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Addiction Biology Mar 2022Chronic alcohol use increases risk of alcohol withdrawal symptoms (AW) and disrupts stress biology and resilient coping, thereby promoting excessive alcohol intake.... (Randomized Controlled Trial)
Randomized Controlled Trial
Chronic alcohol use increases risk of alcohol withdrawal symptoms (AW) and disrupts stress biology and resilient coping, thereby promoting excessive alcohol intake. Chronic alcohol intake and multiple alcohol detoxifications are known to impair brain medial prefrontal cortex (mPFC) and striatal functioning, regions involved in regulating stress, craving and alcohol intake. In two related studies, we examined whether AW predicts this functional brain pathology and whether Prazosin versus Placebo treatment may reverse these effects. In Study 1, patients with Alcohol Use Disorder (AUD) (N = 45) with varying AW levels at treatment entry were assessed to examine AW effects on corticostriatal responses to stress, alcohol cue and neutral visual images with functional magnetic resonance imaging (fMRI). In Study 2, 23 AUD patients entering a 12-week randomised controlled trial (RCT) of Prazosin, an alpha1 adrenergic antagonist that decreased withdrawal-related alcohol intake in laboratory animals, participated in two fMRI sessions at pretreatment and also at week 9-10 of chronic treatment (Placebo: N = 13; Prazosin: N = 10) to assess Prazosin treatment effects on alcohol-related cortico-striatal dysfunction. Study 1 results indicated that higher AW predicted greater disruption in brain mPFC and striatal response to stress and alcohol cues (p < 0.001, family-wise error [FWE] correction) and also subsequently greater heavy drinking days (HDD) in early treatment (p < 0.01). In Study 2, Prazosin versus Placebo treatment reversed mPFC-striatal dysfunction (p < 0.001, FWE), which in turn predicted fewer drinking days (p < 0.01) during the 12-week treatment period. These results indicate that AW is a significant predictor of alcohol-related prefrontal-striatal dysfunction, and Prazosin treatment reversed these effects that in turn contributed to improved alcohol treatment outcomes.
Topics: Alcohol Drinking; Alcoholism; Craving; Humans; Prazosin; Substance Withdrawal Syndrome
PubMed: 34856641
DOI: 10.1111/adb.13116 -
Canadian Journal of Veterinary Research... Jan 2003Prazosin is a readily available alpha-adrenergic antagonist that may be useful in the management of functional urethral obstruction in companion animals. This study used...
Prazosin is a readily available alpha-adrenergic antagonist that may be useful in the management of functional urethral obstruction in companion animals. This study used urethral pressure profilometry to evaluate the urethral effects of prazosin and phenoxybenzamine in healthy, non-sedated, male Beagle dogs. Heart rate, indirect systolic, diastolic and mean arterial blood pressures were measured, and saline perfusion urethral pressure profilometry was performed at 0, 10, 20, and 40 min following intravenous administration of prazosin (0.025 mg/kg), phenoxybenzamine (0.2 mg/kg), or placebo. Maximal urethral pressure, maximal urethral closure pressure, post peak nadir, and all blood pressure parameters decreased significantly at nearly all treatment intervals following administration of prazosin compared with placebo. Less consistently significant reductions were observed following phenoxybenzamine administration. Maximal decreases in urethral pressure parameters were observed 20 min following the injection of prazosin; maximal blood pressure decreases were evident by 10 min postinjection. In this non-sedated dog model, urethral pressure profilometry was a sensitive method of detecting urethral effects of alpha antagonists. Repeatable reductions in urethral pressure measurements were observed, with prazosin effecting more consistently significant changes than phenoxybenzamine. Significant decreases in systolic, diastolic, and mean arterial blood pressures were seen with prazosin, but not phenoxybenzamine or placebo. Further study of selective alpha-1 antagonists in dogs is needed to determine appropriate oral dosing protocols that will produce maximal urethral effects with minimal hemodynamic effects, and to demonstrate clinical efficacy in dogs with functional urethral obstruction.
Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Dog Diseases; Dogs; Heart Rate; Injections, Intravenous; Kinetics; Male; Phenoxybenzamine; Prazosin; Pressure; Random Allocation; Treatment Outcome; Urethra; Urethral Obstruction; Urodynamics
PubMed: 12528826
DOI: No ID Found -
Canadian Medical Association Journal Feb 1978
Topics: Drug Therapy, Combination; Humans; Prazosin; Quinazolines
PubMed: 630494
DOI: No ID Found -
Neuroscience Letters Jan 2021The emission of 50 kHz frequency-modulated ultrasonic vocalizations (FM USVs) in rats has been associated with positive affective states, while a decrease in FM USVs has...
