Alpha-adrenergic Receptor Antagonist Research Articles

Risk of Parkinson’s disease among users of alpha-adrenergic receptor antagonists: a systematic review and meta-analysis

Background: Recent studies have tried to establish an association between the use of alpha-1-adrenergic receptor antagonists (A1ARAs) used in benign prostatic hyperplasia (BPH) and the risk of PD. The objective of the study is to compare the risk of Parkinson’s disease (PD) between terazosin/alfuzosin/doxazosin (TZ/AZ/DZ) users and tamsulosin users. Methods: PubMed, Google Scholar, and Embase were systematically searched from inception to April 2023. Observational studies comparing the risk of PD among patients using different types of A1ARAs were included in the meta-analysis. The primary outcome was the hazard ratio (HR) with a 95% CI for the risk of occurrence of PD among A1ARAs users of two different classes. Results: This study was based on a total of 678 433 BPH patients, out of which 287 080 patients belonged to the TZ/AZ/DZ cohort and 391 353 patients belonged to the tamsulosin cohort. The pooled incidence of PD was higher in tamsulosin users (1.28%, 95% CI: 1.04–1.55%) than in TZ/AZ/DZ drug users (1.11%, 95% CI: 0.83–1.42%). The risk of occurrence of PD was significantly lower in patients taking TZ/AZ/DZ than tamsulosin (n= 610,363, HR = 0.82, 95% CI = 0.71–0.94, P = 0.01; I2 = 87.4%). Conclusion: This meta-analysis demonstrated that patients with BPH who take TZ/AZ/DZ have a lower risk for developing PD than those who take tamsulosin.

Abstract 4526: Inhibition of RNA Pol I transcription and induction of nucleolar stress in cancer cells treated with the experimental alpha-adrenergic receptor antagonist JP-1302

Abstract The inhibition of ribosome biogenesis through pharmacological means has drawn attention as a potential strategy in cancer therapy. In our previous study we highlighted a novel property of the FDA-approved antimalarial drug amodiaquine, demonstrating its ability to dose-dependently inhibit ribosomal RNA (rRNA) transcription, a critical step in ribosome biogenesis (Espinoza JA, et al Cell Death Diff, 2020). Amodiaquine was found to induce the degradation of the catalytic subunit of RNA polymerase I, known as POLR1A (RPA194), and resulting in nucleolar stress and the stabilization of p53. Notably, RNA Pol I shutdown occurred independently of DNA damage. Motivated by these findings, we sought to find additional inhibitors of ribosome biogenesis. Acridine derivatives display anti-cancer properties. The activity of acridines is mainly attributed to the planarity of these structures, which can intercalate within the DNA structure, and inhibition of chromatin associated protein targets including topoisomerases. JP-1302 is an experimental drug, on a 9-aminoacridine structural scaffold, acting as a selective alpha-2 adrenergic receptor antagonist. It was recently shown that JP-1302 inhibits transcription, blocking RNA Pol II phosphorylation and inhibiting p21 expression at a concentration of 10 μM (Mitchell DC, et al Nat Biotech, 2023). Given JP-1302's structural similarity to other acridine derivatives such as aminacrine, ethacridine, and the experimental compound BMH-21, all known to inhibit RNA Pol I transcription, we hypothesized that JP-1302 might share similar properties. The purpose of our new study was to evaluate JP-1302´s effect on ribosome biogenesis, p53, and cancer cell growth. We show here that JP-1302 acts as an inhibitor of RNA Pol I transcription. Treatment with JP-1302 induced a rapid decrease in the levels of POLR1A, cessation of rRNA synthesis and nucleolar stress already within six hours and at a concentration of 0.5 μM. JP-1302 treatment stabilized wild type p53 and enhanced p21 expression in the osteosarcoma line U2OS. RNA Pol I shutdown occurred in the absence of DNA damage response, as determined by gH2A.X staining. JP-1302 impaired the growth of both p53 wild type and p53 null HCT116 cells with GI50 values of around 0.6 μM, as well as in U2OS cells at 0.8 μM, as determined after 48 hours. Paradoxically, at very low concentrations JP-1302 appeared to transiently stimulate RNA synthesis, a phenomenon that will require further investigation. In conclusion, we identified JP-1302 as a novel inhibitor of ribosomal RNA synthesis, exerting this effect at concentrations that do not induce DNA damage, and independently of p53. Given that JP-1302 passes the blood-brain barrier in rodents, and accumulating in different brain regions, it is of future interest to evaluate this drug in brain tumor models. Citation Format: Sheetanshu Saproo, Styliani Papadaki, Jaime A. Espinoza, Jiri Bartek, Mikael S. Lindström. Inhibition of RNA Pol I transcription and induction of nucleolar stress in cancer cells treated with the experimental alpha-adrenergic receptor antagonist JP-1302 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4526.

