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Background: For treating patients with refractory chronic spontaneous urticaria (CSU) resistant to standard doses of 2 nd generation H1-antihistamines (H1AH) the International and Japanese guidelines recommend increasing H1AH dose. The latter also recommends switching to a different H1AH. This study explored if the efficacy of the standard dose of bilastine 20 mg is non-inferior to that of double-dose of H1AH in patients with refractory CSU., Methods: This phase IV, multicenter, open-label, randomized, parallel-group trial evaluated the efficacy and safety of switching treatment to bilastine compared to treatment with a 2-fold dose of H1AH in patients with CSU refractory to standard dose H1AH. The primary endpoint was the mean total symptom score (TSS) at Day 5-7 after the start of administration., Results: Treatment efficacy and safety were evaluated in 128 patients (bilastine, n=64; 2-fold dose of H1AH, n=64). The mean TSS at Day 5-7 after the start of administration was smaller than the non-inferiority margin of 0.8, demonstrating non-inferiority of the bilastine switching group to the double-dose H1AH group (0.17 (95% CI -0.32, 0.67)). No difference in Japanese version of Epworth Sleepiness Scale (JESS), DLQI, and urticaria activity score over 7 consecutive days (UAS7) was observed between the two groups. There were no serious adverse events in either group. H1AH-related adverse events occurred in 5 subjects (8 cases) and 2 subjects (3 cases) in the double-dose H1AH and bilastine groups, respectively., Conclusions: Switching treatment to bilastine demonstrated non-inferiority to a double-dose of H1AH in terms of efficacy in patients with CSU refractory to standard dose H1AH with a favorable safety profile., Clinical Trial Registration: https://jrct.niph.go.jp/latest-detail/jRCTs051180105, identifier jRCTs051180105., Competing Interests: AF reports study grants and honoraria from Novartis and Taiho, and honoraria as a speaker from Sanofi, Kyowa Kirin, Kyorin, Mitsubishi-Tanabe, and Kaken Pharmaceutical. KM reports speaking fees from Sanofi, Eli Lilly Japan K.K. Maruho Co. Ltd, Mitsubishi Tanabe Pharma Corporation, and honoraria as an investigator of Eli Lilly Japan K.K. MJ reports study grants from Sanofi. KW reports speaking fee from Sanofi, Novartis, Eli Lilly, Pfizer, Kyowa Kirin, Otsuka Pharmaceutical, Mitsubishi-Tanabe, Kyorin, and Taiho. HA declares receiving consulting fees and speaker fees from Taiho. ST reports research grant from Sanofi, Maruho, Tanabe-Mitsubishi, Eli Lilly, Torii and Taiho Pharmaceutical, honorarium from Tanabe-Mitsubishi, Taiho Pharmaceutical, CSL Behring, Kaken, Maruho, Otsuka and Abbvie, advisory fees from Sanofi, and gift of a medication for a clinical study from Takeda. NIs reports study grants from Maruho. KH reports study grants and honoraria from Kaken Pharmaceutical, Kyowa Kirin, Meiji Seika Pharma, Mitsubishi-Tanabe, and Taiho, and honoraria as a speaker from Kyorin, and honoraria as a speaker and advisory fees from Novartis and Sanofi. NIn reports study grants and honoraria from Taiho, and honoraria as a speaker from Sanofi, Novartis, Kyowa Kirin, Mitsubishi-Tanabe, and Kaken Pharmaceutical. MH has received lecture and/or consultation fees from Kaken Pharmaceutical, Kyorin Pharmaceutical, Kyowa-Kirin, Mitsubishi Tanabe Pharma, Novartis, Sanofi/Regeneron, TAIHO Pharmaceutical, and Teikoku Seiyaku. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fukunaga, Kakei, Murakami, Kan, Masuda, Jinnin, Washio, Amano, Nagano, Yamamoto, Otsuka, Takahagi, Takenaka, Ishiguro, Hayama, Inomata, Nakagawa, Sugiyama and Hide.)

Purpose: The effects of first-generation antihistamines in preventing postoperative emergence agitation or delirium are unclear. Determining the postoperative effects of first-generation antihistamines may provide important insights into the management of patient safety. Therefore, we performed a systematic review of randomized controlled trials (RCTs) evaluating the efficacy and safety of postoperative first-generation antihistamines., Methods: Patients who used first-generation antihistamines in the intensive care unit or operating room were included. Primary outcomes were assessed postoperative emergence agitation or delirium with binary and continuous variables. The secondary outcome was any adverse event., Results: Nine studies were included. The frequency of postoperative emergence agitation, measured using binary variables, tended to be lower in patients receiving chlorpheniramine or diphenhydramine than those receiving saline. However, evaluation using the Richmond Agitation-Sedation Scale as a continuous variable revealed that only chlorpheniramine was effective at lowering postoperative emergence agitation. Only one study assessed delirium but found no benefit of first-generation antihistamines. Adverse events for first-generation antihistamines did not differ from that of other drugs., Conclusion: Our results provide limited evidence that some first-generation antihistamines may prevent postoperative emergence agitation and are safe. To further verify this possibility, new RCTs with clear and universal assessment criteria for postoperative emergence agitation or delirium should be conducted., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Chronic urticaria (CU) is a prevalent dermatologic disease that negatively affects life, current therapies remain suboptimal. Hence, there is an urgent need to identify effective and safe treatment., Objective: Assess the efficacy and safety of compound glycyrrhizin (CG) combined with second-generation nonsedated antihistamine for the treatment of CU., Methods: Nine databases were queried to screen RCTs related. Two reviewers independently assessed the risk of bias using Cochrane Collaboration. Primary objective was the total efficiency rate, while secondary was rate of recurrence, adverse events, and cure. Statistical analyses using Review Manager 5.4 and Stata17., Results: Twenty-four RCTs were identified. Significant differences were noted in rate of total efficiency ( n  = 2649, RR = 1.36, 95%CI:1.30-1.43, p  < 0.00001), cure ( n  = 2649, RR = 1.54, 95%CI:1.42-1.66, p  < 0.00001) and recurrence ( n  = 446, RR = 0.34, 95%CI:0.20-0.58, p  < 0.00001) between the combination of CG with second-generation non-sedated antihistamine and antihistamine monotherapy. Contrastingly, adverse events rate ( n  = 2317, RR = 0.76, 95% CI:0.59-0.97, p  = 0.03) was comparable between the two groups. Our results indicated that CG combined with second-generation non-sedated antihistamine could significantly mitigate the symptoms in CU compared with antihistamine monotherapy. No serious adverse events were reported., Conclusions: CG combined with second-generation nonsedated antihistamine is effective for CU. Nevertheless, higher-quality studies are warranted to validate our results.

