Search Results (109)

Influenza is still a chronic global health threat, inducing a sustained search for effective antiviral therapeutics. Computational methods have played a pivotal role in developing small molecule therapeutics. In this study, we applied a combined in silico and in vitro approach to explore the potential anti-influenza activity of cyproheptadine, a clinically used histamine H1 receptor antagonist. Virtual screening based on the average quasivalence number (AQVN) and electron–ion interaction potential (EIIP) descriptors suggests similarities between cyproheptadine and several established anti-influenza agents. The subsequent ligand-based pharmacophore screening of a focused H1 antagonist library was aligned with the bioinformatics prediction, and further experimental in vitro evaluation of cyproheptadine demonstrated its anti-influenza activity. These findings provide proof of concept for cyproheptadine’s in silico-predicted antiviral potential and underscore the value of integrating computational predictions with experimental validation. The results of the current study provide a preliminary proof of concept for the predicted anti-influenza potential based on computational analysis and emphasize the utility of integrating in silico screening with experimental validation in the early stages of drug repurposing efforts. Full article

Background/Objectives: The incidence of food allergies and other allergic diseases is rising. Emerging evidence links both antimicrobials and acid-suppressive therapy with gut dysbiosis, which is implicated in allergy development. We investigated the relationship between the use of acid-suppressive medications or antimicrobials in infancy and the risk of developing childhood allergic diseases. Methods: The US network in the TriNetX platform was used to identify patients prescribed proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H₂RAs), antimicrobials ≥1, or antimicrobials ≥3 times during their first year of life from October 2015 to January 2022. ICD-10 diagnoses were used to assess two-year outcomes of anaphylaxis, food allergy, and atopic dermatitis. A sub-analysis in gastroesophageal reflux (GERD) patients was also performed. Results: Risks of anaphylaxis and food allergy increased with the prescription of PPIs (risk ratio [95% CI], 2.49 [1.40–4.41], 5.33 [4.97–5.71]), H₂RAs (4.48 [3.43–5.86], 4.21 [4.01–4.41]), and antimicrobials ≥1 (2.41 [2.13–2.72], 1.90 [1.86–1.94]), or ≥3 times (3.69 [3.12–4.37], 2.79 [2.70–2.88]). Risk of atopic dermatitis was increased in both H₂RA (1.41 [1.35–1.48]) and antimicrobial groups (2.25 [2.22–2.28], 3.35 [3.29–3.41]), but not in the PPI group. In the GERD sub-analysis, anaphylaxis risk was not significantly different, food allergy risk was increased in both PPI (2.30 [2.08–2.53]) and H₂RA groups (1.77 [1.63–1.92]), and atopic dermatitis decreased in the PPI group (0.76 [0.67–0.85]) but slightly increased in the H₂RA group (1.11 [1.03–1.20]). Conclusions: Exposure to acid-suppressive or antimicrobial medications during infancy was associated with increased risk of food allergy and anaphylaxis in early childhood. In infants diagnosed with GERD, exposure to acid-suppressive medications was still associated with increased food allergy risk. Full article

Background/Objectives: The nephrotoxicity of immune checkpoint inhibitors (ICIs) combined with proton pump inhibitors (PPIs) has been recognized but lacks a comprehensive analysis. We conducted an in-depth investigation of renal adverse events (rAEs) associated with ICIs and different acid-suppressing agents (ASAs)—including PPIs, histamine-2 receptor antagonists (H₂RAs), and potassium-competitive acid blockers (P-CABs)—using real-world data from the FDA’s Adverse Event Reporting System (FAERS). Methods: We analyzed rAE reports from the FAERS database covering Q1 2004 to Q1 2023. Disproportionality analysis was conducted to identify rAEs associated with ICI or ASA monotherapy or combination therapy. Univariate logistic regression was employed to explore influencing factors. Results: No eligible rAE reports were retrieved for H₂RAs and P-CABs. However, 6,775 reports in the ICI group, 54,055 reports in the PPI group, and 210 reports in the ICI–PPI combination therapy group were included in the final analysis. In PPI–ICI combination settings, tubulointerstitial nephritis had the highest reporting frequency and signal intensity; the overall risk of rAEs was significantly elevated compared to ICI or PPI monotherapy, with reporting odds ratios of 14. 65 (95% confidence interval [CI] 12.93–16.58) and 3.24 (95% CI 2.87–3.66), respectively; the median onset time was shortest at 21 days (interquartile range 5.5–135); and PD-1 monotherapy, omeprazole, and rabeprazole were associated with higher rAE risks. Conclusions: Our findings confirm that the combination of PPIs (but not other ASAs) with ICIs further increases the risk of various acute and chronic rAEs. Healthcare providers should exercise caution when managing patients on these therapies. Full article

