The combination of doxazosin and metyrosine as a preoperative treatment for pheochromocytomas and paragangliomas.

PURPOSE: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. METHODS: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. RESULTS: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. CONCLUSION: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.

Evaluation of Tamsulosin 0.4 mg versus 0.8 mg in management of lower urinary tract symptoms due to benign prostatic enlargement.

PURPOSE: To compare the efficacy and the safety of Tamsulosin 0.4 mg/day and 0.8 mg/day in patients suffering from lower urinary tract symptoms due to benign prostatic obstruction. PATIENTS AND METHODS: A prospective interventional, double-blinded, controlled study was carried out on 93 patients who met the criteria and divided randomly into two groups: group A for Tamsulosin 0.4 mg/day and group B for Tamsulosin 0.8 mg/day. International prostate symptom score, post void residual urine volume, and maximum flow rate of urine were assessed before and after 4 weeks of treatment. RESULTS: Both study groups showed a significant reduction in storage sub-score but only frequency was significantly reduced in group B (P < 0.001). On the other hand, Tamsulosin 0.8 mg was superior to Tamsulosin 0.4 mg regarding voiding sub-score except for straining (P = 0.325). Accordingly, the total international prostate symptom score was significantly improved in group B versus group A (P < 0.001). Furthermore, maximum flow rate and post-void residual urine volume were notably improved in Group B as compared to Group A (P < 0.001). Of all adverse events only dizziness was noted to be statistically significant in Group B versus Group A (P < 0.001). CONCLUSION: Tamsulosin 0.8 mg has shown better outcomes in treating patients who suffer from lower urinary tract symptoms due to benign prostatic enlargement than Tamsulosin 0.4 mg, and besides that, it is well tolerated. TRIAL REGISTRATION NUMBER: M S 292/2020, SID: 373, date: 22/4/2020.

Tamsulosin and risk of priapism: A causality assessment using Austin Bradford Hill Criteria.

Tamsulosin hydrochloride, a selective alpha-adrenergic blocking agent has been previously associated with priapism. Priapism is a medically serious condition that, if not intervened, can cause permanent erectile dysfunction. This study was conducted to investigate whether the association of tamsulosin and priapism is causal. All currently available evidence such as experimental, biological, toxicological, published studies, and safety data mined from the WHO global pharmacovigilance database was systematically organized into the Austin Bradford Hill causality assessment framework. In the international pharmacovigilance database, a strong association between tamsulosin and priapism (IC025  = 4.1; PRR025  = 19.9; ROR025  = 20) was observed. There were 122 cases of priapism associated with tamsulosin submitted to the database from 23 countries. In 87.7% of the cases, tamsulosin was reported as a 'sole suspect,' and in 50.8%, it was the only drug administered. In several patients, priapism resolved following discontinuation of tamsulosin and recurred after its reintroduction. Both in the published and unpublished data, for majority of the cases, the time to onset of priapism was within few days following the first intake of tamsulosin. Cases of priapism, particularly those published, were consistent in their clinical features with patients experiencing prolonged painful erection that required aspiration of cavernosal blood, irrigation of the corpora cavernosa, and treatment with vasopressors. Other alpha-adrenergic blocking agents that are structurally analogous with tamsulosin have also been associated with priapism. In several cases, tamsulosin was used off-label, for the treatment of ureteral calculi expulsion. Eight patients experienced priapism that ended up with serious complications such as ejaculation disorders and erectile dysfunction. The currently available totality of evidence suggests that the association of tamsulosin and priapism is causal. Healthcare professionals are therefore recommended to cautiously prescribe tamsulosin and ensure that consumers are aware of the potential risk of priapism.

Reassessment of amphetamine- and phencyclidine-induced locomotor hyperactivity as a model of psychosis-like behavior in rats.

Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.

Tamsulosin facilitates depressive-like behaviors in mice: Involvement of endogenous glucocorticoids.