The emission of 50 kHz frequency-modulated ultrasonic vocalizations (FM USVs) in rats has been associated with positive affective states, while a decrease in FM USVs has been associated with anxiety-like states. We tested the hypothesis in male Sprague-Dawley rats that FM USVs would complement measures of aversive memories (decrease in FM USVs) in a conditioned fear task in which we examined extinction or reconsolidation disruption. In Experiment 1, rats were fear conditioned using low-level footshock followed by extinction while monitoring freezing and FM USVs. In Experiment 2, rats were fear conditioned, the alpha-1 antagonist prazosin was used to disrupt reconsolidation of memory, and freezing and FM USVs were measured. Rats fear conditioned with low-level shock showed minimal freezing that rapidly extinguished, despite a persistent decrease in FM USVs throughout extinction. Prazosin reduced freezing in a memory reactivation-dependent manner as expected, but the reduction in FM USVs after fear conditioning remained decreased, suggesting that an affective component of memory was not impacted by prazosin. These findings indicate that FM USVs may be used as an index of fear- or anxiety-like memory, and their measurement could benefit pre-clinical animal models for assessing reduction of aversive memories.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Avoidance Learning; Conditioning, Classical; Electroshock; Extinction, Psychological; Fear; Male; Memory; Memory Consolidation; Prazosin; Rats, Sprague-Dawley; Ultrasonics; Vocalization, Animal; Rats
PubMed: 33166637
DOI: 10.1016/j.neulet.2020.135458 -
NeuroImage. Clinical 2020Higher levels of anxiety, negative affect, and impaired emotion regulation are associated with alcohol use disorder (AUD) and contribute to relapse and worse treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Higher levels of anxiety, negative affect, and impaired emotion regulation are associated with alcohol use disorder (AUD) and contribute to relapse and worse treatment outcomes. Prazosin, while typically used to treat post-traumatic stress disorder (PTSD) and other anxiety disorders, has shown promise for treating AUD. In order to better understand these underlying neural processes in individuals with AUD, our aims in this study were to measure brain activation during an anticipatory anxiety task before treatment to determine whether observed patterns supported previous work. We then aimed to measure the effects of prazosin on patients with AUD and explore whether greater baseline anticipatory anxiety (as measured by subjective and neural measures) predicts better treatment outcomes.
METHODS
Thirty-four individuals seeking treatment for AUD participated in a six-week placebo-controlled study of prazosin and underwent an anticipatory anxiety task during fMRI scans at baseline and three weeks. Alcohol use over six weeks was measured.
RESULTS
Greater levels of subjective anxiety and deactivation in posterior cingulate cortex (PCC) and ventromedial prefrontal cortex (vmPFC) were observed during high-threat stimuli compared to low-threat stimuli. Compared to placebo, prazosin reduced subjective anxiety to high-threat stimuli but there were no observed significant effects of prazosin on brain activation during the task. However, AUD patients with greater vmPFC deactivation during high threat relative to low threat and patients with low baseline anticipatory anxiety during the task had worse clinical outcomes on prazosin.
CONCLUSIONS
Deactivation in PCC and vmPFC to high-threat stimuli replicated previous work and shows promise for further study as a marker for AUD. Although prazosin did not affect brain activation in the regions of interest during the anticipatory anxiety task, subjective levels of anxiety and brain activation in vmPFC predicted treatment outcomes in individuals with AUD undergoing treatment with prazosin, highlighting individuals more likely to benefit from prazosin than others.
Topics: Adolescent; Adrenergic alpha-1 Receptor Antagonists; Adult; Alcoholism; Anticipation, Psychological; Anxiety; Female; Gyrus Cinguli; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Outcome Assessment, Health Care; Prazosin; Prefrontal Cortex; Young Adult
PubMed: 32037283
DOI: 10.1016/j.nicl.2020.102162 -
Toxins Apr 2021Ergotism is a common and increasing problem in Saskatchewan's livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial...
