H1 Receptor Binding Research Articles

In vitro characterisation of the duration of action of the histamine-1 receptor antagonist azelastine

Azelastine is a selective antagonist at the human histamine-1 receptor and is used clinically in the treatment of allergic rhinitis. In this study we have investigated its duration of action in vitro in an effort to characterise the receptor and tissue components involved. Chinese hamster ovary cell membrane fragments were used to determine the kinetics of azelastine at the H₁ receptor in a radioligand binding assay. Further duration of action studies were completed in tissue preparations using guinea-pig trachea and human bronchus. In radioligand binding studies, azelastine reached steady state at the H₁ receptor after approximately 41 min and exhibited a significantly slower dissociation rate constant from the receptor than the first generation antihistamine, diphenhydramine. In washout studies completed in guinea-pig and human airway in vitro tissue preparations, azelastine continued to antagonise the effects of histamine at the H₁ receptor for at least 18 h post-washout of the antagonist. This outcome was reversed following removal of the epithelium from guinea-pig isolated tracheal strips. These studies indicate there is a tissue component contributing to azelastine's duration of action, in addition to its direct H₁ receptor binding, with evidence suggesting a role for the epithelial layer.

Involuntary Movements Associated with Cetirizine Use

Back to table of contents Previous article Next article Communications and UpdatesFull AccessInvoluntary Movements Associated with Cetirizine UseCandace A. Romo, M.D., Kaustubh G. Joshi, M.D., and Brian M. Waters, M.D.Candace A. RomoSan Antonio, Tex.Search for more papers by this author, M.D., Kaustubh G. JoshiSan Antonio, Tex.Search for more papers by this author, M.D., and Brian M. WatersSan Antonio, Tex.Search for more papers by this author, M.D.Published Online:1 Aug 2011https://doi.org/10.1176/appi.ajp.2011.11040534AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Cetirizine is approved by the U.S. Food and Drug Administration (FDA) for allergic rhinitis in all age groups (1). Published reports have described cetirizine-induced dystonic reactions in the pediatric patient population and in one adult (2–4). We present the case of an adult who developed involuntary movements associated with cetirizine use and discontinuation.Case ReportA 24-year-old Caucasian woman presented to the local hospital emergency department with a nose laceration she sustained from walking into a glass window after acute alcohol intoxication (her blood alcohol level was 140 mg/dL). She reported taking 10 mg/day of cetirizine for 3 months, daily valacyclovir (for herpes simplex virus 1), and depot medroxyprogesterone. She denied a history of medication side effects, denied taking more than the recommended dosage, and was not taking over-the-counter or herbal products. She denied a history of head injuries, seizures, or loss of consciousness, and she also denied treatment with psychotropic medications. Initially, results from her physical examination were unremarkable with the exception of a superficial laceration on her nose. The results of laboratory testing, including thyroid-stimulating hormone and urine toxicology, were all within normal limits or negative.While in the emergency department, the patient developed acute involuntary “bizarre grimacing” and dysarthria. There was no evidence of oculogyric crisis, torticollis, tongue protrusions, opisthotonos, gait disturbances, or weakness in her extremities. She did not lose consciousness, and results of her neurological examination were negative. She was given intravenous diphenhydramine (50 mg), benztropine (2 mg), and lorazepam (2 mg). Neuroimaging results of her head and spine were negative, and her dystonia had resolved by the time a neurologist arrived at her bedside.A follow-up call 1 month later revealed that the patient had stopped taking cetirizine after she was discharged from the emergency department. She reported facial twitching on the day after discharge. Over the course of the month, she experienced two episodes of difficulty walking, hand “discoordination,” and “muscle jerks of her throat.” These episodes lasted approximately 20 minutes. An outpatient neurology consultation was arranged at the time of the call, but it is not known whether she kept that appointment.DiscussionCetirizine is a carboxylated metabolite of hydroxyzine (a piperazine histamine H1 receptor antagonist) (1). Piperazines have central dopamine D2 receptor blockade (5). Cetirizine's large size, lipophobic nature, and greater affinity for peripheral H1 receptors are believed to reduce CNS penetration and central side effects (2). However, one positron emission tomography study of cetirizine revealed approximately 30% H1 receptor binding in the cerebral cortex (1, 2). Cetirizine has negligible anticholinergic activity (6). We speculate that as a piperazine derivative, cetirizine blocked the striatal D2 receptors and resulted in an acute dystonic reaction in our patient. In addition, we also speculate that our patient's 3-month cetirizine use resulted in D2 receptor hypersensitivity similar to that observed in long-term antipsychotic use, with subsequent involuntary movements after its discontinuation. It is also possible that her cetirizine use and the subsequent development of involuntary movements are independent events. More research is needed to clarify cetirizine's effect on central D2 receptors.San Antonio, Tex.The authors report no financial relationships with commercial interests. The opinions expressed in this letter do not reflect those of the Department of Defense or the United States Air Force.This letter was accepted for publication in May 2011.

