Revisiting the Pharmacodynamic Uroselectivity of α 1-Adrenergic Receptor Antagonists.

α1-Adrenoceptor (AR) antagonists are widely used for the relief of urinary retention secondary to benign prostatic hyperplasia (BPH). While the five Food and Drug Administration-approved α 1-AR antagonists (terazosin, doxazosin, alfuzosin, tamsulosin, and silodosin) share similar efficacy, they differ in tolerability, with reports of ejaculatory dysfunction. The aim of the present work was to revisit their α 1-AR subtype selectivity as well as of LDT5 (1-(2-methoxyphenyl)-4-[2-(3,4-dimethoxyphenyl) ethyl]piperazine monohydrochloride), a compound previously described as a multitarget antagonist of α 1A-/α 1D-AR and 5-HT1A receptors, and to estimate their affinity for D2, D3, and 5-HT1A receptors, which are putatively involved in ejaculatory dysfunction. Competition binding assays were performed with native (D2, 5-HT1A) or transfected (human α 1A-, α 1B-, α 1Dt-AR, and D3) receptors for determination of the drug's affinities. Tamsulosin and silodosin have the highest affinities for α 1A-AR, but only silodosin is clearly a selective α 1A-AR antagonist, with K i ratios of 25.3 and 50.2 for the α 1D- and α 1B-AR, respectively. Tamsulosin, silodosin, and LDT5 (but not terazosin, doxazosin, and alfuzosin) have high affinity for the 5-HT1A receptor (K i around 5-10 nM), behaving as antagonists. We conclude that the uroselectivity of tamsulosin is not explained by its too-low selectivity for the α 1A- versus α 1B-AR, and that its affinity for D2 and D3 receptors is probably too low for explaining the ejaculatory dysfunction reported for this drug. Present data also support the design of "better-than-LDT5" new multitarget lead compounds with pharmacokinetic selectivity based on poor brain penetration and that could prevent hyperplastic cell proliferation and BPH progression. SIGNIFICANCE STATEMENT: The present work revisits the uroselectivity of the five Food and Drug Administration-approved α1 adrenoceptor antagonists for the treatment of benign prostatic hyperplasia (BPH). Contrary to what has been claimed by some, our results indicate that the uroselectivity of tamsulosin is probably not fully explained by its too-weak selectivity for the α1A versus α1B adrenoceptors. We also show that tamsulosin affinity for D3 and 5-HT1A receptors is probably too low for explaining the ejaculatory dysfunction reported for this drug. Based on our lead compound LDT5, present data support the search for a multitarget antagonist of α1A-α1D and 5-HT1A receptors with poor brain penetration as an alternative for BPH treatment.

Perceptions and Feelings of Brazilian Health Care Professionals Regarding the Effects of COVID-19: Cross-sectional Web-Based Survey.

BACKGROUND: The importance of health professionals has been recognized in COVID-19 pandemic-affected countries, especially in those such as Brazil, which is one of the top 3 countries that have been affected in the world. However, the workers' perception of the stress and the changes that the pandemic has caused in their lives vary according to the conditions offered by these affected countries, including salaries, individual protection equipment, and psychological support. OBJECTIVE: The purpose of this study was to identify the perceptions of Brazilian health workers regarding the COVID-19 pandemic impact on their lives, including possible self-contamination and mental health. METHODS: This cross-sectional web-based survey was conducted in Brazil by applying a 32-item questionnaire, including multiple-choice questions by using the Google Forms electronic assessment. This study was designed to capture spontaneous perceptions from health professionals. All questions were mandatory and divided into 2 blocks with different proposals: personal profile and COVID-19 pandemic impact. RESULTS: We interviewed Brazilian health professionals from all 5 Brazilian regions (N=1376). Our study revealed that 1 in 5 (23%) complained about inadequate personal protective equipment, including face shields (234/1376, 17.0%), masks (206/1376, 14.9%), and laboratory coats (138/1376, 10.0%), whereas 1 in 4 health professionals did not have enough information to protect themselves from the coronavirus disease. These professionals had anxiety due to COVID-19 (604/1376, 43.9%), difficulties in sleep (593/1376, 43.1%), and concentrating on work (453/1376, 32.9%). Almost one-third experienced traumatic situations at work (385/1376, 28.0%), which may have led to negative feelings of fear of COVID-19 and sadness. Despite this situation, there was hope and empathy among their positive feelings. The survey also showed that 1 in 5 acquired COVID-19 with the most classic and minor symptoms, including headache (274/315, 87.0%), body pain (231/315, 73.3%), tiredness (228/315, 72.4%), and loss of taste and smell (208/315, 66.0%). Some of their negative feelings were higher than those of noninfected professionals (fear of COVID-19, 243/315, 77.1% vs 509/1061, 48.0%; impotence, 142/315, 45.1% vs 297/1061, 28.0%; and fault, 38/315, 12.1% vs 567/1061, 53.4%, respectively). Another worrying outcome was that 61.3% (193/315) reported acquiring an infection while working at a health facility and as expected, most of the respondents felt affected (344/1376, 25.0%) or very affected (619/1376, 45.0%) by the COVID-19. CONCLUSIONS: In Brazil, the health professionals were exposed to a stressful situation and to the risk of self-contamination-conditions that can spell future psychological problems for these workers. Our survey findings showed that the psychological support for this group should be included in the future health planning of Brazil and of other hugely affected countries to assure a good mental health condition for the medical teams in the near future.