H2-receptor Antagonists Research Articles

The effect of antibiotics, proton pump inhibitors, H2-receptor antagonists, and steroids on survival among ovarian cancer patients receiving PARP inhibitor therapy

The effect of antibiotics, proton pump inhibitors, H2-receptor antagonists, and steroids on survival among ovarian cancer patients receiving PARP inhibitor therapy

Impact of acid blocker therapy on growth, gut microbiome, and lung disease in young children with cystic fibrosis.

Acid blocker therapy (ABT) has become common in cystic fibrosis (CF), despite insufficient evidence for benefits and studies showing potentially negative effects. We examined associations between ABT usage and growth, gut microbiome (GM), and early-onset lung disease in young children with CF. One hundred forty-five infants with CF born during 2012-2017, diagnosed through newborn screening by age 3 months and followed to 36 months of age at six CF centers were evaluated. Longitudinal data on growth, pancreatic functional status, pulmonary symptoms, and acid blocker medications were prospectively collected. Early-onset lung disease severity was evaluated by a clinical scoring system. GM composition was assessed by 16S rRNA methodology. ABT use before age 3 years was frequent, with 81 (56%) of patients on H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI), and higher among pancreatic insufficient (60%) versus pancreatic sufficient (26%) children. H2RA was commonly prescribed in infancy before transitioning to PPI. Growth improvements were not significantly greater, while GM α-diversity at 3 years of age was significantly lower and early-onset lung disease more severe, in persistent ABT users compared to nonusers of ABT. In our cohort of young children with CF, early and persistent ABT use was not associated with significant growth benefits and instead showed associations with reduced GM diversity and negative effects on early-onset lung disease. Consequentially, there is a critical need for systematic evaluation and comprehensive risk-benefit analysis of ABT to ensure proper guidelines for children with CF.

Pancreaticogastrostomy: A Safe and Effective Reconstruction Method After Pancreaticoduodenectomy: A Short Observational Study

Background: Pancreaticoduodenal resection is usually performed in patients with a localised small carcinoma in the head of the pancreas, at the lower end of the common bile duct or at the ampulla and occasionally for chronic pancreatitis.The mortality following pancreaticoduodenal resection has fallen and is now below 5% 1-6 .However, leakage from the anastomosis between pancreas and the jejunum has been and remains, one of the most worrying complications of the operation. The data from papers published in the last 8 years show that the incidence of pancreatic leak is 14% and the mortality of this complication 24%3,4,6-16 .Pancreaticogastrostomy is a potentially safer alternative to pancreaticojejunostomy in the reconstruction following Whipple's operation. Aim: The aim of the study was to observe pancreaticogastrostomy is a potentially safer alternative to pancreaticojejunostomy after pancreaticoduodenectomy. Methods: This prospective observational study was conducted at the Department of Surgery in Shaheed Suhrawardy Medical College Hospital, for One year (August 2021 to July 2022). Patients with a localised small carcinoma in the head of the pancreas, at the lower end of the common bile duct or at the ampulla, and occasionally for chronic pancreatitis admitted in the department of surgery were approached for inclusion in the study. Total 41 patients were selected according to inclusion and exclusion criteria. Informed written consent was taken from each patient. All patients underwent pancreaticogastrostomy. Detail clinical and demographic history was taken along with thorough physical examination relevant investigations. All patients were evaluated preoperatively and post operatively at discharge, 1 month and 3 months. Outcome was assessed post operatively. Collected data were checked and analysed in SPSS 23. Results: Two patients died within 30 days of the operation (mortality 4.9%), one from perioperative haemorrhage and another from septicaemia due to a biliary infection, which may have resulted from preoperative transhepatic biliary drainage. Both operations were carried out for carcinoma of the head of the pancreas. One patient developed a biliary leak which closed in 6 days. A postoperative pancreatic leak occurred in one patient with carcinoma of the ampulla; the fistula closed after 5 mdays, and did not delay his discharge from hospital. This patient remains well 36 months after operation, although he has now developed mild diabetes.One other patient developed diabetes mellitus postoperatively. This woman had evidence of obstructive pancreatitis at operation. She died 6 months later of recurrent carcinoma of the head of the pancreas. One patient with chronic pancreatitis has uncontrolled steatorrhoea, with up to four bowel movements a day. Four other patients take regular pancreatic supplements together with H2 receptor antagonists in order to maintain normal defaecation. There has been no case of stomal ulceration. None of the patients were lost to follow-up. The median survival for patients operated on for carcinoma of the head of the pancreas was 13 months, and for patients with carcinoma of the bile duct, 14 months. Median survival of patients with ampullary carcinoma was 38 months. Conclusion: Seventy two percent of patients had good outcome after Pancreaticogastrostomy(PG). Significant relief in symptoms of pain were noted after PG. Further larger study is recommended to validate this findings. J Shaheed Suhrawardy Med Coll 2023; 15(1): 66-72

