RESUMEN
OBJECTIVE: The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. METHODS: Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose-response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). RESULTS: Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2-3; S23) of ROP progression compared with its administration at earlier stages (stages 0-1; S01). OR values for oral propranolol 1.5 and 2 mg/kg/day given at S23 were 0.13 (95% CrI 0.04-0.37) and 0.16 (95% CrI 0.04-0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02-2.96) and 0.78 (95% CrI 0.14-4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09-1.00) versus an S01 OR of 0.64 (95% CrI 0.21-2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5-2 mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose-response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5 mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02-0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05-0.93) and laser (OR 0.16; 95% CrI 0.02-1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5-1.0 mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5 mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5 mg/kg/day and the highest risk difference for oral propranolol 2.0 mg/kg/day (0.06; 95% CI -0.01 to 0.13). CONCLUSION: A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies.
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Metaanálisis en Red , Propranolol , Retinopatía de la Prematuridad , Propranolol/administración & dosificación , Propranolol/uso terapéutico , Propranolol/efectos adversos , Retinopatía de la Prematuridad/tratamiento farmacológico , Humanos , Administración Oral , Recién Nacido , Relación Dosis-Respuesta a Droga , Administración Oftálmica , Teorema de Bayes , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVES: To perform a comparative analysis of the extended APPROPRIATE trial of measures of reactive nitrogen species and antioxidant capacity in patients having resistant hypertension with controlled hypertension and healthy controls. RESULTS: Mean serum NO2- and NOx levels were significantly lower and mean AOC was significantly higher in patients with controlled hypertension (n = 38) and healthy controls (n = 38) compared to resistant hypertension (RHTN) patients (n = 40) at the pre-intervention stage (p < 0.001). The serum NO2-, NOx and AOC levels of both controlled hypertension and healthy controls were comparable to those of the RHTN patients following treatment with propranolol (n = 18). Considering all samples (n = 114) we noted that there were significant weak and moderate positive correlations between NO2- levels with systolic blood pressure (SBP) and diastolic blood pressure (DBP) (r = 0.396, p < 0.001 and r = 0.292, p = 0.004) as well as total NOx levels with SBP and DBP (r = 0.636 and r = 0.480 respectively, p < 0.001). Conversely, there was a significant negative correlation between AOC levels with SBP and DBP (r= -0.846 and r = -0.626 respectively, p < 0.001).
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Antihipertensivos , Antioxidantes , Hipertensión , Propranolol , Especies de Nitrógeno Reactivo , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/sangre , Hipertensión/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Antioxidantes/metabolismo , Propranolol/uso terapéutico , Propranolol/farmacología , Antihipertensivos/uso terapéutico , Estudios de Casos y Controles , Especies de Nitrógeno Reactivo/sangre , Especies de Nitrógeno Reactivo/metabolismo , Presión Sanguínea/efectos de los fármacos , Adulto , Estudios de Seguimiento , AncianoRESUMEN
Background: The positive predictive value (PPV) of the International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9-CM) code for "essential and other specified forms of tremor" in identifying essential tremor (ET) cases was found to be less than 50%. The ability of the ICD-10-CM G25.0 code for "essential tremor" to identify ET has not been determined. The study objective was to determine the PPV of the G25.0 code. Methods: Patients in a tertiary health system with a primary care encounter associated with ICD-10-CM code G25.0 in 2022 underwent medical record review to determine if the consensus criteria from the International Parkinson and Movement Disorder Society for an ET diagnosis were met. Results: 442 patients were included. The PPV of G25.0 in identifying probable ET cases was 74.7% (95% confidence interval (CI) 70.4-78.5%). Among patients prescribed propranolol, the PPV improved to 87.8% (95% CI 78.0-93.6%). Discussion: Compared to the ICD-9-CM code 333.1, G25.0 is superior for identifying ET cases. A potential limitation of this study is that the consensus criteria applied relies on nonspecific physical exam findings which may lead to an overestimation of the PPV of G25.0. Highlights: The ICD-10-CM diagnosis code for essential tremor has not been previously validated. The objective of this study was to determine the PPV of the G25.0 code. The PPV in identifying essential tremor cases was 74.7%. The PPV improved among patients prescribed propranolol.
