Nonselective Β-blockers Research Articles

Impact of ascites grading and non-selective β-blockers on 1-year prognosis of Acute-on-chronic liver failure

Objective: To investigate the influence of ascites grading and non-selective β- blockers (NSBBs) on the 1-year prognosis of patients with acute-on-chronic liver failure (ACLF). Methods: A total of 1 386 patients with ACLF were graded for ascites and followed up for one year. Kaplan-Meier Log-rank test and Cox regression were used for multivariate regression to analyze the effects of ascites grading and NSBBs on the 1-year prognosis of ACLF. Results: The incidence of ascites in 1 836 patients with ACLF was 77.56% on admission. Ascites grade was related to the 1-year prognosis of ACLF [log rank (Mantel-Cox) χ2=21.384, p=0.000]. Cox stepwise regression analysis showed that ascites grade, age, gastrointestinal bleeding, pulmonary infection, acute kidney injury, prothrombin time activity(PTA), urea, MELD-Na score, and application of NSBBs were closely related to the 1-year prognosis of ACLF. The result of Kaplan-Meier Log-rank test for patients treated with NSBBs in the grade 2/3 ascites group suggest that NSBBs can improve the 1-year survival rate of ACLF patients with grade 2 and grade 3 ascites ( log rank (Mantel-Cox) χ2=6.113, p=0.013). Conclusions: Ascites grading and application of NSBBs can affect the 1-year prognosis of ACLF. NSBBs may be beneficial to the long-term prognosis of ACLF. Patients treated with NSBBs before the onset of ACLF should continue NSBBs treatment.

Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized-trial.

Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal-hypertension and suboptimal response to traditional-NSBBs. Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v.propranolol. Suboptimal responders (HVPG-decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6-weeks, repeating HVPG-measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters. Of 184 eligible patients, 82 were randomized to carvedilol+simvastatin (N=41) or carvedilol+placebo (N=41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol+simvastatin (18.6±4-to-15.7±4mm Hg, p<0.001) and carvedilol+placebo (18.9±3-to-16.9±3mm Hg, p<0.001). The decrease was greater with carvedilol+simvastatin (2.97±2.5 vs. 2.05±1.6mm Hg, p=0.031). An HVPG-decrease ≥20% occurred in 37% versus 15% patients respectively (OR:3.37, 95% CI=1.15-9.85; p=0.021). With test-meal, HVPG increased in both groups (p<0.01), although carvedilol+simvastatin attenuated such increment (12±8% vs. 23±16%, p<0.001). Cytokine levels (IL-6,MCP-1,MDA) decreased significantly more with carvedilol+simvastatin (p<0.01). Incidence of adverse events was similar. In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal-pressure reduction achieved with carvedilol-monotherapy, improves endothelial dysfunction and reduces pro-inflammatory cytokines.

Evidence for preventing EVRB in cirrhotic patients: A systematic review.

Systematic strategies for preventing and treating esophagogastric variceal rebleeding (EVRB) are currently inadequate. This systematic review aimed to update this critical gap by searching contemporary studies from major guideline websites, databases, and professional associations focused on EVRB prevention in cirrhosis patients. Key findings highlight evaluation methods, risk management, preventive measures, health education, and follow-up strategies. Notably, a hepatic venous pressure gradient exceeding 18 mmHg is identified as a reliable predictor of gastroesophageal varices (GOV) rebleeding. Effective management of primary diseases is crucial, with methods including antiviral and anti-fibrotic therapies, alcohol avoidance, vaccination, and careful medication management. The combination of nonselective β-blockers (NSBBs) and endoscopic variceal ligation (EVL) is established as the gold standard for secondary EVRB prevention. For patients experiencing recurrent bleeding despite NSBBs and EVL, transjugular intrahepatic portosystemic shunt (TIPS) therapy is recommended. Surgical options, such as surgical shunt and devascularization, are advised for those unsuitable for endoscopic therapy or TIPS, particularly in Child-Pugh A and B patients unresponsive to treatment. Additionally, traditional Chinese medicine options, such as Fufang Biejia Ruangan Tablets, Fuzheng Huayu Capsules, and Anluo Huaxian Pills, have shown promise in improving hepatic fibrosis and GOV in cirrhotic patients. This review offers a comprehensive overview of current prevention and treatment strategies for EVRB, providing valuable insights for clinicians and healthcare professionals.

