-
Cancer Biology & Therapy Dec 2024Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of...
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 β-adrenergic receptor (β-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-β (TGF-β) receptor Type I kinase (Ly2157299) . TGF-β1 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-β1 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-β1 signaling during this process. In addition, β-AR/TGF-β1 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.
Topics: Animals; Colorectal Neoplasms; Humans; Neovascularization, Pathologic; Mice; Transforming Growth Factor beta1; Hypoxia-Inducible Factor 1, alpha Subunit; Signal Transduction; Bevacizumab; Propranolol; Cell Line, Tumor; Vascular Endothelial Growth Factor A; Male; Cell Movement; Norepinephrine; Stress, Psychological; Adrenergic beta-Antagonists; Angiogenesis; Pyrazoles; Quinolines
PubMed: 38857055
DOI: 10.1080/15384047.2024.2366451 -
Cellular Physiology and Biochemistry :... May 2024Adrenaline quickly inhibits the release of histamine from mast cells. Besides β2-adrenergic receptors, several in vitro studies also indicate the involvement of...
BACKGROUND/AIMS
Adrenaline quickly inhibits the release of histamine from mast cells. Besides β2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties.
METHODS
Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists.
RESULTS
Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a β2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high dose prazosin, a selective α1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells.
CONCLUSION
This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell-stabilizer. The pharmacological blockade of α1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by β2-adrenergic receptors.
Topics: Animals; Mast Cells; Epinephrine; Rats; Prazosin; Cell Degranulation; Male; Exocytosis; Patch-Clamp Techniques; Adrenergic alpha-1 Receptor Antagonists; Rats, Wistar
PubMed: 38852193
DOI: 10.33594/000000703 -
JBJS Case Connector Apr 2024We 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...
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.
Topics: Humans; Female; Thigh; Hemangioma; Young Adult; Muscle Neoplasms; Propranolol; Radiography; Adrenergic beta-Antagonists
PubMed: 38848412
DOI: 10.2106/JBJS.CC.24.00060 -
Annals of Medicine and Surgery (2012) Jun 2024Recent studies have tried to establish an association between the use of alpha-1-adrenergic receptor antagonists (A1ARAs) used in benign prostatic hyperplasia (BPH) and...
BACKGROUND
Recent studies have tried to establish an association between the use of alpha-1-adrenergic receptor antagonists (A1ARAs) used in benign prostatic hyperplasia (BPH) and the risk of PD. The objective of the study is to compare the risk of Parkinson's disease (PD) between terazosin/alfuzosin/doxazosin (TZ/AZ/DZ) users and tamsulosin users.
METHODS
PubMed, Google Scholar, and Embase were systematically searched from inception to April 2023. Observational studies comparing the risk of PD among patients using different types of A1ARAs were included in the meta-analysis. The primary outcome was the hazard ratio (HR) with a 95% CI for the risk of occurrence of PD among A1ARAs users of two different classes.
RESULTS
This study was based on a total of 678 433 BPH patients, out of which 287 080 patients belonged to the TZ/AZ/DZ cohort and 391 353 patients belonged to the tamsulosin cohort. The pooled incidence of PD was higher in tamsulosin users (1.28%, 95% CI: 1.04-1.55%) than in TZ/AZ/DZ drug users (1.11%, 95% CI: 0.83-1.42%). The risk of occurrence of PD was significantly lower in patients taking TZ/AZ/DZ than tamsulosin (= 610,363, HR = 0.82, 95% CI = 0.71-0.94, = 0.01; I = 87.4%).
CONCLUSION
This meta-analysis demonstrated that patients with BPH who take TZ/AZ/DZ have a lower risk for developing PD than those who take tamsulosin.
PubMed: 38846867
DOI: 10.1097/MS9.0000000000002117 -
Journal of Controlled Release :... Jul 2024The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and...
The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
Topics: Dogs; Animals; Solubility; Molecular Dynamics Simulation; Felodipine; Probucol; Carvedilol; Lipids; Body Fluids; Bile Acids and Salts; Male; Intestinal Secretions
PubMed: 38844179
DOI: 10.1016/j.jconrel.2024.06.008 -
International Journal of Cardiology Sep 2024Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse....
BACKGROUND
Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied.
METHODS
In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders).
RESULTS
Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most.
CONCLUSIONS
In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided.
Topics: Humans; Female; Pregnancy; Adrenergic beta-Antagonists; Registries; Adult; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Infant, Newborn; Heart Diseases; Infant, Small for Gestational Age; Perinatal Mortality
PubMed: 38844094
DOI: 10.1016/j.ijcard.2024.132234 -
International Journal of Cardiology Sep 2024This research analyzed the demographics, management, and outcomes of patients with heart failure (HF) in Thailand.
BACKGROUND
This research analyzed the demographics, management, and outcomes of patients with heart failure (HF) in Thailand.
