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Nippon Shinyaku’s R&D Activities

Publication of R&D

Annual achievement of Nippon Shinyaku's R&D


Yamazaki H, Tsujimoto N, Koyanagi M, Katoh MC, Tajima K, Komori M.
Real-World Safety and Effectiveness of Tadalafil in Patients with Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Japanese Post-Marketing Surveillance Study.

Pragmat Obs Res. 2020 May 4;11:45-54.

Yamaguchi H, Kurita M, Yoshinaga R, Asao Y, Oka M.
Experimental rodent models of chronic prostatitis: effect of phosphodiesterase 5 inhibitor on chronic pelvic-pain-related behavior.

Nihon Yakurigaku Zasshi. 2019;154(5):259-264.

Yoshinaga R, Fukui T, Yoshifuji M, Fujimura M, Oyama T, Oka M.
Comparison of the Effects of Tadalafil and α1-Adrenoceptor Antagonists onSpontaneous Seminal Emission and Electrical Field Stimulation-Induced Seminal Vesicle Contraction in Rats.

J Sex Med. 2019 May;16(5):680-690.

Yamaguchi H, Kurita M, Okamoto K, Kotera T, Oka M.
Voiding behavior and chronic pelvic pain in two types of rat nonbacterial prostatitis models: Attenuation of chronic pelvic pain by repeated administration of tadalafil.

Prostate. 2019 Apr;79(5):446-453.

Kurita M, Yamaguchi H, Okamoto K, Kotera T, Oka M.
Chronic pelvic pain and prostate inflammation in rat experimental autoimmune prostatitis: Effect of a single treatment with phosphodiesterase 5 inhibitors on chronic pelvic pain.

Prostate. 2018 Nov;78(15):1157-1165.

Okamoto K, Kurita M, Yamaguchi H, Numakura Y, Oka M.
Effect of tadalafil on chronic pelvic pain and prostatic inflammation in a rat model of experimental autoimmune prostatitis.

Prostate. 2018 Jul;78(10):707-713.

Takeda M, Yokoyama O, Yoshida M, Nishizawa O, Hirata K, Nakaoka R, Takita Y, Murakami M.
Safety and efficacy of the combination of once-daily tadalafil and alpha-1 blocker in Japanese men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A randomized, placebo-controlled, cross-over study.

Int J Urol. 2017 Jul;24(7):539-547.

Dogishi K, Okamoto K, Majima T, Konishi-Shiotsu S, Homan T, Kodera M, Oyama S, Oyama T, Shirakawa H, Yoshimura N, Nakagawa T, Kaneko S.
A rat long-lasting cystitis model induced by intravesical injection of hydrogen peroxide.

Physiol Rep. 2017 Feb;5(4). pii: e13127.

Murachi K, Kumagai T, Masuda T, Nakanishi T, Tanaka S, Tajima K, Takebe Y, Oda T.
[Efficacy and Prognostic Factors of Estracyt ® in Patients with Castration-Resistant Prostate Cancer (CRPC) : From the Data Analysis of Estracyt ® Special Drug Use Investigation].

Hinyokika Kiyo. 2016 Jun;62(6):295-306. Japanese.

Kawai Y, Oka M, Yoshinaga R, Fuchikami C, Oyama T.
Effects of the phosphodiesterase 5 inhibitor Tadalafil on bladder function in a rat model of partial bladder outlet obstruction.

Neurourol Urodyn. 2016 Apr;35(4):444-9.

Yoshinaga R, Kawai Y, Oka M, Fuchikami C, Oyama T.
Effect of a single treatment with tadalafil on blood flow in lower urinary tract tissues in rat models of bladder overdistension/emptying and abdominal aorta clamping/release.

Eur J Pharmacol. 2015 May 5;754:92-7.

Kawai Y, Oka M, Kyotani J, Oyama T, Matsumoto S, Kakizaki H.
Effect of the phytotherapeutic agent eviprostat on the bladder in a rat model of bladder overdistension/emptying.

Neurourol Urodyn. 2013 Sep;32(7):1031-7.