The benign prostatic hyperplasia (BPH) is the main source of lower urinary tract symptoms. The BPH is a common age-dependent disease and tamsulosin is an α1-adrenoceptor blocker widely prescribed for BPH. Beyond the common adverse effects of tamsulosin, increased diagnosis of dementia after prescription was observed. Importantly, a clinical study suggested that tamsulosin may exert antidepressant effects in BPH patients. Considering the expression of α1-adrenoceptors in the brain, this study aimed to investigate the effects of tamsulosin in the forced swimming and open field tests in mice. For this, tamsulosin (0.001-1 mg/kg) was orally administered subacutely (1, 5 and 23 hr) and acutely (60 min) before tests. Mifepristone (10 mg/kg), a glucocorticoid receptor antagonist, and aminoglutethimide (10 mg/kg), a streoidogenesis inhibitor, were intraperitoneally injected before tamsulosin to investigate the role of the hypothalamic-pituitary-adrenal axis in the mediation of tamsulosin-induced effects. Subacute and acute administrations of tamsulosin increased the immobility time in the first exposition to an inescapable stressful situation. In the re-exposition to the swim task, controls displayed a natural increase in the immobility time, and the treatment with tamsulosin further increased this behavioral parameter. Tamsuslosin did not affect spontaneous locomotion neither in naïve nor in stressed mice. Our findings also showed that mifepristone and aminoglutethimide prevented the tamsulosin-induced increase in the immobility time in the first and second swimming sessions, respectively. In conclusion, tamsulosin may contribute to increased susceptibility to depressive-like behaviors, by facilitating the acquisition of a passive stress-copying strategy. These effects seem to be dependent on endogenous glucocorticoids.

Free combination of dutasteride plus tamsulosin for the treatment of benign prostatic hyperplasia in South Korea: analysis of drug utilization and adverse events using the National Health Insurance Review and Assessment Service database.

OBJECTIVE: To assess the use and safety of free combination therapy (dutasteride and tamsulosin), dutasteride monotherapy, or tamsulosin monotherapy in patients with benign prostatic hyperplasia (BPH). METHODS: This non-interventional retrospective cohort study used claims data from the Korea Health Insurance Review and Assessment-National Patient Sample database. Patients with BPH ≥ 40 years of age receiving combination therapy (dutasteride 0.5 mg and tamsulosin 0.4 mg daily) or dutasteride 0.5 mg, or tamsulosin 0.4 mg daily dose between 2012 and 2017 were included. The frequency, duration of treatment and risk of any adverse event (AE) or serious AE (SAE) was compared for combination therapy versus each monotherapy using non-inferiority testing. RESULTS: Of 14,755 eligible patients, 1529 (10.4%) received combination therapy, 6660 (45.1%) dutasteride monotherapy, and 6566 (44.5%) tamsulosin monotherapy. The proportion of patients treated with combination therapy exceeded the pre-specified 3% threshold for 'frequent' use. Safety results indicated a similar risk of any AE and SAE irrespective of treatment group. The adjusted relative risk for any AE over the treatment observation period comparing combination therapy with dutasteride monotherapy was 1.07 (95% confidence interval [CI] 1.03, 1.12), and with tamsulosin monotherapy was 0.98 (95% CI 0.95, 1.02) demonstrating non-inferiority. The adjusted relative risk for any SAE was 1.07 (95% CI 0.66, 1.74) and 0.90 (95% CI 0.56, 1.45), compared with dutasteride and tamsulosin monotherapy, respectively. Although the SAE results did not statistically demonstrate non-inferiority of combination therapy based on pre-specified margins, the 95% CI for the risk ratio estimates included the null with a lower limit below the non-inferiority margins, indicating no meaningful differences in SAE risk between groups. Absolute SAE risks were low. CONCLUSION: Combination therapy with dutasteride and tamsulosin is frequently used in real-world practice in South Korea for treatment of BPH and demonstrates a safety profile similar to either monotherapy.

Physiologically based pharmacokinetic (PBPK) modelling of tamsulosin related to CYP2D6*10 allele.

