Japanese guidelines for allergic rhinitis 2020.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Japanese guidelines for allergic rhinitis 2017.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Inhibition of IL-13-induced periostin in airway epithelium attenuates cellular protein expression of MUC5AC.

BACKGROUND AND OBJECTIVE: Serum periostin is increased in asthma and serves as a surrogate marker for IL-13 activity in the lung. Serum levels of periostin are the most robust biomarker predicting a favourable response to the anti-IL-13 drug, lebrikizumab. We investigated the mechanisms of IL-13 stimulation of periostin, the polarized secretion of periostin and whether periostin would have a direct effect on mucin secretion by airway cells. METHODS: Normal human bronchial epithelial (NHBE) cells were cultured at air-liquid interface (ALI) in the presence of IL-13, and we evaluated the effect of the specific inhibitors, leflunomide (Janus kinase (JAK)/signal transducer and activator of transcription factor 6 (STAT6) inhibitor) or PD98059 (MEK/extracellular regulated protein kinase (ERK) inhibitor), on periostin production. We examined MUC5AC secretion from NHBE cells exposed to recombinant human (rh) periostin or IL-13 in the presence and absence of OC-20, a periostin-neutralizing antibody. RESULTS: IL-13 induced periostin protein which was predominantly secreted towards the basal surface of the cells. Periostin production was much greater from goblet cells than ciliated cells (P < 0.001). Periostin production after exposure to IL-13 was attenuated by both leflunomide (P < 0.001) and PD98059 (P < 0.001). The addition of exogenous periostin modestly increased MUC5AC secretion (P < 0.01), but did not visibly change cell morphology. IL-13-induced MUC5AC secretion was attenuated by OC-20 (P < 0.01). CONCLUSION: Periostin production in differentiated airway cells is mediated by JAK/STAT6 and MEK/ERK pathways. Periostin secretion is much greater from immunologically active goblet cells. IL-13-driven mucin production is partially inhibited by OC-20.

Past, present and future of macrolide therapy for chronic rhinosinusitis in Japan.

In 1984, the effectiveness of low-dose, long-term erythromycin treatment (macrolide therapy) for diffuse panbronchiolitis (DPB) was first reported in Japan. The 5-year survival rate for DPB improved from 62.9 to 91.4% after implementation of macrolide therapy. The usefulness of this treatment has since been demonstrated in patients with other chronic airway diseases, such as chronic bronchitis, cystic fibrosis, bronchiectasis, bronchial asthma, and chronic rhinosinusitis (CRS). The new 14-membered macrolides clarithromycin and roxithromycin and the 15-membered macrolide azithromycin are also effective for treating these inflammatory diseases. The mechanism of action of the 14- and 15-membered macrolides may involve anti-inflammatory rather than anti-bacterial activities. Macrolide therapy is now widely used for the treatment of CRS in Japan; it is particularly effective for treating neutrophil-associated CRS and is useful for suppressing mucus hypersecretion. However, macrolide therapy is not effective for eosinophil-predominant CRS, which is characterized by serum and tissue eosinophilia, high serum IgE levels, multiple polyposis, and bronchial asthma. Recent reports have described the clinical efficacy of macrolides in treating other inflammatory diseases and new biological activities (e.g., anti-viral). New macrolide derivatives exhibiting anti-inflammatory but not anti-bacterial activity thus have therapeutic potential as immunomodulatory drugs. The history, current state, and future perspectives of macrolide therapy for treating CRS in Japan will be discussed in this review.

ICON: chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a public health problem that has a significant socio-economic impact. Moreover, the complexity of this disease due to its heterogeneous nature based on the underlying pathophysiology - leading to different disease variants - further complicates our understanding and directions for the most appropriate targeted treatment strategies. Several International/national guidelines/position papers and/or consensus documents are available that present the current knowledge and treatment strategies for CRS. Yet there are many challenges to the management of CRS especially in the case of the more severe and refractory forms of disease. Therefore, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), a collaboration between EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus (ICON) on Chronic Rhinosinusitis. The purpose of this ICON on CRS is to highlight the key common messages from the existing guidelines, the differences in recommendations as well as the gaps in our current knowledge of CRS, thus providing a concise reference. In this document we discuss the definition of the disease, its relevance, pharmacoeconomics, pathophysiology, phenotypes and endotypes, genetics and risk factors, natural history and co-morbidities as well as clinical manifestations and treatment options in both adults and children comprising pharmacotherapy, surgical interventions and more recent biological approaches. Finally, we have also highlighted the unmet needs that wait to be addressed through future research.

