Second-generation Antihistamines Research Articles

A Pilot Study of Ketotifen in Patients Aged 8-17 Years with Functional Dyspepsia Associated with Mucosal Eosinophilia.

Mast cells have been implicated in abdominal pain-associated disorders of gut-brain interaction, such as functional dyspepsia. As such, ketotifen, a second-generation antihistamine and mast cell stabilizer, could represent a viable treatment option in these conditions. The primary aim of the current pilot study was to assess clinical response to ketotifen and assess pharmacokinetics in youth with functional dyspepsia. We conducted a pilot randomized, double-blind, placebo-controlled, cross-over trial of ketotifen in 11 youth with functional dyspepsia and duodenal mucosal eosinophilia with 4 weeks of active treatment at a dose of 1 mg twice daily. Global clinical response was graded on a 5-point Likert Scale. A single plasma sample was obtained at steady state for pharmacokinetic analysis. Ketotifen was not superior to placebo with regard to global clinical response. Only 18% of patients demonstrated a complete or near-complete clinical response. The estimated half-life was 3.3 h. While ketotifen was not superior to placebo, this study highlights several important challenges for developing drug trials for youth with chronic abdominal pain. Recommendations are made for designing a larger treatment trial for ketotifen in this patient group. This study was registered at ClinicalTrials.gov: NCT02484248.

A Practical Approach to Diagnosing and Managing Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is an unpredictable inflammatory skin condition characterized by the spontaneous onset of itchy wheals, angioedema, or both, which occurs for longer than 6weeks overall. Despite the relatively straightforward diagnostic algorithm for CSU, relying primarily on a detailed medical history and only limited laboratory tests, patients often wait years to be diagnosed, with many cycling through different healthcare practitioners before a diagnosis is made. Even then, current treatment options for CSU are limited, with approximately half of patients resistant to standard-of-care second-generation antihistamines at standard or higher doses. As such, there is an unmet need for improved, streamlined management for patients with CSU. Here, we review the evidence-based diagnostic algorithm for CSU, consider the required steps of the diagnostic workup, and provide practical, real-world advice on the management of CSU to improve the timely diagnosis and care of patients with this debilitating disease.

English

Background: Bilastine is a second-generation antihistamine for the symptomatic treatment of allergic rhinoconjunctivitis (ARC) and urticaria in adults, adolescents, and children. The pharmacokinetics and safety of oral bilastine 10 mg/d in children aged 2 to 5 years were evaluated. Methods: This was a multicenter, open-label clinical trial in children aged 2 to 5 years with seasonal or perennial ARC or urticaria treated once daily with bilastine 10 mg orodispersible tablets. The safety evaluation included treatment-emergent adverse events (TEAEs), vital signs, and physical examination. Pharmacokinetic data were pooled with data from a prior pediatric study, and pharmacokinetic modeling was performed to assess consistency. Results: A total of 37 children with ARC (81.1%), urticaria (8.1%), or both (10.8%) were included in the study, with a mean (SD) age of 3.7 (1.2) years. The highest plasma concentrations of bilastine were observed 1 hour after administration (634.91 ng/mL). Eight patients (21.6%) experienced 1 TEAE each, none of which was severe. Body weight and age were not covariates of variation in either systemic clearance or the volume of distribution in children aged 2 to 5 years and did not affect the pharmacokinetic parameters of bilastine. Conclusions: The pharmacokinetics of bilastine was linear and consistent with data from a previous trial, suggesting that a 10-mg dose may be used in children (2 to <12 years). No dose adjustments are deemed necessary. Oral once-daily bilastine 10 mg presented a good safety profile in children aged 2 to 5.

Bilastine for the treatment of allergic rhinoconjunctivitis and urticaria: results from an international Delphi study.

Second-generation oral H1-antihistamines, including bilastine, represent the emerging treatments of allergic rhinitis (including rhinoconjunctivitis) and chronic urticaria in both adults and children. This study analyses available evidence supporting the use of bilastine amongst second-generation antihistamines for the symptomatic treatment of allergic rhinitis and urticaria in adults and children. Consensus amongst experts from 17 countries on the ideal treatment of rhinitis and urticaria, and the specific role of bilastine was measured by means of a modified Delphi process. A total of 12 statements were voted on by the experts using a five-point Likert scale (1 = strongly disagree; 2 = disagree; 3 = undecided; 4 = agree; 5 = strongly agree). The definition of consensus was set at a minimum of 80% concordance for 4+5 scores (agree or strongly agree). All proposed statements reached consensus, with a concordance of ≥98% for five statements and ≥96% for seven. The wide consensus obtained for the proposed statements suggests a prominent role for bilastine in the management of allergic rhinitis and urticaria.

