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European Journal of Pharmacology Apr 2024Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells...
Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells (VSMCs), degradation of extracellular matrix (ECM), inflammation, and oxidative stress. Despite the severity of AAA, effective drugs for treatment are scarce. At low doses, terazosin (TZ) exerts antiapoptotic and anti-inflammatory effects in several diseases, but its potential to protect against AAA remains unexplored. Herein, we investigated the effects of TZ in two AAA animal models: Angiotensin II (Ang II) infusion in Apoe mice and calcium chloride application in C57BL/6J mice. Mice were orally administered with TZ (100 or 1000 μg/kg/day). The in vivo results indicated that low-dose TZ alleviated AAA formation in both models. Low-dose TZ significantly reduced aortic pulse wave velocity without exerting an apparent antihypertensive effect in the Ang II-induced AAA model. Paternally expressed gene 3 (Peg3) was identified via RNA sequencing as a novel TZ target. PEG3 expression was significantly elevated in both mouse and human AAA tissues. TZ suppressed PEG3 expression and reduced the abundance of matrix metalloproteinases (MMP2/MMP9) in the tunica media. Functional experiments and molecular analyses revealed that TZ (10 nM) treatment and Peg3 knockdown effectively prevented Ang II-induced VSMC senescence and apoptosis in vitro. Thus, Peg3, a novel target of TZ, mediates inflammation-induced VSMC apoptosis and senescence. Low-dose TZ downregulates Peg3 expression to attenuate AAA formation and ECM degradation, suggesting a promising therapeutic strategy for AAA.
Topics: Mice; Humans; Animals; Muscle, Smooth, Vascular; Pulse Wave Analysis; Mice, Knockout; Mice, Inbred C57BL; Aortic Aneurysm, Abdominal; Apoptosis; Inflammation; Angiotensin II; Disease Models, Animal; Myocytes, Smooth Muscle; Kruppel-Like Transcription Factors; Prazosin
PubMed: 38331337
DOI: 10.1016/j.ejphar.2024.176397 -
Neuropharmacology Apr 2024Sleep is an instinct behavior, and its significance and functions are still an enigma. It is expressed throughout one's life and its loss affects psycho-somatic and...
Sleep is an instinct behavior, and its significance and functions are still an enigma. It is expressed throughout one's life and its loss affects psycho-somatic and physiological processes. We had proposed that it might maintain a fundamental property of the neurons and the brain. In that context, it was shown that sleep, rapid eye movement sleep (REMS) in particular, by regulating noradrenaline (NA), maintains the brain excitability. It was also reported that sleep-loss affected memory, reaction time and decision-making ability among others. However, as there was lack of clarity on the cause-and-effect relationship as to how the sleep-loss could affect these basic behaviors, their association was questioned and it was difficult to propose a cure or at least ways and means to ameliorate the symptoms. Also, we wanted to conduct the studies in a simpler model system so that conducting future molecular studies might be easier. Hence, using zebrafish as a model we evaluated if sleep-loss affected the basic decision-making ability, a cognitive process and if the effect was induced by NA. Indeed, our findings confirmed that upon sleep-deprivation, the cognitive decision-making ability of the prey zebrafish was compromised to protect itself by running away from the reach of the exposed predator Tiger Oscar (TO) fish. Also, we observed that upon sleep-loss the axonal arborization of the prey zebrafish brain was reduced. Interestingly, the effects were prevented by prazosin (PRZ), an α1-adrenoceptor (AR) antagonist and when the zebrafish recovered from the lost sleep.
Topics: Animals; Norepinephrine; Zebrafish; Sleep Deprivation; Sleep; Neurons; Receptors, Adrenergic, alpha-1
PubMed: 38331315
DOI: 10.1016/j.neuropharm.2024.109861 -
JFMS Open Reports 2024An 8-month-old female spayed domestic shorthair cat was presented for chronic urinary incontinence (UI). Since being adopted 6 months earlier, the cat had a history of...
CASE SUMMARY
An 8-month-old female spayed domestic shorthair cat was presented for chronic urinary incontinence (UI). Since being adopted 6 months earlier, the cat had a history of urine leakage during both activity and rest. Baseline blood work and urine culture showed no significant abnormalities and no evidence of a urinary tract infection. An abdominal CT with excretory urography followed by a focal urinary tract ultrasound revealed a suspected right intramural ectopic ureter (EU) and potential left EU. Cystoscopy confirmed bilateral intramural EUs. Cystoscopic-guided laser ablation (CLA) of both EUs was performed. The cat developed temporary urinary obstruction (UO) 36 h after the procedure, which was medically managed with prazosin and buprenorphine. Ultimately, the cat's urinary signs completely resolved with no UI recognized after the procedure and the cat has remained continent during 18 months of follow-up.
RELEVANCE AND NOVEL INFORMATION
CLA of intramural EUs is routinely performed in dogs, but this technique has not been previously reported in cats with this condition. Although post-procedural urinary tract signs were initially present, the cat ultimately had an excellent outcome with resolution of UI after this procedure.
