[Antihistamines : An ongoing narrative]. / Antihistaminiques : une histoire sans fin.

Histamine is responsible for many processes mediated by different receptors expressed on a variety of cells. The discovery of the first H1 antihistamines in the 1940s led to the development of numerous H1 and H2 antagonists with a broad application in many indications. The recent identification of two new histamine receptors (H3, H4) in the 1980s and 2000s led to the market authorization in Switzerland of new drugs since 2018. The purpose of this review is to provide a brief overview of the physiology of histamine, the recent development of new compounds in this field, antihistamine drug indications and relevant side effects.

L'histamine possède de nombreuses propriétés physiologiques, tant centrales que périphériques, via son action sur différents récepteurs. La découverte des premiers antihistaminiques H1 dans les années 1940 stimula le développement de nombreux autres antagonistes H1, puis H2, utilisés dans diverses spécialités médicales. L'identification plus récente de deux récepteurs à l'histamine (H3, H4) dans les années 1980 et 2000 relança le développement de nouveaux composés avec, en Suisse, une première autorisation de mise sur le marché en 2018. L'objectif de cet article de revue est de présenter brièvement la physiologie de l'histamine, l'histoire du développement des antihistaminiques, leurs utilisations actuelles, ainsi que leurs effets indésirables notables.

Biomarkers to predict therapeutic response in chronic spontaneous urticaria: a review.

Chronic spontaneous urticaria (CSU) is a relatively common dermatological disorder characterized by sudden and unpredictable onset of pruritic wheals and/or angioedema, for more than six weeks. It is a mast cell-mediated histaminergic disorder, considerably worsening patients' quality of life. Current treatment options include anti-histamines, omalizumab and cyclosporine, in a step-wise algorithmic approach, aimed at complete symptom control. Patients do not respond uniformly to these therapeutic options due to phenotypic and endotypic heterogeneity, and often remain uncontrolled/poorly controlled. Recent research is focused on identifying certain biomarkers to predict therapeutic response and facilitate patient-targeted personalized treatment, for maximum benefit. The current article summarizes various biomarkers explored to date, and also elaborates their role in predicting therapeutic response to anti-histamines, omalizumab and cyclosporine, in CSU patients. High disease activity, elevated CRP/ESR and elevated D-dimer are the most important predictors of non/poor-response to antihistamines. Low and very low baseline IgE, elevated CRP/ESR, ASST+, BAT/BHRA+, basopenia, eosinopenia, and elevated D-dimer are predictors of poor and good response to omalizumab and cyclosporine, respectively. Additionally, normal or slightly elevated baseline IgE and FceR1 overexpression are predictors of a faster response with omalizumab. However, none of these predictors have so far been completely validated and are not yet recommended for routine use. Thus, large-scale prospective studies are needed to confirm these predictive biomarkers and identify new ones to achieve the goal of personalized medicine for CSU.

Medicinal plants for allergic rhinitis: A systematic review and meta-analysis.

Herbal medicine is popularly used among patients who suffer from allergic rhinitis. This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of single medicinal plants in the management of allergic rhinitis. We searched MEDLINE, CENTRAL, and Web of Science for randomised controlled trials which evaluated the use of single medicinal plant for allergic rhinitis among adults and children. Twenty-nine randomised controlled trials (n = 1879) were eligible while 27 (n = 1769) contributed data for meta-analyses. Most studies (studies = 20) compared medicinal plants against placebo and Petasites hybridus was most frequently investigated (studies = 5). Very-low-to-low-certainty evidence suggests that compared to placebo, single medicinal plants may improve overall total nasal symptoms (SMD -0.31, 95% CI -0.59 to -0.02; participants = 249; studies = 5; I2 = 21%) especially nasal congestion and sneezing; and rhinoconjunctivitis quality of life (RQLQ) scores (MD -0.46, 95% CI -0.84 to -0.07; participants = 148; studies = 3; I2 = 0%). Moderate-certainty evidence show no clear differences between single medicinal plants and antihistamine in overall symptoms (Total nasal symptoms: SMD -0.14, 95% CI -0.46 to 0.18; participants = 149; studies = 2; I2 = 0%). As adjunctive therapy, moderate-certainty evidence shows that medicinal plants improved SNOT-22 scores when given as intranasal treatment (MD -7.47, 95% CI -10.75 to -4.18; participants = 124; studies = 2; I2 = 21%). Risk of bias domains were low or not clearly reported in most studies while heterogeneity was substantial in most pooled outcomes. Route of administration and age were identified to be plausible source of heterogeneity for certain outcomes. Medicinal plants appear to be well tolerated up to 8 weeks of use. Clear beneficial evidence of medicinal plants for allergic rhinitis is still lacking. There is a need for improved reporting of herbal trials to allow for critical assessment of the effects of each individual medicinal plant preparation in well-designed future clinical studies.

Structural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor.

The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.

Synergism of polysaccharide polymers in antihistamine eye drops: Influence on physicochemical properties and in vivo efficacy.