Current treatment options for Alzheimer’s disease target neurotransmitters following the disease onset, and they offer limited efficacy without slowing down the disease progression. There has been an increasing concern in recent years targeting the histamine H3 receptor (H3R) in treating cognitive disorders, including dementia. Preclinical studies have shown that antagonists of H3R or inverse agonists enhance the cognitive function in animal models with dementia by increasing the release of neurotransmitters associated with learning and memory. This review employed a systematic literature search across databases including PubMed, Scopus, Google Scholar, and ClinicalTrials.gov, selecting peer-reviewed studies. The results of this study illustrate the complex landscape of research on H3R modulators in dementia, highlighting both promising findings and ongoing challenges in translating preclinical discoveries into effective clinical interventions. Knowing the role of H3R in dementia and developing novel pharmacological interventions targeting these receptors represent a promising avenue for future research, leading to the development of new treatments for this devastating condition. Full article

Background: The four subtypes of G protein-coupled receptors (GPCRs) regulated by histamine play critical roles in various physiological and pathological processes, such as allergy, gastric acid secretion, cognitive and sleep disorders, and inflammation. Previous experimental structures of histamine receptors (HRs) with agonists and antagonists exhibited multiple conformations for the ligands and G protein binding. However, the structural basis for HR regulation and signaling remains elusive. Methods: We determined the cryo-electron microscopy (cryo-EM) structure of the H4R-histamine-Gi complex at 2.9 Å resolution, and predicted the models for all four HRs in the ligand-free apo and G protein subtype binding states using AlphaFold3 (AF3). Results: By comparing our H4R structure with the experimental HR structures and the computational AF3 models, we elucidated the distinct histamine binding modes and G protein interfaces, and proposed the essential roles of Y^6.51 and Q^7.42 in receptor activation and the intracellular loop 2 (ICL2) in G protein bias. Conclusions: Our findings deciphered the molecular mechanisms underlying the regulation of different HRs, from the extracellular ligand-binding pockets and transmembrane motifs to the intracellular G protein coupling interfaces. These insights are expected to facilitate selective drug discovery targeting HRs for diverse therapeutic purposes. Full article

Background: This study explored the prescribing patterns of proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs) across the UK during the COVID-19 pandemic, highlighting the dynamic relationship between emerging evidence, regulatory actions, and clinical practices. Methods: Using a repeated cross-sectional design, prescription data from July 2019 to May 2024 were analyzed across England, Scotland, Wales, and Northern Ireland. Segmented regression analysis was employed to assess trends before and after January 2022, reflecting the impact of emerging evidence on prescribing behaviors. Results: The results revealed a significant increase in famotidine prescriptions, from 57.56 to 303.31 per 100,000 population in England post-January 2022, reflecting early adoption of preliminary findings despite the lack of randomized controlled trial confirmation. Ranitidine prescriptions fell to near zero due to contamination concerns, while PPIs like omeprazole remained the most prescribed, with Wales reporting the highest post-2022 usage at 7445.71 per 100,000 population. Conclusions: Adherence to deprescribing guidelines was inconsistent, with a possibility that many PPI users lacked documented indications. Regional variations in prescribing trends highlighted differences in guideline implementation. These findings underscore the need for improved evidence dissemination and adherence to prescribing guidelines. Future research should include patient-level data and long-term evaluations to optimize healthcare practices. Full article

