Beta-adrenergic Blockers Research Articles

Acquired long QT interval syndrome as a predictor of sudden cardiac death: Causes, diagnostic criteria, and management strategy

Despite medical advances in diagnosis and treatment, cardiovascular disease remains the leading cause of death worldwide. Sudden cardiac death, an extreme and irreversible outcome of cardiac arrest, is observed in 50% of cases and is often the first suddenly detected pathology. Long QT syndrome is a variant of electrical heart disease resulting from both congenital and acquired dysfunction and/or regulation of cardiomyocyte ion channels, accompanied by impaired depolarization and repolarization of the ventricular myocardium and characterized by QT prolongation and T abnormalities on the electrocardiogram, clinically accompanied by syncope, bidirectional spindle ventricular tachycardia of the “pirouette” type (torsade de pointes), associated with a high risk of sudden cardiac death or sudden arrhythmic death syndrome. Effective management of these patients requires an individualized approach: careful examination, calculation of corrected QT, determination of typology (hereditary or acquired syndrome), risk assessment using the Tisdale scale, and selection of optimal therapy. Treatment should be comprehensive and include pharmacological (beta-adrenergic blockers, correction of electrolyte balance) and surgical (implantable cardioverter-defibrillator and left-sided thoracic sympathetic denervation of the heart), lifestyle (avoidance of drugs that contribute to prolongation of the QT interval, avoidance of specific arrhythmia triggers (active swimming, exposure to loud noises)) and regular consultation with a cardiologist. Early diagnosis and a comprehensive approach are key to successful prevention of sudden cardiac death in patients with Long QT syndrome.

The Effects of Nebivolol-Gefitinib-Loratadine Against Lung Cancer Cell Lines.

Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines. A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay. The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells). The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment.

Topical application of beta-blockers accelerates epithelialization to mesh skin grafted full-thickness burn in sheep

Aim : Beta-adrenergic receptor blockers are conventionally used for the treatment of hypertension, tachycardia, and glaucoma. Research has shown that beta-blockers can accelerate wound epithelialization. In this study, we tested the efficacy of the beta-blocker timolol in an ovine model of grafted full-thickness burn wound healing, which closely mimics clinical scenarios. Methods : Six full-thickness burn wounds were created on the sheep’s posterior surface. Twenty-four hours later, eschars were excised and meshed skin was grafted (Day0). The wounds in the treatment group received topical application of timolol. Blood flow was measured using a blood perfusion imager. Cardiovascular hemodynamics and blood glucose levels were recorded daily. The epithelialization rate on Day 14 was determined by planimetric assay and analyzed by paired t -test. The days that the epithelialization rate exceeded 85%, 90%, and 95% were analyzed by survival analysis. To assess the potential influence of TGFβ, epithelial-mesenchymal transition (EMT), or myofibroblast activation (MFA) on wound healing, the RNA abundance of gene products related to these pathways was measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). Results : The epithelialization rate on Day 14 was significantly higher in the treatment group. The days that the epithelialization rate exceeded 85%, 90%, and 95% were significantly shorter in the treatment group. There was no significant difference in wound blood flow or RNA abundance related to TGFβ, EMT, or MFA-related pathways among the groups at any time point. Conclusion : The results demonstrate that the beta-blocker timolol accelerates epithelialization of mesh skin grafted full-thickness burn wounds through a mechanism other than improving wound blood flow.