Effect of different alpha-receptor antagonists on metabolic parameters: a head-to-head comparison.

Although it is known that alpha-adrenergic receptor antagonists have positive effects on metabolic parameters such as glucose metabolism, lipid profile, and insulin sensitivity, it is unclear whether this is a class effect. Tamsulosin is reported to have adverse effects on glucose metabolism and insulin resistance, and this may be because of its lack of glycolysis-enhancing effect compared with other alpha-adrenergic receptor antagonists with glycolysis-enhancing effects such as doxazosin, terazosin, and alfuzosin. The aim of this study was to compare the effect of tamsulosin on metabolic parameters with another alpha-1 adrenergic receptor antagonist, doxazosin. In this prospective, observational, controlled, 12-week clinical study, a total of 60 male patients aged ≥ 40years who were first started on tamsulosin (n = 30; 0.4mg/day, oral; mean age, 59.20 ± 8.97years) or doxazosin (n = 30; 4 or 8mg/day, oral; mean age, 58.50 ± 8.93years) for benign prostatic hyperplasia (BPH) or lower urinary tract symptoms (LUTS) were enrolled. The groups were compared according to the changes in anthropometric and biochemical parameters (glycemia, lipid profile, and insulin sensitivity) at the end of treatment. In intragroup analyses, systolic blood pressure, diastolic blood pressure, total cholesterol, and HbA1c levels decreased significantly in the doxazosin group compared with baseline (p < 0.05 for all), while no significant change was observed in the tamsulosin group. In comparisons between groups, systolic blood pressure, total cholesterol, and low-density lipoprotein cholesterol levels showed a significant decrease in the doxazosin group compared with the tamsulosin group (percent change: - 6.68 ± 13.08 vs. 0.53 ± 11.02, p = 0.025; - 3.63 ± 9.56 vs. 4.02 ± 10.86, p = 0.005; and - 5.62 ± 18.18 vs. 5.24 ± 15.42, p = 0.015, respectively). Although these results do not support previous findings that tamsulosin has adverse effects on metabolic parameters, they suggest that doxazosin treatment may be a reason for preference in patients with BPH or LUTS accompanied by metabolic disorder.

Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5-alpha reductase inhibitor resistance.

The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.

Mechanism of action of &lt;i&gt;Pterorhachis&lt;/i&gt; &lt;i&gt;zenkeri&lt;/i&gt; (Meliaceae), a sexual enhancer: effect on vas deferens contractility

Background: Pterorhachis. zenkeri commonly known as “Ayilalou” or “Démareur” is an aphrodisiac plant used by Cameroonian traditional healers to enhance libido and sperm production. This study was undertaken to investigate the aphrodisiac mechanism of P. zenkeri on the contractile activity of vas deferens with regard to its function on ejaculation. Materials and Methods: The proximal parts of rat vas deferens were mounted in a 20 mL organ bath containing Krebs solution at 37°C. Cumulative dose-response curves were recorded with KCl (35-280 mM), adrenaline (7-70 µM) and aqueous extract of P. zenkeri (3,55-21,3 mg/mL). Prazosin (type 1 alpha-adrenergic receptor antagonist, 10 µM), Nifedipine (a specific L-type calcium channel antagonist, 5 µM), 2-AminoethoxydiPhenyl Borate (2-APB, IP3 receptor antagonist, 200 μM) and calcium-free medium were further used to study the mechanism of action. Results: KCl, adrenaline and aqueous extract of P. zenkeri showed a concentration-dependent effect on vas deferens contractibility. Nifedipine and Pazosin partially inhibited the effects of P. zenkeri. In calcium-free medium containing Ethylene Glycol-bis (2-aminoethylether)-N,N,N’N’-tetraacetic acid (EGTA, 1µM), P. zenkeri triggered vas deferens contraction which was completely abolished in the presence of 2-APB. These results suggest that the aqueous extract of P. zenkeri possesses bioactive compounds capable of inducing vas deferens contractions through type 1 alpha adrenergic receptors and mobilization of extra and intracellular calcium. Conclusion: These results confirm the aphrodisiac properties of P. zenkeri through the activation of the emissive phase of ejaculation.

