H2-receptor Antagonists Research Articles

Design, synthesis and biological evaluation of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues as multiple functional agents with the potential for the treatment of Alzheimer’s disease

A novel series of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues were designed and synthesized as H3 receptor antagonism based multitarget-directed ligands (MTDLs) for AD therapy using pharmacophore-combine strategy. The 2-styryl-5-hydroxy-4-pyrone pharmacophore with metal ion chelation, antioxidation, and Aβ aggregation inhibition activities was employed as the “eastern part”, and a typical phenoxyalkylamine moiety was used as “central ring + western part” of the H3 receptor antagonist. The biological evaluation revealed that the majority of the target compounds demonstrated desirable multiple functions. The two most promising compounds 8a and 8b exhibited nanomolar IC50 values on H3 receptor antagonism, excellent metal ion chelating capability, more potent ABTS+ scavenging activity than Trolox, efficient Aβ self-aggregation and Cu2+-induced aggregation inhibitory activities, as well as disaggregation activities against Aβ self/Cu2+-induced aggregation.

Utilization-review-of-anti-peptic-ulcer-drugs-at-an-outpatient-pharmacy-setting-of-a-private-hospital-in-malaysia

Anti-peptic ulcer drugs (APUDs) such as proton pump inhibitors (PPI), H2 receptor antagonists (H2A), antacids are widely prescribed. This study is aimed to describe the utilisation pattern of APUDs based on WHO Defined Daily Dose (DDD) and identify most commonly used APUD in the selected hospital. A retrospective study was carried out in outpatient of the selected hospital for year 2017. Sample size was calculated using Raosoft. DDD of APUDs and direct drug cost were calculated. Data were collected through electronic medical record by retrieving patients’ registration number. Inclusion criteria were patients above 18 years old and APUDs prescribed for gastrointestinal related indications. A total of 160 prescriptions were randomly selected for data analysis. Based on the DDD calculated, Rabeprazole 20mg was most prescribed drug among PPI (n=33), while Maalox is most prescribed drug among the antacids (n=23). Based on the DDD calculated, Pantoprazole 20mg recorded highest rates per user per day about 1.26 DDD / user / day while antacids, Actal reported highest usage rate with 7.11 DDD / user / day. Besides, there are 5.4 days supplied per user for this drug. Dexlansoprazole 60mg is the most expensive drug among all the PPI listed in hospital formulary. It has 18.5 days supplied/user, which is the second shortest duration of treatment among all the other PPIs. In contrast, omeprazole 20mg is the lowest cost PPI but the duration supplied per user is longer resulting in higher total cost of therapy. In conclusion, PPIs were the most commonly prescribed.

Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection

Apart from prevention using vaccinations, the management options for COVID-19 remain limited. In retrospective cohort studies, use of famotidine, a specific oral H2 receptor antagonist (antihistamine), has been associated with reduced risk of intubation and death in patients hospitalized with COVID-19. In a case series, nonhospitalized patients with COVID-19 experienced rapid symptom resolution after taking famotidine, but the molecular basis of these observations remains elusive. Here we show using biochemical, cellular, and functional assays that famotidine has no effect on viral replication or viral protease activity. However, famotidine can affect histamine-induced signaling processes in infected Caco2 cells. Specifically, famotidine treatment inhibits histamine-induced expression of Toll-like receptor 3 (TLR3) in SARS-CoV-2 infected cells and can reduce TLR3-dependent signaling processes that culminate in activation of IRF3 and the NF-κB pathway, subsequently controlling antiviral and inflammatory responses. SARS-CoV-2-infected cells treated with famotidine demonstrate reduced expression levels of the inflammatory mediators CCL-2 and IL6, drivers of the cytokine release syndrome that precipitates poor outcome for patients with COVID-19. Given that pharmacokinetic studies indicate that famotidine can reach concentrations in blood that suffice to antagonize histamine H2 receptors expressed in mast cells, neutrophils, and eosinophils, these observations explain how famotidine may contribute to the reduced histamine-induced inflammation and cytokine release, thereby improving the outcome for patients with COVID-19.