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Temblor Esencial , Clasificación Internacional de Enfermedades , Humanos , Temblor Esencial/diagnóstico , Temblor Esencial/clasificación , Clasificación Internacional de Enfermedades/normas , Femenino , Masculino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Propranolol/uso terapéuticoRESUMEN
OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing propranolol for migraine prophylaxis. METHODS: We report methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared propranolol with placebo for migraine prophylaxis in adults. The outcomes of interest were informed by the Core outcome set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in monthly migraine days, the reduction of monthly migraine days, and the number of adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB (risk of bias) 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded twenty trials (n = 1291 patients) eligible for data synthesis and analysis. The analysis revealed a moderate certainty evidence that propranolol leads to a reduction in monthly migraine days versus placebo (-1.27; 95% CI: -2.25 to -0.3). We found moderate certainty evidence that propranolol increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo with a relative risk of 1.65 (95% CI 1.41 to 1.93); absolute risk difference: 179 more per 1,000 (95% CI 113 to 256). We found high certainty evidence that propranolol increases the proportion of patients who discontinue due to adverse events compared to placebo with a risk difference of 0.02 (95% CI 0.00 to 0.03); absolute risk difference: 20 more per 1,000 (95% CI 0 to 30). CONCLUSIONS: The present meta-analysis shows that propranolol has a prophylactic role in migraine, with an overall acceptable tolerability profile. Combining these results with its long-standing use and its global availability at a low cost confirms its role as a first line agent in the prophylaxis of migraine.
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Antagonistas Adrenérgicos beta , Trastornos Migrañosos , Propranolol , Propranolol/uso terapéutico , Propranolol/administración & dosificación , Humanos , Trastornos Migrañosos/prevención & control , Trastornos Migrañosos/tratamiento farmacológico , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/uso terapéutico , Administración Oral , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Labilization-reconsolidation, which relies on retrieval, has been considered an opportunity to attenuate the negative aspects of traumatic memories. A therapeutic strategy based on reconsolidation blockade is deemed more effective than current therapies relying on memory extinction. Nevertheless, extremely stressful memories frequently prove resistant to this process. Here, after inducing robust fear memory in mice through strong fear conditioning, we examined the possibility of rendering it susceptible to pharmacological modulation based on the degree of generalized fear (GF). To achieve this, we established an ordered gradient of GF, determined by the perceptual similarity between the associated context (CA) and non-associated contexts (CB, CC, CD, and CE) to the aversive event. We observed that as the exposure context became less similar to CA, the defensive pattern shifted from passive to active behaviors in both male and female mice. Subsequently, in conditioned animals, we administered propranolol after exposure to the different contexts (CA, CB, CC, CD or CE). In males, propranolol treatment resulted in reduced freezing time and enhanced risk assessment behaviors when administered following exposure to CA or CB, but not after CC, CD, or CE, compared to the control group. In females, a similar change in behavioral pattern was observed with propranolol administered after exposure to CC, but not after the other contexts. These results highlight the possibility of indirectly manipulating a robust contextual fear memory by controlling the level of generalization during recall. Additionally, it was demonstrated that the effect of propranolol on reconsolidation would not lead to a reduction in fear memory per se, but rather to its reorganization resulting in greater behavioral flexibility (from passive to active behaviors). Finally, from a clinical viewpoint, this would be of considerable relevance since following this strategy could make the treatment of psychiatric disorders associated with traumatic memory formation more effective and less stressful.
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Condicionamiento Clásico , Miedo , Propranolol , Miedo/efectos de los fármacos , Miedo/fisiología , Animales , Masculino , Propranolol/farmacología , Femenino , Ratones , Condicionamiento Clásico/efectos de los fármacos , Consolidación de la Memoria/efectos de los fármacos , Consolidación de la Memoria/fisiología , Ratones Endogámicos C57BL , Memoria/efectos de los fármacos , Memoria/fisiología , Generalización Psicológica/efectos de los fármacos , Generalización Psicológica/fisiología , Extinción Psicológica/efectos de los fármacosRESUMEN
Left ventricular assist devices (LVADs) are widely used as end-stage therapy in patients with advanced heart failure, whereas implantation increases the risks of development of sustained ventricular tachycardia at the later postimplantation stage. Therefore, this study aimed to evaluate the clinical efficacy of orally administered amiodarone and propranolol in 3 patients with ventricular tachycardia (VT) after LVAD implantation who were resistant to initial anti-antiarrhythmic drugs. This retrospective cohort study consisted of the initial evaluation of the clinical data of 14 adult patients who underwent implantation of LVAD between January 2019 and March 2021. A total of 3 patients with resistant VT were finally included. In all cases, the patients were initially administered amiodarone in the different doses intravenously to stabilize the critical condition, whereas its oral form along with that of propranolol was used as maintenance therapy in the first 2 cases. In the third case, amiodarone was withdrawn because of the risk of development of hyperthyroidism, while oral propranolol was used in the treatment. The assessment in the 16-month follow-up period after discharge did not show presence of non-sustained and sustained VT in all 3 cases. In the ventricular arrhythmia-free group, the total mortality rate within the follow-up period was 11.1â ±â 7.78 months in the 3 patients. We suggest that maintenance oral therapy of propranolol and amiodarone can significantly decrease the risks of complications in patients with VT after implantation of ventricular assist device in the long term.
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Amiodarona , Antiarrítmicos , Propranolol , Taquicardia Ventricular , Humanos , Amiodarona/administración & dosificación , Amiodarona/efectos adversos , Propranolol/administración & dosificación , Propranolol/uso terapéutico , Masculino , Antiarrítmicos/administración & dosificación , Estudios Retrospectivos , Administración Oral , Persona de Mediana Edad , Taquicardia Ventricular/tratamiento farmacológico , Femenino , Adulto , Insuficiencia Cardíaca/tratamiento farmacológico , AncianoAsunto(s)
Neoplasias Cardíacas , Hemangioma , Propranolol , Rabdomioma , Esclerosis Tuberosa , Humanos , Propranolol/administración & dosificación , Propranolol/uso terapéutico , Rabdomioma/complicaciones , Rabdomioma/tratamiento farmacológico , Rabdomioma/diagnóstico , Esclerosis Tuberosa/complicaciones , Neoplasias Cardíacas/complicaciones , Neoplasias Cardíacas/tratamiento farmacológico , Neoplasias Cardíacas/diagnóstico , Lactante , Hemangioma/tratamiento farmacológico , Hemangioma/complicaciones , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Femenino , MasculinoRESUMEN
Ultradian rhythms of metabolism, body temperature and activity are attenuated or disappear completely during torpor in Djungarian hamsters, for all three ultradian periodicities (URsmall, URmedium and URlarge). URsmall and URmedium disappear during entrance into torpor, whereas URlarge disappear later or continue with a low amplitude. This suggests a tight functional link between torpor and the expression of ultradian rhythms, i.e. torpor is achieved by suppression of metabolic rate as well as silencing of ultradian rhythms. Spontaneous torpor is often initiated after an ultradian burst of activity and metabolic rate, beginning with a period of motionless rest and accompanied by a decrease of metabolic rate and body temperature. To extend previous findings on the potential role of the adrenergic system on torpor induction we analysed the influence of the ß3-adrenergic agonist Mirabegron on torpor in Djungarian hamsters, as compared to the influence of the ß-adrenergic antagonist Propranolol. Hamsters were implanted with 10 day release pellets of Mirabegron (0.06 mg day-1) or Propranolol (0.3 mg day-1). Mirabegron transiently supressed and accelerated ultradian rhythms but had no effect on torpor behaviour. Propranolol did not affect torpor behaviour nor the expression of ultradian rhythms with the dosage applied during this study.
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Phodopus , Letargo , Ritmo Ultradiano , Animales , Letargo/fisiología , Phodopus/fisiología , Cricetinae , Masculino , Ritmo Ultradiano/fisiología , Propranolol/farmacología , Antagonistas Adrenérgicos beta/farmacología , Temperatura Corporal , Actividad Motora , Metabolismo BasalRESUMEN
BACKGROUND Visual hallucinations occur in a variety of clinical settings and may be extremely troubling to individuals experiencing them. We report a case of delayed-onset visual hallucinations 20 years after initiation of medical therapy to highlight the importance of considering iatrogenic causes when managing such patients. CASE REPORT An 88-year-old woman presented with recurring hypnopompic formed visual hallucinations for the past 20 years. These hallucinations began 20 years after she was started on propranolol to treat her systemic hypertension 40 years earlier. Her hallucinations began with plants and insects. They later progressed to vivid, detailed human figures of different races, ages, genders, and religious personnel such as monks, nuns, and priests. The hallucinations occurred almost daily and upon awakening from sleep. Each episode of visual hallucinations lasted for 10 to 20 seconds, occurring when she awoke after dozing off, multiple times each day. The patient became mentally distressed by her visual hallucinations and began to attribute them to supernatural causes. After substituting her propranolol with atenolol, the patient's hallucinations decreased dramatically and became rare and non-frightening. The dramatic improvement suggested a drug-induced etiology. CONCLUSIONS Our case illustrates the importance of considering iatrogenic causes in the diagnosis of visual hallucinations and having a high index of suspicion, even if the onset of symptoms is delayed for many years after initiation of therapy. This iatrogenic condition can easily be rectified to drastically improve the quality of life in affected patients.
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Alucinaciones , Hipertensión , Propranolol , Humanos , Femenino , Alucinaciones/inducido químicamente , Propranolol/uso terapéutico , Propranolol/efectos adversos , Hipertensión/tratamiento farmacológico , Hipertensión/inducido químicamente , Anciano de 80 o más Años , Antihipertensivos/efectos adversosAsunto(s)
Coriorretinopatía Serosa Central , Inyecciones Intravítreas , Propranolol , Rifampin , Factor A de Crecimiento Endotelial Vascular , Humanos , Administración Oral , Coriorretinopatía Serosa Central/tratamiento farmacológico , Coriorretinopatía Serosa Central/diagnóstico , Rifampin/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Propranolol/administración & dosificación , Inhibidores de la Angiogénesis/administración & dosificación , Antagonistas Adrenérgicos beta/administración & dosificaciónRESUMEN
Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to posttransplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (ß-adrenergic blockage), or placebo infusion. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate was lower with propranolol versus placebo (P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine versus placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase (P < 0.05 for both). These results indicate that neither physiological α- nor ß-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation.NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or ß-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor ß-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.
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Antagonistas Adrenérgicos beta , Estudios Cruzados , Diabetes Mellitus Tipo 1 , Técnica de Clampeo de la Glucosa , Hipoglucemia , Trasplante de Islotes Pancreáticos , Fentolamina , Propranolol , Humanos , Femenino , Masculino , Diabetes Mellitus Tipo 1/metabolismo , Persona de Mediana Edad , Adulto , Trasplante de Islotes Pancreáticos/efectos adversos , Hipoglucemia/inducido químicamente , Hipoglucemia/metabolismo , Método Doble Ciego , Antagonistas Adrenérgicos beta/farmacología , Fentolamina/farmacología , Propranolol/farmacología , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Insulina/metabolismo , Glucagón/metabolismo , Glucagón/sangre , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismoRESUMEN
ABSTRACT: Hypercatecholaminergic conditions are known to cause heart failure and cardiac fibrosis when severe. Although previous investigations have studied the effects of beta-blockade in experimental models of catecholaminergic states, the detailed benefits of beta-blockade in more realistic models of hyper-adrenergic states were less clear. In this study, we examined acute cardiac changes in rats with hyperacute catecholamine-induced heart failure with and without propranolol treatment. Male Sprague-Dawley rats (n = 12) underwent a 6-hour infusion of epinephrine and norepinephrine alone, with an additional propranolol bolus (1 mg/kg) at hour 1 (n = 6). Cardiac tissues were examined after 6 hours. Cardiac immunohistochemistry revealed significantly decreased expression of phosphorylated p-38 (left ventricle, P = 0.021; right ventricle, P = 0.021), with upregulation of reactive oxidative species and other profibrosis proteins, after catecholamine infusion alone. After 1 propranolol 1 mg/kg bolus, the levels of phosphorylated-p38 returned to levels comparable with sham (left ventricle, P = 0.021; right ventricle, P = 0.043), with additional findings including downregulation of the apoptotic pathway and profibrotic proteins. We conclude that catecholamine-induced heart failure exerts damage through the p-38 mitogen-activated protein kinase pathway and demonstrates profibrotic changes mediated by matrix metalloproteinase 9, alpha-smooth muscle actin, and fibroblast growth factor 23. Changes in these pathways attenuated acute catecholamine-induced heart failure after propranolol bolus 1 mg/kg. We conclude that propranolol bolus at 1 mg/kg is able to mediate the effects of catecholamine excess through the p-38 mitogen-activated protein kinase pathway, profibrosis, and extrinsic apoptosis pathway.
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Antagonistas Adrenérgicos beta , Fibrosis , Insuficiencia Cardíaca , Norepinefrina , Propranolol , Ratas Sprague-Dawley , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Masculino , Propranolol/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Ratas , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/inducido químicamente , Norepinefrina/metabolismo , Epinefrina/toxicidad , Epinefrina/administración & dosificación , Fosforilación , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Miocardio/patología , Miocardio/metabolismo , Miocardio/enzimología , Catecolaminas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Chronic stress negatively affects the immune system and promotes tumor progression. Tumor-associated macrophage (TAM) is an important component of the tumor immune microenvironment. However, the influence of chronic stress on M1-M2 polarization of TAM is unclear. We used flow cytometry to measure the M1-M2 polarization of TAM in chronic stress hepatocellular carcinoma (HCC) bearing mice. We also measured the level of norepinephrine and blocked ß-adrenergic signaling to explore the role of ß-adrenergic receptor in the effect of chronic stress on M1-M2 polarization of TAM. We found that chronic stress disrupts the M1-M2 polarization in tumor tissues, increased the level of CD11b+Ly6C+CCR2+ monocyte and interleukin-1beta in blood and promoted the growth of HCC. Furthermore, chronic stress upregulated the level of CCL2 in tumor tissues. Finally, we found chronic stress increased norepinephrine level in serum and propranolol, a blocker of ß-adrenergic signaling, inhibited HCC growth, recovered the M1-M2 polarization balance of TAM in tumor tissues, blocked the increase of CD11b+Ly6C+CCR2+ monocytes in blood, and blocked the increase of CCL2 in tumor tissues induced by chronic stress. Our study indicated that chronic stress disrupts the M1-M2 polarization balance of TAMs through ß-adrenergic signaling, thereby promoting the growth of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Norepinefrina , Receptores Adrenérgicos beta , Transducción de Señal , Animales , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Ratones , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Norepinefrina/metabolismo , Norepinefrina/sangre , Masculino , Receptores Adrenérgicos beta/metabolismo , Propranolol/farmacología , Ratones Endogámicos C57BL , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Línea Celular Tumoral , Interleucina-1beta/metabolismo , Quimiocina CCL2/metabolismo , Microambiente Tumoral/inmunología , Humanos , Antagonistas Adrenérgicos beta/farmacología , Macrófagos/inmunología , Macrófagos/metabolismo , Estrés Fisiológico , Monocitos/inmunología , Monocitos/metabolismoRESUMEN
