One-day systemic corticosteroid administration for asthma and future "short bursts" risk in real clinical practice.

OBJECTIVE: Systemic corticosteroid administration, also called short bursts (SB), is harmful for patients with asthma; however, the actual burden of one-day SB remains unsolved. This study aimed to elucidate the characteristics of patients requiring one-day SB against asthma in clinical practice. METHODS: Consecutive patients who regularly visited our hospital for asthma treatment between January 2019 and December 2020 were reviewed and followed for one year. SB was defined as ≥3 days of systemic corticosteroid treatment for an exacerbation. One-day SB was defined as one-day of systemic corticosteroid to treat an exacerbation. The one-day SB group included patients who received only one-day SB but no SB during the preceding year. Frequent SB was defined as that occurring ≥2 times/year. RESULTS: Data on 229 patients were analyzed. Among them, 2.6% (95% confidence interval 1.2-5.6%) were in the one-day SB group. The one-day SB group was female-dominant, obese, non-eosinophilic, and non-atopic. The median one-day SB was 1.5 times/year and almost half of one-day SB were performed by patients themselves. Independent of the low pulmonary function, high blood eosinophil count, and inhaled corticosteroid dose, one-day SB was associated with future frequent SB (adjusted odds ratio = 18.2, 95% confidence interval 1.1-288, P = 0.040, compared to the no SB group). CONCLUSIONS: Although one-day SB was not frequently experienced, even one-day SB without conventional SB was associated with future frequent SB. It is important to grasp the actual condition of one-day SB and to reinforce the treatment used.

Effects of 6-O-α-maltosyl-ß cyclodextrin on lipid metabolism in Npc1-deficient Chinese hamster ovary cells.

Niemann-Pick disease Type C (NPC) is a lysosomal storage disorder caused by mutation of the NPC1/NPC2 genes, which ultimately results in the accumulation of unesterified cholesterol (UEC) in lysosomes, thereby inducing symptoms such as progressive neurodegeneration and hepatosplenomegaly. This study determines the effects of 6-O-α-maltosyl-ß cyclodextrin (Mal-ßCD) on lipid levels and synthesis in Npc1-deficient (Npc1-KO cells) and vehicle CHO cells. Compared to vehicle cells, Npc1-KO cells exhibited high level of UEC, and low levels of esterified cholesterols (ECs) and long-chain fatty acids (LCFAs). The difference in lipid levels between Npc1-KO and CHO cells was largely ameliorated by Mal-ßCD administration. Moreover, the effects of Mal-ßCD were reproduced in the lysosomes prepared from Npc1-KO cells. Stable isotope tracer analysis with extracellular addition of D4-deuterated palmitic acid (D4-PA) to Npc1-KO cells increased the synthesis of D4-deuterated LCFAs (D4-LCFAs) and D4-deuterated ECs (D4-ECs) in a Mal-ßCD-dependent manner. Simultaneous addition of D6-deuterated UEC (D6-UEC) and D4-PA promoted the Mal-ßCD-dependent synthesis of D6-/D4-ECs, consisting of D6-UEC and D4-PA, D4-deuterated stearic acid, or D4-deuterated myristic acid, in Npc1-KO cells. These results suggest that Mal-ßCD helps to maintain normal lipid metabolism by restoring balance among UEC, ECs, and LCFAs through acting on behalf of NPC1 in Npc1-KO cells and may therefore be useful in designing effective therapies for NPC.

Therapeutic plasma exchange for clinically amyopathic dermatomyositis (CADM) associated with rapidly progressive interstitial pneumonia.

BACKGROUND: Patients with clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) frequently develop rapidly progressive interstitial pneumonia (RPIP), often with fatal outcomes. Therapeutic plasma exchange (TPE) has been reported as effective against CADM-RPIP refractory to conventional immunosuppressive therapy. However, the detailed mechanisms by which TPE improves disease activity of CADM-RPIP remain unclear. AIM: To elucidate the clinical and demographic characteristics of patients with anti-MDA5 Ab-positive CADM-RPIP treated with TPE and to analyze changes in laboratory findings before, during, and after TPE. MATERIALS & METHODS: Patients hospitalized for CADM-RPIP and treated with TPE in 2017 and 2018 were analyzed retrospectively. RESULTS: Three patients were successfully treated with TPE, with good tolerance. Anti-MDA5 Ab titers decreased significantly over the course of TPE. CONCLUSION: We emphasize that TPE could represent an effective treatment option for CADM-RPIP refractory to traditional therapy. Removal of anti-MDA5 Ab and other pathogenic factors may facilitate favorable outcomes.

