Evaluation of Montelukast for the Treatment of Children With Japanese Cedar Pollinosis Using an Artificial Exposure Chamber (OHIO Chamber).

Background: This study evaluated the efficacy of montelukast in reducing seasonal allergic rhinitis symptoms in Japanese children with Japanese cedar (JC) pollinosis induced in an artificial exposure chamber (OHIO Chamber). Methods: Pediatric patients aged 10 to 15 years sensitive to JC pollen entered a randomized, double-blind, single-site, crossover study. After confirmation of an allergic response to a JC pollen exposure for 3 hours in the OHIO Chamber during the screening period, subjects received either montelukast 5 mg chewable tablets or placebo for a 7-day treatment period, followed by a 3-hour pollen exposure in the chamber. After a 7-day washout period, subjects crossed over to the other treatment. Subjects were instructed to self-assess their nasal symptoms using 5-point scale for every 30 minutes. The primary end point was the change from baseline (just before entering the exposure chamber for each exposure) in total nasal symptom score (TNSS; the sum of nasal congestion, nasal discharge, and sneezing scores) over 3 hours of pollen exposure. Adverse events (AEs) were evaluated throughout the study. Results: A total of 220 subjects (median age, 12 years) received treatment. For TNSS, the between-group difference in the change (95% confidence interval) was -0.01 (-0.11 to 0.10); the change between placebo and montelukast 5 mg was not significant. TNSS in the screening and treatment periods after receiving placebo for 7 days was 1.58 and 1.31, respectively, suggesting a placebo response. On account of high placebo response, a post hoc analysis was conducted. The analysis in a subgroup of subjects who did not show placebo response demonstrated a difference in the efficacy between montelukast and placebo (nominal P < .037). The most common AE was positive urine protein (4.6% with montelukast vs 7.8% with placebo). Conclusions: Although montelukast was well tolerated, this study did not demonstrate a treatment difference between active drug and placebo in Japanese children exposed to JC pollen in the OHIO Chamber.Trial Registry: ClinicalTrials.gov, NCT01852812.

Therapeutic effect of bilastine in Japanese cedar pollinosis using an artificial exposure chamber (OHIO Chamber).

BACKGROUND: Environmental exposure chambers have been used to expose subjects to aeroallergens to investigate the efficacy of prophylactic treatment with symptomatic agents in Japan. We first examined the therapeutic effect of bilastine (BIL), a novel non-sedative second-generation H1-antihistamine, in subjects with Japanese cedar pollinosis using an artificial exposure chamber (OHIO Chamber). METHODS: This was a randomized, double-blind, four-way crossover, placebo- and active-controlled phase II study (trial registration number JapicCTI-132213). Subjects were exposed to cedar pollen (8000 grains/m3) for 2 h on Day -1 and 4 h each on Day 1 and 2. BIL 10 or 20 mg, placebo, or fexofenadine hydrochloride (FEX) 60 mg was administered orally 1 h after the start of pollen exposure on Day 1. Placebo or FEX was administered 12 h after the first dosing. The primary efficacy endpoint was the sum of total nasal symptom score (TNSS) from 0 to 3 h after the Day 1 dosing. RESULTS: We enrolled 136 subjects and the sum of TNSS on Day 1 of the three active treatments was significantly lower than that of placebo and was maintained up to 26 h after the first dosing (Day 2). The sum of TNSS or sneezing score on Day 1 after BIL 20 mg was more significantly decreased than after FEX. Moreover, BIL showed a faster onset of action than FEX. CONCLUSIONS: We demonstrated the efficacy, rapid onset, and long duration of action of BIL in subjects with Japanese cedar pollinosis exposed to cedar pollen using the OHIO Chamber.

Histamine antagonist Bepotastine suppresses nasal symptoms caused by Japanese cedar and cypress pollen exposure.

