Neural aspects of allergic rhinitis

PURPOSE OF REVIEW: Recent advances have helped to clarify the role of nerves in allergic rhinitis. RECENT FINDINGS: Mast cell histamine release activates histamine H1 receptors on a subset of nonmyelinated Type C afferent trigeminal neurons to convey the sensation of itch. The itch nerves may be distinct from those responsible for burning pain and the dull ache of congestion. Activation of brain stem centers leads to cognition of nasal pruritus, generation of the systemic sneeze reflex and recruitment of local nasal parasympathetic reflexes. These cholinergic reflexes stimulate M3 muscarinic receptors on the submucosal glands to cause exocytosis and the thick mucous discharge of allergic rhinitis. The importance of these neural pathways is demonstrated by the benefits of antihistamines to block itch and sneeze, and anticholinergic drugs to block glandular secretion. One open question remains the role of mediators of allergic inflammation on the sensitivity and reactivity of afferent neurons and these secretory reflexes. SUMMARY: The neurology of the nose helps to explain the sensations encountered in allergic rhinitis and opens new frontiers for drug discovery.     

抗组胺药在变应性鼻炎中的作用机制及应用进展

变应性鼻炎（AR）是一种鼻黏膜的慢性非感染性炎症,主要是由机体接触致敏变应原后诱发的由特异性免疫球蛋白E（IgE）介导的、多种炎性细胞（如肥大细胞、嗜碱性粒细胞等）参与的鼻黏膜的高敏反应。组胺在AR发病中发挥重要作用,是引起鼻痒、喷嚏、流涕等临床症状的核心介质。抗组胺药物通常通过拮抗组胺相关受体来阻断组胺与受体结合,从而影响变态反应发生的过程。因此,抗组胺药在AR治疗中的应用也越来越重要而广泛。本文主要就抗组胺药在AR中的作用机制及治疗进展作一综述,探讨其在AR的应用价值。     

组胺H4受体及其拮抗剂对变应性鼻炎大鼠的作用研究

目的 通过变应性鼻炎(allergic rhinitis,AR)动物模型,观察组胺H4受体拮抗剂JNJ 7777120对AR大鼠的影响.方法 60只Wistar大鼠以随机数字表法分为5组,每组12只,分别为:正常对照(NC)组、AR模型未处理(AR)组、组胺H1受体拮抗剂氯雷他定处理(HR1)组、组胺H4受体拮抗剂JNJ 7777120处理(HR4)组及组胺H1、H4受体拮抗剂联合处理(HR1+4)组.以卵清蛋白建立大鼠AR模型,比较各组大鼠喷嚏、抓鼻次数、血清总IgE、白细胞介素(interleukin,IL)4、γ干扰素(interferon-γ,IFN-γ)以及及鼻腔灌洗液中趋化因子Eotaxin含量的差异.采用SPSS 13.0软件对数据进行分析.结果 各干预(HR1、HR4、HR1+4)组与AR组相比喷嚏、抓鼻次数、血清总IgE、IL-4、趋化因子Eotaxin含量均显著下降,而IFN-γ显著升高,差异有统计学意义(P值均0.05).HR4组大鼠平均((x)±s,下同)喷嚏、抓鼻次数、血清总IgE、IL-4分别为(29.3±6.5)次、(28.4±7.0)次、(147.67±28.79)mg/ml、(289.05±16.94)Pg/ml,较HR1组的(23.2±5.6)次、(21.4±5.2)次、(100.32±6.00)mg/ml、(267.71±24.26)Pg/ml升高,差异有统计学意义(q值分别为3.72、4.16、8.01、4.96,P值均<0.05),而INF-γ水平在HR4组为(28.17±1.97)pg/ml,低于HRI组的(35.45±1.35)pg/ml,差异有统计学意义(q=3.18,P<0.05).各干预组(HR1、HR4、HRI+4)中Eotaxin含量差异无统计学意义(P=0.096).结论 组胺H4受体拮抗剂JNJ 777120与组胺H1受体拮抗剂氯雷他定同样可以缓解AR症状及炎性反应状态,两者之间未发现有协同作用,JNJ 7777120与氯雷他定相比作用相对较弱.     