[USEFULNESS OF RUPATADINE FOR PRURITUS OF PATIENTS WITH ATOPIC DERMATITIS].

BACKGROUND: Histamine H1 receptor antagonists (antihistamines) are recommended as adjunctive therapy for atopic dermatitis (AD). However, their long-term usefulness and the effect of updosing have not been clarified. PURPOSE: To analyzed the long-term usefulness and the effect of updosing of rupatadine, a second generation antihistamine, for patients with AD. METHODS: Efficacy and safety of rupatadine were evaluated in 66 AD patients, including 50 patients with dose escalation by post hoc analysis of the phase III trial of rupatadine for Japanese patients with pruritus associated with skin diseases. RESULTS: The mean score at baseline total pruritus score (TPS) was 4.682. It decreased to 3.885 at 2 weeks, and 2.376 at 52 weeks by rupatadine administration. The change (of one week after baseline TPS) was significant. Baseline TPS of dose escalation groups, either after 2 weeks or after week 4, were higher than those of 10mg maintenance dose cases, but no significant difference was shown in the change from baseline TPS among the groups at 52 weeks. The occurrence of adverse drug reactions and somnolence were observed in 19.7% and 15.2% of the subjects. CONCLUSION: These results suggest the long-term usefulness of rupatadine for pruritus in AD.

Efficacy and safety of rupatadine in Japanese patients with seasonal allergic rhinitis: A double-blind, randomized, multicenter, placebo-controlled clinical trial.

BACKGROUND: Rupatadine is a novel non-sedating second-generation H1-antihistamine with antiplatelet-activating factor activity, first marketed in Spain in 2003. It is used for treating allergic rhinitis in more than 80 countries. This study investigated its efficacy and safety in Japanese patients with seasonal allergic rhinitis (SAR). METHODS: This was a randomized, placebo-controlled, double-blind study conducted at 4 medical institutions in Japan (JapicCTI-152785). Adolescent and adult SAR outpatients aged 12-64 years entered a 1-week placebo run-in period. After eligibility was confirmed, patients orally received placebo, rupatadine 10 mg, or 20 mg once daily for 2 weeks. The primary endpoint was a change from baseline to second week of treatment in total 4 nasal symptom score (T4NSS). RESULTS: Nine hundred patients were randomly assigned to placebo, rupatadine 10 mg, or rupatadine 20 mg (302, 298, and 300 patients, respectively). The least squares mean difference in the primary endpoint between rupatadine and placebo was -1.085 for 10 mg, and -1.415 for 20 mg (analysis of covariance, both P < 0.001). The rates of adverse events were 6.6%, 14.1%, and 15.0% for placebo, rupatadine 10 mg, and rupatadine 20 mg, respectively. Somnolence was most frequently reported: 7.0% for rupatadine 10 mg and 7.3% for rupatadine 20 mg. No serious adverse drug reactions were observed, and no adverse events resulted in premature discontinuation. CONCLUSIONS: Rupatadine 10 and 20 mg were significantly superior to placebo in improving nasal and ocular symptoms of SAR, and were well tolerated.

Efficacy and safety of rupatadine in Japanese adult and adolescent patients with chronic spontaneous urticaria: A double-blind, randomized, multicenter, placebo-controlled clinical trial.

BACKGROUND: Rupatadine, a novel nonsedating second-generation H1-antihistamine with antiplatelet-activating factor activity, has been used in the treatment of allergic rhinitis and urticaria in European countries since 2003. However, its efficacy and safety in Japanese patients with chronic spontaneous urticaria (CSU) are unknown. METHODS: We conducted a prospective, multicenter, randomized, placebo-controlled, double-blind study in adolescent and adult CSU outpatients aged 12 to < 65 years (JAPIC-CTI No. 152786). Overall, 94, 91, and 92 eligible patients orally received placebo, rupatadine 10 mg, and 20 mg once daily for 2 weeks, respectively. The primary endpoint was change from baseline to the second week of treatment in total pruritus score (TPS, sum of daytime and nighttime pruritus scores). RESULTS: The results yielded a least squares mean TPS difference of -1.956 between rupatadine 10 mg versus placebo, and -2.121 between rupatadine 20 mg versus placebo (analysis of covariance, both P < 0.001). The incidence of adverse events was 8.5% for placebo, 20.9% for rupatadine 10 mg, and 17.4% for rupatadine 20 mg. Somnolence was the only adverse drug reaction to rupatadine reported in 2 or more subjects. No serious or clinically significant adverse events were observed. CONCLUSIONS: The primary and secondary efficacy endpoints consistently favored rupatadine 10 and 20 mg doses over the placebo. No noteworthy dose-related increase in the incidence of adverse drug reactions was observed. Rupatadine is safe and effective at a dose of 10 mg once daily, and can be safely increased to 20 mg once daily, as necessary.