Objectives: Gastroesophageal reflux disease (GERD) is commonly encountered in adults and children. A subset of patients with GERD are refractory to acid suppressants, implicating other factors in the refluxate. Duodenogastric reflux (DGR) produces similar symptoms through reflux of non-acidic duodenal content and the cytotoxic effect of bile in the esophageal mucosa. Various methods have been utilized to detect DGR using a Bilitec device or Hepatobiliary scintigraphy, amongst the most common, each with their own limitations. We aimed to use combined multichannel intraluminal impedance and pH (MII-pH) monitoring with an additional gastric pH sensor to collect information about acidic and non-acidic gastroesophageal refluxes and to assess whether continuous gastric pH measurement in children provides indirect evidence of DGR for better understanding of the symptoms. Methods: From 2022 through 2023, clinically symptomatic pediatric patients scheduled for esophagogastroduodenoscopy (EGD) and MII-pH at Arnold Palmer Hospital for Children in the United States were included (n = 26). Exclusions included patients taking acid suppressants prior to the start of this study. The data were analyzed for subjects completing at least 18 h of the study protocol. Results: Subjects with a normal pH impedance (n = 5) showed a median non-meal gastric pH of 1.8. Subjects with an abnormal pH impedance (n = 21) showed a median non-meal gastric pH of 2.2. Of the 26 subjects enrolled, the duration of non-meal gastric pH 4.0–7.0 was positively correlated with non-acidic gastroesophageal refluxes. Although all acidic reflux events occurred at gastric pH < 4.0, there was no correlation between the duration of non-meal gastric pH < 4.0 and impedance changes or reflux index. Conclusions: The results showed daily variability in the non-meal gastric pH of pediatric patients and a statistically significant correlation between its duration at pH 4.0 to 7.0 and non-acidic refluxes suggestive of the implication of DGR. Further research is required to assess this association with gastroesophageal reflux and dyspeptic symptoms to investigate the diagnostic tools and therapeutic interventions, including the role of prokinetics and surface protective agents for DGR. Full article

Background/Objectives: Postoperative nausea and vomiting (PONV) is a common and distressing complication after surgery. Hydroxyzine, an affordable histamine H1 receptor antagonist with anxiolytic, moderate sedative, and antiemetic properties, is often used perioperatively; however, few studies have investigated its effect on PONV. In this study, we examined the efficacy of hydroxyzine in preventing PONV. Methods: This single-center, retrospective, observational cohort study included 647 female patients at risk of PONV between July 2021 and September 2022. The primary endpoint was PONV incidence on the day of surgery, and secondary endpoints included PONV incidence up to postoperative day 2 and emergence time, analyzed using propensity score matching. Results: The patients were categorized into two groups: 71 received hydroxyzine 25 mg (HYD group), and 576 received no prophylactic antiemetic treatment (NOT group). After adjustment for confounders, PONV incidence on the day of surgery was significantly lower in the HYD (n = 69) group compared to the NOT (n = 193) group (34.8% vs. 57.0%, p = 0.002), and similar results were observed up to postoperative day 2 (47.8% vs. 65.3%, p = 0.016). Emergence time did not differ between groups. Conclusions: Prophylactic administration of hydroxyzine could be effective in decreasing PONV incidence, though further randomized controlled trials are warranted to confirm these results. Full article