Thresholds in nasal histamine challenge in patients with allergic rhinitis, patients with hyperreflectory rhinopathy, and healthy volunteers

BACKGROUND: Characteristic symptoms of hyperreflectory rhinopathy include recurrent sneezing, nasal obstruction, and nasal secretion without an allergic background. The diagnosis can only be made if all differential diagnoses have been excluded. So far no clinical test has been established to reliably diagnose hyperreactivity of the nasal mucosa. The present study aimed to investigate whether nasal provocation with histamine allows identification of patients with hyperreflectory rhinopathy. MATERIALS AND METHODS: One-sided nasal challenge with histamine was applied to 13 patients with allergic rhinitis, 13 patients with hyperreflectory rhinitis, and 12 healthy volunteers. Histamine concentrations used were 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 mg/mL. Test results were quantified using a symptom score (positive at values above 3) and active anterior rhinomanometry (positive at a reduction of airflow of 40% or more in comparison to challenge with solvent). RESULTS: While there was a significant difference between controls and patients with allergic rhinitis or hyperreflectory rhinopathy, respectively, no significant difference was observed between the two groups of patients. Results indicated that one-sided nasal provocation with histamine at a concentration of 1 mg/mL is sufficient to separate healthy subjects from patients with hyperreactivity of the nasal mucosa. In terms of the differentiation between subjects with hyperreactivity of the nasal mucosa and healthy controls, the sensitivity of one-sided nasal histamine provocation with 1 mg/mL was found to be 100%; its specificity was 83% if it was evaluated by rhinomanometry and symptom score. CONCLUSION: The present results indicate that one-sided nasal challenge with histamine at a concentration of 1 mg/mL is sufficient to separate healthy subjects from patients with hyperreactivity of the nasal mucosa. However, the test does not differentiate between patients with allergic rhinitis and patients with hyperreflectory rhinitis.     

Effect of histamine on the permeability of the nasal mucosa in vivo

OBJECTIVE: Histamine is one of the chemical mediators released during the acute phase of allergic rhinitis and is considered to cause the increase in epithelial permeability observed. We tried to examine the effect of histamine on nasal mucosal permeability in vivo. MATERIAL AND METHODS: Histamine at different concentrations was administered to the nostrils of healthy subjects and the nasal transepithelial potential difference (PD) was measured. We also examined nasal mucosal permeability by means of a histochemical technique using horseradish peroxidase (HRP) in guinea pigs. RESULTS: Administration of 10(-1) M histamine significantly reduced the nasal PD in healthy subjects. After administration of 5.4 x 10(-1) M histamine to the noses of guinea pigs, most ofthe intercellular spaces showed positive reactions to HRP and this effect was significantly inhibited by pretreatment with mepyramine and the antihistamine bepotastine besilate. CONCLUSION: These results indicate that histamine plays an important role in the change in mucosal permeability observed in allergic rhinitis in vivo via the histamine H1 receptor.     

Effects of intranasal azelastine on the response to nasal allergen challenge.

OBJECTIVES/HYPOTHESIS: Azelastine, a second-generation H1-receptor antagonist, is available for topical administration. The aim of the study was to evaluate the effects of topical intranasal azelastine on the early-phase and the late-phase allergic responses and on nasal hyper-responsiveness to methacholine. STUDY DESIGN: Double-blind, placebo-controlled, two-way crossover study in 20 subjects with seasonal allergic rhinitis, out of their allergy season. METHODS: Subjects were randomly assigned to receive either placebo or two puffs of azelastine twice a day (548 microg/d) for 2 weeks followed by nasal challenge with allergen. Twenty-four hours later, while still receiving treatment, subjects underwent a nasal lavage and a nasal challenge with methacholine. End points included symptom scores, levels of mediators and number of eosinophils in nasal lavages, and the weight of secretions after methacholine challenge. RESULTS: Compared with placebo, treatment with intranasal azelastine resulted in significant reductions in allergen-induced sneezing, rhinorrhea, itching, nasal congestion, and levels of albumin during the early-phase response (P <.05). Azelastine had no effect on levels of histamine or tryptase during the early-phase response. There was a significant eosinophil influx 24 hours after challenge, which was not inhibited by azelastine. Treatment with azelastine had no effect on the levels of albumin, interleukin-4, interleukin-5, intercellular adhesion molecule-1, tumor necrosis factor-alpha, and eosinophil cationic protein during the late-phase response. However, azelastine did show a significant inhibitory effect on the methacholine response 24 hours after nasal allergen challenge (P <.05). CONCLUSIONS: The effects of intranasal azelastine are similar to those of oral second-generation antihistamines.     

