Propranolol Promotes Monocyte-to-Macrophage Differentiation and Enhances Macrophage Anti-Inflammatory and Antioxidant Activities by NRF2 Activation.

Adrenergic pathways represent the main channel of communication between the nervous system and the immune system. During inflammation, blood monocytes migrate within tissue and differentiate into macrophages, which polarize to M1 or M2 macrophages with tissue-damaging or -reparative properties, respectively. This study investigates whether the ß-adrenergic receptor (ß-AR)-blocking drug propranolol modulates the monocyte-to-macrophage differentiation process and further influences macrophages in their polarization toward M1- and M2-like phenotypes. Six-day-human monocytes were cultured with M-CSF in the presence or absence of propranolol and then activated toward an M1 pro-inflammatory state or an M2 anti-inflammatory state. The chronic exposure of monocytes to propranolol during their differentiation into macrophages promoted the increase in the M1 marker CD16 and in the M2 markers CD206 and CD163 and peroxisome proliferator-activated receptor É£ expression. It also increased endocytosis and the release of IL-10, whereas it reduced physiological reactive oxygen species. Exposure to the pro-inflammatory conditions of propranolol-differentiated macrophages resulted in an anti-inflammatory promoting effect. At the molecular level, propranolol upregulated the expression of the oxidative stress regulators NRF2, heme oxygenase-1 and NQO1. By contributing to regulating macrophage activities, propranolol may represent a novel anti-inflammatory and immunomodulating compound with relevant therapeutic potential in several inflammatory diseases.

Infantile hemangioma: the common and enigmatic vascular tumor.

Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of newborns. The tumor follows a life cycle of rapid proliferation in infancy, followed by slow involution in childhood. This unique life cycle has attracted the interest of basic and clinical scientists alike as a paradigm for vasculogenesis, angiogenesis, and vascular regression. Unanswered questions persist about the genetic and molecular drivers of the proliferating and involuting phases. The beta blocker propranolol usually accelerates regression of problematic IHs, yet its mechanism of action on vascular proliferation and differentiation is unclear. Some IHs fail to respond to beta blockers and regrow after discontinuation. Side effects occur and long-term sequelae of propranolol treatment are unknown. This poses clinical challenges and raises novel questions about the mechanisms of vascular overgrowth in IH.

Successful interventional treatment of huge hepatic haemangioma in a neonate following failed medical approach.

An outborn male term neonate presented with a complaint of respiratory distress since birth on day 9 of life. On examination, baby was having tachypnoea, tachycardia and hepatomegaly. The baby was delivered at term gestation and cried immediately after birth. The chest X-ray showed cardiomegaly. The abdomen ultrasound showed a complex cystic vascular lesion suggestive of hepatic haemangioma. The echocardiography showed an atrial septal defect. The baby was initially treated conservatively along with specific treatment (steroids and propranolol) for haemangioma for 6 weeks. However, the symptoms persisted and there was non-resolution, therefore, particle embolisation of the right hepatic artery was performed. Subsequently, it resulted in complete resolution of the lesion.

Non-radical activation of persulfate with Bi2O3/BiO1.3I0.4 for efficient degradation of propranolol under visible light.

Non-radical activation of persulfate (PS) by photocatalysts is an effective approach for removing organic pollutants from aqueous environments. In this study, a novel Bi2O3/BiO1.3I0.4 heterojunction was synthesized using a facile solvothermal approach and used for the first time for non-radical activation of PS to degrade propranolol (PRO) in the presence of visible light. The findings found that the degradation rate of PRO in the Bi2O3/BiO1.3I0.4/PS system was significantly increased from 19% to more than 90% within 90 min compared to the Bi2O3/BiO1.3I0.4 system. This indicated that the composite system exerted an excellent synergistic effect between the photocatalyst and the persulfate-based oxygenation. Quenching tests and electron paramagnetic resonance demonstrated that the non-radical pathway with singlet oxygen as the active species played a major role in the photocatalytic process. The existence of photo-generated holes during the reaction could also be directly involved in the oxidation of pollutants. Meanwhile, a possible PRO degradation pathway was also proposed. Furthermore, the impacts of pH, humic acid and common anions on the PRO degradation by the Bi2O3/BiO1.3I0.4/PS were explored, and the system's stability and reusability were also studied. This study exhibits a highly productive catalyst for PS activation via a non-radical pathway and provides a new idea for the degradation of PRO.

