- 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.
- Alpha1-adrenergic receptor blockade in the ventral tegmental area modulates conditional stimulus-induced cocaine seeking. [Journal Article]
- NNeuropharmacology 2019 Jun 24; 158:107680
- Exposure to drug-associated cues evokes drug-craving and upregulates noradrenaline (NA) and dopamine (DA) system activity. Importantly, conditional stimulus-induced drug-seeking behavior depends part…
Exposure to drug-associated cues evokes drug-craving and upregulates noradrenaline (NA) and dopamine (DA) system activity. Importantly, conditional stimulus-induced drug-seeking behavior depends particularly on phasic DA signaling downstream from the ventral tegmental area (VTA), a midbrain structure key for the regulation of cocaine seeking. In particular, the activity of the alpha1-adrenergic receptor (α1-AR), which has recently been hypothesized to modulate salience encoding, is capable of bidirectional regulation of VTA dopaminergic activity. Thus, the impact of the conditional stimuli (CSs) on drug-seeking behavior might involve α1-AR signaling in the VTA. To date, the role of VTA α1-ARs in regulating CS-induced cocaine seeking has not been studied. In male Sprague-Dawley rats, we found that intra-VTA terazosin, a selective α1-AR antagonist, attenuated CS-induced cocaine seeking in a novel context and under extinction conditions, as well as CS-induced reinstatement of cocaine seeking. In contrast, terazosin microinfusion in a dose that attenuated CS-induced cocaine seeking had no effects on CS-induced food seeking or stress (2 mg/kg yohimbine)-evoked reinstatement of cocaine seeking. The potential nonspecific effects (sedative, anxiogenic) of α1-AR blockade of the VTA were also measured in the open-field test. Finally, using immunostaining, we demonstrated dopamine β-hydroxylase (DBH)-positive afferents in the VTA of cocaine-abstinent rats, providing a neuroanatomical substrate for the α1-AR mechanism. These results demonstrated for the first time that NAergic signaling via VTA α1-ARs potently and selectively regulates CS-induced cocaine seeking. Our findings provide new neuronal mechanisms that regulate cocaine craving.
- Efficacy and tolerability of Roystonea regia lipid extract (D-004) and terazosin in men with symptomatic benign prostatic hyperplasia: a 6-month study. [Journal Article]
- TATher Adv Urol 2019 Jan-Dec; 11:1756287219854923
- CONCLUSIONS: D-004 administered at a dose of 320 mg/day for 6 months showed comparable efficacy with terazosin (5 mg/day) in reducing the LUTS (IPSS score), producing a significant decrease in prostate volume and postvoid residual volume. Both treatments were safe, with better tolerability for D-004 as compared with terazosin.
- Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling. [Journal Article]
- JNJ Neurochem 2019; 149(6):747-759
- Phasic dopamine (DA) release from the ventral tegmental area (VTA) into forebrain structures is implicated in associative learning and conditional stimulus (CS)-evoked behavioral responses. Mounting …
Phasic dopamine (DA) release from the ventral tegmental area (VTA) into forebrain structures is implicated in associative learning and conditional stimulus (CS)-evoked behavioral responses. Mounting evidence points to noradrenaline signaling in the VTA as an important regulatory input. Accordingly, adrenergic receptor (AR) blockade in the VTA has been shown to modulate CS-dependent behaviors. Here, we hypothesized that α1 - and α2 -AR (but not β-AR) activity preferentially modulates phasic, in contrast to tonic, DA release. In addition, these effects could differ between forebrain targets. We used fast-scan cyclic voltammetric measurements in rats to assess the effects of intra-VTA microinfusion of terazosin, a selective α1 -AR antagonist, on electrically evoked phasic DA release in the nucleus accumbens (NAc) core and medial prefrontal cortex (mPFC). Terazosin dose-dependently attenuated phasic, but not tonic, DA release in the NAc core, but not in the mPFC. Next, we measured the effects of intra-VTA administration of the α2 -AR selective antagonist RX-821002 on evoked DA in the NAc core. Similar to the effects of α1 -AR blockade, intra-VTA α2 -AR blockade with RX-0821002 strongly and dose-dependently attenuated phasic, but not tonic, DA release. In contrast, no regulation by RX-821002 was observed in the mPFC. This effect was sensitive to intra-VTA blockade of D2 receptors with raclopride. Finally, the β-AR antagonist propranolol ineffectively modulated DA release in the NAc core. These findings revealed both α1 - and α2 -ARs in the VTA as selective regulators of phasic DA release. Importantly, we demonstrated that AR blockade modulated mesolimbic, in contrast to mesocortical, DA release in previously unstudied heterogeneity in AR regulation of forebrain phasic DA.
- α-Blocker and Risk of Dementia in Patients with Benign Prostatic Hyperplasia: A Nationwide Population Based Study Using the National Health Insurance Service Database. [Journal Article]
- JUJ Urol 2019; 202(2):362-368
- CONCLUSIONS: The study findings indicate that benign prostatic hyperplasia medication is not associated with a risk of dementia by duration of use or by type.