Effect of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogels on frozen-thawed human ovarian tissue in a xenograft model.

AIM: Ovarian tissue cryopreservation before cancer treatment is the only option to preserve fertility under some circumstances. However, tissue ischemia after transplantation while awaiting angiogenesis induces dysfunctional folliculogenesis and reduces ovarian reserve and is one of the disadvantages of frozen-thawed ovarian tissue transplantation. Basic fibroblast growth factor (bFGF) is a major regulator of angiogenesis. However, bFGF rapidly loses biological activity when its free form is injected in vivo. This study investigated whether administration of active bFGF helps establish a nurturing environment for follicular survival. METHODS: A sheet form of a sustained release drug delivery system for bFGF was developed using biodegradable acidic gelatin hydrogel (bFGF sheet). The bFGF sheets or phosphate-buffered saline sheets, as a negative control, were transplanted with frozen-thawed human ovarian tissues subcutaneously into the backs of severe combined immunodeficient mice. Neovascularization, cell proliferation, fibrosis and follicular survival of ovarian grafts were analyzed at 6 weeks after xenografting. RESULTS: The bFGF sheets were optimized to release bFGF for at least 10 days. The transplantation of bFGF sheets with frozen-thawed ovarian tissues significantly increased human and mouse CD31-positive areas and stromal and endothelial cell proliferations. The administration of bFGF also significantly decreased the percentage of the fibrotic area in the graft, resulting in a significant increase in primordial and primary follicular density. CONCLUSION: Local administration of a sustained release of biologically active bFGF induced neovascularization in frozen-thawed ovarian tissue grafts, which could establish the nurturing environment required for follicular survival in heterotopic xenografts.

γ-SNAP stimulates disassembly of endosomal SNARE complexes and regulates endocytic trafficking pathways.

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) that reside in the target membranes and transport vesicles assemble into specific SNARE complexes to drive membrane fusion. N-ethylmaleimide-sensitive factor (NSF) and its attachment protein, α-SNAP (encoded by NAPA), catalyze disassembly of the SNARE complexes in the secretory and endocytic pathways to recycle them for the next round of fusion events. γ-SNAP (encoded by NAPG) is a SNAP isoform, but its function in SNARE-mediated membrane trafficking remains unknown. Here, we show that γ-SNAP regulates the endosomal trafficking of epidermal growth factor (EGF) receptor (EGFR) and transferrin. Immunoprecipitation and mass spectrometry analyses revealed that γ-SNAP interacts with a limited range of SNAREs, including endosomal ones. γ-SNAP, as well as α-SNAP, mediated the disassembly of endosomal syntaxin-7-containing SNARE complexes. Overexpression and small interfering (si)RNA-mediated depletion of γ-SNAP changed the morphologies and intracellular distributions of endosomes. Moreover, the depletion partially suppressed the exit of EGFR and transferrin from EEA1-positive early endosomes to delay their degradation and uptake. Taken together, our findings suggest that γ-SNAP is a unique SNAP that functions in a limited range of organelles - including endosomes - and their trafficking pathways.

Three Novel Triterpenoids from Taraxacum officinale Roots.

Three novel lupane-, bauerane-, and euphane-type triterpenoids (1-3), in addition to seven known triterpenoids (4-10)-18ß,19ß-epoxy-21ß-hydroxylupan-3ß-yl acetate (4), 21-oxolup-18-en-3ß-yl acetate (5), betulin (6), officinatrione (7), 11α-methoxyolean-12-en-3-one (8), eupha-7,24-dien-3-one (9), and 24-oxoeupha-7,24-dien-3ß-yl acetate (10)-were isolated from the roots of Taraxacum officinale. Their structures were elucidated on the basis of spectroscopic analyses using 1D and 2D-NMR spectra and electron ionization mass spectrometry (EIMS). The effects of compounds 1-10 on the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages were evaluated. Compounds 4, 6, and 10 exhibited similar NO inhibitory activities to N(G)-monomethyl-l-arginine acetate (l-NMMA). These compounds did not exhibit cytotoxicity at an effective concentration. The results of present study suggest that compounds 4, 6, and 10 have potential as anti-inflammatory disease agents.

