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Biomedicine & Pharmacotherapy =... Apr 2020Prazosin, a non-selective α1-adrenoceptor and a selective α2B-adrenoceptor antagonist, is reported to possess anti-cancer activity in some types of cancer. The aim of...
BACKGROUND
Prazosin, a non-selective α1-adrenoceptor and a selective α2B-adrenoceptor antagonist, is reported to possess anti-cancer activity in some types of cancer. The aim of this study was to investigate the effect of prazosin on acute myeloid leukemia (AML) and the underlying relevant mechanisms.
METHODS
AML cell lines U937 and HL60 were treated with different concentration of prazosin (5, 10 and 15 μM), CCK8 and flow cytometry assays were performed to examine the effects of prazosin on cell viability, cell cycle distribution and apoptosis. Western blot assay was used to detect the expression of related proteins.
RESULTS
We observed that prazosin inhibited cell viability of U937 and HL60 cells and induced the rate of apoptosis in a dose-dependent manner, as well as induced cell cycle arrest at G1 phase. The activation of PI3K/Akt/mTOR signaling pathway was significantly suppressed by prazosin via reducing the phosphorylation of Akt and mTOR. Moreover, by RNA-seq analysis, we found that the expression of tensin 1 (TNS1) was down-regulated by prazosin, and down-regulation of TNS1 could inhibit cell viability of U937 and HL60 cells, as well as induced cell apoptosis. The PI3K/Akt/mTOR signaling pathway was also suppressed by depletion of TNS1. Furthermore, up-regulation of TNS1 could reverse the effects of prazosin on viability and apoptosis in U937 and HL-60 cells, as well as the PI3K/Akt/mTOR signaling pathway.
CONCLUSION
These results highlight an anti-cancer activity of prazosin on AML by inhibiting the PI3K/Akt/mTOR pathway and targeting TNS1.
Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Leukemia, Myeloid, Acute; Phosphatidylinositol 3-Kinases; Phosphorylation; Prazosin; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Tensins
PubMed: 31954876
DOI: 10.1016/j.biopha.2019.109731 -
The Mental Health Clinician Mar 2021Knowledge about fundamental sleep disorders and dysregulation that occurs in children with PTSD is limited. Prazosin is an alpha-1 receptor antagonist often used off...
INTRODUCTION
Knowledge about fundamental sleep disorders and dysregulation that occurs in children with PTSD is limited. Prazosin is an alpha-1 receptor antagonist often used off label for the treatment of PTSD-associated nightmares in adults; however, evaluation of its use in pediatrics and adolescents is limited. The primary objective of this study was to assess the impact of prazosin on nightmares associated with PTSD in this population. Secondary objectives included assessing side effects, changes in blood pressure, and 30-day readmission rates.
METHODS
This was a retrospective, single-center chart review of inpatients diagnosed with PTSD nightmares from January 1, 2017, to July 31, 2019. Patients 4 to 18 years old with a PTSD diagnosis, experiencing nightmares, and initiating any dose of prazosin were assessed to determine efficacy and tolerance.
RESULTS
Forty-two patients were evaluated to determine symptom improvement after initiation of prazosin for PTSD nightmares in children and adolescents. Of the 42 patients, 24 (57.1%) reported improvement in nightmares (average dose 1.05 mg). For secondary results, 38 (90.5%) patients continued prazosin at discharge, and 2 (5%) were readmitted within 30 days for reasons other than PTSD-associated nightmares. Thirty-four (81%) reported having no adverse effects to prazosin. There was no significant difference in systolic ( = .1883) or diastolic ( = .2777) blood pressure preinitiation and postinitiation of prazosin.
DISCUSSION
Despite the limitations of this retrospective study, the data suggests that prazosin may be associated with an improvement in nightmares in children and adolescents with PTSD. Adverse events were rarely reported, and there was no significant change in blood pressure with initiation of prazosin.
PubMed: 33850681
DOI: 10.9740/mhc.2021.03.045 -
International Journal of Molecular... Dec 2021Gastrointestinal disease is the most common health concern that occurs due to environmental, infectious, immunological, psychological, and genetic stress. Among them,...