The incorporation of polymers into drug delivery vehicles has been shown to be a useful approach to prolong the residence time of drugs in the precorneal tear film and to improve penetration into biological membranes. The main objective of this research was to formulate novel viscous eye drops with ketotifen as the active ingredient, containing the polysaccharides: chitosan (MCH), hydroxypropyl guar gum (HPG) and hyaluronic acid (SH) alone and in combination as functional polymers. DSC and FT-IR techniques showed the compatibility between ketotifen and polymers. Physicochemical and rheological analysis at ambient and simulated physiological conditions, as well as the evaluation of mucoadhesive properties showed that vehicles containing combinations of polymers have suitable physicochemical and functional properties with demonstrated synergism between combined polymers (MCH and HPG i.e. SH and HPG). The drug permeability was successfully estimated in vitro using HCE-T cell-based models. MTT cytotoxicity assay demonstrates that the tested formulations were non-toxic and well tolerated. In vivo preclinical study on mice revealed that both vehicles containing mixed polymers enhanced and prolonged the antipruritic/analgesic-like effect of ophthalmic ketotifen. Based on these results, both combinations of polysaccharide polymers, especially SH-HPG, could be considered as potential new carriers for ketotifen for ophthalmic use.

Allergic Rhinitis: A Review.

Importance: Allergic rhinitis affects an estimated 15% of the US population (approximately 50 million individuals) and is associated with the presence of asthma, eczema, chronic or recurrent sinusitis, cough, and both tension and migraine headaches. Observations: Allergic rhinitis occurs when disruption of the epithelial barrier allows allergens to penetrate the mucosal epithelium of nasal passages, inducing a T-helper type 2 inflammatory response and production of allergen-specific IgE. Allergic rhinitis typically presents with symptoms of nasal congestion, rhinorrhea, postnasal drainage, sneezing, and itching of the eyes, nose, and throat. In an international study, the most common symptoms of allergic rhinitis were rhinorrhea (90.38%) and nasal congestion (94.23%). Patients with nonallergic rhinitis present primarily with nasal congestion and postnasal drainage frequently associated with sinus pressure, ear plugging, muffled sounds and pain, and eustachian tube dysfunction that is less responsive to nasal corticosteroids. Patients with seasonal allergic rhinitis typically have physical examination findings of edematous and pale turbinates. Patients with perennial allergic rhinitis typically have erythematous and inflamed turbinates with serous secretions that appear similar to other forms of chronic rhinitis at physical examination. Patients with nonallergic rhinitis have negative test results for specific IgE aeroallergens. Intermittent allergic rhinitis is defined as symptoms occurring less than 4 consecutive days/week or less than 4 consecutive weeks/year. Persistent allergic rhinitis is defined as symptoms occurring more often than 4 consecutive days/week and for more than 4 consecutive weeks/year. Patients with allergic rhinitis should avoid inciting allergens. In addition, first-line treatment for mild intermittent or mild persistent allergic rhinitis may include a second-generation H1 antihistamine (eg, cetirizine, fexofenadine, desloratadine, loratadine) or an intranasal antihistamine (eg, azelastine, olopatadine), whereas patients with persistent moderate to severe allergic rhinitis should be treated initially with an intranasal corticosteroid (eg, fluticasone, triamcinolone, budesonide, mometasone) either alone or in combination with an intranasal antihistamine. In contrast, first-line therapy for patients with nonallergic rhinitis consists of an intranasal antihistamine as monotherapy or in combination with an intranasal corticosteroid. Conclusions and Relevance: Allergic rhinitis is associated with symptoms of nasal congestion, sneezing, and itching of the eyes, nose, and throat. Patients with allergic rhinitis should be instructed to avoid inciting allergens. Therapies include second-generation H1 antihistamines (eg, cetirizine, fexofenadine, desloratadine, loratadine), intranasal antihistamines (eg, azelastine, olopatadine), and intranasal corticosteroids (eg, fluticasone, triamcinolone, budesonide, mometasone) and should be selected based on the severity and frequency of symptoms and patient preference.

Omalizumab in the treatment of Morbihan syndrome in an adolescent girl – case report and literature review

Morbihan syndrome (MS) is characterized by solid facial edema, usually related to rosacea or acne vulgaris. The facial edema deforms the patient’s features, can impair peripheral vision, and affects quality of life. Its pathophysiology remains unclear. The disease usually has a slow and chronic course. MS most commonly affects middle-aged Caucasian men with rosacea and is rare in people below 20 years of age. MS is a diagnosis of exclusion. There is no standard treatment for MS, though systemic isotretinoin and antihistamines are mainly used. We present the case of an adolescent girl with MS nonresponding to 19 months of isotretinoin treatment with add-on antihistamines. Therapy with monthly administration of omalizumab (anti-IgE) for 6 months was an effective therapeutic option, improving the quality of life. Our case is the second description of omalizumab use in Morbihan syndrome, the first in an adolescent. (AU)

Omalizumab in the treatment of Morbihan syndrome in an adolescent girl - case report and literature review.

