H1-antihistamines Research Articles

Designing and evaluation of ebastine–benzamide cocrystals

Background: Ebastine (EB) is a selective nonsedating H1 antihistamine belonging to Class II(BCS); it has inadequate oral bioavailability due to its poor water solubility. Cocrystal is one of the most recent methods that has been utilized to improve some physicochemical characteristics of a drug, such as solubility and dissolution rate. This research's main objective was to design and evaluate EB cocrystal as a trial to enhance its solubility. Methods: Various techniques were employed to formulate cocrystals, such as solvent evaporation, slurry, and drop asset grinding using benzamide (BENZ) as a co-former in different molar ratios. The prepared formulas were characterized by percentage yield, drug content, saturation solubility, in vitro dissolution studies, infrared spectroscopy (FTIR), Raman spectroscopy, powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC), Results: Solubility enhanced by 347 fold in distilled water with enhanced dissolution profile. Conclusions: Co-crystallization is a potential solid formation method due to its ability to enhance physicochemical and mechanical characteristics. Co-crystals have been successfully formed from a variety of medicines and co-former, using distinct hydrogen bond synthon motifs.

Use of Combination Premedication Prior to Motixafortide Administration Reduced Severity and Frequency of AEs in the Phase 3 Genesis Trial - a Single Center Analysis

Background: Motixafortide is a novel, high affinity CXCR4 antagonist with extended receptor occupancy that facilitates the migration of hematopoietic stem and progenitor cells from the bone marrow into the peripheral blood in preparation for autologous stem cell transplantation (ASCT). In prior pre-clinical and clinical studies, motixafortide was associated with transient hypersensitivity and injection site reactions. Strategies to mitigate such adverse events (AEs) commonly include agents with antihistamine activity. The Phase 3 GENESIS trial demonstrated that 88.8% of Multiple Myeloma patients mobilized ≥6x10 6 CD34+ cells/kg (local labs) in 1 leukapheresis procedure (LP) following the administration of 1 dose of motixafortide in combination with GCSF. Per initial protocol, premedication with an antihistamine H1 blocker prior to motixafortide administration was provided to all patients. However, during the course of the GENESIS study a protocol amendment was implemented to include premedication with an antihistamine H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen prior to motixafortide administration. Here we report the safety findings in a cohort of patients at who received single drug premedication with an H1 antihistamine prior to the protocol amendment and those who received the updated combination pre-medication regimen following protocol amendment. Methods:The GENESIS trial was a multicenter, randomized, double-blind, placebo-controlled study in 122 transplant-eligible multiple myeloma patients, as previously described (PMID: 37069359). Included in this analysis are 46 patients enrolled at the Washington University in St. Louis; 32 patients were randomized to the motixafortide treatment arm and 14 patients were randomized to the placebo arm. Among motixafortide-treated patients, 22 received a single-agent H1 blocker pre-medication and 10 received a combination pre-medication regimen comprising of an H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen. All pre-medications were administered within 1 hour prior to motixafortide administration. Hypersensitivity AEs included all events coded to the MedDRA terms of urticaria, pruritus, flushing, erythema, rash, hypersensitivity or anaphylaxis. Injection site reactions included all events coded to the MedDRA High Level Term of Injection Site Reaction. All AEs were graded using CTCAE criteria and were recorded up to 30 days from the last dose of motixafortide. Results: Overall, motixafortide was safe and well tolerated with no episodes of anaphylaxis, no Grade 4 AEs and no deaths. The most commonly observed AEs included transient hypersensitivity and injection site reactions. The frequency of motixafortide-associated hypersensitivity AEs of any grade was reduced from 90.9% with single-agent H1 blocker pre-medication to 20% with the combination pre-medication regimen, similar to the 20-25% rate of hypersensitivity AEs reported in the placebo + GCSF cohort (Table 1). In addition, all hypersensitivity AEs that occurred following combination pre-medication were graded mild in severity (Figure 1). Meanwhile the frequency of injection site AEs of any grade was reduced from 95.5% with single-agent H1 blocker pre-medication to 80.0% with the combination pre-medication regimen (Table 1). Furthermore, a notable improvement in severity of injection site AEs was observed, with moderate-severe injection site AEs reduced from 27% with single-agent H1 blocker pre-medication to 0% with the combination pre-medication regimen (Figure 1). Conclusions:Motixafortide was safe and well tolerated with no episodes of anaphylaxis, no Grade 4 AEs and no deaths. Following implementation of a protocol amendment using combination pre-medication with an antihistamine H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen, the frequency and severity of hypersensitivity and injection site AEs associated with motixafortide were markedly improved.