Gastrointestinal disease is the most common health concern that occurs due to environmental, infectious, immunological, psychological, and genetic stress. Among them, the most frequent diseases are gastric ulcer (GU) and ulcerative colitis (UC). DSS-induced UC and ethanol-stimulated GU models resemble the pathophysiology of human gastrointestinal disease. The current study was designed to explore the anti-oxidation, anti-inflammation, anti-cell death properties of terazosin, an α-adrenergic receptor antagonist, in vivo and in vitro. Our results indicate that terazosin dramatically activates Pgk1, and upregulates glycose metabolism, evidenced by the enhanced ATP production and higher LDH enzymatic activity. Also, terazosin significantly enhances p-AKT expression and inhibits NF-κB p65 activation through abrogating the phosphorylation of IKBα, as well as lowers Caspase-1 and GSDMD expression. The findings in this study demonstrate that terazosin exhibits anti-inflammatory effects by downregulating NF-κB-GSDMD signal pathway, along with enhancing glycolysis for gastrointestinal disease treatment. Meanwhile, we also find terazosin ameliorates ethanol-induced gastric mucosal damage in mice. Collectively, as a clinical drug, terazosin should be translated into therapeutics for gastrointestinal disease soon.
Topics: Apoptosis; Caco-2 Cells; Cell Survival; Colitis; Cytokines; Deoxyglucose; Dextran Sulfate; Gastric Mucosa; Gastrointestinal Diseases; Glucose; Humans; Hydrogen Peroxide; Inflammation Mediators; Lactic Acid; Malondialdehyde; Models, Biological; Peroxidase; Phosphoglycerate Kinase; Prazosin; Pyroptosis; Stomach Ulcer; Superoxide Dismutase
PubMed: 35008842
DOI: 10.3390/ijms23010416 -
Alcoholism, Clinical and Experimental... Jul 2020Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the hypothalamic-pituitary-adrenal axis responses, high stress-induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake. Thus, we hypothesized that prazosin would reduce stress-induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence. We secondarily also assessed the role of lifetime anxiety disorders on these prazosin effects.
METHODS
Forty inpatient treatment-seeking alcohol-dependent individuals were randomly assigned to receive placebo (n = 18) or 16 mg/d, T.I.D., prazosin (n = 22) in a double-blind manner, titrated over 2 weeks. In weeks 3 to 4 after achieving full dose, patients were exposed to 3 5-minute personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue), on 3 consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, heart rate, cortisol, and adrenocorticotropic hormone (ACTH) levels were assessed at baseline, following imagery and at repeated recovery timepoints.
RESULTS
Prazosin reduced stress cue-induced alcohol craving (p < 0.05) and stress- and alcohol cue-induced anxiety (p < 0.05) and increased heart rate responses in all imagery conditions (p < 0.05). Prazosin lowered basal cortisol and ACTH (p's < 0.05) and attenuated stress cue-induced rises in cortisol (p < 0.05) versus placebo. Finally, in those without lifetime anxiety disorder, the placebo group showed stress- and alcohol cue-induced increases in cortisol (p's < 0.05), while the prazosin group did not.
CONCLUSIONS
Prazosin may attenuate stress cue-induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenocorticotropic Hormone; Adult; Alcoholism; Anxiety; Anxiety Disorders; Craving; Cues; Double-Blind Method; Female; Heart Rate; Humans; Hydrocortisone; Imagery, Psychotherapy; Male; Middle Aged; Prazosin; Stress, Psychological
PubMed: 32449942
DOI: 10.1111/acer.14378 -
Chronic Stress (Thousand Oaks, Calif.) 2021The α-adrenoreceptor antagonist prazosin has in many but not all studies been found to be effective for PTSD associated nightmares, hyperarousal symptoms, and total...
BACKGROUND
The α-adrenoreceptor antagonist prazosin has in many but not all studies been found to be effective for PTSD associated nightmares, hyperarousal symptoms, and total symptom severity. The particular efficacy of prazosin for nightmares and hyperarousal symptoms suggests there may be a subset of PTSD symptoms that are more tightly associated with an α-adrenoreceptor mediated noradrenergic mechanism, but cross traditional diagnostic symptom clusters. However, the efficacy of prazosin for individual symptoms other than nightmares and sleep disruption has not previously been examined.
METHODS
In a reanalysis of a previously published, randomized controlled trial of twice daily prazosin for PTSD, we examined the relative effect of prazosin on individual items of the CAPS for DSM-IV, and tested whether prazosin responsiveness predicted the partial correlation of the changes in symptom intensity at the level of individual subjects. Results were not adjusted for multiple comparisons.