Progress in the drug management of allergic rhinitis

The diagnosis of allergic rhinitis is based on the case history, rhinoscopy and allergy testing. Therapy consists of allergen avoidance, pharmacotherapy, immunotherapy and/or surgery. This review deals only with pharmacotherapy, since there has been significant progress in this area. The first advance was the introduction of topical nasal steroids in the mid-1970s and the second the introduction of the second generation of H₁ antihistamines in the early 1980s. The task for future developments is to optimize therapy by rational and combined use of available drugs, especially the steroid sprays and non-sedating antihistamines. A systematic approach to the choice of drug for the treatment of rhinitis is presented.     

Immunohistochemical localization of histamine receptor subtypes in human inferior turbinates

Histamine is an important chemical mediator in allergic rhinitis and plays an important role in eliciting the nasal symptoms of the disorder. However, the immunohistochemical localization of histamine receptor subtypes (H1R, H2R, H3R, and H4R) in human nasal mucosa is unknown. There are also no prior studies of H3R and H4R in human nasal mucosa. The objective of this study was to examine the distribution of histamine receptor subtypes in the human inferior turbinates by an immunohistochemical method. H1R was localized primarily in the epithelium, vessels, and nerves. H2R was localized primarily in the epithelium and the glands. H3R and H4R were clearly distributed on the nerves. In addition, H1R, H3R, and H4R were clearly localized on the same nerves. This result indicates that H1R, H3R, and H4R adjoin and regulate each other in the same nerves. All histamine receptor subtypes may play some role in patients with allergic rhinitis.     

The symptomatic therapy of allergic rhinitis

For the symptomatic treatment of allergic rhinitis the following groups of drugs are available: decongestants (sympathicomimetics), stabilizers of the mast cell membrane (DNCG, nedocromil), corticosteroids (aerosols), antihistamines, ketotifen, anticholinergics. The world wide use (and abuse) of decongestants (sympathicomimetics) is limited by the so-called rhinopathia medicamentosa, when the necessary treatment exceeds 3 or 4 weeks. The antiallergic preparations like sodiumcromoglycat and nedocromil prevent sneezing, rhinorrhea and eye irritations. Their reported effect is "stabilisation" of the mast cell membrane. They have practical no side effects, but the patients compliance is limited by the short, prophylactic effect, necessitating frequent topical applications up to 6 times daily. As the overall symptom scores are only reduced between 30% to 50%, they are not suited for severe cases of allergic rhinitis. Nedocromil should have a significantly better efficiency than DNCG. The development of efficient topical glucocorticosteroid aerosols was a great progress in the treatment of allergic rhinitis. With daily doses of 100 micrograms to 800 micrograms they are very effective against hypersecretion, sneezing, itching and also blocking of the nose. Because of the so-called "first pass" effect after resorption through the nasal mucosa they have minimal general side effects, especially on the balance of the endocrine system. Their rate local side effects on the nasal respiratory mucosa include local irritations, crusting, dryness and seldom nose bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

HISTAMINE RECEPTORS IN THE HUMAN NOSE

The aim of this study was to derermine the role of histomine receptors in the nose. The effects of intranasal histamine challenge were compared with those of a specific HI-receptor agonist, betahistine and a specific H2-receptor agonist, impromidine, in 11 normal individuals and four with rhinitis. Sneezing, nasal irritation and hypersecretion were induced by histamine and the Hl-receptor agonist, betahistine only. Nasal airway resistance (Rna) was measured by passive anterior rhinomanometry. Histamine, betahistine and impromidine all induced rises in Rna in both normal individuals and those with rhinitis but histamine had the most potent effect; the H2-receptor effect on Rna was predominant over that of the Hl-receptor. The sensitivity to all three agonists was greater in the individuals with rhinitis.     

卵白蛋白经鼻致敏建立变应性鼻炎动物模型

目的　建立豚鼠变应性鼻炎动物模型,并对其速发和迟发症状、病理学和免疫学指标进行观察。方法　实验豚鼠分为模型组、治疗组和阴性对照组,每组 12只。阴性对照组未予致敏和激发,模型组和地氯雷他定治疗组由卵白蛋白经鼻反复致敏和激发后,对其喷嚏、抓鼻、鼻腔分泌物及鼻塞做动态症状学观察;通过被动皮肤过敏实验,测定血清IgG1和IgE水平;计量鼻腔灌洗液中白细胞总数、嗜酸粒细胞数及组胺水平;并且观察鼻腔组织的病理改变。结果　经抗原激发后,模型组出现典型的喷嚏、抓鼻、鼻塞和分泌物增多的表现;鼻腔灌洗液中炎性细胞和嗜酸粒细胞增多、组胺水平升高、血清IgG1和IgE滴度升高。上述表现与阴性对照组比较差异有统计学意义 (P<0.05或<0.01),也比治疗组明显增高(P<0.05或<0.01)。模型组的鼻腔黏膜嗜酸粒细胞浸润明显,小血管扩张,杯状细胞扩大。此外,模型组还可观察到迟发相鼻塞。结论　此模型能良好地反映变应性鼻炎的各项表现,方法简易,建模时间短,亦能观察迟发性鼻塞,且对组胺H1受体拮抗剂的治疗反应明确,是研究变应性鼻炎的良好工具。     