7046 Thyroid Storm After Thyroidectomy Without Underlying Hyperthyroidism

Abstract Disclosure: A.J. White-Cotsmire: None. B. Kodali: None. C. McHenry: None. M. Rahhal: None. Background: Thyroid storm is a feared complication of total thyroidectomy; however, this is a rare phenomenon seen primarily in patients with undiagnosed or poorly controlled thyrotoxicosis from Graves’ disease. Preoperative treatment of patients with hyperthyroidism with beta-adrenergic blockers and anti-thyroid medication to ensure that patients are euthyroid prior to thyroidectomy have largely eliminated this risk of thyroid storm. (1) We report a case of thyroid storm caused by release of preformed thyroid hormone, following extensive manipulation and resection of a large retrosternal nontoxic multinodular goiter. To our knowledge, this has not yet been previously described. Clinical Case: A 57yo female underwent a total thyroidectomy with resection of a large benign multinodular goiter with retrosternal extension, which was causing compressive symptoms. She had a nodular goiter for 7 years that was increasing in size. Fine needle aspiration 2 years prior to surgery demonstrated colloid and adenomatoid nodules with Hurthle cell changes. She had no history of hypo- or hyperthyroidism. TSH prior to surgery was 0.576µIU/ml (normal = 0.450-5.330µIU/ml). Extensive manipulation was required to deliver the goiter from beneath the manubrium. Pathology from her thyroid revealed a multinodular goiter without evidence of malignancy. Post-operative course was uncomplicated, and after an overnight stay, the patient was discharged home with 150mcg (1.5mcg/kg) levothyroxine daily. She presented to the emergency department 4 days later and was admitted to the intensive care unit with diffuse abdominal pain, nausea, vomiting, and myalgias, and she was diagnosed with atrial fibrillation with rapid ventricular response. TSH on admission was 0.020 µIU/ml, thyroglobulin levels were >2,250.0ng/mL (n=0.8 – 48.0 ng/mL), thyroglobulin antibodies were negative. Her levothyroxine was stopped, her heart rate was controlled with metoprolol, and she was started on oral anticoagulation with rivaroxaban. She was discharged after a 7-day hospital stay. At 3 weeks follow-up her TSH was 35.67µIU/ml and her thyroglobulin levels were 23.9ng/mL. Her symptoms had resolved, and levothyroxine was resumed at a lower dose of 137mcg daily. Six weeks later her TSH level was 7.785µIU/ml, and her thyroglobulin was 1.8ng/mL. Conclusion: To our knowledge, this is the first case of thyroid storm reported following thyroidectomy in a patient with nontoxic multinodular goiter in a clinically and biochemically euthyroid patient. Massive increase in thyroglobulin postoperatively and rapid resolution of symptoms suggest that the release of preformed thyroid hormone related to vigorous thyroid manipulation was likely the cause. Reference: (1) Christou N, Mathonnet M. Complications after total thyroidectomy. Journal of Visceral Surgery. 2013;150(4):249-256. doi:10.1016/j.jviscsurg.2013.04.003 Presentation: 6/1/2024

B-257 Dont go breaking my heart: use and misuse of beta-blockers in clinical and forensic casework (2019-2023)

Abstract Background Beta-adrenergic antagonists, or beta-blockers, are commonly prescribed for the treatment and prevention of a variety of cardiovascular issues and other health conditions. These include, but are not limited to heart failure, heart rhythm disturbances, high blood pressure, hypertension, anxiety, asthma, glaucoma, and migraines. Beta-blockers work by blocking access to beta-receptors, which then enhance or inhibit cellular activity and result in dilating blood vessels and relaxing the heart muscle. When misused, accidentally or intentionally, serious adverse effects including dizziness, seizure, heart failure, QTc prolongation, coma, and death can occur. In routine toxicology testing, beta-blockers are often reported qualitatively, which likely underestimates the reporting of related adverse events. We performed a retrospective review to evaluate quantitative levels of beta-blockers in blood and identify trends of potential misuse. Methods We queried our laboratory’s data management system from 2019-2023 for reported findings of beta-blockers in blood. Analytes were quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results were analyzed using Microsoft Office software. Results Blood results and a comparison of known therapeutic and adverse concentrations are shown in Table 1. Age and sex were reported in 50% and 74% of cases, respectively. Average age ranged from 43 years old (propranolol) to 59 years old (atenolol and metoprolol), without major differences between sexes. Overall use of beta-blockers was split evenly between men and women. Importantly, each analyte provided examples which far exceeded known therapeutic levels, with several cases submitted as potential overdoses. Conclusions Since beta-blockers are generally reported qualitatively during routine toxicology testing, concentrations are unknown. Quantitative testing has shown that beta-blocker concentrations often exceed known therapeutic ranges, which can lead to adverse effects and fatal outcomes. Physicians and death investigators should be aware of these adverse effects and the need for specialized testing in the event of suspected beta-blocker toxicity.

