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.     

Studies on the function of mast cells infiltrating in nasal polyps]

The function of nasal polyp mast cells has not been elucidated despite the large number of these cells observed in tissues. We examined these mast cells histochemically, immunohistologically and functionally. Ninety-three percent of collagenase dispersed cells in a nasal polyp were formalin-sensitive. These dispersed cells released histamine in reaction to calcium ionophore A23187 in a dose dependent manner, but not in response to C5a, Compound 48/80 or Substance P. From these results, dispersed mast cells from nasal polyps were considered to be analogous to dispersed mast cells from the human lung and nasal mucosa but not those from human skin. On the other hand, in the reaction with anti-human IgE, dispersed mast cells from a non allergic nasal polyp could not be seen to release histamine. In only 2 of 7 patients, could histamine release in response to Japanese red cedar antigen, from mast cells sensitized passively with the serum of Japanese red cedar pollinosis, seen. Using small tissue samples from polyps, histamine was released by anti-human IgE in allergic patients but not in non allergic patients. Immunohistologically in allergic nasal polyps, some IgE positive mast cells could be seen, whereas in non allergic polyps these cells were absent. These observations suggest that mast cells which had accumulated in nasal polyps both with and without allergy were capable of functional histamine release, whereas in the nasal polyps of allergy patients but not in non-allergic patients these cells are involved in IgE mediated reactions.     

In vivo model for the evaluation of topical antiallergic medications

A novel human in vivo model of intranasal challenge with antigen is used to demonstrate the effectiveness of a topical antirelease drug. Previous experimentation has established a highly significant correlation between the physiologic response of sneezing, which occurs after insufflation of antigen into the nose of allergic individuals, and the recovery of putative mast cell mediators: histamine, tosyl arginine methyl ester (TAME)-esterase(s), and prostaglandin D2- Azatadine base, a tricyclic antihistamine, which also inhibits mediator release in vitro, applied prior to antigen administration not only reduces the clinical symptom of sneezing but simultaneously reduces the concentration of the inflammatory mediator, TAME-esterase(s), recovered from nasal washes. To our knowledge, this is the first observation that an antirelease drug can stop mediator release in vivo in the nose.     

Allergen-induced specific and non-specific nasal reactions. Reciprocal relationship and inhibition by topical glucocorticosteroids

The correlation between allergen-induced specific and non-specific (histamine) nasal reactions was studied, especially as regards topical glucocorticosteroid effects on the non-specific reactions. Thirteen patients with strictly seasonal allergic rhinitis participated. A nasal challenge with histamine and three increasing doses of allergen was performed on the first day. The patients were rechallenged 24 h later with the same histamine dose and the lowest allergen dose from the previous day. The same 2-day challenge was also performed after pretreatment for one week with budesonide in 8 of these patients. Symptom scores were recorded. The N-alpha-tosyl-L-arginine-methyl-esterase (TAME esterase) activity in nasal lavages was determined. The nasal symptoms and the TAME-esterase activity increased at rechallenge for both histamine and allergen, compared with the initial challenge. The mean ( +/- SE) composite nasal symptom score after histamine increased from 3.5 +/- 0.49 to 4.9 +/- 0.35 (p less than 0.01) and after allergen from 1.62 +/- 0.3 to 3.2 +/- 0.5 (p less than 0.01) at rechallenge. Similar increases were recorded for the TAME-esterase activity. A close correlation between the allergen-induced increase in specific (allergen) and non-specific (histamine) reactivity was found (r = 0.7, p less than 0.01, composite nasal symptom score). Treatment with topical glucocorticosteroids abolished the allergen-induced increase in both specific (p less than 0.001) and non-specific (histamine) (p less than 0.01) nasal reactivity.     

