Combination Of Propranolol Research Articles

Is the combination of propranolol and flunarizine better than propranolol, flunarizine and amitriptyline alone in prophylaxis of migraine? An observational study at a tertiary care centre of North India

Background: Migraine is a primary headache disorder marked by recurrent attacks of pain and associated symptoms. Propranolol is traditionally considered highly effective for migraine prophylaxis, but other drugs have recently shown promise. Methods: This study was a prospective, observational, randomized, parallel-arm, unicentric trial conducted in the neurology department of a tertiary care hospital in North India. Patients with migraine without aura were randomly assigned to one of four treatment groups. After obtaining consent, patients were randomized using a random number table. Group 1 received propranolol (80 mg), group 2 received flunarizine (10 mg), group 3 received a combination of propranolol (40 mg) and flunarizine (10 mg), and group 4 received amitriptyline (10 mg) daily. The primary outcome was a change in the frequency of migraine days, while secondary outcomes included changes in moderate-to-severe headache days and disability levels. Results: The combination of propranolol (40 mg) and flunarizine (10 mg) was significantly more effective in reducing the frequency of migraine attacks at the end of 3 months compared to the group receiving amitriptyline (10 mg). However, no significant differences between the groups were observed at baseline, 1 month, and 2 months. For other outcomes, including adverse drug reactions (ADRs), there were no significant differences between the groups. Conclusions: The combination of propranolol (40 mg) and flunarizine (10 mg) demonstrated superior efficacy over amitriptyline (10 mg) after prolonged treatment, while its effectiveness was comparable to other groups at earlier time points. ADRs were similar across all groups.

Study on attenuation of miR-1-mediated ischemia-induced arrhythmias and infarction in rats by means of fulvning granule

Patients post myocardial infarction (MI) have a high incidence of frequent and complex ventricular arrhythmias. miR-1 is involved in ischemia-induced arrhythmias. Fulvning Granule (FG) is a prescription for treating ischemia-induced arrhythmias. This research investigated therapeutic effect of FG on ischemia-induced arrhythmias in an depth way, focusing on expression of miR-1. 60 healthy Sprague Dawly rats were assigned to operation group, MI+normal saline group, MI+low dose of FG group, MI+moderate dose of FG group and MI+high dose of FG group, MI+propranolol group and MI+moderate dose of FG+propranolol group. Hemodynamic measurement, arrhythmia classification, infarct area evaluation and miR-1 level quantification with expression of PKA and SRF were adopted 4 weeks after operation. FG improved hemodynamic indexes and inhibited expression of miR-1. The optimal dose of FG was medium (P < 0.05). Combination of FG and propranolol further improved the hemodynamics indexes and inhibited the expression of miR-1, PKA and SRF (P < 0.05). FG regulated miR-1 expression via inhibition of Protein Kinase A (PKA) and serum response factor (SRF) expressions. Meanwhile, β-adrenoceptor/PKA signaling pathway played a role in regulating miR-1 expression, while Fulvning granule combined with propranolol and showed an antiarrhythmic role and improved cardiac function after myocardial infarction.

Impact of combined propranolol and oxytocin on the process and outcomes of labor: a meta-analysis of randomized controlled trials.

To systematically review the impact of propranolol combined with oxytocin on the process and outcomes of labor. A comprehensive literature search was performed across multiple databases, including China National Knowledge Infrastructure (CNKI), VIP, Wanfang, China Biomedical Literature Database, PubMed, Embase, and the Cochrane Library. All publicly published randomized controlled trials (RCTs) of propranolol combined with oxytocin compared to the use of oxytocin alone in labor were collected. After screening the literature and extracting data, the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 recommended bias risk assessment tool was used to assess the quality of the included studies. A meta-analysis was conducted using RevMan 5.3 software, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to rate the quality of evidence for outcome measures. Meta-analysis results showed that the group receiving propranolol combined with oxytocin was more capable of reducing the cesarean section rate (eight studies, 815 women, RR = 0.67, 95% CI (0.53, 0.86), P = 0.001) and shortening the duration of the latent phase (two studies, 206 women, MD = - 1.20, 95% CI (- 1.97, - 0.43), P = 0.002) and the duration of the active phase on day 1 (two studies, 296 women, MD = - 0.69, 95% CI (- 0.83, - 0.54), P < 0.00001), compared to the oxytocin monotherapy group. No significant difference was found between the two groups in terms of the 5-min Apgar score (five studies, 609 women, MD = - 0.05, 95% CI (- 0.14, 0.04), P = 0.32) and the rate of admissions to the Neonatal Intensive Care Unit (NICU) (three studies, 359 women, RR = 0.82, 95% CI (0.38, 1.79), P = 0.62). The combined use of propranolol and oxytocin can significantly reduce the cesarean section rate, shorten the duration of the latent phase and the duration of the active phase on day 1, and is safe. However, due to the limitations, the conclusions of this article still need to be verified by large-sample, multicenter, rigorously designed high-quality clinical RCTs. Registration number is INPLASY202390107.

