The Experts below are selected from a list of 10992 Experts worldwide ranked by ideXlab platform
Kazuhiko Yanai - One of the best experts on this subject based on the ideXlab platform.
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brain Histamine H1 Receptor occupancy measured by pet after oral administration of levocetirizine a non sedating antiHistamine
Expert Opinion on Drug Safety, 2015Co-Authors: Kotaro Hiraoka, Manabu Tashiro, Marcus Maurer, Thomas Grobosch, Keiichi Oda, Jun Toyohara, Kenji Ishii, Kiichi Ishiwata, Kazuhiko YanaiAbstract:Objective: Histamine H1 Receptor (H1R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the Histaminergic neurons. We examined the brain H1R occupancy (H1RO) and the subjective sleepiness of levocetirizine, a new second-generation antiHistamine, comparing fexofenadine, another non-sedating antiHistamine, as a negative active control.Methods: Eight healthy volunteers underwent positron emission tomography (PET) imaging with [11C]doxepin, a PET tracer that specifically binds to H1Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H1ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale.Results: There was no significant difference between the mean brain H1RO after levocetirizine administration (8.1%; 95% CI: −9.8 to 26.0%) an...
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dose dependency of brain Histamine H1 Receptor occupancy following oral administration of cetirizine hydrochloride measured using pet with 11c doxepin
Human Psychopharmacology-clinical and Experimental, 2009Co-Authors: Manabu Tashiro, Motohisa Kato, M Miyake, Shoichi Watanuki, Yoshihito Funaki, Yoichi Ishikawa, Ren Iwata, Kazuhiko YanaiAbstract:Aims The strength of sedation due to antiHistamines can be evaluated using positron emission tomography (PET). The purpose of the present study is to measure Histamine H1 Receptor (H1R) occupancy following oral administration of cetirizine (10 and 20 mg) in order to examine dose dependency. Methods Fifteen healthy male volunteers (age range, 20–35 years) were divided into 3 subgroups and were studied following single oral administration of cetirizine at 10 mg (n = 5) and 20 mg (n = 5) or hydroxyzine at 30 mg (n = 5) using PET with 11C-doxepin. Each subject was scanned also following the administration of placebo. Binding potential and H1RO values were calculated in the prefrontal and anterior cingulate cortices. Subjective sleepiness was also measured, and the correlation to H1RO was examined for each antiHistamine. Results The averaged H1ROs of cetirizine 10 mg, 20 mg, and hydroxyzine 30 mg in the prefrontal and cingulate cortices was 12.6%, 25.2%, and 67.6%, respectively. The H1RO of hydroxyzine 30 mg correlated well with subjective sleepiness (p < 0.001); however, those of cetirizine 10 and 20 mg showed no correlation with subjective sleepiness. Conclusion It was demonstrated that the brain penetration of orally administered cetirizine was dose-dependent. Cetirizine 10 mg, with its low H1RO and thus minimal sedation, could be more safely used than cetirizine 20 mg for the treatment of various allergic disorders. Copyright © 2009 John Wiley & Sons, Ltd.
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brain Histamine H1 Receptor occupancy of orally administered antiHistamines bepotastine and diphenhydramine measured by pet with 11c doxepin
British Journal of Clinical Pharmacology, 2008Co-Authors: Manabu Tashiro, Motohisa Kato, M Miyake, Shoichi Watanuki, Yoshihito Funaki, Yoichi Ishikawa, Ren Iwata, Xudong Duan, Masatoshi Itoh, Kazuhiko YanaiAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • ‘Bepotastine besilate’ is a novel second-generation antiHistamine developed in Japan and its antiallergic effects have already been demonstrated by various studies. • However, only a few clinical studies regarding its sedative property are available. • In addition, Histamine H1 Receptor occupancy (H1RO) of this new antiHistamine has never been measured by positron emission tomography (PET). WHAT THIS STUDY ADDS • This paper provides the first measurement result of cerebral H1RO of bepotastine besilate (approximately 15%) as determined by PET. • This result is in accordance with the clinical classification of bepotastine as a second-generation antiHistamine. • In addition, the relationship between subjective sleepiness and cerebral H1RO of this second-generation antiHistamine is demonstrated for the first time using a placebo-controlled crossover study design. AIMS AntiHistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring Histamine H1 Receptor occupancy (H1RO) in the brain using positron emission tomography (PET). The aim was to measure H1RO of bepotastine, a new second-generation antiHistamine, and to compare it with that of diphenhydramine. METHODS Eight healthy male volunteers (mean age ± SD 24.4 ± 3.3 years) were studied after single oral administration of bepotastine (10 mg), diphenhydramine (30 mg) or placebo, by PET imaging with 11C-doxepin in a crossover study design. Binding potential ratio and H1ROs were calculated using placebo data and were compared between bepotastine and diphenhydramine in the anterior and posterior cingulate gyri (ACG and PCG, respectively), superior and inferior frontal cortices (SFC and IFC, respectively), orbitofrontal cortex (OFC), insular cortex (IC), lateral and medial temporal cortices (LTC and MTC, respectively), parietal cortex (PC), occipital cortex (OC) and sensorimotor cortex (SMC). Plasma concentration of each antiHistamine was measured, and its correlation to H1RO was examined. RESULTS H1RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H1ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H1ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001). CONCLUSION Oral bepotastine (10 mg), with its relatively low H1RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antiHistamine in the treatment of various allergic disorders.