Tamsulosin, a selective [Formula: see text]-adrenoceptor blocker, is commonly used for alleviation of lower urinary tract symptoms related to benign prostatic hyperplasia. Tamsulosin is predominantly metabolized by CYP3A4 and CYP2D6 enzymes, and several studies reported the effects of CYP2D6 genetic polymorphism on the pharmacokinetics of tamsulosin. This study aims to develop and validate the physiologically based pharmacokinetic (PBPK) model of tamsulosin in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 genotypes, using Simcyp® simulator. Physicochemical, and formulation properties and data for absorption, distribution, metabolism and excretion were collected from previous publications, predicted in the simulator, or optimized in different CYP2D6 genotypes. The tamsulosin PBPK model in CYP2D6*wt/*wt and CYP2D6*wt/*10 genotypes were developed based on the clinical pharmacokinetic study where a single oral dose of 0.2 mg tamsulosin was administered to 25 healthy Korean male volunteers with CYP2D6*wt/*wt and CYP2D6*wt/*10 genotypes. A previous pharmacokinetic study was used to develop the model in CYP2D6*10/*10 genotype. The developed model was validated using other clinical pharmacokinetic studies not used in development. The predicted exposures via the PBPK model in CYP2D6*wt/*10 and CYP2D6*10/*10 genotype was 1.23- and 1.76-fold higher than CYP2D6*wt/*wt genotype, respectively. The simulation profiles were visually similar to the observed profiles, and fold errors of all development and validation datasets were included within the criteria. Therefore, the tamsulosin PBPK model in different CYP2D6 genotypes with regards to CYP2D6*10 alleles was appropriately established. Our model can contribute to the implementation of personalized pharmacotherapy of patients, appropriately predicting the pharmacokinetics of tamsulosin reflecting their demographic and CYP2D6 genotype characteristics without unnecessary drug exposure.

Doxazosin Attenuates Liver Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via Activation of the PI3K/Akt/mTOR Signaling Pathway.

PURPOSE: To investigate the effect of doxazosin on autophagy and the activation of hepatic stellate cells (HSCs) in vivo and in vitro and determine the underlying mechanism. METHODS: In vivo, a mouse liver fibrosis model was induced by the intraperitoneal injection of carbon tetrachloride (CCl4). Doxazosin was administered at doses of 2.5, 5 and 10 mg/(kg*day) by gavage. After 20 weeks, blood and liver tissues were collected for serological and histological analysis, respectively. Blood analysis, hematoxylin and eosin (HE) staining, Masson's trichrome staining, immunohistochemistry and immunofluorescence staining were used to measure the extent of liver fibrosis in model and control mice. In vitro, the human HSC cell line LX-2 was cultured and treated with different doses of doxazosin for the indicated times. The effects of doxazosin on LX-2 cell proliferation and migration were examined by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The number of autophagosomes in LX-2 cells was observed by transmission electron microscopy (TEM). Infection with green fluorescent protein (GFP)-LC3B adenovirus, GFP-red fluorescent protein (RFP)-LC3B adenovirus and mCherry-EGFP-LC3 adeno-associated virus was performed to examine changes in autophagic flux in vitro and in vivo. Cell apoptosis was measured by flow cytometry in vitro and by TUNEL assays both in vitro and in vivo. Immunoblotting was performed to evaluate the expression levels of proteins related to fibrosis, autophagy, apoptosis, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR). RESULTS: Doxazosin inhibited HSC proliferation and migration. HSC activation was attenuated by doxazosin in a concentration-dependent manner in vivo and in vitro. Doxazosin also blocked autophagic flux and induced apoptosis in HSCs. In addition, the PI3K/Akt/mTOR pathway was activated by doxazosin and regulated fibrosis, autophagy and apoptosis in HSCs. CONCLUSION: The study confirmed that doxazosin could inhibit autophagy by activating the PI3K/Akt/mTOR signaling pathway and attenuate liver fibrosis.

Blood Pressure Control in Acute Stroke: Labetalol or Nicardipine?

