Publications by authors named "Rikako Tanaka"

8 Publications

  • Page 1 of 1

Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials.

Int J Chron Obstruct Pulmon Dis 2021 3;16:1621-1636. Epub 2021 Jun 3.

Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.

Background: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD).

Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD.

Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry.

Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals -46, 315mL) with a probability that the true treatment ratio was >0% (Pr(θ>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged.

Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.
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http://dx.doi.org/10.2147/COPD.S309303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184158PMC
June 2021

Protracted course of coronavirus disease with severe acute respiratory distress syndrome: a case report.

Acute Med Surg 2020 Jan-Dec;7(1):e521. Epub 2020 Jun 18.

Department of Emergency and Critical Care Medicine Wakayama Medical University Wakayama Japan.

Background: Coronavirus disease (COVID-19) is a growing concern worldwide. Approximately 5% of COVID-19 cases require intensive care. However, the optimal treatment for respiratory failure in COVID-19 patients is yet to be determined.

Case Presentation: A 79-year-old man with severe acute respiratory distress syndrome due to COVID-19 was admitted to our intensive care unit. Prone ventilation was effective in treating the patient's hypoxemia. Furthermore, the patient received lung protective ventilation with a tidal volume of 6-8 mg/kg (predicted body weight). However, the patient's respiratory failure did not improve and he died 16 days after admission because of multiple organ failure. Serial chest computed tomography revealed a change from ground-glass opacity to consolidation pattern in both lungs.

Conclusions: We report a protracted case of COVID-19 in a critically ill patient in Japan. Although prone ventilation could contribute to treating hypoxemia, its efficacy in preventing mortality from COVID-19 is unknown.
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http://dx.doi.org/10.1002/ams2.521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276737PMC
June 2020

Unique Hydration/Dehydration-Induced Vapochromic Behavior of a Charge-Transfer Salt Comprising Viologen and Hexacyanidoferrate(II).

Inorg Chem 2018 Feb 7;57(4):2209-2217. Epub 2018 Feb 7.

Toyota Physical and Chemical Research Institute , Yokomichi, Nagakute-shi, Aichi 480-1192, Japan.

We successfully prepared and crystallographically characterized the first intermolecular charge-transfer (CT)-based vapochromic compound, (EV)(HO)[Fe(CN)] (1-Wet, EV: 1,1'-diethyl-4,4'-bipyridine-1,1'-diium), an ethyl viologen-containing CT salt. 1-Wet, which is purple in color, is transformed into a brown powder (1-Dry) upon exposure to methanol vapor, drying over silica gel, or heating; 1-Dry returns to 1-Wet upon exposure to water vapor. These color changes are induced by hydration and dehydration, and gravimetric analyses suggest that 1-Dry is the dehydrated form of 1-Wet, namely, (EV)(H)[Fe(CN)]. Interestingly, desorption of water molecules from the oxonium ions in 1-Wet produces isolated protons (H) that remain in 1-Dry as counter cations. Powder X-ray crystal structure analysis of 1-Dry reveals the presence of very short contacts between the nitrogen atoms of adjacent [Fe(CN)] anions in the crystal. The isolated protons are trapped between the nitrogen atoms of cyanido ligands to form very short N···H···N hydrogen bonds. A detailed comparison of the crystal structures of 1-Wet and 1-Dry reveals that hydration and dehydration induce changes in crystal packing and intermolecular CT interactions, resulting in reversible color changes.
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http://dx.doi.org/10.1021/acs.inorgchem.7b03100DOI Listing
February 2018

Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5-HT receptor.

Br J Pharmacol 2017 Oct 23;174(19):3370-3381. Epub 2017 Aug 23.

Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan.

Background And Purpose: Visceral hypersensitivity is responsible for pathogenesis of irritable bowel syndrome (IBS). Therefore, its prevention can help avoid abdominal pain and discomfort in IBS. To find candidate drugs for visceral hypersensitivity, we screened existing medicines for their ability to prevent visceral sensitivity induced by colorectal distension (CRD) in rats and identified chlorpromazine, a typical antipsychotic drug, as a candidate compound. In this study, we investigated the effect of chlorpromazine on visceral hypersensitivity.

Experimental Approach: Visceral sensitivity (visceromotor response) was monitored by measuring the electrical activity of the abdominal external oblique muscle contraction in response to CRD using a barostat apparatus. Visceral hypersensitivity was induced by a colonic instillation of sodium butyrate or acetic acid in neonates.

Key Results: Oral administration of chlorpromazine suppressed butyrate-induced visceral hypersensitivity to CRD. Interestingly, atypical antipsychotic drugs, quetiapine and risperidone, ameliorated butyrate-induced visceral hypersensitivity, whereas the typical antipsychotic drugs, haloperidol and sulpiride, did not. Pharmacological analysis using specific inhibitors showed that a selective 5-HT receptor antagonist, ketanserin, suppressed butyrate-induced visceral hypersensitivity, whereas a selective dopamine D receptor antagonist, L-741626, did not. Furthermore, the 5-HT receptor agonist AL-34662 stimulated visceral sensitivity to CRD in healthy control rats but not in butyrate-treated rats. These findings suggest that increased 5-HT levels in the colon contribute to the induction of visceral hypersensitivity.

