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Background: Treatment with commonly used drugs such as antidepressants (ADs), antipsychotics (APs), and benzodiazepines (BDs) may hamper the use of allergy skin testing due to possible antihistaminic effects. Objective: To examine the antihistaminic effect of AD, AP, and BD as measured by the ability of these drugs to suppress the normal wheal reaction caused by skin prick test (SPT). Methods: Skin prick test was performed in patients receiving treatment with AD, AP, and/or BD. Double SPT was performed with histamine solutions of 10, 30, and 100 mg/ml and mean wheal diameter calculated. Results: A total of 313 patients were included. 236 (75%) patients were treated with one of the examined drugs and 77 (25%) patients with more than one of these drugs. Drugs most frequently used was sertraline (n = 65), citalopram (n = 63), mirtazapine (n = 36), venlafaxine (n = 33), and quetiapine (n = 32). Treatment with mirtazapine and/or quetiapine was associated with negative SPTs in 30/36 (83%) and 22/32 (69%), and the antihistaminic effect of these drugs was dose-dependent. For patients treated with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs), or BD alone, almost all SPTs were positive (94%, 95%, 100%, and 100%, respectively). Negative SPTs in patients treated with SSRI, TCA, SNRI, or BD and ≥1 other of the examined drugs were associated with simultaneous treatment with mirtazapine or quetiapine in 39/44 (89%) patients. Conclusion: Skin testing has little meaning in patients treated with mirtazapine or quetiapine. Treatment with SSRI, SNRI, and BD does not seem to affect the results of SPTs, whereas skin tests in patients treated with TCA should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Using knockout (KO) mice lacking the histamine (HA)-synthesizing enzyme (histidine decarboxylase, HDC), we have previously shown the importance of histaminergic neurons in maintaining wakefulness (W) under behavioral challenges. Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for such a role. We have therefore compared the cortical-EEG, sleep and W under baseline conditions or behavioral/pharmacological stimuli in littermate wild-type (WT) and H1-receptor KO (H1−/−) mice. We found that H1−/− mice shared several characteristics with HDC KO mice, i.e. 1) a decrease in W after lights-off despite its normal baseline daily amount; 2) a decreased EEG slow wave sleep (SWS)/W power ratio; 3) inability to maintain W in response to behavioral challenges demonstrated by a decreased sleep latency when facing various stimuli. These effects were mediated by central H1-receptors. Indeed, in WT mice, injection of triprolidine, a brain-penetrating H1-receptor antagonist increased SWS, whereas ciproxifan (H3-receptor antagonist/inverse agonist) elicited W; all these injections had no effect in H1−/− mice. Finally, H1−/− mice showed markedly greater changes in EEG power (notably in the 0.8–5 Hz band) and sleep-wake cycle than in WT mice after application of a cholinergic antagonist or an indirect agonist, i.e., scopolamine or physostigmine. Hence, the role of HA in wake-promotion is largely ensured by H1-receptors. An upregulated cholinergic system may account for a quasi-normal daily amount of W in HDC or H1-receptor KO mice and likely constitutes a major compensatory mechanism when the brain is facing deficiency of an activating system. This article is part of the Special Issue entitled ‘Histamine Receptors’. [ABSTRACT FROM AUTHOR]

We previously reported that allergic responses to nickel (Ni) were minimal in mice deficient in the histamine-forming enzyme histidine decarboxylase ( HDC- KO), suggesting an involvement of histamine in allergic responses to Ni. However, it remains unclear how histamine is involved in the process of Ni allergy. Here, we examined the role of histamine in Ni allergy using a murine model previously established by us. Mice were sensitized to Ni by intraperitoneal injection of a NiCl2-lipopolysaccharide ( LPS) mixture. Ten days later, allergic inflammation was elicited by challenging ear-pinnas intradermally with NiCl2. Then, ear-swelling was measured. Pyrilamine (histamine H1-receptor antagonist) or cromoglicate (mast cell stabilizer) was intravenously injected 1 h before the sensitization or the challenge. In cell-transfer experiments, spleen cells from Ni-sensitized donor mice were intravenously transferred into non-sensitized recipient mice. In both sensitized and non-sensitized mice, 1 m m or more NiCl2 (injected into ear-pinnas) induced transient non-allergic inflammation (Ni- TI) with accompanying mast cell degranulation. LPS did not affect the magnitude of this Ni- TI. Pyrilamine and cromoglicate reduced either the Ni- TI or the ensuing allergic inflammation when administered before Ni- TI (at either the sensitization or elicitation step), but not if administered when the Ni- TI had subsided. Experiments on HDC- KO and H1-receptor- KO mice, and also cell-transfer experiments using these mice, demonstrated histamine's involvement in both the sensitization and elicitation steps. These results suggest that mast cell histamine-mediated Ni- TI promotes subsequent allergic inflammatory responses to Ni, raising the possibility that control of Ni- TI by drugs may be effective at preventing or reducing Ni allergy. [ABSTRACT FROM AUTHOR]

Abstract: Analogs of the known H1-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study. [Copyright &y& Elsevier]

