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H1 Receptor Antagonist (h1 + receptor_antagonist)
Selected AbstractsSynthesis and Biological Evaluation of Novel 5,8-Disubstituted-2-methyl-2,3,4,5-tetrahydro-1H -pyrido[4,3- b] indoles as 5-HT6 and H1 Receptors AntagonistsARCHIV DER PHARMAZIE, Issue 12 2009Alexandre V. Ivachtchenko Abstract Synthesis, biological evaluation, and structure-activity relationships (SAR) for a series of novel ,-carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro-,-carboline 5b (2,8-dimethyl-5-[cis -2-pyridin-3-ylvinyl]-2,3,4,5-tetrahydro-carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H1 and serotonin 5-HT6 receptors (IC50 < 0.45 ,M and IC50 = 0.73 ,M, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity. [source] Endogenous histamine in the medial septum,diagonal band complex increases the release of acetylcholine from the hippocampus: a dual-probe microdialysis study in the freely moving ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2002Lucia Bacciottini Abstract The effects of histaminergic ligands on both ACh spontaneous release from the hippocampus and the expression of c-fos in the medial septum,diagonal band (MSA-DB) of freely moving rats were investigated. Because the majority of cholinergic innervation to the hippocampus is provided by MSA-DB neurons, we used the dual-probe microdialysis technique to apply drugs to the MSA-DB and record the induced effects in the projection area. Perfusion of MSA-DB with high-KCl medium strongly stimulated hippocampal ACh release which, conversely, was significantly reduced by intra-MSA-DB administration of tetrodotoxin. Histamine or the H2 receptor agonist dimaprit, applied directly to the hippocampus, failed to alter ACh release. Conversely, perfusion of MSA-DB with these two compounds increased ACh release from the hippocampus. Also, thioperamide and ciproxifan, two H3 receptor antagonists, administered into MSA-DB, increased the release of hippocampal ACh, whereas R-,-methylhistamine, an H3 receptor agonist, produced the opposite effect. The blockade of MSA-DB H2 receptors, caused by local perfusion with the H2 receptor antagonist cimetidine, moderated the spontaneous release of hippocampal ACh and antagonized the facilitation produced by H3 receptor antagonists. Triprolidine, an H1 receptor antagonist, was without effect. Moreover, cells expressing c-fos immunoreactivity were significantly more numerous in ciproxifan- or thioperamide-treated rats than in controls, although no colocalization of anti-c-fos and anti-ChAT immunoreactivity was observed. These results indicate a role for endogenous histamine in modulating the cholinergic tone in the hippocampus. [source] Neurochemical regulation of swallowing reflex in guinea pigsGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 1-2 2001Yu X Jia Background: Most peripheral afferent fibers involved in swallowing travel through the glossopharyngeal and vagus nerves and terminate in the nucleus of the tractus solitarius (NTS) and nodose ganglion (NG). Sensory neurons within the NTS and NG contain several neurotransmitters, including acetylcholine, histamine, serotonin and dopamine. The roles of these four neurotransmitters were investigated. Methods: The effects of atropine (muscarinic cholinergic receptor antagonist); pyrilamine maleate (PM, histamine H1 receptor antagonist); cimetidine (histamine H2 receptor antagonist); 8-hydroxy-2-(di- n -propylamino)-tetralin (8-OH-DPAT, specific 5-HT1A receptor agonist); and selective dopamine D1 receptor antagonist (Sch-23390) on the number of swallows elicited by distilled water in anesthetized guinea pigs were investigated. Results: Atropine (0.2 mg/kg) inhibited swallowing by approximately 70%; PM (30 mg/kg) inhibited swallowing by approximately 60%; cimetidine (30 mg/kg) inhibited swallowing by approximately 52.9% and Sch-23390 (chronic treatment) inhibited swallowing by approximately 40%. In contrast, 8-OH-DPAT did not alter the number of swallows. Chronic pretreatment of Sch-23390 markedly decreased the substance P (SP) content in the pharyngeal mucosa and the esophagus. Conclusion: These findings indicate that acetylcholine, histamine and dopamine are involved in the regulation of the swallowing reflex, whereas it is unlikely that serotonin is involved. [source] A combined loop-SPE method for the automated preparation of [11C]doxepinJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 4 2002R. Iwata Abstract A simple and versatile loop-solid phase extraction (SPE) method was developed for the automated preparation of [11C]doxepin, a histamine H1 receptor antagonist, from [11C]methyl triflate ([11C]MeOTf). This labeling agent was passed through a Teflon or Tefzel loop coated internally with a film of the precursor solution. The reaction products were then flushed from the loop to a short SPE column, where they were concentrated and then injected onto a semi-preparative HPLC column simply by switching an injection valve. By applying this combined loop-SPE technique the whole procedure turned out to be easily automated. The formation of [11C]methylated doxepin ([11C]methyldoxepin) was observed and the ratio of doxepin