The pancreas does not contribute to the non-adrenergic-non-cholinergic stimulation of heart rate in digesting pythons

Vertebrates elevate heart rate when metabolism increases during digestion. Part of this tachycardia is due to a non-adrenergic-non-cholinergic (NANC) stimulation of the cardiac pacemaker, and it has been suggested these NANC factors are circulating hormones that are released from either gastrointestinal or endocrine glands. The NANC stimulation is particularly pronounced in species with large metabolic responses to digestion, such as reptiles. To investigate the possibility that the pancreas may release hormones that exert positive chronotropic effects on the digesting Burmese python heart, a species with very large postprandial changes in heart rate and oxygen uptake, we evaluate how pancreatectomy affects postprandial heart rate before and after autonomic blockade of the muscarinic and the beta-adrenergic receptors. We also measured the rates of oxygen consumption and evaluated the short-term control of the heart using the spectral analysis of heart rate variability and the baroreflex sequence method. Digestion caused the ubiquitous tachycardia, but the intrinsic heart rate (revealed after the combination of atropine and propranolol) was not affected by pancreatectomy and therefore hormones, such as glucagon and insulin, do not appear to contribute to the regulation of heart rate during digestion in Burmese pythons.

Treatment of infantile hemangioma with topical β-blockers in pediatric practice: a review of the literature

The purpose of this review is to acquaint the audience with the benefits of infantile hemangioma (IH) treatment with local β-blockers, which are safe for the child, allow for the complete cure of hemangiomas without surgery, complications, scars, and cosmetic defects, and have practically no systemic side effects. We aimed to analyze the effectiveness and limitations of the use of local β-blockers, to show the possibility and expediency of IH management in pediatric practice, and to demonstrate that the goal of therapy is not the treatment of complications, but the prevention of their occurrence and complete resolution of the hemangioma without surgical intervention. The use of topical β-blockers, such as timolol gel or solution, provides a non-surgical, non-invasive treatment option for IH, minimizing the systemic exposure and possible side effects associated with oral β-blockers. Local treatment is best started before the age of 2 months - at an early stage, when IHs are small in size, potentially preventing the need for more invasive treatment methods. Topical use is associated with a lower risk of systemic side effects, such as hypotension or bradycardia, that can occur with oral β-blockers. Topical treatment can be applied at home, which can be more convenient for parents and caregivers, and also increases the opportunity for treatment and follow-up by pediatricians. In case of natural disasters or military operations, treatment can be done remotely using teledermatology. The effectiveness of local β-blockers mostly depends on the age at which treatment was started: the earlier it was started, the higher the effectiveness. Treatment of complicated IH with deep soft tissue, mucosal, or airway involvement usually requires a combination of systemic propranolol and topical β-blockers or other interventions such as laser therapy. The choice of treatment should be selected individually according to the degree of risk of IH, its size, localization, child's age, weight, and other parameters in each clinical case. β-adrenoblockers are the most modern, effective, non-surgical, and safe method of treating IH, they can be used both for systemic and local application. IH can be successfully treated by pediatricians and dermatologists. No conflict of interests was declared by the authors.

Combination of Propranolol and a Novel CXCR4 Antagonist Burixafor (GPC-100) for Enhanced Hematopoietic Cell Mobilization