Prescription Pattern of Beta Blockers in Patients Diagnosed with Heart Failure

This study will be helpful to detect the dosage, frequency and duration of beta blockers which is prescribed for heart failure patients that is followed the guideline. The goal of the study was to describe the prescription pattern of beta blockers in patients diagnosed with heart failure. Hypothyroidism, hypertension, type 2 diabetes mellitus patients are very prone to get Heart failure. Beta blockers should be prescribed, respective with the symptoms that occurred specifically to a particular patient. This study helped to detect the parameters of prescribing beta blockers in different symptoms and co morbidities. A Total of 39 patients, among them It was observed that (46.05%) patients having heart failure were from age group 48-57, followed by (2.5%) of 78-87 age group, of which the males (58.96%) proportion where seems more than the females (41.04%). The prescription pattern for heart failure patients were found as 100% Beta adrenergic blockers, such as metoprolol-65%, bisoprolol-22%, Carvedilol-15% were given. It is evident that the beta blockers are mainly prescribed according to the symptoms, carvedilol exhibits a more pronounced BP lowering effect as a consequence of its α1- receptor blocking activities and thus causes more frequent dizziness and hypotension. In patients predisposed to symptomatic hypotension, metoprolol succinate may be the more desirable whereas in patients with uncontrolled hypertension, carvedilol may be preferred. A selective β1-blocker such as metoprolol succinate is a reasonable option for patients with reactive airway disease.

Topical Anti-ulcerogenic Effect of the Beta-adrenergic Blockers on Diabetic Foot Ulcers: Recent Advances and Future Prospectives.

Patients with diabetes suffer from major complications like Diabetic Retinopathy, Diabetic Coronary Artery Disease, and Diabetic Foot ulcers (DFUs). Diabetes complications are a group of ailments whose recovery time is especially delayed, irrespective of the underlying reason. The longer duration of wound healing enhances the probability of problems like sepsis and amputation. The delayed healing makes it more critical for research focus. By understanding the molecular pathogenesis of diabetic wounds, it is quite easy to target the molecules involved in the healing of wounds. Recent research on beta-adrenergic blocking drugs has revealed that these classes of drugs possess therapeutic potential in the healing of DFUs. However, because the order of events in defective healing is adequately defined, it is possible to recognize moieties that are currently in the market that are recognized to aim at one or several identified molecular processes. The aim of this study was to explore some molecules with different therapeutic categories that have demonstrated favorable effects in improving diabetic wound healing, also called the repurposing of drugs. Various databases like PubMed/Medline, Google Scholar and Web of Science (WoS) of all English language articles were searched, and relevant information was collected regarding the role of beta-adrenergic blockers in diabetic wounds or diabetic foot ulcers (DFUs) using the relevant keywords for the literature review. The potential beta-blocking agents and their mechanism of action in diabetic foot ulcers were studied, and it was found that these drugs have a profound effect on diabetic foot ulcer healing as per reported literatures. There is a need to move forward from preclinical studies to clinical studies to analyze clinical findings to determine the effectiveness and safety of some beta-antagonists in diabetic foot ulcer treatment.

Application of UHPLC-QqQ-MS/MS Method for Quantification of Beta-Adrenergic Blocking Agents (β-Blockers) in Human Postmortem Specimens.

Betablockers are one of the most frequently used medications in cardiology. They can lead to fatal drops in blood pressure and heart rhythm disturbances. Death is functional, and poisoning with this group of drugs can be difficult to detect. The liquid-liquid extraction (LLE) method developed using ethyl acetate at pH 9 successfully identified 18 β-blockers in human blood. The method's limit of quantification (LOQ) was in the range of 0.1 to 0.5 ng/mL. No carryover of substances between samples was detected, and no interfering ion current signals were observed in the biological samples at the retention times of the compounds or internal standards. All compounds had a coefficient of determination (R2) above 0.995. Intraday and interday precision (RSD%) and accuracy (RE%) for low and high QC levels were within 1.7-12.3% and -14.4 to 14.1%, respectively. Very good recovery (80.0-119.6%) and matrix effect (±20.0%) values were achieved for all compounds. In addition, fragmentation spectra were collected for all the examined substances, and high-resolution spectra were presented for landiolol and metipranolol, because they are not available in commercial HRMS spectra databases. The developed method was applied in authentic postmortem samples.