PURPOSE: To assess the safety and efficacy of continuous infusion (CIV)-labetalol compared to -nicardipine in controlling blood pressure (BP) in the acute stroke setting. MATERIALS: Patients were eligible if they had a diagnosis of an acute stroke and were administered either CIV-labetalol or CIV-nicardipine. Study outcomes were assessed within the first 24 h of the antihypertensive infusion. RESULTS: A total of 3,093 patients were included with 3,008 patients in the CIV-nicardipine group and 85 in the CIV-labetalol group. No significant difference was observed in percent time at goal BP between the nicardipine (82%) and labetalol (85%) groups (p = 0.351). There was also no difference in BP variability between nicardipine (37%) and labetalol (39%) groups (p = 0.433). Labetalol was found to have a shorter time to goal BP as compared to nicardipine (24 min vs. 40 min; p = 0.021). While CIV-nicardipine did have a higher incidence of tachycardia compared to labetalol (17% vs. 4%; p <0.001), the incidence of hypotension (13% vs. 15%; p = 0.620) and bradycardia (24% vs. 22%; p = 0.797) were similar. CONCLUSIONS: These results indicate that CIV-labetalol and CIV-nicardipine are comparable in safety and efficacy in controlling BP for patients with acute stroke.

A Randomized Crossover Pilot Study Examining the Effect of Carvedilol and Terazosin plus Enalapril on Urinary Symptoms of Patients with Hypertension and Benign Prostatic Hyperplasia.

PURPOSE: The present study aims to assess and compare the effects of carvedilol and terazosin plus enalapril on lower urinary tract symptoms (LUTS), the urine flow, and blood pressure (BP) in patients with moderate hypertension (HTN) and benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: In this randomized crossover trial, a total of 40 men with HTN and LUTS symptoms were enrolled. The first group was treated with carvedilol, and the second one received terazosin plus enalapril. After eight weeks of treatment, the patients experienced a one-month washout period, and the treatments changed and continued for eight weeks. To diagnose BPH in the study, the international prostate symptom score (IPSS) questionnaire was used. Moreover, the prostate-specific antigen (PSA), the post-void residual (PVR) urine volume, and the maximum urinary flow rate (Q-max using the uroflowmetry test) were measured. RESULTS: Effect assessment results in this crossover trial illustrated neither carryover effects nor significant treatment effects on all primary outcomes (P > 0.05). Moreover, the results for the period effect indicated a significant reduction in BP (systolic and diastolic), PVR, and IPSS, yet a significant raise in Qmax. CONCLUSION: The effects of carvedilol are similar to those of the combination of terazosin and enalapril in patients with moderate HTN and BPH in controlling LUTS. Carvedilol could be used as an appropriative drug in patients with moderate HTN and cardiac problems with LUTS of BPH. Further studies are recommended to be conducted to investigate and compare the efficacy of carvedilol with that of other alpha-blockers with a larger sample size and over a longer period of time.

Parkinson disease among patients treated for benign prostatic hyperplasia with α1 adrenergic receptor antagonists.

BACKGROUNDRecently the α1 adrenergic receptor antagonist terazosin was shown to activate PGK1, a possible target for the mitochondrial deficits in Parkinson disease related to its function as the initial enzyme in ATP synthesis during glycolysis. An epidemiological study of terazosin users showed a lower incidence of Parkinson disease when compared with users of tamsulosin, an α1 adrenergic receptor antagonist of a different class that does not activate PGK1. However, prior research on tamsulosin has suggested that it may in fact potentiate neurodegeneration, raising the question of whether it is an appropriate control group.METHODSTo address this question, we undertook an epidemiological study on Parkinson disease occurrence rate in 113,450 individuals from the United States with 5 or more years of follow-up. Patients were classified as tamsulosin users (n = 45,380), terazosin/alfuzosin/doxazosin users (n = 22,690), or controls matched for age, sex, and Charlson comorbidity index score (n = 45,380).RESULTSIncidence of Parkinson disease in tamsulosin users was 1.53%, which was significantly higher than that in both terazosin/alfuzosin/doxazosin users (1.10%, P < 0.0001) and matched controls (1.01%, P < 0.0001). Terazosin/alfuzosin/doxazosin users did not differ in Parkinson disease risk from matched controls (P = 0.29).CONCLUSIONThese results suggest that zosins may not confer a protective effect against Parkinson disease, but rather that tamsulosin may in some way potentiate Parkinson disease progression.FUNDINGThis work was supported by Cerevel Therapeutics.