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Histamine H1 Receptor occupancy in human brains after single oral doses of Histamine H1 antagonists measured by positron emission tomography
British Journal of Pharmacology, 1995Co-Authors: Kazuhiko Yanai, Ren Iwata, Takehiko Watanabe, Jong Hoon Ryu, Tatsuo Ido, Yoneichi Sawai, Kazumi Ito, Masatoshi ItohAbstract:1. Histamine H1 Receptor occupancy in the human brain was measured in 20 healthy young men by positron emission tomography (PET) using [11C]-doxepin. 2. (+)-Chlorpheniramine, a selective and classical antiHistamine, occupied 76.8 +/- 4.2% of the averaged values of available Histamine H1 Receptors in the frontal cortex after its administration in a single oral dose of 2 mg. Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [11C]-doxepin to H1 Receptors (H1 Receptor occupancy: 98.2 +/- 1.2%). 3. Terfenadine, a nonsedative antiHistamine, occupied 17.2 +/- 14.2% of the available H1 Receptors in the human frontal cortex after its administration in a single oral dose of 60 mg. 4. There was no correlation between H1 Receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject. 5. PET data on human brain were essentially compatible with those on H1 Receptor occupancy in guinea-pig brain determined by in vivo binding techniques, although for the same H1 Receptor occupancy the dose was less in human subjects than in guinea-pigs. 6. The PET studies demonstrated the usefulness of measuring H1 Receptor occupancy with classical and second-generation antiHistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively.
Ekrem Dere - One of the best experts on this subject based on the ideXlab platform.
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Histamine H1 Receptor knockout mice exhibit impaired spatial memory in the eight arm radial maze
British Journal of Pharmacology, 2009Co-Authors: Armin Zlomuzica, Adolfo G. Sadile, Joseph P Huston, L A Ruocco, Ekrem DereAbstract:Background and purpose: In the mammalian brain, Histaminergic neurotransmission is mediated by the postsynaptic Histamine H1 and H2 Receptors and the presynaptic H3 autoReceptor, which also acts as a heteroReceptor. The H1 Receptor has been implicated in spatial learning and memory formation. However, pharmacological and lesion studies have revealed conflicting results. To examine the involvement of Histamine H1 Receptor in spatial reference and working memory formation, H1 Receptor knockout mice (KO) were tested in the eight-arm radial maze. Previously, we found that the H1 Receptor-KO mice showed reduced emotionality when confronted with spatial novelty. As it is known that emotions can have an impact on spatial learning and memory performance, we also evaluated H1 Receptor-KO mice in terms of emotional behaviour in the light–dark box. Experimental approach: Mice lacking the H1 Receptor and wild-type mice (WT) were tested for spatial reference and working memory in an eight-arm radial maze with three arms baited and one trial per day. Emotional behaviour was measured using the light–dark test. Key results: The H1 Receptor-KO mice showed impaired spatial reference and working memory in the radial maze task. No significant differences between H1 Receptor-KO and WT mice were observed in the light–dark test. Conclusions and implications: The spatial memory deficits of the H1 Receptor-KO mice might be due to the reported changes in cholinergic neurochemical parameters in the frontal cortex and the CA1 subregion of the hippocampus, to impaired synaptic plasticity in the hippocampus, and/or to a dysfunctional brain reward/reinforcement system.