Recurrent Kounis Syndrome: A Case Report and Literature Review.

Kounis syndrome is a condition where inflammatory cells (mostly mast cells with the contribution of macrophages and T-lymphocytes) cause an acute coronary syndrome. Kounis syndrome comes in four variants: type I in patients with normal coronary arteries; type II in patients with inactive pre-existing atheromatous disease; type III in patients with pre-existing coronary artery stenting; type IV in patients with a pre-existing coronary artery bypass. Recently, we came across a case of recurrent type I Kounis syndrome in our clinical practice. The purpose of the paper is to present our case and conduct a review using the Pubmed scientific database about the most relevant cases of recurrent Kounis syndrome. This review shows that recurrent Kounis syndrome is a rare condition and is mostly associated with Kounis syndrome type III. Recurrent Kounis syndrome may be also triggered by vaccination and it could be associated with chronic spontaneous urticaria. In the last condition, therapy is represented by second-generation anti-histamines and corticosteroids, but also by an anti-IgE monoclonal antibody (omalizumab) in the recalcitrant cases.

Diagnosis and Treatment of Chronic Urticaria: The Importance of Autoimmune Aspects and Comorbidity

The study aimed to conduct a comprehensive systematic review of the literature on the autoimmune mechanisms associated with chronic spontaneous urticaria (CSU) in adults, explore the association between chronic urticaria (CU) and autoimmune disorders, analyze two case reports, and develop a diagnostic algorithm considering the autoimmune pathogenesis.
 Materials and Methods. The literature review was conducted to study the mechanisms underlying autoimmune CU. Two case reports were analyzed and a diagnostic algorithm for patients suspected of autoimmune urticaria was formulated.
 Results. CU significantly impairs patients’ quality of life, posing problems in daily activities and is often associated with concomitant autoimmune diseases. Though the pathogenesis of CSU remains incompletely understood, in recent years, there has been significant progress in understanding the pathophysiology of this condition, prompting researchers to explore new agents, especially biological ones, in cases with severe refractory urticaria. We have developed a diagnostic algorithm aimed at improving the management tactics for CSU and autoimmune pathology, that involves a thorough collection of complaints, medical history, performing a series of basic laboratory tests for specific markers of autoimmune disorders, and expanding their spectrum with detailed differential diagnostics.
 Conclusions. CU is an important medical and social issue that requires an interdisciplinary personalized approach to patients. The diagnosis of the condition involves a comprehensive approach, considering potential concomitant autoimmune disorders and detailed laboratory investigations, especially in cases refractory to standard second-generation antihistamine therapy. The treatment of CU, specifically the stepwise therapy protocol based on symptom severity and response to treatment and aimed at reducing symptoms, improving patients’ quality of life, and achieving CU remission, is outlined in various national and international guidelines, and is carried out gradually, involving three lines of therapy.

Approved therapies and their effects on the main symptoms of urticaria : When symptom control of itchy wheals is not adequate-does updosing help?

International guidelines for the treatment of chronic spontaneous urticaria support the updosing of second-generation antihistamines to four times of the approved dose when adequate symptom control cannot be achieved with the standard dosage. However, this recommendation is primarily based on expert opinions, and there is alack of large, well-designed, double-blind clinical trials. Most the existing trials provide insufficient data, and due to the heterogeneity of the conducted trials on antihistamine effects (definition of control, design, quality, lack of an active comparator, no placebo arm, small sample size, outcomes) and their short duration, comparative analysis is challenging. However, it can be concluded that the use of modern second-generation antihistamines is both effective and safe based on the available data and our own long-term experiences in the specialized outpatient clinic of auniversity dermatology department, even though increased dosages (up to fourfold as per the current international guidelines) may be necessary for symptom control. Another therapeutic option for refractory symptoms in chronic spontaneous urticaria is subcutaneous administration of omalizumab at adosage of 300 mg at 4‑week intervals as avery safe and effective treatment.