Use of proton pump inhibitors and risk of severe COVID-19: A case-control study in United States Medicare beneficiaries.

Concerns have been raised regarding proton pump inhibitor (PPI) use and risk of severe coronavirus disease 2019 (COVID-19). Observational studies have yielded heterogeneous results and were subject to important methodological limitations. To examine the association between the receipt of PPIs and risk of COVID-19 hospitalizations and severe in-hospital outcomes or death. Case-control study among Medicare fee-for-service beneficiaries 66+ years old with gastroesophageal reflux disorder (GERD). Within this population, we identified cases by an incident hospital discharge diagnosis of COVID-19 from April 1 to December 11, 2020, using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) U07.1, and randomly selected up to 10 controls per case, matched on date and neighborhood. We defined PPI use as a prescription providing ≥15 days of supply in the 30 days before admission, with H2-receptor antagonist (H2RA) use as the reference to account for indication. We analyzed uncomplicated hospitalizations and hospitalizations with severe outcomes (intensive/coronary care unit admission, invasive mechanical ventilation, or death), estimating odds ratios (ORs), and 95% confidence intervals (CIs) with multinomial conditional logistic regression adjusted for demographics, comorbidities, chronic medications, and health care utilization. We matched 25,867 uncomplicated and 12,954 severe hospitalized COVID-19 cases to 146,972 and 73,104 controls, respectively. Cases tended to be older and have more comorbidities. Relative to H2RA use, we found no association of PPI use with uncomplicated COVID-19 hospitalization (OR 0.99, 95% CI 0.93-1.06) or severe COVID-19 hospitalization (OR 1.00, 95% CI 0.91-1.10). Relative to H2RA use, PPI use was not associated with uncomplicated or severe COVID-19 hospitalizations among Medicare beneficiaries with GERD.

Proton Pump Inhibitors Worsen Colorectal Cancer Outcomes in Patients Treated with Bevacizumab

Background: Approximately one-third of patients with advanced colorectal cancer (CRC) and treated with bevacizumab are prescribed proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs). However, there is limited data on the effects of PPIs and H2RAs in these patients. To investigate the oncological outcomes of PPI and H2RA use in CRC patients treated with bevacizumab, we performed a retrospective cohort study using the Taiwan National Health Insurance Research Database and Taiwan Cancer Registry Database from 2005 to 2020. Methods: In CRC patients treated with bevacizumab, the PPI users and H2RA users were matched with patients without acid-reducing agents (ARAs) by 1:4 propensity score matching. PPI users and H2RA users were matched with propensity scoring in a 1:1 ratio. We divided patients into 4 cumulative PPI dosage levels to assess the dose–response relationship. The primary endpoints were 5-year overall survival and cancer-specific survival. Results: Compared with ARA non-users, both H2RA users and PPI users were associated with reduced overall survival. PPI users were associated with more significant negative effects on overall survival. Compared with H2RA users, PPI users were associated with lower 5-year overall survival (aHR: 1.19, 95% CI: 1.09–1.31) and cancer-specific survival (aHR: 1.20, 95% CI: 1.09–1.31). A similar dose–response relationship was observed for PPI users in terms of 5-year overall survival and cancer-specific overall survival. Conclusions: Compared to H2AR use, PPI use was associated with dose-dependent poorer oncological outcomes in metastatic CRC patients treated with bevacizumab.

