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Pharmacology Research & Perspectives Aug 2019The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state... (Review)
Review
The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state pharmacokinetic studies from the literature. PubMed was searched for pharmacokinetic studies of beta-adrenergic blocking agents, both single-dose and steady-state studies. The studies included reported maximum plasma concentration (C) and/or area under the concentration curve (AUC). The coefficient of variation (CV%) was calculated for all studies, and a CV% <40% was considered low or moderate variability, and a CV% >40% was considered high variability. The C and AUC were reported a total of 672 times in 192 papers. Based on AUC, metoprolol, propranolol, carvedilol, and nebivolol showed high pharmacokinetic variability (highest first), whereas bisoprolol, atenolol, sotalol, labetalol, nadolol, and pindolol showed low to moderate variability (lowest first). We have shown a high interindividual pharmacokinetic variability that varies markedly in different beta-adrenergic blocking agents; the extreme being steady state ratios as high as 30 in metoprolol. A more personalized approach to the medical treatment of patients may be obtained by combining known pharmacokinetic information about variability, pharmaco-genetics and -dynamics, and patient characteristics, to avoid adverse events or lack of treatment effect.
Topics: Adrenergic beta-Antagonists; Area Under Curve; Biological Availability; Carvedilol; Healthy Volunteers; Humans; Male; Metoprolol; Propranolol
PubMed: 31338197
DOI: 10.1002/prp2.496 -
Chirurgia (Bucharest, Romania : 1990) 2020Hemangiomas are the most common benign tumors in infancy and the uncontrolled increase in size can cause serious complications, requiring treatment in specialized...
Hemangiomas are the most common benign tumors in infancy and the uncontrolled increase in size can cause serious complications, requiring treatment in specialized centers. Despite their high frequency and possible complications, there is currently no consensus on optimal treatment. The strategy may vary from simple observation to the involvement of several medical, radiological and surgical specialties, requiring both pharmacological and surgical treatment. Aim: The current study analyzes the results of the treatment of hemangiomas performed in a tertiary hospital in Romania, in order to compare the data with those in the recent literature. In our retrospective study we analyzed the data of 142 patients treated in our tertiary hospital for a period of approximately 2 years. Demographics, localization of hemangiomas, duration of hospitalization and treatment, and complications were statistically analyzed. We achieved favourable outcomes in over 80-90% of cases by combining propranolol treatment with bleomycin injections, topical application of timolol and surgical excision, depending on the location and complexity of the hemangioma, and the age of the patient. The goal of hemangioma therapy is to stop hemangioma growth in its tracks, and has to provide relief and reassurance to patients and families. Such therapies might consist of combinations of drugs given concurrently or perhaps sequentially to target cells that are most active in the proliferating phase.
Topics: Antineoplastic Agents; Bleomycin; Child; Hemangioma; Humans; Infant; Propranolol; Retrospective Studies; Romania; Timolol; Treatment Outcome
PubMed: 33138909
DOI: 10.21614/chirurgia.115.5.643 -
Cell Reports. Medicine Feb 2023While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and... (Randomized Controlled Trial)
Randomized Controlled Trial
While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and responsible for noradrenergic activation. Therefore, we performed a randomized double-blinded crossover trial in young lean men to compare the effects of single intravenous bolus of the ADRB2 agonist salbutamol without and with the ADRB1/2 antagonist propranolol on glucose uptake by BAT, assessed by dynamic 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan (i.e., primary outcome). Salbutamol, compared with salbutamol with propranolol, increases glucose uptake by BAT, without affecting the glucose uptake by skeletal muscle and white adipose tissue. The salbutamol-induced glucose uptake by BAT positively associates with the increase in energy expenditure. Notably, participants with high salbutamol-induced glucose uptake by BAT have lower body fat mass, waist-hip ratio, and serum LDL-cholesterol concentration. In conclusion, specific ADRB2 agonism activates human BAT, which warrants investigation of ADRB2 activation in long-term studies (EudraCT: 2020-004059-34).
Topics: Male; Humans; Albuterol; Adipose Tissue, Brown; Propranolol; Glucose; Receptors, Adrenergic; Receptors, Adrenergic, beta-3
PubMed: 36812890
DOI: 10.1016/j.xcrm.2023.100942 -
Scientific Reports May 2023Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on...
Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on breast cancer. These results contributed to the search for new and safe treatments for colorectal and triple-negative carcinomas.
Topics: Humans; Animals; Mice; Triple Negative Breast Neoplasms; Propranolol; Chloroquine; Cell Line, Tumor; Xenograft Model Antitumor Assays; Apoptosis; Colorectal Neoplasms; Cell Proliferation
PubMed: 37193722
DOI: 10.1038/s41598-023-34793-6 -
Annals of Clinical and Translational... Sep 2022Assess whether propranolol modulates the trigeminovascular system in both men and women. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Assess whether propranolol modulates the trigeminovascular system in both men and women.