Oyama T, Kawai Y, Oka M.
Tramadol enhances urethral continence function through µ-opioid receptors in rats.

Neurourol Urodyn. 2013 Jan;32(1):98-103.

Oyama T, Homan T, Kyotani J, Oka M.
Effect of tramadol on pain-related behaviors and bladder overactivity in rodent cystitis models.

Eur J Pharmacol. 2012 Feb 15;676(1-3):75-80.

Matsui T, Oka M, Fukui T, Tanaka M, Oyama T, Sagawa K, Nomiya M, Yamaguchi O.
Suppression of bladder overactivity and oxidative stress by the phytotherapeutic agent, Eviprostat, in a rat model of atherosclerosis-induced chronic bladder ischemia.

Int J Urol. 2012 Jul;19(7):669-75.


Honda A, Kuramoto K, Niwa T, Naito H.
NS-018 reduces myeloma cell proliferation and suppresses osteolysis through inhibition of the JAK2 and Src signaling pathways.

Blood Cancer J. 2018 Jun 25;8(7):62.

Kuroda J, Kodama A, Chinen Y, Shimura Y, Mizutani S, Nagoshi H, Kobayashi T, Matsumoto Y, Nakaya Y, Tamura A, Kobayashi Y, Naito H, Taniwaki M.
NS-018, a selective JAK2 inhibitor, preferentially inhibits CFU-GM colony formation by bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients.

Leuk Res. 2014 May;38(5):619-24.

Nakaya Y, Shide K, Naito H, Niwa T, Horio T, Miyake J, Shimoda K.
Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis.

Blood Cancer J. 2014 Jan 10;4: e174.

Ichikawa T, Suda Y, Nakagawa T, Nonaka K, Nakamura A, Ochi S.
Absorption, distribution and excretion of radioactivity by male rats after a single intravenous or subcutaneous dose of 14C-azacitidine.

Drug Res (Stuttg). 2013 Feb;63(2):84-9.

Kimura S, Kuramoto K, Homan J, Naruoka H, Ego T, Nogawa M, Sugahara S, Naito H.
Antiproliferative and antitumor effects of azacitidine against the human myelodysplastic syndrome cell line SKM-1.

Anticancer Res. 2012 Mar;32(3):795-8.

Intractable / Rare Diseases

Komaki H, Takeshima Y, Matsumura T, Ozasa S, Funato M, Takeshita E, Iwata Y, Yajima H, Egawa Y, Toramoto T, Tajima M, Takeda S.
Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study.

Ann Clin Transl Neurol. 2020 Dec;7(12):2393-2408.

Tone Y, Mamchaoui K, Tsoumpra MK, Hashimoto Y, Terada R, Maruyama R, Gait MJ, Arzumanov AA, McClorey G, Imamura M, Takeda S, Yokota T, Wood MJA, Mouly V, Aoki Y.
Immortalized Canine Dystrophic Myoblast Cell Lines for Development of Peptide-Conjugated Splice-Switching Oligonucleotides.

Nucleic Acid Ther. 2021 Apr;31(2):172-181.

Kuwano K, Kosugi K, Fuchikami C, Funaki S.
Pharmacological characteristics and clinical study results of Selexipag (Uptravi® tablets), a selective prostacyclin receptor agonist.

Nihon Yakurigaku Zasshi. 2021;156(3):178-186.

Honda Y, Kosugi K, Fuchikami C, Kuramoto K, Numakura Y, Kuwano K.
The selective PGI2 receptor agonist selexipag ameliorates Sugen 5416/hypoxia-induced pulmonary arterial hypertension in rats.

PLoS One. 2020 Oct 15;15(10): e0240692.

Seki R, Ohta A, Niwa A, Sugimine Y, Naito H, Nakahata T, Saito MK.
Induced pluripotent stem cell-derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity.

PLoS One. 2020 Aug 18;15(8): e0237030.