Population Pharmacokinetics of Bruton Tyrosine Kinase Inhibitor, Acalabrutinib, in Healthy Volunteers and Patients with B-Cell Malignancies

▪Background:Acalabrutinib (ACP-196) is a highly selective, potent, covalent inhibitor of Bruton tyrosine kinase (BTK), in development for the treatment of hematologic malignancies. In the class of irreversible covalent binding kinase inhibitors, the duration of pharmacodynamic activity is a function of the de novo synthesis rate of the target protein, as inhibition of signal transduction is maintained until functional levels of the target kinase are restored (Barf and Kaptein 2012). Acalabrutinib has rapid absorption and a short pharmacokinetic (PK) half-life; twice daily dosing resulted in near complete and continuous BTK inhibition in patients with chronic lymphocytic leukemia (CLL) (Byrd JC et al., 2016).The objective of this population PK analysis was to describe the PK of acalabrutinib in healthy volunteers (HV) and patients with B-cell malignancies, including mantle cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma and Waldenström macroglobulinemia, and investigate effects of covariates on exposure to acalabrutinib.Methods:Data originated from 6 Phase 1 trials in healthy volunteers (HV) and 6 Phase 1/2 trials in patients with B-cell malignancies. Rich acalabrutinib concentration data had been collected on Day 1 and Day 8, 14 or 22 (for multiple dose studies). Acalabrutinib concentration-time data were analyzed using a population modelling approach in NONMEM (v. 7.3). Body weight was added to the base model according to allometric principles (Anderson BJ et al., 2008). A full covariate model approach was conducted to investigate if race, sex, health group (Eastern Cooperative Oncology Group [ECOG] performance status [0 vs. 1]), renal (eGFR) and hepatic (NCI Criteria) impairment, dose or concomitant use of acid-reducing agents, resulted in clinically relevant changes in acalabrutinib exposure.Results:The pooled dataset comprised 11196 acalabrutinib plasma concentrations from 285 HV and 292 patients over a dose range of 15-400 mg. A 2-compartment model with sequential zero- and first-order absorption and a lag time, adequately described the concentration-time profiles. Acalabrutinib had fast absorption and elimination, with no accumulation at the suggested therapeutic dosing regimen of 100 mg BID (fig1). A decrease in apparent clearance (CL/F) was observed with increasing dose. However, the change in CL/F was negligible in the dose range of 75 mg-250 mg and the PK can be considered linear in that range.Neither age (42 to 90 years), sex, race (Caucasian and African American), ECOG performance status (0 or 1), nor body weight had clinically meaningful effects on the pharmacokinetics of acalabrutinib.No clinically relevant pharmacokinetic difference was observed in subjects with mild or moderate renal impairment. Acalabrutinib pharmacokinetics have not been studied in patients with severe renal impairment or renal impairment requiring dialysis.There was no clinically relevant difference in acalabrutinib exposures between subjects with mild or moderate hepatic impairment (NCI Criteria) and subjects with normal hepatic function. Patients with severe hepatic impairment have not been studied.Use of acid-reducing agents (H2-receptor antagonists and/or proton pump inhibitors) resulted in a 32% decrease in maximum concentration (Cmax,ss) and a 17% decrease in 24h area under the curve (AUC24h,ss). The clinical relevance of this finding is unknown and will be the subject of further investigation.Conclusions:The population PK model adequately described the concentration-time profiles of acalabrutinib in healthy subjects and patients.The suggested therapeutic dose of 100 mg BID did not result in accumulation of acalabrutinib, and in the dose range of 75 mg-250 mg, PK can be considered linear.The pharmacokinetics of acalabrutinib were not meaningfully affected by age, sex, race, ECOG performance status, mild or moderate hepatic or renal impairment, or body weight. The effect of acid-reducing agents will be further explored. [Display omitted] DisclosuresEdlund:Astra Zeneca: Employment. Andrew:Acerta Pharma: Employment; Astra Zeneca: Equity Ownership. Jin:Theravance Biopharma: Employment. Patel:Acerta Pharma: Employment. Masson:Astra Zeneca: Employment, Equity Ownership. Slatter:Acerta Pharma: Employment; Astra Zeneca: Equity Ownership. Aksenov:Astra Zeneca: Employment. Al-Huniti:Astra Zeneca: Employment.