Burixafor (GPC-100), a novel CXCR4 antagonist, has shown safe and effective mobilization of hematopoietic stem and progenitor cells (HSPC) in a phase I clinical study. In multiple myeloma patients, GPC-100 combined with granulocyte-colony stimulating factor (G-CSF) elicited a significant increase in circulating HSPCs that was comparable with the historical results from G-CSF plus the CXCR4 antagonist plerixafor. GPC-100 is currently being investigated for HSPC mobilization in combination with the FDA-approved ß-adrenergic receptor (ß-AR) blocker propranolol in a phase II clinical trial for autologous stem cell transplant (ASCT) in multiple myeloma. Here, we present preclinical findings indicating that the addition of propranolol to GPC-100 alone or GPC-100 and G-CSF combination can address the unmet needs of patients undergoing mobilization. Additionally, we show an enhanced and unique pattern of lymphoid cell mobilization that may have applications in adoptive cell therapies. Compared to chemotherapy, ASCT significantly improves survival in multiple myeloma patients. Because HSPCs constitute a very small fraction (~ 0.1%) of circulating mononuclear cells, it is critical to mobilize a sufficient number of HSPC into peripheral blood during the ASCT process. Current therapies for HSPC mobilization include G-CSF as a monotherapy or combined with plerixafor. However, mobilization failure is experienced by 15-50% patients, leading to potential loss of ASCT as a treatment option and significant toxicity from repeated mobilization attempts. Moreover, G-CSF is contraindicated in sickle cell disease and may exacerbate autoimmune diseases. Therefore, our goal is to identify novel strategies that will not only address the mobilization failure, but also explore non-G-CSF options for adequate mobilization. G protein-coupled receptors like CXCR4 can form heteromers with other receptors and result in altered signaling pathways. Using Proximity Ligation Assay in Namalwa (lymphoma) cells, we show that endogenously expressed CXCR4 and ß 2AR form heteromers, which are absent in CXCR4 knockout cells. In cell-based assays, co-activation of both receptors with their respective ligands, CXCL12 and epinephrine, leads to a synergistic increase in calcium flux (Figure 1) as well as ß-arrestin recruitment, indicating functional consequences of the heteromerization. Complete blockade of this enhanced signaling is only achieved with co-inhibition by both antagonists. Like CXCR4, ß 2AR is also expressed by HSPCs, and in lymph nodes was shown to heteromerize with CXCR4 to increase lymphocyte retention. In multiple myeloma patients, propranolol upregulated stem-cell like gene signature. Therefore, we sought to understand the effects of propranolol on HSPC mobilization by GPC-100. In mice, single injection of GPC-100 effectively mobilized hematopoietic stem cells characterized as Lin negSca1 +cKit +(LSK) cells as well as mature Lin negCD34 + progenitor cells by 2-4-fold, respectively. Seven-day pretreatment with propranolol enhanced LSK cell mobilization by GPC-100 resulting in a 4-fold increase in circulating HSPCs (Figure 2). Addition of propranolol to G-CSF and GPC-100 led to 8-17-fold increases in mobilization of long-term repopulating HSCs (CD34 negLSK and CD150 +LSK), which were greater than the 4-7-fold increases elicited by G-CSF and G-CSF with plerixafor. Additionally, propranolol enhanced GPC-100 induced mobilization of white blood cells, neutrophils, and lymphocytes (Figure 2). Immune cell subset analyses revealed that GPC-100 induced a 3-fold increase in circulating CD8 +T cells, which was increased to 7-fold when combined with propranolol (Figure 2). For comparison, plerixafor increased CD8 + T cell mobilization by only 2-fold. GPC-100 induced mobilization of NK and B cells was also improved by propranolol. These pre-clinical data support our phase II clinical trial currently in progress (NCT05561751). In the first arm of this two-arm trial, GPC-100 is combined with orally administered propranolol, and in the second arm, G-CSF is added to this combination. We anticipate that our clinical studies can fill the gap in the current standard of care without adding a significant financial burden or co-morbidities. Furthermore, enhanced mobilization of CD8+ T cells can provide extended opportunities for improved adoptive cell therapies.

The Anti-Virulence Activities of the Antihypertensive Drug Propranolol in Light of Its Anti-Quorum Sensing Effects against Pseudomonas aeruginosa and Serratia marcescens.

The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the β-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol's effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies.

Trial in Progress: An Open-Label, Multi-Center Phase 2 Study to Assess the Safety and Efficacy of Burixafor (GPC-100) and Propranolol with and without G-CSF for the Mobilization of Stem Cells in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplant

Background and Significance: Poor stem cell mobilization with failure to produce the target cell dose of ≥2x10 6 CD34 cells/kg required for autologous stem cell transplant (ASCT) occurs in 15-50% of patients with lymphoma or multiple myeloma (MM). Newer therapies may also have a negative impact on mobilization, supporting a need for newer treatment options. Burixafor (GPC-100) is a potent and selective small molecule antagonist of CXCR4. Previous clinical trials with burixafor alone or in combination with G-CSF have demonstrated safe and effective mobilization of stem cells. Preclinical murine studies demonstrated that burixafor in combination with propranolol is a potent mobilizer of white blood cells and mouse stem cells, and mobilization was further augmented with the addition of G-CSF. The goal of the current clinical study is to evaluate the efficacy of burixafor and propranolol in the presence and absence of G-CSF. The triple combination is predicted to be best in class and can target patients at risk for poor mobilization while burixafor plus propranolol will allow for an option when G-CSF is not tolerated, such as in sickle cell disease or patients with autoimmune disease. Study Design and Methods: This study (NCT05561751) is an open-label, randomized, multi-site (U.S. only) Phase 2 trial. Approximately 40 participants will be enrolled across 8-10 sites and randomized in a 1:1 ratio to one of two treatment arms: Burixafor in combination with propranolol or burixafor in combination with propranolol and G-CSF. The study will employ a Bayesian Optimal Phase 2 (BOP2) design for participant enrollment to characterize the safety and clinical activity of burixafor. Participants must be at least 18 years of age, be diagnosed with MM and be eligible for ASCT. Key exclusion criteria include: no more than one year of therapy administered prior to stem cell mobilization, previous stem cell transplant, history of another malignancy, and history of poorly controlled or uncontrolled cardiovascular or pulmonary disease. All participants will self-administer 30 mg propranolol orally twice daily from Days 1 to 8. For participants in the treatment arm receiving G-CSF, they will receive SC injections of 10g/kg/day G-CSF in the afternoon on Days 3 to 7. On days 7 and 8, participants will receive 3.14 mg/kg dose of burixafor via IV and undergo leukapheresis for stem cell collection two hours post drug administration. Participants may undergo additional optional days of the treatment regimen and stem cell collection, per Investigator's discretion to meet institutional standards. The primary objective is to determine the proportion of patients that will achieve at least ≥2 x 10 6 CD34 + cells/kg in 2 leukapheresis sessions following the treatment regimens. Key secondary objectives include: assessment of safety and tolerability of GPC-100 and propranolol with and without G-CSF, evaluation of the pharmacodynamics by determining levels of circulating CD34 + cell counts and levels of the chemokine CXCL12 in peripheral blood, and assessment of mean time to ANC and platelet count recovery after ASCT. Exploratory objectives are also included to discover key biomarkers for patient selection, to evaluate cancer/stem/immune cell profiles, and to evaluate treatment impact on patient quality of life.