Antidiabetic Properties of the Histamine H3 Receptor Protean Agonist Proxyfan

Proxyfan is a histamine H3 receptor protean agonist that can produce a spectrum of pharmacological effects including agonist, inverse agonist, and antagonist. We have discovered that proxyfan (10 mg/kg orally) significantly improved glucose excursion after an ip glucose tolerance test in either lean or high-fat/cholesterol diet-induced obese mice. It also reduced plasma glucose levels comparable to that of metformin (300 mg/kg orally) in a nongenetic type 2 diabetes mouse model. The dose-dependent decrease in glucose excursion correlated with inhibition of ex vivo H3 receptor binding in the cerebral cortex. In addition, glucose levels were significantly reduced compared with vehicle-treated mice after intracerebroventricular administration of proxyfan, suggesting the involvement of central H3 receptors. Proxyfan-induced reduction of glucose excursion was not observed in the H3 receptor knockout mice, suggesting that proxyfan mediates this effect through H3 receptors. Proxyfan reduced glucose excursion by significantly increasing plasma insulin levels in a glucose-independent manner. However, no difference in insulin sensitivity was observed in proxyfan-treated mice. The H1 receptor antagonist chlorpheniramine and the H2 receptor antagonist zolantidine had modest effects on glucose excursion, and neither inhibited the glucose excursion reduced by proxyfan. The H3 receptor antagonist/inverse agonist, thioperamide, had weaker effects on glucose excursion compared with proxyfan, whereas the H3 receptor agonist imetit did not affect glucose excursion. In conclusion, these findings demonstrate, for the first time, that manipulation of central histamine H3 receptor by proxyfan can significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism.

Effects of simvastatin and 6-hydroxydopamine on histaminergic H1 receptor binding density in rat brains

Statins have been widely used for the treatment of a variety of medical conditions including psychoneurological disorders beyond their original use in lowering cholesterol. Histamine receptors play an important role in the regulation of neural activity, however, it is unknown whether statins act on histamine receptors, particularly for their neural regulatory effects. This study examined the effects of simvastatin and 6-hydroxydopamine (6-OHDA) lesions on histamine H1 receptors using [ 3H] pyrilamine binding autoradiography. Compared to the saline group, simvastatin (1 mg/kg/day) significantly decreased H1 receptor bindings in the primary motor cortex (M1), ventromedial hypothalamic nucleus (VMH), caudate putamen (CPu), accumbens core (AcbC) and prefrontal cortex (PfC) (all p < 0.05); however 10 mg/kg/day simvastatin increased H1 receptor density only in the medial amygdaloid nucleus (Mep) (p < 0.05), but had no significant effect in other regions examined. The 6-OHDA lesion did not alter H1 receptor binding density in most brain areas, except a trend decrease in the hippocampus (p = 0.07) and a trend increase in the cingulate cortex (p = 0.06). These results suggested that simvastatin has different effects on the H1 receptors in different rat brain regions depending on the doses. Therefore, simvastatin can modulate histaminergic neurotransmission in the brain, and support the role of H1 receptors in psychoneurological disorders.

