著者

塚原 克平

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集

巻号頁・発行日

vol.94, pp.1-S07-3, 2021

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<p>Eritoran (E5564) is Eisai's in-house discovered and developed investigational TLR4 (Toll-Like Receptor 4) antagonist created with natural product organic synthesis technology. It is a structural analogue of Lipid A, which is an activator of endotoxins of bacteria. It has been previously observed to be safe in 14 clinical studies including a large Phase 3 randomized trial in severe sepsis. We are participating in the international network REMAP-CAP-COVID (Randomized, Embedded, Multi-factorial, Adaptive Platform-Community Acquired Pneumonia COVID) which aims for novel coronavirus medicine development through drug repurposing, and began an international collaborative clinical trial in October 2020 which is designated for confirmed novel coronavirus patients who are hospitalized and are in a progressing disease state. It is hoped that through suppressing the most upstream TLR4 activity which controls production of multiple cytokines, the cytokine storm in patients can be suppressed and pneumonia can thus be prevented from becoming severe.</p>

著者

Tamiko Suzuki-Nishimura Masayoshi Baba Shiori Otani Arisa Yamamoto Yasushi Kodama

出版者

Japanese Pharmacological Society

雑誌

日本薬理学会年会要旨集 (ISSN:24354953)

巻号頁・発行日

pp.PO3-4-11, 2018 (Released:2020-09-10)

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The manic depression drug lithium carbonate has many mechanisms of action. As one of these mechanisms is the inhibition of amine release from the end of synapses, we examined the effects of lithium carbonate on the IgE-independent histamine release from rat peritoneal mast cells. In the presence of 0.3 mM CaCl2, at concentrations from 0.3 to 3.0 mM, lithium carbonate inhibited the histamine release induced by bradykinin (BK) (10 μM), substance P (SP) (10 μM) or compound 48/80 (48/80) (1 μg/mL). The histamine release induced by 1 μg/mL of 48/80 was inhibited by lithium carbonate, but that by 5 μg/ml of 48/80 was not. The IgE independent activator GlcNAc-specific Datura stramonium agglutinin (DSA) releases histamine from rat mast cells similar with 48/80, and lithium carbonate also inhibited the histamine release induced by DSA at 100 μg/mL. BK, SP and 48/80 are well-known activators against MRGPR. Mouse MrgprB2 and human MRGPRX2 on mast cells are possible targets of the pseudo-allergic drug reactions involving mast cell activation. Rat peritoneal mast cells have similar MRGPR calcium-dependent and calcium-independent pathways for mast cell activation. Inhibition of BK- or SP-induced histamine release by lithium carbonate did not recover after increasing the extracellular calcium concentration, suggesting that MRGPR in rat mast cells may be a calcium-independent, G-protein dependent receptor. The effects of lithium carbonate suggested that lithium carbonate inhibited downstream of the common signal transduction pathway, following MRGPR activation induced by BK, SP, 48/80 or DSA. The clinical dose of lithium carbonate is from 0.5 to 1 mM, and addiction occurs from 1.8 to 2.5 mM. The inhibitory effects of lithium carbonate on the IgE-independent histamine release were observed at both the clinical and addictive doses in humans, suggesting that lithium carbonate similarly inhibits both histamine release from mast cells and brain amine release from synapses.

著者

Chie Sakanaka Ryoko Ihara Akiko Kishi Kenji Kirihara Gaku Oguri Mihoko Shibuya Kazushi Suzuki Keiko Ueda Yumi Umeda-Kameyama Mitsutaka Yakabe Tomohiro Haga Hidenori Yamasue

出版者

Japanese Pharmacological Society

雑誌

日本薬理学会年会要旨集 (ISSN:24354953)

巻号頁・発行日

pp.OR6-3, 2018 (Released:2020-09-10)

