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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 -
Heliyon Dec 2023To determine the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma through QuEChERS pre-treatment combined with...
To determine the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma through QuEChERS pre-treatment combined with ultra-performance liquid chromatography-tandem mass spectrometry. Plasma samples were extracted with 3 mL of acetonitrile, 400 mg of anhydrous magnesium sulfate as a salting agent, and 20 mg of C18 as a sorbent. An Agilent Poroshell 120 EC-C18 column (4.6 × 100 mm, 2.7 μm) was selected and methanol-0.1 % water was used as the mobile phase, and ESI positive ion detection mode was selected. Results: The plasma concentrations of nisoldipine, metoprolol, and prazosin exhibited good linearity within the range of 0.05-4.0 ng/mL (r > 0.99), while atenolol, bisoprolol, propranolol, rosuvastatin, and atorvastatin showed linearity within the range of 0.5-40 ng/mL (r > 0.99). Fluvastatin showed good linearity within the range of 5.0-400 ng/mL. The accuracy of the method ranged from 94.15 to 110.62 %, while the recovery levels were in the range of 85.23 %-115.13 %. The matrix effects were observed between-6.54 % and 12.43 %. The intra-day and inter-day RSD was <15 % for the three concentrations of low, medium, and high. Conclusion The proposed method is rapid, accurate, specific, simple, reproducible, and suitable for the simultaneous measurement of the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma.
PubMed: 38094060
DOI: 10.1016/j.heliyon.2023.e22543 -
Hypertension (Dallas, Tex. : 1979) Dec 2019The α1-AR (α1 adrenergic receptor) blockers currently on the market cannot meet clinical needs because of low-selectivity for subtypes of α1-ARs, short half-life, and... (Comparative Study)
Comparative Study
The α1-AR (α1 adrenergic receptor) blockers currently on the market cannot meet clinical needs because of low-selectivity for subtypes of α1-ARs, short half-life, and uncertain role in cardiovascular end point events. The study sought to find a vaccine specifically against α1D-AR (α1D-adrenergic receptor) for treating hypertension. A short peptide ADR-004 (cgiteeagy) belonging to α1D-AR was screened, and the ADRQβ-004 vaccine was produced and injected into spontaneously hypertensive rats model (including a short-term study, 10 weeks, and a long-term observation study, 39 weeks) and NG-nitro-l-arginine methyl ester + spontaneously hypertensive rats model (15 weeks). The antihypertensive effect and target organ protection of the ADRQβ-004 vaccine were carefully evaluated. The possible immune-mediated damage was detected in normal vaccinated Sprague Dawley rats. The ADR-004 peptide has perfect immunogenicity, and the ADRQβ-004 vaccine could induce strong antibody production. In the short-term study, the ADRQβ-004 vaccine averagely decreased the systolic blood pressure of spontaneously hypertensive rats up to 15 mm Hg and that of NG-nitro-l-arginine methyl ester+spontaneously hypertensive rats up to 29 mm Hg. In the long-term observation model, the antihypertensive effect of the ADRQβ-004 vaccine was quite stable, and the average decline of systolic blood pressure was 22 mm Hg. The ADRQβ-004 vaccine effectively prevented vascular structural remodeling, cardiac hypertrophy and fibrosis, and renal injury of hypertensive animals, superior to prazosin at renal level. Moreover, the ADRQβ-004 vaccine obviously downregulated the expression of α1D-AR, but not α1A-AR. Additionally, no significant immune-mediated damage was detected in immunized animals. The present results demonstrate that the ADRQβ-004 vaccine may provide a novel and promising method for the treatment of hypertension.
Topics: Animals; Biopsy, Needle; China; Disease Models, Animal; Down-Regulation; Hypertension; Immunohistochemistry; Kidney Function Tests; Male; Molecular Targeted Therapy; NG-Nitroarginine Methyl Ester; Random Allocation; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Vaccines
PubMed: 31607175
DOI: 10.1161/HYPERTENSIONAHA.119.13700 -
Saudi Journal of Biological Sciences May 2022anethole (ANE) is a monoterpene present in many aromatic plants, especially (PA) In this regard, we previously reported the anti-depressant potential of PA. Here, we...
anethole (ANE) is a monoterpene present in many aromatic plants, especially (PA) In this regard, we previously reported the anti-depressant potential of PA. Here, we examined the anti-depressant activity of ANE and its possible mechanism in mice. In experiment 1 the animals received ANE (12.5-50 mg.kg ) 60 min prior to forced swimming and open-field tests. In experiment 2, the animals received several receptor antagonists to assess the possible mechanism of ANE. The administration of ANE (25 and 50 mg.kg ; p < 0.01 and p < 0.001, respectively) exhibited an anti-depressive-like effect in FST without any significant effect on animal locomotion(p > 0.05). Moreover, haloperidol(p < 0.001), SCH23390(p < 0.001), sulpiride(p < 0.001), ketanserin(p < 0.001), -chlorophenylalanine(p < 0.001), WAY100135(p < 0.001), reserpine, (p < 0.001) prazosin(p < 0.001), and yohimbine(p < 0.001) inhibited the anti-depressive-like effect of ANE. Furthermore, co-treatment of a subeffective dose of ANE with imipramine or fluoxetine induced synergistic anti-depressant-like effects(p < 0.001). Our data mainly showed that the anti-depressive-like effect of ANE, which can be attributed to the contribution of the monoaminergic system.