Morbihan syndrome (MS) is characterized by solid facial edema, usually related to rosacea or acne vulgaris. The facial edema deforms the patient's features, can impair peripheral vision, and affects quality of life. Its pathophysiology remains unclear. The disease usually has a slow and chronic course. MS most commonly affects middle-aged Caucasian men with rosacea and is rare in people below 20 years of age. MS is a diagnosis of exclusion. There is no standard treatment for MS, though systemic isotretinoin and antihistamines are mainly used. We present the case of an adolescent girl with MS nonresponding to 19 months of isotretinoin treatment with add-on antihistamines. Therapy with monthly administration of omalizumab (anti-IgE) for 6 months was an effective therapeutic option, improving the quality of life. Our case is the second description of omalizumab use in Morbihan syndrome, the first in an adolescent.

H2 antihistamines: May be useful for combination therapies in cancer?

Cancer morbimortality is still a great concern despite advances in research and therapies. Histamine and its receptors' ligands can modulate different biological responses according to the cell type and the receptor subtype involved. Besides the wide variety of histamine functions in normal tissues, diverse roles in the acquisition of hallmarks of cancer such as sustained proliferative signaling, resistance to cell death, angiogenesis, metastasis, altered immunity and modified microenvironment have been described. This review summarizes the present knowledge of the various roles of histamine H2 receptor (H2R) ligands in neoplasias. A bioinformatic analysis of human tumors showed dissimilar results in the expression of the H2R gene according to tumor type when comparing malignant versus normal tissues. As well, the relationship between patients' survival parameters and H2R gene expression levels also varied, signaling important divergences in the role of H2R in neoplastic progression in different cancer types. Revised experimental evidence showed multiple effects of H2R antihistamines on several of the cited hallmarks of cancer. Interventional and retrospective clinical studies evaluated different H2R antihistamines in cancer patients with two main adjuvant uses: improving antitumor efficacy (which includes regulation of immune response) and preventing toxic adverse effects produced by chemo or radiotherapy. While there is a long path to go, research on H2R antihistamines may provide new opportunities for developing more refined combination therapeutic strategies for certain cancer types to improve patients' survival and health-related quality of life.

Pharmaceutical Residues in Edible Oysters along the Coasts of the East and South China Seas and Associated Health Risks to Humans and Wildlife.

The investigation of pharmaceuticals as emerging contaminants in marine biota has been insufficient. In this study, we examined the presence of 51 pharmaceuticals in edible oysters along the coasts of the East and South China Seas. Only nine pharmaceuticals were detected. The mean concentrations of all measured pharmaceuticals in oysters per site ranged from 0.804 to 15.1 ng g-1 of dry weight, with antihistamines being the most common. Brompheniramine and promethazine were identified in biota samples for the first time. Although no significant health risks to humans were identified through consumption of oysters, 100-1000 times higher health risks were observed for wildlife like water birds, seasnails, and starfishes. Specifically, sea snails that primarily feed on oysters were found to be at risk of exposure to ciprofloxacin, brompheniramine, and promethazine. These high risks could be attributed to the monotonous diet habits and relatively limited food sources of these organisms. Furthermore, taking chirality into consideration, chlorpheniramine in the oysters was enriched by the S-enantiomer, with a relative potency 1.1-1.3 times higher when chlorpheniramine was considered as a racemate. Overall, this study highlights the prevalence of antihistamines in seafood and underscores the importance of studying enantioselectivities of pharmaceuticals in health risk assessments.

Discovery of Novel Steroid-Based Histamine H3 Receptor Antagonists/Inverse Agonists.

Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H3 receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R activity together with significant in vivo H3 antagonism. Optimization of the chemotype was initiated with special emphasis on the elimination of the hERG and muscarinic affinity. Additionally, ligand-based SAR considerations and molecular docking studies were performed to predict binding modes of the molecules. The most promising compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed antagonist/inverse agonist property in the in vitro functional tests that was apparent in the rat in vivo dipsogenia test. They were considerably stable in human and rat liver microsomes and provided significant in vivo potency in the place recognition and novel object recognition cognitive paradigms.

[Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)].