β-Blockers and Asthma: Surprising findings from the FAERS database

Introductionβ-Blockers are essential for cardiovascular disease management but can induce respiratory issues, particularly with non-selective β-blockers. Their safety in asthmatic patients is debated. ObjectiveThis study investigates the link between different classes of β-blockers and the risk of asthma and asthma-like adverse events (AEs) using data from the Food and Drug Administration's Adverse Event Reporting System (FAERS). Methodsβ-Blockers were first reviewed according to European Society of Cardiology classification and then using the Vashistha and Kumar classification. The risk associated with different β-blocker classes was evaluated through disproportionality analysis using the reporting odds ratio (ROR). ResultsAmong 251,145 AEs reported for β-blockers, 4104 were asthma-related. Selective β1-blockers had a higher asthma risk signal (ROR: 1.15) compared to non-selective β-blockers (ROR: 0.90). α- and β-Blockers showed the lowest risk (ROR: 0.51). The Vashistha and Kumar classification detailed risk profiles for various β-blockers, highlighting differences even within the same class. Dual α- and β-blockers, hydrophilic, and lipophilic β-blockers posed lower asthma risks, while selective β1-blockers had higher risks regardless of intrinsic sympathomimetic activity. ConclusionAlthough the signals detected by disproportionality analysis are only candidate risks, the risk stratification resulting from our analysis highlights the need for cautious β-blocker selection in asthmatic patients or those predisposed to asthma. Furthermore, despite the limitations associated with the FAERS data, the study reveals significant variability in risk among different β-blocker classes, crucial for clinical decisions and patient management. Drugs like esmolol, metoprolol, nebivolol, and nadolol may be safer for asthmatic patients, whereas betaxolol, bisoprolol, timolol, and propranolol should be avoided.

Coronary artery disease and the risk of life-threatening cardiac events after age 40 in long QT syndrome.

Long QT syndrome (LQTS) and coronary artery disease (CAD) are both associated with increased risk of ventricular tachyarrhythmia. However, there are limited data on the incremental risk conferred by CAD in adult patients with congenital LQTS. We aimed to investigate the risk associated with CAD and life threatening events (LTEs) in patients with LQTS after age 40 years. The risk of LTEs (comprising aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shock) from age 40 through 75 years was examined in 1,020 subjects from the Rochester LQTS registry, categorized to CAD (n = 137) or no-CAD (n = 883) subgroups. Survival analysis showed that patients with CAD had a significantly higher cumulative event rate of LTEs from 40 to 75 years (35%) compared with those without CAD (7%; p < 0.001 for the overall difference during follow-up). Consistently, multivariate analysis showed that the presence of CAD was associated with a 2.5-fold (HR = 2.47; p = 0.02) increased risk of LTEs after age 40 years. Subgroup analyses showed that CAD vs. no CAD was associated with a pronounced >4-fold (p = 0.008) increased risk of LTEs among LQTS patients with a lower-range QTc (<500 ms). The increased risk of LTEs associated with CAD was not significantly different among the 3 main LQTS genotypes. Patient treatment was suboptimal, with only 63% on β-blockers and 44% on non-selective β-blockers. Our findings suggest that CAD is associated with a higher risk of LTEs in LQTS patients, with the risk being more pronounced in those with QTc <500 ms.

Comparison of Endoscopic Ultrasound-guided Cyanoacrylate Injection and Transjugular Intrahepatic Portosystemic Shunt in the Prevention of Gastric Varices Rebleeding.

