Role of noradrenergic and dopaminergic systems in the antinociceptive effect of N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide in mice.

Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore, there is a need to develop new analgesic compounds. Due to promising results regarding the antinociceptive effect of N-(3-(phenylselanyl)prop-2-in-1-yl)benzamide (SePB), this study aimed to evaluate the participation of the dopaminergic and noradrenergic systems in this effect in mice, as well as its toxicity. To this, the antagonists sulpiride (D2/D3 receptor antagonist, 5 mg/kg), SCH-23390 (D1 receptor antagonist, 0.05 mg/kg), prazosin (α1 adrenergic receptor antagonist, 0.15 mg/kg), yohimbine (α2-adrenergic receptors, 0.15 mg/kg) and propranolol (non-selective ß-adrenergic antagonist, 10 mg/kg) were administered intraperitoneally to mice 15 min before SePB (10 mg/kg, intragastrically), except for propranolol (20 min). After 26 min of SePB administration, the open field test was performed for 4 min to assess locomotor activity, followed by the tail immersion test to measure the nociceptive response. For the toxicity test, animals received a high dose of 300 mg/kg of SePB. SePB showed an increase in the latency for nociceptive response in the tail immersion test, and this effect was prevented by SCH-23390, yohimbine and propranolol, indicating the involvement of D1, α2 and ß-adrenergic receptors in the antinociceptive mechanism of the SePB effect. No changes were observed in the open field test, and the toxicity assessment suggested that SePB has low potential to induce toxicity. These findings contribute to understanding SePB's mechanism of action, with a focus on the development of new alternatives for pain treatment.

Characteristics of α1-adrenoceptor antagonists-induced ejaculatory dysfunction on spontaneous seminal emission in rats.

Although α1-adrenoceptor (α1-AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still controversial. Therefore, we investigated the effects of antagonists with different affinities for α1-AR subtypes on ejaculatory function and their mechanisms of action in normal rats. In the spontaneous seminal emission (SSE) test, systemically administered prazosin, terazosin, tamsulosin and naftopidil decreased the weight of ejaculated seminal material in a dose-dependent manner; the potency order was as follows: tamsulosin > terazosin > prazosin > naftopidil. The selective α1D-AR antagonist BMY7378 had no effect on SSE. Intrathecal tamsulosin and naftopidil did not inhibit SSE. Tamsulosin, the most potent, was ineffective as a single dose and significantly increased seminal vesicle fluid in rats treated for 2 weeks but did not significantly change retrograde ejaculation. These results indicated that the difference in inhibitory potency of the five α1-AR antagonists against SSE was due to the involvement of α1A-AR subtypes. Our results further suggested that α1-AR antagonist-induced ejaculatory dysfunction at the peripheral level was mainly due to the loss of seminal emission, although some retrograde ejaculation may also be involved.

Prospective analysis of anatomic features predisposing patients to intraoperative floppy iris syndrome.

PURPOSE: To aid preoperative risk assessment by identifying anatomic parameters corresponding with a higher risk of intraoperative floppy iris syndrome (IFIS) during cataract surgery. METHODS: Prospective cohort study of 55 patients with α1-adrenergic receptor antagonist (α1-ARA) treatment and 55 controls undergoing cataract surgery. Anterior segment optical coherence tomography (AS-OCT), video pupilometer, and biometry measurements were performed preoperatively and analyzed regarding anatomic parameters that corresponded with a higher rate of IFIS. Those statistically significant parameters were evaluated with logistic regression analysis and receiver operating characteristic (ROC) curve. RESULTS: Pupil diameter was significantly smaller in patients who developed IFIS compared to those who did not develop IFIS (AS-OCT 3.29 ± 0.85 vs. 3.63 ± 0.68, p = 0.03; Pupilometer 3.56 ± 0,87 vs. 3.95 ± 0.67, p = 0.02). Biometric evaluation revealed shallower anterior chambers in the IFIS group (ACD 3.12 ± 0.40 vs. 3.32 ± 0.42, p = 0.02). Cutoff values for 50% IFIS probability (p = 0.5) were PD = 3.18 mm for pupil diameter and ACD = 2.93 mm for anterior chamber depth. ROC curves of combined parameters were calculated for α1-ARA medication with pupil diameter and anterior chamber depth, which yielded an AUC of 0.75 for all IFIS grades. CONCLUSION: The combination of biometric parameters with history of α1-ARA medication can improve assessment of risk stratification for IFIS incidence during cataract surgery.