"Tranq-dope" overdose and mortality: lethality induced by fentanyl and xylazine.

Introduction: The recreational use of fentanyl in combination with xylazine (i.e., "tranq-dope") represents a rapidly emerging public health threat characterized by significant toxicity and mortality. This study quantified the interactions between these drugs on lethality and examined the effectiveness of potential rescue medications to prevent a lethal overdose. Methods: Male and female mice were administered acute doses of fentanyl, xylazine, or their combination via intraperitoneal injection, and lethality was determined 0.5, 1.0, 1.5, 2.0, and 24 h after administration. Both fentanyl and xylazine produced dose-dependent increases in lethality when administered alone. Results: A nonlethal dose of fentanyl (56 mg/kg) produced an approximately 5-fold decrease in the estimated LD50 for xylazine (i.e., the dose estimated to produce lethality in 50% of the population). Notably, a nonlethal dose of xylazine (100 mg/kg) produced an approximately 100-fold decrease in the estimated LD50 for fentanyl. Both drug combinations produced a synergistic interaction as determined via isobolographic analysis. The opioid receptor antagonist, naloxone (3 mg/kg), but not the alpha-2 adrenergic receptor antagonist, yohimbine (3 mg/kg), significantly decreased the lethality of a fentanyl-xylazine combination. Lethality was rapid, with death occurring within 10 min after a high dose combination and generally within 30 min at lower dose combinations. Males were more sensitive to the lethal effects of fentanyl-xylazine combinations under some conditions suggesting biologically relevant sex differences in sensitivity to fentanyl-xylazine lethality. Discussion: These data provide the first quantification of the lethal effects of "tranq-dope" and suggest that rapid administration of naloxone may be effective at preventing death following overdose.

Impact of alpha-adrenergic receptor antagonists use on outcomes in patients with heart failure. A post-hoc analysis using Polish National Health Fund database

Impact of alpha-adrenergic receptor antagonists use on outcomes in patients with heart failure. A post-hoc analysis using Polish National Health Fund database

Post-traumatic Stress Disorder: A Narrative Review of Pharmacological and Psychotherapeutic Interventions.

Post-traumatic stress disorder (PTSD) is a complex mental health condition affecting individuals exposed to traumatic events. This paper is a narrative review of the existing literature on pharmacological and psychotherapeutic interventions for PTSD. Treatment includes selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and alpha-1 adrenergic receptor antagonists. By exploring the outcomes of these interventions, the review seeks to provide valuable insights into their potential as PTSD treatment options. The paper also highlights the importance of tailoring treatment plans to individual needs and discusses emerging treatments, such as mindfulness-based therapies, virtual reality therapy, and neurostimulation techniques. By integrating findings from various studies, it aims to offer valuable information to optimize treatment strategies and enhance outcomes for individuals suffering from PTSD. The goal is to support informed decision-making, ultimately leading to more effective and tailored approaches to address the challenges posed by this debilitating condition.

Abstract P319: Eliminating Cardiotoxicity In Alpha1-adrenergic Receptor Antagonists