被引用文献数

3 4

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Background:Autism spectrum disorder (ASD) is a neurodevelopmental disorder, mainly exhibit problems in social communication/interaction behaviors. ASD is shown to affect one out of 100 individuals, however, the cause and the established treatments on the core symptoms of ASD are unavailable. Recently, peptide hormone Oxytocin showed some promises in treating ASD core symptoms, and various clinical studies are currently underway. The objective of this study is to evaluate the safety and pharmacokinetics of new formulation of intra-nasal Oxytocin in healthy Japanese male.Methods:In this double-blind, randomized, placebo-controlled Phase1 study, 5 cohorts of eight subjects received a single dose of intranasal TTA-121 at dose levels of 5, 10, 30, 100 and 200 U/ml or placebo and 3 cohorts of eight subjects received 30, 100 and 200 U/ml or placebo at repeated doses for 9 days. Safety assessments were conducted throughout the study.Results:Regarding safety, no serious adverse events were reported and no clinically significant findings were observed throughout the study. A linear relationship between plasma concentration of Oxytocin and administered dose of TTA-121 (5 to 200 U/ml) was observed. There was no drug accumulation after multiple doses of intra-nasal Oxytocin.Conclusions:TTA-121 was well tolerated and safe in Japanese healthy male subjects after administration of multiple doses up to 200U/ml, BID for 9 days.Trial Registration:UMIN000025922

著者

Chan Melissa V Warner Timothy D Barwari Temo Huffman Daniela Armstrong Paul C Santer Peter Kiechl Stefan Willeit Johann Mayr Manuel Johnson Andrew D

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集

巻号頁・発行日

vol.2018, pp.OR25-2, 2018

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<p><u>Background</u></p><p>Cardiovascular disease (CVD), including myocardial infarction (MI) and stroke, is the largest cause of morbidity and mortality worldwide. CVD is intrinsically linked to hemostasis and thrombosis and, therefore, platelet reactivity. As such, secondary prevention of CVD usually includes inhibitors of platelet function. Though the majority of CVD patients are over the age of 65, large healthy population studies of platelet reactivity have been performed in younger (<40) volunteers. The Bruneck Study is unique in that all participants are over the age of 65. Therefore, the aim of this study was to phenotype platelet reactivity in this elderly population.</p><p><u>Methods</u></p><p>Fasting blood was taken from 338 people into citrate (0.105M) anti-coagulant and platelet rich (PRP) and poor (PPP) plasma was obtained by centrifugation. All experiments were performed within 2 hours of blood draw. Traditional light transmission aggregometry (LTA) in response to arachidonic acid (AA), ADP, collagen, TRAP-6 amide and U46619 was performed. In addition, platelet aggregometry was also assessed using the Optimul plate-based method in response to AA (0.3-1.5mM), ADP (1-30µM), collagen (0.4-30µg/ml), epinephrine (0.6-10µM), ristocetin (0.1-1.5mg/ml), TRAP-6 (0.1-25µM) and U46619 (0.01-10µM). % aggregation was calculated and data were analysed using R with the nlpr package and GraphPad Prism. Data is reported as mean±sem.</p><p><u>Results</u></p><p>The cohort was evenly split between sex (49% female) with a mean age of 76.1±7.1 years. There was a low incidence of MI (4.7%), stoke (6.5%) and diabetes (6.2%). Concentration-response curves for Optimul aggregometry were generated and final % aggregation was compared to LTA (LTA vs Optimul, respectively): AA 1mM (29±2% vs 68±2%), ADP 5µM (54±1% vs 77±1%), ADP 20µM (59±1% vs 80±1%), collagen 0.4µg/ml (34±1% vs 76±1.2%), 4µg/ml (59±1% vs 81±1%), 10µg/ml (58±1% vs 80±1%), TRAP-6 25µM (62±1% vs 87±1%), U46619 10µM (63±1% vs 84±1%).</p><p><u>Conclusions</u></p><p>This is the first extensive platelet reactivity using multiple concentrations of a broad range of agonists in a large, healthy, elderly population. Subgroup analyses will allow us to determine whether there are any associations with platelet reactivity, age, and cardiovascular disease.</p>

