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CNS Drugs Sep 2023Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories.... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories. However, in contrast to ordinary migraine, vestibular migraine patients have distinct characteristics, and the detailed treatment strategy for vestibular migraine is different and more challenging than ordinary migraine treatment. Currently, there is no conclusive evidence regarding its management, including vestibular migraine prophylaxis.
AIM
The objective of this current network meta-analysis (NMA) was to compare the efficacy and acceptability of individual treatment strategies in patients with vestibular migraine.
METHODS
The PubMed, Embase, ScienceDirect, ProQuest, Web of Science, ClinicalKey, Cochrane Central, and ClinicalTrials.gov databases were systematically searched for randomized controlled trials (RCTs), with a final literature search date of 30 December 2022. Patients diagnosed with vestibular migraine were included. The PICO of the current study included (1) patients with vestibular migraine; (2) intervention: any active pharmacologic or non-pharmacologic intervention; (3) comparator: placebo-control, active control, or waiting list; and (4) outcome: changes in migraine frequency or severity. This NMA of RCTs of vestibular migraine treatment was conducted using a frequentist model. We arranged inconsistency and similarity tests to re-examine the assumption of NMA, and also conducted a subgroup analysis focusing on RCTs of pharmacological treatment for vestibular migraine management. The primary outcome was changes in the frequency of vestibular migraines, while the secondary outcomes were changes in vestibular migraine severity and acceptability. Acceptability was set as the dropout rate, which was defined as the participant leaving the study before the end of the trial for any reason. Two authors independently evaluated the risk of bias for each domain using the Cochrane risk-of-bias tool.
RESULTS
Seven randomized controlled trials (N = 828, mean age 37.6 years, 78.4% female) and seven active regimens were included. We determined that only valproic acid (standardized mean difference [SMD] -1.61, 95% confidence interval [CI] -2.69, -0.54), propranolol (SMD -1.36, 95% CI -2.55, -0.17), and venlafaxine (SMD -1.25, 95% CI -2.32, -0.18) were significantly associated with better improvement in vestibular migraine frequency than the placebo/control groups. Furthermore, among all the investigated pharmacologic/non-pharmacologic treatments, valproic acid yielded the greatest decrease in vestibular migraine frequency among all the interventions. In addition, most pharmacologic/non-pharmacologic treatments were associated with similar acceptability (i.e. dropout rate) as those of the placebo/control groups.
CONCLUSIONS
The current study provides evidence that only valproic acid, propranolol, and venlafaxine might be associated with beneficial efficacy in vestibular migraine treatment.
TRIAL REGISTRATION
CRD42023388343.
Topics: Adult; Female; Humans; Male; Migraine Disorders; Network Meta-Analysis; Propranolol; Valproic Acid; Venlafaxine Hydrochloride
PubMed: 37676473
DOI: 10.1007/s40263-023-01037-0 -
Advanced Science (Weinheim,... Dec 2023Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little...
Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs downstream of a reduced prostaglandin E2 (PGE2)-mediated ascending interoceptive signaling of the skeletal interoception. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes rescue bone loss in the unloading model. Moreover, depletion of TH sympathetic nerves or inhibition of norepinephrine release ameliorated bone resorption. Stereotactic inhibition of NPY expression in the hypothalamic neurons reduces the food intake with altered energy expenditure with a limited effect on bone, indicating hypothalamic neuroendocrine factor NPY in the facilitation of bone formation by sympathetic TH activity. These findings suggest that reduced PGE2-mediated interoceptive signaling in response to microgravity or unloading has impacts on the skeletal and central nervous systems that are reciprocally regulated.
Topics: Humans; Mice; Animals; Dinoprostone; Interoception; Neuropeptide Y; Hypothalamus; Neurons
PubMed: 37880864
DOI: 10.1002/advs.202305042 -
Noro Psikiyatri Arsivi 2023Newly acquired memory traces have been thought to become stable and resistant to interruption after they are stored in long-term memory. However, according to a recent... (Review)
Review
Newly acquired memory traces have been thought to become stable and resistant to interruption after they are stored in long-term memory. However, according to a recent research drugs such as beta-adrenergic receptor antagonists enable memories to be updated and rewritten when administered during consolidation and reconsolidation. Propranolol is a widely used beta-adrenergic receptor antagonist that disrupts the consolidation and reconsolidation processes of memory formation as it inhibits protein synthesis in the central nervous system. This review aims to discuss the memory impairing effect of the systemic and intracerebral administration of propranolol during the consolidation and reconsolidation processes associated with different learning tasks. In doing so, this review will help elucidate the effects of propranolol on different stages of memory formation. Since learning and maladaptive memories underpin some of the most common psychological disorders, such as phobias, post-traumatic stress disorder, addiction, drug-seeking behavior, and so on, a thorough understanding of propranolol's memory-impairing effect has significant clinical value and the potential to help people suffering from these disorders.
