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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 -
Stress (Amsterdam, Netherlands) Sep 2011The 2010 Neurobiology of Stress Workshop brought together scientists from all over the world to share and discuss their results from studies examining the consequences...
The 2010 Neurobiology of Stress Workshop brought together scientists from all over the world to share and discuss their results from studies examining the consequences of acute, repeated, and chronic stressor exposure on health and disease. Session IV entitled "The neurobiology of the stress-resistant brain" explored how we can intervene to promote stress resistance and stress resilience. Four scientists, who explore this topic from unique and convergent perspectives, presented their experimental results derived from studies in rat (Fleshner and Maier), non-human primates (Lyons), and human (Raskind). Summaries of each presentation, supporting publications, and overall take-home messages from the session are presented.
Topics: Adaptation, Psychological; Animals; Brain; Exercise; Helplessness, Learned; Humans; Motor Activity; Neurobiology; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Saimiri; Stress Disorders, Post-Traumatic; Stress, Physiological; Stress, Psychological
PubMed: 21790482
DOI: 10.3109/10253890.2011.596865 -
Journal of Psychosomatic Research Feb 2012Pharmacological and cognitive-behavioral treatments targeting insomnia and nightmares have been shown to be effective in the treatment of military veterans with sleep... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
Pharmacological and cognitive-behavioral treatments targeting insomnia and nightmares have been shown to be effective in the treatment of military veterans with sleep complaints comorbid with symptoms of stress-related disorders, including Post-Traumatic Stress Disorder (PTSD), but the two approaches have not been directly compared. This randomized controlled trial compared the effects of prazosin vs. a behavioral sleep intervention (BSI), targeting nightmares and insomnia against a placebo pill control condition on sleep and daytime symptoms.
METHODS
Fifty United States military veterans (mean age 40.9years, SD=13.2years) with chronic sleep disturbances were randomized to prazosin (n=18), BSI (n=17), or placebo (n=15). Each intervention lasted 8weeks. Participants completed self-report measures of insomnia severity, sleep quality, and sleep disturbances. All kept a sleep diary throughout the intervention period. Polysomnographic studies were conducted pre- and post-intervention.
RESULTS
Both active treatment groups showed greater reductions in insomnia severity and daytime PTSD symptom severity. Sleep improvements were found in 61.9% of those who completed the active treatments and 25% of those randomized to placebo.
CONCLUSION
BSI and prazosin were both associated with significant sleep improvements and reductions in daytime PTSD symptoms in this sample of military veterans. Sleep-focused treatments may enhance the benefits of first-line PTSD treatments.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Cognitive Behavioral Therapy; Combat Disorders; Double-Blind Method; Dreams; Female; Humans; Male; Middle Aged; Prazosin; Severity of Illness Index; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Treatment Outcome; Veterans
PubMed: 22281448
DOI: 10.1016/j.jpsychores.2011.11.010 -
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 -
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 Medical Association Journal Feb 1978
Topics: Drug Therapy, Combination; Humans; Prazosin; Quinazolines
PubMed: 630494
DOI: No ID Found -
The American Journal of Psychiatry Dec 2018Current medications for alcohol use disorder do not target brain noradrenergic pathways. Theoretical and preclinical evidence suggests that noradrenergic circuits may be... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Current medications for alcohol use disorder do not target brain noradrenergic pathways. Theoretical and preclinical evidence suggests that noradrenergic circuits may be involved in alcohol reinforcement and relapse. After a positive pilot study, the authors tested the α-1 adrenergic receptor antagonist prazosin to treat alcohol use disorder in a larger sample.
METHOD
Ninety-two participants with alcohol use disorder but without posttraumatic stress disorder were randomly assigned to receive prazosin or placebo in a 12-week double-blind study. Medication was titrated to a target dosing schedule of 4 mg in the morning, 4 mg in the afternoon, and 8 mg at bedtime by the end of week 2. The behavioral platform was medical management. Participants provided daily data on alcohol consumption. Generalized linear mixed-effects models were used to examine the impact of prazosin compared with placebo on number of drinks per week, number of drinking days per week, and number of heavy drinking days per week.
RESULTS
Eighty participants completed the titration period and were included in the primary analyses. There was a significant interaction between condition and week for both number of drinks and number of heavy drinking days, such that the rate of drinking and the probability of heavy drinking showed a greater decrease over time for participants in the prazosin condition compared with those in the placebo condition. Participants in the prazosin condition were more likely to report drowsiness and edema than participants in the placebo condition.
CONCLUSIONS
Prazosin holds promise as a harm-reduction pharmacologic treatment for alcohol use disorder and deserves further evaluation by independent research groups.