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits β-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (β2AR). Co-treatment with CXCL12 and the β2AR agonist epinephrine synergistically increases β-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

Propranolol restores susceptibility of XDR Gram-negative pathogens to meropenem and Meropenem combination has been evaluated with either tigecycline or amikacin

BackgroundInfection with extensive-drug-resistant (XDR) carbapenem-resistant (CR) Gram-negative bacteria (GNB) are viewed as a serious threat to human health because of the limited therapeutic options. This imposes the urgent need to find agents that could be used as adjuvants or combined with carbapenems to enhance or restore the susceptibility of XDR CR- GNB. Therefore, this study aimed to examine the effect of propranolol (PR) in combination with Meropenem (MEM) on the susceptibility profile of XDR CR-GNB recovered from severely infected patients as well as to evaluate combining MEM with either tigecycline (TGC) or amikacin (AK).MethodsA total of 59 non-duplicate CR- GNB were investigated for carbapenemase production by the major phenotypic methods. Molecular identification of five major carbapenemase-coding genes was carried out using polymerase chain reactions (PCR). Antimicrobial susceptibility tests were carried out using standard methods. Phenotypic and genotypic relatedness was carried out using the heatmap and ERIC PCR analysis. PR, 0.5 -1 mg/mL against the resulting non-clonal XDR CR-GNB pathogens were evaluated by calculating the MIC decrease factor (MDF). A combination of MEM with either AK or TGC was performed using the checkerboard assay.ResultsA total of 21 (35.6%) and 38 (64.4%) CR-GNB isolates were identified as enterobacterial isolates (including 16 (27.1%) Klebsiella Pneumoniae and 5 (8.5%) Escherichia coli) and non-fermentative bacilli (including, 23 (39%), Acinetobacter baumannii, and 15 (25.4%) Pseudomonas aeruginosa). The heatmap and ERIC PCR analysis resulted in non-clonal 28 XDR CR isolates. PR, at a concentration of 0.5 mg /ml, decreased MICs values of the tested XDR CR isolates (28; 100%) and restored susceptibility of only 4 (14.3%) isolates. However, PR (1 mg/mL) when combined with MEM has completely (28; 100%) restored the susceptibility of the tested XDR CR- GNB to MEM. The MEM + AK and MEM + TGC combination showed mostly additive effects (92.8% and 71.4%, respectively).ConclusionPR at a concentration of 1 mg/mL restored the susceptibility of XDR CR- GNB to MEM which is considered a promising result that should be clinically investigated to reveal its suitability for clinical use in patients suffering from these life-threatening pathogens.

The Association of Propranolol with 2-Deoxy-D-Glucose Reduces the Metabolism and the Proliferation of Cutaneous Squamous Carcinoma A431 Cell Line

Non-selective β-blocking (±)-Propranolol Hydrochloride was demonstrated to improve the progression-free survival of oncological patients. Since the expression of β-adrenoceptors in the epidermal squamous cell carcinoma was described, we hypothesized that the topical application of a β- adrenoceptors-blockers over the tumor lesion may decrease its extension before the surgical excision, becoming an adjuvant therapy against cutaneous squamous cell carcinoma. However, it is known that β-AR-blocker anti-cancer activity as a single agent is limited. Hence, we suggested that the combination of propranolol with the glucose analog 2-Deoxy-D-glucose could improve its antiproliferative effect through the induction of metabolic stress. Propranolol and 2-Deoxy-D-glucose effect on A431 squamous cell carcinoma and normal keratinocytes evaluating metabolic activity, proliferation and apoptosis through MTT, immunofluorescence Ki-67 and AnnexinV assays, cell cycle analysis and migration assay. Our results demonstrated that the addition of 2-Deoxy-D-glucose low dose to propranolol improve its effect on reduction of A431 cells metabolism and proliferation, similar effect was observed on HaCaT viability and mobility. However, the HaCaT migration ability is not completely compromised. The combination of propranolol with a low dose of 2-Deoxy-D-glucose could be a promising treatment to be topically applied avoiding systemic adverse effects in patients with cutaneous squamous cell carcinoma.