Investigation of the Histamine H3 Receptor Binding Site. Design and Synthesis of Hybrid Agonists with a Lipophilic Side Chain

As a part of our search for novel histamine H3 receptor agonists, we designed and synthesized hybrid compounds in which the lipophilic (4'-alkylphenylthio)ethyl moiety of a novel H3 receptor agonist, 4-(2-(4'-tert-butylphenylthio)ethyl)-1H-imidazole (1), was incorporated into N(alpha)-methylhistamine, immepip, and immethridine derivatives. These hybrid compounds were expected to interact concurrently with the histamine-binding site and a putative hydrophobic region in the H3 receptor. Among them, piperidine- and pyridine-type derivatives displayed partial agonist activity, and (S)-4-(1-(1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenylthio)ethyl)piperidine (36) was identified as a potent H3 agonist. We performed computational docking studies to examine the binding mode of the agonists. The results indicated that immepip interacts with the key residues, Asp114 and Glu206, in a different manner from histamine. The binding mode of 36 to these residues is similar to that of immepip, and the lipophilic tail of 36 has an additional interaction with a hydrophobic region in transmembrane helix 6 of the receptor. These results indicated that 36 served as a useful tool for studies on receptor-agonist interactions and drug design.

9-Aminomethyl-9,10-dihydroanthracene (AMDA) analogs as structural probes for steric tolerance in 5-HT2A and H1 receptor binding sites

9-Aminomethyl-9,10-dihydroanthracene (AMDA) analogs as structural probes for steric tolerance in 5-HT2A and H1 receptor binding sites

The role of histaminergic H1 and H3 receptors in food intake: A mechanism for atypical antipsychotic-induced weight gain?

Atypical antipsychotics such as olanzapine and clozapine are effective at treating the multiple domains of schizophrenia, with a low risk of extra-pyramidal side-effects. However a major downfall to their use is metabolic side-effects particularly weight gain/obesity, which occurs by unknown mechanisms. The present paper explores the potential candidature of histaminergic neurotransmission in the mechanisms of atypical antipsychotic-induced weight gain, with a focus on the histaminergic H1 and H3 receptors. Olanzapine and clozapine have a high affinity for the H1 receptor, and meta-analyses show a strong correlation between risk of weight gain and H1 receptor affinity. In addition, olanzapine treatment decreases H1 receptor binding and mRNA expression in the rat hypothalamus. Furthermore, a complex role is emerging for the histamine H3 receptor in the control of hunger. The H3 receptor is a pre-synaptic autoreceptor that inhibits the synthesis and release of histamine, and a heteroreceptor that inhibits other neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and acetylcholine (ACh), which are also implicated in the regulation of food intake. Thus, the H3 receptor is in a prime position to regulate food intake, both through its control of histamine and its influence on other feeding pathways. We proposed that a mechanism for atypical antipsychotic-induced weight gain may be partly through the H3 receptor, as a drug-induced decrease in H1 receptor activity may decrease histamine tone through the H3 autoreceptors, compounding the weight gain problem. In addition, atypical antipsychotics may affect food intake by influencing 5-HT, NA and ACh release via interactions with the H3 heteroreceptor.

Mast Cell Stabilizing Properties of Antihistamines

Histamine is a key mediator of allergic inflammation, primarily through competitive antagonism of binding to H1 receptors. In this issue, Weller and Maurer report that the H1 antagonist desloratadine possesses mast cell-stabilizing properties when challenged in an IgE-dependent or -independent fashion. Thus, desloratadine provides benefits that are independent of H1 receptor binding and based on mast cell stabilization.

