Efficacy and safety of iguratimod on patients with primary Sjögren's syndrome: a randomized, placebo-controlled clinical trial.

Objective: To evaluate the clinical efficacy and safety of iguratimod for the treatment of primary Sjögren's syndrome (pSS) and explore its possible mechanism of action.Method: We conducted a randomized, placebo-controlled clinical trial in 66 pSS patients. Patients were randomized in a 2:1 ratio to receive oral iguratimod for 24 weeks or matching placebo. The primary endpoint was the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI). Secondary endpoints included mental discomfort visual analogue scale (VAS) score, patient global assessment (PGA), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Schirmer's test values, unstimulated whole salivary flow, erythrocyte sedimentation rate (ESR), and immunoglobulin G (IgG). The proportions of B cells in peripheral blood and levels of serum B-cell activating factor (BAFF) were measured at baseline and week 24 in the iguratimod group. All adverse events were recorded during the trial period.Results:ESSPRI improved more in the iguratimod than in the placebo group (p = 0.016). Mental discomfort VAS score, PGA, Schirmer's test, ESR, and IgG also improved more in the iguratimod than in the placebo group (all p < 0.05). Adverse events were reported 13.6% of the iguratimod group. Levels of BAFF and proportions of plasma cells in patients decreased significantly after iguratimod treatment. The proportions of peripheral plasma cells had positive correlations with both serum IgG and BAFF.Conclusion: Iguratimod improved some dryness symptoms and disease activity in pSS patients, and reduced the level of BAFF and percentage of plasma cells over 24 weeks. Iguratimod seems to be an effective and safe treatment for pSS.

Iguratimod treatment reduces disease activity in early primary Sjögren's syndrome: An open-label pilot study.

OBJECTIVES: To evaluate the efficacy and safety of iguratimod in patients with early primary Sjögren's syndrome (pSS). METHODS: Twenty-seven disease-modifying antirheumatic drug-naive female patients met the revised American-European Consensus Group criteria for pSS were enrolled in this open-label pilot study. Patients were treated with iguratimod 25 mg twice a day for 24 weeks. The disease activity was assessed with European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at 12 and 24 weeks. Salivary and lacrimal gland function, laboratory, and subjective variables were also assessed. Generalized estimating equations were used to analyze parameters over time. RESULTS: ESSDAI (median, 5 versus 2 versus 2, p < .01), IgG (median, 26.6 versus 22.4 versus 21.4 g/L, p < .01) and rheumatoid factor (median, 119.9 versus 94.1 versus 83.8 lU/mL, p < .01) levels decreased significantly during iguratimod treatment. ESSPRI, salivary and lacrimal gland function, fatigue and health-related quality of life did not change during treatment. One patient experienced thrombocytopenia, and no other serious adverse effects were observed. CONCLUSION: In this study, iguratimod treatment is safe and effective for improving disease activity and laboratory parameters in early pSS patients.

Post-transcriptional regulation activity through alternative splicing involved in the effects of Aloe vera on the Wnt/ß-catenin and Notch pathways in colorectal cancer cells.

Aloe vera (L.) Burm.f. is widely used as laxative drugs, cosmetics, and functional food due to a variety of therapeutic effects. However, several studies indicated a colonic carcinogenic activity of Aloe vera. But the underline mechanism has not been well clarified. This study aimed to explore the potential mechanism at the post-transcriptional level. Identification of Differential Expressed Alternative Splicing (DEAS) genes and events and the corresponding functional enrichment analyses were conducted on RKO cells after treated with Aloe vera aqueous extract and its two active components, aloin and aloesin. And RT-qPCR was conducted for validation. Results indicated that they induced 2200, 2342 and 2133 DEAS events, respectively. The GO enrichment and the COG classification results of DEAS genes showed that they were associated with transcription, as well as functions like signal transduction mechanisms. Moreover, DEAS genes related to the two colorectal cancerous pathways, Wnt and Notch pathways, were annotated. In conclusion, aloe extract, aloin and aloesin significantly regulated the DEAS profile of RKO cells. The colonic carcinogenicity of Aloe vera may due to its post-transcriptional regulatory activity through Alternative Splicing (AS) on genes, especially on Wnt-related and Notch-related key genes.