Background/Objectives: Drugs exhibiting poor aqueous solubility present a challenge to efficient delivery to the site of action. Spanlastics (a nano, surfactant-based drug delivery system) have emerged as a powerful tool to improve solubility, bioavailability, and delivery to the site of action. This study aimed to better understand factors affecting the physicochemical properties of spanlastics, quantify their effects, and use them to enhance the bioavailability of famotidine (FMT), a model histamine H2 receptor antagonist (BCS class IV). Methods: FMT was incorporated into nano-spanlastics drug delivery system. The ethanol injection method, Box–Behnken design, and mathematical modeling were utilized to fabricate famotidine-loaded nano-spanlastics and optimize the formula. Spanlastics were characterized for their particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, compatibility of the excipients (using DSC), in vitro drug release, and in vivo pharmacokinetics. Results: Span 60 (the non-ionic surfactant) and tween 60 (the edge activator) gave rise to spanlastics with the best characteristics. The optimal spanlastic formulation exhibited small particle size (<200 nm), appropriate polydispersity index (<0.4), and zeta potential (>−30 mV). The entrapment efficiency and drug loading of the optimum formula assured its suitability for hydrophobic drug entrapment as well as practicability for use. DSC assured the compatibility of all formulation components. The drug release manifested a biphasic release pattern, resulting in a fast onset and sustained effect. Spanlastics also showed enhanced C_max, AUC_0–24, and bioavailability. Conclusions: Spanlastics manifested improved FMT dissolution, drug release characteristics, membrane permeation, and pharmacokinetic behavior. Full article

Famotidine is a histamine H2 receptor antagonist used in the treatment of gastrointestinal disorders. It is available in multiple formulations, including film-coated tablets, chewable tablets, oral suspension, and injections. The purpose of this study was to develop and evaluate the film-coated tablet (FT) containing famotidine, magnesium hydroxide, and precipitated calcium carbonate, designed to be pharmaceutically equivalent to the marketed chewable tablet (CT). To achieve the pharmaceutical equivalence of two tablets, the dissolution profiles of FT should be similar to those of CT. However, since CT is intended to be chewed before swallowing, testing it in its intact form would not provide accurate results. Therefore, pulverized chewable tablets (PCT) were used as the reference product. The dissolution, performed by the paddle method at 50 rpm, was analyzed by the validated UV method. Similarity factor (f₂) and difference factor (f₁) were calculated to assess the equivalence of the dissolution profiles. The results demonstrated that the dissolution profiles of the FT and CT were similar. Additionally, the acid-neutralizing capacity test confirmed the equivalence of the two antacids. This study is one of the first to propose that dissolution tests for pharmaceutical equivalence should be conducted on pulverized CTs when developing generic equivalents to CTs. Full article

Autism spectrum disorder is a complex neurodevelopmental disorder. The available medical treatment options for autism spectrum disorder are very limited. While the etiology and pathophysiology of autism spectrum disorder are still not fully understood, recent studies have suggested that wide alterations in the GABAergic, glutamatergic, cholinergic, and serotonergic systems play a key role in its development and progression. Histamine neurotransmission is known to have complex interactions with other neurotransmitters that fit perfectly into the complex etiology of this disease. Multitarget-directed compounds with an affinity for the histamine H₃ receptor indicate an interesting profile of activity against autism spectrum disorder in animal models. Here, we present the results of our research on the properties of (4-piperazin-1-ylbutyl)guanidine derivatives acting on histamine H₃ receptors as potential multitarget ligands. Through the virtual screening approach, we identified promising ligands among 32 non-imidazole histamine H₃ receptor antagonists/inverse agonists with potential additional activity against the dopamine D₂ receptor and/or cholinesterases. The virtual screening protocol integrated predictions from SwissTargetPrediction, SEA, and PPB2 tools, along with molecular docking simulations conducted using GOLD 5.3 and Glide 7.5 software. Among the selected ligands, compounds 25 and 30 blocked radioligand binding to the D₂ receptor at over 50% at a screening concentration of 1 µM. Further experiments allowed us to determine the pK_i value at the D₂ receptor of 6.22 and 6.12 for compounds 25 and 30, respectively. Our findings suggest that some of the tested compounds could be promising multitarget-directed ligands for the further research and development of more effective treatments for autism spectrum disorder. Full article

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social interaction difficulties, repetitive behaviors, and immune dysregulation with elevated pro-inflammatory markers. Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer’s disease. Methods: This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice. Results: E159 (2.5, 5, and 10 mg/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements. Conclusions: These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors. Full article