Ergotism is a common and increasing problem in Saskatchewan's livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial vasoconstriction and gangrene through the activation of adrenergic and serotonergic receptors on vascular smooth muscles. The acute vascular effects of a single oral dose with high-level exposure to ergot alkaloids remain unknown and are examined in this study. This study had two main objectives; the first was to evaluate the role of α-adrenergic receptors in mediating the acute vasocontractile response after single-dose exposure in sheep. The second was to examine whether terazosin (TE) could abolish the vascular contractile effects of ergot alkaloids. Twelve adult female sheep were randomly placed into control and exposure groups ( = 6/group). Ergot sclerotia were collected and finely ground. The concentrations of six ergot alkaloids (ergocornine, ergocristine, ergocryptine, ergometrine, ergosine, and ergotamine) were determined using HPLC/MS at Prairie Diagnostic Services Inc., (Saskatoon, SK, Canada). Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water. Animals were euthanized 12 h after the treatment, and the pedal artery (dorsal metatarsal III artery) from the left hind limb from each animal was carefully dissected and mounted in an isolated tissue bath. The vascular contractile response to phenylephrine (PE) (α-adrenergic agonist) was compared between the two groups before and after TE (α-adrenergic antagonist) treatment. Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control (Ctl EC = 1.74 × 10 M; Exp EC = 1.079 × 10 M, = 0.046). TE treatment resulted in a significant dose-dependent increase in EC in both exposure and control groups ( < 0.05 for all treatments). Surprisingly, TE effect was significantly more pronounced in the ergot exposed group compared to the control group at two of the three concentrations of TE (TE 30 nM, = 0.36; TE 100 nM, < 0.001; TE 300 nM, < 0.001). Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE. TE is a more potent dose-dependent antagonist for the PE contractile response in sheep exposed to ergot compared to the control group. This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α-adrenergic receptor. This effect may be reversed using TE, especially at early stages of the disease before cell death occurs. This study may also indicate that acute-single dose exposure scenario may be useful in the study of vascular effects of ergot alkaloids.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Arteries; Ergot Alkaloids; Ergotism; Female; Hindlimb; Muscle, Smooth, Vascular; Prazosin; Receptors, Adrenergic, alpha-1; Sheep, Domestic; Signal Transduction; Vasoconstriction; Vasoconstrictor Agents
PubMed: 33924041
DOI: 10.3390/toxins13040291 -
Sleep Medicine Mar 2020Nightmares are a highly prevalent and distressing feature of post-traumatic stress disorder (PTSD). Previous studies have reached mixed conclusions regarding the effects... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Nightmares are a highly prevalent and distressing feature of post-traumatic stress disorder (PTSD). Previous studies have reached mixed conclusions regarding the effects of prazosin on nightmares, sleep quality, and overall PTSD symptoms in patients with PTSD.
METHODS
MEDLINE, EMBASE, all EBM databases, PsycIFNO, and CINAHL were systematically searched from inception date to October 2018 for randomized clinical trials that included reporting of nightmares, sleep quality or overall PTSD symptoms. The analysis included data from eight trials involving 286 PTSD patients in the prazosin group and 289 PTSD patients in the placebo group.
RESULTS
In our meta-analysis, prazosin resulted in a statistically significant improvement in nightmares (standardized mean difference (SMD) = -1.13, 95% confidence interval (CI) = -1.91 to -0.36), but was not more beneficial than placebo for overall PTSD symptoms (SMD = -0.45, 95% CI = -0.95 to 0.05) and sleep quality (SMD = -0.44, 95% CI = -1.44 to 0.55). In terms of acceptability, there was no significant difference between the prazosin group and the placebo group with respect to discontinuation for all causes (odds ratio (OR) = 1.00, 95% CI = 0.62-1.62). In conclusion, the use of prazosin was associated with an improvement of nightmare symptoms.
CONCLUSION
Our findings indicate that additional studies are needed before considering downgrading the use of prazosin in the treatment of nightmares in patients with PTSD.
Topics: Antihypertensive Agents; Dreams; Humans; Prazosin; Randomized Controlled Trials as Topic; Sleep Wake Disorders; Stress Disorders, Post-Traumatic
PubMed: 31972510
DOI: 10.1016/j.sleep.2019.06.010 -
Alcoholism, Clinical and Experimental... May 2012Previous studies show that prazosin, an α(1) -adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence [Rasmussen et...
BACKGROUND
Previous studies show that prazosin, an α(1) -adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence [Rasmussen et al. (2009) Alcohol Clin Exp Res 3:264-272; Walker et al. (2008) Alcohol 42:91-97] and in alcohol-dependent men [Simpson et al. (2009) Alcohol Clin Exp Res 33:255-263]. This study extended these findings by using a paradigm that allows for separate assessment of prazosin on motivation to seek versus consume alcohol or sucrose in selectively bred rats.
METHODS
Alcohol-preferring (P) rats were trained to complete an operant response that resulted in access to either 2% sucrose or 10% alcohol. A 4-week Seeking Test Phase examined responding in single, weekly extinction sessions when no reinforcer could be obtained. A 4-week Drinking Test Phase consisted of rats lever-pressing to "pay" a specified amount up front to gain access to unlimited alcohol (or sucrose) for a 20-minute period. On Seeking and Drinking test days, prazosin (0.0, 0.5, 1.0, and 1.5 mg/kg) was administered intraperitoneally 30 minutes prior to behavioral sessions.
RESULTS
Rats were self-administering an average of 0.9 (±0.09) g/kg alcohol on vehicle test day and had pharmacologically relevant blood ethanol concentrations. Prazosin significantly decreased alcohol seeking at all doses tested. The highest dose of prazosin also increased the latency to first response for alcohol and decreased alcohol intake. While sucrose-seeking and intake were similarly affected by prazosin, the high dose of prazosin did not increase response latency.
