H2 Antagonists Research Articles

Guanidine Derivative ADS1017, a Potent Histamine H3 Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile.

In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H3 and H4 receptors (H3R and H4R, respectively). Moreover, we also checked their intrinsic activity toward H3R and muscarinic M1, M2, and M4 receptors (M1R, M2R, and M4R, respectively). Since ADS1017 has been proved to be the most selective and highly potent H3 antagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of its in vivo efficacy, we proposed an alternative synthetic route that resulted in an increased yield. Interestingly, ADS1017 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models. Finally, as a result of comprehensive analysis of its off-target activity and ADMETox parameters, we confirmed the moderate selectivity of ADS1017 and its promising drug-like properties.

Characteristics of Cerebrovascular Response to Intrinsic Vasoactive Substances in Sika Deer (Cervus nippon yesoensis) and the Possible Effects of Gravity on Adrenergic Responses.

Gravity may exert species-specific effects on quadrupedal vasoreactivity, reflecting variations in the vertical displacement of the cardiocranial axis from the dorsal plane. Deer show markedly displaced cardiocranial axes compared to their closest phylogenetic relatives, but their relative cerebrovascular responses remain unelucidated. Accordingly, we investigated the responses to noradrenaline (NA), acetylcholine (ACh), 5-hydroxytryptamine (5-HT), histamine, angiotensin (Ang) II, and bradykinin (BK) in cervine basilar arterial rings. NA and 5-HT induced slight contraction, and ACh induced relaxation, which contrasts with the findings reported in pigs and cattle. The cumulative response to ACh was abolished by endothelial denudation and inhibited by Nω-nitro-L-arginine (a nitric oxide synthase inhibitor), atropine (a nonselective muscarinic antagonist), and p-fluoro-hexahydro-sila-difenidol (an M3 antagonist). Pirenzepine (an M1 antagonist) and methoctramine (an M2 antagonist) showed no significant effects. Histamine induced contractions, with its concentration-response curve shifted to the right in parallel by diphenhydramine (an H1 antagonist). However, cimetidine (an H2 antagonist) showed no significant effects. Ang II and BK had no vasomotive effects. NA and ACh induced different cerebrovascular responses in sika deer versus cattle, but histamine and BK did not. Our findings suggest that cerebrovascular responses are influenced by the similarity of animal species and the head and heart positions relative to gravity.

Efficacy of Omitting H2 Antagonists versus Famotidine in Taxane Hypersensitivity Reactions Prophylaxis: A Randomized, Prospective, Open-Label, Controlled Trial.

This study aims to evaluate the efficacy of premedication protocols in preventing immediate hypersensitivity reactions (HSRs) to taxane chemotherapy by comparing protocols that omit H2 antagonists with those that include famotidine. This was an open-label, single-center, randomized clinical trial. Randomization was 1:1 to two groups. The experimental arm omitted H2 antagonists from the premedication protocol, while the control arm included famotidine. The efficacy of the premedication protocol for preventing HSRs in the experimental group was compared with that of the control group using a multilevel regression analysis with a random intercept and random effect model. Between September 2022 and December 2023, 150 patients enrolled. The group without H2 antagonists had 331 cycles, averaging 3.15 per patient. The famotidine group had 327 cycles, averaging 3.39 per patient. The total number of cycles was not significantly different (p = 0.951). There were six HSRs (1.81%) in the group without H2 antagonists and five (1.53%) in the famotidine group. The HSRs risk difference between groups was 0.28% (95% CI -0.02 to 0.02, p = 1.000). A multilevel regression analysis with a random intercept and effect model compared the efficacy of premedication protocols for preventing HSRs between the experimental and control groups. The risk ratio for HSRs in the group without H2 antagonists was 1.00, which was not statistically significant compared to the famotidine group (95% CI 0.98 to 1.04, p = 0.528). The clinical trial demonstrated that omitting the H2 antagonists premedication protocol for taxane chemotherapy is as effective in preventing HSRs as using famotidine. These findings suggest that this protocol can be implemented in clinical practice.

ICOSLG Is Associated with Anti-PD-1 and Concomitant Antihistamine Treatment Response in Advanced Melanoma.