Structures of receptor complexes formed by hemagglutinins from the Asian Influenza pandemic of 1957

The viruses that caused the three influenza pandemics of the twentieth century in 1918, 1957, and 1968 had distinct hemagglutinin receptor binding glycoproteins that had evolved the capacity to recognize human cell receptors. We have determined the structure of the H2 hemagglutinin from the second pandemic, the "Asian Influenza" of 1957. We compare it with the 1918 "Spanish Influenza" hemagglutinin, H1, and the 1968 "Hong Kong Influenza" hemagglutinin, H3, and show that despite its close overall structural similarity to H1, and its more distant relationship to H3, the H2 receptor binding site is closely related to that of H3 hemagglutinin. By analyzing hemagglutinins of potential H2 avian precursors of the pandemic virus, we show that the human receptor can be bound by avian hemagglutinins that lack the human-specific mutations of H2 and H3 pandemic viruses, Gln-226Leu, and Gly-228Ser. We show how Gln-226 in the avian H2 receptor binding site, together with Asn-186, form hydrogen bond networks through bound water molecules to mediate binding to human receptor. We show that the human receptor adopts a very similar conformation in both human and avian hemagglutinin-receptor complexes. We also show that Leu-226 in the receptor binding site of human virus hemagglutinins creates a hydrophobic environment near the Sia-1-Gal-2 glycosidic linkage that favors binding of the human receptor and is unfavorable for avian receptor binding. We consider the significance for the development of pandemics, of the existence of avian viruses that can bind to both avian and human receptors.

Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over‐expressing TASTPM mice

Histamine H3 receptor antagonists are currently being evaluated for their potential use in a number of central nervous system disorders including Alzheimer's Disease (AD). To date, little is known about the state of H3 receptors in AD. In the present study we used the radiolabelled H3 receptor antagonist [3H]GSK189254 to investigate H3 receptor binding in the amyloid over-expressing double mutant APPswe x PSI.MI46V (TASTPM) transgenic mouse model of AD and in post-mortem human AD brain samples. No significant differences in specific H3 receptor binding were observed between wild type and TASTPM mice in the cortex, hippocampus or hypothalamus. Specific [3H]GSK189254 binding was detected in sections of human medial frontal cortex from AD brains of varying disease severity (Braak stages I-VI). With more quantitative analysis in a larger cohort, we observed that H3 receptor densities were not significantly different between AD and age-matched control brains in both frontal and temporal cortical regions. However, within the AD group, [3H]GSK189254 binding density in frontal cortex was higher in individuals with more severe dementia prior to death. The maintenance of H3 receptor integrity observed in the various stages of AD in this study is important, given the potential use of H3 antagonists as a novel therapeutic approach for the symptomatic treatment of AD.

Diamine Derivatives Containing Imidazolidinylidene Propanedinitrile as a New Class of Histamine H3 Receptor Antagonists: Conformationally Restricted Derivatives

Novel conformationally restricted diamine derivatives containing imidazolidinylidene propanedinitrile were synthesized and evaluated for human and rat histamine H(3) receptor (H(3)R) binding affinities. Among them, compounds 2b, 2c, 2j, 2k and 2m were found to be potent ligands for both H(3)Rs with K(i) values in the sub-nanomolar range, and showed potent H(3) receptor antagonism.

Increased Brain Histamine H1 Receptor Binding in Patients with Anorexia Nervosa

The central histaminergic neuron system modulates various brain functions, including eating behavior. We hypothesized that women have higher density of histamine H1 receptor (H1R) in the limbic system than men and that the density of central H1R is increased in patients with anorexia nervosa (AN). Subjects were 12 female AN patients, 12 healthy female subjects, and 11 healthy male subjects. Positron emission tomography with H1R radioligand [(11)C]doxepin was performed on all subjects and regions of interest based analysis was conducted to evaluate brain H1R binding potential (BP). Abnormal eating behavior, depression, and anxiety of subjects were evaluated using the Eating Attitude Test-26 (EAT-26), Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI), respectively. Binding potential of [(11)C]doxepin in female subjects was significantly higher than that in male subjects at the following brain sites: amygdala, hippocampus, medial prefrontal cortex, orbitofrontal cortex, and temporal cortex. Anorexia nervosa patients showed significantly higher BP of [(11)C]doxepin in the amygdala and lentiform nucleus than the control female subjects. In AN patients, BP of [(11)C]doxepin in the amygdala and thalamus negatively correlated with EAT-26 scores. There was a significant negative correlation between BP of [(11)C]doxepin and SDS or STAI scores in the amygdala, anterior cingulate cortex, and orbitofrontal cortex of AN patients. These findings support the hypothesis that women have higher H1R density in the limbic system than men and suggest that AN patients may have higher expression of H1R in the limbic brain, particularly in the amygdala.