Studies on Propranolol hydrochloride floating tablets formulated with different concentrations of Aegle marmelos gum

This research employs Aegle marmelos gum in various ratios as a natural polymer to formulate and assess Propranolol hydrochloride floating tablets. Because of its high solubility and permeability, propranolol hydrochloride, a non-selective beta-adrenergic receptor blocker, has a restricted bioavailability. Floating tablets are intended to improve the absorption and bioavailability of drugs by staying afloat in the stomach. Aegle marmelos gum (AMG) was used as a polymer in varied ratios to create distinct formulations. The tablets were then tested for a number of characteristics, including hardness, friability, drug content, in vitro buoyancy, and drug release profiles. The findings showed that the Aegle marmelos gum content had a major impact on the tablets' floating qualities and drug release characteristics.

High-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent anthracycline cardiotoxicity: the Cardiac CARE RCT

Background Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by rises in plasma cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. Methods In a multicentre prospective randomised open-label blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent plasma high-sensitivity cardiac troponin concentration monitoring and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Randomised controlled trial – patients at high risk of cardiotoxicity (plasma cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomised to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary end point was 6-month change in left ventricular ejection fraction. Prognostic cohort study – in low-risk non-randomised patients with plasma cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (± 2%). Results Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomised to cardioprotection (n = 29) or standard care (n = 28) had mean left ventricular ejection fractions of 65.7 ± 6.6% and 64.9 ± 5.9%, respectively, at 6 months. Twenty patients (68.9%) were adherent to cardioprotection therapy at 6 months. Adverse events were more commonly reported in the cardioprotection group, with 71.4% of patients having at least one adverse event compared with 12.7% non-randomised and 10.3% standard care patients. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean percentage-point difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was –0.4% (95% confidence interval –3.59 to 2.85%; p = 0.82). In low-risk non-randomised patients, baseline and 6-month left ventricular ejection fractions were 69.3 ± 5.7% and 66.4 ± 6.3%, respectively (estimated mean difference 2.9%, 95% confidence interval 1.45 to 4.28%; p = 0.92, not equivalent). The main secondary objective of demonstrating zero percentage-point change with equivalence of ± 2% was not met. Conclusions Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment plasma cardiac troponin I concentrations. Low-risk non-randomised patients had similar modest declines in left ventricular ejection fraction, suggesting that the clinical utility of routine cardiac troponin monitoring remains undefined. The modest short-term declines in left ventricular ejection fraction suggest that early cardioprotection therapy has a limited role in patients receiving anthracycline-based chemotherapy. Limitations Treatment effect might have been influenced by several patients stopping cardioprotection treatment within 2 months of randomisation. Across all groups, reduction in left ventricular ejection fraction was lower than expected and patients with high-risk cardiac troponin I concentrations did not exhibit a greater fall in left ventricular ejection fraction than low-risk patients. These factors, together with the trial being powered to detect a 5-percentage-point change in left ventricular ejection fraction, mean that a small treatment effect was not excluded. Future work Future work should aim to understand the transition from small changes in cardiac function, 6 months after completion of anthracycline chemotherapy, to the late development of heart failure in this population. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Retrospective analysis for the utility of beta-adrenergic blockers in thyroid storm: the double-edged sword

Retrospective analysis for the utility of beta-adrenergic blockers in thyroid storm: the double-edged sword

Abstract LB135: Effects of acute psychological stress on DNA damage levels in peripheral blood mononuclear cells: An experimental study with healthy human volunteers