Potential effect of chloroquine and propranolol combination to treat colorectal and triple-negative breast cancers

Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on breast cancer. These results contributed to the search for new and safe treatments for colorectal and triple-negative carcinomas.

Intravitreal bevacizumab plus propranolol for neovascular age-related macular degeneration (the BEVALOL study): a phase I clinical trial

BackgroundGiven the persistently large public health impact of neovascular age-related macular degeneration (nARMD) despite many years of anti-VEGF therapy as the first-line treatment and the demonstrated ability of b-blockers to reduce neovascularization, a synergistic effect between an anti-VEGF agent and an intravitreal beta-blocker is important to investigate in the quest for therapeutic alternatives that maximize efficacy and/or reduce costs. The main purpose of this study is to investigate the safety of a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) to treat nARMD.MethodsProspective phase I clinical trial that included patients with nARMD. Comprehensive ophthalmic evaluation was performed at baseline and included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), biomicroscopy of the anterior and posterior segments, binocular indirect ophthalmoscopy, color fundus photography, spectral domain optical coherence tomography (OCT), OCT angiography (OCT-A), fluorescein angiography (Spectralis, Heidelberg), and full-field electroretinography (ERG). All eyes were treated with a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) within 1 week of baseline evaluation. The patients were reexamined at weeks 4, 8 and 12, and clinical evaluation and SD-OCT were performed at all follow-up visits. Additional injections of combination bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) were administered at weeks 4 and 8. At the final study evaluation (week 12), color fundus photography, OCT-A, fluorescein angiography, and full-field ERG were repeated.ResultsEleven patients (11 eyes) completed all study visits of the 12 week study. Full field ERG b-waves did not show significant (p < 0.05) changes at week 12 compared to baseline. During the 12 week follow-up period, none of the study eyes developed intraocular inflammation, endophthalmitis or intraocular pressure elevation more than 4 mmHg over baseline. Mean ± SE BCVA (logMAR) was 0.79 ± 0.09 at baseline and was significantly (p < 0.05) improved to 0.61 ± 0.10 at week 4; 0.53 ± 0.10 at week 8; and 0.51 ± 0.09 at week 12. Mean ± SE central subfield thickness (CST) (μm) was 462 ± 45 at baseline and was significantly (p < 0.05) lower at 4, 8 and 12 weeks (385 ± 37; 356 ± 29 and 341 ± 24, respectively).ConclusionsIn this 12 week trial of a combination of intravitreal bevacizumab and propranolol for treatment of nARMD, no adverse events or signals of ocular toxicity were observed. Further studies using this combination therapy are warranted.Trial Registration Project registered in Plataforma Brasil with CAAE number 28108920.0.0000.5440 and approved in ethics committee of Clinics Hospital of Ribeirao Preto Medicine School of São Paulo University—Ribeirão Preto, São Paulo, Brazil (appreciation number 3.999.989 gave the approval).

Kombinasi Injeksi Triamsinolon Asetat Intralesi dan Propanolol Oral pada Kasus Hemangioma Kapiler Palpebra

Capillary hemangioma is a benign tumor developed from the abnormal proliferation of blood vessels. This tumor appears on eyelids and orbit. Around 75% of hemangioma resolves spontaneously in the first 4-5 years of life. Intervention is needed in hemangioma that obstructs the visual axis. It has been reported that a two-year-old girl came to Polyclinic with a mass on the left superior eyelid 1,5 years ago. At first, the left superior eyelid looked puffy, then developed slowly until it covered the left eye. On the examination of the left eye, visual acuity assessment was hard to perform. Mass in superior palpebral was 8mm x 8mm x 8mm, reddish colored (different with adjacent skin), consistency supple, mobile, painful (-), edema (+), horizontal palpebral fissure (FPH) 30 mm, vertical palpebral fissure (FPV) 0 mm. CT scan showed suspected hemangioma. The patient was diagnosed with capillary hemangioma and given an injection of triamcinolone acetate intralesional and oral propranolol under the supervision of a pediatrician. Significant clinical improvement was observed after 40 days of injection, where the mass was resolved completely. The FPV and FPH of the left eye had improved to 9 mm and 30 mm, respectively, with the patient finally able to follow the object. The combination of intralesional triamcinolone acetate and oral propranolol in this case is quite effective in providing complete resolution of capillary hemangioma.Keywords: capillary hemangioma, triamcinolone acetate injection, propanolol

β2-AR Signaling Enhances MDSC Survival through Metabolic Reprograming and Impairs Therapeutic Efficacy in Hematologic Malignancies