Intravenous Cetirizine Premedication to Mitigate Infusion-Related Reactions

Infusion-related reactions (IRRs) are a recognized concern for chemotherapy, biologic agents, and newer immunotherapies. Antihistamines are frequently recommended to prevent or manage these reactions. For over 60 years, diphenhydramine has been the only H1 antihistamine for intravenous (IV) administration. It has been considered the standard of care as part of premedication regimens to prevent IRRs associated with these therapies despite the lack of a US Food and Drug Administration (FDA)-approved indication and no evidence of efficacy data. Intravenous cetirizine was approved in 2019 for acute urticaria treatment, making it the only second-generation H1 antihistamine that can be administered intravenously. Compared with diphenhydramine, cetirizine has an improved safety profile with less sedation, fewer contraindications, lower incidence of anticholinergic side effects, and minimal risk of adverse events in elderly patients. A head-to-head study demonstrated that IV cetirizine is as effective as IV diphenhydramine in reducing IRRs and may decrease chair time, treatment center visits, and the need for rescue medication. Over the past 3 decades, the FDA has addressed the issue of IRRs by mandating language regarding the requirement or recommendation for premedication in the label of over 50 FDA-approved infusion products. As more therapeutics have premedication required or recommended, IV cetirizine should be considered an antihistamine for preventing and treating IRRs. In this article, we describe a patient whose IRR was successfully managed with IV cetirizine and discuss first- vs. second-generation H1 antihistamines and their use in treating and preventing IRRs.

Clinical efficacy of Zhiyang Xiaozhen granules combined with second-generation antihistamine in the treatment of chronic urticaria.

Chronic urticaria presents a chronic process of recurrent attacks, and its first-line treatment is second-generation antihistamine with limited treatment options. The efficacy of antihistamine varies among individuals and cannot meet the needs of all patients. This study aims to explore the clinical efficacy and safety of Zhiyang Xiaozhen granules combined with antihistamine in the treatment of chronic urticaria patients. We retrospectively analyzed the clinical data of patients with chronic urticaria who visited the Xiangya Hospital of Central South University from April 2020 to March 2021. The patients who received conventional second-generation antihistamine treatment were selected as a control group, while the patients who received combined treatment with Zhiyang Xiaozhen granules on the basis of conventional second-generation antihistamine treatment were selected as an observation group. The differences in the Weekly Urticaria Activity Score (UAS7) and Dermatology Life Quality Index (DLQI) between the 2 groups before and 4 weeks after treatment were compared. The Symptom Score Reduce Index (SSRI) was used to evaluate and compare the efficacy of the 2 treatment regimens. After 4 weeks of treatment, the UAS7 levels in both groups were significantly reduced (P=0.001 and P<0.001, respectively). The effective rates of the control group and the observation group were 61.11% and 59.38%, respectively when converting UAS7 to SSRI for efficacy evaluation, and there was no statistically significant difference in efficacy between the 2 groups (P>0.05); however, when converting DLQI to SSRI for efficacy evaluation, the effective rates of the control group and the observation group were 33.33% and 46.88%, respectively, and the difference in efficacy between the 2 groups was statistically significant (P<0.001). There were 3 patients with adverse drug reactions related to drowsiness in both groups. The combination of Zhiyang Xiaozhen granules and second-generation antihistamine can effectively improve disease activity in patients with chronic urticaria, and the improvement in quality of life is better than that with the second-generation antihistamine alone.

Emedastine Inhibits Th1 and Th2 Cell Differentiation Mediated by Mast Cells.

We have previously clarified that emedastine, a second-generation antihistamine drug, inhibits T helper 1(Th1)/Th2 cell differentiation mediated by Langerhans cells (LCs). In addition, although we have recently found that mast cells also function as antigen-presenting cells (APCs) and induce Th1/Th2 cell differentiation, any influence of emedastine on this function remained unclear. Here we investigated the influence of emedastine on Th1/Th2 cell differentiation via mast cells. Mast cells were obtained by long-term culture of murine splenocytes in medium supplemented with tumor necrosis factor (TNF)-α. The mast cells were then incubated in the presence or absence of emedastine, and cultured with naïve CD4+ T cells in the presence of ovalbumin (OVA) peptide. Five days later, Th cells in the culture were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and Th1/Th2 cytokine production was examined by enzyme-linked immunosorbent assay. When mast cells treated with emedastine were used as APCs, production of interferon (IFN)-γ and interleukin (IL)-4 from activated Th cells was significantly suppressed. This suppression was associated with inhibition of CD86 expression on mast cells, and mast cells treated with emedastine were shown to obstruct the differentiation of both Th1 and Th2 cells by down-regulating their cell surface expression of CD86. The present data provide additional information that topical application of emedastine to the lesional skin of patients with atopic dermatitis (AD) would reduce not only LC- but also mast cell-mediated skin inflammation.