The aim of the present study was to investigate the cellular pathway involved in histamine-stimulated internalization of the human H1-receptor in CHO-K1 cells expressing N-terminal myc-tagged H1-receptor (Myc-H1) or N-terminal myc-C-terminal green fluorescent protein (Myc-GFP H1) versions of the receptor.Studies of 3H-mepyramine binding and histamine-stimulated 3H-inositol phosphate accumulation in these cells showed that the Myc-H1 and Myc-GFP H1-receptors had identical pharmacology to the wild-type H1-receptor.The Myc-H1-receptor was rapidly internalized in CHO-K1 cells following stimulation with histamine (0.1 mM). This response occurred within 15 min, and could be prevented by the quaternary H1-receptor antagonist α-pirdonium. Similar data were obtained with the Myc-GFP H1-receptors.Internalization of the Myc-GFP H1-receptor was maintained in the absence of extracellular calcium and was not inhibited by the CAM kinase II inhibitor KN-62 (10 μM).Phorbol dibutyrate, an activator of protein kinase C, was also able to stimulate internalization of the H1-receptor. However, inhibition or downregulation of protein kinase C (which significantly modified histamine-stimulated inositol phosphate responses) was without effect on the internalization of the H1-receptor stimulated by histamine.Hypertonic sucrose did not prevent histamine-induced internalization of the Myc-GFP H1-receptor, but was able to attenuate internalization of transferrin via clathrin-mediated endocytosis in the same cells. In contrast, preincubation of cells with filipin or nystatin, which disrupts caveolae and lipid rafts, completely inhibited the histamine-induced internalization of the Myc-GFP H1-receptor, but was without effect on the sequestration of transferrin.The H1-receptor and cholera toxin subunit B were colocalized under resting conditions at the cell surface. Immunohistochemical studies with an antibody to caveolin-1 confirmed that this protein was also localized predominantly to the plasma membrane. However, following stimulation of CHO-Myc-GFP H1 cells with histamine, there was no evidence for internalization of caveolin-1 in parallel with the H1-receptor.These data provide strong evidence that the H1-receptor is internalized via a clathrin-independent mechanism and most likely involves lipid rafts.British Journal of Pharmacology (2005) 146, 612–624. doi:10.1038/sj.bjp.0706337; published online 8 August 2005 [ABSTRACT FROM AUTHOR]

The present work sets out to investigate how Ca2+ regulates the volume-sensitive taurine-release pathway in HeLa cells. Addition of Ca2+-mobilizing agonists at the time of exposure to hypotonic NaCl medium augments the swelling-induced taurine release and subsequently accelerates the inactivation of the release pathway. The accelerated inactivation is not observed in hypotonic Ca2+-free or high-K+ media. Addition of Ca2+-mobilizing agonists also accelerates the regulatory volume decrease, which probably reflects activation of Ca2+-activated K+ channels. The taurine release from control cells and cells exposed to Ca2+ agonists is equally affected by changes in cell volume, application of DIDS and arachidonic acid, indicating that the volume-sensitive taurine leak pathway mediates the Ca2+-augmented taurine release. Exposure to Ca2+-mobilizing agonists prior to a hypotonic challenge also augments a subsequent swelling-induced taurine release even though the intracellular Ca2+-concentration has returned to the unstimulated level. The Ca2+-induced augmentation of the swelling-induced taurine release is abolished by inhibition of calmodulin, but unaffected by inhibition of calmodulin-dependent kinase II, myosin light chain kinase and calcineurin. The effect of Ca2+-mobilizing agonists is mimicked by protein kinase C (PKC) activation and abolished in the presence of the PKC inhibitor Gö6850 and following downregulation of phorbol ester-sensitive PKC isoforms. It is suggested that Ca2+ regulates the volume-sensitive taurine-release pathway through activation of calmodulin and PKC isoforms belonging to the novel subclass (nPKC). [ABSTRACT FROM AUTHOR]

BackgroundDesloratadine is a non-sedating, clinically effective, anti-allergic therapy that has been shown to exhibit anti-inflammatory properties that extend beyond its ability to antagonize histamine at H1-receptor sites. This latter effect has been shown in vitro to be both IgE-dependent and -independent. ObjectiveIn this study, we addressed the ability of desloratadine to inhibit the in vitro generation of interleukin (IL)-4 and IL-13 from human basophils while concurrently comparing its efficacy in preventing mediator release by these cells. MethodsBasophil-enriched suspensions were treated with various concentrations of desloratadine for 15 min before stimulating with either anti-IgE antibody, calcium ionophore, IL-3 or phorbol ester. Histamine (fluorimetry), LTC4 (RIA) and IL-4 (ELISA) were all assayed using the same 4-h culture supernatants. IL-13 (ELISA) was measured in supernatants harvested after 20 h incubation. IL-4 mRNA expression (dilutional RT-PCR) was also examined. ResultsDesloratadine was found to be nearly six–seven times more potent in preventing the secretion of IL-4 and IL-13 induced by anti-IgE than it was at inhibiting the release of histamine and LTC4. These cytokines were equally inhibited by desloratadine following activation with ionomycin despite the lack of an effect on the histamine induced with ionomycin. Desloratadine had a lesser effect regarding inhibition of the IL-13 secreted in response to IL-3 and PMA. There was no evidence that desloratadine mediated its inhibitory effects by causing decreased cell viability. Finally, IL-4 mRNA accumulation was remarkably inhibited, by as much as 80%, following pretreatment with desloratadine. ConclusionWhile capable of inhibiting histamine and LTC4 release by human basophils, desloratadine is more effective at targeting the signals regulating IL-4 and IL-13 generation in these cells. This inhibitory effect on cytokine generation provides... [ABSTRACT FROM AUTHOR]