Efficacy of iguratimod vs. salazosulfapyridine as the first-line csDMARD for rheumatoid arthritis.

Objectives: We retrospectively evaluated the retention rate and clinical responses following treatment for rheumatoid arthritis (RA) with iguratimod (IGU) vs. salazosulfapyridine (SASP) as the first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD).Methods: We analyzed 197 RA patients who were treated with IGU or SASP as the initial treatment in the 3-year study period. The retention rate, clinical response, the dosage and percent user of prednisolone (PSL), and safety profiles were evaluated.Results: At month 36, the retention rates of the IGU and SASP groups were 52.4 vs. 32.1%. The rate of responders (good or moderate response) at month 36 was 85.8 vs. 65.2% in the IGU and SASP groups, respectively. At month 36 for the IGU and SASP groups, the percentages of PSL users were 16.7 vs. 46.7%, and the PSL dosage was 0.3 mg/d vs. 2.0 mg/d, respectively. The cumulative rates of any adverse event (AE) at month 36 were 19.8 vs. 29.2% in the IGU and SASP groups, respectively.Conclusion: IGU is a useful first-line csDMARD treatment for RA patients, showing a high retention rate and good efficacy without an increased risk of serious AEs, including serious infections. Our findings also indicate a PSL dose-sparing effect of IGU treatment.

Factors influencing physician decisions to discontinue treatment after onset of liver dysfunction: Post-hoc analysis of an all-case post-marketing surveillance study of iguratimod.

Objectives: Adverse drug reactions (ADRs) related to liver dysfunction are a common problem in patients with rheumatoid arthritis (RA) receiving iguratimod, but which patient subgroups go on to discontinue iguratimod treatment is unclear. A post-hoc analysis of a post-marketing surveillance study was performed to investigate factors influencing treatment continuation after the onset of liver dysfunction.Methods: Types of ADR were compared between patients in whom iguratimod treatment was discontinued or continued in accordance with the judgment of the patient's physician after the patient developed liver dysfunction as an ADR. Stepwise logistic regression analysis was also conducted to investigate factors associated with treatment discontinuation.Results: The multivariate analysis found that concomitant use of methotrexate (MTX) at >8 mg/week (vs. no use) was associated with a significantly lower risk of discontinuation (OR: 0.136; 95%CI: 0.030-0.620), and previous treatment with MTX (vs. no use) was associated with a significantly higher discontinuation risk (OR: 4.045; 95%CI: 1.098-14.908).Conclusion: Although concomitant use of MTX during iguratimod treatment does not appear to influence treatment discontinuation due to abnormal liver function, liver function tests are of importance to continued treatment in patients receiving iguratimod who have a history of MTX use.

The add-on effectiveness and safety of iguratimod in patients with rheumatoid arthritis who showed an inadequate response to tocilizumab.

Objectives: To evaluate the effectiveness of add-on iguratimod (IGU) in patients with rheumatoid arthritis (RA) who showed an inadequate response to tocilizumab (TCZ), especially patients who were intolerant of an effective dose of methotrexate (MTX). Methods: Thirty-one patients with RA (22 women, age 62.4 years, disease duration 13.8 years, prior TCZ duration 35.7 months, 25 intravenous [8 mg/kg/4 weeks] and 6 subcutaneous [162 mg/2 weeks] TCZ treatments, concomitant MTX 8.5 mg/week [35.5%], and prednisolone (PSL) 4.3 mg/day [25.8%]) who showed an inadequate response to TCZ (disease activity score assessing 28 joints with C-reactive protein [DAS28-CRP] 2.9, clinical disease activity index [CDAI] 15.0, 28 secondary inadequate responders) were treated with additional IGU (final dose 41.7 mg/day) and enrolled in this 24-week, multicenter, retrospective study. Results: Twenty-nine patients (93.5%) continued the treatment for 24 weeks (one dropped out for pneumonia and one for digestive symptoms). The TCZ and the concomitant dose and rate of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (MTX, salazosulfapyridine [SASP], and tacrolimus [TAC]) were not significantly changed during this period. Outcome measures improved significantly, as follows: DAS28-CRP from 2.9 to 1.7 (p < .001); CDAI from 15.0 to 6.0 (p < .001); modified Health Assessment Questionnaire (mHAQ) from 0.8 to 0.6 (p < .05); and rheumatoid factor (RF) from 382.1 to 240.3 IU/mL (p < .001). Using the EULAR criteria, 64.5% achieved a moderate response, and 51.6% achieved ACR 20 at 24 weeks. Conclusion: Adding IGU to inadequate responders to TCZ may be a promising and safe complementary treatment option.

