Potential synergistic effects of novel hematopoietic prostaglandin D synthase inhibitor TAS-205 and different types of anti-allergic medicine on nasal obstruction in a Guinea pig model of experimental allergic rhinitis.

Nasal obstruction is one of the most bothersome symptoms of allergic rhinitis (AR) affecting sleep-related quality of life in AR patients. Although several treatments were tested to control nasal obstruction, some patients with moderate to severe AR do not respond to current treatments, including the combined administration of different types of anti-allergic medicine. Thus, new options for AR treatment are needed. This study aimed to evaluate the effects of combined treatment with a novel inhibitor of hematopoietic prostaglandin D synthase (HPGDS), TAS-205, and different types of anti-allergic medicine on nasal obstruction in AR. Firstly, we demonstrated that TAS-205 selectively inhibited prostaglandin D2 (PGD2) synthesis in an enzymatic assay in a cell-based assay and in vivo models of AR. Moreover, treatment with TAS-205 alone suppressed eosinophil infiltration into the nasal cavity and late phase nasal obstruction. The combined administration of TAS-205 with montelukast, a cysteinyl leukotriene receptor 1 antagonist, showed significant additive inhibitory effects on eosinophil infiltration and late phase nasal obstruction compared to treatment with each agent alone. In contrast, concomitant treatment with TAS-205 and fexofenadine, a histamine H1 blocker, showed inhibitory effects on late phase and early phase nasal obstruction, although the magnitude of the inhibitory effects upon combined administration was comparable to that of each single treatment. These results suggest that combined treatment with an HPGDS inhibitor and different types of anti-allergic medicine may be a promising strategy to control nasal obstruction in AR patients.

Increased gene expression of inflammatory markers in nasal turbinate of patients with persistent allergic rhinitis and chronic obstruction.

PURPOSE: The pathogenesis of persistent allergic rhinitis with chronic and refractory nasal obstruction is still unknown. Inflammation and tissue remodeling are known to play a role, but this has not been studied thoroughly. The purpose of this study is to identify the profile of gene expression of inflammatory and remodeling markers in nasal mucosa of patients with PAR and chronic obstruction. METHODS: After informed consent, we obtained nasal mucosa tissue from five aeroallergen-sensitized PAR patients undergoing anterior turbinectomy, and control non-sensitized individuals undergoing cerebrospinal fluid fistula repair or rhinoplasty. We assessed the expression of 34 genes related to inflammation and tissue remodeling using the real-time polymerase chain reaction (qPCR) to quantify each mRNA. RESULTS: IL-4 mRNA was upregulated in nasal mucosa of all five patients; CCR3, CCR8 and Eotaxin-2 were upregulated in four out of five patient samples; while IL-5 and IL-13 were upregulated in two of them. TGF-ß1 was not upregulated in PAR samples. mRNA from metalloproteinases MMP-7, MMP13 and MMP15 were upregulated in three out of five samples. Our results indicate a typical mRNA expression profile of the infiltrating inflammatory Th2 cells and eosinophils, combined with altered gene expression of remodeling-related proteins in stromal cells from the mucosa. CONCLUSION: Prolonged allergen challenge can lead to persistent upregulation of genes for inflammatory mediators such as IL-4 Th2/eosinophil cytokines, chemokines and receptors, which may play an important role in maintaining PAR with chronic nasal obstruction. Our findings may have therapeutic implications, including the use of anti-IL4, -CCR3 or -MMP therapy to ameliorate the condition.

EAACI Position paper on the standardization of nasal allergen challenges.

Nasal allergen challenge (NAC) is an important tool to diagnose allergic rhinitis. In daily clinical routine, experimentally, or when measuring therapeutic success clinically, nasal allergen challenge is fundamental. It is further one of the key diagnostic tools when initiating specific allergen immunotherapy. So far, national recommendations offered guidance on its execution; however, international divergence left many questions unanswered. These differences in the literature caused EAACI to initiate a task force to answer unmet needs and find a consensus in executing nasal allergen challenge. On the basis of a systematic review containing nasal allergen challenges of the past years, task force members reviewed evidence, discussed open issues, and studied variations of several subjective and objective assessment parameters to propose a standardized way of a nasal allergen challenge procedure in clinical practice. Besides an update on indications, contraindications, and preparations for the test procedure, main recommendations are a bilaterally challenge with standardized allergens, with a spray device offering 0.1 mL per nostril. A systematic catalogue for positivity criteria is given for the variety of established subjective and objective assessment methods as well as a schedule for the challenge procedure. The task force recommends a unified protocol for NAC for daily clinical practice, aiming at eliminating the previous difficulty of comparing NAC results due to unmet needs.