PubMed: 37645086
DOI: 10.29399/npa.28203 -
The Journal of Clinical Investigation Apr 2024Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of newborns. The tumor follows a life cycle of rapid proliferation in infancy, followed by slow... (Review)
Review
Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of newborns. The tumor follows a life cycle of rapid proliferation in infancy, followed by slow involution in childhood. This unique life cycle has attracted the interest of basic and clinical scientists alike as a paradigm for vasculogenesis, angiogenesis, and vascular regression. Unanswered questions persist about the genetic and molecular drivers of the proliferating and involuting phases. The beta blocker propranolol usually accelerates regression of problematic IHs, yet its mechanism of action on vascular proliferation and differentiation is unclear. Some IHs fail to respond to beta blockers and regrow after discontinuation. Side effects occur and long-term sequelae of propranolol treatment are unknown. This poses clinical challenges and raises novel questions about the mechanisms of vascular overgrowth in IH.
Topics: Infant, Newborn; Humans; Vascular Neoplasms; Propranolol; Disease Progression; Physicians; Hemangioma
PubMed: 38618963
DOI: 10.1172/JCI172836 -
Frontiers in Pharmacology 2024Prolonged QT intervals are extremely common in patients with cirrhosis and affect their treatment outcomes. Propranolol is often used to prevent gastroesophageal...
BACKGROUND
Prolonged QT intervals are extremely common in patients with cirrhosis and affect their treatment outcomes. Propranolol is often used to prevent gastroesophageal variceal hemorrhage in patients with cirrhosis; however, it is uncertain whether propranolol exerts a corrective effect on QT interval prolongation in patients with cirrhosis.
AIM
The study aimed to investigate the therapeutic effects of propranolol on patients with cirrhosis and prolonged QT intervals.
METHODS
A retrospective cohort study approach was adopted. Patients with cirrhosis complicated by moderate-to-severe gastroesophageal varices, who were hospitalized at the Affiliated Hospital of Guangdong Medical University between 1 December 2020 and 31 November 2022, were included in the study. The patients were divided into the propranolol and control groups based on whether they had received propranolol. Upon admission, the patients underwent tests on liver and kidney functions, electrolytes, and coagulation function, as well as abdominal ultrasonography and electrocardiography. In addition to conventional treatment, the patients were followed up after the use or non-use of propranolol for treatment and subsequently underwent reexamination of the aforementioned tests.
RESULTS
The propranolol group (26 patients) had an average baseline corrected QT (QTc) interval of 450.23 ± 37.18 ms, of which 14 patients (53.8%) exhibited QTc interval prolongation. Follow-up was continued for a median duration of 7.00 days after the administration of propranolol and conventional treatment. Electrocardiographic reexamination revealed a decrease in the QTc interval to 431.04 ± 34.64 ms ( = 0.014), and the number of patients with QTc interval prolongation decreased to five (19.2%; < 0.001). After treatment with propranolol and multimodal therapy, QTc interval normalization occurred in nine patients with QTc interval prolongation, leading to a normalization rate of 64.3% (9/14). The control group (n = 58) had an average baseline QTc interval of 453.74 ± 30.03 ms, of which 33 patients (56.9%) exhibited QTc interval prolongation. After follow-up for a median duration of 7.50 days, the QTc interval was 451.79 ± 34.56 ms ( = 0.482), and the number of patients with QTc interval prolongation decreased to 30 (51.7%; = 0.457). The QTc interval normalization rate of patients in the control group with QTc interval prolongation was merely 10.0% (3/33), which was significantly lower than that in the propranolol group ( < 0.001).
CONCLUSION
In patients with cirrhosis complicated by QT interval prolongation, the short-term use of propranolol aids in correction of a long QT interval and provides positive therapeutic value for cirrhotic cardiomyopathy.
PubMed: 38738176
DOI: 10.3389/fphar.2024.1370261 -
PeerJ 2023Hemangioma (HA) is one of the most common benign vascular tumors among children. Propranolol is used as the first-line treatment for hemangioma and is a non-selective...