The purpose of this study was to investigate the efficacy and safety of endoscopic ultrasound (EUS)-guided injection of cyanoacrylate (CYA) and transjugular intrahepatic portal shunts (TIPSs) in the treatment of patients with cirrhosis with ruptured gastric varices. In this retrospective study, 105 patients with liver cirrhosis and gastric varicose veins who were admitted to the First Affiliated Hospital of Anhui Medical University between April 2018 and April 2023 without nonselective β-blockers treatment and no portal vein thrombosis were evaluated. The patients were divided into the transjugular intrahepatic portal shunt (TIPS) group (n = 60) and the EUS-CYA group (n = 45) for the purpose of evaluating postoperative rebleeding rates, complications, survival rates, and other factors. During the follow-up, there was no significant difference in the rebleeding rates between the TIPS group and EUS-CYA group within 3 months (5% vs 2.2%; P = 0.825; 10% vs 20%, P = 0.147). However, the TIPS group had significantly lower rebleeding rates than the EUS-CYA group at 6 months (10% vs 33.3%; P = 0.030) and 1 year or longer (11.7% vs 42.2%; P < 0.01). In terms of hepatic encephalopathy, the incidence rate of the TIPS group was significantly higher than that of the EUS-CYA group (20% vs 2.2%; P = 0.006). In addition, there was no difference in the survival rates between the two groups (93.3% vs 97.8%; P = 0.552). TIPS is superior to EUS in preventing rebleeding in patients with ruptured varices of the fundus, but it has a higher incidence of hepatic encephalopathy, and there is no difference in long-term survival between the two groups.

β-Adrenergic blockade attenuates adverse adipose tissue responses after burn.

Severe burn injuries are defined by a prolonged hypermetabolic response characterized by increases in resting energy expenditure, systemic catabolism, and multi-organ dysfunction. The sustained elevation of catecholamines following a burn injury is thought to significantly contribute to this hypermetabolic response, leading to changes in adipose tissue such as increased lipolysis and the browning of subcutaneous white adipose tissue (WAT). Failure to mitigate these adverse changes within the adipose tissue has been shown to exacerbate the post-burn hypermetabolic response and lead to negative outcomes. Propranolol, a non-selective β-blocker, has been clinically administered to improve outcomes of pediatric and adult burn patients, but there is inadequate knowledge of its effects on the distinct adipose tissue depots. In this study, we investigated the adipose depot-specific alterations that occur in response to burn injury. Moreover, we explored the therapeutic effects of β-adrenoceptor blockade via the drug propranolol in attenuating these burn-induced pathophysiological changes within the different fat depots. Using a murine model of thermal injury, we show that burn injury induces endoplasmic reticulum (ER) stress in the epididymal (eWAT) but not in the inguinal (iWAT) WAT depot. Conversely, burn injury induces the activation of key lipolytic pathways in both eWAT and iWAT depots. Treatment of burn mice with propranolol effectively mitigated adverse burn-induced alterations in the adipose by alleviating ER stress in the eWAT and reducing lipolysis in both depots. Furthermore, propranolol treatment in post-burn mice attenuated UCP1-mediated subcutaneous WAT browning following injury. Overall, our findings suggest that propranolol serves as an effective therapeutic intervention to mitigate the adverse changes induced by burn injury, including ER stress, lipotoxicity, and WAT browning, in both adipose tissue depots. KEY MESSAGES: Burn injury adversely affects adipose tissue metabolism via distinct changes in both visceral and subcutaneous adipose depots. Propranolol, a non-selective β-adrenergic blocker, attenuates many of the adverse adipose tissue changes mediated by burn injury.

Real world prescription of beta-blockers in patients with asthma.

This study aimed to investigate the prescription of beta-blockers (β-blockers) for patients with asthma. In this retrospective cross-sectional study using the National Patient Sample (NPS) of the Health Insurance Review and Assessment Service (HIRA) of South Korea, β-blockers and asthma medications were investigated using generic name codes provided by HIRA. Concomitant administration was identified when a β-blocker and an asthma medication were co-prescribed in one billing statement or when separate β-blocker and asthma prescriptions had overlapping dates of use. In the 1027 patients with asthma who were prescribed non-selective β-blockers (non-SBs), 3087 non-SB prescriptions were identified, of which 62.3% and 37.3% were for carvedilol and propranolol, respectively. Of the 906 patients with asthma prescribed selective β-blockers (SBs), 2942 SB prescriptions were identified, of which 48.5%, 28.3%, and 20.3% were for bisoprolol, atenolol, and nebivolol, respectively. Overall, 2149 non-SB and 2124 SB prescriptions with overlapping use dates with asthma medications were identified, which were prescribed to 726 and 657 patients, accounting for 70.7% and 72.5% of the patients receiving non-SBs and SBs, respectively. β2-agonists accounted for 39.9% of the concomitant asthma medications with overlapping dates of use with non-SBs. Co-prescribing of bronchodilators occurred at a rate of 38.7% and 45.1% for the 3087 non-SB prescriptions and 2942 SB prescriptions, respectively. Carvedilol and propranolol accounted for half of all β-blockers prescribed to asthma patients. Prescribing β-blockers to patients with asthma requires caution to prevent exacerbation of asthma and drug interactions between β-blockers and co-prescribed asthma medications.