Objectives: The objectives are to determine whether diphenhydramine coadministered with prochlorperazine versus prochlorperazine only is associated with a difference in the risk of migraine treatment failure, as measured by the need for additional therapy, hospitalization rates, and 72-hour return rates, and to compare extrapyramidal adverse effects between groups., Methods: Retrospective cohort of patients aged 7 to 18 years treated in the emergency department for migraines using prochlorperazine with or without diphenhydramine between 2013 and 2019. Patients were included if they had International Classification of Diseases, Ninth or Tenth Revision, codes for migraine or unspecified headache and were treated with prochlorperazine as part of their initial migraine therapy. Data collected included demographics, medications administered, pain scores, neuroimaging, disposition, return visits, and documentation of extrapyramidal adverse effects. Multivariable logistic regression was used to estimate the association between diphenhydramine coadministration and each of the outcomes., Results: A total of 1683 patients were included. Overall, 13% required additional therapy with a 16.7% admission rate and a 72-hour return rate of 5.3%. There was no association between initial treatment with diphenhydramine and the odds of additional therapy (adjusted odds ratio [aOR], 0.74 [95% confidence interval {CI}, 0.53-1.03]), admission rates (aOR, 1.22 [95% CI, 0.89-1.67]), or return visit rates (aOR, 0.91 [95% CI, 0.55-1.51]). Extrapyramidal adverse effects occurred in 2.4% of patients in the prochlorperazine group and 0% in the prochlorperazine with diphenhydramine group., Conclusions: There was no association between diphenhydramine coadministration and the need for additional therapy, 72-hour return visit rates or admission rates. Extrapyramidal effects did not occur in patients treated with diphenhydramine., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chronic spontaneous urticaria (CSU) is a relatively common skin disease associated with hives and angio-oedema. Eosinophils play a role in CSU pathogenesis. Benralizumab, an anti-interleukin-5 receptor-α monoclonal antibody, has been shown to induce nearly complete depletion of eosinophils., Objectives: To determine the clinical efficacy and safety of benralizumab in patients with CSU who were symptomatic despite H1 antihistamine treatment., Methods: The 24-week, randomized, double-blind, placebo-controlled, phase IIb portion of the ARROYO trial enrolled adult patients with CSU who were currently on H1 antihistamine treatment. Patients were randomized to one of five treatment groups according to benralizumab dose and regimen for a 24-week treatment period. The primary endpoint was change from baseline in Itch Severity Score (ISS)7 at week 12. The key secondary endpoint was change from baseline in Urticaria Activity Score (UAS)7 at week 12. Additional secondary endpoints included other metrics to assess CSU at week 24, blood eosinophil levels, and pharmacokinetics and immunogenicity assessments. Exploratory subgroup analyses were conducted to explore responses according to demographics, clinical features and biomarkers. Safety was assessed in all treatment groups., Results: Of 155 patients, 59 were randomized to benralizumab 30 mg, 56 to benralizumab 60 mg and 40 to placebo. Baseline and disease characteristics were consistent with what was expected for patients with CSU. There were no significant differences in change from baseline in ISS7 score at week 12 between benralizumab and placebo [benralizumab 30 mg vs. placebo, least-squares mean difference -1.01, 95% confidence interval (CI) -3.28 to 1.26; benralizumab 60 mg vs. placebo, least-squares mean difference -1.79, 95% CI -4.09 to 0.50] nor in change from baseline in UAS7 score at week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, P = 0.407; benralizumab 60 mg vs. placebo, P = 0.082). Depletion of blood eosinophil levels was observed at week 24 in patients treated with benralizumab. All other secondary endpoints and exploratory/subgroup analyses indicated no significant differences between benralizumab and placebo. Safety results were consistent with the known profile of benralizumab., Conclusions: Although benralizumab resulted in near-complete depletion of blood eosinophils, there was no clinical benefit over placebo., Competing Interests: Conflicts of interest S.A. is or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, BioCryst, Blueprint, CSL Behring, LEO Pharma, Moxie, Novartis, Pfizer, Pharvaris, Sanofi-Regeneron, Takeda and Thermo Fisher Scientific. A.M.G.-A. is or recently was a speaker and/or advisor for and/or has received research funding from Almirall, Amgen, AstraZeneca, Avene, Celldex, Escient Pharmaceuticals, Genentech, GlaxoSmithKline, Instituto Carlos III-FEDER, LEO Pharma, Menarini, Mitsubishi Tanabe Pharma, Novartis, Sanofi-Regeneron, Servier, Thermo Fisher Scientific and Uriach Pharma/Neucor. J.A.B. has been a consultant for Escient Pharmaceuticals, Jasper Therapeutics and Ono Pharmaceutical, and has been a principal investigator and consultant for Amgen, AstraZeneca, Celldex Therapeutics, Genentech, Novartis and Sanofi-Regeneron. M.M. has received honoraria as a speaker and/or consultant for AbbVie, Amgen, argenx, AstraZeneca, Bayer, Beiersdorf, Celldex, Escient Pharmaceuticals, Galderma, GlaxoSmithKline, Incyte, Jasper Therapeutics, Novartis, Pfizer, Pharvaris, Sanofi, Teva, Third Harmonic Bio and Vifor. L. Bahadori, M.B., L.Brooks, C.N.H., P.J., P.B.L., E.R.-S., C.W. and C.J.D. are or were employees of AstraZeneca at the time of the study and may own stock or stock options., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Hydroxyzine hydrochloride is a piperazine derivative antihistamine that is used in the treatment of anxiety. Its tendency to cause somnolence makes it an attractive option for patients with anxiety-induced insomnia. Despite its antihistamine activity, hydroxyzine is noted to have alpha-adrenergic antagonism activity. Other alpha-adrenergic inhibitors have been implicated in medication-induced priapism, including risperidone. Risperidone is a second-generation antipsychotic that primarily blocks serotonin and dopamine receptors, while also inhibiting alpha-1 and alpha-2 receptors with high affinity. Objective: We report a case of a first-of-its-kind case report of a patient who was stable on risperidone and presented with priapism after taking hydroxyzine nightly for the previous 10 days. Results: A 35-year-old male with a past psychiatric history of depression, generalized anxiety disorder, schizoaffective disorder, presented to the emergency department with priapism for 15 hours that required intracaveronsal phenylephrine hydrochloride and manual drainage to achieve detumescence. The patient was on a stable dose risperidone but reported taking hydroxyzine 50 mg nightly for anxiety and insomnia 10 days prior to emergency department admission. Upon resolution of the priapism, the patient stopped hydroxyzine, but continued risperidone. The patient had another prolonged erection 10 days after stopping hydroxyzine; however, he reported that it resolved spontaneously without intervention after 4 hours. Conclusion: This case report demonstrates the risk of addition of hydroxyzine to antipsychotics which can result in an increased risk of priapism or prolonged episodes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To investigate the in vivo efficacy of epinastine cream in type I allergic models. Methods: The dose, timing, and antiallergic effect of epinastine cream on the conjunctiva were evaluated postapplication to the eyelid skin of guinea pigs with histamine- or ovalbumin-induced allergic conjunctivitis. Additionally, we assessed its antiallergic effects on the skin postapplication to the dorsal skin of guinea pigs with ovalbumin-induced passive cutaneous anaphylaxis. Efficacy was estimated by determining the amount of dye that leaked from conjunctival or dorsal skin tissue vessels as a measure of vascular permeability, scoring the severity of allergic symptoms, and observing the scratching behaviors using clinical parameters. Results: In the histamine-induced conjunctivitis model, epinastine cream strongly inhibited conjunctival vascular permeability in a dose-dependent manner. The inhibitory effect of 0.5% epinastine cream 24 h postapplication was significantly higher than that of 0.1% epinastine hydrochloride ophthalmic solution 8 h postadministration. Additionally, the 0.5% epinastine cream inhibited conjunctival vascular permeability 15 min postapplication, and the effect was sustained over 24 h. Furthermore, the 0.5% epinastine cream effectively suppressed clinical symptom scores and exhibited ameliorated scratching bouts in conjunctival allergic reactions in the experimental allergic conjunctivitis model. Additionally, it significantly inhibited vascular permeability in skin allergic reactions in the passive cutaneous anaphylaxis model. Conclusions: The results suggest that epinastine cream is a strong, long-lasting, and skin-penetrating inhibitor of type I allergic reactions. The 0.5% epinastine cream applied once daily could be a promising, potent, and long-acting therapeutic agent for allergic conjunctivitis.