We previously demonstrated that patients with metastatic unresectable stage IIIb-IV melanoma receiving cetirizine (a second-generation H1 antagonist antihistamine) premedication with immunotherapy had better outcomes than those not receiving cetirizine. In this retrospective study, we searched for a gene signature potentially predictive of the response to the addition of cetirizine to checkpoint inhibition (nivolumab or pembrolizumab with or without previous ipilimumab). Transcriptomic analysis showed that inducible T cell costimulator ligand (ICOSLG) expression directly correlated with the disease control rate (DCR) when detected with a loading value > 0.3. A multivariable logistic regression model showed a positive association between the DCR and ICOSLG expression for progression-free survival and overall survival. ICOSLG expression was associated with CD64, a specific marker of M1 macrophages, at baseline in the patient samples who received cetirizine concomitantly with checkpoint inhibitors, but this association was not present in subjects who had not received cetirizine. In conclusion, our results show that the clinical advantage of concomitant treatment with cetirizine during checkpoint inhibition in patients with malignant melanoma is associated with high ICOSLG expression, which could predict the response to immune checkpoint inhibitor blockade.

Exclusion of ranitidine from premedication regimen during paclitaxel treatment: A retrospective single-center analysis.

To minimize the risk of hypersensitivity reactions (HSRs) caused by paclitaxel infusion, premedication with corticosteroid, H1-antagonist and H2 antagonist (ranitidine) was standard of care. Discontinuation of ranitidine in 2020 led to adjustments in premedication regimens and a new regimen without ranitidine was implemented in our center. This study aimed to compare the incidence of HSRs during paclitaxel treatment of a standard premedication regimen including ranitidine with a new premedication regimen without ranitidine and with a titrated infusion rate during the first two administrations. Retrospective data analysis was performed on two cohorts of adult patients with solid tumors who started treatment with paclitaxel and received a premedication regimen with and without ranitidine over the years 2021 and 2023 respectively (before and after ranitidine withdrawal). Univariable and multivariable logistic regression models were used to investigate any associations with H2 antagonist treatment adjusting for confounding variables. A total of 319 patients were included. 158 patients received the standard premedication regimen with ranitidine compared to 161 patients who did not received ranitidine. HSRs were observed in 10 of 1101 administrations of paclitaxel (0,90%) in ranitidine group compared to 2 of 899 (0,22%) in the ranitidine-free cohort (p = 0.048). Analysis incidence per patient also found results with statistically significant differences: 5.7% (9 of 158 patients) in the ranitidine cohort compared to 1.2% (2 of 161 patients) in the ranitidine-free cohort (p = 0.029). The results of the study show the effectiveness of a premedication regimen including only dexchlorpherinamine and dexamethasone, along with a titrated infusion rate during the first two administrations, in reducing the incidence of paclitaxed-induced HSRs.

Quantitative estimation of doxylamine succinate by zero-order derivative area under curve Spectrophotometric methods in bulk and in-tablet dosage form

The purpose of this study is to establish Zero-order UV-Spectrophotometric - absorbance and Zero Order- Area under curve (AUC) methods for estimation of Doxylamine succinate in bulk and in pharmaceutical dosage form . Doxylamine succinate is Histamine H1 antagonist with pronounced sedative properties. It is used in allergies and as an antitussive, antiemetic, and hypnotic. Doxylamine has also been administered in veterinary applications and was formerly used in parkinsonism, distilled water was used as solvent for solubilization of Doxylamine succinate. Maximum absorption for Doxylamine succinate was found to be at wavelength 260nm when dissolved in Distilled water. The methods are based upon measurement of absorbance at 260nm and integration of area under curve for analysis of Doxylamine succinate in the wavelength range of 251.20-267.20 nm. The drug followed linearity in the concentration range of 10 - 60µg/mL with correlation coefficient value r> 0.99 . The proposed methods were validated for accuracy (% recovery), precision, repeatability and ruggedness, as per ICH guidelines. The proposed methods were applied for qualitative and quantitative estimation of Doxylamine succinate in tablet and results were found in good agreement with the label claimed. Developed methods can be used for routine analysis of Doxylamine succinate in bulk and pharmaceutical tablet.

Effect of Switching the Histamine-1 Receptor Antagonist Clemastine to Cetirizine in Paclitaxel Premedication Regimens: The H1-Switch Study.