Dexamethasone is non-inferior to antihistamine plus dexamethasone premedication in preventing ramucirumab plus nab-paclitaxel infusion-related reactions in gastric cancer: a multicenter retrospective study

PurposeRamucirumab (RAM) is recommended as premedication with H1-receptor antagonists (H1RA) to prevent infusion-related reactions (IRRs). However, RAM is a human antibody with a low incidence of IRRs. We evaluated the noninferiority of non-H1RA (dexamethasone [DEX] alone) premedication to H1RA (plus DEX) premedication in terms of IRRs in patients with gastric cancer receiving RAM plus nanoparticle albumin-bound paclitaxel (nab-PTX).MethodsThis was a noninferiority, multicenter, retrospective trial conducted in three Japanese centers to assess the incidence of IRRs in patients receiving RAM plus nab-PTX for gastric cancer between 2018 and 2023. Patients with gastric cancer receiving RAM plus nab-PTX were divided into groups with and without H1RA premedication. The incidence of IRRs was compared between the two groups.ResultsNinety patients were evaluated, with non-H1RA and H1RA premedications in 43 and 47 cases, respectively. After the first dose of RAM, IRRs were not observed in either group. IRRs during the overall doses were 0% for non-H1RA premedication and 2.1% for H1RA premedication (90% confidence interval (CI): –5.6%–1.3% for each comparison). The upper limit of the 90% CI (1.3%) did not exceed the noninferiority margin (Δ) of + 10% and therefore met the noninferiority criteria.ConclusionRAM plus nab-PTX for gastric cancer with DEX premedication may be possible without H1RA premedication.

Omalizumab for Treatment of Anti-GD2 Antibody-related Urticaria.

Outcomes for high-risk neuroblastoma have improved with the addition of antidisialoganglioside (GD2) antibody-mediated immunotherapy to multimodality therapy. Urticaria is an expected side effect of anti-GD2 immunotherapy. Rarely, despite maximal use of antihistamines and H2 receptor antagonists, refractory urticaria can result in impaired quality of life, and delays or discontinuation of immunotherapy. The anti-IgE monoclonal antibody, omalizumab, is approved for the treatment of asthma and chronic spontaneous urticaria. We successfully managed grade 3, naxitamab-related urticaria refractory to standard management in 2 patients using omalizumab, allowing for continued anti-GD2 immunotherapy. Omalizumab did not impact antitumor activity or immunogenicity of naxitamab.

Pharmacokinetics, pharmacodynamics, and safety of izuforant, an H4R inhibitor, in healthy subjects: A phase I single and multiple ascending dose study.

Izuforant is a selective, and potent histamine H4 receptor (H4R) antagonist developed to treat atopic dermatitis (AD). There is an unmet medical need for therapeutic agents to control inflammation and pruritus. Izuforant is a strong candidate for this task based on the findings of non-clinical studies showing that inhibition of the histamine-mediated signaling pathway via H4R by izuforant results in decreased pruritus and inflammation. This study aimed to evaluate the clinical pharmacokinetic (PK) and pharmacodynamic (PD) profiles of izuforant. Dose-block-randomized, double-blind, placebo-controlled, single- and multiple ascending dose studies were conducted in 64 healthy volunteers. For the single ascending dose (SAD) study, 10-600 mg izuforant was administered to the designated groups. For the multiple ascending dose (MAD) study, 100-400 mg izuforant was administered to three groups. The clinical pharmacokinetic (PK) profile of izuforant was evaluated using plasma and urine concentrations. Blood sampling for the PD assay, which measured imetit-induced eosinophil shape changes (ESC), was also conducted. A one-compartment PK model described the distribution and elimination profiles of izuforant. An imetit-induced ESC inhibition test was established and validated for PD evaluation as a measure of the H4R antagonistic effect. ESC inhibition was observed even at doses as low as 10 mg; however, this inhibition became stronger and lasted longer as the dose increased. All izuforant doses were well tolerated, and no discontinuations due to adverse events (AE) or deaths were reported.