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episodic like and procedural memory impairments in Histamine H1 Receptor knockout mice coincide with changes in acetylcholine esterase activity in the hippocampus and dopamine turnover in the cerebellum
Neuroscience, 2008Co-Authors: Ekrem Dere, Armin Zlomuzica, Davide Viggiano, Lucia A. Ruocco, Adolfo G. Sadile, Joseph P Huston, T. Watanabe, M A De SouzasilvaAbstract:Abstract We investigated episodic-like (ELM) and procedural memory (PM) in Histamine H1 Receptor knockout (H1R-KO) mice. In order to relate possible behavioral deficits to neurobiological changes, we examined H1R-KO and wild-type (WT) mice in terms of acetylcholine esterase (AChE) activity in subregions of the hippocampus and AChE and tyrosine hydroxylase (TH) expression in the striatum. Furthermore, we analyzed acetylcholine (ACh), 5-HT and dopamine (DA) levels, including metabolites, in the cerebellum of H1R-KO and WT mice. The homozygous H1R-KO mice showed impaired ELM as compared with the heterozygous H1R-KO and WT mice. The performance of homozygous H1R-KO mice in the ELM task was primarily driven by familiarity-based memory processes. While the homozygous H1R-KO mice performed similar to the heterozygous H1R-KO and WT mice during the acquisition of a PM, as measured with an accelerating rotarod, after a retention interval of 7 days their performance was impaired relative to the heterozygous H1R-KO and WT mice. These findings suggest that, both, ELM and long-term PM are impaired in the homozygous H1R-KO mice. Neurochemical assays revealed that the H1R-KO mice had significantly lower levels of AChE activity in the dentate gyrus (DG) and CA1 subregions of the hippocampus as compared with the WT mice. The homozygous H1R-KO mice also displayed significantly reduced dihydroxyphenylacetic acid (DOPAC) levels and a reduced DOPAC/DA ratio in the cerebellum, suggesting that the DA turnover in the cerebellum is decelerated in homozygous H1R-KO mice. In conclusion, homozygous H1R-KO mice display severe long-term memory deficits in, both, ELM and PM, which coincide with changes in AChE activity in the hippocampus as well as DA turnover in the cerebellum. The importance of these findings for Alzheimer's (AD) and Parkinson's disease (PD) is discussed.
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episodic like and procedural memory impairments in Histamine H1 Receptor knockout mice coincide with changes in acetylcholine esterase activity in the hippocampus and dopamine turnover in the cerebellum
Neuroscience, 2008Co-Authors: Ekrem Dere, Armin Zlomuzica, Davide Viggiano, Adolfo G. Sadile, Joseph P Huston, T. Watanabe, L A Ruocco, M A De SouzasilvaAbstract:Abstract We investigated episodic-like (ELM) and procedural memory (PM) in Histamine H1 Receptor knockout (H1R-KO) mice. In order to relate possible behavioral deficits to neurobiological changes, we examined H1R-KO and wild-type (WT) mice in terms of acetylcholine esterase (AChE) activity in subregions of the hippocampus and AChE and tyrosine hydroxylase (TH) expression in the striatum. Furthermore, we analyzed acetylcholine (ACh), 5-HT and dopamine (DA) levels, including metabolites, in the cerebellum of H1R-KO and WT mice. The homozygous H1R-KO mice showed impaired ELM as compared with the heterozygous H1R-KO and WT mice. The performance of homozygous H1R-KO mice in the ELM task was primarily driven by familiarity-based memory processes. While the homozygous H1R-KO mice performed similar to the heterozygous H1R-KO and WT mice during the acquisition of a PM, as measured with an accelerating rotarod, after a retention interval of 7 days their performance was impaired relative to the heterozygous H1R-KO and WT mice. These findings suggest that, both, ELM and long-term PM are impaired in the homozygous H1R-KO mice. Neurochemical assays revealed that the H1R-KO mice had significantly lower levels of AChE activity in the dentate gyrus (DG) and CA1 subregions of the hippocampus as compared with the WT mice. The homozygous H1R-KO mice also displayed significantly reduced dihydroxyphenylacetic acid (DOPAC) levels and a reduced DOPAC/DA ratio in the cerebellum, suggesting that the DA turnover in the cerebellum is decelerated in homozygous H1R-KO mice. In conclusion, homozygous H1R-KO mice display severe long-term memory deficits in, both, ELM and PM, which coincide with changes in AChE activity in the hippocampus as well as DA turnover in the cerebellum. The importance of these findings for Alzheimer's (AD) and Parkinson's disease (PD) is discussed.
