Targeting the ß2 -adrenergic receptor increases chemosensitivity in multiple myeloma by induction of apoptosis and modulating cancer cell metabolism.

While multi-drug combinations and continuous treatment have become standard for multiple myeloma, the disease remains incurable. Repurposing drugs that are currently used for other indications could provide a novel approach to improve the therapeutic efficacy of standard multiple myeloma treatments. Here, we assessed the anti-tumor effects of cardiac drugs called ß-blockers as a single agent and in combination with commonly used anti-myeloma therapies. Expression of the ß2 -adrenergic receptor correlated with poor survival outcomes in patients with multiple myeloma. Targeting the ß2 -adrenergic receptor (ß2 AR) using either selective or non-selective ß-blockers reduced multiple myeloma cell viability, and induced apoptosis and autophagy. Blockade of the ß2 AR modulated cancer cell metabolism by reducing the mitochondrial respiration as well as the glycolytic activity. These effects were not observed by blockade of ß1 -adrenergic receptors. Combining ß2 AR blockade with the chemotherapy drug melphalan or the proteasome inhibitor bortezomib significantly increased apoptosis in multiple myeloma cells. These data identify the therapeutic potential of ß2 AR-blockers as a complementary or additive approach in multiple myeloma treatment and support the future clinical evaluation of non-selective ß-blockers in a randomized controlled trial. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Effect of Concomitant Drugs on Sodium Zirconium Cyclosilicate Hydrate in Artificial Intestinal Juice.

To explore drug interactions involving sodium zirconium cyclosilicate hydrate (SZC) and concomitant drugs like calcium antagonists (amlodipine and nifedipine) and ß-blockers (carvedilol and bisoprolol), we investigate how these concomitant drugs influenced the administration of SZC in an artificial intestinal juice. Initially, we assessed the potassium ion adsorption capacity, ranking it as follows: calcium polystyrene sulfonate (CPS, 54.9 mg/g) < sodium polystyrene sulfonate (SPS, 62.1 mg/g) < SZC (90.8 mg/g). However, the adsorption equilibrium was achieved in the order of CPS ≒ SPS (within 1 min) < SZC (within 1 h). Subsequently, we determined the residual percentages of amlodipine, nifedipine, carvedilol, and bisoprolol, finding them to be 79.0-91.9% for SZC, 0.38-38.4% for SPS, and 0.57-29.0% for CPS. These results suggest the efficacy of SZC in managing hyperkalemia alongside concomitant drugs in an artificial intestinal juice, with particular emphasis on amlodipine (calcium antagonist) and carvedilol (ß-blocker). Additionally, we identified the presence of carbon, nitrogen, and oxygen components from both drugs on the SZC surface following interaction. We also evaluated how amlodipine, nifedipine, carvedilol, and bisoprolol affected the administration of SZC in the presence of potassium ions. Our results indicate that potassium ions and concomitant drugs did not interfere with each other in the artificial intestinal juice. These results offer valuable insights into the administration of SZC in conjunction with concomitant drugs. Lastly, the presented data shows qualitative results in this study.

Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis.

BACKGROUND & AIMS: Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective ß-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding. METHODS: Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression. RESULTS: Eighty-seven patients (carvedilol/propranolol, n = 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18-24 mm Hg), and 39.1%/48.3%/12.6% had Child-Turcotte-Pugh A/B/C cirrhosis, respectively. Upon nonselective ß-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% [interquartile range: -29% to -10%] vs -11% [-22% to -5%] for propranolol; P = .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P = .034). Cumulative incidences for rebleeding (Gray test, P = .027) and liver-related death (P = .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P = .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P = .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models. CONCLUSIONS: Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation.

Increased circulating phenylacetylglutamine concentration elevates the predictive value of cardiovascular event risk in heart failure patients.