to methyldoxepin was found to be clearly correlated with the mass ratio of nordoxepin to MeOTf. This observation highlights the importance of [11C]MeOTf specific activity in the [11C]methylation of secondary amines. Using this method, [11C]Doxepin was prepared in over 40% radiochemical yield from high specific activity [11C]MeOTf. Copyright © 2002 John Wiley & Sons, Ltd. [source] Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skinTHE JOURNAL OF PHYSIOLOGY, Issue 3 2005Brett J. Wong The neuropeptide substance P is known to be localized in nerve terminals in human skin and substance P-induced vasodilatation is believed to be partially dependent on nitric oxide (NO) and H1 histamine receptor activation. Unlike other neuropeptides investigated in human skin, substance P-induced vasodilatation has been shown to decline during continuous infusion, possibly suggestive of an internalization of neurokinin-1 (NK1) receptors, which are highly specific to substance P. However, questions remain regarding these mechanisms in human skin. Fifteen subjects participated in this series of studies designed to investigate the effect of consecutive infusions and possible mechanisms of substance P-induced vasodilatation in human skin. Two concentrations of substance P (10 ,m and 20 ,m) were tested via intradermal microdialysis in two groups of subjects. Site 1 served as a control and received substance P only. Site 2 received substance P combined with 10 mm l -NAME to inhibit NO synthase. Site 3 received substance P combined with 500 ,m pyrilamine, an H1 receptor antagonist. Site 4 received substance P combined with 10 mm l -NAME plus 500 ,m pyrilamine. Red blood cell (RBC) flux was measured via laser-Doppler flowmetry to provide an index of skin blood flow. Cutaneous vascular conductance was calculated as RBC flux/mean arterial pressure and was normalized to maximal vasodilatation via 28 mm sodium nitroprusside. Substance P was perfused through each microdialysis fibre at a rate of 4 ,l min,1 for 15 min. The subsequent increase in skin blood flow was allowed to return to baseline (,45,60 min) and a stable 5 min plateau was used as a new baseline (post-infusion baseline). A second dose of substance P was then delivered to the skin and skin blood flow was monitored for 45,60 min. Substance P produced a dose-dependent increase in skin blood flow with the concentrations of substance P tested, which was significantly attenuated in the presence of l -NAME and the combination of l -NAME plus pyrilamine. However, substance P-induced vasodilatation was unaffected in the presence of pyrilamine. There was no significant difference between the l -NAME-only sites and the l -NAME plus pyrilamine sites. Importantly, the second dose of substance P did not produce a significant increase in skin blood flow compared to the initial baseline or the post-infusion baseline. These data suggest substance P-induced vasodilatation delivered via microdialysis contains an NO component but does not contain an H1 receptor activation component at the doses tested. Additionally, these data provide evidence for NK1 receptor desensitization as there was no observable increase in skin blood flow following a second administration of substance P. This may provide a useful model for studying the role of substance P in the control of skin blood flow in humans. [source] Nasal Allergic Response Mediated by Histamine H3 Receptors in Murine Allergic RhinitisTHE LARYNGOSCOPE, Issue 10 2005Muneo Nakaya MD Abstract Background: Histamine is one of the most important chemical mediators causing nasal allergic symptoms, and H1 receptor antagonist have been used as the treatment first choice in nasal allergy. The presence of H3 receptors has also been determined in the human nasal mucosa, but few studies have investigated the involvement of H3 receptors in nasal allergy. Objective: We used a murine allergic model to investigate the presence of nasal mucosa H3 receptor mRNA and any H3 receptor agonist or antagonist influences on clinical nasal allergic symptoms. Methods: H3 receptor mRNA in nasal mucosa was investigated by reverse-transcription polymerase chain reaction. OVA-sensitized mice were given an intraperitoneal injection of H3 receptor agonist or antagonist, and clinical nasal allergic symptoms were scored over 10 minutes after nasal provocation of OVA. Inhibition of nasal allergic symptoms was also examined using an H1 receptor antagonist alone and using a both an H3 receptor agonist and an H1 receptor antagonist. Results: H3 receptor mRNA was identified in the murine nasal mucosa. The H3 receptor agonist (R)-,-metylhistamine significantly inhibited clinical nasal allergic symptoms of OVA-sensitized mice. The H3 receptor agonist and H1 receptor antagonist inhibited clinical nasal allergic symptoms in the murine allergic model more strongly than the single drug. Conclusion: The foregoing results indicate that H3 receptors are involved in modulation of nasal allergy. H3 receptor agonists can also be useful as a novel therapeutic approach in nasal allergy. Both H3 receptor agonist and H1 receptor antagonist may be more effective than a single drug. [source] Intracerebroventricular