Influence of further decompensation on survival across clinical stages of decompensated cirrhosis: The role of portal hypertension and HVPG changes.

Decompensated-cirrhosis encompasses several stages with different prognosis, such as bleeding, ascites and bleeding-plus-ascites. Development of further-decompensation worsens survival, while non-selective β-blockers (NSBBs) can modify the risk. However, how this applies to each stage is uncertain. We aimed to investigate, in each stage of decompensated-cirrhosis, the influence of further-decompensation on mortality and whether changes in portal-pressure (HVPG) under NSBBs influence these outcomes. Patients with variceal bleeding were consecutively included differentiating those with bleeding-alone from those who also had ascites. Patients with ascites and high-risk varices referred for primary-prophylaxis were also investigated. A baseline haemodynamic study was performed and was repeated after 1-3-months under NSBBs. Outcomes were investigated by competing-risk. Totally 103 patients had bleeding-alone, 186 bleeding-plus-ascites and 187 ascites-alone. Mean follow-up was 32-months (IQR, 12-60). Patients with bleeding-plus-ascites had higher HVPG and were more hyperdynamic than patients with ascites-alone and these than those with bleeding-alone. At each stage, the mortality risk was more than twice in patients developing further-decompensation vs. those without (p < .001). In each stage, HVPG-decrease under NSBBs showed better discrimination to predict further-decompensation than the baseline MELD, Child-Pugh or HVPG, by time-dependent ROC-curves (c-statistic >70%). At each stage, patients without HVPG-decreases, either ≥10% or ≥20% from the baseline, had higher risk of further-decompensation (sHR from 2.43 to 6.73, p < .01) and worse survival. In each stage of decompensated cirrhosis, mortality risk significantly and very markedly increase with further-decompensation. HVPG-non-response to NSBBs may adequately stratify the risk of further decompensation and death, in each stage. This suggests potential benefit with pre-emptive therapies in HVPG-non-responders at each-stage.

Abstract 6629: Cancer-associated nerves regulate anti-tumor immunity in pancreatic cancer

Abstract Nerves serve an emerging component of the tumor microenvironment (TME), contributing to tumorigenesis and cancer progression. Neural invasion (NI) is a common feature of pancreatic ductal adenocarcinoma (PDAC), accounting for distant metastasis and local recurrence. However, the mechanism by which tumor associated nerves (TANs) regulate anti-tumor immunity remains largely elusive. Here, we investigated the association between TANs and immunosuppressive TME to develop more effective therapeutic strategies for PDAC. Using tumor samples of PDAC patients, we identified that the nerves invaded by cancer cells showed increased adrenergic activation accompanied with no parasympathetic or sensory innervation changes. Patients with severe NI were associated with increased catecholamine levels. Additionally, single-cell RNA-sequencing and spatial transcriptome analysis of tumors from patients with PDAC revealed that peri-neural niches of severe NI patients were characterized by decreased CD8+ T cells and increased activity of M2 polarization of tumor-associated macrophages (TAMs), and regulatory T (Treg) cells, which was validated by multiplexed immunofluorescence staining. We further identified that CD8+ T cells expressing β-adrenaline receptors (β-ARs) reduced proliferation and cytokine production when exposure to catecholamines in a dose-dependent manner or co-cultured with dorsal root ganglia pretreated with cancer cells. KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) mice treated with catecholamines accelerated tumor progression by inhibiting T cell-mediated antitumor responses, which was abrogated by surgical sympathectomy of KPC mice. Especially, in an orthotopic PDAC model, nonselective β-blocker propranolol in combination with immune checkpoint blockade (ICB) significantly enhanced active CD8+ T cells with concurrent reduced tumor growth. We suggest a novel regulatory mechanism of inhibiting anti-tumor immunity that can promote cancer progression mediated by TANs invasion. These data establish a close connection between the nerves, cancer cells, and immune cells and provide the potential novel targets of therapeutic approaches in PDAC. Citation Format: Ruiyuan Xu, Jianlu Song, Yuan Chen, Xinpeng Yin, Chengcheng Wang, Yupei Zhao. Cancer-associated nerves regulate anti-tumor immunity in pancreatic cancer [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 6629.