Initial Results from Summit: An Ongoing, 3-Part, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Study of Bezuclastinib in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

Background: Systemic mastocytosis (SM) is a rare disease characterized by neoplastic mast cell infiltration of extracutaneous tissues and encompasses a spectrum of subtypes that can range from non-advanced to advanced disease. Nonadvanced SM (NonAdvSM) includes two variants of SM: indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). NonAdvSM is often associated with debilitating symptoms which may significantly reduce health-related quality of life (HRQoL). In up to 95% of patients, SM is driven by the somatic KIT D816V gain of function mutation located in exon 17. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preclinical studies demonstrate bezuclastinib inhibits KIT D816V with minimal brain penetration. Early results from Part 1 of a Phase 2 trial of patients with AdvSM demonstrate that bezuclastinib is well-tolerated and is associated with encouraging clinical activity. Bezuclastinib resulted in meaningful reductions in markers of disease burden including serum tryptase, bone marrow mast cell burden, and KIT D816V variant allele fraction (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). These results support the investigation of bezuclastinib as a potential therapy in NonAdvSM. Study Design and Methods: Summit (NCT05186753) is a multi-center, Phase 2, randomized, double-blind, placebo-controlled, 3-part clinical trial of bezuclastinib in patients with NonAdvSM, including ISM and SSM, who have inadequate control of symptoms despite treatment with best supportive care (BSC). Patient-reported outcome measures (PROMs), including mastocytosis activity score (MAS) and mastocytosis quality of life (MC-QoL), are being used to assess treatment impact on symptoms and HRQoL. Approximately 48 patients will be enrolled in Part 1 of the trial with 1:1:1 randomization to one of two doses of bezuclastinib (100 or 200 mg QD for Part 1a; 100 or 150 mg QD for Part 1b) or placebo. Here we report initial data from Part 1a of the Summit trial. Results: Part 1a of Summit enrolled 20 patients; 18 patients had ISM and 2 patients had SSM. In Part 1a, a majority of patients were female (75%) and had an Eastern Cooperative Oncology Group Performance Status of 0-1 (90%) or 2 (10%). Mean age was 54. Patients utilized a median (range) of 3 (2 to 7) BSC medications, with 100% using H1 blockers, 95% using H2 blockers and 40% using leukotriene receptor antagonists. Enrolled patients had a median (range) serum tryptase of 74 (10 to 592) ng/mL and 85% of patients had a serum tryptase ≥20 ng/mL. 75% of patients were KIT D816V positive and median (range) KIT D816V variant allele fraction in whole blood was 0.5% (0 to 32). Median (range) percent bone marrow mast cell burden was 23% (1 to 80%). Utilizing MAS to assess baseline disease severity, a majority of patients self-reported severe disease with a median score of 43 (range 22-79). Patients also self-reported a mean score of 56+/- 19 on the MC-QOL, indicating moderate impact to their HRQoL. Conclusions: The Summit trial evaluating safety and efficacy of bezuclastinib enrolled 20 patients in Part 1a. The patients enrolled in Part 1a of the Summit trial are generally representative of the population of patients with moderate to severe nonadvanced systemic mastocytosis based on number of supportive care medications, symptom severity, and disease impact on HRQoL. Initial safety and efficacy results from Part 1a of the 3-part, randomized, double-blind, placebo-controlled Summit trial will be presented.

Pharmacogenomics to Predict Asparaginase Premedication-Related Hypersensitivity in Pediatric and Adolescent Young Adults (AYAs) with Acute Lymphoblastic Leukemia or Lymphoma