Watanabe N, Nagata T, Satou Y, Masuda S, Saito T, Kitagawa H, Komaki H, Takagaki K, Takeda S.
NS-065/NCNP-01: An Antisense Oligonucleotide for Potential Treatment of Exon 53 Skipping in Duchenne Muscular Dystrophy.

Mol Ther Nucleic Acids. 2018 Dec 7;13: 442-449.

Imai S, Ichikawa T, Sugiyama C, Nonaka K, Yamada T.
Contribution of Human Liver and Intestinal Carboxylesterases to the Hydrolysis of Selexipag In Vitro.

J Pharm Sci. 2019 Feb;108(2):1027-1034.

Ichikawa T, Yamada T, Treiber A, Gnerre C, Nonaka K.
Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats, dogs and monkeys.

Xenobiotica. 2018 Feb;48(2):186-196.

Ichikawa T, Yamada T, Treiber A, Gnerre C, Segrestaa J, Seeland S, Nonaka K.
Cross-species comparison of the metabolism and excretion of selexipag.

Xenobiotica. 2018 Feb 22:1-34.

Yamazaki H, Kobayashi N, Taketsuna M, Tajima K, Suzuki N, Murakami M.
Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance.

Curr Med Res Opin. 2017 Dec;33(12):2241-2249.

Yamazaki H, Kobayashi N, Taketsuna M, Tajima K, Murakami M.
Safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension: Japanese post-marketing surveillance data.

Curr Med Res Opin. 2017 May;33(5):963-971.

Fuchikami C, Murakami K, Tajima K, Homan J, Kosugi K, Kuramoto K, Oka M, Kuwano K.
A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)aceta mide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcine and human pulmonary arteries.

Eur J Pharmacol. 2017 Jan 15; 795:75-83.

Bruderer S, Okubo K, Mukai H, Mant T, Dingemanse J.
Investigation of Potential Pharmacodynamic and Pharmacokinetic Interactions Between Selexipag and Warfarin in Healthy Male Subjects.

Clin Ther. 2016 May;38(5):1228-1236.e1.

Asaki T, Kuwano K, Morrison K, Gatfield J, Hamamoto T, Clozel M.
Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.

J Med Chem. 2015 Sep 24;58(18):7128-37.


Otani Y, Fujita KI, Kameyama T, Mayeda A.
The Exon Junction Complex Core Represses Cancer-Specific Mature mRNA Re-splicing: A Potential Key Role in Terminating Splicing.

Int J Mol Sci. 2021 Jun;22(12):6519.

Okubo S, Terauchi K, Okada S, Saito Y, Yamaura T, Misaka T, Nakajima K, Abe K, Asakura T.
De novo transcriptome analysis and comparative expression profiling of genes associated with the taste-modifying protein neoculin in Curculigo latifolia and Curculigo capitulata fruits.

BMC Genomics. 2021 May;22(1):347.

Numakura Y, Konishi S, Kumabe S, Kotera T, Ueda M.
A case of spontaneous nephroblastoma characterized by two distinct morphologies in a Slc:CD(SD)IGS rat.

J Toxicol Pathol. 2020 Oct;33(4):291-295.

Sakamaki K, Yoshida S, Morita Y, Kamiura T, Iba K, Ogawa N, Suganami H, Tsuchiya S, Fukimbara S.
Challenges on Multiple Endpoints in Clinical Trials: An Industry Survey in Japan.

Ther Innov Regul Sci. 2020 May;54(3):528-533.

Yanagimichi M, Nishino K, Sakamoto A, Kurodai R, Kojima K, Eto N, Isoda H, Ksouri R, Irie K, Kambe T, Masuda S, Akita T, Maejima K, Nagao M.
Analyses of putative anti-cancer potential of three STAT3 signaling inhibitory compounds derived from Salvia officinalis.

Biochem Biophys Rep. 2020 Dec 24;25: 100882.