Design, development and optimization of sustained release floating, bioadhesive and swellable matrix tablet of ranitidine hydrochloride.

Ranitidine HCl, a selective, competitive histamine H2-receptor antagonist with a short biological half-life, low bioavailability and narrow absorption window, is an ideal candidate for gastro-retentive drug delivery system (GRDDS). Controlled release with an optimum retentive formulation in the upper stomach would be an ideal formulation for this drug. The aim of the present study was therefore to develop, formulate and optimize floating, bioadhesive, and swellable matrix tablets of ranitidine HCl. The matrix tablets were prepared using a combination of hydroxypropyl methylcellulose (HPMC) and sodium carboxymethyl cellulose (NaCMC) as release retarding polymers, sodium bicarbonate (NaHCO3) as gas generating agent and microcrystalline cellulose (MCC) as direct compression diluent. Central composite design (CCD) was used to optimize the formulation and a total of thirteen formulations were prepared. Concentration of HPMC/NaCMC (3:1) (X1) and NaHCO3 (X2) were selected as independent variables; and floating lag time (Y1), bioadhesive strength (Y2), swelling index at 12 h (Y3), cumulative drug release at 1 h (Y4), time to 50% drug release (t50%) (Y5) and cumulative drug release at 12 h (Y6) were taken as the response variables. The optimized batch showed floating lag time of 5.09 sec, bioadhesive strength of 29.69 g, swelling index of 315.04% at 12 h, t50% of 3.86 h and drug release of 24.21% and 93.65% at 1h and 12 h, respectively, with anomalous release mechanism. The results indicate that sustained release matrix tablet of ranitidine HCl with combined floating, bioadhesive and swelling gastro-retentive properties can be considered as a strategy to overcome the low bioavailability and in vivo variation associated with the conventional ranitidine HCl tablet.

Changes in synaptic proteins of the complex PSD-95/NMDA receptor/nNOS and mitochondrial dysfunction after levocabastine treatment

Nitric oxide generation is related to the activity of certain proteins located at synaptic sites. Previous findings show that NOS activity, nNOS protein expression, respiratory parameters and mitochondrial complex activities are altered in rat cerebral cortex by administration of levocabastine, an antagonist of histamine H1 and neurotensin NTS2 receptors. ATP provision by mitochondria may play an important role in the functional interaction between synaptic proteins NMDA receptor and PSD-95 with NO synthesis. In this context, our purpose was to evaluate the effect of levocabastine administration on protein expression of PSD-95, GluN2B and iNOS, as well as on mitochondrial ATP production. Male Wistar rats received a single (i.p.) dose of levocabastine (50 μg/kg) or saline solution (controls) and were decapitated 18 h later. Mitochondrial and synaptosomal membrane fractions were isolated from cerebral cortex by differential and sucrose gradient centrifugation. Expression of synaptic proteins was evaluated by Western blot assays in synaptosomal membrane fractions. Oxygen consumption, mitochondrial membrane potential and ATP production rate were determined in fresh crude mitochondrial fractions. After levocabastine treatment, protein expression of PSD-95, GluN2B and β-actin decreased 97, 45 and 55%, respectively, whereas that of iNOS enhanced 3.5-fold versus controls. In crude mitochondrial fractions levocabastine administration reduced roughly 15% respiratory control rate as assayed with malate-glutamate or succinate as substrates, decreased mitochondrial membrane potential (21%), and ATP production rates (57%). Results suggested that levocabastine administration induces alterations in synaptic proteins of the protein complex PSD-95/NMDA receptor/nNOS and in neuron cytoskeleton. Mitochondrial bioenergetics impairment may play a role in the functional link between synaptic proteins and NO synthesis.

Adenosine A2AR/A1R Antagonists Enabling Additional H3R Antagonism for the Treatment of Parkinson's Disease.