Chlorpheniramine Maleate (CPM), also known as chlorphenamine, is a potent alkylamine first-generation H1 antihistamine that has been used since the 1950s. CPM is a widely popular drug commonly used to treat allergic conditions, given its antihistamine properties. Although mainly used in over-the-counter treatment for cough and colds, various studies discuss a wide range of CPM's clinical uses, such as treating asthma, plasma cell gingivitis, chronic urticaria, and depression, among others. This antihistamine is usually taken orally; however, intravenous, intramuscular, and subcutaneous routes have been documented. Intranasal routes of this drug have recently been explored, especially due to its antiviral properties against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Accordingly, given CPM's extensive medical and safety profile, the present review explores this versatile drug's current and potential clinical applications. Although it is widely used mainly for treating common colds and aforementioned allergic conditions, CPM can be used for other clinical indications. The repurposing of CPM for other clinical indications, such as COVID-19, needs to be further explored through more extensive studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The purpose of this study is to (1) to determine if treatment of underlying allergic rhinitis (AR) in children will affect epistaxis outcome, (2) to compare efficacy of three outpatient AR treatment regimens in epistaxis outcomes, and (3) to investigate potential factors in the pathogenesis of epistaxis with underlying AR. A single-blind randomized-controlled study was conducted in the Otolaryngology clinic in KK Women's and Children's Hospital. Sixty children aged below 18 years with underlying untreated AR, with first presentation of epistaxis, were randomized to three different AR treatments: treatment 1, antihistamine (20 patients); treatment 2, nasal steroid spray (20 patients); and treatment 3, both antihistamine and nasal steroid spray (20 patients). Epistaxis severity and frequency were assessed. Pre-treatment, 95% of patients within each of the three treatment groups described epistaxis symptoms. Post-treatment, there was improvement in epistaxis outcome (resolution of epistaxis) with 20% (4/20), 40% (8/20), and 60% (12/20) of patients in treatment groups 1 (antihistamine), 2 (nasal steroid spray), and 3 (combined therapy) respectively, who reported resolution of epistaxis. Treatment regimens containing nasal steroid spray resulted in greater improvement of epistaxis severity and frequency. Combined therapy (treatment 3) resulted in the best epistaxis outcome at 1-month follow-up. Majority (90%) reported nose-picking/rubbing behavior., Conclusions: Intranasal corticosteroids are superior to oral antihistamines in relieving itch or rhinorrhea in AR. Intranasal corticosteroids may be important in treating epistaxis with underlying AR, because digital trauma from itch/rhinorrhea-related nose-picking/rubbing frequently leads to epistaxis. Results from this study will be important to primary and emergency physicians, community pediatricians, and pediatric allergists and otolaryngologists., What Is Known: • Childhood epistaxis commonly co-exists with allergic rhinitis (AR), causing significant symptoms and distress to patients. • There are currently no studies reporti ng on epistaxis outcome aft er treatment of underlying AR., What Is New: • This is a single-blind randomized-controlled study of 60 children aged below 18 years with underlying untreated AR, with first presentation of epistaxis to a children's hospital in Singapore Patients were randomized to three different regimens to treat AR: treatment 1, antihistamine; treatment 2, nasal steroid spray; and treatment 3, both antihistamine and nasal steroid spray. • Treatment regimens containing nasal steroid spray improved epistaxis outcomes, with combined therapy of antihistamine and nasal steroid spray resulting in the best outcome for resolution of epistaxis among the three treatment regimens., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The use of predictors of response to a specific treatment in patients with chronic spontaneous urticaria (CSU) can improve disease management, help prevent unnecessary healthcare costs, and save time. In this study, we aimed to identify predictors of complete response to standard-dosed and higher than standard-dosed antihistamine treatments in patients with CSU., Methods: Medical records of 475 CSU patients, 120 of them <18 years old, from 3 different centers were analyzed. We used 15 machine learning (ML) models as well as traditional statistical methods to predict complete response to standard-dosed and higher than standard-dosed antihistamine treatment based on 17 clinical parameters., Results: CSU disease activity, which was assessed by urticaria activity score (UAS), was the only clinical parameter that predicted complete response to standard-dosed and higher than standard-dosed antihistamine treatment, with ML models and traditional statistics, for all age groups. Based on ROC analyses, optimal cut-off values of disease activity to predict complete response were UAS <3 and UAS <4 for standard-dosed (area under the ROC curve [AUC] = 0.69; p = 0.001) and higher than standard-dosed (AUC = 0.79; p = 0.001) antihistamine treatments, respectively. Also, ML models identified lower total IgE (<150 IU/mL) as a predictor of complete response to a standard-dosed antihistamine and lower CRP (<3.4 mg/mL) as a predictor of complete response to higher than standard-dose antihistamine treatment., Discussion: In this study, we showed that patients with UAS <3 are highly likely to have complete response to standard-dosed AH and those with a UAS <4 are highly likely to have complete response to higher than standard-dosed AH treatment. Low CSU disease activity is the only universal predictor of complete response to AH treatment with both ML models and traditional statistics for all age groups., (© 2023 S. Karger AG, Basel.)

Background: Urticaria following the COVID-19 vaccine was rarely reported and had a short self-limited resolution. However, there has been relatively little literature published on CSU induced by COVID-19 vaccines., Purpose: We describe a case series of patients who experienced CSU after SARS-CoV-2 vaccination., Methods: A retrospective case series of 10 patients referred to the Department of Clinical Pharmacology of the University of Monastir (January 2021-January 2022) and included for evaluation of urticaria after COVID-19 vaccination., Results: The median age was 31 years and patients were mostly female. Atopy was presented in 3 patients and urticaria was accompanied by angioedema in 6 patients. The median time interval between vaccination and the onset of urticaria was 28.5 h. The offended dose was the first one in 8 patients. The resolution of the eruption was observed at least 2 months later, despite the regular use of a full dose of antihistamine in nine patients. Polynuclear leucocytosis was identified in 5 patients. Anti-TPOAb was positive in one patient after receiving the BNT162b2 vaccine. Total serum IgE was elevated in 4 patients. Skin tests for the suspected vaccine as well as the vaccine excipient were negative., Conclusion: We add to the medical literature ten new cases of chronic spontaneous urticarial reactions following COVID-19 vaccines uncontrolled with high-dose first-generation H1 antihistamines., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cetirizine, a second-generation antihistamine, and diphenhydramine, a first-generation antihistamine, are among the most widely used anti-allergic drugs. In addition to longer duration of action and less incidence of sedative side effects, recent clinical studies also indicate a higher potency of cetirizine than diphenhydramine in the treatment or prevention of allergic disorders. In the present study, using the differential-interference contrast (DIC) microscopy, we examined the effects of cetirizine and diphenhydramine (1 μM to 1 mM) on the degranulation from rat peritoneal mast cells. Using fluorescence imaging of a water-soluble dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. At relatively higher concentrations (100 μM, 1 mM), both cetirizine and diphenhydramine significantly reduced the numbers of degranulating mast cells. Of note, at 1 mM, cetirizine more markedly reduced the number than diphenhydramine, almost entirely suppressing the degranulation of mast cells. Additionally, 1 mM cetirizine and levocetirizine, another second-generation antihistamine, almost totally inhibited the process of exocytosis in mast cells and washed out the trapping of the lucifer yellow on the cell surface, while diphenhydramine and chlorpheniramine, another first-generation antihistamine, did not. This study provided in vitro evidence for the first time that cetirizine more potently inhibited the process of exocytosis in mast cells than diphenhydramine, indicating its higher potency as a mast cell-stabilizer. Such mast cell-stabilizing property of cetirizine could be ascribed to its counteracting effect on the plasma membrane deformation in degranulating mast cells.

Aims: The aim of this study is to investigate the rates of hypersensitivity reactions (HSRs) in patients receiving paclitaxel chemotherapy, with and without a histamine-2 (H 2 ) antagonists., Method: This prospective, multi-centre, cohort study compared patients receiving paclitaxel treated with premedication regimens containing chlorphenamine, dexamethasone and an H 2 antagonist vs patients treated without an H 2 antagonist. Rates of HSRs were described and logistic multivariable regression was used to investigate any associations with H 2 antagonist treatment, adjusting for confounding variables., Results: A total of 1043 individuals were included in the study; of these, 638 (61%) patients received an H 2 antagonist and 405 (49%) were not given an H 2 antagonist. Incidence of HSR in the cohort treated with H 2 antagonists was 11.31% (n = 70) vs 9.86% (n = 41) in the cohort without. There was no statistically significant difference between the rates of HSR observed in those receiving and not receiving an H 2 antagonist (odds ratio 1.04, 95% CI 0.65, 1.66, P = .9)., Conclusions: Results presented within the study are consistent with other recently published evidence to suggest that H 2 antagonists do not confer any advantage as part of premedication regimens in reducing the incidence of HSR in patients treated with paclitaxel., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: A standard dose of second-generation H1 -antihistamines is recommended as the first-line treatment of chronic spontaneous urticaria (CSU), previous studies have found that approximately 20-50% of CSU children fail to control their symptoms and required step-up treatments., Objective: To evaluate the predictors of uncontrolled symptoms with first-line medication and describe the treatment outcomes of CSU children in the southern region of Thailand., Methods: This retrospective chart review of CSU patients, aged 2-18 years, who were initially treated with the standard dose of second-generation H1 -antihistamine at the Pediatric Allergy Clinic, Songkhlanagarind Hospital, from January 2008 to July 2018. The data were collected at the initial visit (demographic data, onset of rash, frequency of urticaria, presence of angioedema, previous resolved CU, laboratory investigation results) and follow-up visits (treatment outcome, time to controlled urticaria)., Results: The medical records of 192 CSU children were reviewed; their median age were 8.5 years and the mean frequency of rash was 4 days/week. Forty-seven children (24.4%) fail to controlled symptoms with a standard dose of second -generation H1 -antihistamines and a factor significantly associated was frequency of rash for more than 4 days per week (OR = 4.36, P < 0.001). The median time to controlled urticaria was 1.28 months., Conclusions: Most of CSU children in the southern region of Thailand experienced controlled symptoms with a standard dose of second-generation H1 -antihistamines, and the frequency of urticaria for more than 4 days per week was a factor associated with uncontrolled symptoms that regimen.

The AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) study investigated outcomes in patients with chronic urticaria refractory to H1-antihistamine. The objective of the current study was to analyse the effects of treatment on patients' symptoms and quality of life for a period of up to 2 years. Over the 2 years, there was clear improvement in the high rates of disease burden from baseline, as evidenced by lower scores for disease severity scales, better quality of life, and a decreasing rate of medical resource utilization. However, this is the result of treatment adherence to the guidelines in highly specialized Scandinavian urticaria centres, and has its basis in the relatively low treatment intensity and control at enrolment. There is a need for greater adherence to the treatment guidelines and better management of antihistamine-refractory chronic urticaria.

Current data on use of antihistamines during breastfeeding and risks to the breastfed infant are insufficient. The aim of this systematic review was to provide an overview of studies measuring the levels of antihistamines in human breast milk, estimating the exposure for breastfed infants and/or reporting possible adverse effects on the breastfed infant. An additional aim was to review the antihistamine product labels available in the European Union (EU) and the United States. We searched seven online databases and identified seven human lactation studies that included 25 mother-infant pairs covering cetirizine, clemastine, ebastine, epinastine, loratadine, terfenadine and triprolidine. In addition, one study investigated the impact of chlorpheniramine or promethazine on prolactin levels among 17 women, and one study investigated possible adverse drug reactions in 85 breastfed infants exposed to various antihistamines. The relative infant dose was below 5% for all antihistamines, ranging from 0.3% for terfenadine to 4.5% for clemastine. Most product labels of the 10 antihistamines with available information in both the EU and the United States reported lack of evidence and recommended to avoid use during breastfeeding. The knowledge gap on antihistamines and lactation is extensive, and further human studies are warranted to ensure optimal treatment of breastfeeding women with allergy., (© 2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Since 1955, the only available H 1 antihistamines for intravenous administration have been first-generation formulations and, of those, only intravenously administered (IV) diphenhydramine is still approved in the USA. Orally administered cetirizine hydrochloride, a second-generation H 1 antihistamine, has been safely used over-the-counter for many years. In 2019, IV cetirizine was approved for the treatment of acute urticaria. In light of this approval, this narrative review discusses the changing landscape of IV antihistamines for the treatment of histamine-mediated conditions. Specifically, IV antihistamines will be discussed as a treatment option for acute urticaria and angioedema, as premedication to prevent infusion reactions related to anticancer agents and other biologics, and as an adjunct treatment for anaphylaxis and other allergic reactions. Before the development of IV cetirizine, randomized controlled trials of IV antihistamines for these indications were lacking. Three randomized controlled trials have been conducted with IV cetirizine versus IV diphenhydramine in the ambulatory care setting. A phase 3 trial of IV cetirizine 10 mg versus IV diphenhydramine 50 mg was conducted in 262 adults who presented to the urgent care/emergency department with acute urticaria requiring antihistamines. For the primary efficacy endpoint, defined as change from baseline in a 2-h patient-rated pruritus score, non-inferiority of IV cetirizine to IV diphenhydramine was demonstrated (score - 1.6 vs - 1.5, respectively; 95% CI - 0.1, 0.3). Compared with IV diphenhydramine, IV cetirizine demonstrated fewer adverse effects including less sedation, a significantly shorter length of stay in the treatment center, and fewer returns to the treatment center at 24 and 48 h. Similar findings were demonstrated in another phase 2 acute urticaria trial and in a phase 2 trial assessing IV cetirizine for pretreatment for infusion reactions in the oncology/immunology setting. IV cetirizine is associated with similar patient outcomes, fewer adverse effects, and increased treatment center efficiency than IV diphenhydramine., (© 2021. The Author(s).)

H 1 receptor antagonists, known as H 1 -antihistamines (AHs), inactivate the histamine H 1 -receptor thereby preventing histamine causing the primary symptoms of allergic diseases, such as atopic dermatitis, pollinosis, food allergies, and urticaria. AHs, which are classified into first-generation (fgAHs) and second-generation (sgAHs) antihistamines, are the first line of treatment for allergic diseases. Although fgAHs are effective, they cause adverse reactions such as potent sedating effects, including drowsiness, lassitude, and cognitive impairment; anticholinergic effects, including thirst and tachycardia. Consequently, the use of fgAHs is not recommended for allergic diseases. Today, sgAHs, which are minimally sedating and, therefore, may be used at more effective doses, are the first-line treatment for alleviating the symptoms of allergic diseases. Pharmacologically, the use of sedating fgAHs is limited to antiemetics, anti-motion sickness drugs, and antivertigo drugs. The use of histamine H 1 -receptor occupancy (H 1 RO) based on positron emission tomography (PET) has been developed for the evaluation of brain penetrability. Based on the results of the H 1 RO-PET studies, non-brain-penetrating AHs (nbpAHs) have recently been reclassified among sgAHs. The nbpAHs are rapidly acting and exhibit minimal adverse reactions and, thus, are considered first-line drugs for allergic diseases. In this review, we will introduce recent topics on the pharmacodynamics and pharmacokinetics of AHs and make recommendations for the use of nbpAHs as first-line treatment options for allergic diseases., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Bruton's tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35 ) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU., (© 2021. The Author(s).)

Aims: Antihistamines are routinely taken to control allergic reactions or sedation to induce sleep. There are, however, growing concerns regarding sedating antihistamine misuse. This research aims to evaluate deaths related to antihistamines in England occurring during 2000-2019., Methods: Cases reported to the National Programme on Substance Abuse Deaths from England occurring in 2000-2019 with antihistamine detections at postmortem were extracted for analysis., Results: In total, 1666 antihistamine postmortem detections were identified from 1537 cases. Sedating antihistamines available for purchase under pharmacist supervision but without need for a prescription (pharmacy-only medications) were present in a significant majority of cases (85.2%, P < .01). Despite an increasing trend for antihistamine-related deaths over time, the proportion of deaths where an antihistamine was implicated declined over the same period. Specific concerns with regards to the misuse of these pharmacy-only sedating antihistamines are raised with regards to the significant proportion of cases that were concluded as suicide (20.9%, P < .01), and the high prevalence of their use in combination with other central nervous system depressants (94.8% of cases)., Conclusion: This is the first report in over 40 years regarding antihistamine-related mortality from England. The rising trend in sedating antihistamine-related deaths may be contributed to by their increasing availability and the perceived negligible dangers associated with antihistamines, both from the general public and learned professionals. Awareness of the dangerous sedative properties that some antihistamines possess is, however, heightened in individuals deliberately seeking these effects. Urgent review of sedating antihistamines currently assigned under the pharmacy-only classification is needed to achieve antihistamine harm reduction., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Triprolidine, a first-generation antihistamine for allergic rhinitis, has a shorter half-life and fewer persistent effects relative to other antihistamines and may be useful in the treatment of temporary sleep disturbance. Patients aged ≥18 years old were randomized 1:1:1 to receive either triprolidine 2.5 mg (n = 65), triprolidine 5 mg (n = 66), or placebo (n = 67) on 3 consecutive nights. Sleep disturbance index was monitored via wrist actimeter. Subjective measures were assessed via diary card. Triprolidine 2.5 mg had a significantly lower sleep disturbance index versus placebo on night 1 (P = .02); however, when adjusted for outliers, sleep disturbance index did not significantly differ between either dose of triprolidine versus placebo on night 1. Adjusted sleep disturbance index was significantly lower with triprolidine 2.5 and 5 mg versus placebo on night 3 (P = .0017 and P = .011, respectively) and for the mean of all 3 nights (P = .01 and P = .015, respectively). Sleep latency was significantly improved for triprolidine 2.5 mg versus placebo on nights 2 and 3 and for the mean of all 3 nights and for triprolidine 5 mg versus placebo for the mean of all 3 nights. Subjective measures showed those on both doses of triprolidine felt more refreshed on awakening versus placebo for the mean of all 3 nights, with no increase in daytime sleepiness. The frequency of adverse events was similar across groups. The optimum dose of triprolidine for treatment of temporary sleep disturbance was 2.5 mg. There were improvements in both objective and subjective measures of sleep quality versus placebo, with no safety concerns raised., (© 2021, The American College of Clinical Pharmacology.)