Pediatric acute lymphoblastic leukemia (ALL) patients have had significantly improved outcomes over the last few decades with overall survival (OS) rates exceeding 90%. Several factors, including the incorporation of asparaginase therapy in chemotherapy regimens of pediatric and AYA patients with ALL have played a critical role in improving outcomes. Asparaginase is a bacteria-derived enzyme which depletes the non-essential amino acid asparagine and leads to subsequent apoptosis in lymphoblastic leukemia cells. One of the main limitations of the frontline pegaspargase (PEG) chemotherapy is the development of hypersensitivity reactions and subsequent development of anti-asparaginase neutralizing antibodies that lead to PEG inactivation. When hypersensitivity reactions to PEG occur, patients are often switched to alternative forms of asparaginase, such as that isolated from Erwinia chrysanthemi. A prospective multi-institutional study initiated by Children's Hospital of Orange County (CHOC) and conducted at 6 pediatric cancer centers: 1) evaluated the efficacy of premedicating pediatric and AYA patients with B or T-ALL or lymphoblastic lymphoma (LBL) receiving PEG with antihistamines (H1 and H2 blockers), and 2) performed therapeutic drug monitoring to better identify patients with true hypersensitivity reactions versus those with non-antibody mediated infusion reactions with the goal of reducing incidences of substitution to Erwinia asparaginase. This study also aimed to characterize the pharmacogenomics which may be driving differences in asparaginase hypersensitivity to better understand which single nucleotide polymorphisms (SNPs) are involved in the immunogenicity of PEG and whether certain populations are more at risk for hypersensitivity. Here, we report preliminary evidence showing an association between a combination of 3 SNPs in 3 genes and incidence of hypersensitivity to PEG. The analysis cohort consisted of 126 non-Down syndrome patients premedicated prior to PEG treatment. In this cohort, the median age was 7.7 years, 48 were female (38%) and 78 male (62%), 65 patients identified as Hispanic (52%), 56 as non-Hispanic (44%) and 5 declined to state (4%). Overall, 28 patients had a hypersensitive reaction to PEG within 15 minutes of infusion. Patient characteristics by hypersensitivity incidence are summarized in Fig 1A, with age and National Cancer Institute (NCI) risk groups being the factors that significantly differ by hypersensitivity. DNA from all 126 patients was used to genotype for 6 SNPs in 5 genes involved in pathways implicated in hypersensitivity to PEG. We tested each SNP genotype in 3 modes of inheritance (additive, dominant, and recessive) in all possible combinations of up to two SNPs per model using Cox-proportional hazard models for association with incidences of hypersensitivity post-infusion in 126 patients for whom clinical data was available. We then performed 1000 permutation tests for each model to determine the likelihood of obtaining them falsely. Models were ordered according to their Bayesian Information Criterion (BIC) and weight in favor of each model and those with least BIC and a 1000 permutation p<0.05 were selected for development of Asp_PGx3 score. This was defined by adding the genotype scores of 3 SNPs in 3 genes ( ARHGAP28, CNOT3, and NFATC2), accounting for the mode of inheritance and the direction of their association with outcome. This score ranged from -5 to 0, with patients with score <0 stratified as low score and those with scores of 0 as high score groups. A significantly higher proportion of patients in the low Asp_PGx3 score group (29%) had an incidence of PEG hypersensitivity compared to those in the high Asp_PGx3 score group (16%) (Fig 1B). In conclusion, we show a combination of 3 SNPs (in ARHGAP28, CNOT3, and NFATC2) associated with PEG hypersensitivity in a cohort of 126 pediatric and AYA ALL/LBL patients. Instead of a single SNP association approach, identifying combinations of variations in pathway specific genes provides a more robust means to predict drug response. Our preliminary results provide a rationale for identification of genome level variations in this cohort and association analysis to establish clinically relevant pharmacogenomics score to optimize PEG treatment. Funding for this study was provided by CHOC PSF Tithe Grant, CHOC Hyundai Cancer Institute Research Grant, and Servier Pharmaceuticals.

Role of Bilastine in Allergic Rhinitis: A Narrative Review.

Allergic rhinitis (AR) is considered a trivial disease and is often self-treated with over-the-counter drugs and home remedies. However, AR is a contributing risk factor for asthma associated with complications, including chronic cough, eosinophilic esophagitis, and otitis media with effusion. In AR, inflammation is primarily mediated by histamines. Guidelines advise using second-generation oral H1 antihistamines as the primary treatment for AR. Second-generation H1 antihistamines strongly prefer the H1 receptor, limiting their ability to enter the central nervous system. Thus, they have minimal adverse effects. Among these H1 antihistamines, bilastine is highly specific for H1 receptors with a slight affinity for other receptors. It has a rapid and prolonged action, which reduces the need for frequent dosing and has better compliance. In the long term, bilastine is well-tolerated with minimal adverse effects. It is not associated with drug interactions, so dosage adjustment is unnecessary. Bilastine does not penetrate the brain and is nonsedating at 80 mg once daily. The low possibility of drug-drug interactions and pharmacokinetics of bilastine makes it suitable for elderly patients, even with compromised hepatic and renal function, without dose adjustment. This review comprehensively discusses the guidelines and the role of bilastine in treating AR. How to cite this article: Tiwaskar M, Vora A, Tewary K, et al. Role of Bilastine in Allergic Rhinitis: A Narrative Review. J Assoc Physicians India 2023;71(11):58-61.

Urticária crônica: Tratamento farmacológico

Introduction: Chronic urticaria is a skin condition characterized by recurrent episodes of itching and rashes that persist for more than six weeks. Its effective management is essential for improving patients' quality of life. This study aims to evaluate best practices in the management of chronic urticaria. Objectives: To evaluate the most effective treatment options available for patients with chronic urticaria. Methodology: A literature review was carried out, including clinical studies and recent medical guidelines. Treatment options, diagnosis, drug safety and efficacy, and management strategies in different age groups were analyzed. Results: The results of this review highlight that non-sedating H1 antihistamines are the first line of treatment for chronic urticaria. In cases of treatment resistance, other options such as systemic corticosteroids and immunosuppressants can be considered, although with caution due to potential side effects. In elderly patients, liver and kidney function should be considered when choosing medications. In addition, identifying possible underlying causes is crucial for the effective management of chronic urticaria. Conclusion: The management of chronic urticaria requires a personalized approach based on an assessment of the patient's needs, considering age, comorbidities and drug safety. Identifying and treating the underlying causes, where possible, is essential. With current guidelines and therapeutic options, it is possible to significantly improve the quality of life of patients with chronic urticaria.