Adenosine A1/A2A receptors (A1R/A2AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H3 receptor (H3R) antagonists in combination with the "caffeine-like effects" of A1R/A2AR antagonists, we designed A1R/A2AR/H3R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H3R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H3R affinities (Ki < 55 nM). Compound 4 (ST-2001, Ki (A1R) = 11.5 nM, Ki (A2AR) = 7.25 nM) and 12 (ST-1992, Ki (A1R) = 11.2 nM, Ki (A2AR) = 4.01 nM) were evaluated in vivo. l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg-1, i.p. rats). Compound 12 (2 mg kg-1, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.

The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut.

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.

Chitosan-centered nanosystems as sustained therapeutics for allergic rhinitis intervention: Inhibition of histamine-induced cascades

Allergic rhinitis (AR), histamine-mediated upper airway inflammatory disorder, is characterized by sneezing, itching, airway hyperreactivity, etc. Though it is clinically well-managed by non-invasive inhaled antihistamines, for example, ketotifen (KT, histamine release inhibitor) and cetirizine (CTZ, histamine receptor antagonist), inherent defects of short mucosal in situ retention, frequent administration resulting in irritation to mucosa, and lack of target-specific sequential release of dual drug systems which have been proven to be more effective are inevitable, urging for alternative therapeutic strategies. Recent advances in nanotechnology may be pivotal to generating muco-adhesive nanosystems, which is desirable to prolong local retention, reduce dosing frequency and relieve mucosal irritation. In this regard, KT incorporated and CTZ decorated hydroxybutyl chitosan nanoparticles (K ⊂ CH NPs) were fabricated as nasal adaptive sequential release dual drug system for long-term AR therapy. Nasal adaptive morphology transformation and two-step payload release up to 72 h were achieved in vitro, with ~ 3-fold higher bio-adhesivity over free drugs appeared. K ⊂ CH NPs accomplished longer histamine release inhibition (~ 24 h) and histamine H1 receptor antagonism (~ 6 h), compared with free KT&CTZ of ~ 12 h and ~ 2 h, respectively. The nanosystems provided comparable anti-allergic effect to free antihistamines via successive intranasal dropping in AR rat, while encouragingly, significantly (P < 0.05) better therapeutic efficacy at reduced treatment frequency (every 4 days) and dose (half-dose). Therefore, the outcomes establish K ⊂ CH NPs as effective low-dose and long-interval administered nanosystems to ameliorate histamine-mediated AR inflammation, which could in principal find extensive utilizations in respiratory allergy intervention.

Efficacy and safety of stress ulcer prophylaxis in septic patients: a retrospective cohort study based on large database