Uchiyama N, Hosoe J, Sugimoto N, Ishizuki K, Koide T, Murabayashi M, Miyashita N, Kobayashi K, Fujimine Y, Yokose T, Ofuji K, Shimizu H, Hasebe T, Asai Y, Ena E, Kikuchi J, Kiyota K, Fujita K, Makino Y, Yasobu N, Iwamoto Y, Miura T, Mizui K, Asakura K, Suematsu T, Muto H, Kohama A, Goto T, Yasuda M, Ueda T, Goda Y.
Purity Determination of Cyclophosphamide Hydrate by Quantitative 31P-NMR and Method Validation.

Chem Pharm Bull (Tokyo). 2021 Jul 1;69(7):630-638.

Moroki T, Matsuo S, Hatakeyama H, Hayashi S, Matsumoto I, Suzuki S, Kotera T, Kumagai K, Ozaki K.
Databases for technical aspects of immunohistochemistry: 2021 update.

J Toxicol Pathol. 2021 Apr;34(2):161-180.

Imai S, Arai T, Yamada T, Niwa M.
Improved In Vitro-In Vivo Correlation by Using the Unbound-Fraction-Adjusted IC50 for Breast Cancer Resistance Protein Inhibition.

Pharm Res. 2020 Oct 29;37(12):230.

Sanoh S, Hanada H, Kashiwagi K, Mori T, Goto-Inoue N, Suzuki KT, Mori J, Nakamura N, Yamamoto T, Kitamura S, Kotake Y, Sugihara K, Ohta S, Kashiwagi A.
Amiodarone bioconcentration and suppression of metamorphosis in Xenopus.

Aquat Toxicol. 2020 Nov;228: 105623.

Niwa M, Hara Y, Sengoku S, Kodama K.
Effectiveness of Social Measures against COVID-19 Outbreaks in Selected Japanese Regions Analyzed by System Dynamic Modeling.

Int J Environ Res Public Health. 2020 Aug 27;17(17):6238.

Takenaka Y, Seki S, Nishi T, Tanahashi T.
Two new sesquiterpenes from Artemisia annua L.

J Nat Med. 2020 Sep;74(4):811-818.

Niwa M, Cao J, Kodama K.
Innovation dynamics and globalization trends of high-throughput bioanalytical methods from a literature survey.

Bioanalysis. 2020 Jun;12(12):813-816.

Hasegawa T, Misawa S, Nakagawa S, Tanaka S, Tanase T, Ugai H, Wakana A, Yodo Y, Tsuchiya S, Suganami H; JPMA Task Force Members.
Restricted mean survival time as a summary measure of time-to-event outcome.

Pharm Stat. 2020 Jul;19(4):436-453.

Sakamaki K, Morita Y, Iba K, Kamiura T, Yoshida S, Ogawa N, Suganami H, Tsuchiya S, Fukimbara S.
Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan.

Ther Innov Regul Sci. 2020 Sep;54(5):1097-1105.

Niwa M, Nakai N, Hosaka S, Ishii T, Mayumi T, Ueda A, Yamakawa T, Yasuda Y.
Evaluation of the uncertainty of a quantitative approach to drug metabolites in the absence of authentic standards.

Bioanalysis. 2020 Jan;12(1):7-10.

Munakata R, Takemura T, Tatsumi K, Moriyoshi E, Yanagihara K, Sugiyama A, Suzuki H, Seki H, Muranaka T, Kawano N, Yoshimatsu K, Kawahara N, Yamaura T, Grosjean J, Bourgaud F, Hehn A, Yazaki K.
Isolation of Artemisia capillaris membrane-bound di-prenyltransferase for phenylpropanoids and redesign of artepillin C in yeast.

Commun Biol. 2019 Oct 18; 2:384.

Ishida C, Sanoh S, Kotake Y.
CYP1A2 Downregulation by Obeticholic Acid: Usefulness as a Positive Control for the In Vitro Evaluation of Drug-Drug Interactions.

J Pharm Sci. 2019 Dec;108(12):3903-3910.

Sakamaki K, Yoshida S, Morita Y, Kamiura T, Iba K, Ogawa N, Suganami H, Tsuchiya S, Fukimbara S.
Challenges on Multiple Endpoints in Clinical Trials: An Industry Survey in Japan.

