Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allergic rhinitis (AR) is the most common chronic condition in children and is estimated to affect up to 40% of all children. It is usually diagnosed by the age of 6 years. The major impact in children is due to co-morbidity of sinusitis, otitis media with effusion, and bronchial asthma. AR also has profound effects on school absenteeism, performance and quality of life. Pharmacotherapy for AR should be based on the severity and duration of signs and symptoms. For mild, intermittent symptoms lasting a few hours to a few days, an oral second-generation antihistamine should be used on an as-needed basis. This is preferable to a less expensive first-generation antihistamine because of the effect of the latter on sedation and cognition. Four second-generation antihistamines are currently available for children under 12 years of age: cetirizine, loratadine, fexofenadine and azelastine nasal spray; each has been found to be well tolerated and effective. There are no clearcut advantages to distinguish these antihistamines, although for children under 5 years of age, only cetirizine and loratadine are approved. Other agents include pseudoephedrine, an oral vasoconstrictor, for nasal congestion, and the anticholinergic nasal spray ipratropium bromide for rhinorrhoea. Sodium cromoglycate, a mast cell stabiliser nasal spray, may also be useful in this population. For patients with more persistent, severe symptoms, intranasal corticosteroids are indicated, although one might consider azelastine nasal spray, which has anti- inflammatory activity in addition to its antihistamine effect. With the exception of fluticasone propionate for children aged 4 years and older, and mometasone furoate for those aged 3 years and older, the other intranasal corticosteroids including beclomethasone dipropionate, triamcinolone, flunisolide and budesonide are approved for children aged 6 years and older. All are effective, so a major consideration would be cost and safety. For short term therapy of 1 to 2 months, the first-generation intranasal corticosteroids (beclomethasone dipropionate, triamcinolone, budesonide and flunisolide) could be used, and mometasone furoate and fluticasone propionate could be considered for longer-term treatment. Although somewhat more costly, these second-generation drugs have lower bioavailability and thus would have a better safety profile. In patients not responding to the above programme or who require continuous medication, identification of specific triggers by an allergist can allow for specific avoidance measures and/or immunotherapy to decrease the allergic component and increase the effectiveness of the pharmacological regimen.
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PMID:Clinical prescribing of allergic rhinitis medication in the preschool and young school-age child: what are the options? 1152 Feb 56

The effect of alpha2-selective adrenoreceptor activation on nasal cavity dimension in an experimental model of congestion has not been defined. Presently, we used acoustic rhinometry to evaluate the decongestant activity of BHT-920, a selective alpha2-adrenergic agonist against nasal congestion produced by intranasal compound 48/80. Administration of the mast cell liberator compound 48/80 (1%) into a nasal passageway decreased ipsilateral volume and minimum cross-sectional area by 73 +/- 4% and 42 +/- 6%, respectively. The congestant effect of compound 48/80 was blocked by topical BHT-920 (0.3 and 1%) in a dose related manner. In addition, the decrease in minimum cross-sectional area produced by compound 48/80 was attenuated after topical BHT-920 treatment. As a comparison we also evaluated the topical decongestant activity effects of the alpha1-adrenergic agonist phenylephrine, and the nonselective alpha-agonist oxymetazoline. Both phenylephrine (0.1-1.0%) and oxymetazoline (0.01-0.3%) produced decongestion. The blood pressure effects of these three drugs also were evaluated. At doses of 0.3 and 1.0%, BHT-920 did not produce hypertension. In contrast, oxymetaZoline (0.01-0.1%) produced a transient hypertension that peaked at 15 minutes and fully recovered 45 minutes after administration. The hypertensive effect of phenylephrine at 0.3 and 1.0% lasted over 60 minutes. The present findings indicate that selective alpha2-agonists may produce decongestant activity with an improved cardiovascular profile compared with current sympathomimetic drugs such as phenylephrine.
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PMID:Intranasal application of the alpha2-adrenoceptor agonist BHT-920 produces decongestion in the cat. 1177 50