Premedication, including a histamine-1 receptor (H1) antagonist, is recommended to all patients treated with paclitaxel chemotherapy to reduce the incidence of hypersensitivity reactions (HSRs). However, the scientific basis for this premedication is not robust, which provides opportunities for optimization. Substitution of intravenously administered first-generation H1 antagonist for orally administered second-generation H1 antagonist could reduce side effects, and improve efficiency and sustainability. This study investigates the efficacy and safety of substituting intravenous clemastine for oral cetirizine as prophylaxis for paclitaxel-induced HSRs. This single-center, prospective, noninferiority study compares a historic cohort receiving a premedication regimen with intravenous clemastine to a prospective cohort receiving oral cetirizine. Primary end point of the study is HSR grade ≥3. The difference in incidence was calculated together with the 90% CI. We determined that the two-sided 90% CI of HSR grade ≥3 incidence in the oral cetirizine cohort should not be more than 4% higher (ie, the noninferiority margin) compared with the intravenous clemastine cohort. Two hundred and twelve patients were included in the oral cetirizine cohort (June 2022 and May 2023) and 183 in the intravenous clemastine cohort. HSR grade ≥3 incidence was 1.6% (n = 3) in the intravenous clemastine cohort and 0.5% (n = 1) in the oral cetirizine cohort, resulting in a difference of -1.2% (90% CI, -3.4 to 1.1). Premedication containing oral cetirizine is as safe as premedication containing intravenous clemastine in preventing paclitaxel-induced HSR grade ≥3. These findings could contribute to optimization of care for patients and improve efficiency and sustainability.

Invasive Candida Infections in Neonatal Intensive Care Units: Risk Factors and New Insights in Prevention.

Invasive Candida infections represent a significant cause of morbidity and mortality in neonatal intensive care units (NICUs), with a particular impact on preterm and low-birth-weight neonates. In addition to prematurity, several predisposing factors for Candida colonization and dissemination during NICU hospitalization have been identified, including prolonged exposure to broad-spectrum antibiotics, central venous catheters, parenteral nutrition, corticosteroids, H2 antagonist administration, and poor adherence to infection control measures. According to the literature, the implementation of antifungal prophylaxis, mainly fluconazole, in high-risk populations has proven to be an effective strategy in reducing the incidence of fungal infections. This review aims to provide an overview of risk factors for invasive Candida infections and current perspectives regarding antifungal prophylaxis use. Recognizing and reducing people's exposure to these modifiable risk factors, in conjunction with the administration of antifungal prophylaxis, has been demonstrated to be an effective method for preventing invasive candidiasis in susceptible neonatal populations.

Neuroprotective Effect of Clemastine Improved Oligodendrocyte Proliferation through the MAPK/ERK Pathway in a Neonatal Hypoxia Ischemia Rat Model.

Neonatal hypoxic-ischemic encephalopathy is the most common cause of long-term disability in term neonates, and white matter injury is the primary cause of cerebral palsy. Therapies that focus on the neuroprotection of myelination and oligodendrocyte proliferation could potentially ameliorate long-lasting neurological impairments after hypoxic-ischemic encephalopathy. Clemastine, a histamine H1 antagonist, has been shown to exert neuroprotective effects in multiple sclerosis and spinal cord injury by promoting oligodendrogenesis and re-myelination. In this study, we demonstrated the neuroprotective effects of clemastine in our rat model of neonatal hypoxic-ischemic brain injury. Animals received a single intraperitoneal injection of either vehicle or clemastine (10 mg/kg) for 6 consecutive days. Our results showed a significant reduction in white matter loss after treatment, with a clear effect of clemastine on oligodendrocytes, showing a significant increase in the number of Olig2+ cells. We characterized the MAPK/ERK pathway as a potential mechanistic pathway underlying the neuroprotective effects of clemastine. Altogether, our results demonstrate that clemastine is a potential compound for the treatment of hypoxic-ischemic encephalopathy, with a clear neuroprotective effect on white matter injury by promoting oligodendrogenesis.

The histamine receptor H1 acts as an alternative receptor for SARS-CoV-2.

Numerous host factors, in addition to human angiotensin-converting enzyme 2 (hACE2), have been identified as coreceptors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and diversified druggable potential. We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor. Multiple inhibition assays revealed that antihistamine drugs broadly inhibited the infection of various SARS-CoV-2 mutants with an average IC50 of 2.4 µM. The prophylactic function of these drugs was further confirmed by authentic SARS-CoV-2 infection assays and humanized mouse challenge experiments, demonstrating the therapeutic potential of antihistamine drugs for combating coronavirus disease 19.IMPORTANCEIn addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.