Ther Innov Regul Sci. 2019 Jun 18:2168479019855994.

Yamamoto T, Masuta Y, Momota M, Kanekiyo M, Kanuma T, Takahama S, Moriishi E, Yasutomi Y, Saito T, Graham BS, Takahashi Y, Ishii KJ.
A unique nanoparticulate TLR9 agonist enables a HA split vaccine to confer FcγR-mediated protection against heterologous lethal influenza virus infection.

Int Immunol. 2019 Feb 15;31(2):81-90.

Takahashi A, Sakaguchi H, Higuchi O, Suzuki T, Chiji H.
Intestinal absorption of black chokeberry cyanidin 3-glycosides is promoted by capsaicin and capsiate in a rat ligated small intestinal loop model.

Food Chem. 2019 Mar; 277:323-326.

Koga M, Kuramochi M, Karim MR, Izawa T, Kuwamura M, Yamate J.
Immunohistochemical characterization of myofibroblasts appearing in isoproterenol-induced rat myocardial fibrosis.

J Vet Med Sci. 2019 Jan 25;81(1):127-133.

Niwa M, Ishii T, Ono K, Kuriyama S, Nakai N, Hosaka S, Mayumi T, Yasuda Y, Yamakawa T.
Evaluating exposure using confidence intervals: implication in tiered quantitation of metabolites for safety risks.

Bioanalysis. 2018 Oct;10(19):1553-1556.

Konishi S, Kotera T, Koga M, Ueda M.
Spontaneous hypertrophic cardiomyopathy in a cynomolgus macaque (Macaca fascicularis).

J Toxicol Pathol. 2018 Jan;31(1):49-54.

Masuta Y, Yamamoto T, Natsume-Kitatani Y, Kanuma T, Moriishi E, Kobiyama K, Mizuguchi K, Yasutomi Y, Ishii KJ.
An Antigen-Free, Plasmacytoid Dendritic Cell-Targeting Immunotherapy To Bolster Memory CD8(+) T Cells in Nonhuman Primates.

J Immunol. 2018 Feb 5. pii: ji1701183.

Gnerre C, Segrestaa J, Seeland S, Äänismaa P, Pfeifer T, Delahaye S, de Kanter R, Ichikawa T, Yamada T, Treiber A.
The metabolism and drug-drug interaction potential of the selective prostacyclin receptor agonist selexipag.

Xenobiotica. 2017 Aug 30:1-16.

Koseki N, Ashizawa H, Ishii T, Uchimura T, Ono K, Kuriyama S, Toda A, Soejima K, Nakai N, Nishimura N, Mayumi T, Yasuda Y, Yamakawa T, Niwa M.
Giving consideration to scientific validation in Japanese drug application by Japan Bioanalysis Forum discussion group.

Bioanalysis. 2017 Jul;9(13):963-968.

Takasuna K, Asakura K, Araki S, Ando H, Kazusa K, Kitaguchi T, Kunimatsu T, Suzuki S, Miyamoto N.
Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative.

J Pharmacol Toxicol Methods. 2017 Jan - Feb; 83:42-54.

Ando H, Yoshinaga T, Yamamoto W, Asakura K, Uda T, Taniguchi T, Ojima A, Shinkyo R, Kikuchi K, Osada T, Hayashi S, Kasai C, Miyamoto N, Tashibu H, Yamazaki D, Sugiyama A, Kanda Y, Sawada K, Sekino Y.
A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived

J Pharmacol Toxicol Methods. 2017 Mar - Apr;84: 111-127.

Kawasaki Y, Oda H, Ito J, Niwa A, Tanaka T, Hijikata A, Seki R, Nagahashi A, Osawa M, Asaka I, Watanabe A, Nishimata S, Shirai T, Kawashima H, Ohara O, Nakahata T, Nishikomori R, Heike T, Saito MK.
Identification of a High-Frequency Somatic NLRC4 Mutation as a Cause of Autoinflammation by Pluripotent Cell-Based Phenotype Dissection.

Arthritis Rheumatol. 2017 Feb;69(2):447-459.