The methacholine challenge test (MCT) is a standard evaluation method of assessing airway hyperresponsiveness (AHR) and its severity, and has significant clinical value in the diagnosis and treatment of bronchial asthma. A consensus working group consisting of experts from the Pulmonary Function and Clinical Respiratory Physiology Committee of the Chinese Association of Chest Physicians, the Task Force for Pulmonary Function of the Chinese Thoracic Society, and the Pulmonary Function Group of Respiratory Branch of the Chinese Geriatric Society jointly developed this consensus. Based on the "Guidelines for Pulmonary Function-Bronchial Provocation Test" published in 2014, the issues encountered in its use, and recent developments, the group has updated the Standard technical specifications of methacholine chloride (methacholine) bronchial challenge test (2023). Through an extensive collection of expert opinions, literature reviews, questionnaire surveys, and multiple rounds of online and offline discussions, the consensus addressed the eleven core issues in MCT's clinical practice, including indications, contraindications, preparation of provocative agents, test procedures and methods, quality control, safety management, interpretation of results, and reporting standards. The aim was to provide clinical pulmonary function practitioners in healthcare institutions with the tools to optimize the use of this technique to guide clinical diagnosis and treatment.Summary of recommendationsQuestion 1: Who is suitable for conducting MCT? What are contraindications for performing MCT?Patients with atypical symptoms and a clinical suspicion of asthma, patients diagnosed with asthma requiring assessment of the severity of airway hyperresponsiveness, individuals with allergic rhinitis who are at risk of developing asthma, patients in need of evaluating the effectiveness of asthma treatment, individuals in occupations with high safety risks due to airway hyperresponsiveness, patients with chronic diseases prone to airway hyperresponsiveness, others requiring assessment of airway reactivity.Absolute contraindications: (1) Patients who are allergic to methacholine (MCh) or other parasympathomimetic drugs, with allergic reactions including rash, itching/swelling (especially of the face, tongue, and throat), severe dizziness, and dyspnea; (2) Patients with a history of life-threatening asthma attacks or those who have required mechanical ventilation for asthma attacks in the past three months; (3) Patients with moderate to severe impairment of baseline pulmonary function [Forced Expiratory Volume in one second (FEV1) less than 60% of the predicted value or FEV1<1.0 L]; (4) Severe urticaria; (5) Other situations inappropriate for forced vital capacity (FVC) measurement, such as myocardial infarction or stroke in the past three months, poorly controlled hypertension, aortic aneurysm, recent eye surgery, or increased intracranial pressure.Relative contraindications: (1) Moderate or more severe impairment of baseline lung function (FEV1%pred<70%), but individuals with FEV1%pred>60% may still be considered for MCT with strict observation and adequate preparation; (2) Experiencing asthma acute exacerbation; (3) Poor cooperation with baseline lung function tests that do not meet quality control requirements; (4) Recent respiratory tract infection (<4 weeks); (5) Pregnant or lactating women; (6) Patients currently using cholinesterase inhibitors (for the treatment of myasthenia gravis); (7) Patients who have previously experienced airway spasm during pulmonary function tests, with a significant decrease in FEV1 even without the inhalation of provocative.Question 2: How to prepare and store the challenge solution for MCT?Before use, the drug must be reconstituted and then diluted into various concentrations for provocation. The dilution concentration and steps for MCh vary depending on the inhalation method and provocation protocol used. It is important to follow specific steps. Typically, a specified amount of diluent is added to the methacholine reagent bottle for reconstitution, and the mixture is shaken until the solution becomes clear. The diluent is usually physiological saline, but saline with phenol (0.4%) can also be used. Phenol can reduce the possibility of bacterial contamination, and its presence does not interfere with the provocation test. After reconstitution, other concentrations of MCh solution are prepared using the same diluent, following the dilution steps, and then stored separately in sterile containers. Preparers should carefully verify and label the concentration and preparation time of the solution and complete a preparation record form. The reconstituted and diluted MCh solution is ready for immediate use without the need for freezing. It can be stored for two weeks if refrigerated (2-8 ℃). The reconstituted solution should not be stored directly in the nebulizer reservoir to prevent crystallization from blocking the capillary opening and affecting aerosol output. The temperature of the solution can affect the production of the nebulizer and cause airway spasms in the subject upon inhaling cold droplets. Thus, refrigerated solutions should be brought to room temperature before use.Question 3: What preparation is required for subjects prior to MCT?(1) Detailed medical history inquiry and exclusion of contraindications.(2) Inquiring about factors and medications that may affect airway reactivity and assessing compliance with medication washout requirements: When the goal is to evaluate the effectiveness of asthma treatment, bronchodilators other than those used for asthma treatment do not need to be discontinued. Antihistamines and cromolyn have no effect on MCT responses, and the effects of a single dose of inhaled corticosteroids and leukotriene modifiers are minimal, thus not requiring cessation before the test. For patients routinely using corticosteroids, whether to discontinue the medication depends on the objective of the test: if assisting in the diagnosis of asthma, differential diagnosis, aiding in step-down therapy for asthma, or exploring the effect of discontinuing anti-inflammatory treatment, corticosteroids should be stopped before the provocation test; if the patient is already diagnosed with asthma and the objective is to observe the level of airway reactivity under controlled medication conditions, then discontinuation is not necessary. Medications such as IgE monoclonal antibodies, IL-4Rα monoclonal antibodies, traditional Chinese medicine, and ethnic medicines may interfere with test results, and clinicians should decide whether to discontinue these based on the specific circumstances.(3) Explaining the test procedure and potential adverse reactions, and obtaining informed consent if necessary.Question 4: What are the methods of the MCT? And which ones are recommended in current clinical practice?Commonly used methods for MCT in clinical practice include the quantitative nebulization method (APS method), Forced Oscillalion method (Astograph method), 2-minute tidal breathing method (Cockcroft method), hand-held quantitative nebulization method (Yan method), and 5-breath method (Chai 5-breath method). The APS method allows for precise dosing of inhaled Methacholine, ensuring accurate and reliable results. The Astograph method, which uses respiratory resistance as an assessment indicator, is easy for subjects to perform and is the simplest operation. These two methods are currently the most commonly used clinical practice in China.Question 5: What are the steps involved in MCT?The MCT consists of the following four steps:(1) Baseline lung function test: After a 15-minute rest period, the subjects assumes a seated position and wear a nose clip for the measurement of pulmonary function indicators [such as FEV1 or respiratory resistance (Rrs)]. FEV1 should be measured at least three times according to spirometer quality control standards, ensuring that the best two measurements differ by less than 150 ml and recording the highest value as the baseline. Usually, if FEV1%pred is below 70%, proceeding with the challenge test is not suitable, and a bronchodilation test should be considered. However, if clinical assessment of airway reactivity is necessary and FEV1%pred is between 60% and 70%, the provocation test may still be conducted under close observation, ensuring the subject's safety. If FEV1%pred is below 60%, it is an absolute contraindication for MCT.