RESULTS
Prazosin showed the largest effect for distressing dreams, anhedonia, difficulty falling or staying asleep, difficulty concentrating, and hypervigilance. These items were also (a) of higher baseline severity in the underlying population, and (b) more related in how they fluctuated at the level of individual subjects. Covariance analysis did not support a clear cutoff between highly prazosin responsive items and those showing a smaller, not statistically significant response.
CONCLUSIONS
In this data set, twice daily prazosin substantially reduced not only nightmares and sleep disruption, but the majority of hyperarousal symptoms, with some evidence of efficacy for avoidance symptoms. The relationship of baseline symptom distribution to which symptoms showed significant response to prazosin reinforces the possibility that differences in a clinical trial's participant populations may significantly influence trial outcome. The pattern of symptom endorsement at the level of individual subjects was consistent with prazosin-responsive items sharing a common pathophysiologic mechanism.
PubMed: 33623856
DOI: 10.1177/2470547020979780 -
Archives of Razi Institute Jul 2021Central dopaminergic (DAergic) and adrenergic systems have a prominent role in appetite regulation; however, their interaction(s) have not been studied in neonatal layer...
Central dopaminergic (DAergic) and adrenergic systems have a prominent role in appetite regulation; however, their interaction(s) have not been studied in neonatal layer chickens.Therefore, the current study aimed to determine the interaction of central DAergic and noradrenergic systems in food intake regulation in neonatal layer chickens. In the first experiment, chickens received the intracerebroventricular (ICV) injection of a control solution, prazosin (i.e., α1 adrenergic receptor antagonist; 10 nmol), dopamine (DA; 40 nmol), and prazosin plus DA. The second to fifth experiments were similar to the first experiment except that the birds were injected with yohimbine (i.e., α2 receptor antagonist; 13 nmol), metoprolol (i.e., β1 adrenergic receptor antagonist; 24 nmol), ICI 118,551 (i.e., β2 adrenergic receptor antagonist; 5 nmol), and SR59230R (i.e., β3 adrenergic receptor antagonist; 20 nmol) instead of prazosin. In the sixth experiment, the chickens received ICV injection with the control solution and noradrenaline (NA; 75, 150, and 300 nmol). In the seventh experiment, the birds were injected with the control solution, SCH23390 (i.e., D1 DAergic receptor antagonist; 5 nmol), NA (300 nmol), and SCH23390 plus NA In the eighth experiment, the control solution, AMI-193 (i.e., D2 DAergic receptor antagonist; 5 nmol), NA (300 nmol), and AMI-193 plus NA were injected. Then, cumulative food intake was recorded at 30, 60, and 120 min after the injection. According to the obtained results, the ICV injection of DA (40 nmol) significantly decreased food intake in comparison to that reported for the control group (p <0.05). The co-injection of yohimbine plus DA significantly amplified DA-induced hypophagia in the neonatal chickens (p <0.05). In addition, the co-administration of ICI 118,551 plus DA significantly inhibited the hypophagic effect of DA in the neonatal chickens (p <0.05). Furthermore, NA (75, 150, and 300 nmol) significantly reduced food intake in a dose-dependent manner (p <0.05). The co-injection of SCH23390 plus NA decreased the hypophagic effect of NA in the neonatal chickens, compared to that reported for the control group (p <0.05). The co-injection of AMI-193 plus NA diminished NA-induced hypophagia, compared to that reported for the control group (p <0.05). The aforementioned results suggested that there is an interconnection between central DAergic and noradrenergic systems through α2/β2 adrenergic and D1/D2 DAergic receptors in food intake regulation in neonatal chicks.
Topics: Adrenergic Agents; Animals; Animals, Newborn; Chickens; Dopamine; Eating; Feeding Behavior
PubMed: 34223733
DOI: 10.22092/ari.2020.341240.1425 -
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 -
Research and Reports in Urology 2022Recommendations for alpha-blockers have shifted in the conservative management of ureteral stones. It is unknown whether real-life practices regarding alpha-blocker...
PURPOSE
Recommendations for alpha-blockers have shifted in the conservative management of ureteral stones. It is unknown whether real-life practices regarding alpha-blocker prescriptions reflect updates in evidence. This study aimed to characterise alpha-blocker prescriptions for conservatively managed ureteral stones and relate this to recent literature.