Chiaki Kamei - One of the best experts on this subject based on the ideXlab platform.
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effects of Histamine H1 Receptor antagonists on delayed spatial win shift task in rats
European Journal of Pharmacology, 2010Co-Authors: Akiko Okada, Akane Kato, Chiaki KameiAbstract:Abstract We investigated the effects of Histamine H1 Receptor antagonists in 3 different stages of spatial working memory in comparison with scopolamine. The effects of drugs were measured using an eight-arm radial maze with a delayed spatial win-shift task in rats. Drugs were injected 10 min before the training phase (timing 1), immediately after the training phase (timing 2), or 10 min before the test phase (timing 3). Intrahippocampal injection of pyrilamine and diphenhydramine resulted in significant effects on the number of correct choices and across-phase errors in all 3 timings. Scopolamine impaired the number of correct choices and across-phase errors in timing 1 and 3; however, no significant effect was observed in timing 2. These results indicate that pyrilamine and diphenhydramine impaired encoding, retention and retrieval processes of spatial working memory, whereas scopolamine did not impair the retention process.
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role of Histamine h4 Receptor in allergic conjunctivitis in mice
European Journal of Pharmacology, 2009Co-Authors: Yoshiyuki Nakano, Yasunori Kurata, Yoto Kagawa, Yuji Takahashi, Chiaki KameiAbstract:We investigated the character of Histamine H1 Receptor and H4 Receptor in allergic conjunctivitis. Histamine is the most important mediator in allergic conjunctivitis. We measured eye scratching behavior and allergic-like symptoms score, that is, hyperemia and edema in ICR mice, and examined which Receptors intimately involved in allergic conjunctivitis. Histamine caused a dose-dependent eye scratching behavior and allergic-like symptoms. Histamine H1 Receptor antagonist (levocabastine) and H4 Receptor antagonist (JNJ7777120) inhibited eye scratching behavior and Histamine H1 Receptor antagonist inhibited allergic-like symptoms induced by Histamine. Additionally, combination of levocabastine and JNJ7777120 caused more potent inhibition in allergic conjunctivitis. On the other hand, both selective Histamine H1 Receptor agonist (HTMT) and selective H4 Receptor agonist (4-methylHistamine) induced a dose-dependent eye scratching behavior and allergic-like symptoms. JNJ7777120 inhibited the effect of HTMT. However, levocabastine caused no inhibition on the response of 4-methylHistamine. H4 Receptor was closely related with allergic conjunctivitis. H4 Receptor antagonists may be effective in allergic conjunctivitis which showed no inhibition by Histamine H1 Receptor antagonists.
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Influences of Histamine H1 Receptor antagonists on maximal electroshock seizure in infant rats.
Biological & Pharmaceutical Bulletin, 2007Co-Authors: Takashi Ishikawa, Kenshi Takechi, Ashequr Rahman, Jun Ago, Naotaka Matsumoto, Aya Murakami, Chiaki KameiAbstract:The influences of Histamine H1 Receptor antagonists on maximal electroshock seizure were studied using infant rats. In this study, electroconvulsion was induced by stimulating rats using ear-clip electrodes, and the durations of electroencephalogram (EEG) seizure, tonic extensor (TE) seizure and clonic (CL) seizure induced by maximal electroshock were measured. Diphenhydramine, chlorpheniramine, cyproheptadine and ketotifen caused a dose-dependent and significant prolongation of both EEG seizure and TE seizure induced by maximal electroshock. On the other hand, epinastine and fexofenadine caused no such effects, even at a dose of 50 mg/kg. All drugs used in this study showed no significant effect on CL seizure induced by maximal electroshock. From these findings, it is suggested that epinastine and fexofenadine may cause no harmful influence on epilepsy, even when used in a little child.