Drug Efficacy in the Treatment of Antipsychotic-Induced Akathisia: A Systematic Review and Network Meta-Analysis.

Importance: Antipsychotic-induced akathisia (AIA) occurs in 14% to 35% of patients treated with antipsychotics and is associated with increased suicide and decreased adherence in patients with schizophrenia. However, no comprehensive review and network meta-analysis has been conducted to compare the efficacy of treatments for AIA. Objective: To compare the efficacy associated with AIA treatments. Data Sources: Three databases (MEDLINE, Web of Science, and Google Scholar) were systematically searched by multiple researchers for double-blind randomized clinical trials (RCTs) comparing active drugs for the treatment of AIA with placebo or another treatment between May 30 and June 18, 2023. Study Selection: Selected studies were RCTs that compared adjunctive drugs for AIA vs placebo or adjunctive treatment in patients treated with antipsychotics fulfilling the criteria for akathisia, RCTs with sample size of 10 patients or more, only trials in which no additional drugs were administered during the study, and RCTs that used a validated akathisia score. Trials with missing data for the main outcome (akathisia score at the end points) were excluded. Data Extraction and Synthesis: Data extraction and synthesis were performed, estimating standardized mean differences (SMDs) through pairwise and network meta-analysis with a random-effects model. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. Main Outcomes and Measures: The primary outcome was the severity of akathisia measured by a validated scale at the last available end point. Results: Fifteen trials involving 492 participants compared 10 treatments with placebo. Mirtazapine (15 mg/d for ≥5 days; SMD, -1.20; 95% CI, -1.83 to -0.58), biperiden (6 mg/d for ≥14 days; SMD, -1.01; 95% CI, -1.69 to -0.34), vitamin B6 (600-1200 mg/d for ≥5 days; SMD, -0.92; 95% CI, -1.57 to -0.26), trazodone (50 mg/d for ≥5 days; SMD, -0.84; 95% CI, -1.54 to -0.14), mianserin (15 mg/d for ≥5 days; SMD, -0.81; 95% CI, -1.44 to -0.19), and propranolol (20 mg/d for ≥6 days; SMD, -0.78; 95% CI, -1.35 to -0.22) were associated with greater efficacy than placebo, with low to moderate heterogeneity (I2 = 34.6%; 95% CI, 0.0%-71.1%). Cyproheptadine, clonazepam, zolmitriptan, and valproate did not yield significant effects. Eight trials were rated as having low risk of bias; 2, moderate risk; and 5, high risk. Sensitivity analyses generally confirmed the results for all drugs except for cyproheptadine and propranolol. No association between effect sizes and psychotic severity was found. Conclusions and Relevance: In this systematic review and network meta-analysis, mirtazapine, biperiden, and vitamin B6 were associated with the greatest efficacy for AIA, with vitamin B6 having the best efficacy and tolerance profile. Trazodone, mianserin, and propranolol appeared as effective alternatives with slightly less favorable efficacy and tolerance profiles. These findings should assist prescribers in selecting an appropriate medication for treating AIA.

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

BACKGROUND: Angiosarcoma is a rare and aggressive cancer of the endothelial cells. Propranolol, a non-selective ß-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. METHODS: Propranolol 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 ß-receptor expression levels. RESULTS: Fourteen 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. CONCLUSIONS: This 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.

ß-Receptor blocker enhances the anabolic effect of PTH after osteoporotic fracture.