Objective: To determine the efficacy of the antihistamine bepotastine on treating nasal symptoms in patients with Japanese cedar and cypress pollinosis, based on two previous studies that looked at bepotastine OD's inhibitory effect on symptom onset after exposure. Design and methods: Randomized double-blind placebo controlled, parallel study. Twenty-eight volunteers with Japanese cedar and cypress pollinosis were randomly assigned into two experimental groups: a bepotastine-treated or a placebo control group. Subjects received either 10 mg bepotastine tablets or placebo tablets 1 day before entering an artificial exposure pollen chamber (OHIO Chamber) and also for three or more consecutive days. They were exposed to Japanese cedar and cypress pollen for 3 h per day for 2 days. Nasal and ocular symptoms were self-rated by each patient at regular intervals in addition to being objectively measured. Possible cognitive impairment was assessed by using the digit cancellation test (D-CAT). Results: In Study 1, under controlled conditions, there were no significant differences (p > .05) between subjects exposed to Japanese cedar pollen and those exposed to cypress pollen in terms of total nasal symptom score (TNSS). In Study 2, in the placebo group, the amount of nasal discharge and the number of sneezes did not diminish before cypress pollen exposure on the second day (p < .05). This suggests that an antihistamine can suppress the symptoms of hang over. No deterioration of work performance was observed in the bepotastine group after pollen exposure for 2 days, as measured by D-CAT (p > .05). Conclusion: We conclude that bepotastine can suppress allergy-related symptoms without impairing work performance in subjects with seasonal allergic rhinitis caused by Japanese cedar pollen or cypress pollen.

Efficacy and safety of sublingual immunotherapy for two seasons in patients with Japanese cedar pollinosis.

BACKGROUND: Japanese cedar (JC) pollinosis is the most common seasonal allergic rhinitis in Japan. Standardized JC pollen extract is available for subcutaneous immunotherapy, but this treatment is limited by potentially serious side effects. The aim of this double-blind, randomized comparative study was to evaluate the efficacy and safety of standardized JC pollen extract in a new oral formulation (CEDARTOLEN®, Torii Pharmaceutical Co., Ltd., Tokyo, Japan) for sublingual immunotherapy (SLIT) for JC pollinosis. METHODS: A total of 531 subjects with JC pollinosis were randomized into 2 groups at a ratio of 1:1 to receive daily sublingual administration of standardized JC pollen extract with a maintenance dose of 2,000 Japanese allergy units (JAU) or placebo for 2 consecutive pollen seasons. The efficacy was evaluated using the total nasal symptom and medication score (TNSMS) as the primary end point. Secondary end points included the total ocular symptom and medication score (TOSMS) and scores for individual symptoms and medication. RESULTS: The TNSMS was significantly lower (p < 0.0001) in the SLIT group than in the placebo group in the peak symptom period by 18 and 30% in the first and second seasons, respectively. All secondary end points were also significantly lower in the SLIT group in both seasons. No systemic anaphylaxis occurred. CONCLUSIONS: SLIT with daily administration of standardized JC pollen extract was effective for improving nasal and ocular symptoms of JC pollinosis and reducing the use of relief medication. The JC pollen extract was well tolerated with only local adverse events.

Placebo-controlled study with OHIO chamber of prophylactic pranlukast for children with Japanese cedar pollinosis: TOPIC-J III study.

OBJECTIVE: This double-blind, placebo-controlled comparative study was designed to investigate whether pranlukast dry syrup, a leukotriene receptor antagonist, has a protective effect against priming, controlled pollen exposure, and natural pollen exposure in children with Japanese cedar pollinosis. RESEARCH DESIGN AND METHODS: Thirty children aged 12-15 years with Japanese cedar pollinosis (positive skin test for Japanese cedar pollen), who had suffered from pollinosis for at least 2 years and developed severe nasal obstruction when exposed to Japanese cedar pollen, were enrolled in this study. They were randomly allocated to treatment with pranlukast or placebo orally after breakfast and dinner for 8 weeks during the Japanese cedar pollen season. Soon after the start of the pollen season, all subjects underwent a challenge by exposure for 3 h to Japanese cedar pollen (8000 grains/m(3)) in an artificial exposure chamber (OHIO chamber). CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network in Japan (UMIN000009840). MAIN OUTCOME MEASURES: The effect of pranlukast was evaluated using self-rating of nasal symptoms by the subjects and measurement of eosinophil cationic protein in nasal discharge specimens. RESULTS: Scores for the symptoms of pollinosis were lower in the pranlukast group than in the placebo group during treatment in the priming state, as well as after controlled pollen exposure and natural pollen exposure. Pranlukast significantly improved the score for nasal obstruction, compared with placebo. A correlation was found between changes of the scores for symptoms of pollinosis and changes of the eosinophil cationic protein level. CONCLUSIONS: These results confirm a protective effect of pranlukast against both priming and challenge (controlled and natural) with Japanese cedar pollen. The present findings suggested that pranlukast dry syrup may be useful for prophylaxis against pollinosis in children.