Pharmacokinetic Modeling of Bepotastine for Determination of Optimal Dosage Regimen in Pediatric Patients with Allergic Rhinitis or Urticaria.

Bepotastine, a second-generation antihistamine for allergic rhinitis and urticaria, is widely used in all age groups but lacks appropriate dosing guidelines for pediatric patients, leading to off-label prescriptions. We conducted this study to propose an optimal dosing regimen for pediatric patients based on population pharmacokinetic (popPK) and physiologically based pharmacokinetic (PBPK) models using data from two previous trials. A popPK model was built using NONMEM software. A one-compartment model with first-order absorption and absorption lag time described our data well, with body weight incorporated as the only covariate. A PBPK model was developed using PK-Sim software version 10, and the model well predicted the drug concentrations obtained from pediatric patients. Furthermore, the final PBPK model showed good concordance with the known properties of bepotastine. Appropriate pediatric doses for different weight and age groups were proposed based on the simulations. Discrepancies in recommended doses from the two models were likely due to the incorporation of age-dependent physiological factors in the PBPK model. In conclusion, our study is the first to suggest an optimal oral dosing regimen of bepotastine in pediatric patients using both approaches. This is expected to foster safer and more productive use of the drug.

Cost-effectiveness Analysis of Second-Generation Antihistamine 1 Receptor Blockers and Japanese Kampo Shoseiryuto for Treating Perennial Allergic Rhinitis in Outpatient Settings in Japan

Objectives: Perennial allergic rhinitis (PAR) is common in Japan. Second-generation antihistamines (SGAs) are commonly used for its treatment; however, it remains unclear which SGA is the most cost-effective. Additionally, the pharmacoeconomics of Japanese Kampo shoseiryuto (which was traditionally prescribed to treat PAR in Japan) remains poorly understood. In this study, we aimed to investigate the effectiveness of various SGAs and shoseiryuto for the treatment of PAR in Japanese outpatients, from the healthcare payer’s perspective. Methods: The most cost- and clinically effective SGAs were determined from a list of 6 SGAs (bepotastine, 10 mg; cetirizine, 10 mg; ebastine, 10 mg; epinastine, 20 mg; loratadine, 10 mg; and olopatadine, 5 mg) together with shoseiryuto, using the overall improvement rate through a model-based analysis. The time horizon was 28 days. Costs were determined based on the Medical Fee Index in 2020. Deterministic and probabilistic sensitivity analyses were conducted to address the uncertainty of the base-case results. Results: Overall, bepotastine (10 mg) and ebastine (10 mg) were cost-effective. Shoseiryuto was less cost-effective than ebastine (10 mg) (dominated). Ebastine (10 mg) was the most cost-effective option based on deterministic and probabilistic sensitivity analyses. Conclusions: Ebastine (10 mg) was the most cost-effective treatment strategy for PAR among the agents evaluated in this study. This insight could aid in establishing an appropriate formulary for treating PAR in hospitals and communities.

Clinical predictors of antihistamine resistance in patients with chronic spontaneous urticaria

BACKGROUND: Сhronic spontaneous urticaria is characterized by itchy wheals and/or angioedema on the skin for ≥6 weeks. A large-scale international AWARE study by Russian researchers indicated the ineffectiveness of therapy with standard doses of second-generation antihistamines in 50% of patients with chronic spontaneous urticaria. Clinical predictors of antihistamine resistance include low quality of life based on CU-Q2oL, baseline urticaria activity score for 7 days (UAS7) 16, combination with chronic inducible urticaria, and autoimmune comorbidity. Currently, research into the clinical predictors of antihistamine resistance, including body mass index, in patients with chronic spontaneous urticaria is ongoing.&#x0D; AIM: To examine the degree of symptom control based on body mass index and physical activity in patients with chronic spontaneous urticaria treated with second-generation antihistamines.&#x0D; MATERIALS AND METHODS: The examination of patients with сhronic spontaneous urticaria (n=34) included the clinical history and use of the following international questionnaires: UAS7, urticaria control test, dermatology quality of life index, and global physical activity questionnaire of the World Health Organization. The questionnaires were analyzed in subgroups of patients with controlled and uncontrolled chronic spontaneous urticaria and subgroups of patients with chronic spontaneous urticaria having normal weight, overweight, and obesity.&#x0D; RESULTS: Uncontrolled symptoms were observed in 24 (70.6%) patients with chronic spontaneous urticaria, including 11 (45.8%) with resistance to fourfold doses of second-generation antihistamines. In 52.9% of patients with chronic spontaneous urticaria, the body mass index exceeded normal values. In this study, an inverse correlation was found between the body mass index and the degree of control of chronic spontaneous urticaria symptoms.&#x0D; CONCLUSIONS: Owing to the negative correlation between body mass index and the degree of symptom control, further research into the role of body mass index as a clinical predictor of antihistamine-resistant chronic spontaneous urticaria is needed. In the future, personalized therapy for chronic spontaneous urticaria may consider the degree of disease control, clinical predictors of antihistamine resistance, and proinflammatory biomarkers.

