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Molecular Medicine Reports Feb 2018Ischemic heart disease (including coronary arterial atherosclerosis, or vascular cavity stenosis or occlusion) remains the leading cause of disease‑associated...
Ischemic heart disease (including coronary arterial atherosclerosis, or vascular cavity stenosis or occlusion) remains the leading cause of disease‑associated mortality worldwide. Prazosin, a receptor blocker of postsynaptic adrenaline, is essential in expanding peripheral arteries, which decreases peripheral vascular resistance, and regulates anti‑hypertensive action. However, the mechanisms underlying the effects of prazosin have not been fully elucidated. The aim of the present study was to investigate the protective effects of prazosin on myocardial cells against anoxia‑reoxygenation injury in a mouse model. The regulatory effects of prazosin on blood lipid levels and blood pressure were investigated in experimental mice. Furthermore, inflammation responses and oxidative stress in myocardial cells were analyzed in mice treated with prazosin. Apoptotic myocardial cells were investigated in experimental mice treated with prazosin. In addition, apoptotic gene expression levels were evaluated in myocardial cells. Extracellular signal‑regulated kinase (ERK) expression and phosphorylation was investigated in myocardial cells in mice with anoxia‑reoxygenation injury following prazosin treatment. The activity and expression levels of nuclear factor of activated T cells (NF‑AT), activator protein 1 (AP‑1) and necrosis factor (NF)‑κB were observed in myocardial cells. Furthermore, histological analyses were performed to investigate the benefits of prazosin treatment on anoxia‑reoxygenation injury. The results of the present study identified that prazosin decreased the expression levels of inflammatory factors, interleukin (IL)‑6, tumor necrosis factor (TNF)‑α, IL‑10 and IL‑1 in the serum of mice exhibiting hypoxia/reoxygenation injury. Oxidative stress was observed to be improved and the apoptosis rate was decreased in myocardial cells in anoxia‑reoxygenation injury model mice treated with prazosin. ERK expression and phosphorylation was upregulated, and expression levels of NF‑AT, AP‑1 and NF‑κB were downregulated in the myocardial cells of mice treated with prazosin. Blood lipid levels and blood pressure of the anoxia‑reoxygenation injury model mice were markedly improved following treatment with prazosin. Histological analysis indicated that the area, circumference fragmentation and segmentation of myocardial cells were significantly improved following prazosin treatment. Thus, these results indicate that prazosin treatment decreases inflammation responses, oxidative stress, and apoptosis of myocardial cells via regulation of the ERK signaling pathway. The findings indicate that prazosin may present as a potential therapeutic agent for the treatment of hypoxia/reoxygenation injury.
Topics: Animals; Apoptosis; Biomarkers; Blood Pressure; Cells, Cultured; Cytokines; Disease Models, Animal; Inflammation Mediators; Lipids; MAP Kinase Signaling System; Male; Mice; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oxidative Stress; Prazosin; Protective Agents
PubMed: 29207167
DOI: 10.3892/mmr.2017.8175 -
Molecular Pharmacology Sep 2015The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the influx transporter SLC22A1 (organic cation transporter 1). We recently...
The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the influx transporter SLC22A1 (organic cation transporter 1). We recently hypothesized that alternative uptake and/or retention mechanisms exist that determine intracellular imatinib levels. Here, we systematically investigate the nature of these mechanisms. Imatinib uptake in cells was quantitatively determined by liquid chromatography-tandem mass spectrometry. Fluorescent microscopy was used to establish subcellular localization of imatinib. Immunoblotting, cell cycle analyses, and apoptosis assays were performed to evaluate functional consequences of imatinib sequestration. Uptake experiments revealed high intracellular imatinib concentrations in HEK293, the leukemic cell lines K562 and SD-1, and a gastrointestinal stromal tumor cell line GIST-T1. We demonstrated that imatinib IUR is time-, dose-, temperature-, and energy-dependent and provide evidence that SLC22A1 and other potential imatinib transporters do not substantially contribute to the IUR of imatinib. Prazosin, amantadine, NH4Cl, and the vacuolar ATPase inhibitor bafilomycin A1 significantly decreased the IUR of imatinib and likely interfere with lysosomal retention and accumulation of imatinib. Costaining experiments with LysoTracker Red confirmed lysosomal sequestration of imatinib. Inhibition of the lysosomal sequestration had no effect on the inhibition of c-Kit signaling and imatinib-mediated cell cycle arrest but significantly increased apoptosis in imatinib-sensitive GIST-T1 cells. We conclude that intracellular imatinib levels are primarily determined by lysosomal sequestration and do not depend on SLC22A1 expression.