To evaluate the effects and safety of stress ulcer prophylaxis (SUP) versus no prophylaxis in adult septic patients at risk of gastrointestinal bleeding (GIB). A retrospective cohort study was conducted, the data was extracted from Electronic Intensive Care Unit-Collaborative Research Database (eICU-CRD). All patients who received proton pump inhibitor (PPI) or H2 receptor antagonist (H2RA) or combined/sequential use for SUP within the first 48 hours of intensive care unit (ICU) admission were enrolled in the SUP group, those who did not received any SUP were enrolled in the non-SUP group. The differences of in-hospital mortality, length of ICU stay (LOS), the incidence of GIB and secondary infection complications between the two groups were compared. Propensity score matching (PSM) was conducted to balance the distributions of study variables between the two groups. Further subgroup analysis was performed according to whether SUP was used for more than 3 days. Multivariate Logistic regression analysis was conducted to analyze the factors influencing the outcome of GIB and secondary pneumonia. A total of 11 413 patients were included in the final analysis, with 9 799 patients in SUP group and 1 614 in non-SUP group. A 1:1 PSM created 1 600 patients in each cohort. (1) Baseline characteristics: compared with SUP group, patients in non-SUP group were older [years old: 69.0 (56.0, 80.0) vs. 67.0 (56.0, 78.0)], acute physiology and chronic health evaluation IV (APACHE IV) score and sequential organ failure assessment (SOFA) score were significantly lower [APACHE IV score: 65 (50, 73) vs. 72 (58, 87), SOFA score: 5 (4, 7) vs. 7 (5, 9)], higher rates of underlying diseases such as hypertension and diabetes [hypertension: 15.6% (252/1 614) vs. 12.2% (1 196/9 779), diabetes: 4.5% (72/1 614) vs. 3.3% (325/9 779), both P < 0.05], indicating that patients in the SUP group were more severe. (2) Comparison of clinical outcome: before PSM, SUP group had significantly higher in-hospital mortality [17.2% (1 688/9 799) vs. 10.9% (176/1 614)], longer LOS [days: 4.4 (2.9, 7.7) vs. 3.1 (2.5, 4.3)], and higher incidence of secondary pneumonia than non-SUP group [11.3% (1 112/9 799) vs. 6.8% (110/1 614)], with significant differences (all P < 0.05). There was no significant difference in the incidence of GIB and Clostridium difficile infection (CDI) between the two groups. After PSM, no significant differences were observed between the two groups with regard to in-hospital mortality, incidence of GIB and CDI. However, the SUP group had longer LOS [days: 3.9 (2.8, 6.6) vs. 3.1 (2.5, 4.3)], and higher incidence of secondary pneumonia [10.9% (174/1 600) vs. 6.8% (108/1 600)] compared with non-SUP group, the differences were statistically significant (all P < 0.05). Subgroup analysis showed that compared with SUP < 3 days group, patients in SUP ≥ 3 days group had higher disease severity score [APACHE IV score: 66 (51, 79) vs. 62 (48, 72), SOFA score: 6 (4, 8) vs. 5 (4, 7), both P < 0.05], in addition, patients in SUP ≥ 3 days group had higher in-hospital mortality, incidence of GIB and secondary pneumonia (16.4% vs. 10.7%, 6.1% vs. 1.8%, 19.0% vs. 8.6%, respectively), and longer ICU LOS [days: 6.6 (4.1, 11.8) vs. 3.5 (2.6, 5.3), all P < 0.05]. (3) Multivariate Logistic regression analysis showed that SUP ≥ 3 days group was associated with more GIB than that of non-SUP group [odds ratio (OR) = 1.84, 95% confidence interval (95%CI) was 1.07-3.08, P = 0.030], and the incidence of GIB was less in SUP < 3 days group than that of non-SUP group (OR = 0.57, 95%CI was 0.34-0.94, P = 0.020). When compared with non-SUP group, the risk of secondary pneumonia was increased both in SUP ≥ 3 days group and SUP < 3 days group (OR values were 2.95 and 1.34, 95%CI were 2.10-4.13 and 1.01-1.77, P values were < 0.001 and 0.040, respectively). Among critically ill adult patients with sepsis at risk for GIB, SUP showed no effect on reducing in-hospital mortality, the rate of GIB and CDI, but was associated with increased risk of secondary pneumonia and prolonged LOS.

Could Histamine H1 Receptor Antagonists Be Used for Treating COVID-19?

COVID-19 has rapidly become a pandemic worldwide, causing extensive and long-term health issues. There is an urgent need to identify therapies that limit SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Unbalanced lung inflammation is a common feature in severe COVID-19 patients; therefore, reducing lung inflammation can undoubtedly benefit the clinical manifestations. Histamine H1 receptor (H1 receptor) antagonists are widely prescribed medications to treat allergic diseases, while recently it has emerged that they show significant promise as anti-SARS-CoV-2 agents. Here, we briefly summarize the novel use of H1 receptor antagonists in combating SARS-CoV-2 infection. We also describe the potential antiviral mechanisms of H1 receptor antagonists on SARS-CoV-2. Finally, the opportunities and challenges of the use of H1 receptor antagonists in managing COVID-19 are discussed.