Iguratimod, a synthetic disease modifying anti-rheumatic drug inhibiting the activation of NF-κB and production of RANKL: Its efficacy, radiographic changes, safety and predictors over two years' treatment for Japanese rheumatoid arthritis patients.

OBJECTIVE: To elucidate the clinical and radiographic outcomes for rheumatoid arthritis (RA) patients treated with a synthetic disease-modifying antirheumatic drug, iguratimod (IGU). METHODS: Clinical outcomes for 213 RA patients treated with 25 mg/day oral IGU or 50 mg/day after 4 weeks of 25 mg/day treatment for one day to 104 weeks were assessed. RESULTS: A total of 142 active RA patients (DAS28-ESR ≥3.2) treated for more than 12 weeks showed a significant reduction in both DAS and simplified disease activity index (SDAI) scores at week 4 (p < .001) to week 104. Good and moderate DAS responses were achieved in 54 (38%) and 66 (46%) patients, respectively. Total Genant-modified Sharp scores (GSS) of 31 patients at week 104 showed no progression (total GSS ≤0.84: the smallest detectable change) in 16 (52%) patients with a mean score reduction (95%CI) of -4.3 (-8.1∼-0.5) (p < .05). Predictors were an early response, moderate disease activity at baseline, and male gender. Eleven of the 213 patients had gastric and/or duodenal ulcer. A peculiar haemorrhage was seen in two patients treated concomitantly with IGU and warfarin potassium. CONCLUSION: IGU treatment shows an early and sustained efficacy. Radiographically, no progression of GSS was evident in 16 (52%) patients at week 104. Gastric bleeding or gastric perforation warrants careful attention, especially in patients with concomitant use of both a non-steroidal anti-inflammatory drug and oral prednisolone.

Safety and effectiveness of iguratimod in patients with rheumatoid arthritis: Final report of a 52-week, multicenter postmarketing surveillance study.

OBJECTIVES: We evaluated the long-term (52 weeks) safety and effectiveness of iguratimod (IGU) in patients with rheumatoid arthritis (RA). METHODS: This multicenter, prospective, observational study included all evaluable RA patients who received IGU since its market launch in 2012. We evaluated adverse events (AEs); adverse drug reactions (ADRs); ADRs of special interest, including liver and renal dysfunctions, interstitial lung disease, gastrointestinal and blood disorders, and infection; and change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) at week 52. RESULTS: Safety and effectiveness were analyzed in 2666 and 1614 patients, respectively. The incidences of AEs, serious AEs, ADRs, and serious ADRs were 46.92, 7.35, 38.26, and 4.58%, respectively. The incidence of ADRs peaked at approximately 4 weeks of treatment. Subsequently, the ADR incidence did not increase over time. Improvement of RA activity was shown up to week 52. CONCLUSION: Long-term treatment with IGU in patients with RA resulted in a tolerable safety profile and an improvement in RA activity. IGU could be considered a useful treatment option for patients with RA.

Suspected drug-induced liver injury associated with iguratimod: a case report and review of the literature.