PubMed: 38322250
DOI: 10.1177/20551169231220248 -
Journal of Ethnopharmacology May 2024Olea europaea L. and Hyphaene thebaica L. are commonly employed by traditional healers in Africa for treating and preventing hypertension, either individually or in a... (Observational Study)
Observational Study
Ifanosine: Olea europaea L. and Hyphaene thebaica L. combination, from traditional utilization to rational formulation: Preclinical and clinical efficacy on hypertensives patients.
ETHNOPHARMACOLOGICAL RELEVANCE
Olea europaea L. and Hyphaene thebaica L. are commonly employed by traditional healers in Africa for treating and preventing hypertension, either individually or in a polyherbal preparation (Ifanosine).
AIM OF THE STUDY
The primary aim was to assess the antihypertensive effects of Olea europaea L. leaves aqueous extract (OEL), Hyphaene thebaica L. mesocarp extract (HT), and the Ifanosine on isolated rat aorta rings. The secondary objective was to evaluate the clinical benefits of a new oral formulation of Ifanosine.
MATERIALS AND METHODS
In vitro studies using an isometric transducer examined the antihypertensive effects of HT, OEL, and Ifanosine on rat aorta. Ussing chambers technic were employed to measure mucosal to serosal fluxes and total transepithelial electrical conductance (Gt) to assess the intestinal bioavailability of HT, OEL, and Ifanosine. HPLC was utilized to determine the phytochemical composition of OEL and HT extracts. Subchronic toxicity investigations involved two groups of rats, treated with either water (control) or Ifanosine at 5 g/kg for 28 days. Clinical benefits of the new Ifanosine formulation were evaluated in an observational study with 32 hypertensive patients receiving a fixed oral dose of 3.5 mg three times a day for 30 days.
RESULTS
Aqueous extracts induced dose-dependent relaxation of rat aorta rings, with HT and OEL having higher IC50 values than Ifanosine (IC50 = 44.76 ± 1.35 ng/mL, 58.67 ± 1.02 ng/mL, and 29.46 ± 0.26 ng/mL, respectively). The pA2 values of OEL and HT were 1 and 0.6, respectively, while Ifanosine was 0.06. Intestinal bioavailability studies revealed better Prazosin bioavailability than plant extracts. Toxicological studies demonstrated the safety of Ifanosine, supported by histological examinations and biochemical parameters in rat blood. Biochemical analyses indicated flavonoids and phenolic acids as dominant active constituents. Clinical benefits in humans included reduced SBP, DBP, LDL-c, VLDL-c, and TAG, and increased HDL-c without overt adverse effects.
CONCLUSION
This study validates the traditional use of OEL and HT for hypertension and advocates for alternative and combinatorial polyphytotherapy (ACP) to enhance traditional remedies.
Topics: Humans; Rats; Animals; Antihypertensive Agents; Olea; Hypertension; Plant Extracts; Plant Leaves; Treatment Outcome
PubMed: 38309486
DOI: 10.1016/j.jep.2024.117834 -
Neuroscience Letters Feb 2024Terazosin is an α1-adrenergic receptor antagonist that can relax smooth muscle and is prescribed to treat benign prostatic hyperplasia and, rarely, hypertension. The...
Terazosin is an α1-adrenergic receptor antagonist that can relax smooth muscle and is prescribed to treat benign prostatic hyperplasia and, rarely, hypertension. The present study investigated the antidepressant-like actions of terazosin (TZ) in mice. They were first subjected to chronic unpredictable mild stress (CUMS) and then the effects of TZ were assessed using the forced swimming test (FST) and tail suspension test (TST), sucrose preference test (SPT), actophotometer test (APT). The changes in the PGK1 levels, neurotransmitters, and proinflammatory cytokines levels after chronic stress and TZ treatment were examined. It was found that TZ exhibited an antidepressant-like effect in the FST, TST, SPT, and APT. It was effective in the CUMS model of depression. It was also found that TZ treatment reduced the levels of proinflammatory cytokines and elevated the neurotransmitter levels in mice. Results of this study suggest that TZ has antidepressant-like actions in mice models of CUMS induced depression.
Topics: Mice; Animals; Depression; Antidepressive Agents; Prazosin; Cytokines; Stress, Psychological; Hippocampus; Disease Models, Animal; Behavior, Animal
PubMed: 38266974
DOI: 10.1016/j.neulet.2024.137653 -
Behavioural Brain Research Mar 2024The dorsal raphe nucleus (DRN) is essential for the control of food intake. Efferent projections from the DRN extend to several forebrain regions that are involved in...