Efficacy of fluticasone furoate nasal spray and levocetirizine in patients with Japanese cedar pollinosis subjected to an artificial exposure chamber.

OBJECTIVE: This study investigated the clinical efficacy of a combination therapy of levocetirizine (LCTZ) and fluticasone furoate nasal spray (FFNS), compared with LCTZ monotherapy, for the suppression of seasonal allergic rhinitis (SAR) symptoms induced in an artificial exposure chamber. METHODS: This study was a single-center, placebo-controlled, randomized, 3-way cross-over comparative study performed in 42 Japanese cedar pollinosis patients. These subjects received (1) LCTZ plus FFNS (combination group), (2) LCTZ plus FFNS placebo (monotherapy group), or (3) LCTZ placebo plus FFNS placebo (placebo group) once on the night prior to exposure, with a 1-week washout period between exposures. Nasal (sneezing, rhinorrhea, nasal congestion, and itchy nose) and ocular (eye itching and tearing) symptoms were recorded every 15 min, and the number of sneezes, nose blowing events, and the amount of nasal secretions were measured during exposure. The primary end-point was the cumulative incidence of SAR symptoms during exposure and the 'ime to occurrence of symptoms'. The secondary end-points were the total nasal symptom score, the ocular symptom score, the amount of nasal discharge, and the number of sneezes and nose blowing events. RESULTS: At all the measurement points, the lowest cumulative incidences for the nasal symptoms were observed in the combination group, followed by the monotherapy and placebo groups. All the subjects in the placebo group developed nasal symptoms within 2 h after pollen exposure, while three and eight subjects in the monotherapy and combination groups, respectively, did not develop any nasal symptoms during exposure. In addition, combination therapy delayed the onset of symptoms. CONCLUSIONS: The results demonstrated that combination therapy with FFNS and LCTZ significantly suppressed the induced SAR symptoms and delayed the onset of symptoms compared with LCTZ monotherapy and placebo. Although the conditions of the allergen challenge study using an exposure chamber are different from those in real life, combination therapy with FF and LCTZ was confirmed to be an effective treatment for SAR.

Pranlukast dry syrup inhibits symptoms of Japanese cedar pollinosis in children using OHIO Chamber.

Pranlukast (PLK) is a leukotriene receptor antagonist (LTRA) that has been approved for treatment of asthma in patients of all ages and allergic rhinitis (AR) in adults but not for AR in children in Japan. This randomized, double-blind, placebo-controlled, crossover study used an artificial exposure chamber (OHIO Chamber) to investigate the efficacy and safety of PLK in children from 10 to 15 years old with seasonal AR (SAR) due to Japanese cedar (JC) pollen. Eighty-four subjects were enrolled and randomized to the treatment arm and 74 were included in the per protocol set. Subjects received either PLK dry syrup (DS) or placebo for 1 week. They were challenged with JC pollen in the OHIO Chamber for 3 hours. Total nasal symptom scores (TNSSs) were recorded every 30 minutes during the exposure. PLK DS treatment suppressed the TNSS changes from baseline significantly when compared with placebo. The difference in the least square means in TNSS between the PLK DS-treated group and placebo group was -0.37 (95% CI, -0.54, -0.20) with a value of p < 0.0001, showing that PLK DS significantly suppressed the nasal symptoms. Regarding specific nasal symptoms, PLK DS significantly suppressed sneezing, nasal discharge, and nasal obstruction. The effect of PLK DS on nasal obstruction was most prominent, with significant improvement relative to placebo beginning 60 minutes after the start of exposure. No serious adverse events were reported during the study. In this study, PLK DS is effective and safe for treatment in children with SAR.

Noninvasive biological evaluation of response to pranlukast treatment in pediatric patients with Japanese cedar pollinosis.