Inhibitory action of levocetirizine on the production of eosinophil chemoattractants RANTES and eotaxin in vitro and in vivo.

Eosinophils are well known to play essential roles in the development and maintenance of allergic diseases. However, the influence of histamine H1 receptor antagonists on eosinophil functions, especially chemokine production, are not well-defined. Therefore, in the present study, we examined the influence of histamine H1 receptor antagonist on chemokine production by eosinophils through the use of levocetirizine in vitro and in vivo. Eosinophils prepared from mice were stimulated with specific antigens in the presence of different concentrations of levocetirizine. After 24 h, regulated on activation normal T cell expressed and secreted (RANTES) and eotaxin levels in culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Patients with Japanese cedar pollinosis were treated with 5 mg levocetirizine once a day for four weeks during the pollen season (February 2012 to April 2012). RANTES and eotaxin levels in nasal secretions were also examined by ELISA. The addition of levocetirizine to eosinophil cultures caused a dose-dependent decrease in the ability of cells to produce RANTES and eotaxin in response to antigen stimulation, and the minimum concentration that caused a significant decrease was 0.05 µM. Although cetirizine also exerted suppressive effects on the production of RANTES and eotaxin by eosinophils, the minimum concentration that caused significant suppression was 0.15 µM, which was three-times higher than that of levocetirizine. Oral administration of levocetirizine for four weeks also reduced RANTES and eotaxin levels in nasal secretions from patients with pollinosis, along with attenuation of clinical symptoms. The ability of levocetirizine to reduce RANTES and eotaxin levels may account, at least in part, for the clinical efficacy of the agent for allergic disorders, including allergic rhinitis.

Club cell 10-kDa protein attenuates airway mucus hypersecretion and inflammation.

Bacterial lipopolysaccharide (LPS) and interleukin (IL)-13 increase mucus secretion and inflammatory cytokine production in normal human bronchial epithelial (NHBE) cells. We evaluated the effect of club cell 10-kDa protein (CC10), an anti-inflammatory protein produced by epithelial cells, on mucus secretion, cell morphology and inflammatory cytokine production. NHBE cells were cultured at an air-liquid interface with CC10 or vehicle and exposed to LPS on day 14. Mucin MUC5AC, IL-8 and granulocyte-macrophage colony-stimulating factor were measured in cell supernatants. MUC5AC and IL-8 mRNA expression were measured by real-time PCR. Western blotting was used to evaluate nuclear factor (NF)-κB and extracellular signal-regulated kinase (ERK) activation. Cells were evaluated histologically. Additionally, NHBE cells were exposed to IL-13 and CC10 for 14 days, and secretion of the mucins MUC5AC and MUC5B was measured. MUC5AC secretion stimulated either by LPS or by IL-13 was attenuated by CC10 at 20 ng·mL(-1) (p<0.05). CC10 at 20 ng·mL(-1) also attenuated IL-8 secretion (p<0.05). MUC5AC and IL-8 mRNA expression were also decreased by CC10 (p<0.05). CC10 attenuated phosphorylation of NF-κB (p<0.05) and ERK1/2 (p<0.05). CC10 attenuates LPS-induced mucus secretion in airway cells, in part due to inhibition of NF-κB and ERK phosphorylation.

Effect of prednisone on nasal symptoms and peripheral blood T-cell function in chronic rhinosinusitis.