Topics: Amantadine; Ammonium Chloride; Antineoplastic Agents; Apoptosis; Benzamides; Cell Cycle; Cell Line, Tumor; HEK293 Cells; Humans; Imatinib Mesylate; Lysosomes; Macrolides; Organic Cation Transporter 1; Piperazines; Prazosin; Pyrimidines
PubMed: 26108972
DOI: 10.1124/mol.114.097451 -
Basic & Clinical Pharmacology &... Dec 2021We have investigated the interaction of α - and α -adrenoceptor subtypes in producing isometric contractions to NA in mouse whole spleen. The α -adrenoceptor...
We have investigated the interaction of α - and α -adrenoceptor subtypes in producing isometric contractions to NA in mouse whole spleen. The α -adrenoceptor antagonist prazosin (10 M) or the α -adrenoceptor antagonist yohimbine (10 M) alone produced only small shifts in NA potency in wild type (WT) mice, but the combination produced a large shift in NA potency. In spleen from α -KO mice, the effects of prazosin and the combination of prazosin and yohimbine were similar to their effects in WT mice. Hence, in α -KO mice, in which the only α -adrenoceptor present is the α -adrenoceptor, prazosin still antagonized contractions to NA. The α -adrenoceptor antagonist RS100329 (3 × 10 M) produced significant shifts in the effects of higher concentrations of NA (EC and EC levels) and the α -adrenoceptor antagonist BMY7378 (3 × 10 M) produced significant shifts in the effects of lower concentrations of NA (EC and EC levels). The effects of BMY7378 and RS00329 demonstrate α -adrenoceptor and α -adrenoceptor components and suggest that the α -adrenoceptor interacts with an α -adrenoceptor, and to a lesser extent an α -adrenoceptor, at low, and an α -adrenoceptor at high, NA concentrations. This study demonstrates the complex interaction between α - and α -adrenoceptor subtypes in producing contractions of mouse spleen and may have general implications for α-adrenoceptor mediated control of smooth muscle.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Animals; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Piperazines; Prazosin; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Spleen; Thymine; Yohimbine
PubMed: 34383990
DOI: 10.1111/bcpt.13639 -
Neurology and Therapy Dec 2017Youth exposed to trauma have an increased risk for developing posttraumatic stress disorder (PTSD) and associated sleep disturbances and nightmares. The alpha-1...
INTRODUCTION
Youth exposed to trauma have an increased risk for developing posttraumatic stress disorder (PTSD) and associated sleep disturbances and nightmares. The alpha-1 antagonist prazosin reduces sleep disturbances and nightmares in adults with PTSD; however, its use in youth with PTSD has not been systematically evaluated. We retrospectively examined the tolerability and clinical outcomes associated with prazosin treatment in youth with PTSD-related nightmares and dysomnias.
METHOD
A retrospective chart review identified youth with PTSD (N = 40) treated with prazosin between 2014 and 2016 in a trauma clinic. We assessed the UCLA PTSD Reaction Index for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition scores (and sub-scores for intrusive, hyperarousal, avoidant and negative cognition/mood symptoms) and sleep scale, as well as adverse events and vital signs. Linear mixed effects models were utilized to evaluate the change in symptom severity, and vital signs were monitored throughout treatment.