Repurposing utilizes existing drugs with known safety profiles and discovers new uses by combining experimental and computational approaches. The integration of computational methods has greatly advanced drug repurposing, offering a rational approach and reducing the risk of failure in these efforts. Recognizing the potential for drug repurposing, we employed our Iterative Stochastic Elimination (ISE) algorithm to screen known drugs from the DrugBank database. Repurposing in our hands is based on computer models of the actions of ligands: the ISE algorithm is a machine learning tool that creates ligand-based models by distinguishing between the physicochemical properties of known drugs and those of decoys. The models are large sets of “filters” made out, each, of molecular properties. We screen and score external sets of molecules (in our case- the DrugBank molecules) by our agonism and antagonism models based on published data (i.e., IC₅₀, K_i, or EC₅₀) and pick the top-scoring molecules as candidates for experiments. Such agonist and antagonist models for six G-protein coupled receptors (GPCRs) families facilitated the identification of repurposing opportunities. Our screening revealed 5982 new potential molecular actions (agonists, antagonists), which suggest repurposing candidates for the cannabinoid 2 (CB2), histamine (H1, H3, and H4), and dopamine 3 (D3) receptors, which may be useful to treat conditions such as neuroinflammation, obesity, allergic dermatitis, and drug abuse. These sets of best candidates should now be examined by experimentalists: based on previous such experiments, there is a very high chance of discovering novel highly bioactive molecules. Full article

Histamine (HA), a biogenic monoamine, exerts its pleiotropic effects through four H1R–H4R histamine receptors, which are also expressed in brain tissue. Together with the projections of HA-producing neurons located within the tuberomammillary nucleus (TMN), which innervate most areas of the brain, they constitute the histaminergic system. Thus, while remaining a mediator of the inflammatory reaction and immune system function, HA also acts as a neurotransmitter and a modulator of other neurotransmitter systems in the central nervous system (CNS). Although the detailed causes are still not fully understood, neuroinflammation seems to play a crucial role in the etiopathogenesis of both neurodevelopmental and neurodegenerative (neuropsychiatric) diseases, such as autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Given the increasing prevalence/diagnosis of these disorders and their socioeconomic impact, the need to develop effective forms of therapy has focused researchers’ attention on the brain’s histaminergic activity and other related signaling pathways. This review presents the current state of knowledge concerning the involvement of HA and the histaminergic system within the CNS in the development of neurodevelopmental and neurodegenerative disorders. To this end, the roles of HA in neurotransmission, neuroinflammation, and neurodevelopment are also discussed. Full article

Histamine H₃ receptor (H₃R) antagonists, such as betahistine (BHTE), have shown significant potential in treating central nervous system (CNS) disorders due to their neuroprotective properties. This study investigated BHTE’s effects on lipopolysaccharide (LPS)-induced neurotoxicity, which is associated with neuroinflammation and neurodegeneration. Rats were divided into groups and pre-treated with BHTE (5 or 10 mg/kg, p.o.) for 30 days, followed by LPS administration (1 mg/kg, i.p.) for 4 consecutive days to induce neurotoxicity. LPS exposure resulted in cognitive impairment, as evidenced by performance deficits in maze tests, and a significant reduction in brain acetylcholine (ACh) levels. Additionally, LPS led to increased neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Pre-treatment with BHTE effectively counteracted these effects, improving cognitive performance and restoring ACh levels. BHTE significantly reduced LPS-induced increases in pro-inflammatory markers (COX-2, TNF-α, and IL-6) while enhancing anti-inflammatory cytokines (IL-10 and TGF-β1). Furthermore, BHTE improved mitochondrial function by increasing enzyme levels (MRCC-I, II, and IV) and boosted anti-apoptotic (Bcl-2) and antioxidant defenses (GSH and catalase). BHTE also reduced apoptosis markers, including pro-apoptotic protein caspase-3, and oxidative stress marker malondialdehyde (MDA). Molecular modeling studies revealed that BHTE effectively binds to key enzymes involved in neuroinflammation and apoptosis (AChE, COX-2, and caspase-3), with binding free energies between 4 and 5 kcal/mol, interacting with critical residues. These findings underscore BHTE’s multifaceted neuroprotective effects against LPS-induced neurotoxicity, offering potential therapeutic avenues for managing neuroinflammation and related neurodegenerative disorders. Full article