Nerve-driven chronic adrenergic stress can suppress anti-tumor immunity. However, the mechanistic details of how this occurs are still poorly understood. Catecholamines (epinephrine, norepinephrine) released by the autonomic nervous system (ANS) can activate adrenergic receptors (AR) present on nearly every cell type, including myeloid derived suppressor cells (MDSCs). MDSCs are important regulatory cells that hinder anti-tumor immune responses in hematological malignancies by inhibiting numerous cell types, including effector NK cells, CD8+ T cells, CD4+ T cells, and processes, such as blocking cytokine secretion. Because first line treatment for most hematologic malignancies includes chemotherapy, and MDSCs are known to be detrimental to its efficacy, understanding their role, including through chronic stress pathways, is relevant. Recently, using preclinical models of solid tumors, we have shown β2 adrenergic receptor (β2-AR) signaling, activated by chronic stress, increases the accumulation of MDSCs in the tumor microenvironment (TME). However, the role of β2-AR in MDSC survival and accumulation in hematological malignancies after chemotherapy, and the precise mechanisms by which β2-AR increases MDSC accumulation, remain unresolved. We have discovered β2-AR signaling drives MDSC survival in tumor bearing mice treated with chemotherapy. We have also shown the combination of propranolol, a non-selective β-AR blocker, with doxorubicin prolongs survival in mice bearing EL4 and C1498 tumors. Examination of immune cell compartments demonstrated a significant reduction of both M-MDSC and PMN-MDSC abundance in mice receiving the combination therapy, indicating the key effect of stress induced β2-AR signaling on MDSC accumulation. Further, we implanted EL4 tumors into β2-AR-/- and β2ARfl/fl LysmCre mice and confirmed doxorubicin increases survival in both β2-AR-/- and β2ARfl/fl LysmCre mice compared to WT control mice, suggesting β2-AR signaling in MDSCs is the main receptor driving the effects of propranolol in combination therapy. Using both in vitro and in vivo systems, we showed β2-AR signaling increased MDSC survival by the induction of BCL-2 expression and the suppression of caspase-3 and caspase-8. Seahorse metabolic studies further showed β2-AR signaling induced a metabolic shift to increased mitochondrial respiration (OCR) and ATP production in MDSCs. We then applied single cell RNA sequencing (scRNAseq) pathway analysis and multiplexed D7-Glc plus 13C5-Gln tracing in Stable Isotope-Resolved Metabolomics (SIRM). We found β2-AR signaling induces a metabolic shift toward higher ATP generation and decreased mitochondrial reactive oxygen species (mROS) that serves as a survival signal for MDSCs. We also found β2-AR signaling suppressed the expression of ATPase Inhibitory Factor 1 (ATPIF1) in MDSCs, which is responsible for increased ATP generation. These results show β2-AR signaling induces MDSC survival through metabolic reprogramming in mitochondria by enhancing ATP generation and modulating key survival signals to increase the ratio of ATP/mROS. Altogether, these studies reveal β2-AR signaling plays an important role in mitochondrial metabolic fitness in MDSCs, priming them to survive chemotherapy-induced cytotoxicity. The combination of the stress blocker propranolol, with chemotherapy regimens, could potentially improve the current therapeutic regimens used for hematological malignancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Endoscopic diagnosis and management of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