Yamamoto W, Asakura K, Ando H, Taniguchi T, Ojima A, Uda T, Osada T, Hayashi S, Kasai C, Miyamoto N, Tashibu H, Yoshinaga T, Yamazaki D, Sugiyama A, Kanda Y, Sawada K, Sekino Y.
Electrophysiological Characteristics of Human iPSC-Derived Cardiomyocytes for the Assessment of Drug-Induced Proarrhythmic Potential.

PLoS One. 2016 Dec 6;11(12): e0167348.

Ohtera A, Miyamae Y, Yoshida K, Maejima K, Akita T, Kakizuka A, Irie K, Masuda S, Kambe T, Nagao M.
Identification of a New Type of Covalent PPARγ Agonist using a Ligand-Linking Strategy.

ACS Chem Biol. 2015 Dec 18;10(12):2794-804.

Himeno Y, Asakura K, Cha CY, Memida H, Powell T, Amano A, Noma A. A human ventricular myocyte model with a refined representation of excitation-contraction coupling.

Biophys J. 2015 Jul 21;109(2):415-27.

Asakura K, Hayashi S, Ojima A, Taniguchi T, Miyamoto N, Nakamori C, Nagasawa C, Kitamura T, Osada T, Honda Y, Kasai C, Ando H, Kanda Y, Sekino Y, Sawada K.
Improvement of acquisition and analysis methods in multi-electrode array experiments with iPS cell-derived cardiomyocytes.

J Pharmacol Toxicol Methods. 2015 Sep-Oct; 75:17-26.

Asakura K, Cha CY, Yamaoka H, Horikawa Y, Memida H, Powell T, Amano A, Noma A.
EAD and DAD mechanisms analyzed by developing a new human ventricular cell model.

Prog Biophys Mol Biol. 2014 Sep;116(1):11-24.

Kaneko K, Umehara M, Homan T, Okamoto K, Oka M, Oyama T.
The analgesic effect of tramadol in animal models of neuropathic pain and fibromyalgia.

Neurosci Lett. 2014 Mar 6; 562:28-33.

Oka M, Hirouchi M, Tamura M, Sugahara S, Oyama T. Acamprosate {monocalcium bis(3-acetamidopropane-1-sulfonate)} reduces ethanol-drinking behavior in rats and glutamate-induced toxicity in ethanol-exposed primary rat cortical neuronal cultures.

Eur J Pharmacol. 2013 Oct 15;718(1-3):323-31.

Nagata S, Takagaki K, Wada T.
Improved method for the solid-phase synthesis of oligoribonucleotide 5'-triphosphates.

Chem Pharm Bull (Tokyo). 2012;60(9):1212-5.

Minami T, Kosugi K, Suganuma I, Yamanaka K, Kusuki I, Oyama T, Kitawaki J.
Antiproliferative and apoptotic effects of norethisterone on endometriotic stromal cells in vitro.

Eur J Obstet Gynecol Reprod Biol. 2013 Jan;166(1):76-80.

Inoue N, Ito S, Nogawa M, Tajima K, Kyoi T.
Etodolac blocks the allyl isothiocyanate-induced response in mouse sensory neurons by selective TRPA1 activation.

Pharmacology. 2012;90(1-2):47-54.

Murakami K, Inoue N, Fuchikami C, Tajima K, Hashino A, Fukui H, Noda K, Oka M.
Blockade of voltage-gated calcium channel Cav1.2 and α1-adrenoceptors increases vertebral artery blood flow induced by the antivertigo agent difenidol.

Eur J Pharmacol. 2012 Aug 15;689(1-3):165-71.

Ito S, Tajima K, Nogawa M, Inoue N, Kyoi T, Takahashi Y, Sasagawa T, Nakamura A, Kotera T, Ueda M, Yamashita Y, Banno K.
Etodolac, a cyclooxygenase-2 inhibitor, attenuates paclitaxel-induced peripheral neuropathy in a mouse model of mechanical allodynia.

J Pharmacol Exp Ther. 2012 Jul;342(1):53-60.