Effect of the H1 Antihistamine Chlorpheniramine Maleate on Histamine-Induced Symptoms in the Human Conjunctiva

Earlier studies have shown that intranasal chlorpheniramine (0.77%) can inhibit histamine-induced tickling, sneezing, and hypersecretion by a local effect on nerve fibres. The aim of the present study was to examine whether this solution had local anaesthetic of parasympatholytic properties. If neither of these properties are present it suggests that the anti-pruritic effects of the solution are caused by inhibition of H1 receptors, which in turn is indirect evidence for the presence of H1 receptors on nerve fibers. In a double-blind design 15 normal subjects were provoked with histamine in the eye after pretreatment with chlorpheniramine or with a local anaesthetic, oxybuprocain. Both drugs inhibited itching, but the H1 antihistamine was significantly more effective than the local anaesthetic (P less than 0.01). Corneal sensitivity was measured by an esthesiometer, and pupil difference was used as a measure for atropine activity. Chlorpheniramine had neither a local anaesthetic nor a parasympatholytic effect. This study has therefore strengthened the hypothesis that there are nervous H1 receptors in the mucous membranes of the eye and airways and has extended its application in animals to also include man.     

Regulation of histamine release from human basophil leucocytes: role of H1, H2 and H3 receptors

A novel class of histamine receptors (H3), controlling histamine synthesis and release, was described in rat and human brain and peripheral nerve endings. The present study was undertaken to evaluate whether H3 receptors contribute to the regulation of histamine release from human basophils. Basophil leucocytes were incubated with a H3 antagonist (thioperamide; concentrations ranging from 1 nM to 10 microM) or with a H3 ((R)alpha methyl-histamine; concentrations ranging from 1 to 100 mM), and subsequently were stimulated with optimal doses of anti-IgE and formyl-methionyl-leucyl-phenyl-alanine (f-met peptide). No significant modifications of histamine release were observed after incubation either with the H3 agonist or with the H3 antagonist. By contrast, a H2 antagonist (cimetidine; concentrations ranging from 1 to 100 microM) exerted a dose-dependent enhancing effect on anti-IgE- and, to a lesser extent, on f-met peptide-induced histamine release. A H1 antihistamine (chlorpheniramine; concentrations ranging from 100 nM to 1 microM), at the highest concentration employed, displayed an inhibitory activity on IgE-dependent and IgE-independent histamine release. Exogenous histamine was shown to exert a dose-dependent inhibitory effect on two-staged anti-IgE-induced histamine release. Taken as a whole, these results suggest that H3 receptors are not involved in the regulation of histamine release from human basophils; by contrast, H2 receptors participate in controlling histamine release from human basophils, as previously demonstrated by other authors.     

Pruritus-associated response mediated by cutaneous histamine H3 receptors

BACKGROUND: Histamine is one of the most common chemical mediators causing pruritus, and H1 receptor antagonists have been used as a first choice in its treatment. On the other hand, although the presence of H3 receptors has been identified in the skin, few studies have investigated the involvement of H3 receptors on pruritus. OBJECTIVE: The purpose of this study was to examine whether H3 receptor agonist or antagonist influences the incidence of scratching behaviour in ICR or mast cell-deficient WBB6F1-W/WV mice. METHODS: The mice were given an intradermal injection of H3 receptor agonist or antagonist into the rostral part of the back, and the occurrence of scratching behaviour at the injected site by the hind paws was counted over 60 min. RESULTS: H3 receptor antagonists, thioperamide and AQ0145 significantly increased the incidence of scratching behaviour in ICR mice. H3 receptor agonist, (R)-alpha-methylhistamine, had no effect. On the other hand, (R)-alpha-methylhistamine significantly inhibited thioperamide or AQ0145-induced scratching behaviour. In addition, both thioperamide and AQ0145 elicited scratching behaviour in mast cell-deficient WBB6F1-W/WV mice. CONCLUSION: From these results, it may be concluded that H3 receptors are involved in the modulation of pruritus in the skin, and mast cells are not essential in this response. In addition, H3 receptor agonists can be useful as a novel therapeutic approach against pruritus.     