Hospitalized patients on proton pump inhibitors for stress ulcer prophylaxis have a higher risk of Clostridioides difficile infection compared with those on histamine-2 receptor antagonists

Previous studies on Clostridioides difficile infection (CDI) in proton pump inhibitor (PPIs) users generally enrolled a heterogeneous population and did not include a control group of histamine H2 receptor antagonists (H2RAs) users or adjust for confounding variables, such as previous antibiotics. It is uncertain whether hospitalized patients using PPIs for stress ulcer prophylaxis (SUP) are at a higher risk of CDI compared to those using H2RAs. This study aimed to compare the association between CDI and the usage of antisecretory drugs (ASDs): PPIs and H2RAs, for stress ulcer prophylaxis (SUP) among hospitalized patients, and the impact of the duration of their use on CDI. In this nationwide population-based cohort study using the Taiwan National Health Insurance Database, hospitalized patients using ASDs for SUP were identified between 2017-2018. A total of 63,266 and 69,269 individuals were included in the PPI and H2RA groups, respectively. The primary endpoint was a 90-day monitoring of CDI occurrence. The incidences of CDI were 1·6/10,000 and 0·5/10,000 person-days in the PPIs and H2RAs groups, respectively. After adjusting for confounding factors, the risk of infection in the PPIs group remained significantly higher than in the H2RAs group (Hazard ratio [HR], 2·49; 95% Confidence Interval [CI], 1·63-3·81). In the subgroup analysis, during hospitalization, the risk of CDI for patients using high-risk antibiotics or admitted intensive care unit (ICU), as well as patients with immunodeficiency, using PPIs for SUP, was higher than using H2RAs. Furthermore, the risk of CDI was higher in patients using ASDs for durations > 14 days than in those using them for < 7 days (adjusted HR, 3·66; 95% CI, 2·34-5·75). The risk of occurrence CDI for hospitalized patients using PPIs for SUP was higher than using H2RAs. It is recommended not to exceed 14 days of any gastric ASDs for SUP during hospitalization, especially for patients who have used high-risk antibiotics, been admitted to the ICU, or have immunodeficiency.

Comparison of the Efficacy and Safety of Bilastine 20mg versus Fexofenadine 180mg for Treatment of Perennial Allergic Rhinitis: Randomized Controlled Study.

Antihistamines has always remained the mainstay drug treatment for Allergic Rhinitis (AR). Bilastine is a novel, non-sedative antihistamine with a super-selective H1 receptor antagonist property. Both bilastine and fexofenadine are second generation antihistamine drugs commonly used to manage AR and Chronic Urticaria (CU). Autologous Skin Serum Test (ASST) is a practical test for histamine release in CU. These tests have been studied in AR patients with limited data studies. 114 patients diagnosed with perennial AR were recruited and divided into two groups of 57 each. One group was started Bilastine 20mg once a day and other group, fexofenadine 180mg once a day. Total Nasal Symptom Score (TNSS) was calculated at presentation and two weeks of antihistamine therapy. ASST was hypothesized to be the test for AR and performed at the time of presentation and at two weeks follow-up. Intergroup and Intragroup assessment of TNSS, ASST and its variables were done using unpaired and paired t test respectively. Patients showed reduction in symptoms of AR with both antihistamines. A significant improvement of sneezing and rhinorrhoea was seen in Fexofenadine group as compared to Bilastine group. TNSS showed statistically significant improvement in both the groups. ASST had statistically significant reduction in both the groups. Both Bilastine and fexofenadine were found to be effective in reduction of symptoms of allergic rhinitis. Bilastine was found to be more effective in overall as well as sneezing and rhinorrhoea noted two weeks after therapy. The online version contains supplementary material available at 10.1007/s12070-024-04770-0.