ANTIHISTAMINE AS AN ADJUNCTIVE TREATMENT IN ACNE VULGARIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Approximately one-tenth of the global population suffer from acne vulgaris, which is a skin disease with considerable psychological impact. Recently, antihistamines have been used in the treatment of acne. However, their overall treatment effects for this indication remain unclear. This systematic review and meta-analysis aim to evaluate the clinical efficacy and safety of the antihistamines in the treatment of acne vulgaris. The following databases were searched: PubMed, Scopus, Embase, Cochrane Central Register of Controlled Clinical Trials, and Google Scholar. We included the randomized controlled trials on acne vulgaris patients which compared any H1- antihistamine drug in combination with other medications to placebo, no treatment, or other medications, with acne lesion (non-inflammatory and inflammatory) counts, acne severity score, patient satisfaction, acne flare, or adverse events as an outcome of interest. Six studies contributing to 388 patients were included, involving two H1 antihistamines (i.e., levocetrizine and desloratadine), isotretinoin, azithromycin, and topical azelaic acid cream. From the network meta–analysis, levocetirizine+isotretinoin was better than the isotretinoin alone in the inflammatory lesion count, but not in the non-inflammatory lesion count. The desloratadine+isotretinoin retained the best balance in terms of non-inflammatory lesion count, inflammatory lesion count, acne flare, and mucocutaneous adverse events. The desloratadine+isotretinoin and levocetirizine+isotretinoin were considered safe.

Chronic spontaneous urticaria—status quo and future

AbstractChronic spontaneous urticaria (CsU) is a chronic inflammatory dermatosis whose etiology is not yet fully understood. In affected patients, it is often associated with a high limitation of health-related quality of life, which necessitates effective therapeutic management. Different immune cell populations such as mast cells, eosinophilic and basophilic granulocytes, and T cells are involved in the pathogenesis of CsU, whereby mast cells playing a key role. In addition, type I autoallergic reactions with auto IgE antibodies or type IIb autoimmune reactions with auto IgG antibodies have been identified in a proportion of patients. The current international guideline initially recommends the use of second-generation H1 antihistamines, first in standard, then in off-label quadruple dosing. Subsequently, the anti-IgE antibody omalizumab should be added. However, this therapy algorithm does not lead to freedom from manifestations in all patients. Therefore, various targeted therapies are currently being evaluated for their efficacy in CsU, such as off-label use of the anti-interleukin receptor alpha (IL4Rα) antibody dupilumab, the anti-IL-17A antibody secukinumab, or interleukin‑5 blockade using mepolizumab, reslizumab, or benralizumab. In addition, new promising compounds such as the Bruton tyrosine kinase (BTK) inhibitors remibrutinib and fenebrutinib, the anti-cKIT antibody barzolvolimab, the anti-SIGLEC8 antibody lirentelimab, the anti-TSLP antibody tezepelumab, the anti-C5aR1 antibody advoralimab, or the topical application of Syk kinase inhibitors are being tested, which were developed according to new insights into the pathogenesis of CsU. The BTK inhibitor fenebrutinib is currently not being pursued due to a less favorable side effect profile compared to remibrutinib, as well as the anti-IgE antibody ligelizumab, which was inferior to omalizumab therapy in a phase 3 study. Overall, there is a high need for new therapeutic strategies to better treat CsU both symptomatically and curatively. This requires a more comprehensive understanding of pathogenesis of the disease in order to develop new targeted therapies.

Loratadine oral bioavailability enhancement via solid dispersion loaded oro-dispersible films: Formulation, characterization and pharmacokinetics.

Loratadine (LRD) belongs to second-generation tricyclic H1 antihistamine class, known for its non-sedating properties in allergic reactions. H1 antihistamines avoid and block the responses to allergens or histamine in nose and conjunctivae, thereby abolishing itching, congestion and sneezing. LRD is a Biopharmaceutical Class System (BCS) class II drug with dissolution or solubility limited absorption which limited the oral bioavailability and therapeutic efficacy of LRD. To improve the oral bioavailability of LRD for allergic disease (urticaria) treatment, LRD solid dispersions (LRD-SDs) were integrating into oro-dispersible films (ODFs). LRD-SDs were prepared through hot-melt extrusion method (HME) using d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS-1000), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SP). Subsequently, LRD-SDs were incorporated in ODFs by solvent casting method. The physicochemical and mechanical properties of LRD solid dispersions-loaded oro-dispersible films (LRD-SDs-ODFs), were evaluated. The in-vitro dissolution, ex-vivo permeation, oral bioavailability, and pharmacodynamics studies were conducted to evaluate LRD-SDs-ODFs efficiency. LRD-SDs-ODFs showed superior solubility and in-vitro dissolution results compared to that of pure LRD (p<0.05). The solubility of the LRD-SD coded as LTS-4 was 190 times higher than the pure drug in aqueous media. The average hydrodynamic particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of SD particles were 76±2.1nm, 0.20±0.08 and -19.16±1.4mV, respectively. Moreover, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results confirmed the amorphousness of LRD in LRD-SDs-ODFs. The permeability flux of LRD was 44.6±3.1μg/cm2/h from DPF-5 formulation. Likewise, in vivo oral bioavailability of DPF-5 in Sprague-Dawley rats was significantly increased (p<0.05) compared to free LRD. Further, wheal area was reduced 20 % higher than LRD in 8h (p<0.05). Overall, LRD-SDs-ODFs considerably enhanced LRD solubility, dissolution rate, bioavailability, and antihistaminic efficacy. Our findings show that SDs-ODFs is an effective carrier system for delivering poorly soluble LRD.