Comparison of antigen-induced leukotriene and histamine release from nasal scrapings in allergic rhinitis

BACKGROUND: In the early phase response of allergic rhinitis, the nasal mucosa produces important mediators including histamine and leukotrienes. OBJECTIVE: To investigate the relationship between antigen-induced leukotriene release and histamine secretion in nasal scrapings. METHODS: Using nasal mucosal scrapings from patients sensitized to only house dust mite, we studied the time course of antigen-induced leukotriene release and its relationship to histamine release. RESULTS: Cumulative peptydyl leukotriene (LT) production from nasal scrapings increased from 10 min to approximately 90 min following exposure to mite antigen. The rate of LT release was small (<5 pg/10 min) until 10 min following antigen exposure, increased to approximately 250 to 350 pg LT/10 min from 10 to 45 min post exposure, was reduced to <100 pg/10 min by 60 to 150 min, and by 180 min LT production was negligible. By contrast, histamine secretion began 30 sec after antigen exposure and was complete within approximately 10 min. Net antigen-induced LT secretion strongly correlated (R=0.72) with net antigen induced histamine secretion with a ratio of 1:8.7. In addition, net LT/ng histamine and total LT secretion correlated well with antigen-specific IgE in serum, and with the patients' symptoms. CONCLUSION: There is a close relationship between amounts of histamine and LT secretion from antigen challenged nasal mucosa, although the time course of LT release is delayed. In the early phase response, LT are likely to be generated from mucosal mast cells, and thus, mast cell activation will provide an important therapeutic target.     

The study of chemical mediators in the patients with allergic rhinitis 2). Histamine, leukotriene and kinins in the nasal secretion during dual phase response

In order to clarify the details of a late phase response (LPR) in allergic rhinitis, serial changes of nasal symptoms and concentration of chemical mediators (histamine, leukotriene (LT) C4 and kinins) in nasal lavage fluid were investigated after the nasal antigen challenge in ten patients with perennial allergic rhinitis with a positive intradermal skin reaction to mite extract. Samples were collected periodically for 8 hours following the challenge. Nasal airway resistance (NAR) and clinical symptoms were also recorded serially. Three out of ten patients showed only early phase response (EPR) and the other seven patients showed both early and late phase response after the challenge. The chief nasal symptom in LPR was nasal obstruction. In EPR, concentrations of chemical mediators in the nasal lavage fluid always increased. In dual (early and late) phase responders, increases of chemical mediators in nasal lavage fluids were notable during both early and late phase responses. In EPR, there was a significant correlation between severity of sneezing attack and concentration of histamine. In LPR, increase of LTC4 level was significantly correlated with the increase of NAR. RAST score and daily nasal symptoms tended to be higher and more sever in dual phase responders compared with early phase responders. We suggest that the amounts of released chemical mediators during allergic reaction denoted the LPR in allergic rhinitis patients.     

Acoustic rhinometry evaluation of nasal response to histamine and antigen in guinea pigs

The effects of antigen and histamine on the changes of nasal passage patency in 112 guinea pigs with or without allergic rhinitis were evaluated by acoustic rhinometry. The percent change of volume from the nostril to 2 cm into the nasal cavity showed significant reduction of 31.10 +/- 4.11% at 10 minutes and 31.10 +/- 4.11% at 30 minutes after antigen challenge in sensitized guinea pigs. The pretreatment with ketotifen, an H1-histamine receptor antagonist as well as mast cell stabilizing drug, blocked dose-dependently the effects of antigen on those changes in volume. Furthermore, instillation of 10(4) micrograms/mL histamine reduced significantly nasal passage patency to 33.77 +/- 4.63% at 10 minutes and 42.76 +/- 3.32% at 30 minutes after challenge compared with that before challenge and ketotifen inhibited the effects of histamine, which indicated that histamine is an important mediator of allergic upper airway responses in guinea pigs. These results show that acoustic rhinometry is a useful technique to assess the nasal blockade in allergic guinea pigs.     