1: ESGE recommends that patients with compensated advanced chronic liver disease (ACLD; due to viruses, alcohol, and/or nonobese [BMI < 30 kg/m2] nonalcoholic steatohepatitis) and clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] > 10 mmHg and/or liver stiffness by transient elastography > 25 kPa) should receive, if no contraindications, nonselective beta blocker (NSBB) therapy (preferably carvedilol) to prevent the development of variceal bleeding.Strong recommendation, moderate quality evidence. 2: ESGE recommends that in those patients unable to receive NSBB therapy with a screening upper gastrointestinal (GI) endoscopy that demonstrates high risk esophageal varices, endoscopic band ligation (EBL) is the endoscopic prophylactic treatment of choice. EBL should be repeated every 2-4 weeks until variceal eradication is achieved. Thereafter, surveillance EGD should be performed every 3-6 months in the first year following eradication.Strong recommendation, moderate quality evidence. 3: ESGE recommends, in hemodynamically stable patients with acute upper GI hemorrhage (UGIH) and no history of cardiovascular disease, a restrictive red blood cell (RBC) transfusion strategy, with a hemoglobin threshold of ≤70 g/L prompting RBC transfusion. A post-transfusion target hemoglobin of 70-90 g/L is desired.Strong recommendation, moderate quality evidence. 4 : ESGE recommends that patients with ACLD presenting with suspected acute variceal bleeding be risk stratified according to the Child-Pugh score and MELD score, and by documentation of active/inactive bleeding at the time of upper GI endoscopy.Strong recommendation, high quality of evidence. 5 : ESGE recommends the vasoactive agents terlipressin, octreotide, or somatostatin be initiated at the time of presentation in patients with suspected acute variceal bleeding and be continued for a duration of up to 5 days.Strong recommendation, high quality evidence. 6 : ESGE recommends antibiotic prophylaxis using ceftriaxone 1 g/day for up to 7 days for all patients with ACLD presenting with acute variceal hemorrhage, or in accordance with local antibiotic resistance and patient allergies.Strong recommendation, high quality evidence. 7 : ESGE recommends, in the absence of contraindications, intravenous erythromycin 250 mg be given 30-120 minutes prior to upper GI endoscopy in patients with suspected acute variceal hemorrhage.Strong recommendation, high quality evidence. 8 : ESGE recommends that, in patients with suspected variceal hemorrhage, endoscopic evaluation should take place within 12 hours from the time of patient presentation provided the patient has been hemodynamically resuscitated.Strong recommendation, moderate quality evidence. 9 : ESGE recommends EBL for the treatment of acute esophageal variceal hemorrhage (EVH).Strong recommendation, high quality evidence. 10 : ESGE recommends that, in patients at high risk for recurrent esophageal variceal bleeding following successful endoscopic hemostasis (Child-Pugh C ≤ 13 or Child-Pugh B > 7 with active EVH at the time of endoscopy despite vasoactive agents, or HVPG > 20 mmHg), pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) within 72 hours (preferably within 24 hours) must be considered.Strong recommendation, high quality evidence. 11 : ESGE recommends that, for persistent esophageal variceal bleeding despite vasoactive pharmacological and endoscopic hemostasis therapy, urgent rescue TIPS should be considered (where available).Strong recommendation, moderate quality evidence. 12 : ESGE recommends endoscopic cyanoacrylate injection for acute gastric (cardiofundal) variceal (GOV2, IGV1) hemorrhage.Strong recommendation, high quality evidence. 13: ESGE recommends endoscopic cyanoacrylate injection or EBL in patients with GOV1-specific bleeding.Strong recommendations, moderate quality evidence. 14: ESGE suggests urgent rescue TIPS or balloon-occluded retrograde transvenous obliteration (BRTO) for gastric variceal bleeding when there is a failure of endoscopic hemostasis or early recurrent bleeding.Weak recommendation, low quality evidence. 15: ESGE recommends that patients who have undergone EBL for acute EVH should be scheduled for follow-up EBLs at 1- to 4-weekly intervals to eradicate esophageal varices (secondary prophylaxis).Strong recommendation, moderate quality evidence. 16: ESGE recommends the use of NSBBs (propranolol or carvedilol) in combination with endoscopic therapy for secondary prophylaxis in EVH in patients with ACLD.Strong recommendation, high quality evidence.

Pharmacologic inhibition of beta-adrenergic receptors decreases PD-L1 mediated immunosuppression and improves anti-tumor immune signature in ovarian cancer (126)

<b>Objectives:</b> The immune system is affected by stress hormones, but also plays an important role in activating and suppressing mechanisms controlling epithelial ovarian cancer (EOC). Although EOC is a "cold tumor" the trafficking of tumor infiltrating lymphocytes in the tumor mass and the expression of programmed cell death ligand (PD-L1) are prognostic indicators in EOC. To date PD-1/PD-L1 inhibitors have had limited benefit as single agents or in combination with chemotherapy. This study aimed to explore the impact of adrenergic stress and its blockade with propranolol in both <i>in vitro</i> and <i>in vivo</i> EOC models. <b>Methods:</b> Two high grade serous cell lines SKOV3ip1 and OVCAR8 were used in co-culture experiments and exosome experiments. Western blot was used to detect changes in PD-L1 protein expression in exosomes treated with noradrenaline, propranolol, and interferon-gamma (IFN-g). C57bl/6 mice were injected with ID8 cells and exposed to chronic behavioral stress to activate the beta-adrenergic signalling pathway. Mice were treated with the following combinations: control (saline), propranolol (2mg/Kg/d via Alzet pump for 6 weeks), PD-1/PD-L1 inhibitor (200μg/mouse IP, three times a week for two weeks) or a combination of propranolol and PD-1/PD-L1 inhibitor. CD3, CD4, CD8 and CXCL10 mRNA expression were evaluated in the tumors with qPCR. GraphPad Prism v.7 was used as well as one-way ANOVA with Bonferroni multiple comparison test correction. <b>Results:</b> EOC cell lines were treated with noradrenaline (NA), propranolol, IFN-g or in combination (NA+ IFN-g). NA+IFN-g caused an increase in PD-L1 mRNA and protein expression (p<0.05). IFN-g causes a statistically significant increase in the production of PD-L1 carrying exosomes (p<0.05) while propranolol does not. Combination of propranolol and PD-1/PD-L1 inhibitor significantly reduced tumour weight compared to the cancer control group (p<0.05). Chronic behavioural stress significantly increased the number of organs with metastatic nodules (p<0.05) while propranolol monotherapy and the combined therapy showed a significant decrease in the number of organs affected by metastatic nodules (p<0.001). VEGF expression was significantly reduced in the combined therapy group compared to the propranolol and PD-1/PD-L1 monotherapy (p<0.001). CD8 CD3, CD4 mRNA expression increased significantly in the combined therapy group compared to PD-1/PD-L1 inhibitor monotherapy and the control group (p<0.05). Propranolol also decreased IDO1 and CXCL10 mRNA as well. <b>Conclusions:</b> Propranolol decreases upstream production of IFN-g and the IFN-g-mediated PD-L1 expression on cancer cells. Therefore the combination of propranolol with PD-L1 inhibitors is a promising therapy in this preclinical EOC model.