The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α1-Adrenoceptors Antagonists.

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1-15) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7-9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α1-adrenergic receptors (α1-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α1-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α1A and α1B, was conducted. Selected compounds were tested for their activity towards two α1-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC50 < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.

Effect of Terazosin Hydrochloride Combined with Interventional Embolisation on Prostate Volume and Quality of Life of Elderly Patients with Prostatic Hyperplasia

Objective: This study aimed to explore the effect of terazosin hydrochloride combined with interventional embolisation on prostate volume and quality of life (QOL) of elderly patients with prostatic hyperplasia (PH). Methods: The clinical data of 175 elderly patients with PH admitted to Central Hospital Affiliated to Shandong First Medical University from July 2020 to July 2022 were selected for retrospective analysis. Based on different treatment regimens, 89 patients who received interventional embolisation alone were included in the control group (CG), and 86 patients undergoing interventional embolisation combined with terazosin hydrochloride were included in the study group (SG). The prostate volume, serum indicators, adverse reactions and QOL of the two groups before and after treatment were compared between the two groups. Results: Before treatment, no significant difference in 36-item short-form health survey (SF-36) scores, serum tumour necrosis factor-α (TNF-α) and prostate-specific antigen (PSA) was observed in both groups (p > 0.05). After treatment, the SF-36 score in the SG was 78.20 ± 6.84 points, which was significantly higher than that in the CG (72.67 ± 5.94 points). In addition, the SG had remarkably lower residual urine volume and prostate volume, higher maximum flow rate and lower TNF-α and PSA levels compared with the CG (p < 0.05). The adverse reaction rate of the SG was only 4.65%, which was significantly lower than that of the CG (14.61%, p < 0.05). Conclusions: Terazosin hydrochloride combined with interventional embolisation overtly reduces the prostate volume and improves the clinical symptoms of patients with fewer side effects, which has a certain clinical application value (AU)

Association of silodosin, tamsulosin, and naftopidil with delirium: analysis of the pharmacovigilance database in Japan.

BACKGROUND: An association between adrenergic alpha-1 receptor antagonists and delirium has been suggested, but the details are unclear. AIM: This study investigated the association between adrenergic alpha-1 receptor antagonists and delirium in patients with benign prostatic hyperplasia using the Japanese Adverse Drug Event Report database. METHOD: First, disproportionality analysis compared the frequency of delirium in the adrenergic alpha-1 receptor antagonists silodosin, tamsulosin, and naftopidil. Next, multivariate logistic analysis was performed to examine the association between delirium and adrenergic alpha-1 receptor antagonists where disproportionality was detected. RESULTS: A disproportionality in delirium was observed in patients receiving tamsulosin (reporting odds ratio [ROR] 1.85, 95% confidence interval [CI] 1.38-2.44, P < 0.01) compared with those who did not, and also in patients receiving naftopidil (ROR 2.23, 95% CI 1.45-3.28, P < 0.01) compared with those who did not. Multivariate logistic analysis revealed that in addition to previously reported risk factors for delirium, delirium in patients receiving tamsulosin was significantly increased with concomitant use of anticholinergics (odds ratio 2.73, 95% CI 1.41-5.29, P < 0.01) and delirium in patients receiving naftopidil was significantly increased with concomitant use of beta3-adrenergic receptor agonists (odds ratio 4.19, 95% CI 1.66-10.6, P < 0.01). CONCLUSION: Anticholinergics or beta3-adrenergic receptor agonists to treat overactive bladder in patients receiving tamsulosin and naftopidil was strongly associated with delirium. Confirming the medical history and concomitant medications of patients receiving tamsulosin or naftopidil may contribute to preventing delirium in patients with benign prostatic hyperplasia and to improving their outcomes.

Impact of Nonselective and Selective α-1 Adrenergic Blockers on the Sedative Efficacy of Dexmedetomidine in Urologic Surgery: A Prospective, Observational Study.