Experiments were undertaken to characterize a noninvasive chronic, model of nasal congestion in which nasal patency is measured using acoustic rhinometry. Compound 48/80 was administered intranasally to elicit nasal congestion in five beagle dogs either by syringe (0.5 ml) in thiopental sodium-anesthetized animals or as a mist (0.25 ml) in the same animals in the conscious state. Effects of mast cell degranulation on nasal cavity volume as well as on minimal cross-sectional area (A(min)) and intranasal distance to A(min) (D(min)) were studied. Compound 48/80 caused a dose-related decrease in nasal cavity volume and A(min) together with a variable increase in D(min). Maximal responses were seen at 90-120 min. Compound 48/80 was less effective in producing nasal congestion in conscious animals, which also had significantly larger basal nasal cavity volumes. These results demonstrate the utility of using acoustic rhinometry to measure parameters of nasal patency in dogs and suggest that this model may prove useful in studies of the actions of decongestant drugs.
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PMID:Measurement of nasal patency in anesthetized and conscious dogs. 1179 72

The aim of this project was to develop and pharmacologically characterize an experimental dog model of nasal congestion in which nasal patency is measured using acoustic rhinometry. Solubilized compound 48/80 (0.3-3.0%) was administered intranasally to thiopental anesthetized beagle dogs to elicit nasal congestion via localized mast cell degranulation. Compound 48/80-induced effects on parameters of nasal patency were studied in vehicle-treated animals, as well as in the same animals pretreated 2 hours earlier with oral d-pseudoephedrine or chlorpheniramine. Local mast cell degranulation caused a close-related decrease in nasal cavity volume and minimal cross-sectional area (Amin) together with a highly variable increase in nasal secretions. Maximal responses were seen at 90-120 minutes after 48/80 administration. Oral administration of the adrenergic agonist, d-pseudoephedrine (3.0 mg/kg), significantly antagonized all of the nasal effects of compound 48/80 (3.0%). In contrast, oral administration of the histamine H1 receptor antagonist chlorpheniramine (10 mg/kg) appeared to reduce the increased nasal secretions but was without effect on the compound 48/ 80-induced nasal congestion (i.e., volume and Amin). These results show the effectiveness of using acoustic rhinometry in this anesthetized dog model. The observations that compound 48/80-induced nasal congestion was prevented by d-pseudoephedrine pretreatment, but not by chlorpheniramine, suggest that this noninvasive model system may provide an effective tool with which to study the actions of decongestant drugs in preclinical investigations.
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PMID:Acoustic rhinometry in the dog: a novel large animal model for studies of nasal congestion. 1189 94

Histamine release from mast cells is a primary mediator of rhinorrhea, nasal mucosal swelling, increased secretion, sneezing, pruritus and congestion that occur in allergic rhinitis. It is well known that histamine H(1) receptor antagonists inhibit the itch and rhinorhea, but do not block the allergic nasal congestion. A growing body of evidence shows that in addition to histamine H(1) receptors, activation of H(3) receptors may contribute to the procongestant nasal actions of histamine. Activation of the prejunctional histamine H(3) receptor modulates sympathetic control of nasal vascular tone and resistance. The present study was conducted to further characterize the role of histamine H(3) receptors on neurogenic sympathetic vascular contractile responses in isolated porcine nasal turbinate mucosa. We presently found that the histamine H(3) receptor agonist, (R)-alpha-methylhistamine (10-1000 nM), inhibited electrical field stimulation-induced sympathetic vasomotor contractions in a concentration-dependent fashion. Pretreatment with either of the selective histamine H(3) receptor antagonists, thioperamide and clobenpropit, blocked the sympathoinhibitory effect of (R)-alpha-methylhistamine in porcine turbinate mucosa. The effect of compound 48/80, an agent that elicits the release of endogenous histamine from mast cells on nasal sympathetic contractile responses, was also tested. The action of compound 48/80 to release mast cell-derived histamine in the nose mimics many of the nasal responses associated with allergic rhinitis, extravascular leakage and decreased nasal patency. We presently found that compound 48/80 also inhibited the electrical field stimulation-induced sympathetic response. Pretreatment with the H(3) receptor antagonist clobenpropit blocked the sympathoinhibitory action of compound 48/80 on sympathetic contractile responses in nasal mucosa. Taken together, these studies indicate that histamine H(3) receptors modulate vascular contractile responses by inhibition of noradrenaline release from sympathetic nerve terminals in nasal mucosa. It is further suggested that histamine H(3) receptors may play a role in the regulation of vascular tone and nasal patency in allergic nasal congestive disease.
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PMID:Histamine H3 receptor activation inhibits neurogenic sympathetic vasoconstriction in porcine nasal mucosa. 1235 75