RESULT
Follow-up data were available for 34 patients with PTSD (mean age 13.4 ± 2.9 years, 82% female), of whom 76% had a history of sexual abuse and 65% had at least one comorbid psychiatric disorder. The mean duration of prazosin treatment was 10.2 ± 8.1 (range 2-30) weeks, and the mean number of follow-up visits was 3 ± 1.23. Of these 34 patients, 79% received trauma-focused cognitive behavioral therapy. The dose range of prazosin was 1-15 mg at every bedtime (0.02-0.3 mg/kg), with 35% receiving ≥5 mg/day. Treatment-emergent side effects were reported by 26% (n = 8) of patients, including dizziness (18%), anxiety (9%) and headaches (6%). Prazosin treatment was associated with improved sleep and nightmares over time (pre-treatment 7.3 ± 0.9, post-treatment 3.1 ± 2.4; p < 0.001).
CONCLUSION
Prazosin was well-tolerated and associated with improvements in nightmares and sleep in youth with PTSD. Adverse events were consistent with the known side-effect profile of prazosin and included dizziness and nausea.
PubMed: 28755207
DOI: 10.1007/s40120-017-0078-4 -
Journal of Clinical Sleep Medicine :... Dec 2022Trauma associated sleep disorder is a proposed parasomnia that develops after trauma with clinical features of trauma related nightmares, disruptive nocturnal behaviors,...
STUDY OBJECTIVES
Trauma associated sleep disorder is a proposed parasomnia that develops after trauma with clinical features of trauma related nightmares, disruptive nocturnal behaviors, and autonomic disturbances. The purpose of this case series is to better characterize the clinical and video-polysomnographic features of patients meeting clinical criteria for this proposed parasomnia.
METHODS
Semistructured clinical interview and detailed video-polysomnography review of 40 patients. Movements and vocalizations in rapid eye movement sleep were quantified according to the rapid eye movement sleep behavior disorder severity scale.
RESULTS
Patients (n = 40, 32 males) were service members and veterans with a median age of 38.9 years (range 24-57 years) who reported trauma related nightmares and disruptive nocturnal behaviors at home. On video-polysomnography, 28 (71.8%) patients had disruptive nocturnal behaviors in rapid eye movement sleep consisting of limb, head, and axial movements; vocalizations were present in 8 (20%). On the rapid eye movement sleep behavior disorder severity scale, most (n = 28, 71.8%) had a low rating but those with greater severity (n = 11, 28.2%) had a higher prevalence of posttraumatic stress disorder ( = .013) and markedly less N3 sleep ( = .002). The cohort had a high rate of insomnia (n = 35, 87.5%) and obstructive sleep apnea (n = 19, 47.5%). Most patients were treated with prazosin (n = 29, 72.5%) with concomitant behavioral health interventions (n = 25, 64.1%); 15 (51.7%) patients receiving prazosin reported improved symptomatology.
CONCLUSIONS
Disruptive nocturnal behaviors can be captured on video-polysomnography during rapid eye movement sleep, although they may be less pronounced than what patients report in their habitual sleeping environment. Clinical and video-polysomnographic correlations are invaluable in assessing patients with trauma associated sleep disorder to document objective abnormalities. This case series provides a further basis for establishing trauma associated sleep disorder as a unique parasomnia.
CITATION
Brock MS, Matsangas P, Creamer JL, et al. Clinical and polysomnographic features of trauma associated sleep disorder. . 2022;18(12):2775-2784.
Topics: Male; Humans; Young Adult; Adult; Middle Aged; REM Sleep Behavior Disorder; Dreams; Sleep Wake Disorders; Parasomnias; Prazosin
PubMed: 35962771
DOI: 10.5664/jcsm.10214 -
European Urology Focus Jan 2022Sexual dysfunction is a common side effect of medical therapy for benign prostatic hyperplasia (BPH), whereas prostatic urethral lift (PUL) offers safe and effective...
BACKGROUND
Sexual dysfunction is a common side effect of medical therapy for benign prostatic hyperplasia (BPH), whereas prostatic urethral lift (PUL) offers safe and effective relief of lower urinary tract symptoms while preserving sexual function.
OBJECTIVE
To compare the long-term impact on sexual health of PUL or daily medical therapy of doxazosin or finasteride alone or in combination in BPH patients.