CccDNA-Targeted Drug Screen Reveals a Class of Antihistamines as Suppressors of HBV Genome Levels.

Chronic infection with hepatitis B virus (HBV) is incurable, as the current therapeutics cannot eliminate its persistent genomic material, cccDNA. Screening systems for cccDNA-targeting therapeutics are unavailable, as low copies of cccDNA in vitro complicate detection. To address this, cccDNA copies were massively increased to levels detectable via automated plate readers. This was achieved via continuous infection in a contact-free co-culture of an HBV generator (clone F881), which stably produced clinically relevant amounts of HBV, and HBV acceptors selected to carry high cccDNA loads. cccDNA-targeted therapeutics were then identified via reduced cccDNA-specific fluorescence, taking differences in the cell numbers and viability into account. Amongst the drugs tested, the H1 antihistamine Bilastine, HBVCP inhibitors and, surprisingly, current HBV therapeutics downregulated the cccDNA significantly, reflecting the assay's accuracy and sensitivity in identifying drugs that induce subtle changes in cccDNA levels, which take years to manifest in vivo. Bilastine was the only therapeutic that did not reduce HBV production from F881, indicating it to be a novel direct suppressor of cccDNA levels. When further assessed, only the structurally similar antihistamines Pitolisant and Nizatidine suppressed cccDNA levels when other H1 antihistamines could not. Taken together, our rapid fluorescence cccDNA-targeted drug screen successfully identified a class of molecules with the potential to treat hepatitis B.

A Clinical Approach of Allergic Rhinitis in Children.

Allergic rhinitis is an important disease with a global footprint and a growing prevalence, affecting children and adults. Although it is commonly under-diagnosed and under-treated, it causes important social and economic effects (diminished quality of life, poor academic performance, escalated medical visits, heightened medication usage, and effects in other chronic conditions, e.g., asthma). It is characterized by distinctive, easily identifiable symptoms (sneezing, nasal discharge, nasal congestion, nasal-eye-palatal itching) and indirect accompanying indicators (fatigue and decreased school performance). The classification of allergic rhinitis hinges upon its nature and chronic distribution (seasonal or perennial) and its intensity, which spans from mild to moderate and severe. The diagnostic process primarily relies upon recognizing key clinical indicators, evaluating historical records, and considering risk factors. It is supported by abnormal laboratory findings, like in vitro allergen-specific IgE tests (enzyme immunoassay-EIA, chemiluminense immunoassay-CLIA) or in vivo skin prick tests for specific allergens. In the differential diagnosis, other chronic diseases manifesting with chronic rhinitis should be excluded (e.g., rhinosinusitis, chronic non-allergic rhinitis, rhinitis triggered by medications). The treatment of allergic rhinitis in children is mainly chronic and is focused on allergen exposure prevention, drug therapy, and immunotherapy in severe cases. Locally administered intranasal corticosteroids are the cornerstone of therapy. They are safe, effective, and have a favorable safety profile even during long-term use. Choosing a suitable intranasal corticosteroid drug with low systemic bioavailability makes long-term treatment even safer. Combinations of intranasal corticosteroids and H1 antihistamines are available in several countries and are widely used in more severe cases and the presence of year-round symptoms. Adding newer-generation oral H1-antihistamines broadens the available therapeutic inventory without significant effects compared to using previous-generation, once widely available, H1-antihistamines. Treatment of allergic rhinitis is complex and multi-dimensional, requiring an effective approach by a specialized group of specialized pediatricians, and is severely affected by the concurrent presence or development of other diseases in the spectrum of allergic diseases (conjunctivitis, asthma).

IL-31-Pruritus Interleukin: Serum Values and Clinical Impact in Chronic Spontaneous Urticaria-A Romanian Retrospective Study.

(1) Background: This study aimed to evaluate the implications of interleukin-31 (IL-31) in the pathogenesis of chronic spontaneous urticaria (CSU) and to assess the differences that occur between its serum values compared to controls. Additionally, the serum IL-31 levels were measured alongside other clinical and paraclinical parameters that were identified in the patients to understand its immunological importance in this skin disease and to determine if it could potentially serve as a therapeutic target in CSU in the future. (2) Methods: The serum levels of IL-31 were estimated in 50 patients diagnosed with CSU according to the accepted international guidelines. Additionally, 38 controls who had not experienced any episodes of urticaria during their lifetime were included. (3) Results: Significantly elevated serum IL-31 levels were observed in CSU patients compared to the controls (p < 0.0001). Although no direct correlations were found between IL-31 and inflammatory markers (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)), eosinophils, or total immunoglobulins E (IgE), significant differences in IL-31 levels were identified based on CSU severity, quality of life impact, itch intensity, and response to histamine H1 receptor antagonists (H1 antihistamines) (p < 0.05 for all). (4) Conclusions: Our findings underscore that IL-31 is not directly associated with general inflammation, eosinophilic response, or atopy in CSU. Nevertheless, its expression is influenced by key disease characteristics: severity, pruritus, and H1 antihistamine response. This investigation provides essential insights into CSU pathogenesis, potentially leading to novel therapeutic interventions. An enhanced understanding of these mechanisms is crucial due to the limitations of current treatment modalities in terms of fully managing CSU symptoms.