Histamine H1 receptor binding capacities in the amygdalas of the amygdaloid kindled rat.

The histamine H1 receptor binding capacity of the amygdalas of amygdaloid kindled rats was studied. In the kindled nonstimulated amygdala, significant decreases in K(D) and B(max) values compared with those of control amygdala were found 1 week after the last kindled seizure. One month after the last kindled seizure, the decreased K(D) value was sustained in the kindled nonstimulated amygdala. This decreased Bmax value 1 week after the last kindled seizure in nonstimulated amygdala may partly and transiently contribute to kindled seizure susceptibility. The decreased K(D) value in nonstimulated amygdala observed until 1 month after the last kindled seizure indicates the long-lasting increment of binding affinity of the pyrilamine binding site of the histamine H1 receptor in the steady state of kindled seizure susceptibility.

Autoregulation of McA-RH7777 Hepatoma Cell Proliferation by Histamine H3Receptors

Previous studies have suggested that histamine (HA) acts as an autocrine growth factor. We have explored the modulation of cell proliferation by HA using McA-RH7777 hepatoma cells. High L-histidine decarboxylase (HDC) expression and HA synthesis were found in McA-RH7777 cells. Whereas extracellular HA reached submicromolar concentrations, intracellular levels were very low, indicating that HA was secreted by the cells. McA-RH7777 cells also express H3-receptor (H3R) transcripts and proteins. Reverse transcriptase-polymerase chain reaction analysis detected only transcripts for the long isoform. Immunocytochemistry performed with a selective H3R antibody showed that most cells were immunoreactive. H3R binding sites (Bmax approximately 30 fmol/mg protein) were identified when [125I] iodoproxyfan binding was displaced by the agonist imetit. High-affinity binding also occurred at cytochrome P450 enzymes. This binding was not inhibited by HA, H3R agonists, or by a nonimidazole H3R antagonist but was displaced by imidazole H3R antagonists or by ketoconazole, a imidazole-containing cytochrome inhibitor. HA inhibited proliferation of McA-RH7777 hepatoma cells. The absence of uptake system, its much higher potency at H3Rs, and its low intracellular levels suggested that HA interacted with H3Rs rather than cytochromes. In agreement, both imidazole H3R antagonists, a nonimidazole H3R antagonist, and the HDC inhibitor alpha-monofluoromethyl histidine increased cell proliferation (up to approximately 60%), revealing a H3R-mediated inhibition by endogenous HA. Moreover, exogenous HA inhibited the increase induced by alpha-FMH or H3R antagonists with a nanomolar potency. In conclusion, our findings show that HA regulates proliferation of McA-RH7777 hepatoma cells by interacting with autoinhibitory H3Rs.

Short- and long-term effects of antipsychotic drug treatment on weight gain and H1 receptor expression