Urinary bladder dysfunction might be related to disturbances at different levels of the micturition reflex arc. The current study aimed to further develop and evaluate a split bladder model for detecting and analysing relaxatory signalling in the rat urinary bladder. The model allows for discrimination between effects at the efferent and the afferent side of the innervation. In in vivo experiments, the stimulation at a low frequency (1 Hz) of the ipsilateral pelvic nerve tended to evoke relaxation of the split bladder half (contralateral side; -1.0 ± 0.4 mN; n = 5), in contrast to high frequency-evoked contractions. In preparations in which the contralateral pelvic nerve was cut the relaxation occurred at a wider range of frequencies (0.5-2 Hz). In separate experiments, responses to 1 and 2 Hz were studied before and after intravenous injections of propranolol (1 mg/kg IV). The presence of propranolol significantly shifted the relaxations into contractions. Also, electrical stimulation of the ipsilateral pudendal nerve evoked relaxations of similar magnitude as for the pelvic stimulations, which were also affected by propranolol. In control in vitro experiments, substances with ß-adrenoceptor agonism, in contrast to a selective α-agonist, evoked relaxations. The current study shows that the split bladder model can be used for in vivo studies of relaxations. In the model, reflex-evoked sympathetic responses caused relaxations at low intensity stimulation. The involvement of ß-adrenoceptors is supported by the sensitivity to propranolol and by the in vitro observations.
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Estimulación Eléctrica , Propranolol , Nervio Pudendo , Vejiga Urinaria , Animales , Vejiga Urinaria/inervación , Vejiga Urinaria/fisiología , Vejiga Urinaria/efectos de los fármacos , Nervio Pudendo/fisiología , Nervio Pudendo/efectos de los fármacos , Ratas , Propranolol/farmacología , Femenino , Relajación Muscular/efectos de los fármacos , Relajación Muscular/fisiología , Ratas Wistar , Pelvis/inervación , Antagonistas Adrenérgicos beta/farmacología , Masculino , Ratas Sprague-DawleyRESUMEN
Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2â mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10â mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72â h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.
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Antagonistas Adrenérgicos beta , Condicionamiento Clásico , Modelos Animales de Enfermedad , Maleato de Dizocilpina , Propranolol , Propranolol/farmacología , Animales , Maleato de Dizocilpina/farmacología , Masculino , Ratones , Antagonistas Adrenérgicos beta/farmacología , Condicionamiento Clásico/efectos de los fármacos , Náusea/tratamiento farmacológico , Náusea/inducido químicamente , Reacción de Prevención/efectos de los fármacos , Cloruro de Litio/farmacología , Vómito Precoz , Antagonistas de Aminoácidos Excitadores/farmacología , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood. METHODS: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or ß-adrenergic receptor (ß-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-ß (TGF-ß) receptor Type I kinase (Ly2157299) in vitro. TGF-ß1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested. RESULTS: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-ß1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion. CONCLUSIONS: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-ß1 signaling during this process. In addition, ß-AR/TGF-ß1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.
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Bevacizumab , Neoplasias Colorrectales , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neovascularización Patológica , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Neovascularización Patológica/metabolismo , Ratones , Factor de Crecimiento Transformador beta1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Propranolol/farmacología , Línea Celular Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , Masculino , Movimiento Celular , Norepinefrina/farmacología , Norepinefrina/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Angiogénesis , Pirazoles , QuinolinasRESUMEN
Kaposiform hemangioendothelioma(KHE) without Kasabach-Merritt phenomenon is a rare tumor primarily observed in pediatric patients; however, its documentation in the literature remains limited. We reported about a 1-year-old boy diagnosed with superficial KHE who received oral propranolol in combination with topical sirolimus and reviewed relevant reports and treatment of superficial KHE.