The autonomic nervous system plays a crucial role in regulating bone metabolism, with sympathetic activation stimulating bone resorption and inhibiting bone formation. We found that fractures lead to increased sympathetic tone, enhanced osteoclast resorption, decreased osteoblast formation, and thus hastened systemic bone loss in ovariectomized (OVX) mice. However, the combined administration of parathyroid hormone (PTH) and the ß-receptor blocker propranolol dramatically promoted systemic bone formation and osteoporotic fracture healing in OVX mice. The effect of this treatment is superior to that of treatment with PTH or propranolol alone. In vitro, the sympathetic neurotransmitter norepinephrine (NE) suppressed PTH-induced osteoblast differentiation and mineralization, which was rescued by propranolol. Moreover, NE decreased the PTH-induced expression of Runx2 but enhanced the expression of Rankl and the effect of PTH-stimulated osteoblasts on osteoclastic differentiation, whereas these effects were reversed by propranolol. Furthermore, PTH increased the expression of the circadian clock gene Bmal1, which was inhibited by NE-ßAR signaling. Bmal1 knockdown blocked the rescue effect of propranolol on the NE-induced decrease in PTH-stimulated osteoblast differentiation. Taken together, these results suggest that propranolol enhances the anabolic effect of PTH in preventing systemic bone loss following osteoporotic fracture by blocking the negative effects of sympathetic signaling on PTH anabolism.

Role of noradrenergic and dopaminergic systems in the antinociceptive effect of N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide in mice.

Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore, there is a need to develop new analgesic compounds. Due to promising results regarding the antinociceptive effect of N-(3-(phenylselanyl)prop-2-in-1-yl)benzamide (SePB), this study aimed to evaluate the participation of the dopaminergic and noradrenergic systems in this effect in mice, as well as its toxicity. To this, the antagonists sulpiride (D2/D3 receptor antagonist, 5 mg/kg), SCH-23390 (D1 receptor antagonist, 0.05 mg/kg), prazosin (α1 adrenergic receptor antagonist, 0.15 mg/kg), yohimbine (α2-adrenergic receptors, 0.15 mg/kg) and propranolol (non-selective ß-adrenergic antagonist, 10 mg/kg) were administered intraperitoneally to mice 15 min before SePB (10 mg/kg, intragastrically), except for propranolol (20 min). After 26 min of SePB administration, the open field test was performed for 4 min to assess locomotor activity, followed by the tail immersion test to measure the nociceptive response. For the toxicity test, animals received a high dose of 300 mg/kg of SePB. SePB showed an increase in the latency for nociceptive response in the tail immersion test, and this effect was prevented by SCH-23390, yohimbine and propranolol, indicating the involvement of D1, α2 and ß-adrenergic receptors in the antinociceptive mechanism of the SePB effect. No changes were observed in the open field test, and the toxicity assessment suggested that SePB has low potential to induce toxicity. These findings contribute to understanding SePB's mechanism of action, with a focus on the development of new alternatives for pain treatment.

Organ-specific biotransformation in salmonids: Insight into intrinsic enzyme activity and biotransformation of three micropollutants.