Seasonal allergic rhinitic (SAR) subjects are more sensitive to nasal irritants than nonrhinitic (NR) subjects; however, the mechanism underlying this difference is unclear. This study sought to determine whether irritant-induced nasal congestion involves mast cell degranulation. Eight SAR and eight NR subjects were exposed to both 1.0 parts per million chlorine and filtered air in separate visits; exposures were via nasal mask and lasted 15 min. Rhinomanometry was performed before, immediately after and 15 min after exposure. Following > or = 2 weeks, exposures and symptom reporting were repeated with nasal lavage, rather than rhinomanometry, pre- and postexposure. A separate substudy using rye grass antigen provided a positive control. Mast cell tryptase was measured in nasal lavage fluid from both substudies using an automated fluoroenzyme immunoassay. Chlorine provocation significantly increased nasal airway resistance in SAR but not NR subjects. Conversely, tryptase levels in nasal lavage fluid were unaffected. Nasal allergen challenge significantly increased both nasal obstruction and nasal lavage tryptase in SAR subjects. Irritant-induced nasal congestion is more pronounced among seasonal allergic rhinitic than nonrhinitic subjects. However, unlike nasal allergen challenge, the mechanism of response to chlorine does not appear to involve mast cell degranulation.
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PMID:Chlorine inhalation produces nasal congestion in allergic rhinitics without mast cell degranulation. 1276 52

Perennial allergic rhinitis is an inflammatory disorder characterized by symptoms of nasal congestion, rhinorrhea, sneezing, and itching. The prevalence of allergic rhinitis is quite common and affects 20% or more of various populations. Some patients with allergic rhinitis are symptomatic only during the pollen season, while many others are allergic to multiple allergens including indoor allergens such as house dust mites, animal dander, cockroaches, and fungi, which lead to perennial symptoms. Immunoglobulin (Ig)-E is the proximate cause of perennial allergic rhinitis. Circulating IgE antibodies bind to the high affinity IgE receptor on mast cells and basophils. IgE antibodies, bound to the receptors crosslinked by allergen, initiate the secretion of inflammatory mediators including histamine, leukotrienes, and cytokines. These mediators can induce both acute and chronic changes that result in symptoms of allergy. Many therapies are approved for the treatment of allergic rhinitis including intranasal corticosteroids, antihistamines with or without decongestants, and nasal cromolyn sodium (sodium cromoglicate). Allergen avoidance is the mainstay of therapy for many patients but is not always practical. For those patients who have not responded to appropriate medications, allergen specific immunotherapy may also be effective.A number of studies with omalizumab have shown that it is effective in the treatment of seasonal allergic rhinitis induced by pollen such as ragweed and birch pollen. Omalizumab is a molecularly cloned humanized monoclonal antibody inhibiting human IgE. It binds specifically to the region of the IgE molecule that binds to the IgE receptor on the mast cell or basophils. Because omalizumab cannot bind IgE molecules that are already bound to the surface receptors on mast cells and basophils, it does not stimulate secretion of mediators from these cells. Omalizumab does not appear to stimulate an immune response against itself. It rapidly reduces free serum IgE levels by over 95% when administered at therapeutic doses and also results in the reduction of IgE receptors on mast cells and basophils. The combined effects of reduction of both free IgE in serum and the receptor density on the mast cells or basophils results in decreased allergen-stimulated mediator release. Preliminary studies in the treatment of perennial allergic rhinitis supports omalizumab's efficacy and safety. The compound has been well tolerated. Aside from urticarial reactions, adverse effects appear to be minimal. Omalizumab is the first of several new immune-based specifically targeted molecules that may prove to be extremely valuable in the treatment of perennial allergic rhinitis, as it is often unresponsive to traditional therapies.
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PMID:Etiopathogenesis and management of perennial allergic rhinitis: a state-of-the-art review. 1517 93