Abstract Increased levels of DNA damage in human peripheral blood mononuclear cells (PBMC), as indicated by classic alkaline comet and γ-H2AX assays, have been widely used in toxicology and epidemiology studies of potential environmental carcinogens. To date, however, little research has explored the possibility that exposure to acute psychological stresses in daily life may acutely increase levels of DNA damage and thus, much like repeated tobacco use, may cumulatively contribute to lifetime cancer risk. The purpose of the present experimental study was to provide a first critical test of the hypothesis that exposure of healthy humans to a brief psychological stress results in increased levels of DNA damage. We also tested preventative effects of a beta-adrenergic receptor blocker (propranolol), a mechanistic pathway for psychological stress effects on DNA supported by preclinical research. Healthy volunteers were recruited by multiple strategies including targeted outreach (telephone/email), with oversampling for age, sex, and minority status. Eligibility was confirmed by self-report, clinical testing (blood & urine), and MD review. On the experimental day, participants were randomized to receive either a single dose of propranolol (80mg) or a placebo. After a 60 min rest period with video distraction, all participants (n=123; 48.8% ≥ 40yr; 52% women; 52% minority) underwent a well-established, 15-minute stress challenge, a speech task and mental arithmetic (Trier Social Stress Test, TSST), with psychological stress confirmed by visual analog scales. Blood samples were collected (via IV line) immediately before and after the TSST. As the primary study outcome, DNA damage in PBMC was assessed (blind) with Comet IV software (% tail intensity) following single cell gel electrophoresis under alkaline conditions with and without in vitro exposure to 25uM H2O2 (comet assay). For a subset of participants with sufficient frozen PBMC samples available (n=43), levels of pan-nuclear γ-H2AX were determined with a validated, sensitive, immunoblot method that detects H2AX phosphorylation at Ser139, and expresses γ-H2AX as the ratio of p-Ser139-H2AX to total H2AX. Exploratory nonparametric analyses revealed that undergoing the TSST significantly increased levels of DNA damage in PBMC (H2O2 comet assay [p<.001] and γ-H2AX biomarker [p=.03], Wilcoxon tests) in the group of participants that was randomized to pretreatment with placebo. In the group pretreated with propranolol before the TSST, a significant increase in γ-H2AX was not found. Conclusion. Supporting the study hypothesis that acute stress can increase levels of DNA damage, the results of the present study highlight the potential importance of additional research to address the possibility that repeated exposures to acute life stresses may cumulatively contribute to increased lifetime risk of cancer. Citation Format: Dana H. Bovbjerg, John Schmitz, Kurt D. Ackerman, Scott R. Beach, Albert D. Donnenberg, Jessica Manculich, Matthew F. Muldoon, Patricia L. Opresko, Patrick M. Tarwater, Hong Wang, Frank J. Jenkins. Effects of acute psychological stress on DNA damage levels in peripheral blood mononuclear cells: An experimental study with healthy human volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB135.

Efficiency of Gastric Decontamination and Activated Charcoal in Beta Blocker (Metoprolol) Poisoning; A Case Report

Beta blockers are negative inotrop and cronotrop in miyocardial activity. They are prescribed widely for multipl clinical conditions. Beta blocker overdose may ocur in patients who used it by accidently or for suicidal purposes. These drugs can effect cardiovascular functions as well as mental conditions. Many patients with overdose have fatal clinical conditions and require intensive treatment due to the drug effect. 
 Our case is a 33 year-old-woman, took 100 miligrams of metoprolol (2 blister of a pocket) 1 hour ago with the intention of committing suicide. She had nausea and vomiting, dizziness. Vital signs; her blood pressure was 120/70, heart rate was 85, respiratory rate and saturation were normal. Electrocardiogram was in sinus rtym and there was no change in the ST segment. She was placed under observation and closely monitored. We administered gastric decontamination to throw out the medications she took 1 hour ago. We administered her 1 liter salin and antiemetic medication to manage the nausea. After a while she had bradicardia and vomiting. We applied her a glucagon and atropin injection and she was admitted to the intensive care unit. After 2 hours, she was completely recover and had no clinical symptoms. She got monitorized for a day and was discharged from the hospital after full recovery. Since we know that the use of high doses of beta blockers is mortal and has poor clinical outcome, we think that the patient in this case underwent gastric decontamination and active charcoal early and succesfully, so she was discharged from the hospital with good clinical outcome. 
 As a result, it is thought that gastric decontamination and also active charcoal may be useful and lifesaving in case of drug overdose in early presentations.