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Hemangioendotelioma , Propranolol , Sarcoma de Kaposi , Sirolimus , Humanos , Lactante , Masculino , Administración Oral , Biopsia , Hemangioendotelioma/tratamiento farmacológico , Hemangioendotelioma/diagnóstico , Propranolol/administración & dosificación , Propranolol/uso terapéutico , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/patología , Sirolimus/administración & dosificación , Resultado del TratamientoRESUMEN
CASE: We report a case of an intramuscular thigh hemangioma in a 19-year-old woman with a several year history of atraumatic thigh pain. Radiographs obtained by her primary care physician demonstrated periosteal bone reaction, prompting referral to Orthopaedic Oncology department. The patient had successful symptomatic management with propranolol. CONCLUSION: The case highlights the diagnosis and potential treatments. In a stepwise approach to care for symptomatic benign vascular lesions, propranolol has been a proven therapeutic option and may be a useful first-line therapy for symptomatic hemangiomas.
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Hemangioma , Muslo , Humanos , Femenino , Muslo/diagnóstico por imagen , Hemangioma/diagnóstico por imagen , Adulto Joven , Neoplasias de los Músculos/diagnóstico por imagen , Propranolol/uso terapéutico , Radiografía , Antagonistas Adrenérgicos beta/uso terapéuticoRESUMEN
This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell monolayer through dose sensitivity studies. Metoprolol and propranolol were selected as Biopharmaceutics Classification System (BCS) Class I model drugs, and atenolol as a Class III model drug. The IDAS2 is comprised of a dissolution vessel (500 mL) and two permeation chambers (2 × 8.0 mL) mounted with Caco-2 or MDCK cell monolayer. One or two immediate-release tablet(s) of the model drug were added to the dissolution vessel, and the time profiles of dissolution and permeation were observed. Greater than 85% of metoprolol and propranolol (tested at two dosing concentrations) were dissolved by 15 min, and all drugs were fully dissolved by 30 min. All three drugs were more permeable across Caco-2 cells than MDCK cells with a linear increase in permeation across both cells at both dose concentrations. Thus, the dose sensitivity of the IDAS2 was demonstrated using both cell barriers. These results indicate a successful qualification of IDAS2 for the development/optimization of oral formulations and that MDCK cells can be utilized as a surrogate for Caco-2 cells.
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Atenolol , Metoprolol , Propranolol , Solubilidad , Perros , Células CACO-2 , Humanos , Animales , Células de Riñón Canino Madin Darby , Propranolol/farmacocinética , Metoprolol/farmacocinética , Metoprolol/administración & dosificación , Atenolol/farmacocinética , Atenolol/administración & dosificación , Relación Dosis-Respuesta a Droga , Biofarmacia/métodos , Permeabilidad , Absorción IntestinalRESUMEN
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity amongst trauma patients. Its treatment is focused on minimizing progression to secondary injury. Administration of propranolol for TBI maydecrease mortality and improve functional outcomes. However, it is our sense that its use has not been universally adopted due to low certainty evidence. The literature was reviewed to explore the mechanism of propranolol as a therapeutic intervention in TBI to guide future clinical investigations. Medline, Embase, and Scopus were searched for studies that investigated the effect of propranolol on TBI in animal models from inception until June 6, 2023. All routes of administration for propranolol were included and the following outcomes were evaluated: cognitive functions, physiological and immunological responses. Screening and data extraction were done independently and in duplicate. The risk of bias for each individual study was assessed using the SYCLE's risk of bias tool for animal studies. Three hundred twenty-three citations were identified and 14 studies met our eligibility criteria. The data suggests that propranolol may improve post-TBI cognitive and motor function by increasing cerebral perfusion, reducing neural injury, cell death, leukocyte mobilization and p-tau accumulation in animal models. Propranolol may also attenuate TBI-induced immunodeficiency and provide cardioprotective effects by mitigating damage to the myocardium caused by oxidative stress. This systematic review demonstrates that propranolol may be therapeutic in TBI by improving cognitive and motor function while regulating T lymphocyte response and levels of myocardial reactive oxygen species. Oral or intravenous injection of propranolol following TBI is associated with improved cerebral perfusion, reduced neuroinflammation, reduced immunodeficiency, and cardio-neuroprotection in preclinical studies.