Background: Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents., Objective: We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database., Methods: After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234)., Results: The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used., Conclusion: Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.

Allergic rhinitis (AR) is prevalent, and many patients present with moderate-to-severe symptomatic disease. The majority of patients are not satisfied with their AR treatment, despite the use of concurrent medications. These gaps underscore the need for treatment with more effective options for moderate-to-severe AR. The authors' objective was to review systematically the efficacy and safety of MP-AzeFlu for the treatment of AR. The primary outcomes studied were nasal, ocular, and total symptoms. Other outcomes included time to onset and of AR control, quality of life, and safety. Searches of PubMed and Cochrane databases were conducted on May 14, 2020, with no date restrictions, to identify publications reporting data on MP-AzeFlu. Clinical studies of any phase were included. Studies were excluded if they were not in English, were review articles, did not discuss the safety and efficacy of MP-AzeFlu for AR symptoms. Treatment of AR with MP-AzeFlu results in effective, sustained relief of nasal and ocular symptoms, and faster onset and time to control compared with intranasal azelastine or fluticasone propionate. Long-term use of MP-AzeFlu was safe, with benefits in children, adults, and adults aged ≥65 years. Other treatment options, including fluticasone propionate and azelastine alone or the combination of intranasal corticosteroids and oral antihistamine, do not provide the same level of efficacy as MP-AzeFlu in terms of rapid and sustained relief of the entire AR symptom complex. Furthermore, MP-AzeFlu significantly improves patient quality of life. MP-AzeFlu is a currently available combination that may satisfy all these patient needs and expectations., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background : This study aimed to measure the association of various H1-antihistamines (H1A) with Torsade de Pointes (TdP), and present a comprehensive overview of H1A-induced TdP cases reported to the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods : All H1A-induced TdP cases (n = 406) were retrieved from the FAERS database using the preferred term 'Torsade de Pointes' of MedDRA version-22 from 1990 to 2019. Four data-mining algorithms were used for disproportionality analysis: Reporting Odds Ratio (ROR); Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Content (IC). H1A with >3 TdP cases were included. Results : A total of 12 signals (Astemizole, cetirizine, chlorpheniramine, clemastine, desloratadine, diphenhydramine, hydroxyzine, loratadine, meclizine, promethazine, terfenadine, and trimeprazine) were identified including six new signals (cetirizine, chlorpheniramine, clemastine, desloratadine, loratadine, and meclizine). The number of risk factors (p = 0.031) and concomitant QT-prolonging drugs (p = <0.001) were significantly lower among new signals vs old signals. Moreover, new signals were strongly associated with QT-prolongation, cardiac reactions, and electrolyte abnormalities as compared with old signals. Conclusions : Our study found the increased torsadogenic potential of new signals compared with previously known old signals, hence necessitating clinical studies to determine the actual torsadogenic potential of newly identified signals.

Background: Real-world evidence describing the benefits of recommended therapies and their impact on the quality of life (QoL) of chronic urticaria (CU) patients is limited., Objective: To investigate disease burden, current treatment schedule, and the use of clinical resources by patients with H 1 -antihistamine-refractory CU in Europe., Methods: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global, prospective, non-interventional study in the real-world setting, sponsored by the manufacturer of omalizumab. Disease characteristics, pharmacological treatments, and health-related QoL of patients (N = 2727) ≥18 years of age diagnosed with H 1 -antihistamine-refractory chronic spontaneous urticaria (without inducible urticaria) for >2 months are reported here., Results: Of the 2727 patients included, 1232 (45.2%) and 1278 (46.9%) were successfully followed up for any assessment and for the key outcome, the urticaria control test (UCT) score, respectively, and patients with complete remission (14.1%) were excluded from analyses.The proportion of patients with uncontrolled CSU (UCT score <12) dropped from 78% (n/N = 1641/2104) at baseline to 28.7% (n/N = 269/936) after two years of participation in the AWARE study. In addition, the proportion of patients with no impact of CSU on their QoL (assessed by the Dermatological Life Quality Index) increased to 57% (n/N = 664/1164) from 18.7% (n/N = 491/2621) at baseline. Emergency room visits (2.4% [n/N = 7/296] vs 33.5% [n/N = 779/2322]) and hospital stays (1.7% [n/N = 5/296] vs 24.2% [n/N = 561/2322]) reduced at Month 24 vs baseline. Overall, 23.2% (n/N = 26/112) patients on non-sedating H 1 -antihistamines (nsAH) and 41.9% (n/N = 44/105) patients on up-dosed nsAH had uncontrolled CSU (UCT <12) at Month 24. In omalizumab-treated patients, 27.1% (n/N = 78/288) had uncontrolled CSU at Month 24., Conclusion: These data confirm improvements for most patients with CSU over a 2-year follow-up period. Further studies are needed to understand the differences between guideline recommendations and reported management., (© 2020 John Wiley & Sons Ltd.)

Antihistamines have been in clinical use for more than 70 years to treat allergic and nonallergic symptoms including relief from cold and flu symptoms. Despite their widespread use, pharmacokinetic (PK) data are sparse for older, first-generation antihistamines. This phase 1 single-center open-label, randomized, single-dose, 3-way crossover trial evaluated the PK profiles of 2 doses of film-coated triprolidine caplets (2.5 and 5 mg) compared with a reference combination tablet (triprolidine 2.5 mg + pseudoephedrine 60 mg) in 24 healthy adults. Blood samples were collected predose and at specified intervals across a 24-hour period after administration, and triprolidine was quantified using liquid chromatography-tandem mass spectrometry. Maximum plasma concentration of triprolidine for the 2.5 mg and dose-normalized 5 mg single-agent tablets were comparable (8.4 versus 7.1 ng/mL, respectively) and higher for the combination tablet (9.5 ng/mL). PK parameters, including time to maximum plasma concentration (∼1.5 hours) and elimination half-life (∼4 hours), were comparable between the 3 treatment arms. The safety profile of this sedating antihistamine was as expected; however, adverse effects were reported in a markedly higher proportion of women than men. There were no significant sex differences in any of the measured PK parameters., (© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: Chronic spontaneous urticaria (CSU) is characterized by the spontaneous appearance of wheals, angioedema, or both for > 6 weeks. Continuous treatment with H1-antihistamines is used as a first-line treatment for CSU. However, H1-antihistamine treatment leads to absence of symptoms in less than 50% of patients with CSU. Although Japanese guidelines for the diagnosis and treatment of urticaria recommend an increase in the H1-antihistamine dose or a switch to other H1-antihistamines, there is no evidence supporting a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose., Methods: We will conduct a multicenter, open-label, non-inferiority, randomized, parallel, comparison study to determine if the efficacy of bilastine 20 mg is not inferior to that of a twofold H1-antihistamine dose increase in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. This study will be performed at 15 academic hospitals in Japan, and the administration period (increasing the H1-antihistamine dose twofold vs. switching to bilastine 20 mg) will be 7 days. Participants (n = 150) will be randomized to either an increased H1-antihistamine dose or a switch to bilastine 20 mg at a 1:1 ratio. The primary endpoint, mean of the total symptom score of 5-7 days after the intervention, will be evaluated. The secondary objective is to determine if the safety of bilastine 20 mg regarding somnolence is superior to that of a twofold dose increase of H1-antihistamines. This will be measured by a change in the Japanese version of the Epworth Sleepiness Scale from baseline to 7 days after starting the intervention., Discussion: This multicenter, open-label, non-inferiority, randomized, parallel, comparison study will be, to our knowledge, the first well-designed clinical study to evaluate the efficacy of a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed doses. This trial will provide evidence of the efficacy and safety of bilastine when treatment is switched in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose., Trial Registration: Japan Registry of Clinical Trials (jRCT), jRCTs051180105. Registered on 8 March 2019.

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H 1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H 1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA 2 LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H 1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H 1 antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K + channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism., (© 2019 John Wiley & Sons Ltd.)