BACKGROUND: Phenylacetylglutamine (PAGln)-a newly discovered microbial metabolite produced by phenylalanine metabolism-is reportedly associated with cardiovascular events via adrenergic receptors. Nonetheless, its association with cardiovascular outcomes in heart failure (HF) patients remains unknown. OBJECTIVES: This study aimed to prospectively investigate the prognostic value of PAGln for HF. METHODS: Plasma PAGln levels were quantified by liquid chromatography-tandem mass spectrometry. We first assessed the association between plasma PAGln levels and the incidence of adverse cardiovascular events in 3152 HF patients (including HF with preserved and reduced ejection fraction) over a median follow-up period of 2 years. The primary endpoint was the composite of cardiovascular death or heart transplantation. We then assessed the prognostic role of PAGln in addition to the classic biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP). The correlation between PAGln levels and ß-blocker use was also investigated. RESULTS: In total, 520 cardiovascular deaths or heart transplantations occurred in the HF cohort. Elevated PAGln levels were independently associated with a higher risk of the primary endpoint in a dose-response manner, regardless of HF subtype. Concurrent assessment of PAGln and NT-proBNP levels enhanced risk stratification among HF patients. PAGln further showed prognostic value at low NT-proBNP levels. Additionally, the interaction effects between PAGln and ß-blocker use were not significant. CONCLUSIONS: Plasma PAGln levels are an independent predictor of an increased risk of adverse cardiovascular events in HF. Our work could provide joint and complementary prognostic value to NT-proBNP levels in HF patients.

α/ß- and ß-Blocker Exposure in Pregnancy and the Risk of Neonatal Hypoglycemia and Small for Gestational Age.

BACKGROUND: α/ß- and ß-blockers are essential in pregnant women's perinatal congenital heart disease management. Nevertheless, data on the effects of α/ß- and ß-blockers on pregnant women and fetuses are limited. We examined the risks of neonatal hypoglycemia and small for gestational age (SGA) associated with maternal exposure to α/ß- and ß-blockers.Methods and Results: All consecutive pregnant women with heart disease admitted to our hospital between January 2014 and October 2020 were included. Of 306 pregnancies (267 women), 32 were in the α/ß-blocker group, 11 were in the ß-blocker group, and 263 were in the control group. All 32 pregnancies in the α/ß-blocker group were treated with carvedilol. In the ß-blocker group, 4 women were treated with bisoprolol, 3 were treated with propranolol, 2 were treated with atenolol, 1 was treated with metoprolol, and 1 was treated nadolol. The incidence of neonatal hypoglycemia was higher in pregnant women taking carvedilol than in the control group (P=0.025). SGA was observed significantly more frequently in pregnant women taking ß-blockers than in the carvedilol and control groups (P<0.001). CONCLUSIONS: Carvedilol administration during pregnancy was associated with neonatal hypoglycemia; however, it did not occur in a time- or dose-dependent manner. Routine monitoring of blood glucose levels in newborns exposed to α/ß- and ß-blockers is essential.

Enantiospecific Uptake and Depuration Kinetics of Chiral Metoprolol and Venlafaxine in Marine Medaka (Oryzias melastigma): Tissue Distribution and Metabolite Formation.

The increasing use of chiral pharmaceuticals has led to their widespread presence in the environment. However, their toxicokinetics have rarely been reported. Therefore, the tissue-specific uptake and depuration kinetics of two pairs of pharmaceutical enantiomers, S-(-)-metoprolol versus R-(+)-metoprolol and S-(+)-venlafaxine versus R-(-)-venlafaxine, were studied in marine medaka (Oryzias melastigma) during a 28-day exposure and 14-day clearance period. The toxicokinetics of the studied pharmaceuticals, including uptake and depuration rate constants, depuration half-life (t1/2), and bioconcentration factor (BCF), were reported for the first time. The whole-fish results demonstrated a higher S- than R-venlafaxine bioaccumulation potential, whereas no significant difference was observed between S- and R-metoprolol. O-desmethyl-metoprolol (ODM) and α-hydroxy-metoprolol (AHM) were the main metoprolol metabolites identified by suspect screening, and the ratios of ODM to AHM were 3.08 and 1.35 for S- and R-metoprolol, respectively. N,O-Didesmethyl-venlafaxine (NODDV) and N-desmethyl-venlafaxine (NDV) were the main venlafaxine metabolites, and the ratios of NODDV to NDV were 1.55 and 0.73 for S- and R-venlafaxine, respectively. The highest tissue-specific BCFs of the four enantiomers were all found in the eyes, meriting in-depth investigation.

