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      Elucidation of Inverse Agonist Activity of Bilastine

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          Abstract

          H 1-antihistamines antagonize histamine and prevent it from binding to the histamine H 1 receptor (H1R). Some of them also act as inverse agonists, which are more potent than pure antagonists because they suppress the constitutive H1R activity. Bilastine is a non-sedative antihistamine which is one of the most satisfy the requirements for oral antihistamines. However, there is no information to show the inverse agonist activity of bilastine including inositol phosphates accumulation, and its inverse agonist activity is yet to be elucidated. Here we evaluated whether bilastine has inverse agonist activity or not. Intracellular calcium concentration was measured using Fluo-8. Inositol phosphates accumulation was assayed using [ 3H]myo-inositol. The H1R mRNA level was measured using real-time RT-PCR. At rest, Ca 2+ oscillation was observed, indicating that H1R has intrinsic activity. Bilastine attenuated this fluorescence oscillation. Bilastine suppressed the increase in IPs formation in a dose-dependent manner and it was about 80% of the control level at the dose of 3 μM. Bilastine also suppressed histamine-induced increase in IPs formation to the control level. Furthermore, bilastine suppressed basal H1R gene expression in a dose-dependent manner. Data suggest that bilastine is an inverse agonist. Preseasonal prophylactic administration with bilastine could down-regulate basal H1R gene expression in the nasal mucosa and ameliorate the nasal symptoms during the peak pollen period.

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          Structure of the human histamine H1 receptor complex with doxepin.

          The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp 428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys 191(5.39) and/or Lys 179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R. ©2011 Macmillan Publishers Limited. All rights reserved
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            Japanese guidelines for allergic rhinitis 2017

            Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.
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              H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects.

              This review addresses novel concepts of histamine H1-receptor function and attempts to relate them to the anti-inflammatory effects of H1-antihistamines. Furthermore, the molecular mechanisms underlying the cardiotoxic effects of H1-antihistamines are discussed. H1-receptors are G-protein-coupled-receptors (GPCRs), the inactive and active conformations of which coexist in equilibrium. The degree receptor activation in the absence of histamine is its 'constitutive activity'. In this two-state model, histamine acts as an agonist by combining with and stabilizing the activated conformation of the H1-receptor to shift the equilibrium towards the activated state. Drugs classified previously as antagonists act as either inverse agonists or neutral antagonists. Inverse agonists combine with and stabilize the inactive conformation of the receptor to shift the equilibrium towards the inactive state. Thus, they may down-regulate constitutive receptor activity, even in the absence of histamine. Neutral antagonists combine equally with both conformations of the receptor, do not affect basal receptor activity but do interfere with agonist binding. All H1-antihistamines examined to date are inverse agonists. As the term 'H1-receptor antagonists' is obviously erroneous, we suggest that it be replaced by 'H1-antihistamines'. The observations that H1-receptors modulate NF-kappaB activation and that there are complex interactions between GPCRs, has allowed us to postulate receptor dependent-mechanisms for some anti-inflammatory effects of H1-antihistamines, e.g. inhibition of ICAM-1 expression and the effects of bradykinin. Finally, the finding that blockade of HERG1 K+ channels is the mechanism by which some H1-antihistamines may cause cardiac arrhythmias has allowed the development of preclinical tests to predict such activity.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                08 June 2020
                June 2020
                : 12
                : 6
                : 525
                Affiliations
                [1 ]Laboratory of Pharmacology Faculty of Pharmacy Osaka Ohtani University, Osaka 584-8540, Japan; u4115067@ 123456osaka-ohtani.ac.jp (M.T.); u4115080@ 123456osaka-ohtani.ac.jp (T.N.)
                [2 ]Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan; c401741003@ 123456tokushima-u.ac.jp
                [3 ]TIMELAPS VISION INC., Saitama 353-0004, Japan; sadakata@ 123456timelapsevision.com
                [4 ]Department of Otolaryngology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan; c201756004@ 123456tokushima-u.ac.jp (S.K.); ykitamura@ 123456tokushima-u.ac.jp (Y.K.); takeda@ 123456tokushima-u.ac.jp (N.T.); hfukui@ 123456tokushima-u.ac.jp (H.F.)
                [5 ]Medical Corporation Kinshukai, Osaka 558-0011, Japan; yabumoto.masami@ 123456kinshukai.or.jp
                Author notes
                [* ]Correspondence: mizuguhiro@ 123456osaka-ohtani.ac.jp ; Tel.: +81-721-24-9462
                Article
                pharmaceutics-12-00525
                10.3390/pharmaceutics12060525
                7355758
                32521742
                ff00c2cb-f4a3-4c70-a9be-7591e7826f2c
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 May 2020
                : 05 June 2020
                Categories
                Article

                h1-antihistamines,histamine h1 receptor gene expression,inositol phosphates accumulation,inverse agonist,time-laps ca2+ imaging

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