Rationale: Anaphylaxis is a serious allergic reaction which could be life-threatening. To date, it could be diagnosed by causality between clinical manifestations and triggers. But it is not always easy to find out the clue. Chlorpheniramine maleate (peniramin) is known to safe and it is an antihistamine commonly used to treat almost the whole allergic disease, including urticaria and allergic rhinitis. We recently experienced 2 cases of chlorpheniramine induced anaphylaxis. To document suspected cases of chlorpheniramine-induced adverse reactions, we analyzed a database spontaneously reported adverse drug reactions in the Ajou Regional Pharmacovigilance Center from 2011 to 2017., Patient Concerns: Two female patients presented urticaria and abdominal pain right after chlorpheniramine injection., Diagnoses: Both patients were diagnosed with symptoms. One patient confirmed by assistance with tryptase level and another one confirmed cross-reactivity by skin tests., Interventions: One patient was instructed to avoid future administration of chlorpheniramine. The other patient was advised not to take chlorpheniramine, and piperazine derivatives including cetirizine/levocetirizine, but piperidine derivatives such as fexofenadine, loratadine, and ebastine can be available., Outcomes: The patients fully recovered after prompt treatment for anaphylaxis. After that, no recurrences were observed at the following. Among 54 patients with chlorpheniramine-induced adverse drug reactions from the Pharmacovigilance Center database, 17 (31.5%) were reported as anaphylaxis., Lessons: Physicians should be aware chlorpheniramine could be a cause for allergic reaction. In addition, we suggest that serum tryptase level, skin prick test, and intradermal test could be considered as a supplementary test for diagnosing chlorpheniramine anaphylaxis and cross-reactivity should also be considered.

Rationale: Promethazine is an antihistamine agent used commonly for nausea and allergy. Along with its anticholinergic and antidopaminergic functions, promethazine is also used for psychiatric symptoms, such as troubling sleep, anxiety, and agitation. Previous studies have reported that promethazine may occasionally elicit acute dystonia in some individuals, especially for young children and pregnant women., Patient Concerns: The 68-year-old female patient was admitted to our hospital because of feeling anxious and intermittent palpitation for over 1 year. She developed acute orofacial dystonia following promethazine treatment., Diagnoses: Her diagnoses was generalized anxiety disorder., Interventions: Discontinuation of the offending agent, promethazine, and injection of Botulinum toxin., Outcomes: The acute orofacial dystonia was finally alleviated by local injection of Botulinum toxin., Lessons: Careful assessment of the risk of developing acute dystonia is also needed in old patients when initiating the promethazine treatment.

Background: To report the first case of allergic contact dermatitis (ACD) associated with alcaftadine 0.25% ophthalmic solution., Case Presentation: The patient was a 51-year-old woman with no previous history of side effects to ophthalmic antihistamine agents. She had been prescribed alcaftadine 0.25% for allergic conjunctivitis. On first application of the medication, she did not experience any cutaneous reaction. One day later, after the second alcaftadine 0.25% application, both eyelids became swollen, and erythematous changes were evident. On slit-lamp examination, conjunctival injection was noted in the absence of conjunctival swelling or any other findings. Fundus examination was unremarkable. To evaluate the cause of ACD, a patch test was performed and 48 h later was noted to be positive for alcaftadine 0.25%. Based on the positive patch test, the patient was diagnosed with ACD caused by alcaftadine 0.25%. After 9 days of treatment, the swelling and erythema completely resolved., Conclusions: Although there have been no previous reports of alcaftadine 0.25%-associated ACD, it should be suspected in patients with swelling and erythematous change of both eyes after using alcaftadine 0.25%.

BACKGROUND Diphenhydramine is a commonly available over-the-counter antihistamine; however, there are few documented cases of treatment when ingested in toxic quantities, where it can cause a sodium channel blockade leading to wide-complex tachycardia, seizures, and death. Conventional treatment includes sodium bicarbonate infusion, but few cases have documented the addition of lipid emulsion therapy. CASE REPORT A 24-year-old African American female ingested 18 g (360 pills of 50 mg) over-the-counter diphenhydramine. She presented comatose, with hemodynamic instability and hypotension, intubated with pupil dilation to 6 to 7 mm, and initial electrocardiography findings showing a type 1 AV block with a QT/QTc of 360/402 ms which progressed into sinus tachycardia with widened QRS intervals of 134 ms and prolonged QT/QTc intervals of up to 638/759 ms. Treatment using sodium bicarbonate and magnesium was initiated; however, the intraventricular conduction delay persisted. Infusion of 20% intravenous lipid emulsion was administered; following this, the patient developed narrow complex QRS with sinus rhythm and shortened the QT/QTc interval to 448/516 ms. She recovered quickly and was transferred to inpatient psychiatric unit for further evaluation, and discharged 1 month later. CONCLUSIONS Lipid emulsion therapy has been utilized in treatment of various medication overdoses, but there are few documented cases in the treatment of diphenhydramine overdose. With the amount of diphenhydramine ingested by the patient in this case report, the use of combined conventional and lipid emulsion therapy was utilized in the stabilization and management of the patient, and should be considered in scenarios where conventional treatments have not improved the clinical outcome.

Background: The symptoms of eczema can lead to sleeplessness and fatigue and may have a substantial impact on quality of life. Use of oral H1 antihistamines (H1 AH) as adjuvant therapy alongside topical agents is based on the idea that combining the anti-inflammatory effects of topical treatments with the blocking action of histamine on its receptors in the skin by H1 AH (to reduce the principal symptom of itch) might magnify or intensify the effect of treatment. Also, it would be unethical to compare oral H1 AH alone versus no treatment, as topical treatment is the standard management for this condition., Objectives: To assess the effects of oral H1 antihistamines as 'add-on' therapy to topical treatment in adults and children with eczema., Search Methods: We searched the following databases up to May 2018: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and the GREAT database (Global Resource of EczemA Trials; from inception). We searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). We also searched the abstracts of four conference proceedings held between 2000 and 2018., Selection Criteria: We sought RCTs assessing oral H1 AH as 'add-on' therapy to topical treatment for people with eczema compared with topical treatment plus placebo or no additional treatment as add-on therapy., Data Collection and Analysis: We used standard Cochrane methodological procedures. Primary outcome measures were 'Mean change in patient-assessed symptoms of eczema' and 'Proportion of participants reporting adverse effects and serious adverse events'. Secondary outcomes were 'Mean change in physician-assessed clinical signs', 'Mean change in quality of life', and 'Number of eczema flares'., Main Results: We included 25 studies (3285 randomised participants). Seventeen studies included 1344 adults, and eight studies included 1941 children. Most studies failed to report eczema severity at baseline, but they were conducted in secondary care settings, so it is likely that they recruited patients with more severe cases of eczema. Trial duration was between three days and 18 months. Researchers studied 13 different H1 AH treatments. We could not undertake pooling because of the high level of diversity across studies in terms of duration and dose of intervention, concomitant topical therapy, and outcome assessment. Risk of bias was generally unclear, but five studies had high risk of bias in one domain (attrition, selection, or reporting bias). Only one study measured quality of life, but these results were insufficient for statistical analysis.Although this review assessed 17 comparisons, we summarise here the results of three key comparisons in this review.Cetirizine versus placeboOne study compared cetirizine 0.5 mg/kg/d against placebo over 18 months in 795 children. Study authors did not report patient-assessed symptoms of eczema separately for pruritus. Cetirizine is probably associated with fewer adverse events (mainly mild) (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.46 to 1.01) and the need for slightly less additional H1 AH use as an indication of eczema flare rate (P = 0.035; no further numerical data given). Physician-assessed clinical signs (SCORing Atopic Dermatitis index (SCORAD)) were reduced in both groups, but the difference between groups was reported as non-significant (no P value given). Evidence for this comparison was of moderate quality.One study assessed cetirizine 10 mg/d against placebo over four weeks in 84 adults. Results show no evidence of differences between groups in patient-assessed symptoms of eczema (pruritus measured as part of SCORAD; no numerical data given), numbers of adverse events (RR 1.11, 95% CI 0.50 to 2.45; mainly sedation, other skin-related problems, respiratory symptoms, or headache), or physician-assessed changes in clinical signs, amount of local rescue therapy required, or number of applications as an indicator of eczema flares (no numerical data reported). Evidence for this comparison was of low quality.Fexofenadine versus placeboCompared with placebo, fexofenadine 120 mg/d taken in adults over one week (one study) probably leads to a small reduction in patient-assessed symptoms of pruritus on a scale of 0 to 8 (mean difference (MD) -0.25, 95% CI -0.43 to -0.07; n = 400) and a greater reduction in the ratio of physician-assessed pruritus area to whole body surface area (P = 0.007; no further numerical data given); however, these reductions may not be clinically meaningful. Results suggest probably little or no difference in adverse events (mostly somnolence and headache) (RR 1.05, 95% CI 0.74 to 1.50; n = 411) nor in the amount of 0.1% hydrocortisone butyrate used (co-intervention in both groups) as an indicator of eczema flare, but no numerical data were given. Evidence for this comparison was of moderate quality.Loratadine versus placeboA study of 28 adults compared loratadine 10 mg/d taken over 4 weeks versus placebo. Researchers found no evidence of differences between groups in patient-assessed pruritus, measured by a 100-point visual analogue scale (MD -2.30, 95% CI -20.27 to 15.67); reduction in physician-assessed clinical signs (SCORAD) (MD -4.10, 95% CI -13.22 to 5.02); or adverse events. Study authors reported only one side effect (folliculitis with placebo) (RR 0.25, 95% CI 0.01 to 5.76). Evidence for this comparison was of low quality. Number of eczema flares was not measured for this comparison., Authors' Conclusions: Based on the main comparisons, we did not find consistent evidence that H1 AH treatments are effective as 'add-on' therapy for eczema when compared to placebo; evidence for this comparison was of low and moderate quality. However, fexofenadine probably leads to a small improvement in patient-assessed pruritus, with probably no significant difference in the amount of treatment used to prevent eczema flares. Cetirizine was no better than placebo in terms of physician-assessed clinical signs nor patient-assessed symptoms, and we found no evidence that loratadine was more beneficial than placebo, although all interventions seem safe.The quality of evidence was limited because of poor study design and imprecise results. Future researchers should clearly define the condition (course and severity) and clearly report their methods, especially participant selection and randomisation; baseline characteristics; and outcomes (based on the Harmonising Outcome Measures in Eczema initiative).