Current pathophysiologic aspects of allergic rhinitis. I

Allergic rhinitis is a classic example of a type I immunological reaction. After allergic provocation tests a biphasic reaction is seen in the respiratory tract that is more pronounced in the lower than in the upper respiratory tract due to the physiological changes during the nasal cycle. The early phase of the immediate reaction starts some minutes after allergen provocation. After 5-10 h the nasal symptoms (discharge, blockage, sneezing and itching of the nose) reappear, a phenomenon which is called the "late-phase response" (LPR). The LPR is of great clinical importance in the pathophysiology of perennial allergic rhinitis and phenomena such as nasal priming and nasal hyper-reactivity. The most important effector cell of the early phase of the immediate reaction is the mast cell, whereas basophils, eosinophils and neutrophil granulocytes seem to be more important for the LPR. There is also evidence for morphological and functional heterogeneity of mast cells in man. The role of the chemotactically immigrated eosinophils in allergic reactions has not been clear until now: the eosinophil-derived mediators may enhance or inhibit the allergic reaction. Also the eosinophils show different morphological and functional states (so-called hypo- and hyperdense eosinophils). The symptoms of allergic rhinitis (sneezing, discharge, blockage, itching of the nose) are caused by different mediators, of which the most important is histamine. Other mediators or modulators of the allergic reactions are leucotrienes, prostaglandins, PAF, serotonin, and the kallikrein-kinine and complement systems. In recent years many regulatory peptides have been detected in the human nasal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)     

The ex vivo effect of the herbal medicine Sho-saiko-to on histamine release from rat mast cells

A traditional Japanese herbal medicine, Sho-saiko-to (SST), has been used orally to treat several chronic diseases. Since these have included allergic rhinitis and bronchial asthma, we investigated the effect of SST on histamine release and the intracellular Ca²⁺ response in mast cells ex vivo. A single dose of 1.0 g/kg SST was administered orally to immunized rats 2–12 h before death. Mast cells were then separated from peritoneal lavages and stimulated with antigen. SST at 3 h after oral administration most significantly inhibited histamine release. This inhibitory effect was dose-dependent and was weaker than that of tranilast. In contrast, SST at 3 h had no effect on the antigen-induced Ca²⁺ response of the mast cells and failed to inhibit compound 48/80-induced histamine release. Our findings show that SST indeed has an active anti-allergic effect. We suggest that SST inhibits IgE receptor-associated protein phosphorylation in the histamine release pathway. Received: 24 June 1997 / Accepted: 11 February 1998     

Prostaglandins, leukotrienes, and other arachidonic acid metabolites in nasal polyps and nasal mucosa

Prostaglandins (PGs) and leukotrienes (LTs) are known to play an important role in allergic inflammatory reactions. The triad of aspirin sensitivity, nasal polyposis, and asthma led us to suspect that PGs, LTs and other arachidonic acid metabolites may be involved in the pathogenesis of nasal polyps. The purpose of this study was to determine arachidonic acid metabolites and to measure concentrations of PGs and LTs in nasal polyps and nasal mucosa. Samples of nasal polyps and nasal mucosa were obtained at the time of polypectomies and nasal procedures. Metabolites of arachidonic acid in tissue were determined by incubation of tissue-homogenates with 14C-arachidonic acid and analyses with thin-layer chromatography and high performance liquid chromatography (HPLC). Levels of PGE2, 6-keto-PGF1 alpha, thromboxane (Tx)B2, 15-hydroxyeicosatetraenoic acid (HETE), LTC4, LTB4 were measured by radioimmunoassay. The predominant arachidonic acid metabolite in both nasal polyps and mucosa with 15-HETE. The HPLC analysis showed that the predominant metabolite in nasal polyp was 15-HETE, especially in polyps from aspirin sensitive patients. Levels of 15-HETE and PGE2 were higher in polyps from patients with a history of allergy than from nonallergic patients. Levels of LTC4 and LTB4 in nasal polyps were determined. The findings of this study will help to explain biochemical basis of the pathogenesis of aspirin-sensitive nasal polyps and to develop better medical treatment for them.     