Nasal histamine reactivity; relationships to skin-test responses, allergen provocation and symptom severity in patients with long-continuing allergic rhinitis

It has been reported that skin-test reactivity and rhinitis symptom severity weaken in the course of time. A corresponding weakening might also be seen in non-specific nasal hyper-reactivity, but the relationships of these responses are poorly understood. Our aim was to measure nasal responsiveness to histamine in a series of patients with long-continuing allergic rhinitis and to compare these measurements with skin test responses, allergen provocation and changes in severity of allergic rhinitis symptoms. A total of 73 patients in whom allergic rhinitis had been verified over 20 years earlier were re-interviewed and re-investigated. Skin prick tests with common allergens were performed and the presence of nasal allergy was confirmed by allergen provocation. Non-specific nasal hyper-reactivity was determined with nasal histamine challenge using four concentrations of histamine phosphate. The response was registered by counting sneezes, recording changes in nasal discharge and mucosal swelling and measuring nasal airway resistance. Sneezing and discharge scores showed that milder non-specific nasal hyper-reactivity was associated with lack of reactivity in skin prick tests and nasal allergen challenge. No association was observed between allergy test results and changes in nasal airway resistance during the histamine provocation. In most patients the symptoms of rhinitis had become milder or disappeared during the follow-up, but the results of the histamine challenge showed no relationship with the changes in symptom severity. In patients with allergic rhinitis, reactivity to histamine is associated with a concomitant change in skin and nasal mucosal reactivity to allergens.     

Topical treatment of rhinitis: current status. Physiopathologic and pharmacologic bases

Rhinitis is defined as inflammation of the lining of the nose, characterized by one or more of the following symptoms: nasal congestion, rhinorrhea, sneezing and itching. Modifications of nose secretion and of the blood supply of the nasal mucosa are responsible for development of rhinitis. Cholinergic and adrenergic agents as well as histamine, 5-hydroxytriptamine, kallidin and substance P are mediators of inflammation in rhinitis. The topical pharmacological principles we have today for management of rhinitis include: antihistamines, corticosteroids, anticholinergic agents, decongestants, sodium cromoglycate, nasal douching and aromatic inhalations.     

Nasal Histamine Reactivity; Relationships to Skin-test Responses,Allergen Provocation and Symptom Severity in Patients with Long-continuing Allergic Rhinitis

It has been reported that skin-test reactivity and rhinitis symptom severity weaken in the course of time. A corresponding weakening might also be seen in non-specific nasal hyper-reactivity, but the relationships of these responses are poorly understood. Our aim was to measure nasal responsiveness to histamine in a series of patients with long-continuing allergic rhinitis and to compare these measurements with skin test responses, allergen provocation and changes in severity of allergic rhinitis symptoms. A total of 73 patients in whom allergic rhinitis had been verified over 20 years earlier were re-interviewed and re-investigated. Skin prick tests with common allergens were performed and the presence of nasal allergy was confirmed by allergen provocation. Non-specific nasal hyper-reactivity was determined with nasal histamine challenge using four concentrations of histamine phosphate. The response was registered by counting sneezes, recording changes in nasal discharge and mucosal swelling and measuring nasal airway resistance. Sneezing and discharge scores showed that milder non-specific nasal hyper-reactivity was associated with lack of reactivity in skin prick tests and nasal allergen challenge. No association was observed between allergy test results and changes in nasal airway resistance during the histamine provocation. In most patients the symptoms of rhinitis had become milder or disappeared during the follow-up, but the results of the histamine challenge showed no relationship with the changes in symptom severity. In patients with allergic rhinitis, reactivity to histamine is associated with a concomitant change in skin and nasal mucosal reactivity to allergens.     