Propranolol monotherapy in angiosarcoma – A window-of-opportunity study (PropAngio)

BackgroundAngiosarcoma is a rare and aggressive cancer of the endothelial cells. Propranolol, a non-selective β-blocker, was able to initiate apoptosis in angiosarcoma cell lines and its anti-tumor activity has been described in several case reports. The aim of this trial was to prospectively evaluate the anti-tumor activity of propranolol monotherapy in patients with angiosarcoma before proceeding to standard of care treatment. MethodsPropranolol was dosed 80 mg to 240 mg/day for 3 to 6 weeks according to a dose titration schedule. The primary endpoint was clinical response (response according to RECIST 1.1 or stable disease with improvement of cutaneous lesions) in at least three patients. Exploratory objectives included histologic response (>30% decrease in Ki-67), FDG PET response, and β-receptor expression levels. ResultsFourteen patients were enrolled. The median duration of treatment was 26 days (range 21–42 days). The median highest propranolol dose was 160 mg/day (range 80 – 240 mg). Two patients showed clinical response (14%, 95% CI 3–100%). One of these patients showed a partial metabolic response on PET-CT. None of the tumors showed histologic response. The most common adverse event was grade 1/2 bradycardia (86%). There were no grade ≥ 3 adverse events. ADRB2 was overexpressed in 16 out of 18 tumors, in both responders and non-responders. None of the tumors showed ADRB1 overexpression. ConclusionsThis window-of-opportunity trial did not show clinical efficacy of propranolol monotherapy. However, two out of 14 patients did show clinical benefit. ADRB1/2 expression did not correlate with clinical response.

Circulating noradrenaline leads to release of neuropeptide Y from cardiac sympathetic nerve terminals via activation of β-adrenergic receptors.

Cardiac disease is marked by sympathoexcitation and elevated levels of noradrenaline (NA) and cotransmitter neuropeptide Y (NPY). Increased NPY levels are associated with a greater risk of ventricular arrhythmias and mortality. Nonetheless, the factors that cause NPY release remain poorly understood. We hypothesized that circulating catecholamines might lead to NPY release from myocardial sympathetic nerve terminals via a β-receptor-mediated mechanism that enhances sympathoexcitation. Ventricular interstitial NA and NPY levels were measured in six Yorkshire pigs after i.v. administration of NA (1mg) and before and after propranolol infusion (1mg/kg). Real-time interstitial NPY levels were measured using ventricular capacitive immunoprobes (CIs) affixed with NPY antibodies and quantified as the change in CI input current (INPY ) upon binding of NPY. Interstitial NA was measured with adjacent fast-scan cyclic voltammetry probes (INA ). A left ventricular pressure catheter and continuous ECGs were used for haemodynamic recordings, and an epicardial 56-electrode sock was used for measurements of activation recovery interval, a surrogate of action potential duration. Upon administration of NA, heart rate and left ventricular pressure increased, and activation recovery interval shortened. Notably, NA significantly increased interstitial myocardial NPY levels. After propranolol, changes in heart rate and activation recovery interval were largely mitigated. The INA increased to a similar extent post-propranolol vs. pre-propranolol, but changes in INPY were significantly reduced post-propranolol. Coronary sinus plasma analyses confirmed fast-scan cyclic voltammetry and CI findings. Hence, this study demonstrates that circulating NA induces NPY release from ventricular sympathetic nerve terminals, the mechanism for which is mediated via β-adrenergic receptors and can be blocked by the non-selective β-blocker, propranolol. KEY POINTS: Cardiovascular disease is characterized by sympathovagal imbalance, with increased plasma noradrenaline (NA) and neuropeptide Y (NPY) concentrations. Increased NPY levels are associated with increased ventricular arrhythmias and mortality in heart failure. Limited data are available on the specific factors that cause NPY release. In this study, fast-scan cyclic voltammetry and capacitive immunoprobes were used to allow for real-time in vivo measurements of interstitial myocardial neurotransmitters and neuropeptides, respectively. Using an in vivo porcine model with cardiac fast-scan cyclic voltammetry and capacitive immunoprobes, it was shown that systemic NA can increase ventricular interstitial NPY levels, suggesting that NA induces NPY release from postganglionic sympathetic nerves. The release of NPY was blocked by administration of the non-selective β-blocker propranolol, suggesting that release of NPY is dependent on activation of β-adrenergic receptors by NA.