Acute urticaria—what to do?

SummaryAcute urticaria (AU) is the most common cause of wheal formation. By definition, it does not persist for more than 6 weeks. It can occur at any age and is more commonly seen in atopic diathesis. Acute spontaneous urticaria is distinguished from inducible forms. This review highlights the clinical presentation, differential diagnosis, possible triggers, and therapeutic strategies. In childhood as in adulthood, viral infections are very frequently associated with acute urticaria, whereas drugs and food are less frequently described as triggers. However, it is not uncommon for multiple triggers to be present simultaneously. Therapeutically, oral nonsedating H1 antihistamines are mainly used. In some patients, concomitant short-term administration of glucocorticosteroids is also necessary.

In Silico Screening of Inhibitors of the Venezuelan Equine Encephalitis Virus Nonstructural Protein 2 Cysteine Protease.

The Venezuelan equine encephalitis virus (VEEV) nonstructural protein 2 (nsP2) cysteine protease (EC 3.4.22.B79) is essential for viral replication. High throughput in silico/in vitro screening using a focused set of known cysteine protease inhibitors identified two epoxysuccinyl prodrugs, E64d and CA074 methyl ester (CA074me) and a reversible oxindole inhibitor. Here, we determined the X-ray crystal structure of the CA074-inhibited nsP2 protease and compared it with our E64d-inhibited structure. We found that the two inhibitors occupy different locations in the protease. We designed hybrid inhibitors with improved potency. Virus yield reduction assays confirmed that the viral titer was reduced by >5 logs with CA074me. Cell-based assays showed reductions in viral replication for CHIKV, VEEV, and WEEV, and weaker inhibition of EEEV by the hybrid inhibitors. The most potent was NCGC00488909-01 which had an EC50 of 1.76 µM in VEEV-Trd-infected cells; the second most potent was NCGC00484087 with an EC50 = 7.90 µM. Other compounds from the NCATS libraries such as the H1 antihistamine oxatomide (>5-log reduction), emetine, amsacrine an intercalator (NCGC0015113), MLS003116111-01, NCGC00247785-13, and MLS00699295-01 were found to effectively reduce VEEV viral replication in plaque assays. Kinetic methods demonstrated time-dependent inhibition by the hybrid inhibitors of the protease with NCGC00488909-01 (Ki = 3 µM) and NCGC00484087 (Ki = 5 µM). Rates of inactivation by CA074 in the presence of 6 mM CaCl2, MnCl2, or MgCl2 were measured with varying concentrations of inhibitor, Mg2+ and Mn2+ slightly enhanced inhibitor binding (3 to 6-fold). CA074 inhibited not only the VEEV nsP2 protease but also that of CHIKV and WEEV.

Rapid maxillary expansion and nasal patency in mouth breathing children with maxillary atresia due to or not due to allergic rhinitis.

To evaluate the effects of rapid maxillary expansion (RME) on nasal patency in mouth breathing (MB) children with maxillary atresia due to or not due to allergic rhinitis (AR) associated with asthma. Fifty-three MB children/adolescents (aged 7-14 years) with mixed or permanent dentition and maxillary atresia participated, with or without unilateral or bilateral crossbite. They formed the groups: RAD (AR + asthma; clinical treatment, RME); RAC (AR + asthma; clinical treatment, no RME); and D (mouth breathers; RME only). RAD and RAC patients received topical nasal corticosteroid and/or systemic H1 antihistamine (continuous use) and environmental exposure control. All were evaluated before RME (T1) and 6 months after (T2) with the CARATkids score, acoustic rhinometry, and nasal cavity computed tomography (CT). Patients RAD and D underwent RME (Hyrax® orthopedic appliance). A significant reduction in the CARATkids score occurred in the RAD (-4.06; p < 0.05), similarly when patient and parent/guardian scores were evaluated (-3.28 and -3.16, respectively). Acoustic rhinometry (V5) showed increased nasal volume in all groups, significantly higher in RAD patients than in RAC and D (0.99 × 0.71 × 0.69 cm3, respectively). CT of the nasal cavity documented increased volume in all three groups, with no significant differences between them. In MB patients with AR, asthma, and maxillary atresia, RME increased nasal cavity volume and improved respiratory symptoms. However, it should not be used as the only treatment for managing patients with respiratory allergies.

Effect of second-generation antihistamines on nighttime sleep and daytime sleepiness in patients with allergic rhinitis.