Introduction: Alpha-1 adrenergic receptor (α1-AR) antagonists (α1-blockers) are efficacious antihypertensives, but ALLHAT found that doxazosin (Dzn) doubled the risk of heart failure (HF). We previously demonstrated that α1-ARs, specifically the α1A-AR, protect the heart, explaining the worse outcomes with Dzn in ALLHAT. Interestingly, α1-ARs localize to and signal at the nucleus in cardiac myocytes (CM), whereas α1-ARs localize to the sarcolemma in smooth muscle (SM). Hypothesis: We hypothesize that a membrane impermeant α1-blocker would inhibit α1-ARs in SM, reducing blood pressure, but preserve protective α1-signaling in CMs, preventing HF. Methods: We developed an α1A-AR homology model to define the structural basis of α1-blocker binding and modified existing α1-blocker structure to reduce cardiotoxicity. Using this model, we designed 30 compounds, synthesized 9 in gram quantities, and tested 2 compounds. Results and Conclusions: Binding assays identified 2 novel high affinity α1-ligands; α1705 (IC50 = 5.2 [CI:3.5,7.6] nM, n=3) and α1707 (5.8 [CI:4.2,8.1] nM, n=3) (Dzn: 7.7 [CI:6.3,9.2] nM, n=6). Uptake assays in cultured CM indicated uptake of Prazosin (10 μM Prz: 230 nM in CMs detected by mass spectrometry), whereas α1705 and α1707 were not detected. In HEK cells expressing α1A-AR at the cell surface, Prz, α1705, and α1707 (all 2 μM) inhibited Ca2+ transients (90%, 76%, 88%) induced by the α1A agonist A61603 (20 μM). In CM, A61603 increased ERK phosphorylation (1.55±0.04 fold, n=7, P&lt;0.0001), a survival signal, which was blocked by Prz (1.21±0.06 fold, n=7, P=NS), but not α1705 (1.72±0.13 fold, n=7, P&lt;0.001). Further, A61603 (20 μM) inhibited H202-induced CM death (-17.4±7.6%, n=5), which was reversed by Prz (30.9±15.4%, n=5, P=0.035), but not α1705 (-0.94±11.6%, n=5, P=NS). In DOCA-salt hypertensive mice, infusion of Prz or α1705 (2 mg/kg/d, 3 d) lowered systolic pressure (Cont: +18.9 mmHg, n=1; Prz: 6.4±3.2 mmHg, n=3, α1705: -6.1±5.6 mmHg, n=3), and while Prz was detected in CMs following 4 d, α1705 was not. In conclusion, we have developed a novel membrane impermeant α1-blocker with reduced cardiotoxicity that could improve hypertension outcomes, especially in patients suffering from chronic kidney disease or benign prostatic hyperplasia.

Risk of Severe COVID-19 in Prevalent Users of Alpha-1 Adrenergic Receptor Antagonists: A National Case-Control Study of Medicare Beneficiaries

BackgroundAlpha-1 adrenergic receptor antagonists prevent cytokine storm in mouse sepsis models. This led to the hypothesis that alpha-1 blockers may prevent severe coronavirus disease 2019 (COVID-19), which is characterized by hypercytokinemia and progressive respiratory failure. MethodsWe performed an observational case-control study in male Medicare beneficiaries aged 65 years or older, with or without benign prostatic hyperplasia (BPH), and treated with alpha-1 receptor blockers or 5-alpha reductase inhibitors. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated for outcomes of uncomplicated and severe COVID-19 hospitalization (intensive care unit admission, invasive mechanical ventilation, or death). ResultsThere were 20,963 cases of hospitalized COVID-19 matched to 101,161 controls on calendar date and neighborhood of residence. In the primary analysis (males with BPH), there was no difference in risk of uncomplicated COVID-19 hospitalization (aOR 1.08, 95% CI 0.996-1.17) or hospitalization with severe complications (aOR 0.97, 95% CI 0.88-1.08). In the secondary analysis (males with or without BPH), the corresponding aORs were 1.02 (95% CI, 0.96-1.09) (uncomplicated) and 0.99 (95% CI, 0.91-1.07) (complicated), respectively. Subgroup and sensitivity analyses yielded similar results. Of note, there was no difference in risk of severe COVID-19 hospitalization when comparing non-selective vs selective alpha-1 blocker use (aOR 0.98, 95% CI 0.86-1.10), higher- vs lower-dose alpha-1 blocker use (aOR 0.96, 95% CI 0.86-1.08), or current vs remote alpha-1 blocker use (aOR 1.04, 95% CI 0.91-1.18). ConclusionsPrevalent use of alpha-1 receptor blockers was not associated with a protective or harmful effect on risk of uncomplicated or severe hospitalized COVID-19.