- Drug adherence and drug-related problems in pharmacotherapy for lower urinary tract symptoms related to benign prostatic hyperplasia. [Journal Article]
- JPJ Physiol Pharmacol 2018; 69(4)
- Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is one of the most common urinary disorders in elderly men. In recent years, pharmacotherapy of BPH has increase…
Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is one of the most common urinary disorders in elderly men. In recent years, pharmacotherapy of BPH has increased the efficacy, including combination treatment mostly with two drug classes, namely, 5-α-reductase inhibitors and α-1-adrenolytics (alpha blockers) with a different pharmacological activity. Although pharmacological treatment of BPH is a success story in urology, daily practice suggests that several medical needs remain unmet. We aimed to evaluate drug adherence in patients receiving pharmacological therapy to treat LUTS/BPH, and to analyze drug adherence among monotherapy and combination therapy. The sample population consisted of 758 men aged > 40 years who had been prescribed medications for LUTS/BPH during the index period between June 2015 and August 2016. Only alpha blockers and 5-α-reductase inhibitors (5ARIs) were considered in the analysis. Among ABs there were doxazosin, tamsulosin, alfuzosin, terazosin and among 5-α-reductase inhibitors it was only finasteride. Drug adherence was assessed in patients who were treated for a minimum of 6 months. Two levels of exposure were evaluated, follow-ups: ≥ 6 months, and ≥ 12 months. In patients who were treated for at least 6 months, the drug adherence rate was 32% and the 12-month drug adherence rate was 23%. We observed an inverse relationship between drug adherence rates and the duration of treatment - longer the duration of pharmacological therapy, lower was the drug adherence rate noted. Our study shows a low rate of overall drug adherence in patients diagnosed with BPH. It was observed that a low adherence rate is closely related to drug-related problems (DRP). Furthermore, this is a correlation between the degree of LUTS/BPH and adherence rate - the higher degree of LUTS/BPH, the higher adherence rate. Further studies are warranted focusing on assessing adherence to pharmacological therapy.
- How to Read a Research Paper: An Exercise in Critical Thinking in the Context of an Epidemiologic Study on Tamsulosin and the Risk of Dementia. [Journal Article]
- JCJ Clin Psychiatry 2018 Dec 11; 79(6)
- A recent study of the relationship between tamsulosin and dementia found that, in propensity score-matched analyses that adjusted for measured risk factors for dementia, the use of tamsulosin to trea…
A recent study of the relationship between tamsulosin and dementia found that, in propensity score-matched analyses that adjusted for measured risk factors for dementia, the use of tamsulosin to treat benign prostatic hyperplasia (BPH) was associated with a small but significant increase in the risk of incident dementia relative to untreated BPH, BPH treated with the 5α-reductase inhibitors dutasteride and finasteride, and BPH treated with the α adrenoceptor blockers doxazosin, terazosin, and alfuzosin. The choice of control groups addressed confounding by indication, confounding by disease severity, and confounding by pharmacologic drug class. The authors of the study provided a wealth of detail in their main paper and in supplementary materials, allowing an almost forensic examination of the findings. This article discusses the study from the perspective of whether the hypothesis relating tamsulosin to dementia was set a priori or emerged after an exploratory exercise; whether tamsulosin crosses the blood-brain barrier for dementia as the event of interest to be attributable to treatment; whether the action of tamsulosin is plausibly related to dementia as a possible outcome; whether confounding was adequately addressed in the analyses; whether the duration of follow-up was sufficient for the event of interest to be attributable to tamsulosin; whether the absolute increase in the rate of incident dementia was clinically significant; and what the curiosities in the dose-dependence and subgroup analysis findings could imply. These matters provide considerable food for thought. Thus, this article is intended to serve as an example of how to read a paper critically and how to think about what the findings might suggest.
- Cost-Effectiveness of Combination Therapy Versus Monotherapy in Benign Prostatic Hyperplasia: A Colombian Experience. [Journal Article]
- VHValue Health Reg Issues 2018; 17:174-182
- CONCLUSIONS: The combination of finasteride and doxazosin is cost-effective compared with dutasteride, tamsulosin, terazosin, and alfuzosin in patients with benign prostatic hyperplasia with moderate or severe symptoms who are older than 40 years.
- Factors Affecting Urinary Retention in Critically Ill Trauma Patients. [Journal Article]
- JTJ Trauma Nurs 2018 Nov/Dec; 25(6):356-359
- The objective of this retrospective study was to gain a better understanding of patient and care factors that may contribute to urinary retention in critically ill trauma patients. Fifty trauma patie…
The objective of this retrospective study was to gain a better understanding of patient and care factors that may contribute to urinary retention in critically ill trauma patients. Fifty trauma patients over a 1-year period with an International Classification of Diseases, Tenth Revision (ICD-10) code for urinary retention were identified and analyzed. Most patients had an indwelling urinary catheter placed on admission, and it was reinserted in 39 patients. Male gender, orthopedic trauma, and anesthesia were possible contributing factors for urinary retention in our sample population. The use of paralytics and more than one operative intervention had a significant relationship with prescribing bladder medications. It is imperative to have protocols based on best evidence to guide management of urinary retention in this critically ill trauma patient population.
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- Detection of potential look-alike/sound-alike medication errors using Veterans Affairs administrative databases. [Journal Article]
- AJAm J Health Syst Pharm 2018 Oct 01; 75(19):1460-1466
- CONCLUSIONS: Through the use of administrative databases, potential LASA errors that could be reviewed for an actual error via chart review were identified. While a high rate of potential LASA errors was detected, the number of actual errors identified was low.