The present study investigated body weight gain, food intake, open-field activity and brain histamine H1 receptor mRNA and protein expression in rats treated with three types of antipsychotics. Rats were divided into eight groups and treated with aripiprazole (2.25mg/kg/day), olanzapine (1.5mg/kg/day), haloperidol (0.3mg/kg/day) or vehicle (as control) for 1 or 12 weeks. Administration of olanzapine for 1 week led to a threefold increase in body weight gain and a 35% increase in fat deposits compared to controls (p<0.05). In the 12-week olanzapine treatment group, accumulative food intake was significantly higher in the first 7 weeks of treatment compared to controls (p<0.018), while body weight gain was significantly greater in the first 8 weeks compared to controls (p<0.045). Using in situ hybridization, we found that olanzapine treatment, but not aripiprazole or haloperidol treatment, significantly reduced H1 receptor mRNA expression in the arcuate hypothalamic nucleus (Arc: -18%, p=0.006, 1 week; -20%, p=0.008, 12 weeks) and ventromedial hypothalamic nucleus (VMH: -22%, p=0.006, 1 week; -19%, p=0.042, 12 weeks) compared to controls. The quantitative autoradiography data showed a reduction in VMH H1 receptor binding density after 1 (-12%, p=0.040) and 12 (-10%, p=0.094) weeks of olanzapine treatment. There were significant negative correlations between the levels of H1 receptor mRNA expression, and body weight gain and energy efficiency in the Arc and VMH after 1- and 12-week antipsychotic treatments in all groups. In addition, H1 receptor mRNA expression in the Arc showed a significant negative correlation with food intake and fat mass in all groups. Furthermore, there were negative correlations between H1 receptor binding density in the VMH and total fat mass and body weight gain after 1 week of antipsychotic treatment. The present study suggests that downregulated VMH and Arc H1 receptor expression may be a key factor contributing to olanzapine-induced obesity.

Molecular characterization of specific H1‐receptor agonists histaprodifen and its derivates on bovine aortic H1‐receptors

We determined the molecular properties of the selective and potent H1‐receptor agonist histaprodifen, its Nα substituted analogues (methyl‐, dimethyl‐, and imidazolylethyl‐ histaprodifen (suprahistaprodifen)) and o′‐, m′‐, p′‐pyridylbutylhistaprodifens. All derivates show high affinity for 3H‐mepyramine labelled bovine aortic H1‐receptor binding sites with the folowing order of potency: suprahistaprodifen &gt;dimethylhistaprodifen &gt;p′‐pyridylbutylhistaprodifen &gt;methylhistaprodifen &gt;m'‐pyridylbutylhistaprodifen &gt;histaprodifen &gt;o′‐pyridylbutylhistaprodifen &gt;histamine. Binding of histaprodifen and all derivates except dimethylhistaprodifen was differentially influenced by the addition of GTP.All drugs, except dimethylhistaprodifen, were activators of G‐proteins. Their order of potency was suprahistaprodifen &gt;histamine &gt;p′‐pyridylbutylhistaprodifen &gt;histaprodifen &gt;m′‐pyridylbutylhistaprodifen &gt;methylhistaprodifen &gt;o′‐ pyridylbutylhistaprodifen. Their effect was abolished by the addition of the H1‐receptor antagonist triprolidine (10μM). Our data suggest that histaprodifens are potent H1‐receptor ligands with diverse effects in our model system. Our results for the histaprodifen and its derivates are in agreement with their agonistic nature, as previously shown in the functional studies, dimethylhistaprodifen behaved as an antagonist in our study.

Sensitive determination of G-protein-coupled receptor binding ligands by solid phase extraction–electrospray ionization–mass spectrometry

High affinity Histamine H2-receptor binding ligands were assayed by automated solid phase extraction (SPE) coupled via electrospray ionization with a Quadrupole-Time-of-Flight mass spectrometer (Q-ToF-MS). The mass spectrometric behavior of these analytes was tested in aqueous solutions with several (nine) volatile salts, in different pH, and with various methanol contents. Out of the high amount of available ligands, three fluorescent-labeled molecules (5706, 5707, and 5708) were studied in detail. The limits of detection (LODs) for all three compounds obtained in mass spectrometric detection was 1 fmol (absolute) in continuous flow and FIA (flow injection analysis) measurements. The results obtained with FIA-fluorescence detection gave LODs a factor 10–100 times higher. A systematic investigation of sample solving conditions, loading flow conditions, and elution flow conditions made the automated SPE–MS coupling efficient. Ideally, the ligands were dissolved in MeOH–25 mM phosphate buffer (30:70 v/v; pH 11), the SPE loading flow comprised MeOH–25 mM phosphate buffer (30:70 v/v; pH 11) and the SPE elution flow contained MeOH–100 mM ammonium formate solution (90:10 v/v; pH 3). Using this method on a C 18-modified silica cartridge (C18, 5 μm, 100 A, 300 μm i.d. × 5 mm, LC Packings) assures high recovery and achieved LODs for all three compounds of 5 fmol (absolute). As an absolute amount of ligands specifically bound on H2-receptors in biochemical experiments is, as will be published elsewhere, between 10 and 100 fmol, the SPE–MS method for the basic compounds can be directly applied for these Histamine H2-receptors.