Cost analysis study of price variation among the various brands of proton pump inhibitors available in Benghazi-Libya

Background: A large proportion of patients in developing countries have to pay out of pocket for their medications. The prices of different brands of the same medications vary considerably and may vary from one community pharmacy to another. This study was undertaken to evaluate the variation in costs of proton pump inhibitors (PPI) and histamine H2-receptor antagonists available in Libya. Methods: Prices of various brands of PPI and various formulations were collected from four community pharmacies in the city of Benghazi. Both cost ratio and percentage variation were calculated and compared for various brands of the same strength and number of tablets, capsules, injections, or syrups. Results: The highest cost ratio and percentage price variation were found with omeprazole 20 mg, followed by omeprazole 40 mg. Other significant cost variations (>100%) were seen with pantoprazole 40 mg, Downoprazol (omeprazole + sodium bicarbonate) 40 mg, and esomeprazole 40 mg. Ampoules of omeprazole, cimetidine, and ranitidine had cost ratios of 1:1.7, 1:1.7, and 1:1.8, and cost variation ratios of 71.4, 66.7, and 75, respectively. Variations in prices of PPI and histamine H2 antagonists from the same manufacturer between different community pharmacies were common. The highest percentage cost variation (100) was seen with omeprazole 20 mg. Conclusions: Due to political instability, the prices of all drugs are controlled by importing private companies and the owners of community pharmacies instead of governmental authorities, that leads to cost variations. Therefore, the health authorities exert strict control on pricing of medications.

Green HPLC–DAD method for the analysis of analgesic and antihistamine drugs adulterated in herbal mixtures

This study presents a HPLC-DAD method developed for the simultaneous detection of histamine H1 antagonist drugs and analgesic compounds, including paracetamol, cetirizine hydrochloride, cinnarizine, chlorpheniramine maleate, and loratadine, in herbal formulations. This method systematically investigates critical parameters for enhancing separation and quantification using HPLC-DAD. Chemometric techniques were employed to optimize the method for detecting adulterants, with sample preparation involving liquid-phase extraction and a mobile phase for separation using HPLC-DAD. The calibration curves were linear over concentrations ranging from 10 to 40 µg/mL, with correlation coefficients exceeding 0.99. The method exhibits good accuracy, with mean recoveries ranging from 90 to 105 %, and precision (% RSD) for intraday and interday precision: 0.71 to 2.94 %. The limits of detection (LODs) and limits of quantification (LOQs) for each compound are provided. The HPLC-DAD method ensures rigorous quality control, detecting potential adulteration in 32 traditional medicine samples and emphasizing its safety and efficacy in managing allergic conditions. The proposed approach is considered environmentally friendly based on evaluations from commonly used greenness assessment tools, Green analytical chemistry metrics (ComplexGAPI, AGREE, BAGI) confirm the method's sustainability and practicality.

Development and Evaluation of Ranitidine Floating Tablet for Ulcer Healing and Soothing

In this current work floating tablets of ranitidine and aloe vera was prepared. The objective behind the work was to develop a formulation of H2 antagonist in collaboration with aloe vera to produce an ulcer soothing and ulcer protective effect. Ranitidine is a histamine H2-receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome, gastroesophageal reflux disease, and erosive esophagitis. The effective treatment of erosive esophagitis requires administration of 150 mg of Ranitidine, four times a day. A conventional dose of 150 mg can inhibit gastric acid whereas aloe vera will produce ulcer soothing affect and laxative effect too. In- vitro buoyancy studies were performed for all the ten formulations as per the method described by Rosa et al. The randomly selected tablets from each formulation were kept in a 100ml beaker containing simulated gastric fluid, pH 1.2 as per USP. The time taken for the tablet to rise to the surface and float was taken as floating lag time (FLT).

Assessment of prescribing in under-five paediatric outpatients in Nigeria: an application of the POPI (Pediatrics: Omission of Prescription and Inappropriate Prescription) tool.