(2) Inhalation of diluent and repeat lung function test for control values: the diluent, serving as a control for the inhaled MCh, usually does not significantly impact the subject's lung function. the higher one between baseline value and the post-dilution FEV1 is used as the reference for calculating the rate of FEV1 decline. If post-inhalation FEV1 decreases, there are usually three scenarios: ①If FEV1 decreases by less than 10% compared to the baseline, the test can proceed, continue the test and administer the first dose of MCh. ②If the FEV1 decreases by≥10% and<20%, indicating a heightened airway reactivity to the diluent, proceed with the lowest concentration (dose) of the provoking if FEV1%pred has not yet reached the contraindication criteria for the MCT. if FEV1%pred<60% and the risk of continuing the challenge test is considerable, it is advisable to switch to a bronchodilation test and indicate the change in the test results report. ③If FEV1 decreases by≥20%, it can be directly classified as a positive challenge test, and the test should be discontinued, with bronchodilators administered to alleviate airway obstruction.(3) Inhalation of MCh and repeat lung function test to assess decline: prepare a series of MCh concentrations, starting from the lowest and gradually increasing the inhaled concentration (dose) using different methods. Perform pulmonaryfunction tests at 30 seconds and 90 seconds after completing nebulization, with the number of measurements limited to 3-4 times. A complete Forced Vital Capacity (FVC) measurement is unnecessary during testing; only an acceptable FEV1 measurement is required. The interval between two consecutive concentrations (doses) generally should not exceed 3 minutes. If FEV1 declines by≥10% compared to the control value, reduce the increment of methacholine concentration (dose) and adjust the inhalation protocol accordingly. If FEV1 declines by≥20% or more compared to the control value or if the maximum concentration (amount) has been inhaled, the test should be stopped. After inhaling the MCh, close observation of the subject's response is necessary. If necessary, monitor blood oxygen saturation and auscultate lung breath sounds. The test should be promptly discontinued in case of noticeable clinical symptoms or signs.(4) Inhalation of bronchodilator and repeat lung function test to assess recovery: when the bronchial challenge test shows a positive response (FEV1 decline≥20%) or suspiciously positive, the subject should receive inhaled rapid-acting bronchodilators, such as short-acting beta-agonists (SABA) or short-acting muscarinic antagonists (SAMA). Suppose the subject exhibits obvious symptoms of breathlessness, wheezing, or typical asthma manifestations, and wheezing is audible in the lungs, even if the positive criteria are not met. In that case, the challenge test should be immediately stopped, and rapid-acting bronchodilators should be administered. Taking salbutamol as an example, inhale 200-400 µg (100 µg per puff, 2-4 puffs, as determined by the physician based on the subject's condition). Reassess pulmonary function after 5-10 minutes. If FEV1 recovers to within 10% of the baseline value, the test can be concluded. However, if there is no noticeable improvement (FEV1 decline still≥10%), record the symptoms and signs and repeat the bronchodilation procedure as mentioned earlier. Alternatively, add Ipratropium bromide (SAMA) or further administer nebulized bronchodilators and corticosteroids for intensified treatment while keeping the subject under observation until FEV1 recovers to within 90% of the baseline value before allowing the subject to leave.Question 6: What are the quality control requirements for the APS and Astograph MCT equipment?(1) APS Method Equipment Quality Control: The APS method for MCT uses a nebulizing inhalation device that requires standardized flowmeters, compressed air power source pressure and flow, and nebulizer aerosol output. Specific quality control methods are as follows:a. Flow and volume calibration of the quantitative nebulization device: Connect the flowmeter, an empty nebulization chamber, and a nebulization filter in sequence, attaching the compressed air source to the bottom of the chamber to ensure airtight connections. Then, attach a 3 L calibration syringe to the subject's breathing interface and simulate the flow during nebulization (typically low flow:<2 L/s) to calibrate the flow and volume. If calibration results exceed the acceptable range of the device's technical standards, investigate and address potential issues such as air leaks or increased resistance due to a damp filter, then recalibrate. Cleaning the flowmeter or replacing the filter can change the resistance in the breathing circuit, requiring re-calibration of the flow.b. Testing the compressed air power source: Regularly test the device, connecting the components as mentioned above. Then, block the opening of the nebulization device with a stopper or hand, start the compressed air power source, and test its pressure and flow. If the test results do not meet the technical standards, professional maintenance of the equipment may be required.c. Verification of aerosol output of the nebulization chamber: Regularly verify all nebulization chambers used in provocation tests. Steps include adding a certain amount of saline to the chamber, weighing and recording the chamber's weight (including saline), connecting the nebulizer to the quantitative nebulization device, setting the nebulization time, starting nebulization, then weighing and recording the post-nebulization weight. Calculate the unit time aerosol output using the formula [(weight before nebulization-weight after nebulization)/nebulization time]. Finally, set the nebulization plan for the provocation test based on the aerosol output, considering the MCh concentration, single inhalation nebulization duration, number of nebulization, and cumulative dose to ensure precise dosing of the inhaled MCh.(2) Astograph method equipment quality control: Astograph method equipment for MCT consists of a respiratory resistance monitoring device and a nebulization medication device. Perform zero-point calibration, volume calibration, impedance verification, and nebulization chamber checks daily before tests to ensure the resistance measurement system and nebulization system function properly. Calibration is needed every time the equipment is turned on, and more frequently if there are significant changes in environmental conditions.a. Zero-point calibration: Perform zero-point calibration before testing each subject. Ensure the nebulization chamber is properly installed and plugged with no air leaks.b. Volume calibration: Use a 3 L calibration syringe to calibrate the flow sensor at a low flow rate (approximately 1 L/s).c. Resistance verification: Connect low impedance tubes (1.9-2.2 cmH2O·L-1·s-1) and high impedance tubes (10.2-10.7 cmH2O·L-1·s-1) to the device interface for verification.d. Bypass check: Start the bypass check and record the bypass value; a value>150 ml/s is normal.e. Nebulization chamber check: Check each of the 12 nebulization chambers daily, especially those containing bronchodilators, to ensure normal spraying. The software can control each nebulization chamber to produce spray automatically for a preset duration (e.g., 2 seconds). Observe the formation of water droplets on the chamber walls, indicating normal spraying. If no nebulization occurs, check for incorrect connections or blockages.Question 7: How to set up and select the APS method in MCT?The software program of the aerosol provocation system in the quantitative nebulization method can independently set the nebulizer output, concentration of the methacholine agent, administration time, and number of administrations and combine these parameters to create the challenge test process. In principle, the concentration of the methacholine agent should increase from low to high, and the dose should increase from small to large. According to the standard, a 2-fold or 4-fold incremental challenge process is generally used. In clinical practice, the dose can be simplified for subjects with good baseline lung function and no history of wheezing, such as using a recommended 2-concentration, 5-step method (25 and 50 g/L) and (6.25 and 25 g/L). Suppose FEV1 decreases by more than 10% compared to the baseline during the test to ensure subject safety. In that case, the incremental dose of the methacholine agent can be reduced, and the inhalation program can be adjusted appropriately. If the subject's baseline lung function declines or has recent daytime or nighttime symptoms such as wheezing or chest tightness, a low concentration, low dose incremental process should be selected.Question 8: What are the precautions for the operation process of the Astograph method in MCT?