Transdermal iontophoresis delivery system for terazosin hydrochloride: an in vitro and in vivo study.

This study aimed to construct a transdermal iontophoresis delivery system for terazosin hydrochloride (IDDS-TEH), which included a positive and negative electrode hydrogel prescription. Intact guinea pig skin was used as a model for the skin barrier function, and the current intensity, terazosin hydrochloride (TEH) concentration, pH, competitive salt, and transdermal enhancer properties were studied. The blood drug concentration was determined in Sprague-Dawley (SD) rats using HPLC, and the antihypertensive effects of IDDS-TEH were evaluated in spontaneously hypertensive rats (SHRs). The results showed that the steady-state penetration rate of TEH increased (from 80.36 µg·cm-2·h-1 to 304.93 µg·cm-2·h-1), followed by an increase in the current intensity (from 0.10 mA·cm-2 to 0.49 mA·cm-2). The pH values also had a significant influence on percutaneous penetration. The blood concentration of IDDS-TEH was significantly higher (p < .05) than with passive diffusion, which could not be detected. The main pharmacokinetic parameters of the high current group (0.17 mA·cm-2) and the low current group (0.09 mA·cm-2) were AUC0-t: 5873.0 ng·mL-1·h and 2493.7 ng·mL-1·h, respectively. Meanwhile, the pharmacodynamic results showed that IDDS-TEH significantly decreased the blood pressure of SHRs compared with the TEH hydrogel without loading current. Therefore, TEH could be successfully delivered by the transdermal iontophoresis system in vitro and in vivo, and further clinical studies should be explored to develop a therapeutically useful protocol.

Pharmacokinetics and pharmacodynamics of MT-1207, a novel multitarget blocker of α1 receptor, 5-HT2A receptor, and calcium channel, in healthy subjects.

BACKGROUND: MT-1207 is a novel multitarget blocker of α1 receptor, 5-HT2A receptor, and calcium channel that is currently under development for the treatment of hypertension. In this study, we evaluated the tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MT-1207 in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: We examined the effects of a single-ascending dose (SAD) of MT-1207 (5-40 mg) and MT-1207 (40 mg) administered in combination with food in 56 healthy subjects. RESULTS: No serious adverse events or discontinuations due to adverse events (related to MT-1207) occurred in either study. MT-1207 was rapidly absorbed (median Tmax: 0.5-1.25 h). The mean t1/2 of MT-1207 was approximately 4-7 hours. Systemic exposure (Cmax and AUC) to MT-1207 increased in proportion to dose. Food had little effect on the pharmacokinetics of MT-1207, such as t1/2 and AUC. For 4h-24 h after administration, the blood pressure reduction in the MT-1207 group was higher than that in the placebo group, showing the antihypertensive effect. Blood pressure reduction after MT-1207 administration showed some dose-dependent trend in the 5-20 mg groups. CONCLUSIONS: MT-1207 was well tolerated in all subjects. PD measurements demonstrated the antihypertensive effects of MT-1207.

Association of Glycolysis-Enhancing α-1 Blockers With Risk of Developing Parkinson Disease.