BACKGROUND This study aimed to compare the impact of a-1 adrenergic blockers - nonselective (alfuzosin, doxazosin, and terazosin) and selective (silodosin and tamsulosin) - on the sedative effects of the alpha-2 adrenergic agonist dexmedetomidine (DMT) in patients undergoing urologic surgery. The primary outcome was the sedative effect of DMT as determined by the bispectral index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scores. MATERIAL AND METHODS One hundred eighteen patients undergoing elective urologic surgery with spinal anesthesia were recruited. Patients were assigned based on their medication status to group N (no medication; n=33), group NS (nonselective alpha-1 blocker; n=27), or group S (selective alpha-1 blocker; n=58). Mean blood pressure (MBP), heart rate (HR), oxygen saturation (SpO2), BIS, and MOAA/S scale scores were recorded at 5-minute (min) intervals after DMT administration. RESULTS Group NS had significantly higher BIS scores than groups N and S at 25 min (P=0.045) and 30 min (P=0.030) after DMT administration, indicating lower sedation levels. MBP significantly differed between the 3 groups at all time points, with group N experiencing a lower MBP than groups NS and S. No significant differences were found between the groups in MOAA/S scale scores, SpO2, or HR. CONCLUSIONS Nonselective alpha-1 adrenergic blockers can reduce the sedative effects of DMT. Consequently, there may be a need for individualized anesthesia management considering the specific subtype of alpha-1 adrenergic blocker medication.

Alpha-1 Adrenergic Antagonists Sensitize Neuroblastoma to Therapeutic Differentiation.

Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of approximately 50%. The multimodal therapeutic approach for NB includes treatment with the retinoid isotretinoin (13-cis retinoic acid; 13cRA), which is used in the post-consolidation phase as an antiproliferation and prodifferentiation agent to minimize residual disease and prevent relapse. Through small-molecule screening, we identified isorhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability. The synergistic effect was accompanied by a marked increase in the expression of the adrenergic receptor α1B (ADRA1B) gene. Genetic knockout of ADRA1B or its specific blockade using α1/α1B adrenergic antagonists led to selective sensitization of MYCN-amplified NB cells to cell viability reduction and neural differentiation induced by 13cRA, thus mimicking ISR activity. Administration of doxazosin, a safe α1-antagonist used in pediatric patients, in combination with 13cRA in NB xenografted mice exerted marked control of tumor growth, whereas each drug alone was ineffective. Overall, this study identified the α1B adrenergic receptor as a pharmacologic target in NB, supporting the evaluation of adding α1-antagonists to the post-consolidation therapy of NB to more efficiently control residual disease. SIGNIFICANCE: Targeting α-adrenergic receptors synergizes with isotretinoin to suppress growth and to promote differentiation of neuroblastoma, revealing a combinatorial approach for more effective management of the disease and prevention of relapse.

The effects of silodosin therapy on the parameters and patterns of ureteric jets in patients with lower urinary tract symptoms.

OBJECTIVE: To our knowledge, there is no study in the literature so far to investigate the effect of silodosin therapy on the ureteric jet parameters. Therefore, the objective of this study was to investigate the effect of silodosin 8 mg/day for medical therapy of lower urinary tract symptoms (LUTS) on the color flow Doppler parameters and patterns of the ureteric jets. PATIENTS AND METHODS: This prospective cohort study included 34 male patients who presented to our outpatient clinic with the complaint of lower urinary tract symptoms (LUTS) and received silodosin 8 mg once a day as medical therapy. In the color flow Doppler examinations, ureteric jets were observed and mean flow rate (JETave), maximum flow rate (JETmax), flow duration (JETdura), and flow frequency (JETfre) were examined. In addition, patterns of the ureteric jets (JETpat) were also evaluated. RESULTS: There was no statistically significant difference in JETave; however, JETmax, JETdura and JETfre were significantly higher at post-silodosin treatment. The patterns of ureteric jet were significantly changed following a 6-week treatment with silodosin (p<0.001). One ureter in the monophasic pattern group (9.1%) and three in the biphasic group (13.6%) turned to polyphasic pattern after silodosin use. None of the patients developed side effects that would require discontinuation of the drug. CONCLUSIONS: Six-week silodosin 8 mg/day therapy for the treatment of LUTS in men changed the parameters and patterns of ureteric jets at follow-up examination. Furthermore, comprehensive studies are needed on this issue.