[The role of a leukotriene receptor antagonist in the restoration of the nasal breathing in the patients presenting with polypous rhinosinusitis]. / Rol' blokatora leikotrienovykh retseptorov v vosstanovlenii nosovogo dykhaniia u bol'nykh polipoznym rinosinusitom.

The present study was designed to investigate the clinical. laboratory, and morphological characteristics of the nasal obstruction process. It included 87 patients presenting with polypous rhinosinusitis. The dynamics of the serum leukotriene C4 (LTC4) level in the patients and the morphological changes in their polypous tissue suggested the existence of the pronounced exudative phase of allergic inflammation and provided a basis for the use of the leukotriene receptor antagonist in the form of the sodium montelucast tablets for the treatment of nasal obstruction.

Effect of curcumin on nasal symptoms and airflow in patients with perennial allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a common disorder that can significantly affect patient quality of life. Previous studies have found that curcumin had anti-inflammatory and antioxidant effects and clinical benefits in cancer and asthma. OBJECTIVE: To determine the efficacy of curcumin in the treatment of AR and to explore the molecular mechanisms involved. METHODS: In a randomized, double-blind study, 241 patients with AR received either placebo or oral curcumin for 2 months. The therapeutic effects of curcumin were evaluated by nasal symptoms and nasal airflow resistance. In addition, the production of interferon γ, interleukin (IL) 4, IL-10, and tumor necrosis factor α from mononuclear cells and IL-8, soluble intercellular adhesion molecule, polyethylene glycol 2, and leukotriene C4 from polymorphonuclear neutrophils were compared before and after curcumin treatment. RESULTS: Curcumin alleviated nasal symptoms (sneezing and rhinorrhea) and nasal congestion through reduction of nasal airflow resistance. Curcumin was found to exert diverse immunomodulatory effects, including suppression of IL-4, IL-8, and tumor necrosis factor α and increased production of IL-10 and soluble intercellular adhesion molecule. However, curcumin did not affect the release of prostaglandin E2 and leukotriene C4 from polymorphonuclear neutrophils. CONCLUSION: This pilot study provides the first evidence of the capability of curcumin of improving nasal airflow and modulating immune response in patients with AR.

Clinical characteristics of patients sensitized to Siberian Hamster

No disponible

Oral Phenylephrine HCl for Nasal Congestion in Seasonal Allergic Rhinitis: A Randomized, Open-label, Placebo-controlled Study.

BACKGROUND: Phenylephrine hydrochloride (PE HCl) is widely used for the treatment of nasal congestion, but efficacy at the 10-mg dose is not known for certain. The Food and Drug Administration has requested that sufficiently powered, multicenter, dose-ranging studies be conducted to assess the efficacy and safety of PE HCl. OBJECTIVE: To evaluate subjective nasal congestion symptom relief and safety of 4 different doses of PE HCl immediate-release 10-mg tablets and placebo in adults with seasonal allergic rhinitis (SAR). METHODS: This multicenter, phase 2, parallel, open-label trial randomized 539 adults with SAR (but otherwise healthy) to 7 days of treatment with either PE HCl 10-mg tablets at fixed doses of 10, 20, 30, or 40 mg or placebo. The primary efficacy end point was the mean change from baseline over the entire treatment period in daily reflective nasal congestion score. Other efficacy end points and safety were also evaluated. RESULTS: None of the PE HCl treatment groups had a statistically significant change from baseline in instantaneous or reflective nasal congestion scores compared with the placebo group. PE HCl was well tolerated at doses of up to 30 mg. At least 1 treatment-emergent adverse event was experienced by 18.4% of the participants, the most common being headache (3.0%). CONCLUSIONS: PE HCl, at doses of up to 40 mg every 4 hours, is not significantly better than placebo at relieving nasal congestion in adults with SAR. The phenylephrine section of the Food and Drug Administration monograph on over-the-counter cold, cough, allergy, bronchodilator, and antiasthmatic products should be revised accordingly.