Topics: Adrenergic alpha-1 Receptor Antagonists; Alcohol Drinking; Alcoholism; Double-Blind Method; Drug Administration Schedule; Ethanol; Female; Humans; Male; Middle Aged; Prazosin
PubMed: 30153753
DOI: 10.1176/appi.ajp.2018.17080913 -
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 -
Physiological Reports Jan 2021Black individuals exhibit increased blood pressure (BP) responses to sympathetic stimulation that are associated with an increased risk of hypertension (HTN). We tested... (Randomized Controlled Trial)
Randomized Controlled Trial
Black individuals exhibit increased blood pressure (BP) responses to sympathetic stimulation that are associated with an increased risk of hypertension (HTN). We tested the hypothesis that α -adrenergic blockade inhibits the increased BP response during and after 45-min stress in young normotensive Black adults, which may be mediated, in part, by dampened vasoconstriction and decreased renal sodium retention. Utilizing a double-masked randomized, crossover study design, 51 normotensive Black adults (31 ± 8 yr) were treated with either a placebo or 1 mg/day of prazosin for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before (Rest), during (Stress) and after (Recovery) 45 min of mental stress induced via a competitive video game task. During the Stress period, diastolic BP and total peripheral resistance (TPR) were significantly lower with prazosin compared to placebo (p < .05 for both). Similarly, we observed lower systolic BP, diastolic BP, and TPR during the Recovery period with prazosin versus placebo (p < .05 for both). There was no effect of prazosin on stress-associated UNaV. The change in systolic BP from Rest to Recovery was positively associated with the change in TPR with both treatments (p < .05 for both). In summary, prazosin treatment dampened BP reactivity to 45-min mental stress and lowered post-stress BP over the recovery period, which was linked to reduce TPR in young normotensive Black adults. These results suggest that α -adrenergic receptor activity may contribute to BP responses and delayed BP recovery to prolonged mental stress through increased vasoconstriction in Black adults.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Black People; Blood Pressure; Female; Humans; Male; Prazosin; Reflex; Sodium; Stress, Psychological
PubMed: 33356011
DOI: 10.14814/phy2.14642 -
British Journal of Pharmacology Oct 19791 In spinal dogs, continuous electrical stimulation of the cardioaccelerator nerve produced a transient rise in aortic blood pressure and a sustained increase in both...
1 In spinal dogs, continuous electrical stimulation of the cardioaccelerator nerve produced a transient rise in aortic blood pressure and a sustained increase in both heart rate and coronary sinus blood flow. The latter effects were accompanied by a significant elevation in the coronary sinus plasma noradrenaline concentration without significant changes in the levels of dopamine and adrenaline. The concentrations of the three catecholamines in thoracic aorta plasma were not significantly changed by cardioaccelerator nerve stimulation.2 Clonidine (20 mug/kg, i.v.), given during cardioaccelerator nerve stimulation, increased both mean aortic blood pressure and coronary sinus blood flow and decreased heart rate and coronary sinus venous plasma noradrenaline overflow.3 Phentolamine (0.3 mg/kg, i.v.) completely antagonized these effects of clonidine. Prazosin (0.3 mg/kg, i.v.) inhibited by only 43 and 38% the respective reductions in heart rate and noradrenaline overflow elicited by clonidine.4 On termination of cardioaccelerator stimulation (about 10 min after either prazosin or phentolamine), heart rate and coronary sinus noradrenaline overflow returned to control prestimulation levels.5 Phentolamine or prazosin, administered alone during stimulation of the cardioaccelerator nerve, increased heart rate and noradrenaline overflow into the coronary sinus plasma. However, intravenous phentolamine and prazosin, in contrast to desipramine (0.3 mg/kg, i.v.) or tyramine (1.0 mg, i.a.), failed to change the tachycardia resulting from the local administration of noradrenaline into the sinus node artery (i.a.).6 These results show that in spinal dogs the clonidine-induced reduction in heart rate (elevated by electrical stimulation of the cardioaccelerator nerve) is accompanied by a fall in the quantity of noradrenaline overflowing into the coronary sinus plasma. The latter effect is presumably the result of an action of clonidine on cardiac presynaptic alpha-adrenoceptors, the activation of which is followed by a reduction in the release of noradrenaline per nerve impulse. Phentolamine and prazosin are both antagonists of cardiac presynaptic alpha-adrenoceptors in spinal dogs, as suggested by their action against clonidine and by their positive chronotropic effect when administered during stimulation of the cardioaccelerator nerve.
Topics: Animals; Catecholamines; Clonidine; Coronary Vessels; Dogs; Drug Interactions; Electric Stimulation; Female; Heart; Heart Rate; Male; Phentolamine; Prazosin; Quinazolines; Spinal Cord; Time Factors
PubMed: 497531
DOI: 10.1111/j.1476-5381.1979.tb08678.x