Unraveling the thermodynamics, enzyme activity and denaturation studies of Triprolidine hydrochloride binding with model transport protein

The binding mechanism and stability study of triprolidine hydrochloride (TRP), a H1-receptor antagonist with model transport protein, bovine serum albumin (BSA) has been investigated using isothermal titration calorimetry (ITC), enzyme kinetics, chemical and thermal denaturation along with molecular docking method. The association constant (Ka), standard enthalpy change (ΔH°), standard entropy change (ΔS°) and standard Gibbs free energy change (ΔG°) were obtained from ITC which suggest that the interaction of BSA with TRP is an endothermic process and hydrophobic forces play a major role in complexation. The effect of TRP on chemical and thermal denaturantion of BSA has been shown by CD spectroscopy substantiating that the stability of unfolded state is enhanced due to TRP. The esterase-like activity of BSA in presence of TRP shows that it inhibits the esterase activity of BSA in a competitive manner. Molecular docking was performed to further confirm the binding forces responsible for the complex formation and amino acids involved in this process. Thus, this study will provide useful information regarding the interaction of TRP with BSA, helping to understand the activity, stability and mechanism of TRP binding and highlights its importance in the clinical medicine.

Evaluation of Drug-Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors.

(1) Background. The onset of a drug–drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN® (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line; ECOG PS 0–2; taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN®. (3) Results. Ninety-two patients, median age of 68.5 years (range 43–89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified; the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified (p = 0.02; HR 0.281, 95% CI 0.096–0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.

Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study

ObjectiveTo investigate the use of repurposed and adjuvant drugs in patients admitted to hospital with covid-19 across three continents.DesignMultinational network cohort study.SettingHospital electronic health records from the United States, Spain,...

Formulation Development and Evaluation of Fast Dissolving Films of Oloptadine HCl

Our studies on the performance of formulation development and evaluation of fast dissolving films of Oloptadine HCL its anti-allergic drug. Prepare mouth dissolving film of Oloptadine HCl by solvent casting method. To characterize the prepared mouth dissolving film of Oloptadine HCL in terms of— Thickness, percent elongation, tack test, swelling index, in-vitro disintegration time and dissolution test. Oloptadine OLO), 11-[{z}-3-(Dimethlamino) propylidene]-6-11-dihydrobenz [b, e] oxepin-2-acetic acid hydrochloride, is widely used as an antihistaminic. Oloptadine HCL is a relatively selective histamine H1-receptor antagonist that inhibits the release of histamine from mast cells. Oloptadine does not affect alpha-adrenergic dopamine, muscarinic type 1 and 2 or serotonin receptor. They are hydrophobic in nature and non-polar, sparingly soluble in water and freely soluble methanol, ethanol. Olopatadine HCl is a mouth dissolving film. We is trying to sort out the problem of allergic. They are rapidly onset of action, when placed upon the tongue that it is disperse rapidly swallowing within 3-5 seconds without need of water or chewing.

506 Samelisant: Baseline Characteristics from a Phase 2 Study Evaluating Efficacy and Safety in Patients with Narcolepsy

Abstract Introduction histamine H3 receptor (H3R) antagonists/ inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant (SUVN-G3031) is a potent and selective H3R inverse agonist exhibited selectivity over 70 other targets. Samelisant showed wake-promoting and anticataplectic effects in orexin knockout mice suggesting its potential therapeutic utility in the treatment of EDS and cataplexy associated with narcolepsy. Safety and tolerability studies in animals and healthy humans suggested a favorable risk/benefit profile. Methods The current study is a 2 week treatment, multicenter, double-blind, placebo controlled, parallel-group study in patients with Narcolepsy with or without Cataplexy. Eligibility criteria include age between 18 to 50 years old, an ESS score of ≥ 12; and mean MWT time of &amp;lt; 12 minutes and a confirm diagnosis of narcolepsy as per ICSD-3. Further, the randomization will be stratified according to type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks in a fixed ratio of 1:1:1. The primary efficacy endpoint is change in maintenance of wakefulness test (MWT) score from baseline to week 2. Key secondary endpoints include change from baseline to week 2 in ESS and an improvement in CGI-S scores. Safety will be monitored by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results As of data cutoff date of Dec 20, 2020, a total of 54 subjects were completed in the study. The median age of subjects was 30 years (range: 18 - 50 years) with mean BMI of 28.6 (range: 18.3 - 43.1 kg/m2). Overall, 74% of subjects were female and 83% were Caucasian. Mean (SD) baseline values of MWT and ESS are 5.65 (3.5) and 16.7 (2.5), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling the subjects with Narcolepsy with or without Cataplexy, and the Data readout is expected in the second half of 2021. Support (if any):