(1) Test equipment: The Astograph method utilizes the forced oscillation technique, applying a sinusoidal oscillating pressure at the mouthpiece during calm breathing. Subjects inhale nebulized MCh of increasing concentrations while continuous monitoring of respiratory resistance (Rrs) plots the changes, assessing airway reactivity and sensitivity. The nebulization system employs jet nebulization technology, comprising a compressed air pump and 12 nebulization cups. The first cup contains saline, cups 2 to 11 contain increasing concentrations of MCh, and the 12th cup contains a bronchodilator solution.(2) Provocation process: Prepare 10 solutions of MCh provocant with gradually increasing concentrations.(3) Operational procedure: The oscillation frequency is usually set to 3 Hz (7 Hz for children) during the test. The subject breathes calmly, inhales saline solution nebulized first, and records the baseline resistance value (if the subject's baseline resistance value is higher than 10 cmH2O·L-1·s-1, the challenge test should not be performed). Then, the subject gradually inhales increasing concentrations of methacholine solution. Each concentration solution is inhaled for 1 minute, and the nebulization system automatically switches to the next concentration for inhalation according to the set time. Each nebulizer cup contains 2-3 ml of solution, the output is 0.15 ml/min, and each concentration is inhaled for 1 minute. The dose-response curve is recorded automatically. Subjects should breathe tidally during the test, avoiding deep breaths and swallowing. Continue until Rrs significantly rises to more than double the baseline value, or if the subject experiences notable respiratory symptoms or other discomfort, such as wheezing in both lungs upon auscultation. At this point, the inhalation of the provocant should be stopped and the subject switchs to inhaling a bronchodilator until Rrs returns to pre-provocation levels. If there is no significant increase in Rrs, stop the test after inhaling the highest concentration of MCh.Question 9: How to interpret the results of the MCT?The method chosen for the MCT determines the specific indicators used for interpretation. The most commonly used indicator is FEV1, although other parameters such as Peak Expiratory Flow (PEF) and Rrs can also be used to assess airway hyperresponsiveness.Qualitative judgment: The test results can be classified as positive, suspiciously positive, or negative, based on a combination of the judgment indicators and changes in the subject's symptoms. If FEV1 decreases by≥20% compared to the baseline value after not completely inhaling at the highest concentration, the result can be judged as positive for Methacholine bronchial challenge test. If the patient has obvious wheezing symptoms or wheezing is heard in both lungs, but the challenge test does not meet the positive criteria (the highest dose/concentration has been inhaled), and FEV1 decreases between 10% and 20% compared to the baseline level, the result can also be judged as positive. If FEV1 decreases between 15% and 20% compared to the baseline value without dyspnea or wheezing attacks, the result can be judged as suspiciously positive. Astograph method: If Rrs rises to 2 times or more of the baseline resistance before reaching the highest inhalation concentration, or if the subject's lungs have wheezing and severe coughing, the challenge test can be judged as positive. Regardless of the result of the Methacholine bronchial challenge test, factors that affect airway reactivity, such as drugs, seasons, climate, diurnal variations, and respiratory tract infections, should be excluded.Quantitative judgment: When using the APS method, the severity of airway hyperresponsiveness can be graded based on PD20-FEV1 or PC20-FEV1. Existing evidence suggests that PD20 shows good consistency when different nebulizers, inhalation times, and starting concentrations of MCh are used for bronchial provocation tests, whereas there is more variability with PC20. Therefore, PD20 is often recommended as the quantitative assessment indicator. The threshold value for PD20 with the APS method is 2.5 mg.The Astograph method often uses the minimum cumulative dose (Dmin value, in Units) to reflect airway sensitivity. Dmin is the minimum cumulative dose of MCh required to produce a linear increase in Rrs. A dose of 1 g/L of the drug concentration inhaled for 1-minute equals 1 unit. It's important to note that with the continuous increase in inhaled provocant concentration, the concept of cumulative dose in the Astograph method should not be directly compared to other methods. Most asthma patients have a Dmin<10 Units, according to Japanese guidelines. The Astograph method, having been used in China for over twenty years, suggests a high likelihood of asthma when Dmin≤6 Units, with a smaller Dmin value indicating a higher probability. When Dmin is between 6 and 10 Units, further differential diagnosis is advised to ascertain whether the condition is asthma.Precautions:A negative methacholine challenge test (MCT) does not entirely rule out asthma. The test may yield negative results due to the following reasons:(1) Prior use of medications that reduce airway responsiveness, such as ß2 agonists, anticholinergic drugs, antihistamines, leukotriene receptor antagonists, theophylline, corticosteroids, etc., and insufficient washout time.(2) Failure to meet quality control standards in terms of pressure, flow rate, particle size, and nebulization volume of the aerosol delivery device.(3) Poor subject cooperation leads to inadequate inhalation of the methacholine agent.(4) Some exercise-induced asthma patients may not be sensitive to direct bronchial challenge tests like the Methacholine challenge and require indirect bronchial challenge tests such as hyperventilation, cold air, or exercise challenge to induce a positive response.(5) A few cases of occupational asthma may only react to specific antigens or sensitizing agents, requiring specific allergen exposure to elicit a positive response.A positive MCT does not necessarily indicate asthma. Other conditions can also present with airway hyperresponsiveness and yield positive results in the challenge test, such as allergic rhinitis, chronic bronchitis, viral upper respiratory infections, allergic alveolitis, tropical eosinophilia, cystic fibrosis, sarcoidosis, bronchiectasis, acute respiratory distress syndrome, post-cardiopulmonary transplant, congestive heart failure, and more. Furthermore, factors like smoking, air pollution, or exercise before the test may also result in a positive bronchial challenge test.Question 10: What are the standardized requirements for the MCT report?The report should include: (1) basic information about the subject; (2) examination data and graphics: present baseline data, measurement data after the last two challenge doses or concentrations in tabular form, and the percentage of actual measured values compared to the baseline; flow-volume curve and volume-time curve before and after challenge test; dose-response curve: showing the threshold for positive challenge; (3) opinions and conclusions of the report: including the operator's opinions, quality rating of the examination, and review opinions of the reviewing physician.Question 11: What are the adverse reactions and safety measures of MCT?During the MCT, the subject needs to repeatedly breathe forcefully and inhale bronchial challenge agents, which may induce or exacerbate bronchospasm and contraction and may even cause life-threatening situations. Medical staff should be fully aware of the indications, contraindications, medication use procedures, and emergency response plans for the MCT.