Endogenous cannabinoids may regulate chronic inflammation in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyposis, adult-onset asthma and non-IgE mediated reactions to aspirin and other cyclooxygenase-1 (COX-1) inhibitors. Patients with AERD are dependent on COX-1 activity to maintain production of prostaglandin (PG) species, such as PGE2, which maintain physiologic levels of inflammation and limit the production of pro-inflammatory cysteinyl leukotrienes. The endogenous cannabinoid system is a family of immunomodulatory lipids and their innate g-protein coupled receptors that are closely related to arachidonic acid and may modulate inflammation via several pathways, including the direct production of metabolically active prostaglandin glycerol-esters. A recent pilot study has identified the significant up-regulation of the peripherally expressed, type-2 cannabinoid receptor (CB2) in AERD nasal polyps versus control tissues from patients with either allergic fungal rhinosinusitis or no history of chronic sinonasal inflammation. These early findings suggest the involvement of increased endogenous cannabinoid activity in prostaglandin deficient states such as AERD. Future study is needed to explore the significance of these findings, with specific investigation of the impact of CB2 activation on markers of airway inflammation, as well as the potential to measure CB2 expression as a screening biomarker for the evaluation of unrecognized disease.     

Cholinergic and C-fibre mediated mechanisms in the stimulation of mucociliary activity induced by prostaglandins and histamine

The involvement of cholinergic and C-fibre mediated mechanisms in the stimulation of mucociliary activity induced by prostaglandins and histamine was investigated in vivo in the rabbit maxillary sinus with a photoelectric technique. The prostaglandins E, (PGE,) and F2(2) alpha (PGF2 alpha) in dose of 0.1 microgram/kg and 10 micrograms/kg respectively stimulated the mucociliary activity in a biphasic fashion, with a small initial response during the first 1-2 min and a later maximum response after 3-4 min. These effects were resistant to atropine and to the SP antagonist (D-Pro2, D-Trp7,9)SP. The small initial response was blocked by pretreatment with high doses of capsaicin (13 mg i.a.), while the maximum response was unaffected. This indicates that the mucociliary responses induced by PGE, and PGF2 alpha involve capsaicin-sensitive C-fibres but that neither acetylcholine nor substance P were responsible. Histamine (50 micrograms/kg) stimulated mucociliary activity in the rabbit maxillary sinus and the effect was abolished by pretreatment with high doses of capsaicin and reduced by the SP antagonist (D-Pro2, D-Trp7,9)SP. This indicates that the histamine-induced stimulation of mucociliary activity involves capsaicin-sensitive C-fibres and that the effect might be mediated by substance P.     

Acute bacterial rhinosinusitis causes hyperresponsiveness to histamine challenge in mice

OBJECTIVES: To develop a physiologic test of nasal responsiveness in mice and to evaluate whether mice with acute bacterial sinusitis develop nasal hyperresponsiveness. DESIGN: Several experimental studies will be described. The first was a titration pilot study. The second was a randomized, placebo-controlled study. The remainder were before-and-after trials. SPECIES: BALB/c or C57BL/6 mice. INTERVENTIONS: For these experiments, we exposed mice to histamine intranasally, then counted the number of sneezes and nose rubs as the primary outcome measure of nasal responsiveness. First, we constructed a dose-response curve. Second, we treated the mice with desloratadine, a histamine 1 receptor antagonist, prior to histamine exposure. Third, we challenged, with intranasal histamine, mice made allergic using 2 techniques. Fourth, we infected mice with Streptococcus pneumoniae to determine whether acute sinusitis causes nasal hyperresponsiveness to histamine exposure. RESULTS: Nasal histamine challenge led to a reproducible, dose-dependent increase in sneezing and nose rubs. The response to histamine exposure was blocked by desloratadine (P < or = .05). Allergic mice had a significant increase in responsiveness (P < or = .05) over baseline after exposure to antigen. Mice with acute sinusitis had a sustained increase in responsiveness, although less severe than after allergy, compared with baseline values that lasted 12 days after infection (P < or = .05). CONCLUSIONS: Nasal challenge with histamine is a physiologic test of nasal responsiveness. The hyperresponsiveness of allergic mice to histamine exposure parallels the response to nonspecific stimuli during the human allergic reaction. In addition, we showed that acute bacterial sinusitis causes nasal hyperresponsiveness in mice.     