Incidence and clinical factors associated with ulceration in infantile hemangiomas.

BACKGROUND: Ulceration is an important complication in infantile hemangiomas (IHs). Prior to the use of ß-blockers, the estimated incidence of this complication in a referral population was between 15% and 30%. The incidence and factors associated with ulceration have not been systematically studied since the emergence of ß-blocker therapy. OBJECTIVE: Examine the incidence and clinical predictors for ulceration in IHs. METHODS: Retrospective study at tertiary referral centers. RESULTS: Compared with a previous large pre-propranolol cohort study, ulceration occurred at a significantly lower incidence of 11.4%. Clinical factors associated with ulceration included partial segmental morphology, location in the diaper area, and size greater than 5 cm. Higher risk of ulceration in Black patients was observed, suggesting barriers to care including delayed diagnosis and referral to specialty care. LIMITATIONS: Retrospective design at tertiary referral centers. CONCLUSION: Compared with reports before the use of ß-blockers became widespread, the incidence of ulceration in IHs has decreased. However, it continues to be a relatively frequent complication of IH.

Different effects of medications for hypertension on renal function between patients with and without diabetes mellitus undergoing percutaneous coronary intervention: a retrospective single-center cohort study.

BACKGROUND: Diabetes mellitus (DM) and hypertension are well-known atherosclerosis risk factors. Furthermore, renal dysfunction is a crucial risk factor for patients with coronary artery disease (CAD), and managing renal function in these patients is complicated because of comorbid conditions and potential side effects during treatment. Therefore, this study aimed to investigate the effect of medications for hypertension on renal function after percutaneous coronary intervention (PCI) between patients with and without DM with statins. METHODS: In 297 consecutive patients undergoing PCI for stable angina pectoris, cystatin C (CysC) was evaluated at baseline and 9 months after PCI, and the percent change in CysC (%CysC) was calculated. The association of worsening renal function (WRF: %CysC ≥ 0) and baseline characteristics, including medications, was assessed. RESULTS: Among 297 hypertensive patients with statins, 196 and 101 were with and without DM, respectively. Angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker, and ß-blocker were prescribed in 56 (29%), 82 (42%), and 91 (46%) patients in the DM group, and 20 (20%), 52 (51%), and 52 (51%) in the non-DM group, respectively. The patients with WRF after PCI were 100 (51%) and 59 (58%) in the DM and non-DM groups (p = 0.261). Additionally, the %CysC had no significant differences between groups [median: 0%, interquartile range (IQR): -7.9% to 8.5% vs. median: 1.1%, IQR: -6.6% to 9.6%, p = 0.521]. Multivariate logistic analysis for WRF using relevant factors from univariate analysis showed that only ß-blocker [odds ratio (OR): 2.76, 95% confidence interval (CI): 1.03-7.90, p = 0.048] was independently associated with WRF in the DM group whereas ACEI (OR: 0.07, 95% CI: 0.01-0.47, p = 0.012) was negatively correlated with WRF in the non-DM group. CONCLUSION: The ß-blocker was the independent risk factor for WRF in patients with DM in the late phase after PCI for stable angina pectoris, while the use of ACEI had a renoprotective effect in patients without DM.

The ß-arrestin-biased ß-adrenergic receptor blocker carvedilol enhances skeletal muscle contractility.

A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a ß2-adrenergic receptor (ß2AR) agonist enhances skeletal muscle strength and hypertrophy; however, its clinical utility is limited by side effects such as cardiac arrhythmias mediated by G protein signaling. We recently reported that clenbuterol-induced increases in contractility and skeletal muscle hypertrophy were lost in ß-arrestin 1 knockout mice, implying that arrestins, multifunctional adapter and signaling proteins, play a vital role in mediating the skeletal muscle effects of ß2AR agonists. Carvedilol, classically defined as a ßAR antagonist, is widely used for the treatment of chronic systolic heart failure and hypertension, and has been demonstrated to function as a ß-arrestin-biased ligand for the ß2AR, stimulating ß-arrestin-dependent but not G protein-dependent signaling. In this study, we investigated whether treatment with carvedilol could enhance skeletal muscle strength via ß-arrestin-dependent pathways. In a murine model, we demonstrate chronic treatment with carvedilol, but not other ß-blockers, indeed enhances contractile force in skeletal muscle and this is mediated by ß-arrestin 1. Interestingly, carvedilol enhanced skeletal muscle contractility despite a lack of effect on skeletal muscle hypertrophy. Our findings suggest a potential unique clinical role of carvedilol to stimulate skeletal muscle contractility while avoiding the adverse effects with ßAR agonists. This distinctive signaling profile could present an innovative approach to treating sarcopenia, frailty, and secondary muscle wasting.