Risk calculator of the clinical response to antihistamines in chronic urticaria: Development and internal validation.

Early detection of CSU patients with low probability of a clinical response with antihistamines could undergo prompt initiation of therapeutic alternatives. The aim of the study was to develop and internally validate a model for predicting the clinical response to antihistamines in adult patients with chronic spontaneous urticaria (CSU), who consult allergology and dermatology care centers. A cohort of CSU patients, recruited from four participating centers, were followed up for 12 months. Fifteen candidate variables were selected to be included in the multivariate model and then internal validation was done with bootstrap analysis with 1000 simulations. The outcome variable, clinical response to antihistamines, was evaluated with the UAS (Urticaria Activity Score) scale for seven days: "No response to antihistamines" was defined as UAS7 ≥7 points after at least one month with a maximum dose of antihistamines, while "Response to antiH1" was defined as UAS7 ≤6 points for at least three months with the use of antiH1. A total of 790 patients were included. Among the different models analyzed, the model that included age, angioedema, anxiety/depression, time with the disease, NSAIDs (Non-steroidal anti-inflammatory drugs) intolerance, and UAS7 baseline was considered the one with the best performance (accuracy 0.675, HL 0.87, AUC 0.727). The internal validation analyses demonstrated good consistency of the model. In conclusion, this prediction model identifies the probability of response to antihistamines in patients with chronic spontaneous urticaria. The model could be useful for a personalized therapeutic approach according to individual patient risk.