BACKGROUND: Iguratimod is a novel anti-rheumatic drug with the capability of anti-cytokines as report goes. It has been reported that iguratimod is effective and safe for rheumatoid arthritis and other rheumatisms. As side effects, iguratimod can cause gastrointestinal reactions, dizziness, headache and itchy. CASE PRESENTATION: In this case report, a 60-year-old female patient was admitted with suspected drug-induced liver injury (DILI) caused by iguratimod. The causality assessment was done by the updated RUCAM, and the possibility of the case in our paper diagnosed as highly probable for the score was 9 points. Iguratimod was discontinued immediately, and methylprednisolone was used for acute liver injury and Sjogren's syndrome. The data showed the patient has improved gradually, and she was discharged on day 27. The true incidence of iguratimod-related hepatotoxicity and its pathogenic mechanism are largely unknown. It is difficult to recognize and diagnose DILI, and there is no standard for diagnosis of DILI. At the same time, the DILI is still lack of specific treatment. CONCLUSIONS: Based on this rare case of severe liver injury, we recommend careful monitoring of liver function throughout iguratimod treatment for diseases.

A randomized phase I study to evaluate the safety, tolerability, pharmacokinetics and food-effect of Iguratimod in healthy adult volunteers.

OBJECTIVE: The aim of this study was to investigate the safety, maximum tolerated dose and pharmacokinetics (PK) of iguratimod and the effect of food on PK parameters in healthy adult volunteers. METHODS: This phase 1 study consisted of four parts. Part 1 was a single-ascending dose (3.125, 6.25, 12.5, 25, 50, 75 mg) study to assess the maximum tolerated dose and safety of iguratimod. Part 2 was a single-ascending dose study to analyze the pharmacokinetic (PK) parameters of iguratimod; subjects were divided into three groups, with each group receiving iguratimod at a different dose (25, 50 or 75 mg). Part 3 was designed to compare the pharmacokinetic parameters of iguratimod between single-dose and multiple-dose administration; subjects were divided into two groups, with one group receiving a single dose of 50 mg on day 1 and the other group receiving a multiple dose of 50 mg, once every day, until a stable plasma concentration had been achieved. The aim of part 4 was to evaluate the effect of food on the pharmacokinetic parameters of iguratimod; subjects were divided into two groups, namely a fed group and a fasted group, with each group receiving a single 50 mg dose of iguratimod on day 1. Following a 14-day washout period, the two groups were crossed-over and received a single dose of 50 mg iguratimod on day 15. RESULTS: In part 1 of the study, iguratimod at doses ranging from 3.125 to 50 mg were well tolerated, with most adverse effects (AEs) being mild; no severe AEs occurred. In part 2, there were no significant differences in Tmax, T1/2, Ka and V/F among volunteers receiving doses of 25, 50 and 75 mg iguratimod. The Cmax and AUC0-last in volunteers receiving 75 mg iguratimod were higher than those in volunteers receiving 25 and 50 mg. The Cmax was linear from 25 to 75 mg, with a correlation coefficient (r 2) of 0.9808. The AUC0-last was also linear from 25 to 75 mg, with an r 2 of 0.9839. In part 3, in subjects receiving multiple doses of 50 mg, the T1/2 was 10.25 h, Tmax was 3.63 h, Cmax was 1.88 mg/L, AUC0-last was 31.88 mg/L h, Vd was 1.16 L and Ka was 0.87 1/h.There were no significant differences in the Cmax, AUC0-last, Ka and V/F between the single-dose and multiple-dose groups; there were, however, significant differences in Tmax and T1/2 between the two groups. In part 4, there were no significant differences in T1/2, AUC0-last, Ka and V/F between the fed group and fasted group; however, food may promote the absorption of iguratimod. CONCLUSIONS: The maximum tolerated dose for iguratimod was confirmed to be 50 mg. The ingestion of food was able to increase the peak concentration of iguratimod and shorten the time to peak concentration. Therefore, based on our results, iguratimod can be administered with food. The PK profile and metabolic effects of iguratimod support further clinical development for its application in treating autoimmune diseases.

Pneumocystis jirovecii pneumonia developed in a patient with rheumatoid arthritis after 14 weeks of iguratimod add-on to treatment with methotrexate and etanercept.