Aquatic ecosystems continue to be threatened by chemical pollution. To what extent organisms are able to cope with chemical exposure depends on their ability to display mechanisms of defense across different organs. Among these mechanisms, biotransformation processes represent key physiological responses that facilitate detoxification and reduce the bioaccumulation potential of chemicals. Biotransformation does not only depend on the ability of different organs to display biotransformation enzymes but also on the affinity of chemicals towards these enzymes. In the present study, we explored the ability of different organs and of two freshwater fish to support biotransformation processes through the determination of in vitro phase I and II biotransformation enzyme activity, and their role in supporting intrinsic clearance and the formation of biotransformation products. Three environmentally relevant pollutants were evaluated: the polycyclic aromatic hydrocarbon (PAH) pyrene (as recommended by the OECD 319b test guideline), the fungicide azoxystrobin, and the pharmaceutical propranolol. Comparative studies using S9 sub-cellular fractions derived from the liver, intestine, gills, and brain of brown trout (Salmo trutta) and rainbow trout (Oncorhynchus mykiss) revealed significant phase I and II enzyme activity in all organs. However, organ- and species-specific differences were found. In brown trout, significant extrahepatic biotransformation was observed for pyrene but not for azoxystrobin and propranolol. In rainbow trout, the brain appeared to biotransform azoxystrobin. In this same species, propranolol appeared to be biotransformed by the intestine and gills. Biotransformation products could be detected only from hepatic biotransformation, and their profiles and formation rates displayed species-specific patterns and occurred at different magnitudes. Altogether, our findings further contribute to the current understanding of organ-specific biotransformation capacity, beyond the expression and activity of enzymes, and its dependence on specific enzyme-chemical interactions to support mechanisms of defense against exposure.

Safety and efficacy of transjugular intrahepatic portosystemic shunts vs endoscopic band ligation plus propranolol in patients with cirrhosis with portal vein thrombosis: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to assess the efficacy and safety of transjugular intrahepatic portosystemic shunts (TIPS) against the combined treatment of endoscopic band ligation (EBL) and propranolol in managing patients with cirrhosis diagnosed with portal vein thrombosis (PVT). METHODS: A literature search from inception to September 2023 was performed using MEDLINE, the Cochrane Library, Web of Science, and Scopus. Independent screening, data extraction, and quality assessment were performed. The main measured outcomes were the incidence and recurrence of variceal bleeding (VB), hepatic encephalopathy, and overall survival. RESULTS: A total of 5 studies were included. For variceal eradication, there was initially no significant difference between the groups; however, after sensitivity analysis, a significant effect emerged (risk ratio [RR], 1.55; P < .0001). TIPS was associated with a significant decrease in the incidence of VB (RR, 0.34; P < .0001) and a higher probability of remaining free of VB in the first 2 years after the procedure (first year: RR, 1.41; P < .0001; second year: RR, 1.58; P < .0001). TIPS significantly reduced the incidence of death due to acute GI bleeding compared with EBL + propranolol (RR, 0.37; P = .05). CONCLUSION: TIPS offers a comprehensive therapeutic advantage over the combined EBL and propranolol regimen, especially for patients with cirrhosis with PVT. Its efficacy in variceal eradication, reducing rebleeding, and mitigating death risks due to acute GI bleeding is evident.

Color Doppler Ultrasound Indices as Predictors of Propranolol Response in Infantile Hemangioma: A Prospective Study.

OBJECTIVE: To evaluate the utility of color Doppler ultrasonography in assessing infantile hemangioma response to treatment with oral propranolol. METHODS: A prospective study was conducted between January, 2016 and December, 2022, wherein children with symptomatic (ulceration, bleeding, pain and scarring) infantile hemangioma were given oral propranol (2 mg/kg per day in three divided doses) as outpatient therapy. The clinical response was assessed three months post-initiation of treatment (intermediate clinical response) and three months post-completion of treatment (final clinical response, FCR). The primary outcome measurement was a clinical and radiological response (resistivity index (RI), pulsatility index (PI) and peak systolic velocity) to treatment. The secondary outcomes assessed were the complications related to treatment. RESULTS: Out of 601 patients who were started on propranolol, 99 developed severe adverse effects and were excluded from analysis. At FCR assessment, out of 502 participants, 64.3% (n = 323) showed excellent response, 17.7% (n = 89) showed partial, and 17.9% (n = 90) were non-responders. A significant increase in RI and PI values was noted in all children following propranolol treatment for six months. An increase > 7.5% in RI could identify responders with 92% sensitivity, 91% specificity and area under the curve (AUC) of 0.963. An increase of > 11.5% in PI could identify responders with 86% sensitivity, 91% specificity and AUC of 0.896. Patients initially showing no response but later becoming excellent responders had significantly higher RI and PI values. CONCLUSIONS: Color Doppler ultrasonography is a valuable tool in predicting the treatment outcome of infantile hemangioma using propranolol.