A systematic review and meta-analysis of efficacy and safety of compound glycyrrhizin combined with second-generation non-sedated antihistamine for the treatment of chronic urticaria.

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.

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.

The pharmacotherapeutic management of allergic rhinitis in people with asthma.

INTRODUCTION: Up to 90% of asthmatic patients have comorbid allergic rhinitis (AR). Although appropriate therapy of AR can improve asthma symptoms and management, AR is often underdiagnosed and under-treated in asthmatics.A non-systematic literature research was conducted on AR as a comorbidity and risk factor of asthma. Latest international publications in medical databases, international guidelines, and the Internet were reviewed. AREAS COVERED: Based on the conducted literature research there is proved evidence of the necessity of diagnosis and treatment of AR in patients with asthma because it affects health care utilization. Therefore, it is recommended in national and global guidelines. EXPERT OPINION: AR increases the risk of asthma development and contributes to the severity of an existing asthma. Early treatment of AR with drugs as intranasal steroids, antihistamines, leukotriene receptor antagonists, and especially allergen-specific immunotherapy can reduce the risk of asthma development and the concomitant medication use in addition to severity of symptoms in AR and asthma.

Medicating the coast in a metropolitan city: Enantiomeric profiles and joint probabilistic risk assessment of antidepressants and antihistamines.

Pharmaceuticals are receiving increasing attention as emerging contaminants in the aquatic environment. Herein, we investigated the occurrence of 11 antidepressants, 6 antihistamines and 4 metabolites in treated wastewater effluents, rivers, stormwater, and seawater in Hong Kong, with special focus on chirality. The average levels of ∑pharmaceuticals ranged from 0.525 to 1070 ng/L in all samples and the total annual mass load of target pharmaceuticals in the marine environment of Hong Kong was 756 kg/y. Antihistamines accounted for >80 % of ∑pharmaceuticals, with diphenhydramine and fexofenadine being predominant. The occurrence and enantiomeric profiles of brompheniramine and promethazine sulfoxide were reported in global natural waters for the first time. Among chiral pharmaceuticals, mirtazapine and fexofenadine exhibited R-preference, while others mostly exhibited S-preference, implying that the ecological risks derived from achiral data for chiral pharmaceuticals may be biased. The joint probabilistic risk assessment of fluoxetine revealed that R-fluoxetine and rac-fluoxetine presented different ecological risks from that of S-fluoxetine; Such assessment also revealed that target pharmaceuticals posed only minimal to low risks, except that diphenhydramine posed an intermediate risk. As estimated, 10 % aquatic species will be affected when the environmental level of diphenhydramine exceeds 7.40 ng/L, which was seen in 46.9 % samples. Collectively, this study highlights further investigations on the enantioselectivity of chiral pharmaceuticals, particularly on environmental behavior and ecotoxicity using local aquatic species as target organisms.

Allergic Rhinitis and Its Effect on Sleep.

Allergic rhinitis (AR) is associated with increased sleep disturbances in adults and children. Pathogenesis is multifactorial, with nasal obstruction playing a large role. Intranasal corticosteroids, antihistamines, leukotriene inhibitors, and allergen immunotherapy have been demonstrated to relieve self-reported symptoms of sleep impairment. Given the high prevalence of sleep impairment in AR, providers should consider evaluating any patient with AR for sleep disturbances and sleep-disordered breathing.