Comparison of the central nervous system effects produce by six H1-receptor antagonists

Background A comprehensive comparative study of the central nervous system (CNS) properties of newer H₁-receptor antagonists is needed. Objective Our objective was to investigate the central nervous system eifects of u single manufacturer's recommended dose of six H₁-receptor antagonists, using appropriate controls. Methods Fifteen healthy subjects received astemizole 10mg, cetirizine 10mg, ketotifen 2mg, loratadine 10 mg, terfenadine 60mg, diphenhydramine 50mg or placebo. Before and 2-1.5 h after dosing, cognitive function was assessed using the P300-event-related potential, somnolence was assessed using a subjective score, and histamine skin tests were performed. Results In rank order from least to greatest effect on the P300 latency, the medications were: terfenadine, placebo, cetirizine, ketotifen, loratadine, astemizole and diphenhydramine. Only diphenhydramine increased the P300 latency significantly compared with baseline and placebo. Subjective somnolence was significantly greater than baseline and placebo after cetirizine, ketotifen and diphenhydramine. All the H₁-receptor antagonists suppressed the histamine-induced weal significantly compared with baseline. Conclusions The H₁-receptor antagonists tested affected cognitive functioning and somnolence to different extents, although all produced satisfactory peripheral H₁-blockade.     

Effects of topical treatment with H1 and H2 antagonists on clinical symptoms and nasal vascular reactions in patients with allergic rhinitis

Fifteen asymptomatic subjects with allergic rhinitis participated in a double-blind, randomized, crossover, placebo-controlled study. The subjects were pretreated intranasally with a single dose of a selective H1 receptor antagonist, levocabastine, and/or selective H2 receptor antagonist, ranitidine, prior to a nasal allergen challenge. The nasal symptoms obtained at the challenge were assessed using a scoring technique 15 min after the allergen exposure. The nasal airway resistance was determined twice prior to and once after the allergen challenge using anterior rhinomanometry. The nasal mucosal blood flow was determined before and 15 min after allergen challenge using the 133Xe wash-out technique. After pretreatment with the H1 antagonist there was a statistically significant reduction in the number of sneezes and rhinorrhea compared to pretreatment with placebo. Pretreatment with the H2 receptor significantly decreased the rhinorrhea but not the sneeze. The nasal blockage was unaffected by both the H1 and the H2 antagonists. Pretreatment with the H1 and/or the H2 antagonists inhibited the reduction in the nasal mucosal blood flow induced by the allergen challenge to a significant degree. The present findings suggest that topical treatment with the highly selective histamine antagonist, levocabastine, inhibits allergen-induced reflex-mediated symptoms. H1 and H2 receptors do not appear to be involved in the regulation of the tone of the capacitance vessels. This indicates that a more complex mechanism participates in the induction of nasal blockage than the direct effect of histamine on H1 and H2 receptors on the capacitance vessels of the nasal mucosa alone. Both H1 and H2 receptors are of importance for the regulation of nasal mucosal blood flow during the allergic reaction.     

Reactivity to sodium tetrachloropalladate (Na2[PdCl4]) compared to PdCl2 and NiCl2 in lymphocyte proliferation tests

Background: For patch testing, replacement of the commonly used palladium dichloride (PdCl₂) by sodium tetrachloropalladate (Na₂[PdCl₄]) was recently demonstrated to improve test accuracy and show a significant correlation with nickel (Ni), supporting the concept of cross‐reactivity between Pd and Ni. A promising alternative to metal allergy patch testing is the in vitro lymphocyte proliferation test (LTT). Objectives: The aim of this study was to test whether Na₂[PdCl₄] is also more sensitive for diagnosing Pd allergy with a standardized LTT. Patients/methods: After determining optimal nontoxic and nonmitogenic concentrations for Na₂[PdCl₄], blood samples from 105 patients with clinical suspicion of metal allergy were tested with an LTT called memory lymphocyte immuno stimulation assay for Na₂[PdCl₄], PdCl₂ and NiCl₂. Reaction profiles were analysed for concordant positive reactions. Results: Using the conventional cut‐off of stimulation index ≥ 3, 74.3% showed a positive reaction to NiCl₂, 15.2% to PdCl₂ and 28.6% to Na₂[PdCl₄]. All positive results to PdCl₂ were covered by Na₂[PdCl₄]. From the 30 positive reactions to Na₂[PdCl₄], 26 (87%) were concordant for NiCl₂ reactivity. Conclusion: In LTT, the use of Na₂[PdCl₄] results in more positive reactions in Pd allergy testing which are in concordance with positive reactions to PdCl₂ and NiCl₂.     