Snoring and sleep problems in children with and without allergic rhinitis: a case control study.

OBJECTIVE: To compare the sleep problems between children with and without allergic rhinitis (AR). MATERIAL AND METHOD: A case-control study was conducted in 65 children aged 6-15 years with allergic rhinitis and 104 control subjects matched individually by age, height and weight. Cases were recruited from the Pediatric Allergy Clinic at Thammasat University Hospital. The selection of cases was based on clinical history, physical examination and skin prick test. Matched healthy control children were recruited from the Thammasat primary school. Children and their caregivers who usually sleep with them completed the questionnaire. RESULTS: 86.2% of allergic rhinitis was classified as persistent rhinitis and 63.1% had moderate to severe disease. The most common presenting symptom was nasal blockage (66.2%). Allergic rhinitis patients had significant sleep problems with snoring, sleep apnea, restless, night sweating, mouth breathing, dry throat, morning headache, falling asleep in class, difficulty in waking up and not refreshed in the morning (p<0.05). Patients who categorized as blockers had significantly more restless sleep and dry mouth on waking up compared to that of non-blockers (p<0.05). CONCLUSION: There was a higher prevalence of sleep problems in children with AR then those without AR.

Immunoglobulin G4 related disease isolated to the nasal cavity: a rare cause of nasal obstruction.

BACKGROUND: Immunoglobulin G4 related disease is a rare condition. Cases involving the sinonasal region are exceptionally uncommon. This paper describes a case of immunoglobulin G4 related disease isolated solely to the nasal cavity. METHODS: Case report and literature review. RESULTS: A 34-year-old man presented with painless, progressive bilateral nasal obstruction. Clinical examination and imaging findings demonstrated bilateral submucosal swelling of the anterior septum and right external nasal wall. Biopsy revealed immunoglobulin G4 related disease. The patient responded to oral corticosteroids initially, followed by long-term methotrexate. CONCLUSION: To the best of our knowledge, this case represents the first report in the literature of immunoglobulin G4 related disease isolated solely to the nasal cavity.

Increased IL-22 level in allergic rhinitis significantly correlates with clinical severity.

BACKGROUND: IL-22 regulates various processes and has been linked to diverse effects. However, the importance of IL-22 in the pathogenesis of allergic rhinitis (AR) remains poorly understood. This study sought to evaluate the levels of IL-22 and IL-17A in AR patients and their association with clinical severity ofN AR. METHODS: Thirty-six AR patients and 22 normal controls were enrolled in this study. The frequencies of IL-22(+), IL-17A(+), and IL-9(+) T helper (Th) cells in peripheral blood of AR patients and normal controls were examined by flow cytometry. Serum levels of IL-22 and IL-17A in AR patients and normal controls were determined by ELISA. The clinical relevance of the percentages of IL-22(+) and IL-17A(+) Th cells as well as serum IL-22 and IL-17A levels were evaluated. RESULTS: The frequencies of IL-22(+) and IL-17A(+) Th cells, but not IL-9(+) Th cells, were significantly increased compared with those in normal controls (p < 0.05). Frequencies of IL-22(+) and IL-17A(+) Th cells in peripheral blood of AR patients significantly correlated with visual analog scale scores of nasal symptoms (nasal congestion and rhinorrhea; p < 0.05). Moreover, the serum levels of IL-22 and IL-17A were significantly increased compared with those in normal controls (p < 0.05) and significantly correlated with the levels of Dermatophagoides pteronyssinus and Dermatophagoides farinae specific IgE in AR patients. CONCLUSION: Our findings suggested that IL-22 as well as IL-17A may play an important role in the regulation of Th2-skewed inflammation in AR patients.

Does usage of a room air freshener affect the nasal mucosa?