The dorsal raphe nucleus (DRN) is essential for the control of food intake. Efferent projections from the DRN extend to several forebrain regions that are involved in the control of food intake. However, the neurotransmitters released in the DRN related to the control of food intake are not known. We have previously demonstrated that a tonic α1 action on DRN neurons contributes to satiety in the fed rats. In this study we investigated the participation of norepinephrine (NE) signaling in the DRN in the satiety response. Intra-DRN administration of NE causes an increase in the 2-hour food intake of sated mice, an effect that was blocked by previous administration of yohimbine, an α2 antagonist. Similarly, Intra-DRN administration of clonidine, an α2 agonist, increases food intake in sated mice. This result indicates that in the satiated mice exogenous NE acts on α2 receptors to increase food intake. Furthermore, administration of phenylephrine, an α1 agonist, decreases food intake in fasted mice and prazosin, an α1 antagonist, increases food intake in the sated mice. Taken together these results indicate that, in a satiated condition, a tonic α1 adrenergic action on the DRN neurons inhibits food intake and that exogenous NE administered to the DRN acts on α2 adrenergic receptors to increase food intake. These data reinforce the intricate neuronal functioning of the DRN and its effects on feeding.
Topics: Rats; Mice; Male; Animals; Dorsal Raphe Nucleus; Norepinephrine; Neurons; Prazosin; Eating
PubMed: 38266779
DOI: 10.1016/j.bbr.2024.114872 -
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 -
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 -
Drug Research Feb 2024Nightmare disorder is associated with functional impairment, distress, and low quality of life; however, studies on pharmacotherapy of this debilitating disorder yielded... (Randomized Controlled Trial)
Randomized Controlled Trial
Nightmare disorder is associated with functional impairment, distress, and low quality of life; however, studies on pharmacotherapy of this debilitating disorder yielded mixed results. Prazosin, a non-selective α blocker is reported to be effective in treatment of post-traumatic stress disorder-related nightmares. We aimed at investigating therapeutic effects of tamsulosin which has higher affinity for blocking α and α adrenoceptors in treatment of nightmare disorder. A randomized, double blind, cross-over, placebo-controlled pilot study was conducted. Patients were randomly assigned to receive Tamsulosin 0.4 mg once daily or placebo for period of four weeks. Following a 2-week wash-out period, they were crossed over to the other group and received drug or placebo for duration of 4 additional weeks. Nightmare frequency and intensity measurements were carried out using Disturbing Dreams and Nightmares Severity Index (DDNSI). Blood pressure measurements were also performed. According to per protocol analysis, mean DDNSI scores decreased following administration of tamsulosin and a statistical trend towards significance was reported (p=0.065, d=0.236). Results of intention to treat analysis showed significant difference in DDNSI scores after drug use (p=0.030, d=0.651). Additionally, DDNSI scores dropped significantly following placebo use. However, intention to treat analysis showed no statistically significant difference pre and post placebo period (0.064, d=0.040). Tamsulosin may be effective in treatment of nightmare disorder. However, further larger clinical trials are recommended to clarify the effectiveness of tamsulosin and α subtypes in pharmacotherapy of nightmares.
Topics: Humans; Double-Blind Method; Dreams; Pilot Projects; Quality of Life; Tamsulosin; Treatment Outcome
PubMed: 38237637
DOI: 10.1055/a-2226-3604 -
Burns : Journal of the International... Apr 2024Post-traumatic stress disorder (PTSD) afflicts a significant portion of burn patients. This study aims to analyze the morbidity, prevalence, and treatment of PTSD in the...
INTRODUCTION
Post-traumatic stress disorder (PTSD) afflicts a significant portion of burn patients. This study aims to analyze the morbidity, prevalence, and treatment of PTSD in the burn population.
METHODS
Using the TriNetX database, we identified burned patients > 18 years of age without (A) or with (B) a PTSD diagnosis. Patients were then stratified by percent of total body surface area (TBSA) burned. Morbidity and mortality was analyzed in each cohort. Prevalence and pharmacologic treatments for PTSD were analyzed from 2002 to 2022.
RESULTS
PTSD incidence increased from 2.4% (n = 2281) in patients with < 10% to 3.1% (n = 542) in 10-30%, 7.4% (n = 285) in 30-59%, and 5.3% (n = 90) in > 60% TBSA burned. In patients with < 60% TBSA burned, PTSD diagnosis increased the risk of depression (p = <0.0003) and anxiety (p = <0.0001). In those with < 30% TBSA burned, PTSD diagnosis also increased risk of insomnia (p = <0.0001) and pruritus (p = 0.0211 for TBSA <10% and 0.0059 for TBSA 10-29%). PTSD diagnosis was associated with a decreased risk of mortality in patients with > 30% TBSA burned (p = 0.0179 for TBSA 30-59% and p = 0.0089 for TBSA >60%). From 2002 to 2022, the prevalence of PTSD in all burn patients was relatively stable between 2.2% and 3.2%. We found an increase in the use of serotonergic agents and prazosin for the treatment of PTSD during this timeframe.
CONCLUSION
PTSD is not uncommon in the burn population, and those with burns and concomitant PTSD have an increased risk of morbidity. Screening and preventative measures to reduce morbidity and early implementation of care in burned patients with PTSD are indicated.
Topics: Humans; Burns; Stress Disorders, Post-Traumatic; Incidence; Prevalence; Anxiety Disorders; Retrospective Studies
PubMed: 38233276
DOI: 10.1016/j.burns.2023.12.016