The skeletal muscle relaxer cyclobenzaprine is a potent non‐competitive histamine H1 receptor antagonist

Cyclobenzaprine (Flexeril®) is a tricyclic dimethylpropanamine skeletal muscle relaxant that is used clinically to decrease muscle spasm and hypercontractility, without altering homeostatic muscle function. Although the absolute mechanism of action of cyclobenzaprine is unknown, it acts centrally to reduce tonic somatic motor function, likely via modulation of serotonergic and/or noradrenergic systems. While cyclobenzaprine is effective as a muscle relaxant, greater than 30% of patients experience drowsiness and sedative effects, yet, the mechanisms that cause these side effects are also undescribed. Based on this common adverse effect profile and the structural similarity of cyclobenzaprine to tricyclic antidepressants, we hypothesized that cyclobenzaprine facilitates sedative effects via off-target antagonism of central histamine H1 receptors (H1R). Here, for the first time, we present data that demonstrate that cyclobenzaprine exhibits low nanomolar affinity for the cloned human H1R, as well as that expressed in both rat and mouse brain. Using saturation binding experiments, our results demonstrate that cyclobenzaprine binds to the H1R in a non-competitive manner. Finally, using functional Ca+2 influx assays and novel TRUPATH BRET sensors, we show that cyclobenzaprine also blocks histamine-mediated H1R functional activity in a non-competitive manner. Given that cyclobenzaprine readily crosses the blood-brain barrier and its muscle relaxant effects occur centrally, our data suggest that off-target central antagonism of H1R by cyclobenzaprine facilitate the significant sedative effect of this agent seen in patients.

The mast cell activator Compound 48/80 causes phasic urinary bladder smooth muscle contractions independent of histamine release

Inflammatory mediators released from mast cells cause both transient and phasic contractions of urinary bladder smooth muscle (UBSM). These contractions are viewed as initial disruptors of normal bladder function and can lead to profound bladder pathologies. However, the mechanisms responsible for each of these contractions has not been thoroughly investigated. Previously, we discovered that histamine-mediated contractions rapidly desensitize, whereas the mast cell activator compound 48/80 (10 µg/ml) caused both a long-lasting increase in the amplitude and frequency of phasic contractions in UBSM strips as well as a transient increase in baseline tension. Thus, we hypothesized that phasic contractions caused by compound 48/80 depended on the release of histamine from mast cells. Isometric contractility was performed with urothelium-intact UBSM strips from C57BL/6 mice in the presence or absence of the following drugs: the cholinergic antagonist atropine (2 µM); the 5HT2A receptor antagonist MDL 11939 (1 µM); the histamine H1 receptor antagonist fexofenadine (10 µM), the histamine H2 receptor antagonist roxatidine (25 µM), the H2 antagonist cimetidine (10 µM); or the mast cell stabilizer cromolyn (100 µM). None of the compounds tested significantly reduced the amplitude and duration of the spontaneous phasic contractions caused by compound 48/80. However, both MDL 11939 and cromolyn significantly reduced the baseline contraction. Our data suggest that responses to the mast cell activator compound 48/80 are a superimposition of 2 components: (1) a slowly desensitizing increase in baseline tension caused by release of 5-HT from mast cells, and (2) large-amplitude phasic contractions that are histamine- and 5HT-independent. However, the mechanism responsible for increases in the amplitude of phasic contractions remains unclear.