BACKGROUND: Effects of chemicals emitted from the room air freshener sprays (RAFSs) on nasal mucosa are still unclear. The purpose of this study was to investigate effects of RAFSs on the nasal mucosa of rats for different time intervals. METHODS: Twenty-eight rats were randomly divided into four experimental groups: group 1 (n = 7) was the control group and not exposed to RAFS or other chemicals, group 2 (n = 7) was exposed to RAFS for 1 month, group 3 (n = 7) was exposed to RAFS for 2 months, and group 4 (n = 7) was exposed to RAFS for 3 months. Samples from the nasal septum were stained using hematoxylin and eosin solution, examined by a pathologist using a light microscope, and analyzed with Fisher's exact test. RESULTS: We observed that distinct histopathological differences in the nasal mucosa of exposed rats depends on different time intervals (p < 0.05). Increased congestion was found after the 1st month of exposure (group 2). Although edema and mild inflammatory cell infiltration, including some eosinophils, was seen after the 2nd month (group 3), squamous metaplasia, numerous eosinophils, and intense inflammatory cell infiltration began after 3 months of exposure (group 4). CONCLUSION: Our results showed that continuous use of RAFS can cause inflammation and eosinophilic infiltration in rats, which begins after 2 months of exposure and may lead to metaplasia after 3 months. Because of differences in body size, geometry, and physiological responses of rats, the extrapolation of these results to humans is not straightforward. However, any such comparison should be made with caution. Finally, more performance is necessary to clarify this subject.

Evidence and role of autoantibodies in chronic rhinosinusitis with nasal polyps.

In this study, we review our current knowledge of the autoimmune etiopathogenesis of chronic rhinosinusitis with nasal polyps including bacterial infections, viral infections and immunomediated mechanisms and to discuss pathogenesis with relevance for pharmacotherapy. Relevant publications on the etiopathogenesis and treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) from 1977 to 2013 were analyzed. The characteristic signs and symptoms include appearance of relapsing nasal polyps, with typical symptoms such as nasal obstruction, nasal discharge and, usually, loss of the sense of smell. The etiology and pathogenesis remain unknown. Proposed theories of causation include bacterial or viral infections and immunomediated mechanisms. The autoimmune aetiology of unknown origin or failure to respond to classic pharmacological treatments with nasal and oral steroids is now suspected. At present, the nature of the antigen trigger, the exact role played by B/T cells and anti-dsDNA autoantibodies in the pathogenesis of nasal polyposis remains unclear. Corticosteroids and surgery are the first line of treatment in CRSwNP. In the case of corticosteroid treatment failure, other drugs can be used such as rituximab, belimumab or omalizumab which have demonstrated clinical efficacy in the treatment of nasal polyposis with comorbid asthma. Immunosuppressive drugs such as methotrexate, and cyclophosphamide have also been used with varying degrees of success.

Correlation between nasal eosinophils and nasal airflows in children with asthma and/or rhinitis monosensitised to house dust mites.

BACKGROUND: Allergic rhinitis and asthma due to mite sensitisation are diseases which are frequently associated and characterised by persistent inflammation. In the present study, we aimed to investigate the relationship between nasal airflows and nasal eosinophils in patients with asthma and/or rhinitis due to house dust mite sensitisation. METHODS: Twenty-four children with both rhinitis and asthma (R+A), 13 children with rhinitis and no asthma (R) and 10 non-allergic healthy children were evaluated prospectively. The patients belonging to the first two groups had moderate-severe grade of nasal obstruction. Total nasal symptom scores, peak nasal inspiratory flows (PNIFs) obtained by anterior rhinomanometry, skin prick tests, nasal eosinophils and FEV1 values were all assessed. RESULTS: Percentages of nasal eosinophils and PNIFs in patients with R+A and R (r=-0.415, p=0.04) were found to be statistically significant and to have an inverse correlation. Skin prick tests were also significantly correlated with nasal eosinophils and PNIFs (r=0.372, p=0.01 and r=-0.306, p=0.04, respectively). Both PNIFs and nasal eosinophils of patients with R+A were significantly correlated with FEV1 values (r=-0.641, p=0.001 and r=0.548, p=0.007, respectively). CONCLUSION: In this study, a close relationship was demonstrated between eosinophil infiltration and nasal airflows in children having asthma and/or rhinitis monosensitised to mites. Additionally, the significant association found between FEV1 values and nasal eosinophils or PNIFs supported the close link of upper and lower airways.

Assessing the relationship between serum resistin and nasal obstruction in children with allergic rhinitis.