METHODS
The Thai Heart Failure Registry prospectively enrolled patients diagnosed with HF from 36 hospitals in Thailand. Follow-up data were recorded at 6, 12, 18, and 24 months. This study primarily focused on two outcomes: mortality and HF-related hospitalizations.
RESULTS
The study included 2639 patients aged at least 18. Their mean age was 59.2 ± 14.5 years, and most were male (68.4%). Patients were classified as having HF with reduced ejection fraction (HFrEF, 80.7%), HF with preserved ejection fraction (HFpEF, 9.0%), or HF with mildly reduced ejection fraction (HFmrEF, 10.3%). Guideline-directed medical therapy utilization varied. Beta-blockers had the highest usage (93.2%), followed by mineralocorticoid receptor antagonists (65.7%), angiotensin-converting enzyme inhibitors (39.3%), angiotensin receptor blockers (28.2%), angiotensin receptor-neprilysin inhibitors (16.1%), and sodium-glucose cotransporter-2 inhibitors (8.0%). The study monitored a composite of mortality and HF incidents, revealing incidence rates of 11.74, 12.50, and 8.93 per 100 person-years for the overall, HFrEF, and HFmrEF/HFpEF populations, respectively.
CONCLUSIONS
Despite high guideline-directed medical therapy adherence, the Thai Heart Failure Registry data revealed high mortality and recurrent HF rates. These findings underscore limitations in current HF treatment efficacy. The results indicate the need for further investigation and improvements of HF management to enhance patient outcomes.
Topics: Humans; Heart Failure; Male; Registries; Thailand; Female; Middle Aged; Aged; Prospective Studies; Treatment Outcome; Follow-Up Studies; Stroke Volume; Mineralocorticoid Receptor Antagonists; Adult; Adrenergic beta-Antagonists; Hospitalization; Southeast Asian People
PubMed: 38844093
DOI: 10.1016/j.ijcard.2024.132235 -
Scientific Reports Jun 2024This study in older hospitalized patients with heart failure with reduced ejection fraction (HFrEF) aimed to examine the prevalence of beta-blocker prescription and its... (Observational Study)
Observational Study
This study in older hospitalized patients with heart failure with reduced ejection fraction (HFrEF) aimed to examine the prevalence of beta-blocker prescription and its associated factors. A total of 190 participants were recruited from July 2019 to July 2020. The inclusion criteria included: (1) aged ≥ 60 years, (2) having a diagnosis of chronic HFrEF in the medical records, (3) hospitalized for at least 48 h. The participants had a mean age of 75.5 ± 9.1, and 46.8% were female. Of these, 55.3% were prescribed beta-blockers during admission. To explore the factors associated with beta-blocker prescription, multivariable logistic regression analysis was applied and the results were presented as odds ratios (OR) and 95% confidence intervals (CI). On multivariate logistic regression models, higher NYHA classes (OR 0.49, 95%CI 0.26-0.94), chronic obstructive pulmonary disease (OR 0.17, 95% CI 0.04-0.85), chronic kidney disease (OR 0.40, 95% CI 0.19-0.83), and heart rate under 65 (OR 0.34, 95% CI 0.12-0.98) were associated with a reduced likelihood of prescription. In this study, we found a low rate of beta-blocker prescriptions, with only around half of the participants being prescribed beta-blockers. Further studies are needed to examine the reasons for the under-prescription of beta-blockers, and to evaluate the long-term benefits of beta-blockers in elderly patients with HFrEF in this population.
Topics: Humans; Heart Failure; Female; Adrenergic beta-Antagonists; Male; Aged; Stroke Volume; Aged, 80 and over; Vietnam; Middle Aged; Drug Prescriptions; Hospitalization; Pulmonary Disease, Chronic Obstructive
PubMed: 38839862
DOI: 10.1038/s41598-024-63479-w -
Biological & Pharmaceutical Bulletin 2024This 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...
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.
Topics: Dogs; Caco-2 Cells; Humans; Animals; Madin Darby Canine Kidney Cells; Propranolol; Metoprolol; Atenolol; Solubility; Dose-Response Relationship, Drug; Biopharmaceutics; Permeability; Intestinal Absorption
PubMed: 38839364
DOI: 10.1248/bpb.b24-00150 -
Bioorganic & Medicinal Chemistry Jun 202419 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H-H) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (J-J) have been designed and synthesized as...
19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H-H) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (J-J) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the β-adrenergic receptor (βAR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at βAR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against βAR than Cmpd-15, the first reported βAR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for βAR. Furthermore, the active pyrazole derivatives have relative better drug-like profiles than Cmpd-15. Taken together, we discovered a series of derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides as a novel scaffold of βAR NAM.
Topics: Receptors, Adrenergic, beta-2; Allosteric Regulation; Humans; Structure-Activity Relationship; Pyrazoles; Molecular Structure; Adrenergic beta-2 Receptor Antagonists
PubMed: 38838580
DOI: 10.1016/j.bmc.2024.117787