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development of amygdaloid kindling in histidine decarboxylase deficient and Histamine H1 Receptor deficient mice
Epilepsia, 2004Co-Authors: Tadashi Hirai, Hiroshi Ohtsu, Takeshi Watanabe, Chihiro Okuma, Chie Harada, Mitsunobu Mio, Chiaki KameiAbstract:Summary: Purpose: This study attempted to clarify the role of Histamine or Histamine H1 Receptors in the development of amygdaloid kindling by using histidine decarboxylase (HDC)-deficient and Histamine H1 Receptor (H1R)-deficient mice. Methods: Under pentobarbital anesthesia, mice were fixed to a stereotaxic apparatus, and bipolar electrodes were implanted into the right amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. A bipolar electroencephalogram was recorded; bipolar stimulation of the amygdala was applied every day with a constant-current stimulator and continued until a generalized convulsion was obtained. Results: The development of amygdaloid kindling in HDC-deficient and H1R-deficient mice was significantly accelerated compared with that in their respective wild-type mice. In addition, the afterdischarge (AD) duration and generalized seizure duration in HDC-deficient and H1R-deficient mice were prolonged. Intraperitoneal injection of histidine resulted in an inhibition of amygdaloid kindled seizures in wild-type mice at doses that caused an increase in the Histamine contents of the brain. However, no significant effect was observed with histidine in H1R-deficient mice at the same dose. Conclusions: These findings suggest that Histaminergic mechanisms through H1 Receptors play a crucial role not only in amygdaloid kindled seizures but also in the development of amygdaloid kindling.
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Effects of second-generation Histamine H1 Receptor antagonists on the active avoidance response in rats.
Clinical and experimental pharmacology & physiology, 2003Co-Authors: Miyuki Nishiga, Yoko Fujii, Masako Konishi, Maria Alejandra Hossen, Chiaki KameiAbstract:Summary 1. The aim of the present study was to establish a new schedule of active avoidance response in rats to estimate the central effects of second-generation Histamine H1 Receptor antagonists. 2. With the new schedule, a rat was placed into a dark room. A sliding door was opened after a delay of 5 s and, unless the animal moved into the lit room, an electric shock was delivered for 3 s. With the conventional schedule, the sliding door was opened immediately after the rat was placed into the dark room. 3. Ketotifen, at a dose of 50 mg/kg, showed no significant effect on the retrieval of active avoidance response with the conventional schedule. However, with the new schedule, the drug caused significant inhibition of retrieval of the response, even at a dose of 10 mg/kg. 4. Epinastine showed no significant effect on retrieval of the active avoidance response, even at a dose of 50 mg/kg with the new schedule. 5. Cetirizine, at a dose of 50 mg/kg, caused a significant effect, indicating that cetirizine, at this dose, markedly inhibits memory retrieval. 6. Both olopatadine and loratadine had potent effects; at doses of 20 and 50 mg/kg, respectively, these agents showed significant inhibitory effects on retrieval of the response. 7. In conclusion, we have developed a new schedule of active avoidance response that can be used to estimate the central effects of second-generation Histamine H1 Receptor antagonists.
Rob Leurs - One of the best experts on this subject based on the ideXlab platform.
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exploring the effect of cyclization of Histamine H1 Receptor antagonists on ligand binding kinetics
ACS omega, 2021Co-Authors: Zhiyong Wang, Rob Leurs, Reggie Bosma, Henry F Vischer, Sebastiaan Kuhne, Jelle Van Den Bor, Wrej Garabitian, Maikel Wijtmans, Iwan J P De EschAbstract:There is an increasing interest in guiding hit optimization by considering the target binding kinetics of ligands. However, compared to conventional structure-activity relationships, structure-kinetics relationships have not been as thoroughly explored, even for well-studied archetypical drug targets such as the Histamine H1 Receptor (H1R), a member of the family A G-protein coupled Receptor. In this study, we show that the binding kinetics of H1R antagonists at the H1R is dependent on the cyclicity of both the aromatic head group and the amine moiety of H1R ligands, the chemotypes that are characteristic for the first-generation H1R antagonists. Fusing the two aromatic rings of H1R ligands into one tricyclic aromatic head group prolongs the H1R residence time for benchmark H1R ligands as well as for tailored synthetic analogues. The effect of constraining the aromatic rings and the basic amines is systematically explored, leading to a coherent series and detailed discussions of structure-kinetics relationships. This study shows that cyclicity has a pronounced effect on the binding kinetics.
