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

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.