Metabolic activation of hepatotoxic drug (benzbromarone) induced mitochondrial membrane permeability transition.

The risk of drug-induced liver injury (DILI) is of great concern to the pharmaceutical industry. It is well-known that metabolic activation of drugs to form toxic metabolites (TMs) is strongly associated with DILI onset. Drug-induced mitochondrial dysfunction is also strongly associated with increased risk of DILI. However, it is difficult to determine the target of TMs associated with exacerbation of DILI because of difficulties in identifying and purifying TMs. In this study, we propose a sequential in vitro assay system to assess TM formation and their ability to induce mitochondrial permeability transition (MPT) in a one-pot process. In this assay system, freshly-isolated rat liver mitochondria were incubated with reaction solutions of 44 test drugs preincubated with liver microsomes in the presence or absence of NADPH; then, NADPH-dependent MPT pore opening was assessed as mitochondrial swelling. In this assay system, several hepatotoxic drugs, including benzbromarone (BBR), significantly induced MPT in a NADPH-dependent manner. We investigated the rationality of using BBR as a model drug, since it showed the most prominent MPT in our assay system. Both the production of a candidate toxic metabolite of BBR (1',6-(OH)2 BBR) and NADPH-dependent MPT were inhibited by several cytochrome P450 (CYP) inhibitors (clotrimazole and SKF-525A, 100µM). In summary, this assay system can be used to evaluate comprehensive metabolite-dependent MPT without identification or purification of metabolites.

Increased lung field permeability in young patients.

When the chest radiograph of a young patient shows lung hyperlucency, it is important to obtain a detailed clinical history of any previous episodes of childhood infection. Previous chest radiographs should be reviewed to determine whether the condition is congenital or acquired, and thus assist in a diagnosis of SJMS.

Feasibility of continued treatment with dupilumab in patients with type 2 inflammatory disease who developed eosinophilic pneumonia: 3 case reports.

Several reports have described dupilumab-induced eosinophilic pneumonia (EP) after treatment with dupilumab in patients with type 2 inflammatory disease. Other reports have suggested the efficacy of dupilumab for chronic EP (CEP). Whether dupilumab can be continued in patients with type 2 inflammatory disease who develop EP during dupilumab treatment remains unclear. We present herein three cases with different clinical presentations involving dupilumab and EP. In Case 1, dupilumab was discontinued because of dupilumab-induced EP during the treatment of asthma. In Case 2, although pre-existing idiopathic EP worsened during the treatment of eosinophilic chronic rhinosinusitis (ECRS), dupilumab was continued. In Case 3, CEP and ECRS were successfully treated with dupilumab and corticosteroids were discontinued. In conclusion, treatment with dupilumab in patients with type 2 inflammatory disease and idiopathic EP is worth considering if the benefits are deemed to outweigh the risks and careful attention is given to the clinical course.

Dual biologics for severe asthma and atopic dermatitis: Synopsis of two cases and literature review.

The efficacy and safety of the combination of biologic therapies remain unclear with an ineffective and insufficient single biologic for managing asthma. Herein, we report two cases using dual biologics for severe asthma and atopic dermatitis. A 52-year-old male patient who received dupilumab and mepolizumab, benralizumab, or tezepelumab, followed by bronchial thermoplasty, and a 41-year-old male patient who received dupilumab and omalizumab, both experienced improved asthma and atopic dermatitis. To date, 38 cases are using dual biologics for severe asthma. The success rate was 84%, with no major adverse effects. We report the first case of severe asthma receiving dual biologics with tezepelumab and furthermore bronchial thermoplasty, and comprehensive literature review on dual biologics. Dual biologics may be an effective treatment method for severe asthma, requiring further investigation.

Allergy to Omalizumab: Lessons from a Reaction to the Coronavirus 2019 Vaccine.