The effect of cetirizine on early allergic response

A double blind, placebo-controlled, cross-over study was performed to determine the effect of cetirizine, an H1 antihistamine, on the immediate nasal allergic response. Ten persons underwent nasal challenge with antigen after premedication with 20 mg of cetirizine or placebo QD for 2 days. The response was monitored by counting the number of sneezes and by measuring the levels of histamine, prostaglandin D2, leukotriene C4, albumin, and TAME-esterase activity in recovered nasal lavages. The results showed a significant reduction in sneezing and in the amounts of recovered albumin, TAME-esterase activity, and leukotriene C4 but no reduction in the amounts of recovered histamine and prostaglandin D2. These results suggest that cetirizine does not inhibit mast cell activation but inhibits the consequences of the released histamine on H1 receptors: sneezing and increased vascular permeability. The results further suggest that mast cell release of histamine is the direct result of antigen stimulation, as opposed to reflex activation, and that other cells in addition to mast cells generate leukotrienes during the early allergic response.     

Pathogenic mechanisms underlying the clinical symptoms of allergic rhinitis

This paper reviews our previous studies on an objective evaluation of nasal symptoms, a quantitative determination of biochemical mediators, and inflammatory cells in nasal secretions of atopic patients after nasal allergen challenge (NAC) and during natural allergen exposure. The use of the microsuction technique has proved to be a useful and reliable nasal sampling method permitting quantitative analysis of important mediators in nasal secretions. This has provided accurate data on the activity of some important inflammatory cells such as mast cells, basophils, and eosinophils in allergic rhinitis. Our studies demonstrate that a significant increase in the concentrations of histamine, tryptase, and LTC4 in nasal secretions occurs within seconds or minutes after NAC, and this is accompanied by itching, sneezing, rhinorrhea, and nasal obstruction. The infiltration and activation of eosinophils are found to be the predominant condition during the late-phase reaction (LPR), which is mainly characterized by unilateral and/or bilateral nasal obstruction with little sneezing and rhinorrhea. The latter condition is found to be very much similar to the pathophysiology of patients with ongoing allergic rhinitis. In conclusion, our studies demonstrate that patients with ongoing allergic rhinitis seem to be in a continuous late phase state of eosinophilia and increased mediator release, a condition that can explain priming and nonspecific hyperreactivity of the nasal mucous membrane.     

Effects of cetirizine on substance P release in patients with perennial allergic rhinitis

To evaluate the effect of cetirizine hydrochloride on substance P release in allergic rhinitis, we performed a single-blind placebo-controlled study of 14 patients with perennial allergic rhinitis (7 treated with cetirizine and 7 with placebo). After an initial nasal allergen challenge with lavages, the subjects received treatment with placebo or cetirizine hydrochloride (10 mg by mouth daily) for 1 week, followed by the second nasal allergen challenge with lavages. The levels of albumin, histamine, and substance P in nasal lavages before and after allergen challenge were quantified by enzyme-linked immunosorbent assay. Pretreatment of subjects with cetirizine reduced the level of substance P induced by antigen challenge, but did not significantly reduce levels of histamine. These results suggest that cetirizine may reduce nasal neurogenic inflammation by modulating the release of substance P in allergic rhinitis.     

Efficacy and safety of levocabastine nasal spray for seasonal allergic rhinitis

This multicenter, double-blind, placebo-controlled trial evaluated the efficacy and safety of levocabastine nasal spray, a potent and selective H1-receptor antagonist, in the control of histamine-mediated symptoms of seasonal allergic rhinitis. Adults with > or = 2 year history of allergic rhinitis due to Mountain Cedar were randomized to treatment with levocabastine nasal spray (0.2 mg twice daily) or placebo for 28 days during the 1994-1995 Mountain Cedar allergy season. Patients assessed the severity of their rhinitis symptoms on a four-point scale twice daily. At the end of the trial, patients also performed a global evaluation of treatment efficacy on a five-point scale. Overall for the 4-week treatment period, levocabastine nasal spray significantly reduced major nasal (runny nose and sneezing) and primary rhinitis (runny nose, sneezing, and itchy/gritty eyes) symptoms compared with placebo on both repeated measures (p = 0.023; p = 0.01) and ANOVA (p = 0.003; p < 0.001) analyses. Global evaluations of treatment efficacy at the end of the trial significantly favored levocabastine over placebo (p = 0.002). Overall, the incidence of adverse events was similar for both treatment groups. In general, most adverse events were mild in intensity, with sinusitis (17% each group), headache (17% placebo, 14% levocabastine), and rhinitis (8% placebo, 2% levocabastine) most commonly reported. Levocabastine nasal spray 0.2 mg twice daily was significantly more effective than placebo in the relief of histamine-mediated symptoms in patients with seasonal allergic rhinitis and was well tolerated over the 28-day treatment period.