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bret based β arrestin2 recruitment to the Histamine H1 Receptor for investigating antiHistamine binding kinetics
Pharmacological Research, 2016Co-Authors: Reggie Bosma, Rob Leurs, Ryo Moritani, Henry F VischerAbstract:Ligand residence time is thought to be a critical parameter for optimizing the in vivo efficacy of drug candidates. For the Histamine H1 Receptor (H1R) and other G protein-coupled Receptors, the kinetics of ligand binding are typically measured by low throughput radioligand binding experiments using homogenized cell membranes expressing the target Receptor. In this study, a real-time proximity assay between H1R and β-arrestin2 in living cells was established to investigate the dynamics of antiHistamine binding to the H1R. No Receptor reserve was found for the Histamine-induced recruitment of β-arrestin2 to the H1R and the transiently recruited β-arrestin2 therefore reflected occupancy of the Receptor by Histamine. AntiHistamines displayed similar kinetic signatures on antagonizing Histamine-induced β-arrestin2 recruitment as compared to displacing radioligand binding from the H1R. This homogeneous functional method unambiguously determined the fifty-fold difference in the dissociation rate constant between mepyramine and the long residence time antiHistamines levocetirizine and desloratadine.
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8r lisuride is a potent stereospecific Histamine H1 Receptor partial agonist
Molecular Pharmacology, 2004Co-Authors: Remko A. Bakker, Henk Timmerman, Dave M Weiner, T L Ter Laak, T Beuming, Obbe P Zuiderveld, M Edelbroek, Uli Hacksell, Mark R Brann, Rob LeursAbstract:The human Histamine H1 Receptor (H1R) is an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are known to potently antagonize the H1R, thereby producing some of their side effects. In contrast, the tolerability and potential therapeutic utility of H1R agonism is currently unclear. We have used a cell-based functional assay to evaluate known therapeutics and reference drugs for H1R agonist activity. Our initial functional screen identified three ergot-based compounds possessing heretofore-unknown H1R agonist activity. 8R-lisuride demonstrated potent agonist activity in various assays including Receptor selection and amplification technology, inositol phosphate accumulation, and activation of nuclear factor-κB with pEC50 values of 8.1, 7.9, and 7.9, respectively, and with varying degrees of efficacy. Based on these assays, 8R-lisuride is the most potent stereospecific partial agonist for the human H1R yet reported. Investigation of the residues involved in Histamine and lisuride binding, using H1R mutants and molecular modeling, have revealed that although these ligands are structurally different, the lisuride-binding pocket in the H1R closely corresponds to the Histamine-binding pocket. The discovery of a potent stereospecific partial H1R agonist provides a valuable tool to further characterize this important therapeutic target in vitro.
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Synthesis and Pharmacological Identification of Neutral Histamine H1-Receptor Antagonists
Journal of medicinal chemistry, 2003Co-Authors: Marinella Govoni, Remko A. Bakker, Henk Timmerman, Martine J. Smit, Ineke Van De Wetering, Wiro M.b.p. Menge, Sigurd Elz, Walter Schunack, Rob LeursAbstract:In the present study we searched for neutral antagonists for the human Histamine H1-Receptor (H1R) by screening newly synthesized ligands that are structurally related to H1R agonists for their affinity using radioligand displacement studies and by assessing their functional activity via performing a NF-κB driven reporter-gene assay that allows for the detection of both agonistic and inverse agonistic responses. Starting from the endogenous agonist for the H1R, Histamine, we synthesized and tested various analogues and ultimately identified several compounds with partial inverse agonistic properties and two neutral H1-Receptor antagonists, namely 2-[2-(4,4-diphenylbutyl)-1H-imidazol-4-yl]ethylamine (histabudifen, 18d) (pKi = 5.8, α = 0.02) and 2-[2-(5,5-diphenylpentyl)-1H-imidazol-4-yl]ethylamine (histapendifen, 18e) (pKi = 5.9, α = −0.09).
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Constitutive activity of the Histamine H1 Receptor reveals inverse agonism of Histamine H1 Receptor antagonists
European journal of pharmacology, 2000Co-Authors: Remko A. Bakker, Kerstin Wieland, Henk Timmerman, Rob LeursAbstract:Abstract Transient expression of the wild-type human Histamine H1 Receptor in SV40-immortalised African green monkey kidney cells resulted in an agonist-independent elevation of the basal levels of the second messenger inositoltrisphospate. Several Histamine H1 Receptor antagonists, including the therapeutically used anti-allergics cetirizine, loratadine and epinastine reduced this constitutive Histamine H1 Receptor activity. Inverse agonism, i.e., stabilisation of an inactive conformation of the human Histamine H1 Receptor, may therefore be a key component of the anti-allergic mechanism of action of clinically used antiHistamines.
Masatoshi Itoh - One of the best experts on this subject based on the ideXlab platform.
