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Alcohol, Clinical & Experimental... Mar 2024Alcohol use disorder (AUD) is associated with significant liver pathology marked by elevated liver enzymes. Prazosin, an alpha1-noradrenergic antagonist significantly...
BACKGROUND
Alcohol use disorder (AUD) is associated with significant liver pathology marked by elevated liver enzymes. Prazosin, an alpha1-noradrenergic antagonist significantly improves alcohol drinking outcomes in individuals with alcohol withdrawal symptoms (AW), but effects on liver enzymes are unknown. We assessed the effects of prazosin treatment on the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyltransferase (GGT) in individuals with AUD.
METHODS
Participants (N=100) with AUD were enrolled in a 12-week randomized controlled trial and received either placebo or 16 mg/day of prazosin. Whole blood was drawn from 92 participants to measure liver enzyme levels every 4 weeks, and severity of AW was assessed weekly. Analysis predicting liver function outcomes used linear mixed effects models.
RESULTS
Controlling for alcohol consumption, a significant AW × treatment effect was seen for ALT (p < 0.05), AST (p < 0.05) and GGT (p < 0.01). Additionally, AST (b = 0.2, p < 0.01), ALT (b = 0.2, p < 0.05), and GGT (b = 0.3, p < 0.01) were elevated in individuals with higher AW in the placebo but not in the prazosin group (AST: p > 0.66; ALT: p > 0.65). Only in the prazosin group were lower GGT levels associated with higher withdrawal severity (b = -0.16, p < 0.05).
CONCLUSIONS
We found an interaction of alcohol withdrawal symptoms and prazosin treatment on liver enzyme levels, which were not influenced by week in the trial or the amount of alcohol consumed. Together, these findings suggest that prazosin treatment reduces liver enzymes over the course of AUD treatment among individuals with significant AW, though replication to establish clinical utility is needed.
PubMed: 38258493
DOI: 10.1111/acer.15263 -
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 -
BMJ Supportive & Palliative Care Oct 2023Nightmares can be a distressing symptom in patients living with serious illness. Prazosin, a selective alpha-1 adrenergic antagonist, has been suggested to treat...
Nightmares can be a distressing symptom in patients living with serious illness. Prazosin, a selective alpha-1 adrenergic antagonist, has been suggested to treat nightmares, with most data supporting its use in post-traumatic stress disorder (PTSD). We present the case of a 60-year-old woman with metastatic breast cancer who experienced healthcare-associated nightmares following hospitalisation. She did not meet diagnostic criteria for PTSD. Atypical antipsychotics and benzodiazepines were ineffective in controlling her nightmares, resulting in referral to our outpatient palliative medicine clinic. Prazosin was initiated alongside interdisciplinary psychosocial support, resulting in rapid resolution of her nightmares. To our knowledge, this is the first case to report on use of prazosin to manage nightmares in the outpatient palliative medicine setting.
Topics: Female; Humans; Middle Aged; Prazosin; Dreams; Adrenergic alpha-Antagonists; Stress Disorders, Post-Traumatic; Antipsychotic Agents
PubMed: 33504560
DOI: 10.1136/bmjspcare-2020-002594 -
ACS Chemical Neuroscience Feb 2024α-, α-, and α-adrenoceptors (α-ARs) are members of the adrenoceptor G protein-coupled receptor family that are activated by adrenaline (epinephrine) and...
α-, α-, and α-adrenoceptors (α-ARs) are members of the adrenoceptor G protein-coupled receptor family that are activated by adrenaline (epinephrine) and noradrenaline. α-ARs are clinically targeted using antagonists that have minimal subtype selectivity, such as prazosin and tamsulosin, to treat hypertension and benign prostatic hyperplasia, respectively. Abundant expression of α-ARs in the heart and central nervous system (CNS) makes these receptors potential targets for the treatment of cardiovascular and CNS disorders, such as heart failure, epilepsy, and Alzheimer's disease. Our understanding of the precise physiological roles of α-ARs, however, and their involvement in disease has been hindered by the lack of sufficiently subtype-selective tool compounds, especially for α-AR. Here, we report the discovery of 4-[(2-hydroxyethyl)amino]-6-methyl-2H-chromen-2-one (Cpd1), as an α-AR antagonist that has 10-15-fold selectivity over α-AR and α-AR. Through computational and site-directed mutagenesis studies, we have identified the binding site of Cpd1 in α-AR and propose the molecular basis of α-AR selectivity, where the nonconserved V197 residue plays a major role, with contributions from L314 within the α-AR pocket. By exploring the structure-activity relationships of Cpd1 at α-AR, we have also identified 3-[(cyclohexylamino)methyl]-6-methylquinolin-2(1H)-one (Cpd24), which has a stronger binding affinity than Cpd1, albeit with reduced selectivity for α-AR. Cpd1 and Cpd24 represent potential leads for α-AR-selective drug discovery and novel tool molecules to further study the physiology of α-ARs.