Oral second generation antihistamines in allergic rhinitis

BACKGROUND: Histamine is a key mediator of the allergic immediate reaction. Antihistamines belong to the most frequently used treatment modalities in allergic rhinitis. METHODS: The National Libraray of Medicine was searched for current data of the effects of histamine and antihistamines in allergic rhinitis. RESULTS: Histamine acts on 4 different histamine receptors. Activation of H1-receptors on nasal trigeminal nerve fibers transmits nasal itch and sneezing. Nasal hypersecretion is mainly mediated by an trigeminal-parasympathetic reflex. Activation of H1-receptors results in contraction of nasal endothelial cells with consecutive plasma extravasation and edema formation. Histamine also activates H2-receptors on smooth muscle cells surrounding nasal capacitance vessels. They transmit muscle relaxation, increased blood content and an enlarged volume of nasal mucosa. Via peripheral H3-receptors, histamine modulates neurogenic inflammation and via H4-receptors functions of immune cells. Oral second generation antihistamines inhibit histamine dependent activation of nasal H1-receptors. They mainly reduce nasal itch, sneezing, and hypersecretion. In addition, allergy related activity impairment is reduced resulting in improved physical and mental performance. Second generation antihistamines reduce proinflammatory effects mediated by H1-receptors, however, drug concentrations necessary for mast cell stabilization as observed in vitro are not reached in vivo. Oral second generation antihistamines are readily absorbed and reduce allergy symptoms for approximately 24 hours, allowing convenient once daily medication. Modern antihistamines are generally safe; tachyphylaxis, tolerance or rebound has not been observed. CONCLUSION: Due to their minimal adverse effects and efficient symptom reduction oral second generation antihistamines are particularly useful for the treatment of less severe intermittent forms of nasal allergy.     

Evaluation of a bedtime dose of a combination antihistamine/analgesic/decongestant product on antigen challenge the next morning.

The effects of CAAD (diphenhydramine hydrochloride, 50 mg; pseudoephedrine hydrochloride, 60 mg; acetaminophen, 1 g in 10% ethanol) were evaluated in a double-blind, three-way, placebo-controlled, cross-over study on 18 volunteers with allergic rhinitis. The number of sneezes following nasal challenge with antigen was significantly reduced after a bed-time dose of CAAD (P less than .005) and a single dose of diphenhydramine (P less than .001) given 2 hours before the challenge. The levels of N-alpha-tosyl-L-arginine methyl ester (TAME) activity decreased after diphenhydramine treatment, while histamine levels following challenge were not different. The drowsiness reported after CAAD was equal to placebo, but significantly less than diphenhydramine (P less than .002 for both). The active treatments reduced the actions of histamine without suppressing its release from mast cells. The effect of CAAD persists 10 hours after administration without inducing drowsiness.     

A study of chemical mediators in patients with allergic rhinitis. 3). Release of histamine and leukotrienes from in vitro nasal mucosa]

Responses to mite antigen and nonimmunological stimuli, substance P, of chopped fragments of nasal mucosae were studied from eleven patients with perennial allergic rhinitis who were sensitive to mite antigen. Amount of released histamine significantly increased by either stimulation. However, the release of leukotrienes (LTs) increased only by the stimulation of mite antigen, which correlated with that of histamine. By either stimulation, amount of histamine release tended to be higher in patients with severe nasal symptoms than in those with moderate nasal symptoms. Only by mite antigen stimulation, amount of the release of peptide LTs and LTB4 tended to be higher in patients with severe nasal symptoms. We concluded that the amounts of histamine and LTs released from nasal mucosa in allergic reaction were closely related with the severity of nasal symptoms in patients with allergic rhinitis.     

Immunology for the otolaryngic allergist.