Efficacy and Safety of Oral Propranolol or Topical Timolol for the Treatment of Superficial Infantile Hemangiomas.

Infantile hemangiomas (IHs) are the most common benign soft tissue tumors of infancy. Oral propranolol has become a first-line treatment option since the unexpected discovery of its surprising efficacy in the treatment of IHs in 2008. However, oral propranolol causes systemic complications, including hypotension, bradycardia, and hypoglycemia. To minimize systemic adverse effects of oral propranolol, timolol maleate, a nonselective β-blocker similar to propranolol, has been used as a topical agent to treat superficial IHs. The authors evaluated the efficacy and safety of oral propranolol or topical timolol in 60 patients with IHs. Of the 60 patients recruited, 30 patients were treated using orally administrated propranolol and an additional 30 patients received topical timolol. The efficacy rate of the oral propranolol and topical timolol was 96.7% and 93.3%, respectively. There were no significant differences between the two treatment patterns for the efficacy rate. The incidence of systemic adverse effects for patients treated with oral propranolol was significantly higher than that for cases received topically timolol treatment. Topical timolol maleate is effective and well-tolerated in the treatment of IHs. It could be considered as the first-line treatment choice, especially for superficial IHs.

Anticancer effect of propranolol on diethylnitrosamine-induced hepatocellular carcinoma rat model.

Hepatocellular carcinoma (HCC) is the most widespread type of primary liver cancer. Diethylnitrosamine (DEN), a hepatotoxic hepatocarcinogenic compound, is used to induce HCC in animal models. The non-selective β-blocker propranolol demonstrated antiproliferative activity in many cancer types. This investigation aimed to evaluate the anticancer effect of propranolol against DEN-induced HCC in rats. Thirty adult male rats were divided into the following groups: Group I (C, control), Group II (HCC); received DEN, 70 mg/kg body weight (b.wt.) once a week for 10weeks, to induce HCC, and Group III (HCC/Prop); received DEN for 10weeks for HCC induction, then received 20 mg/kg b.wt. propranolol, intraperitoneally for four successive weeks. HCC was developed in rats' livers and confirmed via significant liver architecture changes, significantly elevated activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), α-fetoprotein (AFP), total- and direct-bilirubin (Bil), and a decline in albumin (ALB) level in serum. HCC group demonstrated elevated levels of malondialdehyde (MDA), nitric oxide (NO), HIF-1α, IL-8, NF-κB, PGE2, TGF-β1, VEGF, and CD8, but significant decline of GSH, and IL-10 level, with suppression of the antioxidant enzymes' activities. In addition, the gene expression of the hepatic inducible nitric oxide synthase (iNOS), and LAG-3 were up-regulated. Moreover, the protein expression of p-PKC was up-regulated, while that of PD-1 and PD-L1 were down-regulated in the liver tissues of the HCC group. However, propranolol ameliorated the investigated parameters in the HCC/Prop group. Propranolol exhibited an anticancer effect and thus can be considered as a promising treatment for HCC. Blocking of PD-1/PD-L1 and LAG-3 signals participated in the anti-tumor effect of propranolol on HCC.

Advances in the Pathogenesis and Treatment of Rosacea: A Phenotype-Based Therapeutic Approach

Rosacea is a common chronic inflammatory skin disorder that mainly affects the central face. It is primarily characterized by recurrent episodes of flushing, persistent erythema, inflammatory papules, telangiectasias, phymatous changes, and ocular symptoms. Its pathogenesis is complex and still not completely understood. It encompasses innate and adaptive immune system dysregulation, neurovascular dysfunction, and genetic and environmental factors. To date, four subtypes of rosacea have been identified, based on the predominant clinical features: erythemato-teleangiectatic, papulopustular, pyhomatous, and ocular rosacea. New insights into this condition have led to several pharmacological treatments, including topical medications, spanning from the conventional azelaic acid, metronidazole, benzoyl peroxide, clindamycin, and erythromycin to new ones including not only brimonidine, oxymetazoline, ivermectine, and minocycline but also systemic drugs such as oral antibiotics, isotretinoin, non-selective β-blockers or α2-adrenergic agonists, and laser- or light-based therapies, together with new therapeutic approaches. The aim of this study was to review the current literature on the pathophysiology of rosacea and to provide an overview of therapeutic approaches that specifically address each clinical subtype.