METHODS
This was a retrospective audit, 01/01/2014 to 01/01/2019, of emergency acute renal colic presentations. Patients were included if they had a confirmed ureteral stone and were conservatively managed. The rates of alpha-blocker prescriptions were analysed using interrupted time-series analyses. May 2015 was selected as the cut-point to analyse before and after trend lines. Results were stratified by stone size and location. Tamsulosin and prazosin prescriptions were also compared.
RESULTS
This study included 2163 presentations: 70.4% were stones ≤5 mm and 61.4% were proximal stones. Altogether, 24.7% of presentations were prescribed alpha-blockers. There was a fall in alpha-blocker prescription rates from before to after May 2015, regardless of stone size or location (p < 0.001). Since May 2015, however, there was a monthly rate increase of 0.5% for patients with stones >5mm.
CONCLUSION
This study demonstrated a significant shift in rates of alpha-blocker prescriptions, possibly related to the influence of updates in available high-quality evidence.
PubMed: 36060307
DOI: 10.2147/RRU.S372208 -
Metabolites Nov 2023Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors...
Manifestations of Liver Impairment and the Effects of MH-76, a Non-Quinazoline α1-Adrenoceptor Antagonist, and Prazosin on Liver Tissue in Fructose-Induced Metabolic Syndrome.
Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors antagonists are antihypertensive agents that exert mild beneficial effects on the metabolic profile in hypertensive patients. However, they are no longer used as a first-line therapy for hypertension based on Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) outcomes. Later studies have shown that quinazoline-based α1-adrenolytics (prazosin, doxazosin) induce apoptosis; however, this effect was independent of α1-adrenoceptor blockade and was associated with the presence of quinazoline moiety. Recent studies showed that α1-adrenoceptors antagonists may reduce mortality in COVID-19 patients due to anti-inflammatory properties. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted anti-inflammatory, antihypertensive properties and reduced insulin resistance and visceral adiposity. In this study, we aimed to evaluate the effect of fructose consumption and treatment with α1-adrenoceptor antagonists of different classes (MH-76 and prazosin) on liver tissue of fructose-fed rats. Livers were collected from four groups (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical and histopathological studies. Both α1-adrenolytics reduced macrovesicular steatosis and triglycerides content of liver tissue and improved its antioxidant capacity. Treatment with MH-76, contrary to prazosin, reduced leucocytes infiltration as well as decreased elevated IL-6 and leptin concentrations. Moreover, the MH-76 hepatotoxicity in hepatoma HepG2 cells was less than that of prazosin. The use of α1-adrenolytics with anti-inflammatory properties may be an interesting option for treatment of hypertension with metabolic complications.
PubMed: 37999226
DOI: 10.3390/metabo13111130 -
Seminars in Oncology Nursing Jun 2024Duloxetine, the only American Society of Clinical Oncology (ASCO) treatment recommended for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors, is not...
OBJECTIVES
Duloxetine, the only American Society of Clinical Oncology (ASCO) treatment recommended for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors, is not effective for 40% of survivors. This study examined the ability of a duloxetine-prazosin combination to prevent the development of allodynia and hyperalgesia in a rat model of oxaliplatin-induced peripheral neuropathy (OPIN).
METHODS
Female (n = 24) and male (n = 41) rats were started on duloxetine (15 mg), prazosin (2 mg), or a duloxetine-prazosin combination one week prior to administration of the chemotherapy drug, oxaliplatin, and continued the duloxetine-prazosin combination for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments over the course of the study.
RESULTS
Overall percent paw withdrawal for rats that received the duloxetine-prazosin combination was significantly lower in female (p < .001 for both conditions) and male (p = .029 for allodynia; p < .001 for hyperalgesia) than those that received water. No significant posttreatment differences were found for allodynia or hyperalgesia between rats treated with duloxetine and rats that received the duloxetine-prazosin combination in either sex.
CONCLUSIONS
These finding provide preliminary evidence that a duloxetine-prazosin combination can prevent the posttreatment development of allodynia and hyperalgesia in both male and female rats; however, the results suggest that the duloxetine-prazosin combination is no more efficacious than duloxetine alone in preventing chronic OIPN.
IMPLICATIONS FOR NURSING PRACTICE
The profession of nursing is built on clinical practice supported by scientific research. The current study addressed the clinical practice problem of prevention and management of painful OIPN, which is a priority area in oncology nursing.
PubMed: 38897856
DOI: 10.1016/j.soncn.2024.151686