BACKGROUND: Systemic corticosteroids are the most effective anti-inflammatory drugs used for controlling chronic rhinosinusitis (CRS) symptoms. The potential mechanisms for their beneficial effects include increasing the number and function of T regulatory cells (Tregs), as reported in the local tissue post-intranasal steroid treatment. We investigated the effect of systemic corticosteroids on peripheral blood (PB) Tregs in subjects with CRS. METHODS: Twenty CRS subjects and 19 controls were recruited. PB mononuclear cells (PBMCs) were isolated from CRS subjects before and after systemic corticosteroid administration in the course of clinical treatment. Control subjects received no treatment and were studied at one visit. Nasal symptoms were recorded. CD4(+) CD25(+) Foxp3(+) cells (Tregs) were analyzed by flow cytometry. Messenger RNA (mRNA) levels for interferon γ (IFN-γ), interleukin 4 (IL-4), IL-10, IL-13, IL-17A, transforming growth factor ß1 (TGF-ß1), forkhead box P3 (FoxP3), and GATA-binding factor 3 (GATA-3) were measured in PBMCs using real-time polymerase chain reaction (PCR). RESULTS: CRS subjects reported improved nasal symptoms (p = 0.005) and significantly reduced PB Tregs after treatment with corticosteroids (p = 0.042). The transcript levels of IL-4 and GATA-3 were significantly higher in the CRS subjects at their first visit when compared to controls (p = 0.019 and p = 0.05, respectively). Corticosteroid treatment lowered the transcript levels of immunoregulatory transcription factors [FoxP3 (p = 0.048) and GATA-3 (p = 0.012)] and IFN-γ (p = 0.036) in PB. CONCLUSION: In contrast to prior work in local nasal tissue, our study reports reduced PB Tregs and decreased T helper 1 (T(H)1) and T(H)2 function after treatment with systemic corticosteroids. These data indicate that corticosteroid effects on Tregs in CRS are complex involving local signals in the tissue that are distinct from those in circulating cells.

Enhancement of thioredoxin production from nasal epithelial cells by the macrolide antibiotic, clarithromycin in vitro.

Low-dose and long-term administration of 14-membered macrolide antibiotics is well-known to be effective in the treatment of chronic airway diseases. Although there is much evidence that the anti-inflammatory action, but not the anti-microbial action of macrolides, is responsible for the clinical efficacy of these agents on chronic airway inflammatory diseases, the precise therapeutic mechanisms are not well-understood. Since thioredoxin (TRX) has now attracted attention as an endogenous peptide with immunomodulatory effects, the present study was undertaken to examine whether macrolide antibiotics could favorably modulate the clinical status of such diseases via the production of TRX from nasal epithelial cells in vitro. Nasal epithelial cells (5×10(5) cells/ml) obtained from five patients were stimulated with 50 µM H2O2 in the presence of different concentrations of macrolide antibiotics for 24 h. TRX levels in culture supernatants were examined by enzyme-linked immunosorbent assay. We also examined the influence of macrolide antibiotics on TRX mRNA expression and mRNA translation by RT-PCR and a wheat germ cell-free protein synthesis technique, respectively. The addition of clarithromycin (CAM) to cell cultures caused an increase in the ability of cells to produce TRX in response to H2O2 stimulation, and the minimum concentration that caused a significant increase was 0.5 µg/ml. On the other hand, josamycin, a 16-membered macrolide antibiotic, did not increase TRX production induced by H2O2 stimulation. Although the treatment of cells with CAM inhibits TRX mRNA transcription, the agent might increase translation of mRNA to produce specific proteins. The ability of CAM to increase TRX production may account, at least in part, for the clinical efficacy of this agent on chronic airway inflammatory diseases, including chronic rhinosinositis.

Rhinosinusitis and asthma-microbiome and new perspectives.

PURPOSE OF REVIEW: Microbiome is one of the new perspectives in human health research, including airway diseases. There are several publications about the relationship of the microbiome and allergic diseases. Although pathogenesis of chronic rhinosinusitis (CRS) as well as its relationship with asthma has been widely investigated, the relationship of the microbiome and CRS is not yet well known. RECENT FINDINGS: The relationship between the hygiene hypothesis and microorganisms inside the human body and in the environment around it has been clearly shown. Furthermore, several researchers have reported that the microorganisms in the gut play a major role in regulating the immune cells that are of relevance to asthma and allergic diseases, such as Th1, Th2, Th17, Treg and dendritic cells as well as Toll-like receptors. Reduced contact of people with natural environmental features and biodiversity may adversely affect the human commensal microbiota and its immunomodulatory capacity.Some studies have shown a close relationship between CRS and Staphylococcus aureus, anaerobes and so on in the nasal cavity or paranasal sinuses, although the relationship between CRS and microorganisms in the gut has not been demonstrated. SUMMARY: In this review, we summarized about the microbiome, mainly in asthma and allergic diseases. The relationship between asthma and CRS has been clearly shown, and in particular, CRS with nasal polyps (CRSwNP) has been considered to be Th2-dominant. Studies examining environmental microbial exposure in populations at risk for CRS are necessary to improve our understanding of the role this factor plays in disease development.