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brain Histamine H1 Receptor occupancy of orally administered antiHistamines bepotastine and diphenhydramine measured by pet with 11c doxepin
British Journal of Clinical Pharmacology, 2008Co-Authors: Manabu Tashiro, Motohisa Kato, M Miyake, Shoichi Watanuki, Yoshihito Funaki, Yoichi Ishikawa, Ren Iwata, Xudong Duan, Masatoshi Itoh, Kazuhiko YanaiAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • ‘Bepotastine besilate’ is a novel second-generation antiHistamine developed in Japan and its antiallergic effects have already been demonstrated by various studies. • However, only a few clinical studies regarding its sedative property are available. • In addition, Histamine H1 Receptor occupancy (H1RO) of this new antiHistamine has never been measured by positron emission tomography (PET). WHAT THIS STUDY ADDS • This paper provides the first measurement result of cerebral H1RO of bepotastine besilate (approximately 15%) as determined by PET. • This result is in accordance with the clinical classification of bepotastine as a second-generation antiHistamine. • In addition, the relationship between subjective sleepiness and cerebral H1RO of this second-generation antiHistamine is demonstrated for the first time using a placebo-controlled crossover study design. AIMS AntiHistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring Histamine H1 Receptor occupancy (H1RO) in the brain using positron emission tomography (PET). The aim was to measure H1RO of bepotastine, a new second-generation antiHistamine, and to compare it with that of diphenhydramine. METHODS Eight healthy male volunteers (mean age ± SD 24.4 ± 3.3 years) were studied after single oral administration of bepotastine (10 mg), diphenhydramine (30 mg) or placebo, by PET imaging with 11C-doxepin in a crossover study design. Binding potential ratio and H1ROs were calculated using placebo data and were compared between bepotastine and diphenhydramine in the anterior and posterior cingulate gyri (ACG and PCG, respectively), superior and inferior frontal cortices (SFC and IFC, respectively), orbitofrontal cortex (OFC), insular cortex (IC), lateral and medial temporal cortices (LTC and MTC, respectively), parietal cortex (PC), occipital cortex (OC) and sensorimotor cortex (SMC). Plasma concentration of each antiHistamine was measured, and its correlation to H1RO was examined. RESULTS H1RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H1ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H1ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001). CONCLUSION Oral bepotastine (10 mg), with its relatively low H1RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antiHistamine in the treatment of various allergic disorders.
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central effects of fexofenadine and cetirizine measurement of psychomotor performance subjective sleepiness and brain Histamine H1 Receptor occupancy using 11c doxepin positron emission tomography
The Journal of Clinical Pharmacology, 2004Co-Authors: Manabu Tashiro, Motohisa Kato, Yoshihito Funaki, Ren Iwata, Masatoshi Itoh, Yumiko Sakurada, Kentaro Iwabuchi, Hideki Mochizuki, Mariko Aoki, Dean F WongAbstract:Histamine H1-Receptor (H1R) antagonists, or antiHistamines, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation antiHistamines, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of Histamine H1-Receptor occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with 1 1 C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing.
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Histamine H1 Receptor occupancy in human brains after single oral doses of Histamine H1 antagonists measured by positron emission tomography
British Journal of Pharmacology, 1995Co-Authors: Kazuhiko Yanai, Ren Iwata, Takehiko Watanabe, Jong Hoon Ryu, Tatsuo Ido, Yoneichi Sawai, Kazumi Ito, Masatoshi ItohAbstract:1. Histamine H1 Receptor occupancy in the human brain was measured in 20 healthy young men by positron emission tomography (PET) using [11C]-doxepin. 2. (+)-Chlorpheniramine, a selective and classical antiHistamine, occupied 76.8 +/- 4.2% of the averaged values of available Histamine H1 Receptors in the frontal cortex after its administration in a single oral dose of 2 mg. Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [11C]-doxepin to H1 Receptors (H1 Receptor occupancy: 98.2 +/- 1.2%). 3. Terfenadine, a nonsedative antiHistamine, occupied 17.2 +/- 14.2% of the available H1 Receptors in the human frontal cortex after its administration in a single oral dose of 60 mg. 4. There was no correlation between H1 Receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject. 5. PET data on human brain were essentially compatible with those on H1 Receptor occupancy in guinea-pig brain determined by in vivo binding techniques, although for the same H1 Receptor occupancy the dose was less in human subjects than in guinea-pigs. 6. The PET studies demonstrated the usefulness of measuring H1 Receptor occupancy with classical and second-generation antiHistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively.