Características clínico-epidemiológicas y consideraciones terapéuticas de los hemangiomas congénitos e infantiles de un hospital de tercer nivel durante un periodo de 3 años: estudio comparativo y revisión de la literatura / Congenital and Infantile Hemangiomas: Epidemiological, Clinical, and Treatment Characteristics Based on 3 Years’ Experience at a Tertiary Care Hospital — A Retrospective Case Comparison and Review of the Literature

El diagnóstico diferencial clínico entre los hemangiomas congénitos (HC) y los infantiles (HI) es complicado pero esencial para el tratamiento. El marcador inmunohistoquímico GLUT-1 ayuda a distinguirlos, sin embargo, la biopsia no es habitual. Se diseñó un estudio retrospectivo incluyendo los HI y a los HC diagnosticados en un hospital terciario en un periodo de 3 años, con el objetivo de describir y comparar los principales aspectos clínicos, epidemiológicos y terapéuticos. Se incluyeron un total de 107 hemangiomas, 34 HC (NICH/PICH/RICH), 70 HI y 3 pendientes de clasificar. El HI superficial de cabeza y cuello fue el tumor más frecuente. El tronco fue la localización más frecuente de los HC. Los factores de riesgo estudiados fueron más frecuentes en el grupo de los HI. Para los HI, el tipo de respuesta obtenida fue independiente de las variables (sexo, fecundación in vitro, profundidad, localización y tipo de tratamiento) (AU)

Distinguishing between congenital and infantile hemangiomas is challenging, but essential for appropriate treatment. The immunohistochemical marker glucose transporter type 1 is helpful, but biopsies are uncommon in this setting. The aim of this retrospective study was to describe and compare epidemiological, clinical, and treatment characteristics of congenital and infantile hemangiomas diagnosed at a tertiary care hospital over 3 years. We studied 107 hemangiomas: 34 congenital hemangiomas (rapidly involuting, partially involuting, and noninvoluting), 70 infantile hemangiomas, and 3 hemangiomas pending classification. Superficial infantile hemangiomas of the head and neck were the most prevalent tumors. Congenital hemangiomas were most often located on the trunk. Studied risk factors were more common in patients with infantile hemangiomas. In this group of patients, treatment response was independent of sex, in vitro fertilization, lesion depth and location, and type of treatment (AU)

[Translated article] Congenital and Infantile Hemangiomas: Epidemiological, Clinical, and Treatment Characteristics Based on 3 Years’ Experience at a Tertiary Care Hospital – A Retrospective Case Comparison and Review of the Literature / Características clínico-epidemiológicas y consideraciones terapéuticas de los hemangiomas congénitos e infantiles de un hospital de tercer nivel durante un periodo de tres años: estudio comparativo y revisión de la literatura

Distinguishing between congenital and infantile hemangiomas is challenging, but essential for appropriate treatment. The immunohistochemical marker glucose transporter type 1 is helpful, but biopsies are uncommon in this setting. The aim of this retrospective study was to describe and compare epidemiological, clinical, and treatment characteristics of congenital and infantile hemangiomas diagnosed at a tertiary care hospital over 3 years. We studied 107 hemangiomas: 34 congenital hemangiomas (rapidly involuting, partially involuting, and noninvoluting), 70 infantile hemangiomas, and 3 hemangiomas pending classification. Superficial infantile hemangiomas of the head and neck were the most prevalent tumors. Congenital hemangiomas were most often located on the trunk. Studied risk factors were more common in patients with infantile hemangiomas. In this group of patients, treatment response was independent of sex, in vitro fertilization, lesion depth and location, and type of treatment (AU)

El diagnóstico diferencial clínico entre los hemangiomas congénitos (HC) y los infantiles (HI) es complicado pero esencial para el tratamiento. El marcador inmunohistoquímico GLUT-1 ayuda a distinguirlos, sin embargo, la biopsia no es habitual. Se diseñó un estudio retrospectivo incluyendo los HI y a los HC diagnosticados en un hospital terciario en un periodo de 3 años, con el objetivo de describir y comparar los principales aspectos clínicos, epidemiológicos y terapéuticos. Se incluyeron un total de 107 hemangiomas, 34 HC (NICH/PICH/RICH), 70 HI y 3 pendientes de clasificar. El HI superficial de cabeza y cuello fue el tumor más frecuente. El tronco fue la localización más frecuente de los HC. Los factores de riesgo estudiados fueron más frecuentes en el grupo de los HI. Para los HI, el tipo de respuesta obtenida fue independiente de las variables (sexo, fecundación in vitro, profundidad, localización y tipo de tratamiento) (AU)

Hemangioma segmentario de la barba / Segmental Beard Hemangioma

Los hemangiomas infantiles son el resultado de la proliferación de células del endotelio vascular y representan los tumores benignos más frecuentes en la infancia, con una incidencia estimada del 4-10% en bebés caucásicos. Se clasifican según el número, la profundidad y la distribución. Dentro de esta última clasificación se encuentran aquellos denominados segmentarios, que se caracterizan por su distribución extensa en áreas de prolongaciones mesodérmicas embrionarias. Se comunica el caso de una paciente evaluada al mes y medio de vida, con un hemangioma extenso del área mandibular y cuello anterior (hemangioma segmentario de la barba). Se describe la importancia de los estudios complementarios para evaluar el compromiso de órganos subyacentes, para detectar síndromes asociados y definir el tratamiento sobre la base de estos resultados. (AU)

Infantile hemangiomas arise from the proliferation of vascular endothelial cells and represent the most common benign tumors in infancy, with an estimated incidence of 4-10% in Caucasian infants. They vary according to their number, depth, and distribution. Within the latter classification are the so-called segmental ones, which feature an extensive distribution in areas of embryonic mesodermal extensions. We report the case of a patient evaluated at one and a half months of life with an extensive hemangioma of the mandibular area and anterior neck (segmental hemangioma of the beard). We describe the importance of complementary studies for evaluating the involvement of underlying organs, detecting associated syndromes, and defining the treatment based on these findings. (AU)

A pilot study to compare propranolol and misoprostol versus misoprostol and placebo for induction of labor in primigravidae; a randomized, single-blinded, placebo-controlled trial.

BACKGROUND: The Induction of labor is the most common obstetric procedure in daily practice. Introducing propranolol as a new drug to augment the action of prostaglandins will help in the induction process and decrease CS rates. Several researchers have used propranolol in the augmentation of labor. AIM: This pilot study compares propranolol and misoprostol versus misoprostol alone for labor induction in primigravids. METHODS: This is a Randomized clinical trial, single-blinded, placebo-controlled trial at Ain Shams University Maternity hospital. This study included 128 pregnant full-term primigravid women candidates for labor induction, randomized into two groups. All candidates underwent labor induction with 25 µg of vaginal misoprostol. Group I received 20 mg of oral propranolol tablets, while group II received sugary pills as a placebo. Candidates who responded successfully to induction were assessed for possible augmentation of labor by amniotomy or oxytocin infusion. The Primary outcome was induction to delivery interval, while the secondary outcomes were the duration of the latent phase, mode of delivery, and APGAR score of the neonate. RESULTS: The induction-delivery time was (11.8 ± 8.1 h. vs. 12.6 ± 8.9 h., P value = 0.027) and the duration of the latent phase of labor (7.9 ± 5.6 h. vs. 9.2 ± 6.03 h., P value = 0.017) were significantly shorter in the group of misoprostol and propranolol compared to the group of misoprostol and placebo. There was no statistically significant difference between both groups' mode of delivery, indications for cesarean section, misoprostol, and oxytocin doses, or neonatal outcome. (P value > 0.05). CONCLUSION: Propranolol, when used with misoprostol for induction of labor, results in augmentation of action of misoprostol and a significantly shorter induction-delivery interval. TRIAL REGISTRATION: We retrospectively registered this trial in clinicaltrial.gov on 01/09/2020 (NCT04533841). https://clinicaltrials.gov/ct2/show/NCT04533841.

Blockade of beta adrenergic receptors protects the blood brain barrier and reduces systemic pathology caused by HIV-1 Nef protein.

Combination antiretroviral therapy (cART) targets viral replication, but early viral protein production by astrocytes may still occur and contribute to the progression of HIV-1 associated neurocognitive disorders and secondary complications seen in patients receiving cART. In prior work with our model, astrocytic HIV-1 Nef expression exhibits neurotoxic effects leading to neurological damage, learning impairment, and immune upregulation that induces inflammation in the lungs and small intestine (SI). In this follow-up study, we focus on the sympathetic nervous system (SNS) as the important branch for peripheral inflammation resulting from astrocytic Nef expression. Male and female Sprague Dawley rats were infused with transfected astrocytes to produce Nef. The rats were divided in four groups: Nef, Nef + propranolol, propranolol and naïve. The beta-adrenergic blocker, propranolol, was administered for 3 consecutive days, starting one day prior to surgery. Two days after the surgery, the rats were sacrificed, and then blood, brain, small intestine (SI), and lung tissues were collected. Levels of IL-1ß were higher in both male and female rats, and treatment with propranolol restored IL-1ß to basal levels. We observed that Nef expression decreased staining of the tight junction protein claudin-5 in brain tissue while animals co-treated with propranolol restored claudin-5 expression. Lungs and SI of rats in the Nef group showed histological signs of damage including larger Peyer's Patches, increased tissue thickness, and infiltration of immune cells; these findings were abrogated by propranolol co-treatment. Results suggest that interruption of the beta adrenergic signaling reduces the peripheral organ inflammation caused after Nef expression in astrocytes of the brain.

Early Propranolol Is Associated With Lower Risk of Venous Thromboembolism After Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) results in an elaborate systemic cascade of secondary injury elicited in part by an intrinsic catecholamine response, which ultimately leads to changes in inflammation and coagulopathy. Attenuation of this catecholamine response with agents such as propranolol confers a survival advantage. The related impact of propranolol on venous thromboembolism (VTE) after TBI is largely unknown. STUDY DESIGN: A single institution retrospective review was conducted of all TBI patients requiring intensive care unit (ICU) admission with an injury severity scale (ISS) ≥ 25 from January 2013 to May 2015. Patients who received at least one dose of propranolol within 24 hours of admission (PROP) were compared to patients who did not receive any doses of propranolol (NPROP) during their hospitalization. RESULTS: Of the 131 patients analyzed, 31 (23.7%) patients received propranolol. The PROP cohort was more severely injured overall (ISS 29 vs 26.5, P = .02). While unadjusted VTE rates were similar (16.1% vs 19.0%, P = .72), the adjusted VTE rate was lower in the PROP cohort (AOR 0.20 (95% CI 0.04-0.97), adjusted P-value < .05). CONCLUSION: Propranolol use in TBI patients who have sustained critical injuries may mitigate the risk of VTE. The mechanism by which this outcome is achieved requires further investigation.

A MULTIFACTORIAL APPROACH FOR IMPROVING THE SURGICAL PERFORMANCE OF NOVICE VITREORETINAL SURGEONS.

PURPOSE: To quantitatively analyze and compare the novice vitreoretinal surgeons' performance after various types of external exposures. METHODS: This prospective, self-controlled, cross-sectional study included 15 vitreoretinal fellows with less than 2 years of experience. Surgical performance was assessed using the Eyesi simulator after each exposure: Day 1, placebo, 2.5, and 5 mg/kg caffeine; Day 2, placebo, 0.2, and 0.6 mg/kg propranolol; Day 3, baseline simulation, breathalyzer reading of 0.06% to 0.10% and 0.11% to 0.15% blood alcohol concentration; Day 4, baseline simulation, push-up sets with 50% and 85% repetition maximum; Day 5, 3-hour sleep deprivation. Eyesi-generated total scores were the main outcome measured (0-700, worst to best). RESULTS: Performances worsened after increasing alcohol exposure based on the total score (χ2 = 7; degrees of freedom = 2; P = 0.03). Blood alcohol concentration 0.06% to 0.10% and 0.11% to 0.15% was associated with diminished performance compared with improvements after propranolol 0.6 and 0.2 mg/kg, respectively (∆1 = -22 vs. ∆2 = +13; P = 0.02; ∆1 = -43 vs. ∆2 = +23; P = 0.01). Propranolol 0.6 mg/kg was positively associated with the total score, compared with deterioration after 2.5 mg/kg caffeine (∆1 = +7 vs. ∆2 = -13; P = 0.03). CONCLUSION: Surgical performance diminished dose dependently after alcohol. Caffeine 2.5 mg/kg was negatively associated with dexterity, and performance improved after 0.2 mg/kg propranolol. No changes occurred after short-term exercise or acute 3-hour sleep deprivation.

Infantile Hemangiomas Cleared by Combined Therapy With Pulsed Dye Laser and Propranolol.

BACKGROUND: Oral propranolol is the first-line therapy for infantile hemangioma. Combining it with pulse dye laser (PDL) (595nm-long PDL) could reduce treatment duration and sequelae incidence and severity. OBJECTIVE: To determine the effect of PDL-propranolol treatment on duration to cure and sequelae. METHODS: All consecutive patients with infantile hemangioma who were cured by PDL-propranolol treatment were identified. RESULTS: In the 27 cases, average age at treatment start was 4.3 ± 3.8 months, mean tumor diameter was 11.1 ± 14.0 cm2, and tumor-type was most common (72.4% of lesions). The patients received 9.8 ± 10.5 PDL sessions. After ensuring patients had no physical contraindications, including heart disease, oral propranolol was started at 1 mg/kg/d, increased up to 3 mg/kg/d as a maintenance dose. Mean propranolol treatment duration was 11.1 ± 4.9 months. Total treatment duration was 15.3 ± 10.8 months. CONCLUSION: Our data in the context of recent literature suggest combining propranolol with PDL may reduce propranolol duration without increasing harms.

Preoperative and perioperative intervention reduces the risk of recurrence of endometriosis in mice caused by either incomplete excision or spillage and dissemination.

RESEARCH QUESTION: Can preoperative or perioperative intervention reduce the risk of recurrence of endometriosis caused by either incomplete excision or spillage and dissemination? DESIGN: A mouse model of endometriosis recurrence caused by spillage and dissemination was first established using 24 female Balb/c mice. The spillage and dissemination model was used to test the efficacy of preoperative use of ketorolac, perioperative use of aprepitant and combined use of propranolol and andrographolide in a prospective, randomized mouse experiment involving 75 mice. The efficacy of these preoperative and perioperative interventions in a mouse recurrence model caused by incomplete excision was also tested using 72 mice. In all experiments, the baseline body weight and hotplate latency of all mice were measured and recorded before the induction of endometriosis, before the primary surgery and before sacrifice. In addition, all lesions were excised, weighed and processed for quantification and immunohistochemistry analysis of E-cadherin, α-SMA, VEGF, ADRB2 and putative markers of recurrence PR-B, p-p65, as well as Masson trichrome staining. RESULTS: All interventions substantially and significantly suppressed the outgrowth of endometriotic lesions and reduced the risk of recurrence caused by either spillage and dissemination or incomplete excision (P = 0.0007 to 0.042). These interventions also significantly attenuated the generalized hyperalgesia, inhibited the staining of α-SMA, p-p65, VEGF and ADRB2 but increased staining of E-cadherin and PR-B, resulting in reduced fibrosis. CONCLUSION: Given the excellent safety profiles of these drugs, these data strongly suggest that preoperative and perioperative intervention may potentially reduce the risk of endometriosis recurrence effectively.

Use of Propranolol in the Treatment of Chylous Effusions in Infants.

Chylothorax and chyloperitoneum are rare in infants and challenging to definitively diagnose by using current criteria extrapolated from the adult population. They can be of primary or secondary etiologies, including congenital lymphatic malformations and postoperatively, after cardiothoracic or abdominal surgery. Current first-line management consists of bowel rest, parenteral nutrition, and a modified diet of medium-chain triglycerides but can often take weeks to be effective. Off-label use of octreotide has been reported in numerous case studies for the management of chylous effusions. However, there are no definitive neonatal data available regarding dosing, safety, and efficacy; moreover, octreotide has a side effect profile that been linked to serious morbidities, such as pulmonary hypertension and necrotizing enterocolitis. Propranolol, commonly used for the treatment of infantile hemangiomas, is currently gaining interest as a novel therapy for chylous effusions. In this case series review, we describe the use of propranolol in 4 infants with presumed chylous effusions: 1 with congenital pleural effusions and 3 infants who developed postoperative chylothorax and/or chylous ascites. Clinical improvement was noted within a few days of initiating oral propranolol, and the maximum dose used in our cases was 6 mg/kg per day. In previous case reports, researchers describe the use of oral propranolol in infants with chylous effusions, with the dose used ranging from 0.5 to 4 mg/kg per day. However, this is the first case series in which researchers report its use exclusively in infants with chylothorax and chyloperitoneum. Although further research is needed to establish safety and efficacy, our experiences suggest that propranolol could be an acceptable treatment option for chylous effusions in infants.

Preliminary Flow Modeling by Hybrid Automata Alternating Continuous Reaction and Discrete Transit for Pharmacokinetics.

In traditional pharmacokinetic models, blood flow or liquid transit is often expressed as first-order kinetics. When the flow expression by first-order kinetics is used for dynamic simulation, the flow velocity illogically depends on the step size of a solver of ordinary differential equations. In this study, we propose flow modeling using hybrid automata that combine ordinary differential equations and recursive equations, and we have preliminarily applied the constructed models to several examples. The blood concentration-time profiles of p-aminohippurate and propranolol after intravenous administration were successfully reproduced by simple hybrid automata. The simulation results of one-dimensional tube flow have demonstrated that the fluid velocity in the hybrid automata was independent of the step size of the ordinary differential equation solver. A body fluid model coordinated various flows in a human body with scheduled daily activities and could be used as a drug container to describe formulation-dependent disposition of 5-aminosalicylic acid and enterohepatic circulation of a virtual drug. These findings suggested that flow modeling using hybrid automata could avoid the logical inconsistency in the traditional pharmacokinetic modeling and that the hybrid automata have high versatility and a wide range of applicability to pharmacokinetic analysis. Because our method can define various intervals for multiple recursive equations, the resolution of a specific part of a model can be adjusted relatively freely while the whole body is being roughly modeled, which would be beneficial to refine a coarse model into a fine model in future. SIGNIFICANCE STATEMENT: There is a logical inconsistency in flow expression by first-order kinetics in ordinary differential equations used in traditional pharmacokinetic modeling. It is difficult to model a whole human body using flow models in partial differential equations because of the excessive calculation costs. Our simulations on tube flow and body fluids have demonstrated that the flow modeling using hybrid automata could avoid the problems. The preliminary applications of hybrid automata to several examples highlighted its high versatility in pharmacokinetic analysis.

Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial.

Importance: Propranolol has become the first-line therapy for problematic infantile hemangiomas (IHs) that require systemic therapy. However, different adverse events have been reported during propranolol treatment. The positive efficacy and safety of atenolol raise the question of whether it could be used as a promising therapy for IH. Objective: To compare the efficacy and safety of propranolol vs atenolol in infants (between age 5 and 20 weeks) with problematic IHs who required systemic therapy. Design, Setting, and Participants: This was a prospective, multicenter, randomized, controlled, open-label clinical trial conducted in collaboration among 6 separate investigation sites in China from February 1, 2015, to December 31, 2018. A total of 377 patients met the criteria for inclusion and were randomized to the propranolol (190 [50.4%]) and atenolol (187 [49.6%]) groups. Data were analyzed in June 2020. Interventions: Participants were randomized to receive either propranolol or atenolol for at least 6 months. They completed efficacy assessments at 2 years after the initial treatment. Main Outcomes and Measures: The primary outcome was any response or nonresponse at 6 months. The key secondary outcome was changes in the hemangioma activity score. Results: Of 377 participants, 287 (76.1%) were female, and the mean (SD) age was 10.2 (4.0) weeks in the propranolol group and 9.8 (4.1) weeks in the atenolol group. After 6 months of treatment, in the propranolol and atenolol groups, the overall response rates were 93.7% and 92.5%, respectively (difference, 1.2%; 95% CI, -4.1% to 6.6%). At 1 and 4 weeks after treatment, and thereafter, the hemangioma activity score in the atenolol group aligned with the propranolol group (odds ratio, 1.034; 95% CI, 0.886-1.206). No differences between the propranolol group and atenolol group were observed in successful initial responses, quality of life scores, complete ulceration healing times, or the rebound rate. Both groups presented a similar percentage of complete/nearly complete responses at 2 years (82.1% vs 79.7%; difference, 2.4%; 95% CI, -5.9% to 10.7%). Adverse events were more common in the propranolol group (70.0% vs 44.4%; difference, 25.6%; 95% CI, 15.7%-34.8%), but the frequency of severe adverse events did not differ meaningfully between the groups. Conclusions and Relevance: In this randomized clinical trial, when compared with propranolol, atenolol had similar efficacy and fewer adverse events in the treatment of infants with problematic IHs. The results suggest that oral atenolol can be used as an alternative treatment option for patients with IH who require systemic therapy. Trial Registration: ClinicalTrial.gov Identifier: NCT02342275.

Chronic restraint stress promotes the mobilization and recruitment of myeloid-derived suppressor cells through ß-adrenergic-activated CXCL5-CXCR2-Erk signaling cascades.

Myeloid-derived suppressor cells (MDSCs) play an important role in tumor immune escape. Recent studies have shown that MDSCs contribute to tumor progression under psychological stress, but the underlying mechanism of MDSCs mobilization and recruitment remains largely unknown. In the present study, a chronic restraint stress paradigm was applied to the H22 hepatocellular carcinoma (HCC) bearing mice to mimic the psychological stress. We observed that chronic restraint stress significantly promoted HCC growth, as well as the mobilization of MDSCs to spleen and tumor sites from bone marrow. Meanwhile, chronic restraint stress enhanced the expression of C-X-C motif chemokine receptor 2 (CXCR2) and pErk1/2 in bone marrow MDSCs, together with elevated chemokine (C-X-C motif) ligand 5 (CXCL5) expression in tumor tissues. In vitro, the treatments of MDSCs with epinephrine (EPI) and norepinephrine (NE) but not corticosterone (CORT)-treated H22 conditioned medium obviously inhibited T-cell proliferation, as well as enhanced CXCR2 expression and extracellular signal-regulated kinase (Erk) phosphorylation. In vivo, ß-adrenergic blockade with propranolol almost completely reversed the accelerated tumor growth induced by chronic restraint stress and inactivated CXCL5-CXCR2-Erk signaling pathway. Our findings support the crucial role of ß-adrenergic signaling cascade in the mobilization and recruitment of MDSCs under chronic restraint stress.

Ultrasound and MRI findings as predictors of propranolol therapy response in patients with infantile hemangioma.

OBJECTIVES: To evaluate the prognostic value of ultrasound and MRI findings in patients with infantile hemangioma undergoing propranolol therapy. METHODS: This study was based on retrospective interpretation of prospectively acquired data. Thirty-eight consecutive patients (28 females and 10 males; mean age ± standard deviation, 3.2 ± 2.2 months) who underwent propranolol treatment for infantile hemangioma were included. Pre-treatment ultrasound images were assessed in terms of echogenicity, lesion height and vascularity. Presence of prominent intratumoral fat, non-fat septa, and enhancement pattern on MRI were retrospectively evaluated. Mann-Whitney test, chi-square, and Fisher's exact tests were used to compare imaging parameters between patients with treatment success and failure. RESULTS: All patients underwent ultrasound and 15 patients underwent MRI. A total of 24 patients showed successful treatment. Between patients with treatment success and failure, there were significant differences in increased vascularity on pre-treatment ultrasound (19/24 vs. 6/14, p = 0.025), decreased vascularity on post-treatment ultrasound (21/24 vs. 5/14, p = 0.001), and prominent intratumoral fat on MRI (1/8 vs. 5/7 p = 0.033). There were no significant differences in echogenicity, lesion height on ultrasound, non-fat septa and MR enhancement pattern. CONCLUSIONS: Increased vascularity on pre-treatment ultrasound was significantly associated with successful treatment for propranolol therapy in patients with infantile hemangioma, whereas prominent fat component on MRI was significantly associated with treatment failure.

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients.

AIM: The study was aimed to understand the underlying causes for the differences in propranolol pharmacokinetics (PK) between healthy and cirrhosis populations by using a systematic whole-body physiologically based pharmacokinetic (PBPK) model-building approach for suggesting model informed propranolol dosing in liver cirrhosis patients with different stages of disease severity. METHODS: A whole-body PBPK model was developed by using population simulator PK-Sim® by using reported physicochemical and clinical data for propranolol in healthy and liver cirrhosis populations. The model evaluation was done by visual verification and comparison of PK parameters using their observed/predicted ratios (Robs/pred). RESULTS: The developed model has effectively described the disposition of propranolol after intravenous and oral application in healthy and liver cirrhosis populations. All the model predictions were comparable to the observed clinical data and the Robs/pred for all the PK parameters were within a 2-fold range. A significant increase in plasma concentration of propranolol and decrease in drug clearance was observed in progressive stages of liver cirrhosis. The developed model after evaluation with the reported clinical PK data was used for suggesting model informed propranolol dosing in different stages of liver cirrhosis based on systemic unbound drug concentration. CONCLUSION: The developed PBPK model has successfully described propranolol PK in healthy and cirrhosis populations after IV and oral administration. The evaluated PBPK propranolol-cirrhosis model can have many implications in predicting propranolol dosing in liver cirrhosis patients with different stages of disease severity.

Propranolol Participates in the Treatment of Infantile Hemangioma by Inhibiting HUVECs Proliferation, Migration, Invasion, and Tube Formation.

OBJECTIVE: Infantile hemangiomas (IHs) are the most common benign tumors in infancy. The purpose of this study was to study the effects of propranolol on the function of human umbilical vein endothelial cells (HUVECs), in order to preliminarily elucidate the mechanism of propranolol in the treatment of IHs. METHODS: HUVECs were treated with different concentrations of propranolol (30 µM, 60 µM, 90 µM, and 120 µM) with or without VEGF. Their proliferation, migration, invasion, adhesion, and tube formation ability were tested by using CCK-8, wound healing assay, transwell, cell adhesion assay, and tube formation assay. The expressions of HUVECs angiogenesis signaling molecules pERK/ERK, pAKT/AKT, p-mTOR/mTOR, and pFAK/FAK were detected by Western blot. RESULTS: Compared with the control group, propranolol could significantly inhibit the proliferation, migration, invasion, adhesion, and tube formation of HUVECs. Further studies showed that it could not only inhibit the migration, invasion, and tube formation ability of HUVECs after VEGF induction but also inhibit the phosphorylated protein expressions of angiogenesis-related signaling molecules like AKT, mTOR, ERK, and FAK in HUVECs, with a concentration-dependent inhibitory effect. CONCLUSION: Propranolol can inhibit the proliferation, migration, invasion, adhesion, and tube formation of hemangioma endothelial cells; block VEGF-mediated angiogenesis signaling pathway; suppress the expressions of downstream angiogenesis-related signaling molecules; and ultimately achieve the effect of treatment of IHs.