Suppression of osteopontin functions by levocetirizine, a histamine H1 receptor antagonist, in vitro.

OBJECTIVES: Osteopontin (OPN), a multifunctional glycoprotein secreted from a wide variety of cells after inflammatory stimulation, is well accepted to contribute to the development of allergic diseases. However, the influence of histamine H1 receptor antagonists (antihistamines) on OPN functions is not well understood. The present study was undertaken to examine the influence of antihistamines on OPN functions in vitro. METHODS: Human nasal epithelial cells (5 × 10(5) cells) were stimulated with 250 ng/mL OPN in the presence of either desloratadine (DL), fexofenadine (FEX), or levocetirizine (LCT). The levels of OPN, GM-CSF, Eotaxin, and RANTES in 24 h culture supernatants were examined by ELISA. The influence of LCT on mRNA expression and transcription factor activation in cells were also examined by real-time RT-PCR and ELISA, respectively. KEY FINDINGS: The antihistamines examined significantly suppressed the production of GM-CSF, Eotaxin, and RANTES from cells after OPN stimulation. LCT also exhibited the suppression of mRNA expression for chemokines and transcription factor, NF- κ B and AP-1, activation, which were increased by the stimulation of cells with OPN. CONCLUSIONS: The suppressive activity of LCT on OPN functions on nasal epithelial cells may be responsible for the attenuating effect of the agent on allergic diseases.

Enhancement of clara cell 10-kD protein (CC10) production from nasal epithelial cells by fexofenadine hydrochloride.

BACKGROUND: Clara cell 10-kD protein (CC10) is well known to be an immuno-suppressive protein secreted from airway epithelial cells after inflammatory stimulation and is involved in the development of allergic disorders. Although histamine H1 receptor antagonists are used for the treatment of allergic disorders, the influence of the agents on CC10 production is not well understood. In the present study, we examined the influence of a histamine H1 receptor antagonist, fexofenadine hydrochloride (FEX) on CC10 production in vitro and in vivo. METHODS: Nasal epithelial cells (5 x 10(6) cells/ml) were stimulated with 20 ng/ml TNF-alpha in the presence of various concentrations of FEX for 24 hours. CC10 levels in culture supernatants were examined by ELISA. Patients with Japanese cedar pollinosis were treated orally with FEX twice a day at a single dose of 60 mg for two weeks during Japanese cedar pollen season (February 2011 to April 2011). CC10 levels in nasal secretions were also examined by ELISA. RESULTS: The addition of FEX into cell cultures caused increase in CC10 production induced by TNF-alpha stimulation, and the minimum concentration that caused significant increase was 200 ng/ml. Oral administration of FEX also increased CC10 levels in nasal secretions from pollinosis patients along with attenuation of clinical symptoms. CONCLUSION: The ability of FEX to enhance CC10 production may account, at least in part, for the clinical efficacy of the agent in allergic disorders, including allergic rhinitis.

Clinical outcomes of ventilation tube placement in children with cleft palate.

OBJECTIVE: The purpose of this study was to investigate the long-term clinical outcomes in children with cleft palate. METHODS: One hundred eight patients with cleft palate (CP) were investigated. Microscopic observation of the middle ears was performed periodically. If chronic otitis media with effusion (OME) was diagnosed at 1 year of age or later, ventilation tube (VT) placement was performed. The air-filled area of the mastoid air cells was checked on X-rays obtained at 1 and 5 years. The data from each measurement were tested statistically by the bootstrap method and Wilcoxon's rank-sum test. The clinical course from age 6 to the final examination (average 9.42 years) and the language development at 5 years were analyzed using data from the medical records of individual patients. RESULTS: VT placements were performed at 5 years of age or younger in 41 CP patients (82 ears, 38%). About 30% of patients treated by VT placement at 5 years of age or younger required myringotomy and/or VT re-placement at 6 years of age or over. Ninety-five percent of patients who had not been treated by VT insertion at 5 years of age or younger showed a favorable subsequent clinical course. Patients treated by VT insertion at 5 years of age or younger had significantly smaller mastoid air cell areas as measured at 5 years of age and also at 1 year of age. No significant difference in language development was observed between the CP patients that underwent /did not undergo VT placement. CONCLUSIONS: VT placement should be positively undertaken in CP children who have small mastoid air cell areas as measured at 1 year of age, because an unfavorable prognosis of OME is expected in such patients. It is considered that patients treated by VT placement at 5 years of age or younger should be carefully followed up for the development of OME even after 6 years of age. Thus, measurement of the mastoid air cell area at the age of 1 year is useful for determining the therapeutic program.