Hemangioma (HA) is one of the most common benign vascular tumors among children. Propranolol is used as the first-line treatment for hemangioma and is a non-selective blocker of the -adrenergic receptor. -elemene is a compound extracted from Rhizoma zedoariae and has been approved for the treatment of tumors in clinical practice. However, the combinatorial effects of -elemene and propranolol in the treatment of HA remains unclear. This study explored the combinative effects and mechanisms of -elemene and propranolol using hemangioma-derived endothelial cells (HemECs). Cytotoxic assays showed that the combinatorial treatment of -elemene and propranolol did not increase the cytotoxic effects of HemECs. Furthermore, functional analysis showed that the combinatorial treatment with -elemene and propranolol significantly inhibited the proliferation, migration, and tube formation of the HemECs compared to the single treatment regimens. Mechanistic analysis showed that combinative treatment with -elemene and propranolol synergistically down-regulated the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor-A (HIF-1-/VEGFA) signaling pathway. Additionally, in a xenograft tumor model, angiogenesis in the combinatorial treatment group was significantly lower than in the control, propranolol, and -elemene treatment alone groups. Our results suggest that -elemene combined with propranolol can significantly inhibit the proliferation, migration, and tube formation of HemECs via synergistically down-regulating the HIF-1-/VEGFA signaling pathway without increasing any cytotoxic side effects.
Topics: Child; Humans; Propranolol; Endothelial Cells; Vascular Endothelial Growth Factor A; Cell Proliferation; Hemangioma; Penicillins
PubMed: 37456875
DOI: 10.7717/peerj.15643 -
BJPsych Open Jun 2024Propranolol is a beta-blocker medication indicated mostly for heart rhythm conditions and for physical symptoms of anxiety. Prescriptions for propranolol in the UK have...
BACKGROUND
Propranolol is a beta-blocker medication indicated mostly for heart rhythm conditions and for physical symptoms of anxiety. Prescriptions for propranolol in the UK have increased since 2008. Recently, there have been concerns about the involvement of propranolol in intentional poisonings, but such deaths are not routinely reported. Therefore, use of coroner-reported and toxicology data enables unique investigation into the scale of involvement of propranolol in suicide.
AIMS
To describe the extent to which propranolol is involved in suicides, including patterns over time and characteristics of people whose suicide involved propranolol compared with other suicides.
METHOD
Data were derived from the National Programme on Substance Use Mortality (NPSUM). All suicides and deaths of undetermined intent between 2010 and 2021 in England, Wales and Northern Ireland were extracted, and a subset was identified where propranolol was involved in death.
RESULTS
There were 4473 suicides of which 297 (6.6%) involved propranolol, with the proportion involving propranolol nearly quadrupling during the study period (3.4% . 12.3%). Compared with all other suicides, a greater proportion of propranolol suicides were in women (56.6% . 37.1%) and in people with diagnoses of depression (39.1% . 27.1%) and anxiety (22.2% . 8.6%). When suicide involved propranolol, an antidepressant was detected at post-mortem in 81.8% of deaths, most commonly a selective serotonin reuptake inhibitor (SSRIs) (51.5%), and most often citalopram (24.6%).
CONCLUSIONS
A small number, but increasing proportion, of suicides reported to the NPSUM involve propranolol. Vigilance to the combined toxicity profile of medicines used alongside propranolol may be pertinent.
PubMed: 38828685
DOI: 10.1192/bjo.2024.714 -
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 -
Stem Cell Research & Therapy Sep 2023Polymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death,...
BACKGROUND
Polymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death, typically exercise-induced. We previously showed a link between the RyR2-H29D mutation and a clinical phenotype of short-coupled PMVT at rest using patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs). In the present study, we evaluated the effects of clinical and experimental anti-arrhythmic drugs on the intracellular Ca handling, contractile and molecular properties in PMVT hiPSC-CMs in order to model a personalized medicine approach in vitro.
METHODS
Previously, a blood sample from a patient carrying the RyR2-H29D mutation was collected and reprogrammed into several clones of RyR2-H29D hiPSCs, and in addition we generated an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. Here, we tested 4 drugs with anti-arrhythmic properties: propranolol, verapamil, flecainide, and the Rycal S107. We performed fluorescence confocal microscopy, video-image-based analyses and biochemical analyses to investigate the impact of these drugs on the functional and molecular features of the PMVT RyR2-H29D hiPSC-CMs.
RESULTS
The voltage-dependent Ca channel inhibitor verapamil did not prevent the aberrant release of sarcoplasmic reticulum (SR) Ca in the RyR2-H29D hiPSC-CMs, whereas it was prevented by S107, flecainide or propranolol. Cardiac tissue comprised of RyR2-H29D hiPSC-CMs exhibited aberrant contractile properties that were largely prevented by S107, flecainide and propranolol. These 3 drugs also recovered synchronous contraction in RyR2-H29D cardiac tissue, while verapamil did not. At the biochemical level, S107 was the only drug able to restore calstabin2 binding to RyR2 as observed in the isogenic control.
CONCLUSIONS
By testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest.
Topics: Humans; Calcium; Myocytes, Cardiac; Flecainide; Propranolol; Anti-Arrhythmia Agents; Precision Medicine; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular; Verapamil
PubMed: 37740238
DOI: 10.1186/s13287-023-03502-5