Repurposing of carvedilol to alleviate bleomycin-induced lung fibrosis in rats: Repressing of TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions.

Idiopathic pulmonary fibrosis (IPF) is the most widely studied interstitial lung disease. IPF eventually leads to respiratory insufficiency, lung cancer, and death. Carvedilol (CAR) is a third-generation ß-adrenergic receptor antagonist with an α1-blocking effect. CAR demonstrates antifibrotic activities in various experimental models of organ fibrosis. AIMS: This work is designed to explore the possible alleviating effects of CAR on bleomycin (BLM)-induced lung fibrosis in rats. MAIN METHODS: The BLM rat model of lung fibrosis was achieved by intratracheal delivery of a single dose of 5 mg/kg of BLM. Seven days following BLM injection, either prednisolone or CAR was orally administered at doses of 10 mg/kg once daily for 21 days to the rats. The actions of CAR were evaluated by lung oxidant/antioxidant parameters, protein concentration and total leucocyte count (TLC) in bronchoalveolar lavage fluid (BALF), fibrosis regulator-related genes along with the coexistent lung histological changes. KEY FINDINGS: CAR effectively decreased lung malondialdehyde level, increased superoxide dismutase activity, declined both protein concentration and TLC in BALF, downregulated TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions, and repaired the damaged lung tissues. SIGNIFICANCE: CAR conferred therapeutic potential against BLM-induced lung fibrosis in rats, at least in part, to its antioxidant, anti-inflammatory, and antifibrotic activities. CAR could be utilized as a prospective therapeutic option in patients with lung fibrosis in clinical practice.

A Double-Blind Randomized Controlled Trial of Doxazosin for Co-Occurring PTSD and Alcohol Use Disorder in Veterans.

Objective: The aim of this study was to determine the efficacy of doxazosin, an α1-adrenergic antagonist, for the treatment of co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD).Methods: This 12-week, double-blind, randomized controlled trial of doxazosin (16 mg/d) was conducted between June 2016 and December 2019 at the Ralph H. Johnson VA Medical Center in Charleston, South Carolina. Participants were military veterans (N = 141) who met DSM-5 criteria for current PTSD and AUD and were randomly assigned to receive doxazosin (n = 70) or placebo (n = 71). Primary outcome measures were the Clinician Administered PTSD Scale (CAPS-5), the PTSD Checklist for DSM-5 (PCL-5), and the Timeline Follow-Back (TLFB).Results: Findings from the intent-to-treat analyses revealed that participants in both groups demonstrated statistically significant reductions in CAPS-5 and PCL-5 scores (P < .0001), but, contrary to hypotheses, no significant differences were observed between groups. Percent drinking days and percent heavy drinking days also decreased significantly during treatment, but there were no differences between groups (P < .0001). Abstinence during treatment was significantly higher in the doxazosin versus the placebo group (22% vs 7%, P = .017); however, participants in the doxazosin group consumed a greater number of drinks on drinking days (6.15 vs 4.56, P = .0096). A total of 74.5% of the sample completed the treatment phase, and there were no group differences in retention or adverse events.Conclusions: Doxazosin was safe and tolerable but was not more effective than placebo in reducing PTSD or AUD severity in this dually diagnosed sample. Clinical considerations such as heterogeneity of PTSD and AUD presentation and potential moderators are discussed in the context of future research directions.Trial Registration: ClinicalTrials.gov Identifier: NCT02500602.

Effect of α1D-adrenoceptor blocker for the reduction of ureteral contractions.