Examination, diagnosis and classification for Japanese allergic rhinitis: Japanese guideline.

Many countries throughout the world have experienced an increase in the prevalence of allergic rhinitis (AR), which has come to be a major cause of morbidity in developed countries. The pathology underlying AR is regarded as IgE-mediated type I allergy characterized by mucosal inflammation that occurs in response to allergen exposure. In Japan, AR caused by Japanese cedar pollen, the most common allergic disease, has become a salient public health challenge. Almost all primary care physicians and otorhinolaryngologists have been consulted by AR patients between February and April. Although most such patients have received treatment, numerous patients with AR have not received proper examinations for AR. Clinical guidelines are systematically developed statements that are designed to help practitioners make decisions about appropriate and effective health care. Guidelines in many countries including Japan have been published for AR. Unfortunately, those guidelines have remained untested. Moreover, they might be difficult for non-specialists to use. In this review, we specifically examine the present standard examination for diagnosis of AR and optimal classification for AR in Japan. We hope that this review would be used not only for the support of daily practice but also for selection of AR patients for clinical trials.

Antiinflammatory role of MUC1 mucin during infection with nontypeable Haemophilus influenzae.

MUC1 (or Muc1 in nonhuman species) is a membrane-tethered mucin expressed on the apical surface of mucosal epithelia (including those of the airways) that suppresses Toll-like receptor (TLR) signaling. We sought to determine whether the anti-inflammatory effect of MUC1 is operative during infection with nontypeable Haemophilus influenzae (NTHi), and if so, which TLR pathway was affected. Our results showed that: (1) a lysate of NTHi increased the early release of IL-8 and later production of MUC1 protein by A549 cells in dose-dependent and time-dependent manners, compared with vehicle control; (2) both effects were attenuated after transfection of the cells with a TLR2-targeting small interfering (si) RNA, compared with a control siRNA; (3) the NTHi-induced release of IL-8 was suppressed by an overexpression of MUC1, and was enhanced by the knockdown of MUC1; (4) the TNF-α released after treatment with NTHi was sufficient to up-regulate MUC1, which was completely inhibited by pretreatment with a soluble TNF-α receptor; and (5) primary murine tracheal surface epithelial (MTSE) cells from Muc1 knockout mice exhibited an increased in vitro production of NTHi-stimulated keratinocyte chemoattractant compared with MTSE cells from Muc1-expressing animals. These results suggest a hypothetical feedback loop model whereby NTHi activates TLRs (mainly TLR2) in airway epithelial cells, leading to the increased production of TNF-α and IL-8, which subsequently up-regulate the expression of MUC1, resulting in suppressed TLR signaling and decreased production of IL-8. This report is the first, to the best of our knowledge, demonstrating that the inflammatory response in airway epithelial cells during infection with NTHi is controlled by MUC1 mucin, mainly through the suppression of TLR2 signaling.

Palatoplasty and growth of the temporal bone mastoid air cells.

OBJECTIVES: The present study was undertaken to analyze the relationship between the method used for manipulation of the levator veli palatini muscle and the area of the mastoid air cells in patients with cleft palate. DESIGN: Retrospective study. PATIENTS: The subjects were 50 patients seen for surgical treatment of cleft palate. INTERVENTIONS: Palatoplasty was carried out using the mucosal flap method in 25 patients and the mucoperiosteal flap method in 25 patients. In the mucosal flap method, the levator veli palatini muscle was overlapped and sutured, followed by posterior movement of the muscle bundle (the posterior relocation group). In the mucoperiosteal flap method (the control group), the mucoperiosteal flap was pushed back, followed by end-to-end suturing of the muscle. The area of the mastoid air cells was measured on X-rays when patients were 5 years old. RESULTS: The mastoid air cell area did not differ significantly between the posterior relocation group (mean, 5.00 cm(2); range, 1.66 to 19.7 cm(2)) and the control group (mean, 5.3 cm(2); range, 2.29 to 15.9 cm(2)). CONCLUSION: No significant growth of mastoid air cells was noted following posterior relocation of the levator veli palatini muscle. Thus, in cases of cleft palate in which significant growth of mastoid air cells is not expected following reconstruction of the levator veli palatini muscle, the results confirm the view that tympanic ventilation tube insertion is the most suitable method for the treatment of otitis media.