A 66-year-old woman who had rheumatoid arthritis and underwent a long-term treatment with methotrexate and etanercept developed Pneumocystis jirovecii pneumonia (PCP) 3 months after iguratimod add-on. Although most rheumatologists might have the impression that iguratimod has less toxicity and immunosuppressive effect compared with methotrexate and biologic disease-modifying antirheumatic drugs, this case suggests that iguratimod may increase the risk of PCP, especially in combination with other drugs.

A randomized controlled phase II clinical trial comparing ONO-4053, a novel DP1 antagonist, with a leukotriene receptor antagonist pranlukast in patients with seasonal allergic rhinitis.

BACKGROUND: Prostaglandin D2 (PGD2 ) is primarily produced by mast cells and is contributing to the nasal symptoms including nasal obstruction and rhinorrhea. OBJECTIVE: This study aimed to evaluate the efficacy and safety of a novel PGD2 receptor 1 (DP1) antagonist, ONO-4053, in patients with seasonal allergic rhinitis (SAR). METHODS: This study was a multicenter, randomized, double-blind, parallel-group study of patients with SAR. Following a one-week period of placebo run-in, patients who met the study criteria were randomized to either the ONO-4053, leukotriene receptor antagonist pranlukast, or placebo group for a two-week treatment period. A total of 200 patients were planned to be randomly assigned to receive ONO-4053, pranlukast, or placebo in a 2:2:1 ratio. Nasal and eye symptoms were evaluated. RESULTS: Both ONO-4053 and pranlukast had higher efficacy than placebo on all nasal and eye symptoms. ONO-4053 outperformed pranlukast in a total of three nasal symptom scores (T3NSS) as well as in individual scores for sneezing, rhinorrhea, and nasal itching. For T3NSS, the Bayesian posterior probabilities that pranlukast was better than placebo and ONO-4053 was better than pranlukast were 70.0% and 81.6%, respectively, suggesting that ONO-4053 has a higher efficacy compared with pranlukast. There was no safety-related issue in this study. CONCLUSIONS: We demonstrated that the efficacy of ONO-4053 was greater than that of pranlukast with a similar safety profile. This study indicates the potential of ONO-4053 for use as a treatment for SAR (JapicCTI-142706).

Safety and effectiveness of 24-week treatment with iguratimod, a new oral disease-modifying antirheumatic drug, for patients with rheumatoid arthritis: interim analysis of a post-marketing surveillance study of 2679 patients in Japan.

OBJECTIVE: To determine the real-world safety and effectiveness of iguratimod (IGU) for rheumatoid arthritis (RA), a 52-week, Japanese, post-marketing surveillance study was conducted. An interim analysis at week 24 was performed. METHODS: This study included all RA patients who received IGU following its introduction to the market. All adverse events (AEs) and adverse drug reactions (ADRs) were collected. Effectiveness was evaluated by the change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) from baseline to week 24. RESULTS: Safety was analyzed in 2679 patients. The overall incidences of AEs, ADRs, and serious ADRs were 38.41, 31.65, and 3.21%, respectively; the most commonly reported serious ADRs were pneumonia/bacterial pneumonia, interstitial lung disease, and Pneumocystis jiroveci pneumonia. Concomitant glucocorticoid use and comorbid conditions associated with respiratory disease were identified as risk factors for serious infections. Pulmonary alveolar hemorrhage and increased international normalized ratio of prothrombin time were observed with concomitant use of IGU and warfarin. The DAS28-CRP decreased from baseline to week 24. CONCLUSION: Although a safety concern was identified with concomitant use of IGU and warfarin, this real-world study showed no other new safety concerns and similar effectiveness to clinical trials. IGU is a new therapeutic option for RA patients.

[DMARDs (Focusing on iguratimod)].

Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) other than methotrexate (MTX: anchor csDMARDs) are effective for single use, reinforcement of MTX, biologics and induction and maintenance of biologics-free condition. Newly developed iguratimod (IGU) does not suppress immunological reaction, therefore, it is useful for single use or combination with other csDMARDs in patients with complications. IGU can be used as a first csDMARDs before MTX use during the screening for MTX. IGU might be effective for reinforcement of MTX, biologics and induction and maintenance of biologics-free condition just like other csDMARDs. IGU can be used in wide variety of situation of the treatment of rheumatoid arthritis and it is desired that after the all-case surveillance condition for approval, IGU become a standard csDMARDs all over the world which was made in Japan.