Histamine causes endothelium‐independent dilation of mouse bladder feeder arterioles

In addition to being highly vascularized, the urinary bladder vasculature has unique properties that help to maintain blood flow during voiding and filling. Unlike other vessels of similar size, however, bladder arterioles do not contract to increases in intraluminal pressure. Prolonged decreases in bladder blood flow are linked to many types of bladder dysfunction, including painful bladder syndrome and interstitial cystitis. Although the vasculature has an important role in bladder dysfunction, the mechanisms regulating vasculature diameter in the bladder are still widely unknown. We tested the hypothesis that histamine, an important pro-inflammatory compound released from mast cells in the bladder wall, also alters bladder arteriolar diameter. Using pressure myography with isolated bladder feed arterioles, concentration-response curves to histamine (1 nM – 10 µM) were performed in vessels constricted with the thromboxane mimetic U-46619 (10 nM). Histamine caused a concentration-dependent vasodilation that was inhibited by the histamine H2 receptor antagonist cimetidine (10 µM) but not the H1 receptor antagonist fexofenadine (10 µM). Histamine-dependent vasodilation was not inhibited by the NOS inhibitor L-NAME (200 µM), the inward rectifier K+ channel blocker BaCl2 (100 µM), or endothelial denudation, suggesting the dilation was endothelium-independent. Alternatively, increasing extracellular K+ (35 mM) or exposure to the KV channel blocker XE-991 (10 µM) attenuated dilations to histamine. These findings suggest the H2 receptors in bladder vascular smooth muscle, and not the endothelium, mediate histamine-induced dilation in bladder arterioles. Since H2 receptors are coupled to GaS, these findings also suggest that histamine dilation results from an increase in cAMP that may hyperpolarize smooth muscle cells via protein kinase A-mediated activation of smooth muscle KV channels.

Histamine Activates Chemosensitive Neurons in the Retrotrapezoid Nucleus

Histaminergic neurons of the posterior hypothalamic tuberomammillary nucleus (TMN) are pH-sensitive and contribute to CO2/H+-dependent behaviors including arousal and respiratory activity. Considering histaminergic neurons project to several brainstem respiratory centers including the retrotrapezoid nucleus (RTN), and since chemosensitive RTN neurons are an important source of CO2/H+-dependent respiratory drive, we wondered whether and how histamine contributes to RTN chemoreception at the cellular level and in anesthetized rats. In brain slices obtained from rat pups (7-12 days old), chemosensitive RTN neurons were identified in cell-attached voltage-clamp mode by their characteristic firing response to CO2 (≥ 0.8 Hz increase in activity in response to 10% CO2). We found that most chemosensitive RTN neurons showed a dose dependent increase in activity in response to bath application of histamine dihydrochloride (HD: 1-25 μM). The increased activity of RTN neurons by HD (25 mM) was blunted by bath application of the H1 receptor antagonist DPH (diphenhydramine hydrochloride; 100 µM) (1.1 ± 0.1 Hz to -0.06 ± 0.2 Hz; n = 7) or the H2 receptor antagonist ranitidine (ranitidine hydrochloride; 10 µM) (1.0 ± 0.2 Hz to 0.3 ± 0.3 Hz; n = 5). At the whole animal level, we measured mean arterial pressure (MAP) and diaphragm muscle activity (DIAEMG) in urethane-anaesthetized, vagotomized and artificial ventilated male Wistar rats. Unilateral injection of HD (25 mM - 50 nl) into the RTN increased DIAEMG amplitude (17.41 ± 3.8 vs. saline: 0.55 ± 1.9%) and DIAEMG frequency (4.72 ± 1.7 vs -1.8 ± 1.5) without changes MAP. Bilateral injections of DPH (0.5 mM) into the RTN decreased DIAEMG amplitude (-62.6 ± 14.5. vs. saline: -1.1 ± 1.3%), DIAEMG frequency (-66.4 ± 13.4 vs. saline: -1.5 ± 1.9%) and MAP (-43.67 ± 8,4 vs. saline: -3.2 ± 1.7 mmHg). Despite the strong inhibitory effect of DPH on baseline breathing, the hypercapnic ventilatory response was preserved in urethane-anesthetized rats under these experimental conditions. These results suggest histamine signaling via H1 and H2 receptors modulates activity of RTN neurons and respiratory activity.