Abstract 3391: Effects of repeated psychological stress on NNK-induced lung cancer development in young female mice

Abstract Lung cancer is the second most common cancer in both men and women in the US and the leading cause of cancer death. Among younger US women, lung cancer incidence rates have in recent years become higher than rates seen in men, despite comparable histories of tobacco use. The possible contribution of stress to higher lung cancer risk in young women has received little research attention despite preclinical evidence that exposure to stress-related neuroendocrine responses can cause DNA damage. The present study used a well-established lung cancer model in young female mice (in vivo exposure to NNK) along with a mouse stress model to explore their independent and combined effects on lung cancer development. In addition, we explored one possible biological pathway by chronic administration of a beta-adrenergic receptor blocker (propranolol). We also tested the use of in vivo imaging for repeated monitoring of tumor development over time. Cohort 1 (n=60) had 4 groups: Home cage control, NNK treatment alone, repeated stress (RS) alone and NNK+RS. Cohort 2 (n=60) had the same 4 groups with the addition of administration of propranolol in drinking water. Cohort 3 (n=48, imaging cohort) had 3 groups: Home cage control, NNK alone and NNK+RS. FVB/N (4-6 wk) were purchased from a commercial supplier and acclimated with gentle handling for two weeks. The repeated stress protocol began week-3 and continued for the duration of the study. It combined two well-established rodent models: social disruption stress via changes in cage mates at the time of cage cleaning (2x/week) and a 90-minute restraint stress immediately prior to cage change (1x/week). NNK or saline treatment began on week-4 (IP; 2x/week; 3 mg/injection) and continued for 4 weeks. 21 weeks after stress initiation, the mice in cohorts 1 and 2 were sacrificed, lungs removed, inflated and tumors counted and sized. Mice in cohort 3 were imaged by Hounsfield-calibrated micro-CT (μCT) at baseline, 14, 19 and 23 weeks. The entire lung space, excluding the heart, was defined as a volumetric region of interests (VOIs). The VOIs were subjected to thresholding to segment the lungs into air space and tissue space compartments. The volume of tissue space of each animal was ratioed against its own baseline tissue space volume. Results from Cohort 1 revealed significantly greater numbers and overall size of lung tumors in stressed mice that received NNK. No significant effects were seen in the absence of NNK. Results from Cohort 2 revealed no significant differences between stressed and unstressed groups treated with propranolol. Cohort 3 revealed a pattern of results with stressed mice generally showing the highest lung tumor volume levels (Hounsfield Units), which reached significance at 19 weeks in preliminary analyses. Conclusion: In this study, we found that repeated stress increased lung tumor burden in female mice treated with NNK, and that a beta-adrenergic pathway may be involved. Citation Format: Frank Jenkins, Laura P. Stabile, Jessie R. Nedrow, Kathryn Day, Joseph D. Latoche, Patrick M. Tarwater, Jessica Manculich, Dana H. Bovbjerg. Effects of repeated psychological stress on NNK-induced lung cancer development in young female mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3391.

Graves Disease - A Comprehensive Review

Graves Disease (GD) is an inflammatory disorder that often results in hyperthyroidism. GD is particularly prone to affecting women, African Americans, individuals with pre-existing autoimmune conditions, and first-degree relatives of those with GD. GD presents through a breakdown of immune tolerance against thyroid antigens. This occurs through a multifactorial autoimmune dysfunction of environmental and mainly genetic contribution. Hereditary predisposition accounts for 79% of the GD risk and increases susceptibility to dysfunction by environmental risk factors such as smoking, vitamin D deficiency, and stressful life events. GD is caused by a disruption of the thyroid gland on a molecular level. The disease is characterized by an overstimulation of the thyroid gland causing hyperthyroidism. This issue is caused by thyroid-stimulating immunoglobulin (TSI) synthesized by B cells. These immunoglobulins bind to the TSH receptors on the thyroid gland, activating it and producing an abundance of the thyroid hormones, levothyroxine (T4) and triiodothyronine (T3). The clinical presentation of GD encompasses a diverse array of signs and symptoms, from common manifestations such as palpitations, weight reduction, and exophthalmos, to less conventional presentations like cardiac complications and cholestatic hepatic injury. There are many methods of diagnosis that are used for GD including the gold standard, which tests for TSI and antibodies against the TSH receptor. Other methods include radioactive iodine uptake and CT scans that test for thyroid enlargement and are used to substitute radioactive iodine uptake tests for pregnant women. The three classical treatments for GD are antithyroid drugs, radioiodine treatment, and thyroidectomy. Additional treatments include corticosteroids which are used to decrease exophthalmos. Beta-adrenergic blockers are used for tachycardia, palpitations, and also blocking the peripheral conversion of T4 to T3. Immunotherapies, such as Mycophenolate mofetil and Azathioprine show promise as potential treatments are currently being investigated. This comprehensive review provides an up-to-date compact analysis of literature pertinent to the epidemiology, etiology, risk factors, genetics, pathophysiology, classifications, clinical presentation, diagnosis, and treatments of GD.