Omalizumab can cause hypersensitivity reactions. We herein report the first case of an 18-year-old woman with refractory cough-predominant asthma that correlated with allergic reactions caused by omalizumab and the coronavirus disease 2019 (COVID-19) vaccine. The patient developed angioedema after taking omalizumab. She had previously experienced intense coughing immediately after receiving a COVID-19 vaccine. A skin prick test was positive for polysorbate 20, which was probably the cause of the allergic reactions to omalizumab and the COVID-19 vaccine. Clinicians should check for an allergic reaction, irrespective of its intensity, triggered by polysorbate and be careful when prescribing biologics to patients in order to avoid allergic reactions.

Impact of adding pethidine on disinhibition during bronchoscopy with midazolam: a propensity score matching analysis.

BACKGROUND: We sometimes experience disinhibition during bronchoscopy with sedation. However, the impact of adding pethidine on disinhibition has not yet been investigated. This study aimed to examine the additive impact of pethidine on disinhibition during bronchoscopy with midazolam. METHODS: This retrospective study involved consecutive patients who underwent bronchoscopy between November 2019 and December 2020 (sedated with midazolam: Midazolam group) and between December 2020 and December 2021 (sedated with midazolam plus pethidine: Combination group). The severity of disinhibition was defined as follows: moderate, disinhibition that always needed restraints by assistants; and severe, disinhibition that needed antagonization of sedation by flumazenil to continue bronchoscopy. One-to-one propensity score matching was used to match baseline characteristics between both groups. RESULTS: After propensity score matching with depression, the type of bronchoscopic procedure, and the dose of midazolam, 142 patients matched in each group. The prevalence of moderate-to-severe disinhibition significantly decreased from 16.2% to 7.8% (P = 0.028) in the Combination group. The Combination group had significantly better scores for sensation after bronchoscopy and feelings toward bronchoscopy duration than did the Midazolam group. Although the minimum SpO2 during bronchoscopy was significantly lower (88.0 ± 6.2 mmHg vs. 86.7 ± 5.0 mmHg, P = 0.047) and the percentage of oxygen supplementation significantly increased (71.1% vs. 86.6%, P = 0.001) in the Combination group, no fatal complications were observed. CONCLUSIONS: Adding pethidine could reduce disinhibition occurrence in patients undergoing bronchoscopy with midazolam, with better subjective patient outcomes during and after bronchoscopy. However, whether more patients may need oxygen supplementation and whether hypoxia occurs during bronchoscopy should be considered. CLINICAL TRIAL REGISTRATION: UMIN000042635.

Two Uncommon Complications Related to Suture Knots After Meniscal All-Inside Suture Repair: A Case Report.

CASE: A 17-year-old male patient suffered a radial lateral meniscus tear and underwent an arthroscopic all-inside suture repair. After 7 months, the patient experienced catching. Magnetic resonance imaging and computed tomography revealed an intra-articular loose body without calcification, which was removed surgically. The excised specimen was histopathologically confirmed to be a necrotic meniscus fragment with a suture knot. In addition, cartilage damage because of suspected impingement by a residual suture knot was observed. After removing the loose body and knot, the patient's symptoms were relieved, and he returned to sports. CONCLUSION: Suture knot-related complications should be considered while performing meniscal repairs.

Severe eosinophilia and subsequent dermatologic immune-related adverse event with squamous cell carcinoma antigen elevation induced by nivolumab and ipilimumab.

Immune checkpoint inhibitors (ICIs) for malignant lesions are associated with immune-related adverse events (irAEs), but reports about severe eosinophilia induced by ICIs are scarce. A 73-year-old man with lung squamous cell carcinoma was treated by chemotherapy (carboplatin plus paclitaxel) and ICIs (nivolumab plus ipilimumab). After two cycles of chemotherapy, the ICIs were continued. After 5 months, the eosinophilia, which had exceeded 5000/µl, increasingly deteriorated, and the only detected irAE was a grade 1 rash. Under continuation of the ICIs, although the eosinophilia decreased, a grade 3 rash and severe pruritis subsequently appeared. Squamous cell carcinoma antigen (SCCA) was steeply increased simultaneously. A complete response had been achieved, and oral prednisolone markedly improved the rash, pruritis, and eosinophilia. Clinicians should be aware that precedent severe eosinophilia and subsequent severe irAE could occur in patients treated by nivolumab and ipilimumab, and SCCA elevation could be associated with dermatologic irAE.

Prevalence and characteristics of disinhibition during bronchoscopy with midazolam.