DESIGN, SETTING, AND PARTICIPANTS
This was a comparative analysis of sexual function outcomes from PUL studies (L.I.F.T. [n=107], Crossover [n=42], and MedLift [n=39]) and the Medical Therapy of Prostatic Symptoms (MTOPS) trial. The men included were sexually active with International Prostate Symptom Score ≥13, Qmax ≤12ml/s, and prostate volume 30-80 cm. MTOPS subjects completed the Brief Male Sexual Function Inventory, while PUL subjects completed the International Index of Erectile Function and the Male Sexual Health Questionnaire for Ejaculatory Function.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Mean percentage changes from baseline in erectile, ejaculatory, and sexual satisfaction domains were compared at 12, 24, 36, and 48 mo.
RESULTS AND LIMITATIONS
PUL significantly improved erectile function through 24 mo, and ejaculatory function and sexual satisfaction across all time points. Medical therapy did not improve sexual function at any time point. Finasteride significantly decreased erectile function at 48 mo, and combined therapy significantly reduced ejaculatory function at 12 and 24 mo. Comparatively, PUL was superior to finasteride in preserving erectile function at 24 and 48 mo, and superior to doxazosin and combined therapy at 12 mo. PUL outperformed all three medical therapies at all time points in improving ejaculatory function and sexual satisfaction. Limitations include the use of distinct patient-reported questionnaires and narrowed data on comorbidities that influence male sexual function.
CONCLUSIONS
Indirect comparison reveals that PUL is superior to BPH medical therapy in preserving erectile and ejaculatory function and sexual satisfaction.
PATIENT SUMMARY
In our non-head-to-head study, only patients undergoing PUL for an enlarged prostate experienced improvements in sexual health. Conversely, patients on medical therapy experienced worsening of erectile and ejaculatory function.
Topics: Doxazosin; Erectile Dysfunction; Finasteride; Humans; Male; Prostate; Prostatic Hyperplasia
PubMed: 33436276
DOI: 10.1016/j.euf.2020.12.013 -
Canadian Journal of Veterinary Research... Oct 2014This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. Five...
This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 2 mg/kg BW xylazine intramuscularly, and saline (as the control); 160 μg/kg BW prazosin; or 40, 160, or 480 μg/kg BW atipamezole or yohimbine intravenously 0.5 h later. Urine and blood samples were collected 10 times over 8 h. Urine volume, pH, and specific gravity; plasma arginine vasopressin (AVP) concentration; and creatinine, osmolality, and electrolyte values in both urine and plasma were measured. Both atipamezole and yohimbine antagonized xylazine-induced diuresis, but prazosin did not. The antidiuretic effect of atipamezole was more potent than that of yohimbine but not dose-dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed xylazine-induced decreases in both urine specific gravity and osmolality, and the increase in free water clearance. Glomerular filtration rate, osmolar clearance, and plasma electrolyte concentrations were not significantly altered. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP concentration, although the highest dose of both atipamezole and yohimbine increased plasma AVP concentration initially and temporarily, suggesting that this may in part influence antidiuretic effects of both agents. The diuretic effect of xylazine in cats may be mediated by α2-adrenoceptors but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against xylazine-induced diuresis in clinically normal cats.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Animals; Area Under Curve; Arginine Vasopressin; Cats; Creatinine; Diuresis; Female; Imidazoles; Male; Osmolar Concentration; Prazosin; Random Allocation; Specific Gravity; Xylazine; Yohimbine
PubMed: 25356000
DOI: No ID Found -
Alcoholism, Clinical and Experimental... Apr 2019The noradrenergic system has been implicated in alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD), with adrenergic agents reducing drinking in... (Randomized Controlled Trial)
Randomized Controlled Trial
Alcohol Abstainer Status and Prazosin Treatment in Association with Changes in Posttraumatic Stress Disorder Symptoms in Veterans with Comorbid Alcohol Use Disorder and Posttraumatic Stress Disorder.
BACKGROUND
The noradrenergic system has been implicated in alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD), with adrenergic agents reducing drinking in individuals with AUD and improving sleep disturbances in individuals with PTSD. In a recent clinical trial, prazosin, an α1-adrenergic antagonist, was not superior to placebo in reducing PTSD symptoms, sleep problems, or alcohol consumption in a comorbid population; however, patients in both treatment conditions improved in all symptom domains over the course of treatment. It remains unknown whether alcohol abstinence is related to changes in PTSD symptoms and medication effects in individuals with this comorbidity.