PURPOSE: Urolithiasis is a common urinary tract disease with growing prevalence. Alpha1-adrenoceptors (α1-ARs) are abundant in ureteral smooth muscle, distributed with different α1-AR subtypes. α1D-AR is the most widely distributed in the ureter. However, the effect of α1D-AR blockade on ureteric contraction remains unknown. MATERIALS AND METHODS: We dissected smooth muscle tissues (3 mm×3 mm) from the rat bladder and human ureter, tied silk strips on both tissue ends, and measured contraction in an organ bath chamber. Contraction activity in ureteral smooth muscle cells (USMCs) was immunocytochemically examined using primary rat and human USMC cultures. RESULTS: Using the organ bath system, we determined the inhibitory effects of silodosin, tamsulosin, and naftopidil. Naftopidil significantly decreased contractility of rat bladder tissue; similar results were observed in human ureteral tissue. To confirm ex vivo experimental results in vitro , we examined the phosphorylation of myosin light chain (MLC), a marker of contractility, in a primary human USMC culture. The examined drugs decreased phospho-MLC levels in human USMCs; however, naftopidil profoundly increased MLC dephosphorylation. CONCLUSIONS: We studied the effects of naftopidil, an α1D-AR inhibitor, on the ureter. Compared with alpha-blockers, naftopidil significantly relaxed ureteral smooth muscle. Therefore, naftopidil could be an effective therapy for patients with ureteral stones.

Silodosin versus Tamsulosin for Medical Expulsive Therapy of Ureteral Stones: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background and Objectives: This systematic review and meta-analysis of randomized controlled trials was performed to compare the therapeutic effects and safety profiles of silodosin and tamsulosin for medical expulsive therapy (MET) of ureteral stones. Materials and Methods: We searched PubMed, EMBASE, the Cochrane Library, and Web of Science to identify articles published before July 2022 that described randomized controlled trials comparing silodosin and tamsulosin for MET of ureteral stones. Endpoints were stone expulsion rate, stone expulsion time, and total complication rate. Results: In total, 14 studies were included in our analysis. The size of ureteral stones was <1 cm. Compared with tamsulosin, silodosin resulted in a significantly higher stone expulsion rate (p < 0.01, odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.91 to 3.06, I2 = 0%) and significantly shorter stone expulsion time (p < 0.01, mean difference = −3.04, 95% CI = −4.46 to −1.63, I2 = 89%). The total complication rate did not significantly differ between silodosin and tamsulosin (p = 0.33, OR = 1.15, 95% CI = 0.87 to 1.52, I2 = 7%). Conclusions: Compared with tamsulosin, silodosin resulted in significantly better expulsion of ureteral stones <1 cm. The total complication rate did not significantly differ between silodosin and tamsulosin. Thus, silodosin may be superior to tamsulosin for MET of ureter stones <1 cm.

Efficacy Of Alpha-Adrenergic Receptor Antagonists In The Treatment Of Distal Ureteric Stones: A Paediatric Study.

BACKGROUND: European association of urology (EAU) recommended α- blockers for managing distal ureteric stones in the paediatric population. This paper will help to understand the efficacy of Silodosin as a medical expulsive agent for distal ureteric stones in children, along with the required time duration of stone expulsion. METHODS: Forty participants were enrolled and evaluated for complaints, pain severity, associated symptoms, and ultrasound was done to confirm the position and size of the distal stone. Follow-ups were scheduled after every 7 days (1 week) for redo ultrasound and assessment of the stone position. Data was entered and analyzed in the SPSS version 23. To evaluate the significance of data chi-square test was performed, p-value <0.005 was considered significant. RESULTS: The minimum and maximum age limits recorded are 3 years and 18 years respectively with a mean age of 9.5±4.5 years and mean stone size was measured as 0.6±0.1 cm. Distribution of stone size indicated the minimum size of 0.4 cm and maximum of 1.0 cm stone in study subjects. Maximum stone expulsion was reported within 14 days or an initial 2 follow-up scans. CONCLUSIONS: The efficacy of Silodosin and medical expulsive therapy evaluated the effect on pain management as pain episodes declined with Silodosin treatment and spontaneous passage of stones were increased within the first 14 days of treatment. This study will be a beneficial contribution in literature especially in a developing country population where paediatric urolithiasis is on expansion and ongoing.

Evolving Role of Silodosin for the Treatment of Urological Disorders - A Narrative Review.