Comprehensive analysis of nizatidine: Pharmacodynamics and pharmacokinetics in anti-ulcer treatment

Ulcers are characterized histologically as lesions that penetrate through the muscularis mucosae into the submucosal layer, affecting any segment of the gastrointestinal (GI) tract mucosa. They often arise due to excessive acid production from peptic secretions. Nizatidine (NZT) is a potent H2-receptor antagonist used to reduce basal, nocturnal, and stimulated gastric acid secretion. This medication is commonly prescribed for conditions such as gastroesophageal reflux disease, peptic ulcers, and duodenal ulcers. As a member of the histamine H2 receptor antagonist class introduced before proton pump inhibitors, Nizatidine is noted for its effectiveness comparable to ranitidine. However, Nizatidine is distinguished by its thiazole ring, in contrast to the furan ring found in ranitidine. When administered orally, Nizatidine, especially in combination with antacids, enhances drug delivery to parietal cell receptors, improving the overall bioavailability of the medication and its ability to suppress acid secretion. Nizatidine is primarily absorbed in the proximal small intestine, exhibiting about 70% absolute bioavailability. Its lower absorption from the colon and a short biological half-life (ranging from 1 to 1.6 hours) suggest the potential benefits of developing sustained-release formulations such as floating gels to prolong its therapeutic effects. Clinical studies indicate that Nizatidine, in doses of 300 mg at bedtime or 150 mg twice daily, shows superior efficacy compared to other H2-receptor antagonists for managing duodenal and gastric ulcers as well as gastroesophageal reflux disease.

Therapeutic potential of histamine H4 receptor antagonist as a preventive treatment for diabetic retinopathy in mice

Diabetic retinopathy (DR) is a prevalent complication of diabetes, often resulting in vision loss and blindness. Existing treatments primarily aim to control blood sugar levels and inhibit angiogenesis. However, current therapies for DR, such as anti-VEGF and laser photocoagulation, are frequently invasive, and can cause adverse side effects. Consequently, there is a critical need for new preventive therapeutics to address DR more effectively. This study aimed to examine the therapeutic potential of a histamine H4 receptor (HRH4) antagonist as a preventive treatment for DR in mice. A mouse model of DR was established by intraperitoneally injecting 200 mg/kg of streptozotocin (STZ). Immune cell infiltration into the retina of mice with STZ-induced diabetes was measured using fluorescence-activated cell sorting (FACS) 12 weeks after STZ injection. The preventive effects of the HRH4 antagonist on inflammation and pathological retinal vessel leakage were determined in a mouse model of DR. Infiltration of HRH4-expressing macrophages increased in the retina of mice with STZ-induced DR. The HRH4 antagonist prevented macrophage infiltration and retinal vascular leakage to prevent STZ-induced DR in mice without causing any retinal toxicity. The infiltration of macrophages increased in the retina of mice with STZ-induced diabetes through HRH4, indicating that HRH4 is potentially a novel preventative therapeutic target in DR. These findings suggest that targeting HRH4 is a promising strategy for the prevention and treatment of DR.

Alleviation of Autophagic Deficits and Neuroinflammation by Histamine H3 Receptor Antagonist E159 Ameliorates Autism-Related Behaviors in BTBR Mice

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.

Mathematical model of the relationship between pH holding time and erosive esophagitis healing rates.

