hayato Ishimoto Manabu Kano Hirokazu Sugiyama Hirofumi Takeuchi Katsuhide Terada Atsushi Aoyama Takuji Shoda Yosuke Demizu Jinen Shimamura Reiji Yokoyama Yuji Miyamoto Koji Hasegawa Masaru Serizawa Kazuomi Unosawa Kazuo Osaki Naochika Asai Yoshihiro Matsuda

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.69, no.2, pp.211-217, 2021-02-01 (Released:2021-02-01)

参考文献数

27

被引用文献数

3

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As a result of the research activities of the Japan Agency for Medical Research and Development (AMED), this document aims to show an approach to establishing control strategy for continuous manufacturing of oral solid dosage forms. The methods of drug development, technology transfer, process control, and quality control used in the current commercial batch manufacturing would be effective also in continuous manufacturing, while there are differences in the process development using continuous manufacturing and batch manufacturing. This document introduces an example of the way of thinking for establishing a control strategy for continuous manufacturing processes.

著者

Yoshitaka Saito Shinya Tamaki Haruka Hasegawa Kenta Takahashi Akira Tokutome Yoh Takekuma Hiroko Yamashita Yoshito Komatsu Mitsuru Sugawara

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.44, no.4, pp.474-477, 2021-04-01 (Released:2021-04-01)

参考文献数

21

被引用文献数

3

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CT-P6 is a biosimilar of trastuzumab and is recommended to be administered for 30–90 min in subsequent maintenance infusions to prevent infusion-related reactions (IRRs). We administered CT-P6 for 30 min as the first injection and as an alternative to reference trastuzumab in the maintenance infusion and evaluated the safety of the administration. A total of 140 patients with breast or gastric cancer, who received a switch from tri-weekly reference trastuzumab to CT-P6 for 30 min in maintenance infusions, were retrospectively evaluated. Premedication was administered prior to an infusion of CT-P6 and a cytotoxic agent. However, premedication was not provided when CT-P6 was co-administered with pertuzumab or administered alone. The primary endpoint was the incidence of IRRs. The secondary endpoint was the incidence of diarrhea and skin toxicity. Ninety-five percent of the patients had breast cancer, and 44.3% had advance-stage cancer. The treatment included CT-P6 alone (17.9%) or with cytotoxic agents (23.6%), antihormonal drugs (25.7%), and pertuzumab (62.9%). Median administration time of trastuzumab at the switch was 13 administrations (range 2–140). Premedication was administered to 20.7% patients. One patient (0.7%) experienced grade 3 IRR. The frequency of diarrhea in the reference trastuzumab group and the CT-P6 group was 7.1 and 6.4%, respectively, and that of skin toxicity was 6.4 and 5.0%, respectively, without differences. In conclusion, we first demonstrated that an initial CT-P6 administration for 30 min during the switch from reference trastuzumab in maintenance infusion is an acceptable administration method.

著者

Huan Ding Jing-jing Wang Xiao-Ya Zhang Lei Yin Tao Feng

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.44, no.3, pp.379-388, 2021-03-01 (Released:2021-03-01)

参考文献数

28

被引用文献数

25

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Lipopolysaccharide (LPS)-induced inflammation is the leading cause of multiple organ failure in sepsis. Pyruvate kinase 2 (PKM2) is a protein kinase and transcriptional coactivator that plays an important role in glycolysis. Recent studies have confirmed that glycolysis maintains the M1 differentiation and induces immune activation in macrophages. Lycium barbarum polysaccharide (LBP), the main bioactive component of Chinese wolfberry, suppresses glycolysis and inflammation. Here, RAW264.7 macrophages were treated with LBP for evaluating its effects against LPS-induced inflammation. The differentiation of M1/M2 macrophages was assessed by flow cytometry for assessing the cell surface markers, CD86 and CD206. The enrichment of hypoxia inducible factor (HIF)-1α and ubiquitin in the PKM2 protein complex was determined by co-immunoprecipitation. LBP suppressed LPS-induced glycolysis, differentiation of M1 macrophages, and the production of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and high mobility group (HMG) 1 proteins. The suppressive effects of LBP were similar to those of PKM2 knockdown, but were abolished by the overexpression of PKM2. LPS elevated the mRNA and protein levels of PKM2. LBP reduced the LPS-induced expression of PKM2 protein, but had no effects on the expression of PKM2 mRNA. LPS inhibited the ubiquitination of PKM2, probably by downregulating the expression of ubiquitin ligases, including Nedd4L, Nedd4, and Gnb2. LBP interfered with the inhibition of PKM2 ubiquitination by upregulating the expression of Nedd4L, Nedd4, and Gnb2. In conclusion, LBP suppressed the LPS-induced inflammation by altering glycolysis and the M1 differentiation of macrophages. The effects of LBP were mediated by the downregulation of PKM2 via enhanced ubiquitination.

著者

Chaoxin Fan Fang Tian Xin Zhao Yi Sun Xiaogai Yang Hongbin Han Xiaoping Pu

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.43, no.9, pp.1306-1314, 2020-09-01 (Released:2020-09-01)

参考文献数

22

被引用文献数

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The extracellular space (ECS) is the space between the neurons and the capillaries in the brain. The volume fraction (α) and the tortuosity (λ) are the main parameters used to describe its characteristics. Thymoquinone has been proved to possess anti-oxidant and anti-inflammatory activity. In this study, we used a gadolinium-diethylenetriaminepentacetate (Gd-DTPA)-enhanced magnetic resonance imaging (MRI) system to determine the effects of thymoquinone on ECS parameters in transient middle cerebral artery occlusion rats (tMCAO) to prove the neuroprotective effect of thymoquinone on brain tissue damage caused by ischemic stroke. Neurological examinations, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin–eosin (H&E) staining and assaying of ECS parameters using MRI were performed 24 h after surgery. We found that thymoquinone could improve the behavioural performance by neurological examinations. TTC staining indicated that thymoquinone significantly decreased the percentage of hemi-cerebral infarction. Also, H&E staining showed that thymoquinone could inhibit the neuron necrosis in the hippocampal CA1 region. We found that thymoquinone treatment could inhibit the changes in ECS diffusion parameters, which might prove that thymoquinone might protect brain tissue damage caused by ischemic stroke. Thymoquinone can protect the brain against cerebral ischemia–reperfusion injury, effectively ameliorate abnormalities in characteristics of ECS and decrease cerebral infarction in tMCAO rats.