Guanfacine inhibits interictal epileptiform events and sodium currents in prefrontal cortex pyramidal neurons

BackgroundGuanfacine (an alpha-2A receptor agonist) is a commonly used drug with recognized efficacy in the treatment of attention deficit hyperactivity disorder (ADHD). This study aimed to assess the effects of guanfacine on short-lasting (interictal) epileptiform discharges in cortical neurons. Moreover, we assessed the effects of guanfacine on voltage-gated sodium currents.MethodsWe conducted patch-clamp recordings in prefrontal cortex pyramidal neurons obtained from young rats. Interictal epileptiform events were evoked in cortical slices in a zero magnesium proepileptic extracellular solution with an elevated concentration of potassium ions.ResultsInterictal epileptiform discharges were spontaneous depolarisations, which triggered action potentials. Guanfacine (10 and 100 µM) inhibited the frequency of epileptiform discharges. The effect of guanfacine on interictal events persisted in the presence of alpha-2 adrenergic receptor antagonist idazoxan. The tested drug inhibited neuronal excitability. Tonic NMDA currents were not influenced by guanfacine. Recordings from dispersed neurons showed that the tested drug (10 and 100 µM) inhibited persistent and fast inactivating voltage-gated sodium currents.ConclusionsThis study shows that guanfacine inhibits interictal discharges in cortical neurons independently of alpha-2A adrenergic receptors. This effect may be mediated by voltage-gated sodium currents. Inhibition of interictal activity by guanfacine may be of clinical importance because interictal events often occur in patients with ADHD and may contribute to symptoms of this disease.Graphical abstract

FORMULATION AND IN VITRO CHARACTERIZATION OF THE SOLID LIPID NANOPARTICLES OF NAFTOPIDIL FOR ENHANCING ORAL BIOAVAILABILITY

Objective: Naftopidil (NAF) is a selective alpha1-adrenergic receptor antagonist with a nearly 20% bioavailability due to poor aqueous solubility, permeability, and extensive first-pass metabolism. To improve the bioavailability of the NAF, the solid lipid nanoparticles (SLN) of NAF were prepared. Methods: SLNs NAF were prepared using the solvent emulsification/evaporation method with excipients Compritol 888 ATO and Poloxamer 188. Formulation F10 shows better entrapment efficiency (EE) as compare to other formulations so, it has selected to optimize the particle size, zeta potential, surface morphology, Fourier transform infrared spectroscopy (FTIR), and in vitro drug release and stability studies were assessed. Results: The results showed that NAF was successfully incorporated in SLN. Having EE of all formulations ranged from 56% to 88%, drug loading ranged from 17% to 20%, drug content ranged from 77% to 98%, particle size and zeta potential of F10 were 270.2 nm and 21.7 mV, respectively, and FTIR revealed no interaction between drug and lipid in the formulation. The release of NAF-SLNs increased significantly, reaching a maximum of 4.547–82.418% in pH 6.8 buffer, the release data were fitted into the Korsmeyer-Peppas model yielding the highest correlation coefficient (R2=0.916). The stability study revealed that the formulation stability and bioavailability might be improved. Conclusion: It can be concluded that SLN could be effective nanoplatforms for increasing NAF oral bioavailability.

Electronic medical records-based retrospective, longitudinal, observational study to understand the patient management of benign prostatic hyperplasia with alpha-blockers monotherapy in Indian population.