Importance: Parkinson disease (PD) is a common neurodegenerative disease. A treatment that prevents or delays development of PD is a critical unmet need. Terazosin and closely related drugs were recently discovered to enhance glycolysis and reduce PD progression in animal models and human clinical databases. Objective: To determine whether use of terazosin, doxazosin, and alfuzosin is associated with a decreased risk of developing PD. Design, Setting, and Participants: This cohort study used active comparator control and propensity score-matched data from Danish nationwide health registries, including the Danish National Prescription Registry, the Danish National Patient Registry, and the Danish Civil Registration System, from January 1996 to December 2017 and data from the Truven Health Analytics MarketScan database from January 2001 to December 2017. Men without PD who newly initiated terazosin/doxazosin/alfuzosin therapy or tamsulosin therapy, which is used for a similar indication (benign prostatic hyperplasia or unspecified urinary problems) but does not enhance glycolysis, and had at least 1 year of follow-up after medication start were included. In Denmark, the database included all residents, while the Truven database is a compilation of insurance claims across the US. Data were analyzed from February 2019 to July 2020. Exposures: Patients who used terazosin/doxazosin/alfuzosin vs tamsulosin. Additional dose-response analyses were carried out. Main Outcomes and Measures: Differences in the hazard of developing PD identified by diagnoses or use of PD-specific medications between patients who ever used terazosin/doxazosin/alfuzosin or tamsulosin. Results: A cohort of 52 365 propensity score-matched pairs of terazosin/doxazosin/alfuzosin and tamsulosin users were identified in the Danish registries, of which all were male and the mean (SD) age was 67.9 (10.4) years, and 94 883 propensity score-matched pairs were identified in the Truven database, of which all were male and the mean (SD) age was 63.8 (11.1) years. Patients in the Danish cohort who used terazosin/doxazosin/alfuzosin had a hazard ratio (HR) for developing PD of 0.88 (95% CI, 0.81-0.98), and patients in the Truven cohort had an HR of 0.63 (95% CI, 0.58-0.69). There was a dose-response association with short-duration, medium-duration, and long-duration use of terazosin/doxazosin/alfuzosin users having a decreasing HR in both the Danish cohort (short: HR, 0.95; 95% CI, 0.84-1.07; medium: HR, 0.88; 95% CI, 0.77-1.01; long: HR, 0.79; 95% CI, 0.66-0.95) and Truven cohort (short: HR, 0.70; 95% CI, 0.64-0.76; medium: HR, 0.58; 95% CI, 0.52-0.64; long: HR, 0.46; 95% CI, 0.36-0.57). Conclusions and Relevance: These data suggest that users of terazosin/doxazosin/alfuzosin are at lower hazard of developing PD compared with users of tamsulosin. Future work is needed to further assess this association.

Impact of early vs. delayed initiation of dutasteride/tamsulosin combination therapy on the risk of acute urinary retention or BPH-related surgery in LUTS/BPH patients with moderate-to-severe symptoms at risk of disease progression.

PURPOSE: To evaluate the effect of delayed start of combination therapy (CT) with dutasteride 0.5 mg and tamsulosin 0.4 mg on the risk of acute urinary retention or benign prostatic hyperplasia (BPH)-related surgery (AUR/S) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) at risk of disease progression. METHODS: Using a time-to-event model based on pooled data from 10,238 patients from Phase III/IV dutasteride trials, clinical trial simulations (CTS) were performed to assess the risk of AUR/S up to 48 months in moderate-to-severe LUTS/BPH patients following immediate and delayed start of CT for those not responding to tamsulosin monotherapy. Simulation scenarios (1300 subjects/arm) were investigated, including immediate start (reference) and alternative delayed start (six scenarios 1-24 months). AUR/S incidence was described by Kaplan-Meier survival curves and analysed using log-rank test. The cumulative incidence of events as well as the relative and attributable risks were summarised stratified by treatment. RESULTS: Survival curves for patients starting CT at month 1 and 3 did not differ from those who initiated CT immediately. By contrast, significant differences (p < 0.001) were observed when switch to CT occurs ≥ 6 months from the initial treatment. At month 48, AUR/S incidence was 4.6% vs 9.5%, 11.0% and 11.3% in patients receiving immediate CT vs. switchers after 6, 12 and 24 months, respectively. CONCLUSIONS: Start of CT before month 6 appears to significantly reduce the risk of AUR/S compared with delayed start by ≥ 6 months. This has implications for the treatment algorithm for men with LUTS/BPH at risk of disease progression.