Study of effectiveness of methotrexate oral pulse in refractory chronic urticaria

Objectives: Chronic urticaria (CU) is an unexplained problem that needs to be addressed, and since patients also experience the morbidity associated with irritable itch, they must take a significant quantum of antihistamines. Autoantibodies in the blood cause recurrent flare-ups in autoreactive urticaria when the symptoms are more noticeable. As a result, the need for an adjuvant drug to lessen the weight of pills is felt. The aim of this study was to find out the effectiveness of oral methotrexate (MTX) pulse with antihistamines in chronic refractory urticaria. Material and Methods: This was the present longitudinal intervention. The study lasted six months and was carried out at the Department of Dermatology in a hospital with tertiary care status. Fifty patients of chronic spontaneous urticaria have been selected by simple random sampling. All subjects have been given Oral Methotrexate, 15 mg once weekly along with folic acid. Besides, MTX all cases have been given oral desloratadine 5 mg twice daily. Results: Most patients have seen a significant decline in urticaria activity score 7 (UAS7) and dermatological life quality index. The baseline mean UAS7 reduced significantly from 30.16 ± 8.65 to 1.24 ± 2.24 with a statistically significant P &lt; 0.01. No serious side effects were seen except mildly raised liver transaminases in seven patients. Conclusion: When standard second-generation antihistamines are insufficient at treating chronic uncontrolled urticaria, MTX is a very safe, well-tolerated, and economical treatment option.

The Efficacy and Safety of High Dose (10 mg) of Desloratadine (Dazit® 10) in the Treatment of Chronic Spontaneous Urticaria in India: A Phase III, Multicentric, Open-Label, Single-Arm Study.

Chronic spontaneous urticaria (CSU) is a debilitating affliction that affects diverse quality of life (QoL) parameters such as sleep, self-esteem, and daily activities. Second-generation antihistamines, such as desloratadine, are more effective and safer in managing CSU. Desloratadine is a nonsedating, potent, and highly selective H1 receptor antagonist. At its daily dose of 5 mg, almost half of CSU patients do not show symptomatic improvement. European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF) (EuroGuiDerm)/Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI) guidelines recommend increasing the dosage to up to four times in such nonresponsive patients. However, there is insufficient clinical evidence in Indian settings. We evaluated the efficacy and safety of 10 mg desloratadine (OD) in 256 nonresponsive patients with moderate to severe CSU. The primary outcome was the change in Urticaria Activity Score (UAS7) from baseline to four weeks. Additionally, change in Chronic Urticaria Quality of Life (CU-Q2oL) scores during the course of treatment was also evaluated. The mean UAS7 scores showed a significant reduction from 31.9 ± 4.8 at baseline to 18.2 ± 8.1 at the end of the study (p < 0.0001). The use of a higher dose of desloratadine also decreased the CU-Q2oL scores significantly from 59.8 ± 14.7 at baseline to 35.4 ± 10 at four weeks (p < 0.0001). The incidence of adverse events (AEs) possibly linked to the drug was low (1.6%), and no serious adverse events were reported. Results indicated improvements in the disease severity as well as its positive impact on participants' QoL. This study confirms the efficacy and safety of daily use of a twofold dose of desloratadine in nonresponsive moderate to severe CSU patients.

How to handle off-label prescriptions of rupatadine, a second-generation antihistamine and PAF antagonist: a review.