In vitro effects of H1-antihistamines on histamine and PGD2 release from mast cells of human lung, tonsil, and skin

Mast cells from different anatomic sites differ in cytochemistry and response to various secretory stimuli. We have investigated whether responsiveness to the second-generation H₁-receptor antagonists, which are important first-line drugs for the relief of symptoms in patients with chronic urticaria and allergic rhinoconjunctivitis, also differs according to the site of origin of mast cells. The effects of terfenadine, ketotifen, and cetirizine were therefore examined in relation to the IgE-dependent release of histamine and prostaglandin D₂ (PGD₂) from dispersed human lung, tonsil, and skin mast cells. Terfenadine had a biphasic effect on lung and skin mast cells: at low concentrations, a concentration-dependent inhibition of histamine release from lung and skin mast cells was observed, whereas at higher concentrations the drug stimulated mediator release. Even at a high concentration, terfenadine inhibited mediator release from tonsil mast cells. Ketotifen had low potency as an inhibitor of mediator release from lung and tonsil mast cells. In skin mast cells, no inhibition of mediator release was observed below 1.0 μM, and above that concentration it induced mediator release. Cetirizine, a much less lipophilic drug than the others tested, did not induce mediator release from mast cells even at concentrations up to 100 μM. This drug showed concentration-dependent inhibition of IgE-dependent mediator release from lung and tonsil mast cells only. Our results show that human mast cells are heterogeneous with respect to modulation of mediator release by these H₁-antihistamines. In particular, differences were observed between skin mast cells and those dispersed from lung and tonsils.     

Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phi p 1, a major grass pollen allergen

Background and Objective The mechanisms operative in specific immunotherapy (SIT) of Type I allergy are not completely understood. In the present study we evaluated immunological changes during SIT in pollinosis. Method Eight patients suffering from pollinosis (monosensitized to grass pollen) were treated with conventional SIT. All subjects had IgE specific for Phi p 1. a major allergen of timothy grass. In vitro changes in the immunological reactivity to grass pollen extract and to recombinant Phi p 1 were evaluated. Subjects were examined at three occasions: before, after 3 months and after I year of SIT. Results Serological analysis revealed a marked increase of grass pollen- and Phi p 1-specific IgG, titres of specific IgE did not change significantly. Lymphoproliferative responses to grass pollen extract and rPhl p 1 were reduced already after 3 months of treatment. Accordingly, the cloning efficiency for Ph1 p 1-specific T-cell clones (TCC) dropped markedly in all patients. The majority of allergen-specific TCC raised before SIT revealed a TH₂-like pattern of cytokine production. TCC established after SIT revealed TH₁ characteristics. This shift was due to a decrease in IL-4 rather than an increase in IFN-production by T cells. Investigations of the epitopes recognized by T cells before and after SIT did not reveal the outgrowth of new (ldquo;protecting”) specificities. We could not observe induction of allergen-speeific CD8⁺ lymphocytes (supressor cells). Conclusion Our data indicate that — on the level of TH lymphocytes — SIT induces tolerance to the allergen and a modulation of the cytokine pattern produced in response to allergen stimulation.     

Molecular properties and signalling pathways of the histamine H1 receptor

With cloning of the gene encoding the histamine H₁ receptor, a new area of histamine research has become reality. Finally, it seems feasible to study the target of the thera-peutically important clans of antihistamine. Expression of the genes in mammalian cells allows detailed investigations of the various signal transduction routes of the histamine H₁ receptor. Moreover, using molecular biological techniques, it is now possible to investigate ligand receptor interaction at the molecular level. Studies with mutant H₁ receptors have shown that H₁ antagonists bind to a specific amino acid residues in TM3 and 5. It is expected that these new developments will provide much fundamental knowledge on the ligand interaction with the H₁ receptor.     

Ganglioside GM2 N-acetyl-ß-D-gafactosaminidase and asialo GM2 (GA2) N-acetyl-ß-D-galactosaminidase; studies in human skin fibroblasts