Influence of subcutaneous adipose tissue index on prognosis in cirrhotic patients following endoscopic therapy: a retrospective cohort study

BackgroundThe relation of adipose tissue depletion with prognostic outcome of variceal bleeding among cirrhotic patients is still inconclusive. The present work explored whether adipose tissue, which was measured based on computed tomography (CT), was valuable for analyzing rebleeding and mortality among patients with variceal bleeding who had undergone endoscopic therapy.MethodsThe study encompassed cirrhotic patients who underwent endoscopic therapy to prevent variceal rebleeding between January 2016 and October 2022. The L3-level CT images were obtained. Besides, impacts of subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), as well as total adipose tissue index (TATI) on rebleeding and mortality among cirrhotic patients following endoscopic therapy were examined.ResultsIn this work, our median follow-up period was 31 months. Among those adipose tissue indexes, only SATI exhibited an independent relation to higher rebleeding (HR 0.981, 95% CI, 0.971–0.991, p < 0.001) and mortality (HR 0.965, 95% CI, 0.944–0.986, p = 0.001) risks. Upon multivariate Cox regression, low SATI (male < 30.15 cm2/m2, female < 39.82 cm2/m2) was independently linked to higher rebleeding risk (HR 2.511, 95% CI, 1.604–3.932, p < 0.001) and increased mortality risk (HR 3.422, 95% CI, 1.489–7.864, p = 0.004) after adjusting for other predictors. Furthermore, subgroups were created based on using nonselective β-blockers (NSBBs), demonstrating that quantitatively assessing SATI exerts a vital role in evaluating rebleeding incidence in patients with or without NSBB therapy.ConclusionThis study underscores the potential of quantifying SATI as a means for achieving a more accurate risk classification for individual patients and identifying patients that can gain more benefits from nutritional intervention.

THE EFFECT OF AYURVEDIC MANAGEMENT OF ARDHAVABHEDAKA W.S.R. MIGRAINE – A CONCEPTUAL STUDY

Migraine is a type of headache characterized by recurrent attack of moderate to severe throbbing kind of pain on one side of the head with symptoms may be include nausea, vomiting, photophobia and phonophobia. Migraine affects more than 1 billion peoples each year in the world, on international prevalence of migraine was 11.6%. In India there are more than 213 million persons to be suffering from migraine while more than 50% of these cases were reported by females. Migraine word arised from Latin word ‘Megrim” means hemi cranial. In most cases pain is limited to one half of the cranium may be corelated to the Ardhavabhedaka presented in ayurveda. As per modern aspect for acute migraine treatment are NSAIDs, 5-HT antagonist, Ergotamine alkaloids, Non-selective B-blockers and calcium channel blocker, have their own complication. Hence an attempt is made to understand Migraine as Ardhavabhedaka in ayurveda and its management is discussed, which can be helpful in improving quality of life of patient of migraine.

B-Blockers in Liver Cirrhosis: A Wonder Drug for Every Stage of Portal Hypertension? A Narrative Review.

In cirrhotic patients, non-selective b-blockers (NSBBs) constitute the reference treatment of choice as monotherapy or combined with band ligation for the prevention of first variceal bleeding and rebleeding, respectively. Furthermore, the last Baveno VII guidelines recommended carvedilol, a b-blocker with additional anti-a1 receptor activity, in all compensated cirrhotics with clinically significant portal hypertension, to prevent liver decompensation. Interestingly enough, NSBBs have been reported to have a potentially positive impact on the short-term mortality of patients with acute-on-chronic liver failure. However, concerns remain about the use of b-blockers in the presence of severe complications, such as refractory ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, or established cirrhotic cardiomyopathy. In addition, it has not been verified yet whether carvedilol supersedes all the other NSBBs in every stage of liver disease, even when severe complications have developed. Therefore, this review aims to illustrate recent data regarding the potential role of b-blockers across all stages of liver disease, beyond the primary and secondary prophylaxis of variceal bleeding, and address the authors' proposals on the use of NSBBs concerning the severity of liver disease and the patient's performance status.

