- Revisiting the pharmacodynamics uroselectivity of Alpha1-Adrenergic Receptor Antagonists. [Journal Article]
- JPJ Pharmacol Exp Ther 2019 Jul 08
- α1-adrenoceptor (AR) antagonists are widely used for the relief of urinary retention secondary to benign prostatic hyperplasia (BPH). While the five FDA-approved α1-AR antagonists (terazosin, doxazos…
α1-adrenoceptor (AR) antagonists are widely used for the relief of urinary retention secondary to benign prostatic hyperplasia (BPH). While the five FDA-approved α1-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 α1-AR subtype selectivity as well as of LDT5, a compound previously described as a multi-target antagonist of α1A-/α1D-AR and 5-HT1A receptors, and to estimate their affinity for D2, D3 and 5-HT1A receptors, putatively involved in ejaculatory dysfunction. Competition binding assays were performed with native (D2, 5-HT1A) or transfected (human α1A-, α1B-, α1Dt-AR and D3) receptors for determination of drug's affinities. Tamsulosin and silodosin have the highest affinities for α1A-AR, but only silodosin is clearly a selective α1A-AR antagonist with Ki ratios of 25.3 and 50.2, for the α1D-AR and α1B-AR, respectively. Tamsulosin, silodosin and LDT5, but not terazosin, doxazosin and alfuzosin, have high affinity for the 5-HT1AR (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 α1A- vs. α1B-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 multi-target lead compounds with pharmacokinetics selectivity based on poor brain penetration and that could prevent hyperplastic cell proliferation and BPH progression. SIGNIFICANCE STATEMENT: Present work revisits the uroselectivity of the five FDA-approved α1 adrenoceptor antagonists for the treatment of benign prostatic hyperplasia (BPH). Contrarily 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 vs. 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 multi-target antagonist of α1A-α1D and 5-HT1A receptors with poor brain penetration as an alternative for BPH treatment.
- [LUTS/BPH who treats?. The results of the epidemiologic study]. [Journal Article]
- UUrologiia 2019; (1):5-15
- CONCLUSIONS: the results of the study indicate a concordance with global trends in the treatment of these patients. Our data reflect a significant influence of the level of education, work experience and involvement in scientific professional life of urologic community on the choice of a particular drug for the treatment of LUTS/BPH and prove the feasibility of further work which should be aimed at popularization of the modern medical knowledges among the urologists and organization of a process of continuous medical education.
- [Efficiency and safety of silodosin for treatment of lower urinary tract symptoms, associated of benign prostatic hyperplasia]. [Journal Article]
- UUrologiia 2019; (2):67-72
- Benign prostatic hyperplasia commonly is the most common cause of bladder outlet obstruction and can result in storage and micturition symptoms in men older than 40 years. Nowadays the 1-adrenorecept…
Benign prostatic hyperplasia commonly is the most common cause of bladder outlet obstruction and can result in storage and micturition symptoms in men older than 40 years. Nowadays the 1-adrenoreceptor antagonists are the first-line drug for treatment of the lower urinary tract symptoms (LUTS). However, 1-adrenoreceptors are known to be present in other tissues and this fact could be a reason of potential risk of adverse events, associated with changes in peripheral vascular tone, such as orthostatic hypotension, syncopal states, dizziness, etc., especially in patients of advanced age, and those affected by cardiovascular diseases and taking essential drugs. A highly selective -adrenergic blocker silodosin is characterized by a lower rate of mentioned adverse events, comparable with placebo. Silodosin is also highly effective in treating of both types of LUTS in these patients, both as monotherapy and in combination with other drugs. A detailed analysis of clinical data confirming the high efficacy and safety of silodosin is presented in this review of the literature.
- [LUTS in BPH patients : Comparison of silodosin versus tamsulosin, naftopidil, alfuzosin and placebo for the treatment of lower urinary tract symptoms]. [Review]
- UUrologe A 2019; 58(7):795-798
- A prospective double-blind, randomized, placebo-controlled study to evaluate the efficacy of silodosin 8 mg as an on-demand, reversible, nonhormonal oral contraceptive for males: a pilot study. [Journal Article]
- WJWorld J Urol 2019 May 10
- CONCLUSIONS: Silodosin 8 mg achieved total reversible azoospermia, hence prevented unintended pregnancies in the female partners of the males who used the drug as an on-demand oral contraceptive.
- Characterization on Responsiveness of Excitatory Synaptic Transmissions to α1-Adrenoceptor Blockers in Substantia Gelatinosa Neurons Isolated From Lumbo-Sacral Level in Rat Spinal Cords. [Journal Article]
- INInt Neurourol J 2019; 23(1):13-21
- CONCLUSIONS: There was a difference in responsiveness in the frequency of mEPSCs to α1-adrenoceptor blockers, with the response to naftopidil being the greatest among the α1-adrenoceptor blockers. These data are helpful to understand the action mechanisms of α1-adrenoceptor blockers for male lower urinary tract symptoms in clinical usage.
- Comparison of the Effects of Tadalafil and α1-Adrenoceptor Antagonists on Spontaneous Seminal Emission and Electrical Field Stimulation-Induced Seminal Vesicle Contraction in Rats. [Journal Article]
- JSJ Sex Med 2019; 16(5):680-690
- CONCLUSIONS: Tadalafil can be a treatment option in cases where there is concern about negative effects on seminal emission.Tadalafil did not inhibit spontaneous seminal emission or electrical field stimulation-induced seminal vesicle contraction in normal rats. The NO-cyclic guanosine monophosphate pathway is unlikely to be involved in the inhibition of seminal vesicle contraction in normal rats. Yoshinaga R, Fukui T, Yoshifuji M, et al. Comparison of the Effects of Tadalafil and α1-Adrenoceptor Antagonists on Spontaneous Seminal Emission and Electrical Field Stimulation-Induced Seminal Vesicle Contraction in Rats. J Sex Med 2019;16:680-690.
- Efficacy and safety of phosphodiesterase type 5 inhibitors for the treatment of distal ureteral calculi of 5 to 10 mm in size: A systematic review and network meta-analysis. [Journal Article]
- KJKaohsiung J Med Sci 2019; 35(5):257-264
- To evaluate the Efficacy and safety of phosphodiesterase type 5 inhibitors as a medical therapy for distal ureteral calculi by means of a systematic review and network meta-analysis (NMA). We searche…
To evaluate the Efficacy and safety of phosphodiesterase type 5 inhibitors as a medical therapy for distal ureteral calculi by means of a systematic review and network meta-analysis (NMA). We searched the Embase, Medline, and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) published before May, 2017. Stone passage rate as the primary outcome. We used random effects model for pairwise meta-analyses and Bayesian random effects model for NMA. We evaluated the quality of evidence by the GRADE framework for each network estimate. Five RCTs (861 patients) comparing four different interventions. The results of NMA showed that compared with tamsulosin alone, tamsulosin combined with tadalafil group was associated with significantly higher stone passage rate (odds radio [OR] 2.55, 95% credible intervals [Crl] 1.11 to 5.89). When considering stone expulsion rate, compared with tamsulosin, silodosin was ranked best (OR 3.58, 95% Crl 1.13 to 11.91), followed by tamsulosin combined with tadalafil (OR 2.55, 95% Crl 1.11 to 5.89) and tadalafil alone (OR 1.86, 95% Crl 0.95 to 4.25). No significant difference was found considering safety profiles between any interventions. This meta-analysis indicates that tamsulosin combined with tadalafil is an effective treatment option for ureteral stones with a low occurrence of side effects. Clinicians should take all known safety and compliance of patients into account when choosing an optimal strategy. Since sample size of included studies, further RCTs are strongly encouraged to address the clinical question.
- Determination of donepezil in spiked rabbit plasma by high-performance liquid chromatography with fluorescence detection. [Journal Article]
- RSR Soc Open Sci 2019; 6(1):181476
- The aim of this paper is to develop sensitive, accurate, reproducible and robust RP-HPLC with fluorescence detection for estimation of donepezil (DZ) in rabbit plasma using silodosin as the internal …
The aim of this paper is to develop sensitive, accurate, reproducible and robust RP-HPLC with fluorescence detection for estimation of donepezil (DZ) in rabbit plasma using silodosin as the internal standard (IS). The prepared samples were quantified on reversed phase column Luna C18(2) (150 × 4.6 mm i.d., 5 µm particle size) operated at room temperature using the mobile phase consisting of methanol: 0.1% acetic acid (50 : 50, v/v) at a flow rate of 1 ml min-1. The method was fully validated according to bioanalytical validation guidelines of FDA in terms of system suitability, selectivity, sensitivity, precision and stability. It was found that the increase in peak areas followed the increase of DZ concentration in the range of 2.56-200.00 ng ml-1 with LOD of 0.85 ng ml-1. The method was successfully applied for the determination of DZ in rabbit plasma using manual shaking dispersive liquid-liquid microextraction.
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- Comparison in the efficacy of fesoterodine or mirabegron add-on therapy to silodosin for patients with benign prostatic hyperplasia complicated by overactive bladder: A randomized, prospective trial using urodynamic studies. [Journal Article]
- NUNeurourol Urodyn 2019; 38(3):941-949
- CONCLUSIONS: Add-on therapy of fesoterodine to silodosin was more effective than adding mirabegron to silodosin for improving OAB symptoms and storage functions, without deteriorating voiding symptoms or functions.