METHODS
We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to T ) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2-1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double-blind, placebo-controlled cross-over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20-39 years old).
RESULTS
Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin-induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients.
INTERPRETATION
Propranolol (80 mg) inhibits capsaicin-induced increases in dermal blood flow in a sex-dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system.
Topics: Adult; Capsaicin; Cross-Over Studies; Female; Humans; Male; Propranolol; Steroids; Tryptamines; Young Adult
PubMed: 36029132
DOI: 10.1002/acn3.51640 -
The Journal of Thoracic and... May 2022Postoperative chylothorax causes significant morbidities in pediatric patients with cardiac disease. New treatment approaches based on evolving understanding of...
OBJECTIVE
Postoperative chylothorax causes significant morbidities in pediatric patients with cardiac disease. New treatment approaches based on evolving understanding of underlying lymphatic dysfunction are being developed. We hypothesized that propranolol reduces morbidities and duration of chest tube requirement in high-output chylous effusion.
METHODS
The postoperative courses of 50 pediatric patients with cardiac disease and high-output chylous effusion (control, n = 25; propranolol-treated, n = 25) were reviewed, including morbidities, length of hospitalization, and duration of chest tube requirement. Statistical analysis was performed using Welch's t test, Kruskal-Wallis tests for continuous variables, and chi-square and Fisher exact tests for categorical variables. Univariable logistic regression was used to determine predictors of response.
RESULTS
Propranolol response was defined as 80% or more drainage reduction in 9 days or less. Treated patients were grouped into responders (<9 days) and nonresponders (>10 days). Neither initial amount of drainage (P = .12) nor day of propranolol initiation (P = .17) correlated with response. When compared with controls and nonresponders, responders had significantly fewer days with chest tube requirement (P < .01), infection (P < .0002), and thrombus (P = .005), and shorter hospitalization (P < .05). All patients had low serum albumin, although nonresponders had significantly decreased serum albumin when compared with responders and control patients (P < .002), and were more likely to receive albumin replacement (P < .01). Malnutrition was prevalent in all patient groups.
CONCLUSIONS
Responders to propranolol had significantly less morbidity and duration of chest tube requirement when compared with control patients and nonresponders. Nonresponders did not have worse outcomes than control patients. We conclude that propranolol may be an effective treatment of patients with refractory chylothorax.
Topics: Cardiac Surgical Procedures; Child; Chylothorax; Heart Diseases; Humans; Postoperative Complications; Propranolol; Retrospective Studies; Serum Albumin
PubMed: 34583843
DOI: 10.1016/j.jtcvs.2021.09.007 -
Human & Experimental Toxicology 2022Propranolol is used to treat several cardiovascular diseases; however, toxic doses of propranolol cause severe myocardial depression and cardiac arrest. The aim of this...
OBJECTIVE
Propranolol is used to treat several cardiovascular diseases; however, toxic doses of propranolol cause severe myocardial depression and cardiac arrest. The aim of this study was to examine the effects of lipid emulsion (LE) on cardiotoxicity induced by toxic doses of propranolol in H9C2 rat cardiomyoblast cell line and to elucidate the underlying mechanism.
METHODS
The experimental groups comprised control, propranolol alone, esmolol alone, or LE followed by propranolol or esmolol treatment, and reactive oxygen species (ROS) inhibitor N-acetyl-L-cysteine (NAC) followed by propranolol treatment. The effects of propranolol, esmolol, NAC, and LE, alone or in combination, on cell viability, apoptosis, and ROS production were examined. Additionally, we investigated the effect of LE on propranolol concentration.
RESULTS
LE and NAC reversed the inhibition of cell viability induced by propranolol ( < .001). However, LE had no effect on the inhibition of cell viability caused by esmolol. The LE inhibited propranolol-induced expressions of cleaved caspase-3 ( < .001), caspase-9 ( < .001), and Bax ( < .01), but not caspase-8. NAC inhibited the propranolol-induced expression of cleaved caspase-3. LE inhibited propranolol-induced early apoptosis, but had no effect on late apoptosis. Additionally, LE inhibited the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells generated by propranolol. It attenuated propranolol-induced ROS production. However, it had no effect on propranolol concentration.
CONCLUSION
LE inhibits early apoptosis caused by a toxic dose of propranolol by suppressing the intrinsic apoptotic pathway, via direct inhibition of ROS production.