Conclusions And Implications: Our results indicate that chlorpromazine ameliorates visceral hypersensitivity and that the 5-HT receptor is a potential therapeutic target for treating abdominal pain and discomfort in IBS.
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http://dx.doi.org/10.1111/bph.13960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595764PMC
October 2017

A charge-transfer salt composed of methyl viologen and hexacyanidoferrate(II).

Acta Crystallogr C Struct Chem 2017 Jun 25;73(Pt 6):476-480. Epub 2017 May 25.

Department of Chemistry and Research Center for Smart Molecules, Rikkyo University, Nishi-Ikebukuro 3-34-1, Toshima-ku, 171-8501 Tokyo, Japan.

The methyl viologen dication, used under the name Paraquat as an agricultural reagent, is a well-known electron-acceptor species that can participate in charge-transfer (CT) interactions. The determination of the crystal structure of this species is important for accessing the CT interaction and CT-based properties. The title hydrated salt, bis(1,1'-dimethyl-4,4'-bipyridine-1,1'-diium) hexacyanidoferrate(II) octahydrate, (CHN)[Fe(CN)]·8HO or (MV)[Fe(CN)]·8HO [MV is the 1,1'-dimethyl-4,4'-bipyridine-1,1'-diium (methyl viologen) dication], crystallizes in the space group P2/c with one MV cation, half of an [Fe(CN)] anion and four water molecules in the asymmetric unit. The Fe atom of the [Fe(CN)] anion lies on an inversion centre and has an octahedral coordination sphere defined by six cyanide ligands. The MV cation is located on a general position and adopts a noncoplanar structure, with a dihedral angle of 40.32 (7)° between the planes of the pyridine rings. In the crystal, layers of electron-donor [Fe(CN)] anions and layers of electron-acceptor MV cations are formed and are stacked in an alternating manner parallel to the direction of the -2a + c axis, resulting in an alternate layered structure.
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http://dx.doi.org/10.1107/S2053229617007616DOI Listing
June 2017

Crystal structure of bis-(1-ethyl-pyridinium) dioxonium hexa-cyanidoferrate(II).

Acta Crystallogr E Crystallogr Commun 2017 Feb 20;73(Pt 2):219-222. Epub 2017 Jan 20.

Department of Chemistry and Research Center for Smart Molecules, Rikkyo University, Nishi-Ikebukuro 3-34-1, Toshima-ku, 171-8501 Tokyo, Japan.

The title compound, (CHN)(HO)[Fe(CN)] or (Etpy)(HO)[Fe(CN)] (Etpy is 1-ethyl-pyridinium), crystallizes in the space group . The Fe atom of the [Fe(CN)] anion lies on a site with site symmetry ..2/, and has an octa-hedral coordination sphere defined by six cyanido ligands. Both the Etpy and the oxonium cations are located on a mirror plane. In the crystal, electron-donor anions of [Fe(CN)] and electron-acceptor cations of Etpy are each stacked parallel to the axis, resulting in a columnar structure with segregated moieties. The crystal packing is stabilized by a three-dimensional O-H⋯N hydrogen-bonding network between the oxonium ions and the cyanide ligands of [Fe(CN)].
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http://dx.doi.org/10.1107/S2056989017000810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290569PMC
February 2017

Aminophylline suppresses stress-induced visceral hypersensitivity and defecation in irritable bowel syndrome.

Sci Rep 2017 01 5;7:40214. Epub 2017 Jan 5.

LTT Bio-Pharma Co., Ltd, Shiodome Building 3F, 1-2-20 Kaigan, Minato-ku, Tokyo 105-0022, Japan.

Pharmacological therapy for irritable bowel syndrome (IBS) has not been established. In order to find candidate drugs for IBS with diarrhea (IBS-D), we screened a compound library of drugs clinically used for their ability to prevent stress-induced defecation and visceral hypersensitivity in rats. We selected the bronchodilator aminophylline from this library. Using a specific inhibitor for each subtype of adenosine receptors (ARs) and phosphodiesterases (PDEs), we found that both AARs and PDE4 are probably mediated the inhibitory effect of aminophylline on wrap restraint stress (WRS)-induced defecation. Aminophylline suppressed maternal separation- and acetic acid administration-induced visceral hypersensitivity to colorectal distension (CRD), which was mediated by both AARs and AARs. We propose that aminophylline is a candidate drug for IBS-D because of its efficacy in both of stress-induced defecation and visceral hypersensitivity, as we observed here, and because it is clinically safe.
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http://dx.doi.org/10.1038/srep40214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214462PMC
January 2017

Design, synthesis, inhibitory activity, and binding mode study of novel DNA methyltransferase 1 inhibitors.

Bioorg Med Chem Lett 2010 Feb 21;20(3):1124-7. Epub 2009 Dec 21.

Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.

To identify novel non-nucleoside DNA methyltransferase (DNMT) inhibitors, we designed and synthesized a series of maleimide derivatives. Among this series, compounds 5-8 were found to be more potent DNMT1 inhibitors than RG108, a DNMT1 inhibitor reported previously by Siedlecki et al. The binding mode analysis of compound 5 is also reported.
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http://dx.doi.org/10.1016/j.bmcl.2009.12.016DOI Listing
February 2010
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