Model of a specific human histamine H3 receptor (hH3R) binding pocket suitable for virtual drug design

Model of a specific human histamine H3 receptor (hH3R) binding pocket suitable for virtual drug design

Traumatic brain injury results in mast cell increase and changes in regulation of central histamine receptors

Experimental fluid-percussion models produce brain injury by rapidly injecting saline into the closed cranium of rats. In this study our purpose was to determine how the central histaminergic system, which controls excitability and neurotransmitter release through G-protein coupled receptors, is affected by the pathophysiology of traumatic brain injury. We found that mast cell infiltration, as a result of the trauma, occurred primarily in the injured cortex and did not proceed beyond the fimbria of the hippocampus. In comparing injured animals with controls we found that H3 receptor binding densities are significantly decreased bilaterally in the cortex but are significantly increased bilaterally in the thalamus. H3 receptor binding densities may well be affected by mast cell secretion of mediators (i.e. histamine, heparin, leukotrienes), evidenced by detection of a cosecreted enzyme (mast cell tryptase) in the extracellular region. Moreover, we detected significant decreases in H1 and H3 receptor mRNA as well as Cu/Zn-dependent superoxide dismutase (SOD) mRNA in the thalamic region closest to the trauma. These significant decreases delineate the extent of cellular damage because of trauma and may underlie sustained cognitive and motor deficits displayed by these animals.

Preclinical Pharmacology of Bilastine,??a New Selective Histamine??H1 ??Receptor Antagonist

This study aimed to establish the receptor selectivity and antihistaminic activity of bilastine, a new selective antihistamine receptor antagonist. In vitro experiments were conducted using a receptor binding screening panel and guinea-pig and rat tissues. Antihistaminic activity was determined using H1 receptor binding studies and in vitro H1 antagonism studies conducted in guinea-pig tissues and human cell lines. Receptor selectivity was established using a receptor binding screening panel and a receptor antagonism screening conducted in guinea-pig, rat and rabbit tissues. Inhibition of inflammatory mediators was determined through the Schultz-Dale reaction in sensitised guinea-pig ileum. Bilastine binds to histamine H1-receptors as indicated by its displacement of [3H]-pyrilamine from H1-receptors expressed in guinea-pig cerebellum and human embryonic kidney (HEK) cell lines. The studies conducted on guinea-pig smooth muscle demonstrated the capability of bilastine to antagonise H1-receptors. Bilastine is selective for histamine H1-receptors as shown in receptor-binding screening conducted to determine the binding capacity of bilastine to 30 different receptors. The specificity of its H1-receptor antagonistic activity was also demonstrated in a series of in vitro experiments conducted on guinea-pig and rat tissues. The results of these studies confirmed the lack of significant antagonism against serotonin, bradykinin, leukotriene D4, calcium, muscarinic M3-receptors, alpha1-adrenoceptors, beta2-adrenoceptors, and H2- and H3-receptors. The results of the in vitro Schultz-Dale reaction demonstrated that bilastine also has anti-inflammatory activity. These preclinical studies provide evidence that bilastine has H1- antihistamine activity, with high specificity for H1-receptors, and poor or no affinity for other receptors. Bilastine has also been shown to have anti-inflammatory properties.