An understanding of immunology is imperative for the practitioner of otolaryngic allergy. Figure 9 provides an overview of the allergic reaction. Complex immunologic mechanisms involving cellular and humoral elements are involved in allergic reactions. The primary cells of the immune response are lymphocytes, macrophages, eosinophils, mast cells, and basophils. Humoral immunity involves five classes of immunoglobulin: IgM, IgA, IgD, IgG, and IgE. Preformed (eg, histamine) and newly formed mediators (eg, prostaglandins, leukotrienes), interleukins, and the complement chain (classical and alternative pathways) are involved in various types of allergic reactions.     

Evidence of mast cell activity in the middle ears of children with otitis media with effusion

OBJECTIVES: This is the first study to report the presence of tryptase, a reflection of mast cell activity, in chronic middle ear effusion of patients whose atopic status was characterized. DESIGN AND METHODS: Mediator activity of mast cells and eosinophils was measured prospectively from effusion of 33 randomly selected patients and 5 control subjects with chronic otitis media with effusion (OME). Atopy was determined by enzyme-linked immunosorbent assay. Middle ear biopsies from a second group of 8 OME patients and 4 controls were fixed in plastic and stained immunohistochemically for mast cells. RESULTS: Sixty-one percent of patients had extensive activation of mast cells in their middle ears. Among those with elevated tryptase in their effusion, 95.6% were atopic and 94.7% also had elevated levels of effusion eosinophilic cationic protein (ECP). Tryptase levels were elevated only in the effusion of atopic patients, as compared with 5 controls (P < .01). Mast cells were present in 6 of 8 OME ears and absent in all 4 normal ears. CONCLUSION: Mast cells and its mediator tryptase, both indicators of a Th2-driven immune response, are present in a majority of ears that have chronic effusion. These findings support the hypothesis that middle ear mucosa is capable of an allergic response and that the inflammation within the middle ear of most OME patients is allergic in nature.     

Revisiting the roles of mast cells in allergic rhinitis and its relation to local IgE synthesis

Mast cells are important effector cells in the immediate-phase allergic reaction. However, in recent years much evidence has accumulated on the versatile role of mast cells in allergic inflammation. The present article is an overview of the roles of mast cells in allergic inflammation, especially in light of the local production of IgE and the IgE-IgE receptor network. Although both nasal mast cells (NMC) and T cells in allergic rhinitics are important sources of Th2-type cytokines like IL-4 and IL-13, and can induce IgE synthesis, we report here that antigen-activated NMC can secrete greater levels of IL-4/IL-13 and induce increased levels of IgE synthesis than antigen-activated nasal T cells. Furthermore, IgE production can occur locally in the nasal mucosa (target organ) and IgE itself can enhance the Fc epsilon RI expression and subsequent mediator release from NMC, thus contributing to the perpetuation of on-going allergic inflammation. Again, mast cells can contribute to the late-phase allergic reaction not only via the upregulation of adhesion molecules like VCAM-1, but also through the interactions of NMC with the extracellular matrix proteins, and interaction of NMC with nasal epithelial cells (NEC). Thus, it is increasingly evident that mast cells are not only important for the genesis of the allergic reaction, but also contribute to the late-phase allergic reaction and on-going allergic inflammation.     

Mast cells and middle ear effusion

The mast cell--an important component of connective tissue--carries in its cytoplasmic granules various biologically active substances, such as heparin, histamine, and a broad spectrum of enzymes. This cell type plays a prominent role in inflammatory and allergic conditions. In the middle ear, the mast cells are mainly localized in the pars flaccida of the tympanic membrane and beneath the tracts of secretory and ciliated cells in the middle ear mucosa. Degranulation of the mast cells by the histamine liberator compound 48/80 causes histamine-rich effusion material to accumulate in the middle ear. Plugging of the eustachian tube and/or tympanic isthmus will bring about a similar accumulation. It would thus seem that mast cells in some way participate in the production of middle ear effusion, probably via their potent mediators.