Effective suppression of gastric acid secretion promotes healing of erosive esophagitis. Treatment guidelines recommend proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs). Emerging evidence also supports potassium-competitive acid blockers (P-CABs). The aim was to construct a mathematical model to examine the relationship between pH holding time ratios (HTRs) and erosive esophagitis healing rates with H2RAs, PPIs and P-CABs. By literature search, we identified studies of H2RAs, PPIs or P-CABs that reported mean pH >4 HTRs at steady state (days 5-8) and erosive esophagitis healing rates after 4 and/or 8 weeks. We aggregated treatments by drug class and developed a non-linear, mixed-effects model to explore the relationship between pH >4 HTRs and healing rates. The pH dataset included 82 studies (4297 participants; 201 dosage arms); healing rate data came from 103 studies (43,417 patients; 196 treatment arms). P-CABs achieved the longest periods with intragastric pH >4, and the highest healing rates after 4 and 8 weeks. The predicted probabilities of achieving ≥90% healing rates at 8 weeks were 74.1% for P-CABs, 17.3% for PPIs and 0% for H2RAs. P-CABs provide the longest duration with intragastric pH >4 and, accordingly, the highest healing rates of erosive esophagitis.

Stimulation of central histaminergic transmission attenuates diazepam-induced motor disturbance on rota-rod and beam walking tests in mice.

Diazepam administration has been shown to influence the release of histamine in various brain areas involved in motor behavior. Therefore, the present study explored the plausible regulatory role of the central histaminergic system in diazepam-induced deficits in motor performance in mice using the rota-rod and beam walking tests. In this study, several doses of diazepam (0.5, 1, 2, and 3 mg/kg, i.p.) were assessed in mice for changes in motor performance on the rota-rod and beam walking test. In addition, the brain histamine levels were determined after diazepam administration, and the diazepam-induced motor deficits were assessed in mice, pretreated centrally (intracerebroventricular) with histaminergic agents such as histamine (0.1, 10 µg), histamine precursor (L-histidine: 0.1, 2.5 µg), histamine neuronal releaser/H 3 receptor antagonist (thioperamide: 0.5, 10 µg), H 1 and H 2 receptor agonist [2-(3-trifluoromethylphenyl) histamine (FMPH: 0.1, 6.5 µg; amthamine: 0.1, 5 µg)/antagonist (H 1 : cetirizine 0.1 µg) and (H 2 : ranitidine: 50 µg)]. Results indicate that mice treated with diazepam at doses 1, 2 mg/kg, i.p. significantly increased the brain histamine levels. Moreover, in mice pretreated with histaminergic transmission-enhancing agents, the diazepam (2 mg/kg, i.p.)-induced motor incoordination was significantly reversed. Contrastingly, diazepam (1 mg/kg, i.p.) in its subeffective dose produced significant motor deficits in mice preintracerebroventricular injected with histamine H 1 and H 2 receptor antagonists on both the employed tests. Therefore, it is postulated that endogenous histamine operates via H 1 and H 2 receptor activation to alleviate the motor-impairing effects of diazepam.

Betahistine's Neuroprotective Actions against Lipopolysaccharide-Induced Neurotoxicity: Insights from Experimental and Computational Studies.

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.

Discovery of New Highly Potent Histamine H3 Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors.

At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.

Scutellarein derivatives with histamine H3 receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer’s disease therapy

A series of scutellarein 7-l-amino acid carbamate-4′-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer’s disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, l-Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC50 values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent H3R antagonistic activities than clobenpropit, with an IC50 value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu2+-induced Aβ1–42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu2+-induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aβ25-35. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood–brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation.