Allergic rhinitis is characterized by a hypersensitive immune response in the upper airways to seasonal or perennial allergens leading to episodes of sneezing, itching, runny nose and nasal congestion. These symptoms are mainly the manifestations of a large number of mediators released by mast cells and basophils localized in the nasal mucosa, following their activation via allergen-specific immunoglobulin E (IgE) receptors. Current medications antagonize the action of distinct mediators such as histamine and leukotrienes for symptom relief, or block the production of pro-inflammatory cytokines to suppress allergic inflammation. Notably, rather than neutralizing individual mediators, Syk kinase inhibitors can block the allergen-induced release of all mast cell mediators and the production of most eicosanoids and cytokines. Thus, Syk kinase represents an attractive therapeutic target for acute and chronic allergic inflammation. Syk kinase inhibitors are now entering clinical trials. Using cell-based structure-activity relationships with primary human mast cells, a series of 2,4-diaminopyrimidine Syk kinase inhibitors was developed. One of these compounds, referred to as R112, exhibited suitable characteristics for intranasal delivery and was tested for safety and efficacy in allergic rhinitis patients. In a park environment, R112 showed remarkable amelioration of acute allergic rhinitis symptoms with rapid onset of action. These results demonstrate the clinical significance of inhibiting Syk in allergic upper airway disorders.
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PMID:Syk inhibitors as treatment for allergic rhinitis. 1766 74

Cold air-induced rhinitis is a common complaint of individuals with chronic allergic or nonallergic rhinitis and those with no chronic nasal disease. It is characterized by rhinorrhea, nasal congestion, and nasal burning that appear within minutes of exposure to cold air and dissipate soon after exposure is terminated. The symptoms of cold-air rhinitis are reproduced experimentally with nasal cold-air provocation. This procedure has shown that nasal mast cell activation and sensory nerve stimulation are associated with the development of nasal symptoms. Sensory nerve activation generates a cholinergic reflex that leads to rhinorrhea; therefore, anticholinergic agents are highly effective in treating cold-air rhinitis. Experimental data suggest that individuals with nasal cold-air sensitivity may have reduced ability to compensate for the water loss that occurs during exposure to cold air. Therefore, the symptoms of cold air-induced rhinitis may reflect the activation of compensatory mechanisms to restore mucosal homeostasis.
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PMID:Upper airways reactions to cold air. 1841 52

Allergic rhinitis (AR) is characterized by inflammation of the nasal mucosa with hypersensitivity resulting from seasonal or perennial responses to specific environmental allergens and by symptoms like nasal rubbing, sneezing, rhinorrhea, lacrimation, nasal congestion and obstruction, and less frequently cough. KOB extracts, which is a polyherbal medicine consisting of 5 different herbs (Atractylodes macrocephala, Astragalus membranaceus, Saposhnikovia divaricata, Ostericum koreanum and Scutellaria baicalensis) had commonly been used for the treatment of various allergic diseases showed an anti-allergic effect by modulating mast cell-mediated allergic responses in allergic rhinitis, recently. On the other hand, pseudoephedrine is a sympathomimetic amine commonly used to relieve congestion in patients with allergic rhinitis and common colds. Considering the KOB's therapeutic mechanism, the combination with pseudoephedrine would be suitable for allergic rhinitis. This study is to obtain an effective extended release formulation using pseudoephedrine and KOB extracts to reduce side effects of drug due to repeated dosing and improve the compliance of patients for treatment of rhinitis and nasal decongestion. So, the fixed-dose combination tablet of pseudoephedrine and KOB extracts was prepared by direct compression and characterized by drug content, flowing characteristics and dissolution test. The drug content of baicalin of KOB extracts was within the range of 95-105% except for T1 formulation. The hardness and friability values of all formulations ranged from 9 to 13 kp and less than 1%, respectively. Taken together, T4 or T8 could be a stable fixed-dose combination tablet for extended release of pseudoephedrine and KOB extracts for nasal rhinitis.
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PMID:A stable fixed-dose combination tablet of pseudoephedrine and KOB extracts for the extended release. 2378 Apr 99


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