BACKGROUND: Disinhibition is sometimes experienced during bronchoscopy with sedation. However, data on disinhibition during bronchoscopy are scarce. We examined the prevalence and characteristics of disinhibition during bronchoscopy with midazolam. METHODS: This retrospective study analyzed consecutive patients who underwent bronchoscopy between November 2019 and December 2020. The severity of disinhibition was defined as follows: mild, disinhibition sometimes requiring restraints by assistants; moderate, disinhibition always requiring restraints by assistants; and severe, disinhibition requiring antagonization of sedation by flumazenil to continue bronchoscopy. RESULTS: Among 251 eligible patients who were sedated using midazolam, 36 (14.3%; 95% confidence interval [CI], 10.5%-19.2%), 42 (16.7%; 95% CI, 12.6%-21.8%), and 7 (2.8%; 95% CI, 1.4%-5.6%) experienced mild, moderate, and severe disinhibition, respectively. Depression (odds ratio [OR] 2.77; 95% CI, 1.20-6.41), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (OR 10.23; 95% CI, 1.02-103.01, referred to brushing/bronchial washing/observation), and increased administration of midazolam (OR 1.20; 95% CI, 1.02-1.42, per 1-mg increase) were independently associated with moderate-to-severe disinhibition. Patients experiencing moderate disinhibition reported significantly better scores for discomfort during bronchoscopy. Besides the maximum systolic and diastolic blood pressures during bronchoscopy, the changes in hemodynamic and respiratory statuses during bronchoscopy or complications did not significantly differ between patients experiencing moderate-to-severe disinhibition and those experiencing none-to-mild disinhibition. CONCLUSIONS: Moderate-to-severe disinhibition occurred in 19.5% of patients during bronchoscopy with midazolam. We should focus on disinhibition when patients have depression or are planning to undergo EBUS-TBNA, and sparing the administration of midazolam might reduce the occurrence of disinhibition. CLINICAL TRIAL REGISTRATION: UMIN000038571.

Drastically Progressive Ethambutol-induced Optic Neuropathy after Withdrawal of Ethambutol: A Case Report and Literature Review.

Ethambutol-induced optic neuropathy (EON) is a well-known complication, although low-dose ethambutol seldom causes EON. An 85-year-old man with non-tuberculous mycobacterial lung disease was taking antibiotics, including low-dose ethambutol. On day 85 of treatment, the diagnosis of EON was made. Despite prior discontinuation, his best corrected visual acuity drastically deteriorated from 20/17 (right eye) and 20/20 (left eye) to 20/330 (right eye) and 20/1,000 (left eye) within 3 weeks, and this symptom did not resolve. To our knowledge, there have been no reported cases with drastically progressing and irreversible EON even after the withdrawal of low-dose and short-term ethambutol.

Long-term safety and efficacy of rupatadine in Japanese patients with perennial allergic rhinitis: a 52-week open-label clinical trial.

Objective: Long-term safety and efficacy of 10- and 20-mg rupatadine in Japanese patients with perennial allergic rhinitis (PAR) were investigated in a 52-week open-label study (JapicCTI-152952, clinicaltrials.jp). Methods: The rupatadine dose was fixed to 10 mg once daily for the first 2 weeks. Thereafter, the study investigator was allowed to increase the dosage to 20 mg if the response was insufficient. Safety was evaluated on the basis of treatment-emergent adverse events, laboratory findings, and vital sign measurements. The primary efficacy endpoint was changed from baseline to Week 2 in the total 4 nasal symptom score. Secondary efficacy endpoints included changes over time in ocular symptoms, patient and physician clinical overall impression, and patient quality-of-life. Results: Seventy-two immunoglobulin E positive patients (mean age = 32.1 years), consisting of 58 adults (age ≥ 18 years) and 14 adolescents (12-17 years), were enrolled. Ninety-four treatment-emergent adverse events were reported in 48 patients (66.7%), including nine adverse drug reactions in nine patients (12.5%). The most frequently reported adverse drug reaction was somnolence (9.7%). The primary and secondary efficacy endpoints demonstrated a statistically significant clinical benefit with rupatadine. The rupatadine dose was increased from 10 to 20 mg in 36 patients (50.0%), which resulted in better symptom management. Conclusions: Rupatadine 10- and 20-mg once-daily doses were well tolerated in long-term use. Updosing to 20 mg is a reasonable option in PAR patients whose symptoms cannot be controlled effectively by the 10-mg dose.