Multi-component forms of the 2nd generation H1 receptor antagonist drug, Bilastine and its enhanced physicochemical characteristics

Bilastine (BIL) is a novel 2nd generation antihistamine medication is used to treat symptoms of chronic urticaria and allergic rhinitis. However, its poor solubility limits its therapeutic efficacy. In order to enhance the physicochemical characteristics of BIL, various molecular adducts of BIL (Salt, hydrate and co-crystal) were discovered in this study using two distinct salt-formers: Terephthalic acid (TA), 2,4-Dihydroxybenzoic acid (2,4-DHBA), and three nutraceuticals (Vanillic Acid (VA), Hydroquinone (HQN) and Hippuric acid (HA)). Various analytical methods were used to examine the synthesised adducts, including Powder X-Ray Diffraction (PXRD), Single Crystal X-ray Diffraction (SCXRD), and thermal analysis (Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC)). Single-crystal X-ray diffraction (SCXRD) studies avowed that the architectures of the molecular adducts are maintained in the solid state by an array of strong (N+H⋯O−, NH⋯O, OH⋯O) and weak (CH⋯O) hydrogen bonds. Additionally, a solubility test was performed to establish the in vitro release characteristics of newly synthesised BIL adducts and it observed that most of the molecular adducts exhibit higher rates of dissolution in comparison to pure BIL; in particular, BIL.TA.HYD showed the highest solubility and the fastest rate of dissolution. Moreover, experiments on flux permeability and diffusion demonstrated that the BIL.TA.HYD and BIL.VA salts had strong permeability and a high diffusion rate. In addition, the synthesized adduct’s stability was assessed at 25 °C and 90 % ± 5 % relative humidity, and it was found that all the molecular salts were stable and did not undergo any phase changes or dissociation. The foregoing result leads us to believe that the newly synthesized molecular adducts’ increased permeability and solubility will be advantageous for the creation of novel BIL formulations.

Preparation and Evaluation of Ranitidine Hydrochloride Floating Microspheres

&amp;lt;i&amp;gt;Introduction&amp;lt;/i&amp;gt;: Ranitidine hydrochloride, a member of the H2-receptor antagonist class, is widely employed in treating gastrointestinal conditions like ulcers, gastroesophageal reflux disease (GERD) and Zollinger-Ellison syndrome by reducing gastric acid production. Microspheres, designed for extended drug delivery and enhanced bioavailability, were formulated and evaluated in this study. &amp;lt;i&amp;gt;Aim&amp;lt;/i&amp;gt;: To develop ranitidine hydrochloride microspheres capable of prolonging drug delivery and improving bioavailability. Methods: The inotropic gelation method was utilized to prepare alginate microspheres incorporating polymers such as ethyl cellulose, sodium carboxymethyl cellulose, HPMC, and carbopol®. The resulting drug-loaded microspheres exhibited spherical rigidity after cross-linking with a 10% w/v calcium chloride solution. Evaluation parameters including Fourier transform infra-red (FTIR) analysis, precompression characteristics, percentage yield, swelling index, and drug content were determined. &amp;lt;i&amp;gt;Results&amp;lt;/i&amp;gt;: The FTIR results obtained, showed there was no incompatibility among the excipients and the active pharmaceutical ingredient. The Scanning electron microscopy (SEM) obtained, indicated the presence of spherical particles present in the formulation. The pre-compression evaluation showed that the angle of repose ranged from 4.85 ± 0.02 to 7.22 ± 0.06o for batched F4 and F1 respectively, while the Carr’s index ranged from 73.5 ± 2.47% to 87.00 ± 3.53% for batches F-7 and F-1 respectively. The percentage yield ranged from 73.5 ± 2.47% to 87.00 ± 3.53% for batches F-7 and F-1 respectively. &amp;lt;i&amp;gt;In vitro&amp;lt;/i&amp;gt; drug release studies revealed sustained drug release over 4 hours, with a maximum release of 69.50 ± 1.77% observed for batch F-1. &amp;lt;i&amp;gt;Conclusion&amp;lt;/i&amp;gt;: Overall, the formulated ranitidine hydrochloride microspheres demonstrated prolonged and controlled release characteristics, indicating their potential for use in controlled drug delivery applications.