Objective: Evaluate effects of a multisymptom tablet on cold and flu symptoms within 4 hours post-administration., Materials and Methods: This was a randomized, double-blind, placebo-controlled study in adults with cold and flu symptoms. Eligible participants with at least moderate common cold or flu symptoms and symptom onset ≤ 48 hours before screening were assigned to a single multiple-active-ingredient tablet (containing paracetamol, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate) or placebo tablet. Participants rated severity of each symptom (sore throat, headache, extremity pain, nasal congestion, sneezing, runny nose, and cough) from 0 (absent) to 3 (severe) at 15 and 30 minutes and 1, 2, 3, and 4 hours post administration. The total symptom score (TSS) was calculated as the sum of the individual symptom scores (primary endpoint). Participants rated global response to treatment on a scale from 0 (ineffective) to 4 (excellent). Adverse events (AEs) were recorded throughout., Results: Of 53 participants randomized, 52 received active tablet (n = 25) or placebo tablet (n = 27). Change from baseline in TSS throughout the 4-hour post-administration period was similar between groups. An efficacy criterion of 30% decrease in TSS at assessment points was not met (range, -1.91 to 8.94%). There were also no significant differences between groups in mean symptom scores for individual symptoms or global response to treatment. Four non-serious treatment-emergent adverse events occurred., Conclusion: In this exploratory pilot study, a multisymptom cold and flu tablet was well tolerated but did not differ from placebo tablet with regard to onset of action following a single dose.
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Aims: Recent data suggest that antidepressants are associated with incident diabetes but the possible pharmacological mechanism is still questioned. The aim of the present study was to evaluate antidepressant's risk for reporting diabetes using disproportionality analysis of the FDA adverse events spontaneous reporting system (FAERS) database and to investigate possible receptor/transporter mechanisms involved., Methods: Data from 2004 to 2017 were analysed using OpenVigil2 and adjusted reporting odds ratio (aROR) for reporting diabetes was calculated for 22 antidepressants. Events included in the narrow scope of the SMQ 'hyperglycaemia/new-onset diabetes mellitus' were defined as cases and all the other events as non-cases. The pharmacodynamic profile was extracted using the PDSP and IUPHAR/BPS databases and the occupancy on receptors (serotonin, alpha adrenoreceptors, dopamine, muscarinic, histamine) and transporters (SERT, NET, DAT) was estimated. The relationship between aROR for diabetes and receptor occupancy was investigated with Pearson's correlation coefficient (r) and univariate linear regression., Results: Six antidepressants were associated with diabetes: nortriptyline with aROR [95% CI] of 2.01 [1.41-2.87], doxepin 1.97 [1.31-2.97], imipramine 1.82 [1.09-3.06], sertraline 1.47 [1.29-1.68], mirtazapine 1.33 [1.04-1.69] and amitriptyline 1.31 [1.09-1.59]. Strong positive correlation coefficients between occupancy and aROR for diabetes were identified for the receptors M 1 , M 3 , M 4 , M 5 and H 1 ., Conclusion: Most of the tricyclic antidepressants, mirtazapine and sertraline seem to be associated with reporting diabetes in FAERS. Higher degrees of occupancy on muscarinic receptors and H 1 may be a plausible pharmacological mechanism. Further clinical assessment and pharmacovigilance data is needed to validate this potential safety signal., (© 2018 The British Pharmacological Society.)

Background: The purpose of this study was to elucidate whether H1 antihistamine administration increases susceptibility to febrile convulsions in children., Methods: A single-center, retrospective observational study was conducted in Japan. The study included 380 children with febrile convulsions between the ages of six months and five years transported via ambulance from 2011 through 2016. They were divided into the preseizure H1 antagonist "use group" and the "nonuse group." The former consisted of children who took H1 antagonists within 24 hours before the seizure onset. The primary outcome (seizure duration) and the secondary outcome (interval from fever to seizure onset) were compared between the two groups., Results: Of the 380 study patients, 70 (18%) were identified as the use group. None of the patients was taking excessive doses of H1 antagonists. The prevalence of seizures lasting 15 minutes or longer was not different between the use group and the nonuse group (11% versus 8%, prevalence ratio 1.47 [95% confidence interval, 0.63 to 3.42], P = 0.37). The prevalence of fever to seizure onset less than six hours was significantly lower in the use group (26% versus 52%, prevalence ratio 0.33 [95% confidence interval 0.19 to 0.60], P < 0.001). Similar results were obtained when analyses were conducted separately by different generations (first and second) of H1 antagonists., Conclusions: Prolonged seizure duration and shortened interval from fever to seizure were not observed in children who received H1 antagonists. This study provides evidence that H1 antagonists at optimal doses could be safely used in febrile children with allergic symptoms., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fixed drug eruption is a delayed type hypersensitivity reaction to a drug seen most frequently with antibiotics such as tetracyclines, sulfonamides, and NSAIDs such as naproxen and ibuprofen. Although H1-antihistamines rarely elicit cutaneous adverse effects, there have been a few reports in the literature implicating them in causing fixed drug eruption, particularly the piperazine derivatives (hydroxyzine, cetirizine, levocetirizine), and loratadine. However, cutaneous drug reactions with the alkylamine derivatives like pheniramine maleate are extremely uncommon and fixed drug eruptions have not been reported with any of the alkylamine antihistamines to date. We herein report a case of multifocal bullous fixed drug eruption following ingestion of pheniramine maleate.

Most of the rare bilateral acute angle closure (AAC) cases are precipitated by systemic factors, such as drug intake, snake bite or general anaesthesia. We present a case of simultaneous bilateral AAC in a middle-aged male, precipitated by the use of medication for flu, containing an alpha-1 adrenergic receptor agonist and an anticholinergic agent. In our case, axial length was shorter, anterior chamber depth was narrower, and the lens was thicker than normal, including the patient within the risk group for AAC. In this circumstance, drugs acted as triggers. Case description and evolution following treatment are completed with the discussion of mechanisms involved in triggering bilateral AAC in predisposed patients, as emerging from literature. This case report brings up the risk of bilateral AAC in patients at risk, of which ophthalmologists, physicians of other specialties and patients should be aware of.