著者

進藤 軌久 豊柴 博義

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集

巻号頁・発行日

vol.94, pp.1-S07-4, 2021

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<p>Although months have passed since WHO declared COVID-19 a global pandemic, only a limited number of clinically effective drugs are available, and the development of drugs to treat COVID-19 has become an urgent issue worldwide. The pace of new research on COVID-19 is extremely high and it is impossible to read every report. In order to tackle these problems, we leveraged our artificial intelligence (AI) system, Concept Encoder, to accelerate the process of drug repositioning. The Concept Encoder is a patented AI system based on natural language processing technology and by deep learning papers on COVID-19, the system identified a large group of genes implicated in COVID-19 pathogenesis. The AI system then generated a molecular linkage map for COVID-19, connecting the genes by deep learning the molecular relationship. By thoroughly reviewing the resulting map and list of the genes with rankings, we found potential key players for disease progression and existing drugs that might improve COVID-19 survival. Here, we focus on potential targets and discuss the perspective of our approach.</p>

著者

木村 温英

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集

巻号頁・発行日

vol.93, pp.3-S28-4, 2020

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<p>The muscarinic M₁ receptor (M₁R) is a promising target for treating cognitive impairment associated with cholinergic deficits. We found that cooperativity (α-value) was key to lowering the risk of diarrhea by M₁R positive allosteric modulators (M₁ PAMs), and discovered a low α-value M₁ PAM, TAK-071 with α-value of 199 and inflection point (IP) of 2.7 nM. T-662, a reference M₁ PAM with high α-value of 1786 and IP of 0.62 nM, but not TAK-071, augmented isolated ileum motility. TAK-071 and T-662 improved scopolamine-induced cognitive deficits in rats at 0.3 and 0.1 mg/kg, respectively, and induced diarrhea at 10 mg/kg and 0.1 mg/kg, respectively, in rats. TAK-071 might have a wider margin between cognitive improvement and diarrhea induction than T-662. M₁R activation increases neural excitability via membrane depolarization, reduced afterhyperpolarization, and generation of afterdepolarization in prefrontal cortical pyramidal neurons. T-662 induced all three processes, whereas TAK-071 selectively induced afterdepolarization. Combining sub-effective doses of TAK-071, but not T-662, with an acetylcholinesterase inhibitor, significantly ameliorated scopolamine-induced cognitive deficits in rats. TAK-071 may therefore provide new therapeutic opportunities for cognitive dysfunction with minimum cholinergic side effects.</p>

著者

Julio C Almanza-Perez Beatriz Mora-Ramiro Wendoline Rosiles-Alanis Francisco J Alarcon-Aguilar Jose L Ventura-Gallegos Luis E Gomez-Quiroz Alejandro Zentlla-Dehesa

出版者

Japanese Pharmacological Society

雑誌

日本薬理学会年会要旨集 (ISSN:24354953)

巻号頁・発行日

pp.PO3-10-20, 2018 (Released:2020-09-10)

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BACKGROUNDThe chronic inflammatory process is a critical characteristic in several diseases. This condition has an important impact on the quality life of patients, as well as on their economic and social state. Patients in this condition use several anti-inflammatory agents, which are classified according to their chemical nature as steroidal (SAIDs) and non-steroidal (NSAIDs). However, It has been reported that its clinical use can generate dangerous adverse effects. For this motive, people use medicinal plants as an alternative of treatment. Several plants have been traditionally used as anti-inflammatory agents worldwide. One example is Psacalium decompositum, which has been reported with anti-inflammatory and antidiabetic effects. In chemical studies, sesquiterpenic compounds have been isolated, being the cacalol the main compound, which is considered the responsible principle of the anti-inflammatory effect of this plant. However, the action mechanisms involved in the anti-inflammatory action of cacalol have not yet been explored.The aim of this investigation was to establish whether the anti-inflammatory action of cacalol involves the Nf-kB pathway, using an in vitro model.METHODSRAW 264.7 macrophages were cultured and pre-stimulated with LPS. Two hours after, the cells were treated with cacalol. The concentration and relative expression of cytokines were quantified by RT-PCR. The cytokines studied were TNF, IL-6, IL-1b and IL-10. The pohosphorylated subunit p65 of Nf-kB and its nuclear translocation were measured by EMSA.RESULTSThe mRNA expression of TNF, IL-6 and IL-1b were significantly decreased in the macrophages due to cacalol. The protein concentrations in the culture of the cytokines also decreased. No changes were detected in the mRNA expression and concentration of IL-10. The cacalol decreased the concentration of the phosphorylated p65 subunit as did the translocation of Nf-kB to the nucleus.CONCLUSIONSCacalol suppressed the concentrations of pro-inflammatory cytokines without affecting the anti-inflammatory cytokines. This could be associated with the inhibition of the Nf-kB pathway, since the levels of the phosphorylated p65 subunit were reduced. It is important to continue with the study of the factors involved in the regulation of said inhibition, as well as of other transcription factors involved in the anti-inflammatory action of cacalol.