Pharmacotherapy causing weight gain and metabolic alteration in those with obesity and obesity-related conditions: A review.

This review aims to summarize pharmacological interventions that may affect adiposity and metabolic equilibrium in individuals with obesity. Pharmacological therapy is frequently used to treat medical conditions that are both directly related to obesity (such as hypertension and type 2 diabetes) and indirectly related to obesity (such as asthma, insomnia, and type 1 diabetes). This pharmacological therapy may result in weight gain and alterations in the metabolic profile. Many medication classes are implicated in the pharmacologic causes of weight gain, including antipsychotics, glucocorticoids, beta-adrenergic blockers, tricyclic antidepressants, antihistamines, insulin, neuropathic agents, sleep agents, and steroids. This article describes the mechanisms of action and pathways of pharmacological interventions causing obesity.

Norepinephrine induces anoikis resistance in high-grade serous ovarian cancer precursor cells.

High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a β-adrenergic receptor-dependent (β-AR-dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the β-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC.

In silico drug repurposing carvedilol and its metabolites against SARS-CoV-2 infection using molecular docking and molecular dynamic simulation approaches

The pandemic of coronavirus disease 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a significant impact on the economy and public health worldwide. Therapeutic options such as drugs and vaccines for this newly emerged disease are eagerly desired due to the high mortality. Using the U.S. Food and Drug Administration (FDA) approved drugs to treat a new disease or entirely different diseases, in terms of drug repurposing, minimizes the time and cost of drug development compared to the de novo design of a new drug. Drug repurposing also has some other advantages such as reducing safety evaluation to accelerate drug application on time. Carvedilol, a non-selective beta-adrenergic blocker originally designed to treat high blood pressure and manage heart disease, has been shown to impact SARS-CoV-2 infection in clinical observation and basic studies. Here, we applied computer-aided approaches to investigate the possibility of repurposing carvedilol to combat SARS-CoV-2 infection. The molecular mechanisms and potential molecular targets of carvedilol were identified by evaluating the interactions of carvedilol with viral proteins. Additionally, the binding affinities of in vivo metabolites of carvedilol with selected targets were evaluated. The docking scores for carvedilol and its metabolites with RdRp were − 10.0 kcal/mol, − 9.8 kcal/mol (1-hydroxyl carvedilol), − 9.7 kcal/mol (3-hydroxyl carvedilol), − 9.8 kcal/mol (4-hydroxyl carvedilol), − 9.7 kcal/mol (5-hydroxyl carvedilol), − 10.0 kcal/mol (8-hydroxyl carvedilol), and − 10.1 kcal/mol (O-desmethyl carvedilol), respectively. Using the molecular dynamics simulation (100 ns) method, we further confirmed the stability of formed complexes of RNA-dependent RNA polymerase (RdRp) and carvedilol or its metabolites. Finally, the drug-target interaction mechanisms that contribute to the complex were investigated. Overall, this study provides the molecular targets and mechanisms of carvedilol and its metabolites as repurposed drugs to fight against SARS-CoV-2 infection.