Topics: Receptors, Adrenergic, alpha-1; Prazosin; Tamsulosin; Norepinephrine
PubMed: 38238043
DOI: 10.1021/acschemneuro.3c00767 -
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 -
European Journal of Applied Physiology Sep 2023We sought to investigate the sympathetic mechanism controlling coronary circulation during trigeminal nerve stimulation in healthy women.
PURPOSE
We sought to investigate the sympathetic mechanism controlling coronary circulation during trigeminal nerve stimulation in healthy women.
METHODS
The protocol consisted of 3 min of trigeminal nerve stimulation (TGS) with cold stimuli to the face, in two conditions: (1) control and β-blockade (oral propranolol), and (2) control and α-blockade (oral prazosin).
RESULTS
Thirty-one healthy young subjects (women: n = 13; men: n = 18) participated in the study. By design, TGS decreased heart rate (HR), and increased blood pressure (BP) and cardiac output (CO). Before the β-blockade coronary blood velocity (CBV-Δ1.4 ± 1.3 cm s) increased along with the decrease of coronary vascular conductance index (CVCi-Δ-0.04 ± 0.04 cm s mmHg) during TGS and the β-blockade abolished the CBV increase and a further decrease of CVCi was observed with TGS (Δ-0.06 ± 0.07 cm s mmHg). During the α-blockade condition before the blockade, the CBV increased (Δ0.93 ± 1.48 cm s) along with the decrease of CVCi (Δ-0.05 ± 1.12 cm s mmHg) during TGS, after the α-blockade CBV (Δ0.98 ± cm s) and CVCi (Δ-0.03 ± 0.06 cm s mmHg) response to TGS did not change.
CONCLUSION
Coronary circulation increases during sympathetic stimulation even with a decrease in heart rate.
Topics: Male; Humans; Female; Blood Pressure; Blood Flow Velocity; Coronary Circulation; Coronary Vessels; Heart Rate; Trigeminal Nerve; Sympathetic Nervous System
PubMed: 37179503
DOI: 10.1007/s00421-023-05208-1 -
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 -
Current Problems in Cardiology Nov 2023The BRASH (bradycardia, renal failure, atrioventricular block, shock, and hyperkalaemia) syndrome is a recently recognized condition which may lead to life-threatening...
The BRASH (bradycardia, renal failure, atrioventricular block, shock, and hyperkalaemia) syndrome is a recently recognized condition which may lead to life-threatening complications if not correctly identified and treated early. We report here the case of a 74-year-old woman with type 2 diabetes, hypertension and atrial flutter who presented to the emergency department with 2-day history of dizziness, presyncope, and bradycardia, and a junctional rhythm at 61 beat per minute on initial ECG. She was on apixaban, digoxin, prazosin, and telmisartan. Serum biochemistry revealed severe hyperkalaemia with a potassium 8.4 mmol/L, creatinine 161 mmol/L, glucose 15.3 mmol/L and an upper normal digoxin level of 1.2 mmol/L (ref. 0.6-1.2). Arterial blood pH was 7.2. Given the constellation of biochemical and clinical findings a diagnosis of BRASH syndrome was made, though her blood pressure values at presentation were rather high (180/65-179/59 mmHg). The patient was rapidly stabilised with the administration of intravenous insulin and dextrose, fluid resuscitation, and zirconium cyclosilicate (SZC), followed by haemodialysis. Following the correction of the serum potassium to 4.7 mmol/L, a further ECG performed 6 hours later, showed a restoration of sinus rhythm with a rate of 65 bpm, normalization of the QRS duration. The digoxin and telmisartan were discontinued, and the patient was commenced on a calcium channel antagonist for hypertension. Clinicians should be alerted to patients who present with either a BRASH (shock) or BRAHH (hypertensive manifestation) where timely intervention is essential to avoid life-threatening brady-and tachyarrhythmias in these patients.