Effects of Histaminergic Agents on Morphine-Induced Anxiolysis in the Elevated Plus-Maze in RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2005Mohammad-Reza Zarrindast It has also been reported that histaminergic system can interfere with some pharmacological effects of morphine. The effects of histaminergic agents on morphine-induced anxiolysis in rats, using elevated plus-maze were investigated in the present study. Intraperitoneal injection of morphine (3, 6 and 9 mg/kg) induced antianxiety effects. Intracerebroventricular administration of histamine at the doses of (5, 10 and 20 ,g/rat) also increased anxiety-related behaviours. Intracerebroventricular injection of pyrilamine, a H1 receptor antagonist (25, 50 and 100 ,g/rat), increased anxiety whereas injection of ranitidine, a H2 receptor antagonist (5, 10 and 20 ,g/rat) at the same site, decreased anxiety. Therefore, it seems that histamine induces anxiogenic response through activation of H2 receptors, while the response of H1 blocker may be due to release of histamine. We also evaluated the interactions between morphine and histaminergic agents. Our data show that histamine (10 ,g/rat), pyrilamine (50 ,g/rat) and ranitidine (5 ,g/rat) did not alter the response induced by different doses of morphine (3, 6 and 9 mg/kg). Similarly, a single dose of morphine did not alter the response induced by different doses of histamine (5, 10 and 20 ,g/rat), pyrilamine (25, 50 and 100 ,g/rat) or ranitidine (5, 10 and 20 ,g/rat). In conclusion, the histaminergic system plays an important role in the modulation of anxiety, although in our experiments, no interaction was found between the effects of histaminergic agents and morphine on anxiety-related indices in the elevated plus-maze. This may imply that morphine-induced anxiolysis probably is independent of the histaminergic system. [source] Desloratadine partially inhibits the augmented bacterial responses in the sinuses of allergic and infected miceCLINICAL & EXPERIMENTAL ALLERGY, Issue 10 2004V. Kirtsreesakul Summary Background Allergic rhinitis (AR) is considered a major predisposing factor for the development of acute bacterial rhinosinusitis. How AR augments a bacterial infection is unknown. Objective Our purpose in this study was to test whether an H1 receptor antagonist, desloratadine, could reduce the augmented effect of an ongoing allergic reaction on acute bacterial rhinosinusitis. Methods Three groups of infected and ovalbumin (OVA)-sensitized mice were studied: (1) infected and allergic mice treated with desloratadine, (2) infected and allergic mice treated with placebo, and (3) infected mice. A fourth group of uninfected, non-sensitized mice served as a control for the cellular changes. BALB/c mice were sensitized by two intraperitoneal injections of OVA given 8 days apart. One day after the second injection, the mice were nasally exposed daily to 6% OVA (the groups treated with desloratadine or placebo) or phosphate-buffered saline (PBS) (the infection-only group) for 5 days. After the second OVA exposure, the mice were intranasally inoculated with Streptococcus pneumoniae. Desloratadine or placebo was given daily throughout the OVA exposure period. Nasal allergic symptoms were observed by counting of nasal rubbing and sneezing for 10 min after OVA or PBS nasal challenge. On day 5 post-infection, nasal lavage culture was done, and the inflammatory cells in the sinuses were evaluated by flow cytometry. Results Mice that were made allergic, infected, and treated with placebo showed more organisms and phagocytes than did only infect mice. They also manifested allergic nasal symptoms and eosinophil influx into the sinuses. Desloratadine treatment during allergen exposure reduced allergic symptoms and reduced sinonasal infection (P<0.05). There tended to be less myeloid cell and neutrophil influx (P=0.09 both), but not eosinophil influx (P=0.85) compared with that in the placebo-treated group. Conclusion Desloratadine treatment during nasal challenge inhibited allergic symptoms and reduced sinonasal infection, suggesting that histamine via an H1 receptor plays a role in the augmented infection in mice with an ongoing allergic reaction. [source] The apparent volumes of distribution of H1 receptor antagonistsDERMATOLOGIC THERAPY, Issue 4 2000Jean-Paul Tillement ABSTRACT: The apparent volume of distribution (VD) of a drug estimates its distribution into the body. Referring to the volume of exchangeable water (0.6 L/kg body weight), it indicates if tissue distribution is extensive when VD is greater than 0.6 L/kg or poor if VD is less than 0.6 L/kg. Its interest in the selection of an appropriate drug is found after comparing the map of selected targets (mainly receptors) to be reached by the drug, the accessibility of these targets by the drug, and the VD necessary and sufficient to reach them. This analysis is here applied to H1 receptor antagonists, a pharmacologic class, where target cells, endothelial cells such as eosinophils, mastocytes, basophils, and smooth fibers have receptors on the external side of cell membranes and thus are more readily accessible from blood than toxic sites located inside