This study evaluated prescribing in children under the age of five attending paediatric outpatient clinics at three Central hospitals in Delta State, Nigeria and determined the conditions mostly associated with inappropriate prescriptions and omissions. This was a retrospective study of prescriptions made to children from 0 to 59 months who attended the clinics. Prescriptions were evaluated using the POPI tool, occurrence of potentially inappropriate prescriptions and prescribing omissions were reported as percentages and inappropriate prescription types and prescription omissions were also reported as frequencies. Relationship between inappropriate prescriptions, omissions of prescriptions and age group and gender were determined, P < 0.05 was considered significant. A total of 1327 prescriptions from the three centres were analyzed. There was a preponderance of infants (>1 month-12 months of age) in the study (43.0%) and a somewhat even gender distribution. Exactly 29.8% of all the prescriptions studied had at least one occurrence of inappropriate prescription. The use of H1 antagonists with sedative or atropine-like effects accounted for the majority of inappropriate prescriptions (49.5%), while the prescription of drinkable amoxicillin or other antibiotics in doses other than mg was the most frequent omission of prescription (97.2%). There was a significant relationship between the occurrence of inappropriate prescription and age group (P > 0.001). Inappropriate prescriptions and omissions of prescriptions were high and effectively detected by the POPI tool.

Emerging strategies for treating autoimmune disorders in patients with type 1 diabetes and multiple sclerosis

In the world as a whole and in Ukraine in partmicular, the incidence of autoimmune pathologies continues to grow steadily. There is an increase in the number of type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) cases in the population. Both diseases have an autoimmune nature and several common features in terms of onset, diagnosis, lack of effective treatment and deve­lopment of complications that are potentially life-threatening. In addition, both diseases have genetic risk factors associated with human leukocyte antigen. There are also other genetic risk factors, such as T-cell alleles of interleukin-2 and protein tyrosine phosphatase, non-receptor type 22 in MS and T1DM, respectively. The environment also plays a significant role in the development of both diseases, with smoking and exposure to viruses increasing the risk of MS and T1DM. To date, the proposed methods of therapy for both diseases are not completely effective, and some of them even have serious side effects. The authors consider the possibility of using clemastine fumarate as a histamine H1 antagonist in the management of T1DM and MS. This histamine H1 antagonist penetrates the blood-brain barrier more easily and thus leads to a sedative effect. The efficacy of clemastine fumarate to enhance remyelination in MS was recently demonstrated in a double-blind crossover clinical trial. In addition, this compound was effective in the treatment of T1DM and its complications in a number of experimental studies. The currently available data allow us to recommend clemastine fumarate as the drug of choice in the comprehensive management of patients with MS. Attention is focused on the need for clinical studies to prove the effectiveness of clemastine fumarate in the treatment of patients with T1DM.

P054 Neurotransmitters of Sleep and Wake in Flatworms

Abstract Introduction Sleep is something that we all do, regardless of how much or how little. But why we sleep, and how sleep evolved is still something of a mystery. This research investigated how neurotransmitters and pharmaceuticals commonly seen in mammalian sleep and wake, play a role in the sleep of free-living flatworms. Methods Using behavioural methods, I observed the behaviour of flatworms under a 12:12 LD lighting condition. Using seven neurotransmitters and one pharmaceutical, I used a novel “yolk and soak” method – feeding the animals the neurotransmitter via hard-boiled egg yolk, as well as bathing them in the same concentration of neurotransmitter, to modulate their behaviour to either induce sleep, or wakefulness. Results We found that GABA, dopamine and histamine appear to be evolutionarily conserved. By dosing the flatworms with these neurotransmitters, we saw that the behaviour changed toward sleep (GABA) or wakefulness (dopamine and histamine) as it does in more recently evolved mammals. We also saw that the H1 antagonist Pyrilamine induced sleep, as it does in other animals. Discussion Understanding how neurotransmitters involved in sleep and wake in humans, and other mammals, may work in animals that are neurologically simple, and older in evolution can lead to many opportunities. We now know that GABA, dopamine and histamine promote sleep and wake in animals that have lost most of their complex systems through secondary simplification, suggesting that these neurotransmitters might be key to the origin of sleep, and may help to understand sleep disorders in humans.

A double-blind, placebo-controlled trial of the efficacy and safety of two doses of azelastine hydrochloride in perennial allergic rhinitis.