α-Adrenergic receptor blockade attenuates pressor response during mental stress in young black adults.

Black individuals exhibit increased blood pressure (BP) responses to sympathetic stimulation that are associated with an increased risk of hypertension (HTN). We tested the hypothesis that α1 -adrenergic blockade inhibits the increased BP response during and after 45-min stress in young normotensive Black adults, which may be mediated, in part, by dampened vasoconstriction and decreased renal sodium retention. Utilizing a double-masked randomized, crossover study design, 51 normotensive Black adults (31 ± 8 yr) were treated with either a placebo or 1 mg/day of prazosin for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before (Rest), during (Stress) and after (Recovery) 45 min of mental stress induced via a competitive video game task. During the Stress period, diastolic BP and total peripheral resistance (TPR) were significantly lower with prazosin compared to placebo (p < .05 for both). Similarly, we observed lower systolic BP, diastolic BP, and TPR during the Recovery period with prazosin versus placebo (p < .05 for both). There was no effect of prazosin on stress-associated UNaV. The change in systolic BP from Rest to Recovery was positively associated with the change in TPR with both treatments (p < .05 for both). In summary, prazosin treatment dampened BP reactivity to 45-min mental stress and lowered post-stress BP over the recovery period, which was linked to reduce TPR in young normotensive Black adults. These results suggest that α1 -adrenergic receptor activity may contribute to BP responses and delayed BP recovery to prolonged mental stress through increased vasoconstriction in Black adults.

Rat ultrasonic vocalizations as an index of memory.

The emission of 50 kHz frequency-modulated ultrasonic vocalizations (FM USVs) in rats has been associated with positive affective states, while a decrease in FM USVs has been associated with anxiety-like states. We tested the hypothesis in male Sprague-Dawley rats that FM USVs would complement measures of aversive memories (decrease in FM USVs) in a conditioned fear task in which we examined extinction or reconsolidation disruption. In Experiment 1, rats were fear conditioned using low-level footshock followed by extinction while monitoring freezing and FM USVs. In Experiment 2, rats were fear conditioned, the alpha-1 antagonist prazosin was used to disrupt reconsolidation of memory, and freezing and FM USVs were measured. Rats fear conditioned with low-level shock showed minimal freezing that rapidly extinguished, despite a persistent decrease in FM USVs throughout extinction. Prazosin reduced freezing in a memory reactivation-dependent manner as expected, but the reduction in FM USVs after fear conditioning remained decreased, suggesting that an affective component of memory was not impacted by prazosin. These findings indicate that FM USVs may be used as an index of fear- or anxiety-like memory, and their measurement could benefit pre-clinical animal models for assessing reduction of aversive memories.

Increased Choroidal Blood Perfusion Can Inhibit Form Deprivation Myopia in Guinea Pigs.

Purpose: In guinea pigs, choroidal thickness (ChT) and choroidal blood perfusion (ChBP) simultaneously decrease in experimental myopia, and both increase during recovery. However, the causal relationship between ChBP and myopia requires further investigation. In this study, we examined the changes of ChBP with three different antimyopia treatments. We also actively increased ChBP to examine the direct effect on myopia development in guinea pigs. Methods: Experiment 1: Guinea pigs wore occluders on the right eye for two weeks to induce form-deprivation myopia (FDM). Simultaneously they received daily antimyopia treatments: peribulbar injections of atropine or apomorphine or exposure to intense light. Experiment 2: The vasodilator prazosin was injected daily into the form-deprivation eyes to increase ChBP during the two-week induction of FDM. Other FDM animals received appropriate control treatments. Changes in refraction, axial length, ChBP, ChT, and hypoxia-labeled pimonidazole adducts in the sclera were measured. Results: The antimyopia treatments atropine, apomorphine, and intense light all significantly inhibited myopia development and the decrease in ChBP. The treatments also reduced scleral hypoxia, as indicated by the decrease in hypoxic signals. Furthermore, actively increasing ChBP with prazosin inhibited the progression of myopia, as well as the increase in axial length and scleral hypoxia. Conclusions: Our data strongly indicate that increased ChBP attenuates scleral hypoxia, and thereby inhibits the development of myopia. Thus ChBP may be a promising target for myopia retardation. As such, it can serve as an immediate predictor of myopia development as well as a long-term marker of it.