The present retrospective study evaluates the effectiveness and tolerability of alpha-blockers as monotherapy in patients with benign prostatic hyperplasia associated with lower urinary tract symptoms (LUTS). A total of 335 male patients >50 years were categorized into four groups (Alfuzosin: 166, Silodosin: 67, Tamsulosin: 70, Prazosin: 32). The efficacy evaluated as a change in International Prostate Symptom Score (IPSS), peak flow rate (Qmax), residual urine volume, and relief from LUTS, and tolerability of the various alpha-blockers was assessed across the study group. At baseline, most of the patients in alfuzosin (60%), silodosin (77%), and tamsulosin (90%) groups presented with severe IPSS (20-35), whereas patients in the prazosin group (69%) presented with a moderate score. At the end of the study, the mean IPSS gradually improved to moderate (41%, 62%, 66%, and 28%) and mild (59%, 38%, 28%, and 72%) in the alfuzosin, silodosin, tamsulosin, and prazosin groups, respectively (P = 0.004), with improvement in mean change in residual urine volume and complete relief from LUTS symptoms with no surgical or radiological interventions. Overall, 194 adverse events (AEs) were observed in 38.8% of patients. Of the total AEs, patients in the alfuzosin, silodosin, tamsulosin, and prazosin groups experienced 21%, 22%, 39%, and 18% of AEs, respectively. The nonselective alpha-adrenergic receptor antagonist, alfuzosin, emerged as noninferior in effectiveness and superior in tolerability than other selective alpha-blockers, silodosin, tamsulosin, and prazosin.

Floppy iris syndrome associated with specific medication intake: A narrative review.

Intraoperative floppy iris syndrome (IFIS) is a cataract surgery complication that remains a challenge for eye surgeons. It is caused by the antagonism of alfa-1-adrenergic receptors within the dilator muscle of the iris, thus preventing the iris from dilation during a cataract surgery. The long-term blocking alfa-1 adrenergic receptors by the chronic use of a number of systemic medications may lead to permanent anatomical atrophy of the dilator muscle of the iris. The most common drugs associated with the development of IFIS are tamsulosin and other alpha-1 adrenergic receptor antagonists prescribed to patients with low urinary tract symptoms (LUTS). There are other systemic medications that have been reported to have increased risk for IFIS. It is crucial for the ophthalmologist to identify the high-risk patients prone to develop IFIS. Its presence may complicate the course of cataract surgery, ultimately negatively affecting visual outcome. Cataract surgery should be performed by an experienced eye surgeon using alternative pharmacological and surgical techniques. Interdisciplinary cooperation is essential to mitigate potential complications. Patients should be informed by their physicians about the need to report a medication history to their eye specialists, especially before cataract surgery.

Tamsulosin versus Fluid Therapy in Management of Ureteric Stone: A Comparative Study

Introduction: Almost all ureteric stone migrates from kidney. The drugs commonly used to assist in the passage of bigger calculi include alpha-blockers, calcium channel antagonists, phosphodiesterase inhibitors, corticosteroids. Tamsulosin is an alpha-1 adrenergic receptor antagonist known to augment the stone expulsion rate.&#x0D; Aims: To evaluate the efficacy of Tamsulosin versus fluid therapy in management of urolithiasis.&#x0D; Methods: The study was carried out on 100 patients (divided into 2 groups) at Nepalgunj Medical college Hospital Nepalgunj from May 2020 to April 2021,between 18-50 years of age of either sex, presenting with a symptomatic urinary calculus as demonstrated on imaging. Group 1 received 0.4mg of tablet tamsulosin once daily for 4 weeks, whereas Group 2 fluid therapy for a period of 4 weeks or until expulsion of stone.&#x0D; Results: Group A reflected 88% (40 patients) expulsion rate, whereas Group B reflected 72.0% (36 patients) expulsion rate. There was a statistically significant difference in the expulsion rate amongst both the groups. 92.0% (46 patients) subjects in Group A demonstrated stone expulsion within 4 weeks, mean time being 8 days. In comparison only 70.0% (35 patients) subjects in Group B demonstrated stone expulsion within 4 weeks, mean time being 14 days.Use of tablet diclofenec 100mg was lower in Group A in comparison to Group B.&#x0D; Conclusion: Tamsulosin is a safe and effective pharmacological agent in management of ureteric stones as it known to increase overall stone expulsion rate, reduced stone expulsion time, decrease acute attacks by acting as a spasmolytic, and fewer pain episodes. It may be considered as a conservative therapeutic option before more invasive procedures like ureteroscopic removal or Extracorporeal shock wave lithotripsy.

Glucocorticoids are induced while dihydrotestosterone levels are suppressed in 5-alpha reductase inhibitor treated human benign prostate hyperplasia patients.

The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS. Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching. BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone(DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching. After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.