Potential Interaction between Sodium Polystyrene Sulfonate and Prescription Drugs in Artificial Intestinal Juice.

This study evaluated the interaction between sodium polystyrene sulfonate (SPS) and several commonly used concomitant drugs, such as carvedilol, bisoprolol, imidapril, atorvastatin and azilsartan. The residual rate of adsorption 6 h after starting the experiment followed the order carvedilol (0.36%) < bisoprolol (19.7%) < imidapril (81.2%) < atorvastatin (86.5%) < azilsartan (87.9%) in artificial intestinal juice (pH 6.8). In addition, the pKa of carvedilol and bisoprolol was 8.0 and 9.6 and that of atorvastatin, azilsartan, and imidapril was 4.5, 6.1, and 2.4, respectively. These results indicate that the form (ionic or uncharged) of each drug is important to its reaction with SPS. Moreover, we demonstrated the effect of potassium ions (concentration of 1000 or 2000 mg/L) on the adsorption of concomitant drugs onto SPS in artificial intestinal juice. Our results show that the residual rate of adsorption of carvedilol and bisoprolol increases with increasing concentration of potassium ions whereas adsorption of potassium ions onto SPS was unaffected by carvedilol and bisoprolol under our experimental conditions. Finally, the obtained results revealed that interactions between SPS and carvedilol or bisoprolol readily occur in artificial intestinal juice.

Photocatalytic Activity of the V2O5 Catalyst toward Selected Pharmaceuticals and Their Mixture: Influence of the Molecular Structure on the Efficiency of the Process.

Due to the inability of conventional wastewater treatment procedures to remove organic pharmaceutical pollutants, active pharmaceutical components remain in wastewater and even reach tap water. In terms of pharmaceutical pollutants, the scientific community focuses on ß-blockers due to their extensive (over)usage and moderately high solubility. In this study, the photocatalytic activity of V2O5 was investigated through the degradation of nadolol (NAD), pindolol (PIN), metoprolol (MET), and their mixture under ultraviolet (UV) irradiation in water. For the preparation of V2O5, facile hydrothermal synthesis was used. The structural, morphological, and surface properties and purity of synthesized V2O5 powder were investigated by scanning electron microscopy (SEM), X-ray, and Raman spectroscopy. SEM micrographs showed hexagonal-shaped platelets with well-defined morphology of materials with diameters in the range of 10−65 µm and thickness of around a few microns. X-ray diffraction identified only one crystalline phase in the sample. The Raman scattering measurements taken on the catalyst confirmed the result of XRPD. Degradation kinetics were monitored by ultra-fast liquid chromatography with diode array detection. The results showed that in individual solutions, photocatalytic degradation of MET and NAD was relatively insignificant (<10%). However, in the PIN case, the degradation was significant (64%). In the mixture, the photodegradation efficiency of MET and NAD slightly increased (15% and 13%). Conversely, it reduced the PIN to the still satisfactory value of 40%. Computational analysis based on molecular and periodic density functional theory calculations was used to complement our experimental findings. Calculations of the average local ionization energy indicate that the PIN is the most reactive of all three considered molecules in terms of removing an electron from it.

In vitro and in silico study on the effect of carvedilol and sorafenib alone and in combination on the growth and inflammatory response of melanoma cells.