METHODS
Veterans with comorbid alcohol dependence and PTSD (n = 96) were randomized to prazosin (16 mg) or placebo in a 12-week outpatient, double-blind clinical trial. In this secondary data analysis, we examined main effects of alcohol abstainer status (abstainer vs. nonabstainer), treatment, and their interaction on changes in PTSD symptoms over time using linear mixed models.
RESULTS
There was a main effect of alcohol abstainer status on symptoms of PTSD (p = 0.03), such that nonabstainers had lower total Clinician-Administered PTSD Scale (CAPS) scores than abstainers. There was a significant treatment by alcohol abstainer status interaction (p = 0.01); specifically, among placebo-treated individuals, those who did not abstain from alcohol had lower total CAPS scores compared to alcohol abstainers. Within the prazosin-treated group, abstainers and nonabstainers did not differ on total CAPS scores. Results were similar for the avoidance (p = 0.02), reexperiencing (p = 0.01), and hyperarousal (p = 0.04) subscales, such that placebo-treated nonabstainers had lower CAPS scores overall.
CONCLUSIONS
Overall, prazosin treatment was not significantly related to changes in PTSD symptoms over the course of the 12-week clinical trial in a comorbid population. Interestingly, placebo-treated alcohol nonabstainers had a significant reduction in PTSD symptoms. Whether placebo-treated individuals continued to use alcohol because of ongoing symptoms of PTSD is not known.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Aged; Alcohol Abstinence; Alcohol Drinking; Alcoholism; Comorbidity; Double-Blind Method; Female; Humans; Male; Middle Aged; New England; Prazosin; Stress Disorders, Post-Traumatic; Treatment Outcome; Veterans; Young Adult
PubMed: 30698839
DOI: 10.1111/acer.13969 -
Frontiers in Pharmacology 2021(TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts and the...
Aqueous Tuber Extracts of (Kotschy ex Schweinf.) Torre and Hillc. (Fabaceae). Possess Significant Antidiarrheal Activity and Spasmolytic Effect Possibly Mediated by Modulation of Nitrous Oxide System, Voltage-Gated Calcium Channels, and Muscarinic Receptors.
(TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts and the putative mechanism (s) of action using Sprague-Dawley rats and New Zealand white rabbits respectively. The antidiarrheal effects of the extract were evaluated in castor oil-induced diarrhea, the castor oil-induced enteropooling, and phenol red gastric motility tests. On the other hand, isolated rabbit's jejunal segments were used to evaluate the spasmolytic effect of TFG on spontaneous contraction, in acetylcholine-induced contraction, in presence of 80mMK, calcium chloride-induced contraction as well as in presence of the following antagonists: naloxone, methylene blue, L-NAME, prazosin, and propranolol in the studies. The data were express as Mean ± S.E.M and analyzed by one-way ANOVA and Tukey's post hoc test in cases of significance which was set at < 0.05. The extract was phytochemically characterized using Liquid chromatography Mass spectroscopy (LC-MS).The extract possessed significant inhibitory effect in the experiments. The extract exhibited significant spasmolytic effect on both spontaneous contraction and in jejunal segment pre-contracted acetylcholine as well as in presence of 80mMK solution. It also attenuated the spasmogenic effect of various concentration of calcium chloride. The extract's spasmolytic effect was, however, significantly attenuated in presence of several antagonists (methylene blue and L-NAME) but the adrenergic blockers (prazosin and propranolol) had no significant effect in the LC-MS identified thirty compounds where Proathocyanidin (11.54%), Syringic acid (7.30%), and 4-Hydroxybenzoic acid (6.19%) had the highest percentage abundance. In conclusion, the results obtained in this study partially validate the traditional uses of the tubers of this plant species as an antidiarrheal. These antidiarrheal effects are probably mediated via modulation of nitrous oxide pathway, voltage gated calcium channels, and muscarinic receptors.
PubMed: 33796023
DOI: 10.3389/fphar.2021.636879 -
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