著者

竹田 誠

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集

巻号頁・発行日

vol.93, pp.2-ES-1, 2020

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<p>In December 2019 a pneumonia outbreak by the novel coronavirus, SARS-CoV-2, occurred in Wuhan City, China. The disease was named as COVID-19. Information on the SARS-CoV-2 genomic sequence was first released on 10 January 2020. We urgently started development of genetic diagnostic methods for SARS-CoV-2. On 14 January, soon after receiving the prototype designed primers, we have received the first clinical specimens suspected for COVID-19. We urgently started assessment of the primers and the laboratory diagnosis testing for SARS-CoV-2 in a parallel way. After the nightlong assessment/testing, the first COVID19 case in Japan was confirmed. The patient was a returnee from Wuhan. Until 22 January, we have established the nested RT-PCR diagnostic method/protocol for SARS-CoV-2, and urgently distributed the primer set/protocol to ~ 80 prefectural public health laboratories (PHLs) nationwide, because the Chun Jie holidays starts in China on 24 January and many Chinese tourists visit Japan. As we concerned, sporadic COVID-19 cases with an epidemiological linkage to Wuhan have detected in Tokyo, Aichi, Nara, Hokkaido, and Osaka prefectures after 24 January. Following the nested RT-PCR method, we have established the real-time RT-PCR diagnostic methods for SARS-CoV-2, and distributed the primer/probe set to ~ 80 PHLs on 30–31 January. However, the laboratory workload increased dramatically, because Japan has started to accept 829 returnees (15 were shown to be SARS-CoV-2-positive later) from Wuhan using government chartered flights on 29 January and screen ~3,500 passengers and crew (&gt;600 were shown to be SARS-CoV-2-positive later) on a cruise ship quarantined in Yokohama for SARS-CoV-2. About one month and a half has passed, a significant number of COVID-19 cases via unknown infection route are currently detected in many prefectures in Japan (total 239 cases, as of 2 March 2020).</p>

著者

北岡 志保

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集

巻号頁・発行日

vol.93, pp.3-YAL-1, 2020

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<p>既存の抗うつ薬の多くはモノアミンなどの神経伝達物質の作用を調節するが、一部の患者で十分な効果が得られないため、新たな創薬標的の開発が期待されている。近年、うつ病などの精神疾患患者の血中で炎症関連物質が高値を示すことから、炎症仮説が注目されるようになった。しかし、うつ病発症と炎症との因果関係は不明であった。社会や環境から受けるストレスは精神疾患のリスク因子であることから、動物に繰り返しストレスを与える反復社会挫折ストレスがうつ病の動物モデルとして使用されている。反復ストレスは情動変容を誘導し、同時に特定の脳領域のミクログリアを活性化することを見出した。この研究に端を発し、反復ストレスによる情動変容の誘導における脳内炎症の関与とその分子実体を明らかにした。また、脳内炎症の関与がすでに知られている神経変性疾患で、炎症を標的とした創薬基盤を開発した。本講演では、精神・神経疾患の病態形成に関与する脳内炎症について最新の知見を紹介したい。</p>