Melanoma is an aggressive skin cancer. Increasing evidence has shown the role of ß-adrenergic receptors in the pathogenesis of melanoma. Carvedilol is a widely used non-selective ß-AR antagonist with potential anticancer activity. The purpose of the study was to estimate the influence of carvedilol and sorafenib alone and in combination on the growth and inflammatory response of C32 and A2058 melanoma cells. Furthermore, this study also aimed to predict the probable interaction of carvedilol and sorafenib when administered together. Predictive study of the interaction of carvedilol and sorafenib was performed using the ChemDIS-Mixture system. Carvedilol and sorafenib alone and in combination showed a growth inhibitory effect on cells. The greatest synergistic antiproliferative effect on both cell lines was observed at Car 5 µM combined with Sor 5 µM. Analysis in silico identified diseases, proteins, and metabolic pathways that can be affected by the interaction of carvedilol and sorafenib. The results obtained demonstrated that carvedilol and sorafenib modulated the secretion of IL-8 by IL-1ß-stimulated by melanoma cell lines but the use of a combination of both drugs did not intensify the effect. In summary, the results presented indicate that the combination of carvedilol and sorafenib may have a promising anticancer effect on melanoma cells.

Control of Heart Rate in Infant and Child Tachyarrhythmia With Reduced Cardiac Function Using Landiolol (HEARTFUL)　- Results of a Prospective, Multicenter, Uncontrolled Clinical Study.

BACKGROUND: The prospective Control of HEART rate in inFant and child tachyarrhythmia with reduced cardiac function Using Landiolol (HEARTFUL) study investigated the effectiveness and safety of landiolol, a short-acting ß1 selective blocker, in children.Methods and Results: Twenty-five inpatients aged ≥3 months to <15 years who developed supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, and inappropriate sinus tachycardia) were treated with landiolol. The primary endpoint, the percent of patients with a reduction in heart rate ≥20% from the initial rate of tachycardia, or termination of tachycardia at 2 h after starting landiolol, was achieved in 12/25 patients (48.0%; 95% CI 28.4-67.6), which exceeded the predetermined threshold (38.0%). At 2 h after starting landiolol administration, heart rate had decreased by ≥20% in 45.8% (11/24) and recovery to sinus rhythm was achieved in 40.0% (6/15) of the patients. Adverse reactions (ARs) occurred in 24.0% (6/25) of patients, and the study was discontinued in 4.0% (1/25) of the patients; however, none of these ARs were considered serious. The most common AR was hypotension (20.0% [5/25] of patients). CONCLUSIONS: The HEARTFUL study has demonstrated the efficacy of landiolol, by reducing heart rate or terminating tachycardia, in pediatric patients with supraventricular tachyarrhythmias. Although serious ARs and concerns were not identified in this study, physicians should be always cautious of circulatory collapse due to hypotension.

Safety of intravitreal metoprolol in eyes with central serous chorioretinopathy.

PURPOSE: To investigate ocular safety of intravitreal metoprolol in eyes with central serous chorioretinopathy. METHODS: Five eyes of five patients diagnosed with chronic central serous chorioretinopathy (cCSC) previously treated unsuccessfully with oral spironolactone, micropulse laser and intravitreal anti-vascular endothelial growth factor agents were enrolled and received off-label intravitreal metoprolol (50 µg/0.05 ml). Baseline and follow-up examinations included measurement of best-corrected visual acuity (BCVA), intraocular pressure, anterior chamber cellular/flare scores, vitritis classification, fluorescein and indocyanine green angiography, spectral domain optical coherence tomography and electroretinography (ERG), recorded by means of DTL electrodes and following the standard suggested by the International Society for Clinical Electrophysiology of Vision (ISCEV). The total follow-up period was 4 weeks. RESULTS: There were no significant differences between baseline and follow-up ERG parameters: scotopic or photopic, a- and b-wave amplitude and implicit time, nor oscillatory potentials amplitude, or whatsoever. No intraocular inflammation sign was observed. In addition, BCVA showed small improvement in 4 or kept baseline values in 1 patient. The subretinal and/or intraretinal fluid volume reduced in all patients at 1 month after treatment. CONCLUSION: Patients with refractory cCSC treated with intravitreal 50 µg/0.05 ml metoprolol showed no signs of acute ocular toxicity, along with intraretinal fluid reduction and slight BCVA improvement 1 month after injection. This data suggest that intravitreal metoprolol may be a safe alternative for cCSC.