In vivo safety evaluation of UP780, a standardized composition of aloe chromone aloesin formulated with an Aloe vera inner leaf fillet.

Safety profiles of the aloe chromone aloesin or Aloe vera inner leaf fillet (Qmatrix) as a well tolerated entity have been reported separately. UP780, a standardized composition of aloe chromone formulated with an Aloe vera inner leaf fillet, has shown a significant beneficial effect in lowering blood glucose and improving insulin resistance in human. Here we evaluate the safety of UP780 after a repeated 14 and 90-day oral administration in CD-1 mice. UP780 was given at doses of 100mg/kg/day, 500mg/kg/day and 1000mg/kg/day to groups of 10 male and 10 female for 90days or administered by oral gavage at a dose of 2g/kg/day to groups of 5 male and 5 female for 14days. Body weight, feed consumption, hematology, clinical chemistry and histopathologic evaluation were performed. UP780 at a dose of 1000mg/kg/day or at 2000mg/kg/day produced no treatment-related toxicity or mortality. Body weight gain or feed consumption was similar between groups. There was no test article-related microscopic change. Spontaneously occurring minor changes in clinical chemistry and hematology were observed. However, these changes were limited to one sex or were not dose correlated. UP780 was well tolerated in this strain. A dose of 2000mg/kg/day was identified as the NOAEL (no-observed-adverse-effect-level).

Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate: an open-label extension of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To obtain safety and efficacy data on combination treatment with iguratimod and methotrexate (MTX) in an open-label extension study in patients with active rheumatoid arthritis (RA). METHODS: Following a 28-week, randomized, double-blind trial of adding iguratimod or placebo to stable MTX therapy, patients entered a 24-week extension. Patients randomized to the iguratimod + MTX group continued treatment. Patients treated with placebo + MTX switched to iguratimod + MTX [the (placebo/iguratimod) + MTX group]. RESULTS: In the iguratimod + MTX group, the rate of 20% improvement in American College of Rheumatology criteria (ACR20) at week 52 (71.3%) was similar to that at week 24 (69.5%). ACR50, ACR70 and Health Assessment Questionnaire Disability Index at week 52 significantly improved compared with the values at week 24. In the (placebo/iguratimod + MTX) group, the switch to iguratimod treatment significantly improved ACR20 from 30.7% at week 24 to 72.1% at week 52. Frequent adverse events for 52 weeks in the iguratimod + MTX group were nasopharyngitis, upper respiratory tract inflammation, stomatitis, lymphocyte decrease, AST increase, ALT increase and blood iron decrease. These adverse events were predominantly mild or moderate in severity. No deaths occurred. CONCLUSION: Efficacy and tolerance of iguratimod + MTX therapy was maintained to 52 weeks in patients with active RA with inadequate response to MTX.

Efficacy and safety of iguratimod for the treatment of rheumatoid arthritis.

All randomized controlled trials (RCTs) of iguratimod for rheumatoid arthritis (RA) to assess its efficacy and safety are included in this paper. The Review Manager software was used for meta-analysis to assess risk bias of the studies included, and GRADE profiler software was used for the evidence quality of the studies included. Four RCTs involving 1407 patients with RA were included. Meta-analyses showed that, after 24-week therapy, ACR20, tender joint count, swollen joint count, rest pain, physician and patient global assessment of disease activity, HAQ score, ESR, and CRP in iguratimod group were better than those in placebo group and that the difference between those of iguratimod group and those of other DMARDs (MTX and SASP) group was not significant. GRADE evidence classification of the studies included was moderate. Iguratimod for RA had few adverse events, and its efficacy and safety were the same as those of MTX and SASP for RA. The results of this systematic review suggest that more high-quality and large-scaled RCTs were needed to determine the efficacy of iguratimod for RA and whether iguratimod is as effective as other DMARDs besides MTX and SASP.

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.