Topics: Aged; Female; Humans; Arrhythmias, Cardiac; Bradycardia; Diabetes Mellitus, Type 2; Digoxin; Hyperkalemia; Hypertension; Potassium; Telmisartan
PubMed: 37473946
DOI: 10.1016/j.cpcardiol.2023.101984 -
Pregnancy Hypertension Dec 2023Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking.
OBJECTIVE
To compare treatment success with antihypertensives and categorize by route of administration.
SEARCH STRATEGY
MEDLINE, Embase, PubMed, Web of Science, Scopus, CINAHL, and clinicaltrials.gov were searched without date restriction.
DATA COLLECTION
Peer-reviewed randomized controlled trials (RCTs) comparing pharmacologic agents used to treat hypertension in parturients were included. Evaluated treatment groups included IV-labetalol (BBIV), IV-hydralazine (DIV), oral-nifedipine (CCBPO), sublingual nifedipine (CCBSL), IV-calcium channel blocker (nonspecific)(CCBIV), IV-nitroglycerine (NTG), epoprostenol infusion (PRO), IV-ketanserin (5HT2B), IV-diazoxide (BZO), oral-nifedipine + methyldopa (CCBAG), oral-methyl-dopa (AAG), and oral prazosin (ABPO).
ANALYSIS
Seventy-four studies (8324 patients) were eligible post PRISMA guidelines screening. Results were pooled using a Bayesian-approach for success of treatment (study defined target blood pressure), time to achieve target pressure, and neonatal intensive-care admissions.
RESULTS
Treatment success (primary outcome, 55 trials with 5518 patients) was analyzed. Surface under the cumulative ranking curve (SUCRA) was categorized for 13 drugs, CCBPO (0.84) followed by CCBSL (0.78) were most likely to be effective in achieving target blood pressure. After sub-grouping by presence/absence of preeclampsia, CCB-PO ranked highest for both [(0.82) vs. (0.77), respectively]. Serotonin antagonists (0.99) and nitroglycerin (0.88) ranked highest for time to target pressure. NICU admissions were lowest for alpha-2 agonists (0.89), followed by BB PO (0.82) and hydralazine IV (0.49).
CONCLUSION
Oral calcium-channel blockers ranked highest for treatment success. Ketanserin achieved target blood pressure fastest, warranting additional research. The results should be interpreted with caution as SUCRA values may not indicate whether the differences between interventions have clinically meaningful effect sizes.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Antihypertensive Agents; Calcium Channel Blockers; Hydralazine; Hypertension; Ketanserin; Methyldopa; Network Meta-Analysis; Nifedipine; Pre-Eclampsia; Randomized Controlled Trials as Topic
PubMed: 37857042
DOI: 10.1016/j.preghy.2023.10.005 -
Neuropharmacology Aug 2023Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), where intake despite negative consequences can be a major clinical obstacle....
Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), where intake despite negative consequences can be a major clinical obstacle. With few treatment options available for AUD, there is a significant need for novel therapies. The noradrenergic system is an important hub for regulating stress responses and maladaptive drives for alcohol. Studies have shown that drugs targeting α1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of β ARs for treating human drinking has received scant investigation, and thus we sought to provide pre-clinical validation for possible AR utility for CLAD by analyzing whether β AR antagonists propranolol (β1/2), betaxolol (β1), and ICI, 118,551 (β2) impacted CLAD and alcohol-only drinking (AOD) in male Wistar rats. We found that the highest dose of propranolol tested systemically (10 mg/kg) reduced alcohol drinking, while 5 mg/kg propranolol reduced drinking with a trend to impact CLAD more than AOD, and with no effects of 2.5 mg/kg. Betaxolol (2.5 mg/kg) also decreased drinking, while ICI 118.551 had no effects. Also, while AR compounds might have utility for AUD, they can also lead to undesirable side effects. Here, a combination of ineffective doses of propranolol and prazosin reduced both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol in two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1-10 μg) in aINS or mPFC did not affect CLAD or AOD. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.
Topics: Rats; Animals; Humans; Male; Propranolol; Alcoholism; Betaxolol; Receptors, Adrenergic, alpha; Rats, Wistar; Alcohol Drinking; Norepinephrine; Receptors, Adrenergic, beta
PubMed: 37100382
DOI: 10.1016/j.neuropharm.2023.109545