Association between topical ß-blocker use and asthma attacks in glaucoma patients with asthma: a cohort study using a claims database.

PURPOSE: To investigate the association between the use of topical ß-blockers and subsequent asthma attacks in glaucoma patients with asthma. METHODS: This was a retrospective longitudinal cohort study using an administrative claims database. All patients aged 20 years or older who were registered in the health insurance claims database updated and managed by JMDC Inc. (Tokyo, Japan). Patients who were newly prescribed eye drops for glaucoma treatment were identified between 2011 and 2017. The patients with glaucoma were divided into two groups: ß-blocker users and non-ß-blocker users, based on the presence of a ß-blocker in the prescribed eye drops. We investigated whether the incidence of asthma attacks in patients with previously treated asthma differed between the two groups. RESULTS: We categorized 17,666 patients in the ß-blocker-user group and 12,609 patients in the non-ß-blocker-user group. A total of 580 patients in the ß-blocker group (3.28%) and 847 in the non-ß-blocker group (6.72%) underwent asthma treatment before the prescription of anti-glaucoma eye drops (P < 0.001). Furthermore, 94 patients in the ß-blocker-user group (0.53%) and 278 in the non-ß-blocker user group (2.20%) were undergoing current treatment for asthma (P < 0.001). The adjusted hazard ratios of asthma attacks were 0.73 (95% confidence interval, 0.46-1.16, P = 0.18) in patients with a history of asthma treatment and 1.22 (95% confidence interval, 0.56-2.70, P = 0.62) in patients with current asthma treatment, compared to the non-ß-blocker-user group. CONCLUSION: Our results clarified that several patients with asthma were prescribed topical ß-blockers for glaucoma treatment. However, asthma attacks may not be significantly attributed to topical ß-blockers, even in glaucoma patients under current asthma treatment. The administration of topical ß-blockers to asthma patients could be a treatment option in the absence of other treatment options, if adequate informed consent is obtained. Further studies are needed to draw a firm conclusion on this clinical question.

What is the Best Agent for Rate Control of Atrial Fibrillation With Rapid Ventricular Response?

BACKGROUND: Atrial fibrillation (AF) is a common dysrhythmia associated with significant morbidity and mortality. Although many patients have stable AF, some patients can present with a rapid ventricular response (RVR). In these patients, it is important to lower their heart rate. However, there are several options available for rate control in the emergency department setting. CLINICAL QUESTION: What is the most effective agent for rate control for the patient with AF in RVR? EVIDENCE REVIEW: Studies retrieved included two prospective, randomized, double-blind studies and six retrospective cohort studies. These studies provide estimates of the efficacy and safety of calcium channel blockers and ß-blockers for rate control in those with AF with RVR. CONCLUSION: Based upon the available literature, diltiazem likely achieves rate control faster than metoprolol, though both agents seem safe and effective. Clinicians must consider the individual patient, clinical situation, and comorbidities when selecting a medication for rate control.

Blockade of ß2-Adrenergic Receptor Reduces Inflammation and Oxidative Stress in Clear Cell Renal Cell Carcinoma.

Von Hippel-Lindau (VHL) syndrome is a rare inherited cancer disease where the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HBs), CNS-HBs, and clear cell renal cell carcinoma (ccRCC). Since standard therapies in VHL have shown limited response, leaving surgery as the only possible treatment, targeting of the ß2-adrenergic receptor (ADRB2) has shown therapeutic antitumor benefits on VHL-retinal HBs (clinical trial), VHL-CNS HBs, and VHL-ccRCC (in vitro and in vivo). In the present study, we wanted to look deep into the effects of the ADRB2 blockers propranolol and ICI-118,551 on two main aspects of cancer progression: (i) the changes on the inflammatory response of ccRCC cells; and (ii) the modulation on the Warburg effect (glycolytic metabolism), concretely, on the expression of genes involved in the cell reactive oxygen species (ROS) balance and levels. Accordingly, in vitro studies with primary VHL-ccRCC and 786-O cells measuring ROS levels, ROS-expression of detoxifying enzymes, and the expression of p65/NF-κB targets by RT-PCR were carried out. Furthermore, histological analyses of ccRCC samples from heterotopic mouse xenografts were performed. The obtained results show that ADRB2 blockade in ccRCC cells reduces the level of oxidative stress and stabilizes the inflammatory response. Thus, these data further support the idea of targeting ADRB2 as a promising strategy for the treatment of VHL and other non-VHL tumors.