Ganglioside G_M2 and its asialo-derivative, G_A2 were radiolabeled in their N-acetyl-D-galactosaminyl moieties by oxidation with galactose oxidase and reduction with tritiated sodium borohydride. Specific activities of 6 × 10⁴ dpm/nmol (G_M2) and 1.8 × 10⁶ dpm/nmol (G_A2) were achieved. About 98% of the label was in N-acetyl-D-galactosamine. Using these substrates, an assay was developed for G_M2-N-acetyl-β-D-galactosaminidase (E.C.3.2.1.30) and G_A2-N-acetyl-β-D-galactosaminidase (E.C.3.2.1.30) activities in human cultured skin fibroblasts. The products of the G_M2 cleaving reaction were identified as N-acetylgalactosamine and ganglioside G_M3- Both G_M2 and G_A2 cleaving activities were stimulated about 5-fold by purified sodium taurocholate, and this stimulation was inhibited by neutral detergents, lipids and albumin at low concentrations. Addition of various salts, reducing agents and a protein activator factor from human liver of Li et al. (1973) did not stimulate G_M2-N-acetyl-β-D-galactosaminidase activity beyond that found with sodium taurocholate. Under optimal conditions, control fibroblast supernates cleaved ganglioside G_M2 at a rate of 3.7 nmol/mg protein/h compared to 1100 for G_A2-N-acetyl-β-D-galactosaminidase and 4700 for 4-methylumbelliferyl-N-acetyl-β-D-glucosaminidase. Supernates from two patients with Tay-Sachs disease had markedly reduced activity levels for G_M2-N-acetyl-β-D-galactosaminidase but not for the other two substrates. Supernates from two patients with Sandhoff's disease had reduced activities for all three substrates. A supernate from one patient with juvenile G_M2 gangliosidosis cleaved G_M2 at a somewhat faster rate than those from Tay-Sachs or Sandhoff's patients. Two healthy adult women with markedly reduced hexosaminidase A activities using 4MU-N-acetyl-β-D-glucosaminide as substrate had approximately half-normal activities using G_M2 as substrate. A patient with the Tay-Sachs phenotype but with a partial deficiency of hexosaminidase A using the 4-MU substrate had a profound deficiency using G_M2 as substrate. In such unusual hexosaminidase mutants, assays using G_M2 as substrate are better indicators of phenotype than those using synthetic substrates.     

Negative crosstalk between M1 and M2 muscarinic autoreceptors involves endogenous adenosine activating A1 receptors at the rat motor endplate

At the rat motor nerve terminals, activation of muscarinic M₁ receptors negatively modulates the activity of inhibitory muscarinic M₂ receptors. The present work was designed to investigate if the negative crosstalk between muscarinic M₁ and M₂ autoreceptors involved endogenous adenosine tonically activating A₁ receptors on phrenic motor nerve terminals. The experiments were performed on rat phrenic nerve-hemidiaphragm preparations loaded with [³H]-choline (2.5 μCi/ml). Selective activation of muscarinic M₁ and adenosine A₁ receptors with 4-(N-[3-clorophenyl]-carbamoyloxy)-2-butyryltrimethylammonium (McN-A-343, 3 μM) and R-N⁶-phenylisopropyladenosine (R-PIA, 100 nM), respectively, significantly attenuated inhibition of evoked [³H]-ACh release induced by muscarinic M₂ receptor activation with oxotremorine (10 μM). Attenuation of the inhibitory effect of oxotremorine (10 μM) by R-PIA (100 nM) was detected even in the presence of pirenzepine (1 nM) blocking M₁ autoreceptors, suggesting that suppression of M₂-inhibiton by A₁ receptor activation is independent on muscarinic M₁ receptor activity. Conversely, the negative crosstalk between M₁ and M₂ autoreceptors seems to involve endogenous adenosine tonically activating A₁ receptors. This was suggested, since attenuation of the inhibitory effect of oxotremorine (10 μM) by McN-A-343 (3 μM) was suppressed by the A₁ receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (2.5 nM), and by reducing extracellular adenosine with adenosine deaminase (0.5 U/mL) or with the adenosine transport blocker, S-(p-nitrobenzyl)-6-thioinosine (NBTI, 10 μM). The results suggest that the negative crosstalk between muscarinic M₁ and M₂ autoreceptors involves endogenous adenosine outflow via NBTI-sensitive (es) nucleoside transport system channelling to the activation of presynaptic inhibitory A₁ receptors at the rat motor endplate.     

Role of tachykinin NK1 and NK2 receptors in allergen-induced early and late asthmatic reactions, airway hyperresponsiveness, and airway inflammation in conscious, unrestrained guinea pigs

Using a guinea pig model of allergic asthma, we investigated the effects of the inhaled, highly selective nonpeptide tachykinin NK₁ and NK₂ receptor antagonists SR 140333 and SR 48968, respectively, on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions, and infiltration of inflammatory cells in the airways. Both SR 140333 (100 nM, 3 min) and SR 48968 (100 nM, 3 min) had no effect on the severity of the EAR, while the NK₂ receptor antagonist SR 48968, but not the NK₁ receptor antagonist SR 140333, caused significant inhibition of the LAR. SR 140333 significantly reduced the allergen-induced AHR to histamine, both after the EAR and the LAR. By contrast, SR 48968 did not affect the AHR after the EAR, but significantly attenuated the AHR after the LAR. Bronchoalveolar lavage studies performed after the LAR indicated that SR 140333 caused significant inhibition of allergen-induced infiltration of eosinophils, neutrophils and lymphocytes, while SR 48968 attenuated the infiltration of neutrophils and lymphocytes, but not of eosinophils. Both NK receptor antagonists tended to reduce the accumulation of ciliated epithelial cells in the airways. These results indicate that NK₁ and NK₂ receptors are importantly, but differentially, involved in the development of allergen-induced airways obstruction, AHR and infiltration of inflammatory cells in the airways. Therefore, both NK₁ and NK₂ receptor antagonists, or dual NK₁ and NK₂ antagonists, could be useful in the treatment of allergic asthma.     