Systemic Alpha1-Adrenoceptor Antagonists and Increased Risk of Open-Angle Glaucoma: A Nationwide Population-Based Cohort Study.

Purpose: To examine the risk of open-angle glaucoma (OAG) among patients receiving alpha1-adrenoceptor (α1-AR) antagonists for lower urinary tract symptoms (LUTS). Methods: This was a nationwide, population-based, retrospective cohort study from Asia/Taiwan. One million beneficiaries were randomly sampled from among 27.38 million individuals enrolled in the National Health Insurance program, and subjects with a diagnosis of LUTS from 2001 to 2012 were identified (N = 105,341). After 1:1 propensity score matching by gender, age, comorbid medical diseases, number of all medical visits during the observational period, and index date, 4081 patients were enrolled in the study group, comprised of patients who had taken α1-AR antagonists, and 4081 patients were enrolled in the control group, comprised of patients who had never taken α1-AR antagonists. The incidence and risk of OAG (defined as two ambulatory visits with a ICD-9 diagnosis code 365, excluding ICD-9 diagnosis codes 365.2-365.6, 365.02, 365.03, 365.13, 365.14, and 365.8) were calculated. Results: Patients taking α1-AR antagonists had a higher incidence ratio of 1.86 (95% confidence interval [CI], 1.30-2.65) for developing OAG. After adjusting for age, gender, and comorbidities, the hazard ratio (HR) for OAG for patients taking α1-AR antagonists was 1.66 (95% CI, 1.16-2.39; P = 0.006). Among patients with hypertension, the hazard ratio for OAG associated with taking α1-AR antagonists increased to 1.79 (95% CI, 1.07-2.99; P = 0.003). On the other hand, the association of α1-AR antagonists with OAG was not significant among patients with diabetes mellitus, hyperlipidemia, or older age. Conclusions: The findings of our study suggest an increased risk for OAG among patients taking α1-AR antagonists for LUTS, especially in patients with hypertension.

The use of doxazosin before adrenalectomy for pheochromocytoma: is the duration related to intraoperative hemodynamics and postoperative complications?

PURPOSE: No conclusion exists for the optimum duration of preoperative administration of doxazosin (DOX) before adrenalectomy for pheochromocytoma. The purpose of this study is to investigate whether perioperative hemodynamics and postoperative outcomes are related to the duration of DOX administration. METHODS: In total, 132 patients managed preoperatively with single α-receptor blocker DOX were enrolled. All patients underwent adrenalectomy for pheochromocytoma in the Department of Urology, Peking University First Hospital, between January 2001 and July 2019. Patients were divided into three groups based on the duration of preoperative administration of DOX: group A (≤14 days), group B (15-30 days), and group C (>30 days). Patient and tumor characteristics, intraoperative hemodynamics, and postoperative outcomes were recorded and compared. RESULTS: These patients included 57 men and 75 women, with an average age of 48 years. Clinical characteristics, preoperative hemodynamics, medicine management and surgical approaches were comparable between the three groups. Among the three groups, we found that group C (>30 days) had the lowest intraoperative minimum heart rate [group A vs. group B vs. group C = 60 (52-67) vs. 59 (50-61) vs. 51.5 (50-58.75), p = 0.024] and highest risk of postoperative hypotension requiring vasopressor support [group A vs. group B vs. group C = 14 (20.3%) vs. 12 (27.9%) vs. 10 (50.0%), p = 0.032]. CONCLUSION: The current study indicated that preoperative management of pheochromocytoma with single α-receptor blocker DOX for more than 30 days after final dose adjustment might lead to intraoperative bradycardia and more postoperative hypotension requiring vasopressor support. Thus, our study does not support long-term (over 30 days) preoperative administration of pheochromocytoma with single α-receptor blocker DOX in the final dose.