Eco-friendly and smart spectrophotometric approaches for quality control analysis of one of ß-blockers in their dosage.

The pharmaceutical industry's rapid progress has spurred the demand for diverse analysis approaches within quality control laboratories to investigate approved drug combinations. Antihypertensive drugs, especially beta-blockers (BB), represent a significant pharmaceutical group, with increasing consumption. The presented research resolves spectral overlay for important binary combination of Propranolol hydrochloride (PRO) and Hydrochlorothiazide (HCT) which its zero order spectrums exhibit interference with a lack of iso-absorptive points, throughout three proposed approaches: Induced Dual Wavelength (IDW), Absorptivity Factor (α-factor), and Amplitude Factor (P-factor). These approaches enable simultaneous spectrophotometric identification of binary mixture without prior separation, with good linearity ranges of (1.5-25) µg/mL (2.0-25) µg/mL for (PRO) and (HCT). The outputs of quality control laboratories involve multiple solvents and reagents, leading to the production of toxic waste that affects the environment and society. While BBs are safe for human and veterinary use, their impact on ecosystems cannot be ignored, thus this research highlights the importance of eco-friendly and smart spectrophotometric approaches for simultaneous identification of the most important ß-blockers combination with minimal waste and energy consumption. Greenness and Whiteness aspects of proposed approaches are assessed via three Green Analytical Chemistry (GAC) metrics: Analytical Greenness Metric approach (AGREE), Green Analytical Procedure Index (GAPI Index) and Red-Green-Blue (RGB) model. Verification of each proposed approaches are proved via ICH confines and statistically compared with USP pharmacopeia approach revealing along with never main deviation.

Rare complication - skin atrophy - after systemic conservative therapy of infantile hemangioma.

BACKGROUND: Hemangiomas, also called infantile hemangiomas (IH) or hemangiomas of infancy are the most frequently seen benign vascular tumors of infancy. Different types of hemangiomas are described in the literature. The current approach is to assess the risk and, if needed, first line treatment is to initiate systemic propranolol. CASE PRESENTATION: A 3-month-old Caucasian female patient was brought as an outpatient. The main complaint was an infantile hemangioma in the facial area, which as per the parents' story appeared within a week of birth like a small reddish line and it rapidly grew. Systemic propranolol was proposed as a first-line treatment and the adverse effects were explained. The parents, afraid of the side effects, wanted to explore other possibilities such as topical timolol, however, since it had no effect, propranolol was initiated in the end. Hemangioma was completely reduced in size; however, a skin defect was detected. As per the dermatologist's counsel, topical cream was initiated. The skin defect was reduced but not fully healed. The child is still being monitored periodically. CONCLUSION: After successful treatment of hemangioma, we identified a skin defect, which was very similar to steroid-induced skin atrophy. However, we cannot attribute this to a single factor. The only thing that can be concluded is that the subject needs a thorough studying, since rate of infantile hemangioma is high, and pediatricians need a clear management strategy of how to approach skin atrophy after successfully treating the hemangioma itself.

Circulating Mesenchymal Stromal Cells in Patients with Infantile Hemangioma: Evaluation of Their Functional Capacity and Gene Expression Profile.