Pulmonary function changes in asthmatics associated with low-level SO2 and NO2 air pollution, weather, and medicine intake

This paper presents the response in subjects with asthma to gaseous air-pollution levels, weather, and medicine intake as identified by principal-component analysis and neutral network techniques. Pulmonary function measured by respiratory peak-flow rate in nonallergic asthmatics was associated with ambient, low level, air-pollution concentrations of sulphur dioxide and nitrogen dioxide, temperature, relative humidity, and medicine intake. Results from 27 nonallergic asthmatics aged 18–60 years with well-characterized bronchial asthma and regular medical treatment were analyzed from two cities. During an 8-month period, each subject kept a diary table, which included symptoms, lung function (evening peak flow), medicine intake, and tobbaco smoking.
High intake of medicine and high ambient temperatures correspondend to decreased peak flow. The changes in temperature did not occur in situations with low medicine intake. During frost periods, peak-flow values decreased independently of medicine intake and levels of so². During other times, increased levels of so² and no² increased temperature, and increased intake of medicine, and low relative humidity corresponded to synergistically to decreased peak flow at levels above 40μ/m³.     

A prostaglandin D2 receptor antagonist modifies experimental asthma in sheep

Background Prostaglandin (PG) D₂ is the major cylooxygenase metabolite released by mast cells upon allergen stimulation, and elicits responses through either the prostanoid DP1 receptor and/or the chemoattractant receptor homologous molecule expressed on T-helper type 2 (Th2) cells (CRTH2/DP2). Experimental evidence suggests that stimulation of one or both these receptors contributes to asthma pathophysiology.
Objective The aim of this study was to test the hypothesis that the prostanoid DP1 receptor contributes to asthma pathophysiology by determining the efficacy of an orally active antagonist for this receptor, S-5751, on allergen-induced bronchoconstriction, airway hyperresponsiveness (AHR) and cellular inflammation in the sheep model of asthma.
Methods PGD₂-induced cyclic adenosine monophosphate (cAMP) production in platelet-rich plasma was used to establish the in vitro efficacy of S-5751. In vivo , sheep naturally allergic to Ascaris suum were challenged with an aerosolized antigen with and without S-5751 treatment (given 4 days before and for 6 days after the challenge).
Results S-5751 inhibited PGD₂-induced cAMP production in platelet-rich plasma with an IC₅₀ value of 0.12 μ m . S-5751 at 30 mg/kg, but not at 3 mg/kg, reduced the early bronchoconstriction and inhibited the late bronchoconstriction. AHR and inflammatory cell infiltration in bronchoalveolar lavage fluid at days 1 and 7 were also inhibited with the 30 mg/kg dose. The responses observed with S-5751 at 30 mg/kg were comparable with those with montelukast treatment (0.15 mg/kg, twice a day, intravenous); however, S-5751 did not block inhaled leukotrieneD₄-induced broncoconstriction.
Conclusion Prostanoid DP1 receptor inhibition may represent an alternative target for asthma therapy.     

GA2LEN (Global Allergy and Asthma European Network) addresses the allergy and asthma 'epidemic'

Allergic diseases represent a major health problem in Europe. They are increasing in prevalence, severity and costs. The Global Allergy and Asthma European Network (GA²LEN), a Sixth EU Framework Program for Research and Technological Development (FP6) Network of Excellence, was created in 2005 as a vehicle to ensure excellence in research bringing together research and clinical institutions to combat fragmentation in the European research area and to tackle Allergy in its globality. The Global Allergy and Asthma European Network has benefited greatly from the voluntary efforts of researchers who are strongly committed to this model of pan-European collaboration. The network was organized in order to increase networking for scientific projects in allergy and asthma around Europe and to make GA²LEN the world leader in the field. Besides these activities, research has also been carried out and the first papers are being published. Achievements of the Global Allergy and Asthma European Network can be grouped as follows: (i) those for a durable infrastructure built up during the project phase, (ii) those which are project-related and based on these novel infrastructures, and (iii) the development and implementation of guidelines. The major achievements of GA²LEN are reported in this paper.