Azelastine hydrochloride (AZE) is a selective, non-sedating H1 antagonist with anti-inflammatory and mast cell stabilizing properties, which can be used as an alternative to intranasal corticosteroids. The objective of this study was to evaluate the efficacy of the new formulation of 0.15% AZE compared to that of the placebo at a dosage of two sprays per nostril twice daily for 4 weeks in patients with perennial allergic rhinitis (PAR). A total of 581 subjects were randomized in this double-blind (DB) placebo-controlled trial (NCT00712920) that compared 0.10% (1,096 μg daily) and 0.15% AZE (1,644 μg daily) to the placebo in PAR patients. The study consisted of a 7-day single-blind placebo lead-in period and a 28-day DB treatment period. The primary endpoint was the change from baseline in the 12-h reflective total nasal symptom score (rTNSS) for the entire 28-day study period of 0.15% AZE, two sprays per nostril BID compared to the placebo. The efficacy and safety of 0.15% AZE were compared to the placebo. Least square (LS) mean improvement from baseline in the morning (AM) and evening (PM) combined rTNSS was statistically significant for the 0.15% AZE group (p = 0.04) compared to the placebo group. LS mean improvement from baseline in the AM and PM combined rTNSS was 4.10 (4.26) units for 0.15% AZE and 3.81 (3.99) for 0.10% AZE. For individual symptoms, there was a statistically significant change in the LS mean (p = 0.04) improvement from baseline on the 12-h reflective assessment for the 0.15% AZE group for runny nose. Further numerical improvements were shown for itchy nose, nasal congestion, runny nose, and sneezing compared to the placebo. No deaths or serious adverse events related to the study medication were reported. The present formulation of 0.15% AZE is safe and effective in relieving PAR symptoms. It effectively relieves nasal and non-nasal symptoms. ClinicalTrials.gov, identifier: NCT00712920.

THU485 The Impact Of Cured, Fried Bacon On The Reemergence From Breast Cancer Dormancy

Abstract Disclosure: C.P. Schane: None. A. Nelczyk: None. C. Chen: None. H. Vidana Gamage: None. M. Kadiri: None. M.T. McHenry: None. S. Bendre: None. N. Krawczynska: None. M.A. Henn: None. D.C. Castro: None. J. Chen: None. R.I. Tejeda: None. S. Hsiao: None. N.J. Engeseth: None. J.V. Sweedler: None. M.K. Wendt: None. T. Fan: None. W.G. Helferich: None. E.R. Nelson: None. One in eight women will develop breast cancer in her lifetime, with metastasis being the leading cause of mortality. Once the cells colonize the metastatic site, they do not always immediately begin to proliferate, but remain dormant. These dormant cells reside in the tissue, until mechanisms, which remain unknown, awaken the dormant cells and they resume malignant proliferation. Due to the large and growing population of breast cancer survivors at risk of metastatic recurrence, there is an urgent need to elucidate the mechanisms of dormancy and develop therapeutics to prevent reemergence. Elevated levels of circulating cholesterol are a risk factor for breast cancer recurrence. Preclinical work has demonstrated that oxysterol cholesterol metabolites such as 27-hydroxycholesterol (27HC) can promote tumor metastasis. Here, we show that exogenous 27HC lead to a more rapid reemergence from dormancy, using the syngeneic mouse D2.0R model of mammary cancer dormancy. Since it would be expected that cooking high cholesterol foods, such as bacon, under oxidative conditions, such as pan-frying, would produce fat containing cancer-promoting cholesterol metabolites, we hypothesized that consumption of such cooked foods would also promote reemergence from dormancy. Interestingly, consumption of cured, fried bacon fat (cfBF), but not uncured fried bacon fat (ufBF) resulted in reemergence. When metastatic tissues were assessed, it was found that consumption of cfBF dramatically reduced mast cell numbers. Since mast cells (MC) are major contributors to local histamine production, we next tested whether various anti-histamines could alter dormancy. This led to the striking finding that H2 antagonists promoted the breaking of dormancy. Our ongoing work is aimed at further elucidating this novel metastatic axis: Diet - MC - H2 - Dormancy, with the ultimate goal of leveraging it to develop novel therapeutic targets or lifestyle interventions. Therefore, our results are expected to provide the foundation for dietary and medical approaches to reduce the risk of recurrence among breast cancer survivors. This work was supported by the American Institute for Cancer Research grant (713063), the National Cancer Institute (R01CA234025) and Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (BC200206). Further support awarded to ATN from a National Institutes of Environment Health Sciences and Research Training in Toxicology and Environmental Health (T32) Fellowship (ES007326). Presentation: Thursday, June 15, 2023

Association of Proton Pump Inhibitor Use and Severe Pneumonitis in Stage III Non-Small-Cell Lung Cancer Treated with Primary Chemoradiation and Adjuvant Durvalumab