Use of α-androgenic receptor blockers remains a mainstay therapeutic approach for the treatment of urological diseases. Silodosin is recommended over other α-blockers for the treatment of lower urinary tract symptoms (LUTS) and benign prostate hyperplasia (BPH), due to its high α1A uroselectivity. Current research data suggest that silodosin is efficacious in the management of various urological diseases. Thus, we herein review the current evidence of silodosin related to its efficacy and tolerability and appraise the available literature that might ultimately aid in management of various urological conditions at routine clinical practice. Literature reveals that silodosin is beneficial in improving nocturia events related to LUTS/BPH. Silodosin exerts effect on relaxing muscles involved in detrusor obstruction, therefore prolonging the need for patients undergoing invasive surgery. Silodosin treatment, either as a monotherapy or combination, significantly improves International Prostate Symptom Score (IPSS) including both storage and voiding symptoms in patients with BPH/LUTS. Patients on other treatment therapies such as phosphodiesterase 5 inhibitors or other α-blockers are well managed with this drug. Steadily, silodosin has proved beneficial in the treatment of other urological disorders such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), overactive bladder/acute urinary retention (AUR), premature ejaculation (PE), and prostate cancer post brachytherapy-induced progression. In patients with distal ureteral stones, silodosin treatment is beneficial in decreasing stone expulsion time without affecting stone expulsion rate or analgesic need. Moreover, there were significant improvements in intravaginal ejaculation latency time, quality of life scores, and decrease in PE profile among patients with PE. Silodosin has also demonstrated promising results in increasing the likelihood of successful trial without catheter in patients with AUR and those taking antihypertensive drugs. Reports from Phase II studies have shown promising role of silodosin in the treatment of CP/CPPS as well as facilitating ureteral stone passage. From the robust data in this review, further silodosin treatment strategies in the management of different urological conditions need to be focused on.

Efficacy and safety of adrenergic alpha-1 receptor antagonists in older adults: a systematic review and meta-analysis supporting the development of recommendations to reduce potentially inappropriate prescribing.

BACKGROUND: Adrenergic alpha-1 receptor antagonists (alpha-1 antagonists) are frequently used medications in the management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and in the management of therapy-resistant arterial hypertension, two conditions frequently found in older adults. This systematic review aims at presenting a complete overview of evidence over the benefits and risks of alpha-1 antagonist treatment in people ≥ 65 years, and at deriving recommendations for a safe application of alpha-1 antagonists in older adults from the evidence found. METHODS: A comprehensive literature search was performed (last update March 25th 2022) including multiple databases (Medline/Pubmed, Embase, the Cochrane Library) and using the PICOS framework to define search terms. The selection of the studies was done by two independent reviewers in a two-step approach, followed by a systematic data extraction. Quality appraisal was performed for each study included using standardised appraisal tools. The studies retrieved and additional literature were used for the development of recommendations, which were rated for strength and quality according to the GRADE methodology. RESULTS: Eighteen studies were included: 3 meta-analyses, 6 randomised controlled trials and 9 observational trials. Doxazosin in the management of arterial hypertension was associated with a higher risk of cardiovascular disease, particularly heart failure, than chlorthalidone. Regarding treatment of LUTS suggestive of BPH, alpha-1 antagonists appeared to be effective in the relief of urinary symptoms and improvement of quality of life. They seemed to be less effective in preventing disease progression. Analyses of the risk profile indicated an increase in vasodilation related adverse events and sexual adverse events for some agents. The risk of falls and fractures as well as the effects of long-term treatment remained unclear. All meta-analyses and 5 out of 6 interventional studies were downgraded in the quality appraisal. 7 out of 9 observational studies were of good quality. CONCLUSIONS: It cannot be recommended to use doxazosin as first-line antihypertensive agent neither in older adults nor in younger patients. In the management of BPH alpha-1 antagonists promise to effectively relieve urinary symptoms with uncertainty regarding their efficacy in preventing long-term progression events.

Therapeutic effects of silodosin and urapidil on underactive bladder associated with diabetic cystopathy.