Dealing with Posttraumatic Nightmares

IntroductionPosttraumatic nightmares are one of the most frequent symptoms in posttraumatic stress disorder. Prevalence can be up to 96%. These nightmares evoke the experienced traumatic event, causing a negative impact. Besides, they are and independent risk for suicide. There are different pharmacological and non-pharmacological options for PTN, despite is no optimal treatment.ObjectivesTo analyse the different treatment options for PTN.MethodsThis was a narrative literature review.ResultsThe two main treatments for PTN nowadays are the Imagery Rehearsal Therapy (IRT) and prazosin. IRT is a cognitive-behavioral intervention, that helps the patient to change the content of the nightmare to a “happier ending”. Prazosin is an alpha-adrenergic receptor antagonist that blocks the stress response in the central nervous system receptors. Although it was a promising drug, significant differences compared to placebo have not been found. There is growing data that suggests nabilone, a synthetic cannabinoid, could be helpful in PTN treatment. A clinical trial made in Canada revealed that 72% of patients experienced a complete disappearance or at least an important reduction of PTN.ConclusionsPTN is a very common and distressing symptom in patients presenting PTSD. Nevertheless, there is no treatment with enough evidence for this pathology. On this account, it is fundamental to do more research in order to find and suitable treatment that can improve the quality of life of these patients.DisclosureNo significant relationships.

The Therapeutic Potential of 2-{[4-(2-methoxyphenyl)piperazin-1-yl]alkyl}-1H-benzo[d]imidazoles as Ligands for Alpha1-Adrenergic Receptor - Comparative In Silico and In Vitro Study.

Adrenergic receptors are among the most studied G protein-coupled receptors. Activation or blockade of these receptors is a major therapeutic approach for the treatment of numerous disorders such as cardiac hypertrophy, congestive heart failure, hypertension, angina pectoris, cardiac arrhythmias, depression, benign prostate hyperplasia, anaphylaxis, asthma, and hyperthyroidism. Among all nine cloned adrenoceptor subtypes and the subsequent development of animal models, a significant target for various neurological conditions treatment is alpha1-adrenergic receptors. 2-{[4-(2-Methoxyphenyl)piperazin-1-yl]alkyl}-1H-benzo[d]imidazoles, their 5 substituted derivatives, and structurally similar, arylpiperazine based alpha1-adrenergic receptors antagonists (trazodone, naftopidil, and urapidil) have been subjects of comparative analysis. Most of the novel compounds showed alpha1-adrenergic affinity in the range from 22 nM to 250 nM. The in silico docking and molecular dynamics simulations, binding data together with absorption, distribution, metabolism, and excretion (ADME) calculations identified the promising lead compounds. The results brought out the conclusions which allowed us to propose a rationale for the activity of these molecules and to highlight six compounds (2-5, 8, and 12) that exhibited an acceptable pharmacokinetic profile to the advanced investigation as the potential alpha1-adrenergic receptor antagonists.

Effect of Noradrenaline on the Facial Stimulation-Evoked Mossy Fiber-Granule Cell Synaptic Transmission in Mouse Cerebellar Cortex.

Noradrenaline is an important neuromodulator in the cerebellum. We previously found that noradrenaline depressed cerebellar Purkinje cell activity and climbing fiber–Purkinje cell synaptic transmission in vivo in mice. In this study, we investigated the effect of noradrenaline on the facial stimulation-evoked cerebellar cortical mossy fiber–granule cell synaptic transmission in urethane-anesthetized mice. In the presence of a γ-aminobutyrateA (GABAA) receptor antagonist, air-puff stimulation of the ipsilateral whisker pad evoked mossy fiber–granule cell synaptic transmission in the cerebellar granular layer, which expressed stimulus onset response, N1 and stimulus offset response, N2. Cerebellar surface perfusion of 25 μM noradrenaline induced decreases in the amplitude and area under the curve of N1 and N2, accompanied by an increase in the N2/N1 ratio. In the presence of a GABAA receptor blocker, noradrenaline induced a concentration-dependent decrease in the amplitude of N1, with a half-maximal inhibitory concentration of 25.45 μM. The noradrenaline-induced depression of the facial stimulation-evoked mossy fiber–granule cell synaptic transmission was reversed by additional application of an alpha-adrenergic receptor antagonist or an alpha-2 adrenergic receptor antagonist, but not by a beta-adrenergic receptor antagonist or an alpha-1 adrenergic receptor antagonist. Moreover, application of an alpha-2 adrenergic receptor agonist, UK14304, significantly decreased the synaptic response and prevented the noradrenaline-induced depression. Our results indicate that noradrenaline depresses facial stimulation-evoked mossy fiber–granule cell synaptic transmission via the alpha-2 adrenergic receptor in vivo in mice, suggesting that noradrenaline regulates sensory information integration and synaptic transmission in the cerebellar cortical granular layer.