The off-label use of second-generation antihistamines, used outside of the formal indications authorized by regulatory authorities, in different age groups, doses or in special populations, is very common for many allergic, autoimmune and dermatological diseases. The off-label use of rupatadine (a second-generation antihistamine with PAF antagonist activity) in these conditions is reviewed here, including in combination with immunotherapy in the treatment of food allergy or allergic rhinitis, at high doses in chronic urticaria, and with prescriptions of less common but challenging conditions such as skin pruritus or mast cell activation disorders like mastocytosis. Rupatadine use is reviewed herein to confirm if its off-label management is supported by well-designed clinical trials or by published real-world cases. This review will contribute to increasing compliance and achieving better results in clinical practice. Off-label use of rupatadine should be left to the discretion of the prescribing healthcare professional after careful clinical evaluation.

Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor

Histamine receptors are a group of G protein-coupled receptors (GPCRs) that play important roles in various physiological and pathophysiological conditions. Antihistamines that target the histamine H1 receptor (H1R) have been widely used to relieve the symptoms of allergy and inflammation. Here, to uncover the details of the regulation of H1R by the known second-generation antihistamines, thereby providing clues for the rational design of newer antihistamines, we determine the cryo-EM structure of H1R in the apo form and bound to different antihistamines. In addition to the deep hydrophobic cavity, we identify a secondary ligand-binding site in H1R, which potentially may support the introduction of new derivative groups to generate newer antihistamines. Furthermore, these structures show that antihistamines exert inverse regulation by utilizing a shared phenyl group that inserts into the deep cavity and block the movement of the toggle switch residue W4286.48. Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.

Evaluation of the efficacy of combinations of second-generation antihistamines in pruritus based on shared decision making

Evaluation of the efficacy of combinations of second-generation antihistamines in pruritus based on shared decision making

Unraveling the Structure of Meclizine Dihydrochloride with MicroED.

Meclizine (Antivert, Bonine) is a first-generation H1 antihistamine used in the treatment of motion sickness and vertigo. Despite its wide medical use for over 70 years, its crystal structure and the details of protein-drug interactions remained unknown. Single-crystal X-ray diffraction (SC-XRD) is previously unsuccessful for meclizine. Today, microcrystal electron diffraction (MicroED) enables the analysis of nano- or micro-sized crystals that are merely a billionth the size needed for SC-XRD directly from seemingly amorphous powder. In this study, MicroED to determine the 3D crystal structure of meclizine dihydrochloride is used. Two racemic enantiomers (R/S) are found in the unit cell, which is packed as repetitive double layers in the crystal lattice. The packing is made of multiple strong N-H-Cl- hydrogen bonding interactions and weak interactions like C-H-Cl- and pi-stacking. Molecular docking reveals the binding mechanism of meclizine to the histamine H1 receptor. A comparison of the docking complexes between histamine H1 receptor and meclizine or levocetirizine (a second-generation antihistamine) shows the conserved binding sites. This research illustrates the combined use of MicroED and molecular docking in unraveling elusive drug structures and protein-drug interactions for precision drug design and optimization.

Intranasal corticosteroids reduced acute rhinosinusitis in children with allergic rhinitis: A nested case–control study

BackgroundChildren with allergic rhinitis (AR) have substantially more acute rhinosinusitis than children without AR. We evaluated whether intranasal corticosteroids (INCS), second-generation antihistamines (SGH), and/or intranasal antihistamines (INH) for AR affect acute rhinosinusitis in children with AR aged 2–18 years. MethodsBy using the National Health Research Institutes Database 2005 of Taiwan, a cohort of patients with AR aged 2–18 years treated with AR medications between 2002 and 2018 was made, within which a nested case–control study was performed. Risk settings for acute rhinosinusitis cases matched controls for age, sex, and comorbidities. Current users of INCS, INH, and/or SGH were compared with remote and recent users of any AR medications and current users of INCS with and without SGH were compared with current users of SGH. ResultsCurrent users of SGH and/or INCS had a higher risk of acute rhinosinusitis than remote users of AR drugs, and current users of SGH had a higher risk of acute rhinosinusitis than recent users; however, no difference in the risk of acute rhinosinusitis was found between current users of INCS and recent users of AR drugs. Current users of INCS with and without SGH had a lower risk of acute rhinosinusitis than current users of SGH alone. ConclusionsTreatment of INCS with and without SGH diminished the risk of acute rhinosinusitis compared with treatment using SGH alone. Adequate INCS treatment for patients with AR is important to reduce the incidence of acute rhinosinusitis.