Pranlukast (PLK) is a cysteinyl leukotriene receptor 1 antagonist approved for the treatment of bronchial asthma and allergic rhinitis in Japan. We previously reported that PLK dry syrup (DS) improved the total nasal symptom score, as well as sneezing, nasal discharge, and nasal obstruction scores over placebo. We investigated the efficacy of PLK DS with a noninvasive method in 10- to 15-year-old children with Japanese cedar (JC) pollinosis challenged with pollen allergen using an artificial exposure chamber (OHIO Chamber). Levels of eosinophil cationic protein (ECP) in nasal secretions, nasal obstruction score, and the relationship with nasal obstruction scores were analyzed. The estimated difference of means in ECP levels (PLK DS--placebo) was -22.9 micrograms (95% CI, -45.2 to -0.5), suggesting PLK DS reduced ECP significantly when compared with placebo (p = 0.0454). The difference in the least square means for nasal obstruction between the PLK DS and placebo was -0.25 (95% CI, -0.36 to -0.14) with a value of p < 0.0001. In addition, a statistically significant, although weak, positive correlation between the nasal obstruction score and nasal ECP levels was observed with placebo treatment (correlation coefficient = 0.2394; p = 0.0428). Moreover, the inhibition rate of nasal ECP with PLK DS relative to placebo was statistically significant, although weak, positively correlated with the inhibition rate of nasal obstruction (correlation coefficient = 0.3373; p = 0.0219). PLK DS significantly decreases nasal ECP levels and nasal obstruction score compared with placebo in children with JC pollinosis challenged with pollen allergen. Suppression of mucosal eosinophilic inflammation is one of the pathways by which PLK DS improves pollinosis-induced nasal obstruction.

The assessment of the optimal duration of early intervention with montelukast in the treatment of Japanese cedar pollinosis symptoms induced in an artificial exposure chamber.

OBJECTIVE: The study objective was to investigate the prophylactic efficacy of montelukast (MLK) 10 mg in suppressing seasonal allergic rhinitis (SAR) symptoms induced by Japanese cedar (JC) pollen and to determine how many days before exposure to JC in the artificial exposure chamber (OHIO chamber) would be optimal to start administration. METHODS: This was a single-institution, double-blind, randomized placebo-controlled four-group parallel inter-group comparison study. Adult volunteers with JC pollinosis were divided into four groups: an MLK 7-day administration group (n = 27), an MLK 3-day administration group (n = 27), an MLK 1-day administration group (n = 26), and a placebo group (n = 26). The mean change in total nasal symptom scores (nasal obstruction, nasal discharge and sneezing) (TNSS) and each of the nasal symptom scores during exposure of JC pollen in the OHIO chamber were investigated. RESULTS: The mean change in TNSS was significantly lower in the MLK treatment group, regardless of the number of days of administration, than in the placebo group (p = 0.0192). The results for the individual nasal symptoms showed that nasal obstruction was significantly suppressed in the 1-day administration group as compared with placebo (p = 0.0076), but no differences were found in sneezing score between any of the groups. For nasal discharge, we found a trend towards the effect clearing up after 3 days of administration. No serious adverse events were observed during the study. CONCLUSION: Although this study was acute and this artificial exposure model was conducted out of the pollen season, nasal symptoms that developed in the pollen exposure chamber, especially nasal obstruction, were significantly suppressed by starting oral administration of MLK 10 mg at least 1 day before exposure. These results suggest that prophylactic administration of MLK is effective and safe in the treatment of SAR.

Trial of pranlukast inhibitory effect for cedar exposure using an OHIO chamber.