The Sympathetic Nervous System Modulates Cancer Vaccine Activity through Monocyte-Derived Cells.

The sympathetic nervous system (SNS) is an important regulator of immune cell function during homeostasis and states of inflammation. Recently, the SNS has been found to bolster tumor growth and impair the development of antitumor immunity. However, it is unclear whether the SNS can modulate APC function. Here, we investigated the effects of SNS signaling in murine monocyte-derived macrophages (moMФ) and dendritic cells (DCs) and further combined the nonspecific β-blocker propranolol with a peptide cancer vaccine for the treatment of melanoma in mice. We report that norepinephrine treatment dramatically altered moMФ cytokine production, whereas DCs were unresponsive to norepinephrine and critically lack β2-adrenergic receptor expression. In addition, we show that propranolol plus cancer vaccine enhanced peripheral DC maturation, increased the intratumor proportion of effector CD8+ T cells, and decreased the presence of intratumor PD-L1+ myeloid-derived suppressor cells. Furthermore, this combination dramatically reduced tumor growth compared with vaccination alone. Taken together, these results offer insights into the cell-specific manner by which the SNS regulates the APC immune compartment and provide strong support for the use of propranolol in combination with cancer vaccines to improve patient response rates and survival.

Efficacy Evaluation of 755-nm Long-Pulse Alexandrite Laser Combined with 0.5% Timolol Maleate Eye Drops in the Treatment of Thicker Infantile Hemangioma.

PurposeAssessment of the clinical effectiveness and safety of 755-nm long-pulse alexandrite laser combined with 0.5% timolol maleate eye drops in treating thicker infantile hemangioma (IH).Materials and MethodsRetrospective analysis of IH treated with 755-nm long-pulse alexandrite laser and topical timolol in the Second Affiliated Hospital of Wenzhou Medical University from October 2019 to October 2020. Seventy-eight cases were included, with a five-week laser treatment interval. Treatment status was documented during the 35 weeks before each treatment, the effect was assessed at the visual analog scale (VAS), and side effects were recorded. During the 6-month follow-up period, the recurrence and residual skin lesions were monitored. The relationship between IH thickness, treatment duration and VAS was analyzed.ResultsAmong the 78 children with hemangioma, 4 children were treated with a combination of propranolol, fractional laser and cinnamyl alcohol injection due to poor curative effect. Finally, the lesions were effectively alleviated. At the 5th, 15th, 25th, and 35th weeks of treatment, the average VAS of 74 children were 3.56 ± 1.20, 4.61 ± 1.43, 5.63 ± 1.60, and 6.63 ± 1.72, respectively. We analyzed VAS in different thickness groups with Repeated Measures Analysis of Variance(RMANOVA). The results show that the VAS of the thickness 2–3 mm and 3–5mm groups were higher than the 5–7mm and 7–8mm groups (F group = 440.54, P <0.05, F time = 448.31, P <0.05). During the 6-month follow-up period, none of the 74 children relapsed and the residual skin lesions gradually vanished.ConclusionCombined treatment of IHs with a 755-nm long-pulse alexandrite laser and 0.5% timolol maleate eye drops which has apparent clinical efficacy and safety reduce residual skin lesions and decrease the IH recurrence rate.

Maintained barostatic regulation of heart rate in digesting snakes (Boa constrictor).

When snakes digest large meals, heart rate is accelerated by withdrawal of vagal tone and an increased non-adrenergic-non-cholinergic tone that seems to stem from circulating blood-borne factors exerting positive chronotropic effects. To investigate whether this tonic elevation of heart rate impairs the ability for autonomic regulation of heart during digestion, we characterised heart rate responses to pharmacological manipulation of blood pressure in the snake Boa constrictor through serial injections of sodium nitroprusside and phenylephrine. Both fasting and digesting snakes responded with a robust tachycardia to hypotension induced by sodium nitroprusside, with digesting snakes attaining higher maximal heart rates than fasting snakes. Both fasting and digesting snakes exhibited small reductions of the cardiac chronotropic response to hypertension, induced by injection of phenylephrine. All heart rate changes were abolished by autonomic blockade with the combination of atropine and propranolol. The digesting snakes retained the capacity for compensatory heart rate responses to hypotension, despite their higher resting values, and the upward shift of the barostatic response curve enables snakes to maintain the cardiac limb of barostatic regulation for blood pressure regulation.