BACKGROUND: Nasal obstruction has been reported as a "key symptom" of allergic rhinitis (AR) because it is deeply associated with impaired quality of life and it reflects more directly the allergic inflammation in the nasal mucosa. Resistin is known to be involved in inflammatory processes exerting an important role in the regulation of cytokine production even though its effective proinflammatory activity at nasal level has never been fully established. This study investigates the relationship between resistin levels and nasal obstruction assessed by an objective method such as active anterior rhinomanometry. METHODS: Fifty-three children between 4 and 10 years of age affected by persistent allergic rhinitis (PAR) were enrolled and subdivided in two groups. Serum resistin levels were detected in all children. The same day patients underwent rhinomanometry, which was considered negative (no nasal obstruction) when the fraction of predicted values (p.v.'s) was between 71 and 100% and it was considered positive when the fraction of p.v. was ≤70%. RESULTS: The serum resistin levels were significantly higher in children with moderate-severe PAR than in patients with mild PAR (p < 0.03). Furthermore, serum resistin levels were significantly higher in children with positive rhinomanometry compared with negative rhinomanometry (p < 0.03). The fraction of p.v.'s of nasal flows in patients with nasal obstruction had a significant negative correlation with serum resistin levels (p < 0.001). CONCLUSION: This study provides evidence that resistin levels are increased in children with severe nasal obstruction measured by an objective and quantitative approach.

Methacholine bronchial challenge effects on nasal symptoms and function in patients with allergic rhinitis.

BACKGROUND: Allergic rhinitis and asthma may be associated, bronchial hyperreactivity (BHR) is quite common in AR patients. It has been reported that allergen bronchial challenge induces nasal inflammation. Methacholine (MCH) is a stimulus able to elicit BHR. There is no study that investigated the effect of MCH bronchial challenge on the nose. OBJECTIVE: The aim of this study was to evaluate whether MCH bronchial challenge is able to induce changes in nasal symptom perception and nasal function in patients with AR. METHODS: 122 patients (117 males, median age 28 years) suffering from AR were evaluated. Values for bronchial function (FVC, FEV1, FEF25-75, and FEV1/FVC ratio), MCH bronchial challenge, VAS for nasal and bronchial symptoms, and nasal airflow and resistance were assessed. RESULTS: 23 patients (18.9%) had BHR. MCH bronchial challenge induced a significant reduction of nasal obstruction perception (p<0.001), but did not affect the nasal function. Most of patients (91) did not perceive impairment of respiration. The perception of nasal obstruction was strongly related to the AR duration (r=0.65). The highest values of both baseline rhinoVAS and Δ bronchial VAS predicted BHR (OR 1.7 and 2.9 respectively). CONCLUSIONS: The present study demonstrates that in AR patients MCH bronchial challenge does not substantially affect nasal symptoms and function, also in subjects with an acute bronchospasm, such as in BHR patients. However, severity of nasal obstruction perception might predict BHR.

The role of nasal cytology in the management of inferior turbinate hypertrophy.

Inferior turbinate hypertrophy (ITH) is the main cause of nasal obstruction symptom. This study aimed at investigating whether a particular cellular pattern could be a predictive factor for failure of medical treatment for ITH in patients with rhinitis. Globally, 258 patients with chronic nasal obstruction due to ITH were evaluated by: visual analogue scale assessment of symptoms, skin prick tests, fiber-endoscopy, active anterior rhinomanometry, and nasal cytology. All patients were treated with drugs for 3 months and then re-evaluated. The symptom improvement depended on the different cellular pattern. There was improvement in: 54 (51.4 percent) patients with allergic rhinitis, 72 (69.2 percent) with non-allergic rhinitis with neutrophils (NARNE), 15 (42.8 percent) with non-allergic rhinitis with eosinophils (NARES), and 9 (64.3 percent) with non-allergic rhinitis with mast cells/non-allergic rhinitis with eosinophils and mast cells (NARMA/NARESMA). The non-responders (108; 41.9 percent) were therefore directed towards surgical treatment. Both patients with allergic rhinitis and patients affected by NARES had a higher failure rate to medical treatment compared with NARMA and NARESMA groups (pless than0.01). In conclusion, elevated number of eosinophils, in the nasal secretion of both allergic (allergic rhinitis) and non-allergic (NARES) patients with ITH, can be associated to a higher medical treatment failure rate.

The potential role of prostaglandin D2 in nasal congestion observed in a guinea pig model of allergic rhinitis.