Rats with Postinfarction Heart Failure: Effects of Propranolol Therapy on Intracellular Calcium Regulation and Left Ventricular Function

Patients with heart failure may live longer if they receive chronic treatment with beta-adrenergic blocking medications. Unresolved are the mechanisms underlying the beneficial effects and if they may be applied to ischemic heart failure. Rats (n = 28) underwent echocardiographic-Doppler exams one and six weeks following a simulated operation or myocardial infarction (MI). After the first echocardiography, rats were randomized to either no therapy or 500 mg/l of propranolol in their drinking water. The noninfected left ventricular (LV) papillary muscles were used to record isometric contractions and intracellular Ca transients simultaneously. Untreated MI rats had a restrictive LV diastolic filling pattern, decreased systolic function (13% ± 2%), and significant LV dilatation (10.6 ± 0.4 mm vs. 8.9 ± 0.3 mm, MI vs. control). The LV chamber diameters of the propranolol-treated MI rats were 10.6 ± 0.5 mm, and systolic performance (13% ± 2%). Higher LV end-diastolic pressures (27 ± 2 mmHg vs. 20 ± 3 mmHg) and a more constrained LV diastolic filling pattern (increased ratio of early to late filling velocities and faster E wave deceleration rate) were seen in the propranolol-treated animals. Papillary muscle contractility in untreated MI rats was lower (1.6 ± 0.3 g mm²). Furthermore, the inotropic response to isoproterenol was attenuated, and Ca transients were extended. During isoproterenol stimulation, beta-adrenergic blocking administration had no effect on force development (1.6 ± 0.3 g mm²) or the length of Ca transients. Rats with postinfarction heart failure receiving chronic propranolol treatment did not have improvements in systolic function or LV remodeling. Propranolol exacerbated LV diastolic pressures and filling patterns. Additionally, there was no discernible improvement in intracellular contractility following treatment, Calcium control, or beta-adrenergic sensitivity in the myocardium that is not infarcted).

The association between polypharmacy and health-related quality of life among non-dialysis chronic kidney disease patients.

The United States government spends over $85 billion annually on treating non-dialysis chronic kidney disease (CKD). Patients with CKD are prescribed a multitude of medications to manage numerous comorbidities associated with CKD. Thus, this study aims to investigate the association between polypharmacy and health-related quality of life (HRQoL) in non-dialysis CKD patients. This cross-sectional study utilized data from the Medical Expenditure Panel Survey (MEPS) from 2010 through 2019. We classified polypharmacy into three groups based on the number of medication classes: ≤ 4 (minor polypharmacy), 5 through 9 (major polypharmacy), and ≥ 10 (hyperpolypharmacy). To measure HRQoL, a Physical Component Summary (PCS) and a Mental Component Summary (MCS) were obtained from the 12-item Short-Form Health Survey version 2 and Veteran's Rand 12 item. We applied multivariable ordinary least squares regression to assess the association between polypharmacy and HRQoL in non-dialysis CKD patients. A total of 649 CKD patients (weighted n = 667,989) were included. Patients with minor polypharmacy, major polypharmacy, and hyperpolypharmacy were 22.27%, 48.24%, and 29.48%, respectively. Major polypharmacy and hyperpolypharmacy were significantly and negatively associated with lower PCS scores when compared with minor polypharmacy [Beta = -3.12 (95% CI: -3.62, -2.62), p-value<0.001; Beta = -4.13 (95CI: -4.74, -3.52), p-value<0.001]. Similarly, major polypharmacy and hyperpolypharmacy were significantly and negatively associated with lower MCS scores when compared to minor polypharmacy [Beta = -0.38 (95% CI: -0.55, -0.20), p-value<0.001; Beta = -1.70 (95% CI: -2.01, -1.40), p-value<0.001]. The top 5 classes of medications used by CKD patients were antihyperlipidemic (56.31%), beta-adrenergic blockers (49.71%), antidiabetics (42.14%), analgesics (42.17%), and diuretics (39.65%). Our study found that both major polypharmacy and hyperpolypharmacy were associated with lower HRQoL among non-dialysis CKD patients. This study highlights the need for further evaluation of the combination of medications taken by non-dialysis CKD patients to minimize unnecessary and inappropriate medication use.