Background: Uremic pruritus is a common symptom in chronic renal failure patients with undefined pathophysiology. Initial treatment involves topical therapy mainly in the form of moisturizers, however, in many cases, this is not sufficient to relieve itching. Systemic adjuvant therapy is therefore necessary, which commonly includes oral antihistamines, with limited success. Positive effects have been reported for gabapentin., Objectives: To evaluate the efficacy and safety of gabapentin vs. dexchlorpheniramine in reducing uremic pruritus., Materials & Methods: A randomized, controlled, double-blinded clinical trial for haemodialysis patients with persistent pruritus was performed. Pre-randomisation, cold cream was used for 15 days by 71 participants. Those with pruritus who remained in the study (60 patients) were randomised to receive gabapentin (30 patients; GABA group) or dexchlorpheniramine (30 patients; DEX group) for 21 days. The primary outcome was the decrease in pruritus score and improvement in quality of life., Results: After cold cream use, the participants demonstrated a 37.5% median reduction in Visual Analogue Scale (p<0.01) and a 50% reduction in Quality of Life in Dermatology (DLQI) score (p<0.01). There was an additional reduction of pruritus in both groups (p<0.01), with no difference between the two (p>0.7). The median DLQI was reduced from 2 to 1 in the GABA group and from 2 to 0 in the DEX group. Nineteen patients (32%) reported mild/moderate side effects without differences between the groups., Conclusions: Uremic pruritus was reduced upon treatment with gabapentin or dexchlorpheniramine with good safety profiles; no difference was observed between the two treatments.

Chronic spontaneous urticaria (CSU) is characterized by heterogeneous activity, evolution, associated comorbidities and response to treatment. The aim of this study was to identify prognostic factors in patients with CSU that predict disease course and response to standard treatments. An observational retrospective study was conducted in a cohort of 549 patients with CSU, comparing patients with isolated CSU and those with CSU with concomitant inducible urticaria (CSU-CIndU). The factors associated with a worse prognosis in terms of duration and/or CSU activity and its episodes were: multiple episodes of CSU (19.2% had more than one lifetime episode of CSU), late-onset (63.6% of patients developed first onset of CSU after the age of 45 years), concomitant CIndU (20.2%) and functional serum autoreactivity. Patients with CSU-CIndU required more frequent therapy after 5 years and higher doses of 2nd-generation H1-antihistamines. Of patients with a baseline Urticaria Activity Score 7 (UAS7) between 16 and 42, 84.6% required cyclosporine or omalizumab to achieve symptom control, compared with 15.4% of patients with a baseline UAS7 between 0 and 15 (p?=?0.0013). Baseline CSU activity is the only factor found to be predictive for refractoriness to treatment with H1-antihistamines.

Introduction: Doxylamine tablets are approved as an over-the-counter sleep aid. We developed a doxylamine succinate intranasal metered-dose delivery system with the expectation of a more rapid onset of action with reduced side-effect potential compared with the oral tablet., Methods: This phase I study randomized 24 adults with chronic intermittent sleep impairment to receive either single doses of intranasal doxylamine succinate 3.2, 6.3, or 12.7 mg or doxylamine succinate 25-mg oral tablet. Doxylamine pharmacokinetics were assessed using noncompartmental methods; pharmacodynamics were evaluated using the Karolinska Sleepiness Scale (KSS) and numerous psychomotor tests. Adverse events (AEs) were monitored., Results: None of the intranasal dose levels produced a mean maximum plasma concentration (C max ) above the 50 ng/mL target level or a time to maximum concentration shorter than that of the oral tablet. At the highest intranasal dose, C max and area under the doxylamine concentration-time curve were approximately 25% of the values achieved with the oral dose. Variation in most pharmacokinetic parameters was higher with intranasal compared with oral dosing. A relationship between plasma doxylamine concentration and KSS change from baseline was evident for the 25-mg tablet and, to a lesser extent, for the 12.7-mg intranasal dose. Changes from baseline in psychomotor parameters did not show a relationship to intranasal dose, and did not distinguish between intranasal versus oral dosing. The most common AEs with intranasal dosing were nasal congestion, nasal dryness, and frontal headache., Conclusion: The nasal spray did not increase doxylamine absorption or systemic bioavailability compared with the oral tablet.

Introduction: Allergic rhinitis is a prevalent condition warranting special aeromedical consideration due to its potential for acute and painful manifestations involving the middle ear or paranasal sinuses during rapid barometric pressure changes. Although second generation antihistamines and intranasal steroids are safe and effective treatments for this common condition, aeromedical management varies., Methods: An aeromedical policy review of 14 public access civil and military data repositories was undertaken. Policy within a convenience sample of nine countries (Australia, Canada, Croatia, France, New Zealand, Norway, Sweden, United Kingdom, and United States) was further ascertained through subject matter expert consultation. A convenience sample of recent primary care review articles and ENT guidelines were reviewed in order to substantiate the evidence basis for aeromedical practices., Results: Policies range from disqualification of flight applicants with any history of allergic rhinitis to the authorization of short-term, select undeclared medication use for the management of mild symptoms, with military authorities applying a more conservative approach. A range of intranasal and oral therapies are approved and requirements for waiver vary across most authorities., Discussion: Variation in practices must be considered when managing flight crews as part of military coalition peacetime and combat operations, as well as for international civil aviation missions conducted in support of natural disaster relief, rescue, and other stability efforts. Standardization of approved therapies for allergic rhinitis could be a useful starting point for the harmonization of aeromedical global policies in the future. Beneficial national specific policy updates may be undertaken on the basis of international experience.Powell-Dunford N, Reese C, Bushby A, Munkeby BH, Coste S, Pezer VL, Rosenkvist L. The aeromedical management of allergic rhinitis. Aerosp Med Hum Perform. 2018; 89(5):453-463.

Previous studies demonstrated that both diabetes and flunarizine use can increase the risk of parkinsonism. The aim of the current study was to investigate the risk of developing parkinsonism after flunarizine treatment, in a cohort of patients newly diagnosed with type 2 diabetes. We conducted a nested case-control study of a type 2 diabetic cohort from the Taiwan Longitudinal Health Insurance Database 2005 (LHID 2005). Each incident case of parkinsonism, during the period from 2001 to 2013, was randomly matched with 3-10 controls, according to age, sex, calendar year of cohort entry, and the duration of follow-up. Conditional logistic regression was used to estimate the odds ratio (OR) of parkinsonism associated with flunarizine use. The cohort consisted of 44,644 patients with newly diagnosed type 2 diabetes from 2001 to 2013, of whom 464 patients had a parkinsonism event during the follow-up period. The adjusted OR of parkinsonism with relation to flunarizine use was 2.75 (95% confidence interval: 2.26-3.36). There were also duration- and dose-response effects. Compared to those who had not used it, the OR for developing parkinsonism was 1.77 for patients who used flunarizine for less than 1 month. When the exposure period expanded over 3 months, the OR increased to 7.03. Our findings suggested that flunarizine use is a potential risk factor for parkinsonism in patients with newly diagnosed type 2 diabetes, especially when the drug is persistently used for over 3 months., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Percutaneous allergen skin testing remains an established benchmark for diagnosing atopic disease. The reliability of skin testing depends greatly on the performance of allergen extracts used, methods used, and the presence of antihistamine medications., Objective: To determine the differential effect of cetirizine on 2 different concentrations of histamine control solution and 5 common allergens used for percutaneous skin testing., Methods: Twelve individuals underwent skin testing with histamine (1 and 6 mg/mL), control diluent, and 5 common aeroallergens. Wheal and flare measurements were measured in a masked fashion by a single operator. Cetirizine was administered for 4 consecutive days to determine the effect on both histamine and allergen wheal and flare responses., Results: A total of 384 skin tests were performed on 12 volunteers. Cetirizine began to suppress wheal and flare responses at 1 hour (P < .05), with maximum suppression at day 5 (P < .05). Wheal and flare responses returned to greater than 90% baseline within 4 days of not taking cetirizine. Suppression was more apparent with 1 vs 6 mg/mL of histamine (62% vs 33%). Four of the 12 individuals taking cetirizine had a positive skin test result using 6 mg/mL of histamine control when the 1-mg/mL histamine test result was negative. Importantly, twice as many individuals had false-negative allergen responses using 6 mg/mL of histamine vs the 1 mg/mL as a positive control, although this finding did not reach statistical significance., Conclusion: The use of a 6-mg/mL histamine control for some percutaneous skin test devices may result in more false-negative allergen responses because of the inability to detect the presence of antihistamines., (Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)