BACKGROUND: Allergic rhinitis is the most common allergic disease, displaying the typical nasal symptom of congestion. Prostaglandin D(2) (PGD(2)), a chemical mediator released in large amounts by mast cells upon allergic stimulation in humans, is known to be involved in nasal congestion. However, the mechanism by which this congestion occurs remains unclear. METHODS: The effect of PGD(2) on the nasal airflow in guinea pigs was measured using a noninvasive approach that avoided any anesthetic effect. Isometric tension of isolated nasal mucosa and the nasal vascular corrosion resin cast technique were used to clarify the area of nasal mucosal vessels affected by PGD(2), and to examine the mechanism of PGD(2)-induced nasal congestion. Moreover, the involvement of second messengers in PGD(2)-induced mucosal relaxation was investigated. RESULTS: PGD(2) induced an increase in intranasal pressure in a guinea pig model of rhinitis. Additionally, sinusoidal microvessel dilatation appeared around the septum using the vascular corrosion resin cast technique in the nasal mucosa. Moreover, relaxation of the nasal mucosa following stimulation of the prostanoid DP-1 receptor was associated with cAMP levels in the tissue. CONCLUSIONS: PGD(2)-induced nasal congestion is caused by direct dilatation of the sinusoid vessels through the increase of cAMP levels in the nasal mucosa, demonstrating that the mechanism of PGD(2)-induced nasal congestion is different from other chemical mediators. Consequently, antagonists for the prostanoid DP-1 receptor would be an alternative approach for the relief of nasal congestion. Alternatively, the combined administration with antagonists for other mediators involved in nasal congestion may also be a valuable therapy for allergic rhinitis.

Effect of Ganoderma lucidum on pollen-induced biphasic nasal blockage in a guinea pig model of allergic rhinitis.

Ganoderma lucidum (GL), an oriental medical mushroom, has been used in Asia for the prevention and treatment of a variety of diseases. However, the effect of GL on allergic rhinitis has not been well defined. The current study describes the inhibitory effect of GL on the biphasic nasal blockage and nasal hyperresponsiveness induced by repeated antigen challenge in a guinea pig model of allergic rhinitis. Intranasally sensitized guinea pigs were repeatedly challenged by inhalation of Japanese cedar pollen once every week. Ganoderma lucidum was orally administered once daily for 8 weeks from the time before the first challenge. The treatment with GL dose-dependently inhibited the early and late phase nasal blockage at the fifth to ninth antigen challenges. Furthermore, nasal hyperresponsiveness to intranasally applied leukotriene D4 on 2 days after the eighth antigen challenge was also inhibited by the treatment with GL. However, Cry j 1-specific IgE antibody production was not affected by the treatment. In conclusion, we demonstrated that the pollen-induced biphasic nasal blockage and nasal hyperresponsiveness were suppressed by the daily treatment with GL in the guinea pig model of allergic rhinitis. These results suggest that GL may be a useful therapeutic drug for treating patients with allergic rhinitis.

Role of hematopoietic prostaglandin D synthase in biphasic nasal obstruction in guinea pig model of experimental allergic rhinitis.

We investigated the role of hematopoietic prostaglandin D synthase (H-PGDS) in biphasic nasal obstruction in allergic rhinitis using a new specific inhibitor, (N-methoxy-N-methyl)-4-(5-benzoylbenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide hydrochloride (TAS-204). First, we developed a novel guinea pig model of allergic rhinitis. Guinea pigs sensitized to ovalbumin without adjuvant were challenged with intranasal exposure to ovalbumin once a week. After the 3rd antigen challenge, they exhibited biphasic nasal obstruction. Additionally, analysis of nasal lavage fluid revealed an increase in the level of prostaglandin D(2) in both early and late phases. Treatment with oral TAS-204 for 15 days during the period of antigen challenges suppressed increases in nasal airway resistance in both phases. It is noteworthy that the late phase nasal obstruction was almost completely abrogated by inhibiting H-PGDS alone. Eosinophil infiltration in nasal lavage fluid and nasal hyperresponsiveness to histamine was also reduced by TAS-204 administration. These findings suggest that H-PGDS plays a critical role in the development of allergic rhinitis, especially in the induction of late phase nasal obstruction.