Carvedilol attenuates inflammatory reactions of lipopolysaccharide-stimulated BV2 cells and modulates M1/M2 polarization of microglia via regulating NLRP3, Notch, and PPAR-γ signaling pathways.

Microglial cells coordinate immune responses in the central nervous system. Carvedilol (CVL) is a non-selective β-blocker with anti-inflammatory and anti-oxidant effects. This study aims to investigate the anti-inflammatory effects and the underlying mechanisms of CVL on lipopolysaccharide (LPS)-induced inflammation in microglial BV2 cells. BV2 cells were stimulated with LPS, and the protective effects of CVL were investigated via measurement of cell viability, reactive oxygen species (ROS), and interleukin (IL)-1β liberation. The protein levels of some inflammatory cascade, Notch, and peroxisome proliferator-activated receptor (PPAR)-γ pathways and relative markers of M1/M2 microglial phenotypes were assessed. Neuroblastoma SH-SY5Y cells were cultured with a BV2-conditioned medium (CM), and the capacity of CVL to protect cell viability was evaluated. CVL displayed a protective effect against LPS stress through reducing ROS and down-regulating of nuclear factor kappa B (NF-κB) p65, NLR family pyrin domain containing-3 (NLRP3), and IL-1β proteins. LPS treatment significantly increased the levels of the M1 microglial marker inducible nitric oxide synthase (iNOS) and M1-associated cleaved-NOTCH1 and hairy and enhancer of split-1 (HES1) proteins. Conversely, LPS treatment reduced the levels of the M2 marker arginase-1 (Arg-1) and PPAR-γ proteins. CVL pre-treatment reduced the protein levels of iNOS, cleaved-NOTCH1, and HES1, while increased Arg-1 and PPAR-γ. CM of CVL-primed BV2 cells significantly improved SH-SY5Y cell viability as compared with the LPS-induced cells. CVL suppressed ROS production and alleviated the expression of inflammatory markers in LPS-stimulated BV2 cells. Our results demonstrated that targeting Notch and PPAR-γ pathways as well as directing BV2 cell polarization toward the M2 phenotype may provide a therapeutic strategy to suppress neuroinflammation by CVL.

Improving primary prophylaxis of variceal bleeding by adapting therapy to the clinical stage of cirrhosis. A competing-risk meta-analysis of individual participant data.

Non-selective β-blockers (NSBBs) and endoscopic variceal-ligation (EVL) have similar efficacy preventing first variceal bleeding. Compensated and decompensated cirrhosis are markedly different stages, which may impact treatment outcomes. We aimed to assess the efficacy of NSBBs vs EVL on survival in patients with high-risk varices without previous bleeding, stratifying risk according to compensated/decompensated stage of cirrhosis. By systematic review, we identified RCTs comparing NSBBs vs EVL, in monotherapy or combined, for primary bleeding prevention. We performed a competing-risk, time-to-event meta-analysis, using individual patient data (IPD) obtained from principal investigators of RCTs. Analyses were stratified according to previous decompensation of cirrhosis. Of 25 RCTs eligible, 14 failed to provide IPD and 11 were included, comprising 1400 patients (656 compensated, 744 decompensated), treated with NSBBs (N = 625), EVL (N = 546) or NSBB+EVL (N = 229). Baseline characteristics were similar between groups. Overall, mortality risk was similar with EVL vs. NSBBs (subdistribution hazard-ratio (sHR) = 1.05, 95% CI = 0.75-1.49) and with EVL + NSBBs vs either monotherapy, with low heterogeneity (I2 = 28.7%). In compensated patients, mortality risk was higher with EVL vs NSBBs (sHR = 1.76, 95% CI = 1.11-2.77) and not significantly lower with NSBBs+EVL vs NSBBs, without heterogeneity (I2 = 0%). In decompensated patients, mortality risk was similar with EVL vs. NSBBs and with NSBBs+EVL vs. either monotherapy. In patients with compensated cirrhosis and high-risk varices on primary prophylaxis, NSBBs significantly improved survival vs EVL, with no additional benefit noted adding EVL to NSBBs. In decompensated patients, survival was similar with both therapies. The study suggests that NSBBs are preferable when advising preventive therapy in compensated patients.