We previously published that in patients with infantile hemangioma (IH) at the onset (T0) colony forming unit-fibroblasts (CFU-Fs) are present in in vitro cultures from PB. Herein, we characterize these CFU-Fs and investigate their potential role in IH pathogenesis, before and after propranolol therapy. The CFU-F phenotype (by flow cytometry), their differentiation capacity and ability to support angiogenesis (by in vitro cultures) and their gene expression (by RT-PCR) were evaluated. We found that CFU-Fs are actual circulating MSCs (cMSCs). In patients at T0, cMSCs had reduced adipogenic potential, supported the formation of tube-like structures in vitro and showed either inflammatory (IL1ß and ESM1) or angiogenic (F3) gene expression higher than that of cMSCs from CTRLs. In patients receiving one-year propranolol therapy, the cMSC differentiation in adipocytes improved, while their support in in vitro tube-like formation was lost; no difference was found between patient and CTRL cMSC gene expressions. In conclusion, in patients with IH at T0 the cMSC reduced adipogenic potential, their support in angiogenic activity and the inflammatory/angiogenic gene expression may fuel the tumor growth. One-year propranolol therapy modifies this picture, suggesting cMSCs as one of the drug targets.

[Stridor due to a subglottic hemangioma compressing the trachea]. / L'image du mois. Stridor secondaire à un hémangiome sous-glottique comprimant la trachée.

Subglottic haemangioma can cause stridor in young children, and sometimes be life-threatening. Larynx ultrasound is a useful, non-irradiating screening test, but the diagnosis must be confirmed by bronchial fibroscopy and injected chest CT scan. Nowadays propranolol is the first-line treatment. If treated early, the prognosis is excellent.

L'hémangiome sous-glottique peut être responsable d'un stridor chez le jeune enfant et, parfois, menacer le pronostic vital. L'échographie du larynx est un examen utile et non irradiant pour le dépistage, mais le diagnostic sera confirmé par une fibroscopie bronchique et un scanner thoracique avec injection de produit de contraste. Le traitement en première intention est le propranolol. Lors d'une prise en charge précoce, le pronostic est excellent.

Preventive treatment of migraine: Non-specific oral agents.

Migraine headache is highly prevalent and the most common neurologic disorder, affecting one billion people worldwide. It is also the most disabling condition in people under 50, with a huge impact on working ability, family, and social life. Access to effective preventive medication is important and may be considered if the patient has 6 or more migraine days per month, ineffective abortive agents, or disability on 2 or more days per month. Propranolol, metoprolol, candesartan, topiramate, divalproex, lisinopril, amitriptyline, and venlafaxine have the strongest evidence to support for use. Flunarizine and pizotifen may also be effective. Selection of preventive treatments is based on individual characteristics, comorbid conditions, efficacy, contraindications, side effects, cost, compliance, and drug. An adequate trial of migraine prophylaxis is usually 2 months at the target dose, and it is always important to re-evaluate indication for prophylactic use after a period of time.

Chiral separation of propranolol by electrokinetic chromatography using nanodiamonds and human serum albumin as a pseudo-stationary phase in river water.

Propranolol is currently considered as an emerging contaminant in water bodies. In this study, R- and S-propranolol were determined in river samples by electrokinetic chromatography (EKC) using nanodiamonds (NDs) and human serum albumin (HSA) as a pseudo-stationary phase in order to achieve enantioseparation. Previously, river samples were preconcentrated using a column filled with Amberlite® IR-120 and Dowex® 50WX8 resins. The setting up of influential factors such as temperature, voltage, pH, and HSA and NDs concentration is accurately described along this manuscript. A multivariate study and optimization was carried out to obtain the enantioseparation of propranolol (Rs = 2.91), which was reached under the following experimental conditions: voltage of 16 kV, temperature of 16°C, phosphate buffer pH 9.5, NDs of 0.20%, and HSA of 15 µmol l-1 . The recoveries of analytes under optimal conditions were higher than 98%. The limits of detection were 0.85 µg l-1 for R- and S-propranolol. The method was applied to real samples, and the obtained results in three different water sources studied were 1.02, 0.59, and 0.30 µg l-1 for the R-enantiomer and 0.99, 0.54, and 0.28 µg l-1 for the S-enantiomer. The accuracy of the proposed methodology (including bias and precision) has allowed us to propose it as a successful tool for the control of water quality.