The daytime tiredness experienced by the vast majority of allergic rhinitis (AR) sufferers is directly related to the fact that they experience disrupted sleep at night. This study compared the effects of recently marketed second-generation H1 antihistamines (SGAs) on nighttime sleep and daytime sleepiness in patients with AR, with patients grouped into those taking non-brain-penetrating antihistamines (NBP group) and those taking brain-penetrating antihistamines (BP group). Patients with AR completed self-administered questionnaire-based surveys to determine Pittsburgh Sleep Quality Index (PSQI) before and after taking SGAs. Statistical analysis was performed on each evaluation item. Of 53 Japanese patients with AR between 6 and 78years old, median (SD) agewas 37.0 (22.4) years old and 21 weremen (40%). Of the 53 patients, 34 were the NBP group and 19 were the BP group. In the NBP group, mean (SD) subjective sleep quality score after medication was 0.76 (0.50), which was significantly lower (better) than the score of 0.97 (0.52) before medication (p = 0.020). In the BP group, mean (SD) subjective sleep quality score after medication was 0.79 (0.54), which was not significantly different from the score of 0.74 (0.56) before medication (p = 0.564). In the NBP group, mean (SD) global PSQI score was 3.47 (1.71) after medication, which was significantly lower (better) than the score of 4.35 (1.92) before medication (p = 0.011). In the BP group, mean (SD) global PSQI score was 2.47 (2.39) after medication, which was not significantly different from the score of 3.00 (2.71) before medication (p = 0.125). Subjective sleep quality and global PSQI score were improved only in the group taking non-brain-penetrating SGAs.

PD04 Real-life experience of Scottish patients with idiopathic solar urticaria

Abstract We conducted a retrospective study to characterize our most recent cohort of patients with idiopathic solar urticaria (SU), to compare with our previous findings (Beattie PE, Dawe RS, Ibbotson SH, Ferguson J. Characteristics and prognosis of idiopathic solar urticaria: a cohort of 87 cases. Arch Dermatol 2003; 139:1149–54). We analysed data derived from our in-house database and paper and electronic records of patients with SU seen through the Scottish Photobiology Service between 2003 and 2022. Eighty-four patients with SU were seen in this period, 57 (68%) women and 27 (32%) men. Twenty-nine (35%) had a single consultation/phototesting and 55 (65%) had follow-up assessments. The average age of onset was 37 years, with the average age of diagnosis being 41 years, with delays from symptom onset to diagnosis ranging from 6 months to 24 years. Importantly, 20 (24%) patients self-reported systemic symptoms, most commonly fatigue, dizziness and nausea. Of 61 patients using antihistamines before diagnosis, 31 (51%) reported benefit. Of patients who tried sunscreens, 31 of 65 (48%) reported benefit. On monochromator phototesting, sensitivity predominantly involved the ultraviolet (UV)A waveband (335–400 + 27 nm in 55%), extending into the visible spectrum (&amp;gt; 430 + 27 nm) in 44% and UVB waveband (305 + 5 nm) in 1%, consistent with previous reports of predominant UVA/visible light dependency in SU. On review of follow-up data, we analysed the fold benefit in minimal urticaria dose (MUD) from testing on H1 antihistamines alone, H1 and H2 antihistamines combined and the addition of montelukast. Most (65%) responded with a more than twofold improvement in MUD after a single dose of H1 antihistamine, with only 35% not responding. Increasing the dose of H1 antihistamine did not provide notable additional benefit. There was a suggestion of improved responses by the addition of an H2 antagonist (in 76% vs. 66% with H1 antagonist alone), but this was not statistically significant (P &amp;gt; 0.05). No additional improvement in threshold sensitivity (MUD) was observed by the addition of montelukast. Small numbers of patients used other treatments such as photo(chemo)therapies and systemic immunosuppressants, and these were found to be of limited benefit. Since 2011, we have used omalizumab for patients with treatment-resistant SU. Of the current cohort, 13 received omalizumab, with 62% reporting a good clinical response and a further 15% a partial clinical response. Phototesting in these patients showed complete abolition of photosensitivity or excellent responses (more than fivefold increase in MUD) in 73%, demonstrating the efficacy of omalizumab in recalcitrant SU. Given the systemic features reported by some patients with SU, this supports a management approach, which includes systemic immunomodulation as a potentially effective option.