CONCLUSIONS
These findings are consistent with and extend previous research and suggest that prazosin decreases motivation to initiate and engage in alcohol consumption. The specificity of prazosin in attenuating the initiation of alcohol- but not sucrose-seeking suggests that this effect is not because of prazosin-induced motor-impairment or malaise. Together with previous findings, these data suggest that prazosin may be an effective pharmacotherapy, with specific application in people that drink excessively or have a genetic predisposition to alcohol abuse.
Topics: Adrenergic alpha-1 Receptor Antagonists; Alcohol Drinking; Animals; Appetitive Behavior; Central Nervous System Depressants; Consummatory Behavior; Ethanol; Male; Prazosin; Rats; Sucrose; Sweetening Agents
PubMed: 21981346
DOI: 10.1111/j.1530-0277.2011.01653.x -
British Journal of Clinical Pharmacology Apr 2007To assess the mechanistic relationship between doxazosin (alpha(1)-receptor antagonist) and receptor occupancy and a measure of pharmacological effect (Q(max), the... (Review)
Review
AIMS
To assess the mechanistic relationship between doxazosin (alpha(1)-receptor antagonist) and receptor occupancy and a measure of pharmacological effect (Q(max), the maximum urinary flow rate) and to compare the mean receptor occupancy ratio at clinical doses of doxazosin, tamsulosin, terazosin and prazosin in benign prostatic hyperplasia (BPH).
METHODS
A ternary complex model, which described the mechanism of alpha(1)-receptor antagonists, was fitted to the pharmacological effects and receptor occupancy ratio data for doxazosin (standard tablet). In addition, mean receptor occupancy was calculated for other alpha(1)-receptor antagonists and the optimal receptor occupancy was evaluated. The clinical pharmacological effects of the controlled release formulation of doxazosin (doxazosin GITS) were estimated based on the receptor occupancy.
RESULTS
The mechanistic based model was able to describe the pharmacological effects of doxazosin. Regardless of the plasma concentrations or clinical dose of each drug, the results suggest that receptor occupancy is useful to assess quantitatively and compare the pharmacological effects of drugs with similar mechanisms of action. The clinical dosage for doxazosin GITS was estimated to be at least 8 mg and the stable pharmacological effect is expected based on the estimated receptor occupancy.
CONCLUSIONS
A model for Q(max) improvement in BPH based on the receptor occupancy theory was able to describe the clinical effects of the alpha(1)-receptor antagonists. Receptor occupancy is a useful index for predicting the clinical effects of alpha(1)-receptor antagonists.
Topics: Adrenergic alpha-Antagonists; Doxazosin; Humans; Male; Prostatic Hyperplasia; Receptors, Adrenergic; Urination
PubMed: 17052252
DOI: 10.1111/j.1365-2125.2006.02783.x -
British Heart Journal Mar 1986A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the... (Clinical Trial)
Clinical Trial
A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the renin-angiotensin-aldosterone system (captopril) and of the alpha 1 adrenoceptors of the sympathetic system (prazosin) both at rest and during upright exercise in patients with chronic heart failure. Sixteen patients completed one month's treatment with each drug. During conventional diuretic treatment (control) plasma renin activity, aldosterone, and noradrenaline were increased at rest and on exercise. Control left ventricular filling pressures were raised, and correlated significantly with plasma renin activity both at rest and on exercise. Systemic vascular resistance was increased at rest, and its reduction during exercise correlated inversely with the increase in plasma renin activity and plasma noradrenaline. After one month's treatment with captopril there were reductions in plasma aldosterone, weight, left ventricular filling pressure, and systemic vascular resistance at rest and on exercise. Dyspnoea was relieved and exercise capacity increased. The greater fall in systemic vascular resistance on exercise no longer correlated with the increase in plasma renin activity. During treatment with prazosin there were increases in plasma noradrenaline and, transiently, in plasma aldosterone. Fluid retention occurred, and left ventricular filling pressure was unchanged. Compared with control values systemic vascular resistance was reduced at rest but not on exercise. Dyspnoea and exercise capacity did not improve. In chronic heart failure, vasodilatation by inhibition of the alpha adrenergic system with prazosin causes compensatory stimulation of the renin-angiotensin-aldosterone system and does not result in clinical benefit. Inhibition of the renin-angiotensin-aldosterone system with captopril causes secondary vasodilatation at rest and on exercise and results in improvement in symptoms and exercise capacity.
Topics: Aged; Captopril; Clinical Trials as Topic; Double-Blind Method; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Prazosin; Renin-Angiotensin System; Rest; Vasodilation; Vasopressins
PubMed: 3513808
DOI: 10.1136/hrt.55.3.265