Long QT Syndrome Management during and after Pregnancy.

Long QT syndrome (LQTS) is majorly an autosomal dominantly inherited electrical dysfunction, but there are exceptions (Jervell and Lange-Nielsen syndrome is inherited in an autosomal recessive pattern). This disorder prolongs ventricular repolarization and increases the risk of ventricular arrhythmias, syncope, and even sudden cardiac death. The risk of fatal events is reduced during pregnancy, but dramatically increases during the 9 months after delivery, especially in patients with LQT2. In women with LQTS, treatment with ß-blockers at appropriate doses is recommended throughout pregnancy and the high-risk postnatal period. In this review, we summarize the management of LQTS during pregnancy and beyond.

Association between Pre-Existing Long-Term ß-Blocker Therapy and the Outcomes of Sepsis-Associated Coagulopathy: A Retrospective Study.

Background and Objectives: Previous studies have suggested that long-term ß-blocker therapy before sepsis is associated with reduced mortality. Sepsis-associated coagulopathy (SAC) remains a common complication in patients with sepsis and is associated with increased mortality. Adrenergic pathways are involved in the regulation of the coagulation system. Pre-existing long-term ß-blocker therapy may have potentially beneficial effects on SAC and has yet to be well characterized. We aimed to assess the potential association between pre-existing long-term ß-blocker therapy and the outcomes of patients with SAC. Materials and Methods: This study retrospectively screened the clinical data of adult patients with SAC admitted to the Intensive Care Unit (ICU) and respiratory ICU between May 2020 and October 2022. Patients with SAC who took any ß-blocker for at least one year were considered pre-existing long-term ß-blocker therapy. All enrolled patients were followed up for 28 days or until death. Results: Among the 228 SAC patients, 48 received long-term ß-blocker therapy before septic episodes. Pre-existing long-term ß-blocker therapy was associated with reduced vasopressor requirements and a decreased 28-day mortality (log-rank test: p = 0.041). In particular, long-term ß-blocker therapy was related to substantially lower D-dimer levels and a trend of improved activated partial thromboplastin time in patients with SAC during initial ICU admission. Multivariable regression analysis showed that long-term ß-blocker therapy was significantly and independently associated with a 28-day mortality among patients with SAC (adjusted odds ratio, 0.55; 95% confidence interval, (0.32-0.94); p = 0.030). Conclusions: Pre-existing long-term ß-blocker therapy might be associated with reduced vasopressor requirements and a decreased 28-day mortality among patients with SAC, providing evidence for the protective effect of ß-blockers against SAC in managing sepsis.

Takotsubo Cardiomyopathy and ß-Blocker Poisoning: A Case Report.

ß-blocker poisoning is frequently observed because of its primary use for the treatment of cardiovascular diseases. The management of ß-blocker toxicity is dependent on the cardiovascular response and the severity of presentation. The present study describes the case of a patient with combined drug intoxication, ß-blocker, digoxin, benzodiazepines, acetaminophen and opiates in a suicidal attempt. A 63-year-old female was found somnolent and in a confused state at her residence following intentional poly-drug ingestion. Upon presentation, she was found to be hemodynamically unstable and was thus treated with vasopressors. The toxicological screening performed upon presentation was positive for polydrug ingestion. On day 3, the patient developed chest pain and ST-segment elevation in anterior leads, while transthoracic echocardiographic assessment disclosed a non-dilated left ventricle with moderate dysfunction and akinesia of the apex. Coronary angiogram revealed normal coronary arteries and, subsequently, the diagnosis of Takotsubo cardiomyopathy (TTC) was suspected. Supportive treatment was initiated with favorable evolution and left ventricular ejection fraction normalization. The management of hemodynamic instability with vasopressors should be judiciously administered in the treatment of ß-blocker poisoning, in view of the adverse effects on cardiac functions, including stress cardiomyopathy.