Assay of Diphenhydramine HCl in Syrup by High Performance Liquid Chromatography

Cough is a natural response from the respiratory tract by increasing the clearance of secretions and particles from mucus, irritants, foreign particles, and microbes, so that it can act as a body defense. One way that can be done to relieve cough symptoms is to use symptomatic drugs. Diphenhydramine HCl is an antihistamine that belongs to the first generation H1 receptor antagonist (H1 blocker) group which has sedative and anti-allergic properties. Diphenhydramine HCl is used to treat sneeze, runny nose, watery eyes, itches, skin rashes, and other cold symptoms or other allergies. Diphenhydramine HCl is also used to treat motion sickness and to induce sleep. The purpose of this study was to determine the contents of diphenhydramine HCl syrup sold in the market. This test uses the High Performance Liquid Chromatography (HPLC) method with acetonitrile as a mobile phase; water; triethylamine (50;50;0.5). The results obtained the average content of Diphenhydramine HCl 102.5%. So it can be concluded that the cough medicine sample meets the requirements because the contents are not less than 90% and not more than 110% based on the Indonesian Pharmacopoeia Edition VI 2020.&#x0D; Keywords: Cough, Diphenhydramine HCl, High Performance Liquid Chromatography (HPLC)

The efficacy of cationic amphiphilic antihistamines on outcomes of patients with pancreatic ductal adenocarcinoma.

e16253 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. H1 antihistamines with cationic amphiphilic properties have been shown to possess antitumor effects and were associated with reduced mortality in several cancer types. We aimed to investigate the effects of cationic amphiphilic antihistamines on the outcomes of patients with PDAC. Methods: We conducted a retrospective cohort study at two tertiary centers in Taiwan between 2010 and 2021. We included all adult patients with histologically confirmed PDAC. Cationic amphiphilic antihistamines included desloratadine, cyproheptadine, and ebastine. The rest of the antihistamines were classified as non-cationic amphiphilic. Patients treated with cationic amphiphilic antihistamines were matched in a 1:2 ratio to patients treated with non-cationic amphiphilic antihistamines based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS) and objective response rates (ORR). Results: Among 407 patients included in the study, 28 cationic amphiphilic antihistamine users were matched to 56 non-cationic amphiphilic antihistamine users. Over a median follow-up of 6.3 [IQR, 2.0-13.8] months, 67 patients died. Compared with non-users, patients who received cationic amphiphilic antihistamines had a longer OS (median 16.4 [IQR, 2.8 – 89.0] vs. 5.8 [IQR, 2.0 – 9.8] months; p &lt; 0.001) and PFS (median 12.2 [IQR, 2.2 – 83.3] vs. 5.2 [IQR, 1.7 – 8.4] months; p = 0.002). In Cox proportional hazard models, the use of cationic amphiphilic antihistamines was associated with an approximately 60% lower risk of all-cause mortality and disease progression. Cationic amphiphilic antihistamine users also had greater ORR than non-users (complete or partial response, 39% vs. 7%, p = 0.004). Conclusions: The use of cationic amphiphilic antihistamines was associated with improved survival among patients with pancreatic cancer. [Table: see text]

Are antimuscarinic effects common in hydroxyzine overdose? A cohort analysis of antimuscarinic effects in hydroxyzine and diphenhydramine-poisoned patients

Introduction Exposures to hydroxyzine, a first-generation H1 antihistamine, have increased rapidly over the last two decades. Many assumptions about hydroxyzine poisoning are based on other antihistamines, like diphenhydramine. However, the receptor affinities of hydroxazine suggest that there should be fewer antimuscarinic findings than diphenhydramine. Methods This was a cohort study that compared hydroxyzine and diphenhydramine exposures reported to the National Poison Data System between January 1, 2000, and December 31, 2020, and the Toxicologic Investigators Consortium Core Registry between January 1, 2010, and December 31, 2020. The primary outcome was to assess for antimuscarinic findings in hydroxyzine-poisoned patients, using diphenhydramine-poisoned patients as a comparison group. The secondary outcomes were to assess for markers of overall toxicity. Inclusion criteria were single-substance exposures with known outcomes. Exclusion criteria for National Poison Data System exposures were chronic exposures, unintentional exposures, and patients younger than 12 years old. There were no exclusion criteria for exposures reported to the Toxicologic Investigators Consortium Core Registry. Results There were 17,265 hydroxyzine and 102,354 diphenhydramine exposures reported to the National Poison Data System and 134 hydroxyzine and 1,484 diphenhydramine exposures reported to the Toxicologic Investigators Consortium Core Registry that met inclusion criteria. In both datasets, hydroxyzine-poisoned patients had lower rates and relative risk of developing antimuscarinic findings or receiving physostigmine, with the exception of hyperthermia in the Toxicologic Investigators Consortium Core Registry dataset. Coma/central nervous system depression (major), respiratory depression, seizures, ventricular dysrhythmias, intubation, and benzodiazepine administration were less likely in hydroxyzine-poisoned patients, but central nervous system depression (mild) was more likely in exposures reported to the National Poison Data System. The mortality in hydroxyzine-poisoned patients was rare: 0.02% and 0.8% of exposures reported to the National Poison Data System and Toxicologic Investigators Consortium Core Registry, respectively. Discussion The clinical manifestations of hydroxyzine exposures are consistent with the pharmacology of hydroxazine. The clinical effects were consistent across two United States national datasets. Clinicians should not generalize the illness script of diphenhydramine exposures to hydroxyzine exposures. Conclusions Hydroxyzine-poisoned patients were less likely to develop antimuscarinic findings than diphenhydramine-poisoned patients. Hydroxyzine-poisoned patients were more likely to have mild central nervous system depression than an antimuscarinic toxidrome.