OBJECTIVES: Pharmacological treatment options for underactive bladder (UAB) syndrome are limited. Urapidil is the only alpha1 -adrenoceptor (AR) antagonist that can be used for urinary disorders in women in some countries. However, no studies have directly verified the effects of alpha1 -AR antagonists on the female urethra and UAB-like dysfunctions. We investigated the effects of silodosin (alpha1A -AR antagonist) and urapidil (nonselective alpha1 -AR antagonist) on the voiding function in female rats with diabetes mellitus (DM). METHODS: Changes in intraurethral pressure (IUP) induced by midodrine (alpha1 -AR agonist) and mean blood pressure (MBP) were continuously measured in normal female rats to verify the pharmacological profiles of the drugs. To establish a DM model, rats were administered streptozotocin (STZ; 50 mg/kg, intravenous). Eight weeks after STZ administration, drugs were subcutaneously delivered through an osmotic pump. Four weeks after drug administration, emptied bladder blood flow (BBF), intravesical pressure, and the micturition volume were measured. RESULTS: Both silodosin and urapidil inhibited the midodrine-induced increase in IUP and decreased MBP in a dose-dependent manner. Silodosin had a more substantial effect on the lower urinary tract than on MBP. Twelve weeks after STZ administration, DM rats exhibited UAB-like dysfunction (increased bladder capacity/bladder weight and residual volume and decreased bladder voided efficiency) and decreased BBF. Both drug treatments controlled this dysfunction. CONCLUSIONS: Alpha1 -AR antagonists induced dose-dependent urethral relaxation in female rats. These drugs ameliorated UAB-like dysfunction in STZ-induced DM rats. In addition, alpha1A -AR antagonists such as silodosin, which have limited effects on blood pressure, appear to be useful for treating UAB.

Factors predisposing to intraoperative floppy-iris syndrome: An up-to-date meta-analysis.

Intraoperative floppy-iris syndrome (IFIS) is an increasingly recognized condition that is proven to lead to higher rates of intraoperative complications. This study provides an updated systematic review and meta-analysis regarding all the identified factors predisposing to IFIS. The study was performed in accordance with the PRISMA guidelines. 38 studies were finally included in the meta-analysis. The factors that were found to predispose to IFIS significantly were male sex (odds ratio [OR], 4.25; CI, 2.58-7.01), hypertension (OR, 1.55; CI, 1.01-2.37), tamsulosin (OR, 31.06; CI, 13.74-70.22), finasteride (OR, 4.60; CI, 1.97-10.73), benzodiazepines (OR, 2.88; CI, 1.17-7.12), and antipsychotics intake (OR, 6.91; CI, 2.22-21.50). A decreased dilated pupil preoperatively was found predisposing to IFIS (weighted mean difference -0.93; CI, -1.19 to -0.67). Intracameral epinephrine, which was investigated as a potential prophylactic measure for preventing IFIS, did not reach statistical significance (OR, 0.29; CI, 0.08-1.06). A comprehensive preoperative assessment of all risk factors is vital to stratify the surgical risk, which is crucial in addressing IFIS because unanticipated IFIS could turn a routine surgery into one of significant visual morbidity.

Intrathecal Administration of the α1 Adrenergic Antagonist Phentolamine Upregulates Spinal GLT-1 and Improves Mirror Image Pain in SNI Model Rats.

Mirror image pain (MIP) is a type of extraterritorial pain that results in contralateral pain or allodynia. Glutamate transporter-1 (GLT-1) is expressed in astrocytes and plays a role in maintaining low glutamate levels in the synaptic cleft. Previous studies have shown that GLT-1 dysfunction induces neuropathic pain. Our previous study revealed bilateral GLT-1 downregulation in the spinal cord of a spared nerve injury (SNI) rat. We hypothesized that spinal GLT-1 is involved in the mechanism of MIP. We also previously demonstrated noradrenergic GLT-1 regulation. Therefore, this study aimed to investigate the effect of an α1 adrenergic antagonist on the development of MIP. Rats were subjected to SNI. Changes in pain behavior and GLT-1 protein levels in the SNI rat spinal cords were then examined by intrathecal administration of the α1 adrenergic antagonist phentolamine, followed by von Frey test and western blotting. SNI resulted in the development of MIP and bilateral downregulation of GLT-1 protein in the rat spinal cord. Intrathecal phentolamine increased contralateral GLT-1 protein levels and partially ameliorated the 50% paw withdrawal threshold in the contralateral hind paw. Spinal GLT-1 upregulation by intrathecal phentolamine ameliorates MIP. GLT-1 plays a role in the development of MIPs.