OBJECTIVE: In practical guidelines for management of allergic rhinitis in Japan, pranlukast is a leukotriene receptor antagonist recommended for the treatment of pollinosis. However, the effect of pranlukast on nasal symptoms for cedar pollinosis has not been thoroughly investigated. The aim of this study is to examine this effect in a double-blind controlled crossover study using a pollen challenge chamber (the OHIO Chamber) developed in Japan. RESEARCH DESIGN AND METHODS: A total of 39 patients with cedar pollinosis were targeted. The subjects were exposed to a specific amount of cedar pollen (8000/m(3)) in the OHIO Chamber during the non-cedar pollen season. Efficacy of pranlukast for the treatment of artificially induced nasal symptoms was compared with that of a placebo using the crossover method. Pranlukast was administered orally for 3 days, after dinner on the day before cedar pollen exposure, after breakfast and after dinner on the day of cedar pollen exposure, and after breakfast on the following day. Pollen testing was carried out twice, with a 1-week wash-out interval. CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network in Japan (UMIN), number UMIN000001282. MAIN OUTCOME MEASURES: The effect of pranlukast was evaluated using self-rating of nasal symptoms by the subjects. RESULTS: All 39 subjects demonstrated a positive skin reaction to cedar pollen by a positive CAP-RAST score (class 2 or higher) within the last 3 years, and experienced aggravated congestion during the cedar pollen season for more than 2 years. Nasal congestion was inhibited significantly in the pranlukast group compared to the placebo group during cedar pollen exposure. Furthermore, pranlukast significantly inhibited nasal congestion compared to the placebo on the day after exposure and on the following day. CONCLUSIONS: The effect of pranlukast on cedar pollinosis indicates immediate action, and such an effect could take place continuously after cedar pollen exposure. These results demonstrate that pranlukast is effective for the relief of congestion due to pollinosis.

Efficacy of epinastine hydrochloride for antigen-provoked nasal symptoms in subjects with orchard grass pollinosis.

BACKGROUND: Among the gramineae species, orchard grass is a typical causative pollen that provokes seasonal rhinitis. The purpose of this study was to examine the protective efficacy of epinastine hydrochloride for signs and symptoms caused by repeated nasal provocation with discs containing orchard grass pollen. METHODS: A single-dose, placebo-controlled, double-blind, crossover clinical study was conducted in subjects with orchard grass pollinosis. The pollen challenge was conducted with the use of provocation discs containing orchard grass pollen. RESULTS: Epinastine hydrochloride suppressed nasal symptoms caused by nasal provocation tests using orchard grass pollen discs. Among the nasal symptoms, the number of sneezing was significantly inhibited 30 minutes and 60 minutes after the administration of epinastine hydrochloride, as compared with placebo. There were no adverse reactions to the study drugs. CONCLUSIONS: Our results suggest that nasal provocation tests with discs containing orchard grass pollen is a useful method for evaluating the onset of action of antiallergic drugs. As compared with placebo, epinastine hydrochloride decreased early-phase sneezing and the total nasal symptom score after repeated nasal provocations with orchard grass pollen discs.

Bepotastine besilate OD tablets suppress nasal symptoms caused by Japanese cedar pollen exposure in an artificial exposure chamber (OHIO Chamber).

OBJECTIVE: To investigate the efficacy and safety of bepotastine, we conducted a randomized, investigator-blind, placebo-controlled and parallel study to evaluate the allergic symptoms and the cognitive function of the subjects with Japanese cedar (JC) pollinosis in response to JC pollen exposure in an artificial exposure chamber. METHODS: Twenty-four volunteers with JC pollinosis were enrolled in this study. The subjects were randomly divided into two groups: a bepotastine group and a placebo group (12 subjects each). Subjects received either a 10-mg bepotastine OD (orally disintegrating) tablet or a placebo 10 min before entering the chamber for a 3-h exposure. The nasal and ocular symptoms were evaluated by each patient at regular intervals. The amount of nasal discharge was measured and the number of sneezes recorded. To evaluate the cognitive function, a digit cancellation test (D-CAT), in which the subjects have to eliminate certain numbers within a fixed time, was conducted. RESULTS: Twelve subjects in the placebo group developed nasal and/or ocular symptoms, whereas six subjects in the bepotastine group showed none of the symptoms during exposure. Mean secretion weights and number of sneezes were significantly lower in the bepotastine group than in the placebo group. In D-CAT, no deterioration of work performance was observed in the bepotastine group. No adverse effects were observed in either group. CONCLUSION: Bepotastine treatment is effective and well tolerated in patients with allergen-induced symptoms exposed to JC pollen in an exposure chamber.

Validation study of the OHIO Chamber in patients with Japanese cedar pollinosis.