Prior studies have suggested gut microbiome changes induced by long-term acid-reducing medication use could modulate immunotherapy efficacy and toxicity. We assessed the relationship between baseline acid-reducing medication use (proton pump inhibitors [PPI] or H2 antagonists [H2A]) on treatment-related toxicity and efficacy in a large cohort of stage III non-small-cell lung cancer (NSCLC) patients treated with or without immunotherapy. Patients with unresectable stage III NSCLC treated with primary concurrent chemoradiation with or without adjuvant durvalumab from 2015 to 2021 were identified in the Veterans Affairs (VA) system. We defined baseline acid-reducing medication use with VA and non-VA pharmacy records in the year prior to radiation start; the number of prescriptions and the cumulative duration of therapy were quantified. Using multivariable Cox models adjusting for potential baseline confounders and stratified by adjuvant durvalumab use, we estimated the association between PPI or H2A use and subsequent severe pneumonitis, progression-free survival, and overall survival. Pneumonitis was determined and graded by manual chart review. We included 1994 patients with stage III NSCLC treated with primary chemoradiation, of whom 1005 (50%) received adjuvant durvalumab, 1064 (53%) received any PPI and 1030 (52%) received any H2A. In the overall sample, baseline use of any PPI was associated with increased risk of grade 3-5 pneumonitis (adjusted hazard ratio [aHR] 1.53, 95% CI 1.12-2.10, p = 0.008) and was found to be significant only in durvalumab-treated patients (aHR 1.67, 95% CI 1.10-2.54, p = 0.016), but not for patients treated without durvalumab (aHR 1.34, 95% CI 0.82-2.20, p = 0.2). Higher number of PPI prescriptions were associated with increased risk of severe pneumonitis (aHR 1.38 per 5 prescriptions, 95% CI 1.03-1.85, p = 0.03) and longer duration of PPIs trended toward significance (aHR 1.04 per 90 days, 95% CI 1.00-1.09, p = 0.066). Any PPI use was associated with worse OS in durvalumab-treated patients (aHR 1.30, 95% CI 1.05-1.61, p = 0.016) but not for patients without durvalumab use (aHR 0.99, 95% CI 0.86-1.14, p = 0.9). PPI use had no association with progression-free survival in either cohort. No significant associations between baseline H2A use and pneumonitis, PFS, or OS in either cohort were seen. PPIs, but not H2As, are associated with increased risk of treatment-related pneumonitis and inferior OS in stage III NSCLC patients treated with chemoradiation and immunotherapy. This association was not observed among patients treated with chemoradiation alone. No association was found between PPI use and cancer progression. Further work is warranted to confirm these findings in other immunotherapy-treated cohorts.

Antioxidant and Anti-Glycation Potential of H2 Receptor Antagonists-In Vitro Studies and a Systematic Literature Review.

Background: Histamine H2 receptor antagonists are a group of drugs that inhibit gastric juice secretion in gastrointestinal diseases. However, there is evidence to suggest that H2 blockers have a broader spectrum of activity. The antioxidant properties of H2 blockers have not been fully elucidated, and their anti-glycation potential has not been studied to date. Therefore, this is the first study to compare the antioxidant and antiglycation potentials of the most popular H2 antagonists (ranitidine, cimetidine, and famotidine) on protein glycoxidation in vitro. Methods: Bovine serum albumin (BSA) was glycated using sugars (glucose, fructose, galactose, and ribose) as well as aldehydes (glyoxal and methylglyoxal). Results: In the analyzed group of drugs, ranitidine was the only H2 blocker that significantly inhibited BSA glycation in all tested models. The contents of protein carbonyls, protein glycoxidation products (↓dityrosine, ↓N-formylkynurenine), and early (↓Amadori products) and late-stage (↓AGEs) protein glycation products decreased in samples of glycated BSA with the addition of ranitidine relative to BSA with the addition of the glycating agents. The anti-glycation potential of ranitidine was comparable to those of aminoguanidine and Trolox. In the molecular docking analysis, ranitidine was characterized by the lowest binding energy for BSA sites and could compete with protein amino groups for the addition of carbonyl groups. H2 blockers also scavenge free radicals. The strongest antioxidant properties are found in ranitidine, which additionally has the ability to bind transition metal ions. The systematic literature review also revealed that the anti-glycation effects of ranitidine could be attributed to its antioxidant properties. Conclusions: Ranitidine showed anti-glycation and antioxidant properties. Further research is needed, particularly in patients with diseases that promote protein glycation.