cells (heart, brain, liver). Of the H1 receptor antagonists marketed today, cetirizine has the lowest VD, 0.4 L/kg, enough to reach selected targets without extensive distribution in organs where it would be useless. These characteristics are related to its chemical amphoteric structure. [source] Sedation and antihistamines: an update.HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2008Review of inter-drug differences using proportional impairment ratios Abstract Background The use of antihistamines (AHs) has been associated with cognitive and psychomotor impairments, largely caused by the sedative properties of many of these drugs. Due to the ambulant nature of the population using AHs, it is important to evaluate these effects using standardised methodology and psychometric tests. A previous extensive review of the literature collated the results of studies of H1 receptor antagonists to determine the extent to which a particular AH produced impairments on a battery of psychometric tests by calculating a proportional impairment ratio for each AH. Objective In light of a number of major studies published following the previous review, and the development of the second and new-generation AHs, the present review aims to add to the database and update the review, using the same methodology. Results and Conclusion The newer generation AHs appear to be the least impairing, and the first generation, as expected, appear to be the most impairing. There are also differences within the AH drug generations. The review highlights the necessity to consider the sedating potential of AHs, along with other factors such as efficacy, when prescribing AHs to ambulant patients. Copyright © 2008 John Wiley & Sons, Ltd. [source] Thr105Ile, a Functional Polymorphism of Histamine N-Methyltransferase, Is Associated with Alcoholism in Two Independent PopulationsALCOHOLISM, Issue 3 2005Gabor Oroszi Background: Histamine is expressed in cortical and limbic areas that are involved in emotion and cognition and modulates these behaviors. H1 receptor antagonists are sedative. Histamine N-methyltransferase (HNMT) catalyzes the N, methylation of histamine, the sole pathway for termination of the neurotransmitter action of histamine in mammalian brain. A common and functionally significant polymorphism, a C314T transition in exon 4 of the HNMT gene results in a Thr105Ile substitution of the protein encoded. The Thr105 allele is associated with ,2-fold higher enzyme activity, leading to the prediction that it might be associated with diminished histamine levels, resulting in differences in anxiety, cognition, and sedation that play important roles in alcoholism. In two ethnically distinct populations, we tested whether the Thr105Ile polymorphism was associated with alcoholism and with harm avoidance, a dimensional measure of anxious personality. Methods: A 5, exonuclease assay (TaqMan) was used to genotype Thr105Ile in psychiatrically interviewed Finnish Caucasian (n= 218) and Plains American Indian (n= 186) alcoholics, along with ethnically matched, psychiatrically interviewed, controls (Finns: n= 313, Plains Indian: n= 140). Results: Ile105 allele frequencies were significantly lower in alcoholics compared with nonalcoholics in both populations (Finns: 0.12 vs. 0.17, ,2= 6, p= 0.015; Plains Indians: 0.03 vs. 0.08, ,2= 5, p= 0.023). Genotype distributions also differed significantly. In Finns, Ile105 showed borderline significance for an association with lower harm avoidance (p= 0.070) after correcting for alcoholism diagnosis. Conclusions: Decreased levels of brain histamine consequent to the Thr105 allele may result in higher levels of anxiety and, as a consequence, vulnerability to alcoholism. [source] Mechanisms and clinical implications of glucocorticosteroids in the treatment of allergic rhinitisCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2009M. Okano Summary Allergic rhinitis is a common airway disease characterized by hypersensitivity, exudation, hypersecretion, inflammatory cell infiltration and remodelling. Intranasal glucocorticosteroids are the most effective drugs for controlling the inflammation caused by allergic rhinitis. Glucocorticosteroids exert anti-inflammatory effects through at least two pathways: the transactivation pathway and the transrepression pathway. Glucocorticosteroids also exert regulatory functions by inducing regulatory cytokines and forkhead box P3 (FoxP3+) regulatory T cells. Evidence suggests that intranasal glucocorticosteroids control not only nasal symptoms but also ocular symptoms. In contrast to sedating H1 receptor antagonists, intranasal glucocorticosteroids can improve impaired performance symptoms, such as daytime sleepiness, associated with allergic rhinitis. Recent studies suggest that intranasal glucocorticosteroids might also be useful for the prophylactic treatment of pollinosis; this possibility is supported by the molecular mechanism of the anti-inflammatory action of glucocorticosteroids. These findings suggest that intranasal glucocorticosteroids might be positioned as first-line drugs for the treatment of both perennial and seasonal allergic rhinitis. [source] | ||||||||||||||||