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms.

Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α-reductase inhibitor (5ARI) or an alpha-adrenergic receptor antagonist (α-blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease. However, medical therapies for BPH/LUTS are not effective in many patients. The reasons for nonresponse or loss of therapeutic response in the remaining patients over time are unknown. A better understanding of why patients fail to respond to medical therapy may have a major impact on developing new approaches for the medical treatment of BPH/LUTS. Prostaglandins (PG) act on G-protein-coupled receptors (GPCRs), where PGE2 and PGF2 elicit smooth muscle contraction. Therefore, we measured PG levels in the prostate tissue of BPH/LUTS patients to assess the possibility that this signaling pathway might explain the failure of medical therapy in BPH/LUTS patients. Surgical BPH (S-BPH) was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy and underwent surgical intervention to relieve LUTS. Control tissue was termed Incidental BPH (I-BPH). I-BPH was TZ obtained from men undergoing radical prostatectomy for low-volume, low-grade prostatic adenocarcinoma (PCa, Gleason score ≤ 7) confined to the peripheral zone. All TZ tissue was confirmed to be cancer-free. S-BPH patients divided into four subgroups: patients on α-blockers alone, 5ARI alone, combination therapy (α-blockers plus 5ARI), or no medical therapy (none) before surgical resection. I-BPH tissue was subgrouped by prior therapy (either on α-blockers or without prior medical therapy before prostatectomy). We measured prostatic tissue levels of prostaglandins (PGF2α , PGI2 , PGE2 , PGD2 , and TxA2 ), quantitative polymerase chain reaction levels of mRNAs encoding enzymes within the PG synthesis pathway, cellular distribution of COX1 (PTGS1) and COX2 (PTGS2), and tested the ability of PGs to contract bladder smooth muscle in an in vitro assay. All PGs were significantly elevated in TZ tissues from S-BPH patients (n = 36) compared to I-BPH patients (n = 15), regardless of the treatment subgroups. In S-BPH versus I-BPH, mRNA for PG synthetic enzymes COX1 and COX2 were significantly elevated. In addition, mRNA for enzymes that convert the precursor PGH2 to metabolite PGs were variable: PTGIS (which generates PGI2 ) and PTGDS (PGD2 ) were significantly elevated; nonsignificant increases were observed for PTGES (PGE2 ), AKR1C3 (PGF2α ), and TBxAS1 (TxA2 ). Within the I-BPH group, men responding to α-blockers for symptoms of BPH but requiring prostatectomy for PCa did not show elevated levels of COX1, COX2, or PGs. By immunohistochemistry, COX1 was predominantly observed in the prostatic stroma while COX2 was present in scattered luminal cells of isolated prostatic glands in S-BPH. PGE2 and PGF2α induced contraction of bladder smooth muscle in an in vitro assay. Furthermore, using the smooth muscle assay, we demonstrated that α-blockers that inhibit alpha-adrenergic receptors do not appear to inhibit PG stimulation of GPCRs in bladder muscle. Only patients who required surgery to relieve BPH/LUTS symptoms showed significantly increased tissue levels of PGs and the PG synthetic enzymes. Treatment of BPH/LUTS by inhibition of alpha-adrenergic receptors with pharmaceutical α-blockers or inhibiting androgenesis with 5ARI may fail because of elevated paracrine signaling by prostatic PGs that can cause smooth muscle contraction. In contrast to patients who fail medical therapy for BPH/LUTS, control I-BPH patients do not show the same evidence of elevated PG pathway signaling. Elevation of the PG pathway may explain, in part, why the risk of clinical progression in the MTOPS study was only reduced by 34% with α-blocker treatment.