Long-term pharmacological torpor of rats with feedback-controlled drug administration.

The maintenance of pharmacological torpor and hypothermia (body temperature 28 °C - 33 °C) in rats for a week is presented. For this purpose, our laboratory has developed a device (BioFeedback-2) for the feed-back controlled multiple injections of small doses of a pharmacological composition that we created earlier. On the 7th day, the rat spontaneously come out of the pharmacological torpor, the body temperature returned to normal, and on the 8th day, the animal could consume food and water. The proposed approach for maintaining multi-day pharmacological torpor can be applied in medicine, as well as for protecting astronauts during long missions in space.

Anti-CGRP monoclonal antibodies for migraine prevention: A systematic review and likelihood to help or harm analysis.

INTRODUCTION AND OBJECTIVE: Monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) have shown promising efficacy in randomised clinical trials for the prevention of episodic and chronic migraine, but no head-to-head comparisons with established treatments are available. We aimed to examine absolute differences in benefit-risk ratios between anti-CGRP mAbs, topiramate and propranolol for the prevention of episodic migraine and between anti-CGRP mAbs, topiramate and onabotulinumtoxinA for the prevention of chronic migraine using a likelihood to help versus harm analysis. METHODS: The number of patients needed to be treated for a patient to achieve ≥ 50% reduction in migraine days (NNTB50%) was used as an effect size metric of efficacy. The number of patients needed to be treated for a patient to experience an adverse event that led to treatment discontinuation (NNTHD-AE) was used as a measure of risk. Likelihood to help versus harm values - which are the ratios of NNTH:NNTB - were calculated using data from phase 3 randomised clinical trials. RESULTS: All agents tested were more likely to be beneficial than harmful (likelihood to help versus harm > 1) with the exception of topiramate at 200 mg per day for the prevention of episodic migraine. Anti-CGRP mAbs in all tested doses had higher LHH values than propranolol or topiramate for episodic migraine and onabotulinumtoxinA or topiramate for chronic migraine prevention. Fremanezumab had the highest LHH ratio in episodic migraine and galcanezumab in chronic migraine. CONCLUSION: This analysis showed that anti-CGRP mAbs exhibit a more favourable benefit-risk ratio than established treatments for episodic and chronic migraine. Head-to-head studies are needed to confirm these results.

Ocular Versus Oral Propranolol for Prevention and/or Treatment of Oxygen-Induced Retinopathy in a Rat Model.

Purpose: Propranolol, a nonselective B1/B2 adrenoceptor antagonist, promotes the regression of infantile hemangiomas likely through suppression of vascular endothelial growth factor (VEGF), which prompted its use for the prevention of retinopathy of prematurity. We tested the hypothesis that topical ocular propranolol is safe and effective for reducing the severity of oxygen-induced retinopathy (OIR) in the neonatal rat intermittent hypoxia (IH) model. Methods: At birth (P0), rat pups were randomly assigned to room air or neonatal intermittent hypoxia (IH) consisting of 50% O2 with brief episodes of hypoxia (12% O2) from P0 to P14, during which they received a single daily dose of oral propranolol (1 mg/kg/day in 50 µL in sterile normal saline) or topical ocular propranolol (0.2% in 10 µL in normal saline) from P5 to P14. Placebo-controlled littermates received 50 µL oral or 10 µL topical ocular sterile normal saline. Retinal vascular and astrocyte integrity; retinal histopathology and morphometry; and angiogenesis biomarkers were determined. Results: Topical ocular propranolol improved retinal vascular damage and preserved the astrocytic template, but did not completely prevent OIR. The beneficial effects of propranolol were associated with reduced ocular VEGF and increased endogenous soluble inhibitor, sVEGFR-1, when administered topically. Conclusions: Propranolol failed to completely prevent severe OIR, however, it prevented astrocyte degeneration resulting from neonatal IH-induced damage. We conclude that the mechanisms of propranolol's beneficial effects in neonatal IH may involve in part, astrocyte preservation.