PubMed: 35844399
DOI: 10.1016/j.sjbs.2022.01.060 -
Journal of Family Medicine and Primary... Sep 2022Scorpion envenomation is a life-threatening condition, particularly for children. Therefore, it is essential for primary care health providers to suspect, identify, and...
INTRODUCTION
Scorpion envenomation is a life-threatening condition, particularly for children. Therefore, it is essential for primary care health providers to suspect, identify, and manage this condition early to prevent death and minimize morbidity.
OBJECTIVE
To identify the key epidemiological characteristics of scorpion envenomation and update the primary care health workers regarding the latest management practices of scorpion envenomation.
METHODOLOGY
A non-systematic review was performed by searching the key terms on databases such as PubMed, Medline, Scopus, Google Scholar, and ResearchGate.
RESULTS
Worldwide, over 2.5 billion people are living at risk of scorpion stings. Every year, over 1.2 million are stung by scorpions leading to the death of at least 3,250 people globally. The most vulnerable group includes farmers, laborers, and those living in rural areas. Adults are most frequently stung but envenomation is more severe among children. Prazosin is a key drug to prevent death due to cardiovascular complications.
CONCLUSION
Most of these stings and deaths could be preventable with proper awareness, safety precautions, and timely access to treatment. Government and local hospitals should ensure the availability of key drugs such as prazosin.
PubMed: 36505581
DOI: 10.4103/jfmpc.jfmpc_2300_21 -
Parkinsonism & Related Disorders Jan 2022Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances glycolysis and increases ATP levels. Preclinical and epidemiologic data suggest that TZ may be neuroprotective in PD. We aimed to assess target engagement and safety of TZ in people with PD.
METHODS
We performed a 12-week pilot study in people with PD. Participants were randomized to receive 5 mg TZ or placebo. Participants and study personnel were blinded. We assessed TZ target engagement by measuring brain ATP with P-magnetic resonance spectroscopy (MRS) and whole blood ATP with a luminescence assay. Robust linear regression models compared changes between groups controlling for baseline brain and blood ATP levels, respectively. We also assessed clinical measures of PD and adverse events.
RESULTS
Thirteen participants were randomized. Mild dizziness/lightheadedness was more common in the TZ group, and three participants taking TZ dropped out because of dizziness and/or orthostatic hypotension. Compared to the placebo group, the TZ group had a significant increase in the ratio of βATP to inorganic phosphate in the brain. The TZ group also had a significant increase in blood ATP levels compared to the placebo group (p < 0.01).
CONCLUSIONS
This pilot study suggests that TZ may engage its target and change ATP levels in the brain and blood of people with PD. Further studies may be warranted to test the disease-modifying potential of TZ.
Topics: Adenosine Triphosphate; Dizziness; Humans; Parkinson Disease; Pilot Projects; Prazosin
PubMed: 34894470
DOI: 10.1016/j.parkreldis.2021.11.022 -
The International Journal of... Nov 2019Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key...
BACKGROUND
Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488.
METHODS
We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression.
RESULTS
Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area.
CONCLUSIONS
These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.
Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic alpha-1 Receptor Antagonists; Alcoholism; Animals; Behavior, Animal; Brain; Central Nervous System Depressants; Disease Models, Animal; Ethanol; Gene Expression; Genes, fos; Male; Prazosin; Rats; Rats, Long-Evans; Receptors, Opioid, kappa; Stress, Psychological
PubMed: 31556948
DOI: 10.1093/ijnp/pyz049 -
Pharmaceutical Medicine May 2023Suicide is a serious and growing public health concern yet randomized controlled trials (RCTs) that inform pharmacologic treatment remain limited. We emphasize the... (Review)
Review
Suicide is a serious and growing public health concern yet randomized controlled trials (RCTs) that inform pharmacologic treatment remain limited. We emphasize the overall need for such trials and review the literature to highlight examples of trials that have aimed to study patients at elevated risk of suicide. We discuss key examples of existing psychotropic medication trials as well as psychotherapy intervention studies that can yield important design insights. Medications that have been studied in individuals at risk for suicide include lithium, clozapine, zolpidem, prazosin, ketamine, esketamine, and aripiprazole. While important design challenges should be considered-RCTs to study suicide are feasible and much needed. Issues such as overall trial design, patient-selection criteria, and the scales/tools used to assess suicidality are discussed.
Topics: Humans; Suicidal Ideation; Suicide
PubMed: 37046135
DOI: 10.1007/s40290-023-00467-x -
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 -
Journal of Basic and Clinical... Jun 2021Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist...
OBJECTIVES
Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles.
METHODS
The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1-BX471, BX513, BI639667; CCR2-RS504393, INCB3284; CCR3-SB328437; and CCR4-AZD2098, and C021; CCR5-Maraviroc; CCR10-BI6901. The pan-α-adrenoceptor antagonist prazosin was used as control.
RESULTS
Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine.
CONCLUSIONS
Our data suggest that CCR antagonists should be screened for cross-reactivity with α-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Phenylephrine; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Receptors, Chemokine; beta-Arrestins
PubMed: 34144642
DOI: 10.1515/jbcpp-2020-0523