BACKGROUND: An artificial exposure chamber (OHIO Chamber), which allows dispersal of a fixed concentration of Japanese cedar (JC) pollen under stable conditions, was constructed. This study was conducted to identify the exposure conditions assuring validity of the clinical tests conducted using this chamber. METHODS: Twenty-four adult patients with JC pollinosis were exposed to different concentrations of JC pollen: 0 (only during the summer period), 4,000, 8,000 and 12,000 grains/m3, and the nasal and ocular symptoms were self-assessed during a 4-hour period of exposure. The amount of nasal discharge was measured and the sneezing frequency was recorded. This study was conducted twice during the summer and winter periods, i.e. non-pollen seasons. The reproducibility of the symptoms between the two seasons was assessed. RESULTS: None of the subjects developed any symptom at the pollen concentration of 0 grains/m3. No significant differences in the time to the onset of symptoms were found between the summer and winter study, regardless of the pollen concentration. There were no significant differences between the summer and winter study in the total symptom score and total nasal symptom score at any pollen concentration, suggesting the very favorable reproducibility of symptoms. CONCLUSIONS: Efficient and reproducible results are obtained in patients exposed to JC pollen in the OHIO Chamber. The results suggest the conditions of JC pollen exposure have scientific validity and the OHIO Chamber has the potential to contribute significantly to basic and clinical studies of JC pollinosis.

Preliminary study on Japanese cedar pollinosis in an artificial exposure chamber (OHIO Chamber).

BACKGROUND: A pollen exposure chamber (OHIO Chamber) was built in central Tokyo, Japan, in order to study seasonal allergic rhinitis (SAR). Since satisfactory outcomes were obtained from the controlled pollen exposure at the chamber, we conducted preliminary studies in volunteers with SAR. METHODS: Ten volunteers with SAR sensitive to Japanese cedar (JC) pollen were enrolled in this study. In order to investigate the intranasal and intraocular pollen number, volunteers were initially exposed to a low concentration of JC (2500 grains/m3) for at most 1 hour in this chamber. Before and after the exposure, nasal cavities and eyes were washed with 100ml and 25 ml of saline, respectively. Nasal and eye washing solutions were collected and the number of JC pollen was counted. After 3 hours the volunteers were subsequently exposed to a moderate concentration of JC (4500 grains/m3) for 2 hours. Subjective nasal and ocular symptoms were recorded and the amount of nasal secretion was measured during the allergen exposure periods. RESULTS: During the initial exposure, all volunteers except one stayed in the chamber for 1 hour without any nasal or ocular symptoms. The number of pollen in the nose and eyes was 249.2 +/- 120.9 and 13.6 +/- 13.6 grains, respectively. During the subsequent 2-hour exposure to JC pollen, nasal and ocular symptoms developed gradually in a time dependent manner in all the volunteers except one. CONCLUSIONS: This is the first clinical study using Japanese cedar pollen under well-controlled conditions in the OHIO chamber in which the induction of allergic symptoms was observed. The OHIO chamber will be useful for studying allergic rhinitis in Japan.

Induction of macrophage migration inhibitory factor precedes the onset of acute tonsillitis.

We investigated the serum macrophage migration inhibitory factor (MIF) levels of palmoplantar pustulosis patients, before and after the tonsillar provocation test. Higher serum MIF levels of palmoplantar pustulosis patients were decreased after the tonsillar provocation test (n=29). To confirm these phenomena, two patients with acute tonsillitis had their changes in body temperature, C-reactive protein (CRP) and serum MIF levels examined during the course of their illness. Surprisingly, increased MIF preceded fever and CRP elevation, and MIF subsequently decreased at the onset of fever and CRP elevation. Since MIF is an initiator of other proinflammatory cytokines, we suggest that the induction of MIF may precede other inflammatory conditions.

Malignant transformation of sialadenoma papilliferum of the palate: a case report.

We report a case of a 79-year-old woman with an unusual salivary gland tumor that developed at the junction between the soft and hard palates. The tumor consisted of sialadenoma papilliferum (SP) with areas of an epithelial-myoepithelial carcinoma (EMC) component and a high-grade carcinoma component. There were also transitional regions among the SP, the EMC and the high-grade carcinoma components. The high-grade carcinoma component, which was similar to invasive micropapillary carcinoma of the breast, infiltrated into the right parapharyngeal space and metastasized to the lungs and cervical vertebrae. The high-grade carcinoma cells were positively immunostained for p53 protein. SP has been considered to be a benign tumor with exceptionally good prognosis, and, to the best of our knowledge, there has never been a confirmed case of malignant SP. This is the first report of SP with a definite malignant component.