Efficacy of combined treatment with S-carboxymethylcysteine (carbocisteine) and clarithromycin in chronic rhinosinusitis patients without nasal polyp or with small nasal polyp.

OBJECTIVE: In Japan, fourteen-membered ring macrolides, antibacterial agents, and S-carboxymethylcysteine (SCMC; carbocisteine), a mucolytic, are commonly used to treat chronic rhinosinusitis (CRS), and they are also used in combination. However, no large-scale randomized study has examined the effects of these pharmacotherapies. The aim of this study is to evaluate the effect of combined administration of clarithromycin (CAM), a fourteen-membered ring macrolide, and SCMC, compared with CAM single therapy. METHODS: Patients with CRS were centrally registered and randomly assigned to treatment with CAM (200mg/day) alone (monotherapy group) or CAM (200mg/day) in combination with SCMC (1500mg/day; combination group) for 12 weeks. We assessed the clinical efficacy of the treatments using measures of subjective symptoms and objective findings, health-related quality of life (HRQOL) determined by the 20-Item Sino-Nasal Outcome Test (SNOT-20) score and computed tomography (CT) score. RESULTS: Four hundred twenty-five subjects were enrolled (combination group, 213; monotherapy group, 212). At week 12 of treatment, the rate of effectiveness was significantly higher in the combination group (64.2%) compared with the monotherapy group (45.6%; P=0.001). In addition, objective findings, including characteristics of nasal discharge (P=0.008) and post-nasal discharge (P=0.002) were significantly improved in the combination group. In both groups, SNOT-20 and CT scores were significantly improved from week 0 (P<0.001), and were not significantly different between groups. CONCLUSION: The results indicated that long-term combination therapy with SCMC at a dose of 1500mg/day and CAM at a dose of 200mg/day is effective for improving subjective symptoms and objective findings in adult patients with CRS.

Suppression of IL-8 production from airway cells by tiotropium bromide in vitro.

BACKGROUND: COPD is characterized by persistent and progressive airway inflammation. Although neutrophilic airway inflammation is generally accepted to be a major factor in the pathogenesis of COPD, the influence of the agents used for the treatment of COPD on neutrophil functions such as chemotaxis is not fully understood. PURPOSE: The present study aimed to examine the influence of tiotropium bromide on the production of interleukin (IL)-8 from human airway epithelial cells and lung fibroblasts (LFs) after lipopolysaccharide (LPS) stimulation in vitro. METHODS: BEAS-2B cells, human bronchial epithelial cell line, and LFs, at a concentration of 5 × 10(5) cells/mL, were stimulated with LPS in the presence of various concentrations of tiotropium bromide. IL-8 in culture supernatants was examined by enzyme-linked immunosorbent assay (ELISA). IL-8 messenger ribonucleic acid (mRNA) expression was examined by real-time polymerase chain reaction. The influence of tiotropium bromide on LPS-induced signaling pathways was also analyzed by examining nuclear factor-kappa (NF-κ)B activation and signaling protein phosphorylation by ELISA. RESULTS: Tiotropium bromide at > 15 pg/mL inhibited IL-8 production from both BEAS-2B cells and LFs after LPS stimulation. Tiotropium bromide also suppressed IL-8 mRNA expression through the inhibition of NF-κB activation and signaling protein, extracellular-signal-regulated kinase 1/2, and c-Jun N-terminal kinase, phosphorylation. CONCLUSION: The present results strongly suggest that tiotropium bromide exerts the inhibitory effect on neutrophilic inflammation through the suppression of IL-8 production from epithelial cells and LFs by interfering with LPS-mediated signaling pathways and thus may contribute to lower cellular inflammation in COPD, which is responsible for favorable modification of the disease.

[Clinical study of smoking cessation clinic subjects].

The Cigarette-associated diseases will be decreased only by stopping smoking. At a smoking cessation clinic, we evaluated 22 subjects for smoking cessation after a three-month smoking cessation program. The program was completed by 20 subjects, or 90%, of whom 15, or 68%, quit smoking. Varenicline tartrate was used to treat 90% of subject, of whom 8, or 40%, suffered nausea. This was treated using an anti-nausea agent, which relieved symptoms immediately.