Topics: Acetylcysteine; Animals; Apoptosis; Caspase 3; Emulsions; Lipids; Propranolol; Rats; Reactive Oxygen Species
PubMed: 35738838
DOI: 10.1177/09603271221110852 -
Journal of Cancer Research and Clinical... Jan 2024This study will focus on 4T1 cells, a murine mammary adenocarcinoma cell line, as the primary research subject. We aim to investigate the inhibitory effects and...
PURPOSE
This study will focus on 4T1 cells, a murine mammary adenocarcinoma cell line, as the primary research subject. We aim to investigate the inhibitory effects and mechanisms of propranolol on epithelial-mesenchymal transition (EMT) in breast cancer cells, aiming to elucidate this phenomenon at the miRNA level.
METHODS
In this study, the EMT inhibitory effect of propranolol was observed through in vitro and animal experiments. For the screening of potential target miRNAs and downstream target genes, second-generation sequencing (SGS) and bioinformatics analysis were conducted. Following the screening process, the identified target miRNAs and their respective target genes were confirmed using various experimental methods. To confirm the target miRNAs and target genes, Western Blot (WB), reverse transcription polymerase chain reaction (RT-PCR), and immunofluorescence experiments were performed.
RESULTS
In this study, we found that propranolol significantly reduced lung metastasis in 4T1 murine breast cancer cells (p < 0.05). In vitro and in vivo experiments demonstrated that propranolol inhibited the epithelial-mesenchymal transition (EMT) as evidenced by Western Blot analysis (p < 0.05). Through next-generation sequencing (SGS), subsequent bioinformatics analysis, and PCR validation, we identified a marked downregulation of miR-499-5p (p < 0.05), suggesting its potential involvement in mediating the suppressive effects of propranolol on EMT. Overexpression of miR-499-5p promoted EMT, migration, and invasion of 4T1 cells, and these effects were not reversed or attenuated by propranolol (Validated via Western Blot, wound healing assay, transwell migration, and invasion assays, p < 0.05). Sox6 was identified as a functional target of miR-499-5p, with its downregulation correlating with the observed EMT changes (p < 0.05). Silencing Sox6 or overexpressing miR-499-5p inhibited Sox6 expression, further promoting the processes of EMT, invasion, and migration in 4T1 cells. Notably, these effects were not alleviated by propranolol (validated via Western Blot, wound healing assay, transwell migration, and invasion assays, p < 0.05). The direct interaction between miR-499-5p and Sox6 mRNA was confirmed by dual-luciferase reporter gene assay.
CONCLUSION
These results suggest that propranolol may have potential as a therapeutic agent for breast cancer treatment by targeting EMT and its regulatory mechanisms.
Topics: Animals; Mice; Blotting, Western; Cell Line; Epithelial-Mesenchymal Transition; MicroRNAs; Propranolol; SOXD Transcription Factors; Breast Neoplasms
PubMed: 38294713
DOI: 10.1007/s00432-023-05599-w -
Scientific Reports Feb 2017There is no definitive conclusion regarding the optimal timing for terminating propranolol treatment for infantile hemangioma (IH). A total of 149 patients who underwent...
There is no definitive conclusion regarding the optimal timing for terminating propranolol treatment for infantile hemangioma (IH). A total of 149 patients who underwent detailed color Doppler ultrasound examination were included in this study. The characteristics and propranolol treatment of all patients were summarized and analyzed. Patients were divided into two groups according to the lesion regression rate. Among the 149 patients, 38 were assigned to the complete regression group, and 111 were assigned to the partial regression group. The age at which propranolol treatment started, duration of follow-up after treatment discontinuation and rate of adverse events were not significantly different between the two groups. The duration of oral propranolol treatment was shorter in the complete regression group. The age at which propranolol was terminated was younger in the complete regression group, and this group had a lower recurrence rate. Propranolol is safe and effective for the treatment of IHs that require intervention, but it should be stopped at an appropriate time, which is determined primarily by the lesion regression rate after propranolol treatment. Ultrasound is helpful in determining when to stop propranolol for IH.
Topics: Administration, Oral; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Female; Hemangioma; Humans; Infant; Male; Propranolol; Time Factors; Treatment Outcome
PubMed: 28225076
DOI: 10.1038/srep43292 -
Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment.Scientific Reports Apr 2021Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development...
Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.
Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Repositioning; Drug Resistance, Neoplasm; Drug Therapy, Combination; Epithelial-Mesenchymal Transition; Female; Humans; Metformin; Mice; Mice, Nude; Propranolol; Transplantation, Heterologous; Triple Negative Breast Neoplasms; beta Catenin
PubMed: 33854147
DOI: 10.1038/s41598-021-87525-z