Search Results (41)

Background/Objectives: Silodosin (SLD) is a selective α1A-adrenoceptor antagonist used in the treatment of benign prostatic hyperplasia. Bioequivalence failures have been reported for hard capsule formulations, largely due to the effect of disintegrant excipients, making soft capsules a promising alternative dosage form. This study investigated the stability of SLD soft capsules stored in two different packaging materials, PVC/PVDC and AquaBa^®. Methods: Storage temperatures at 25 °C/60%, 30 °C/65% RH, 30 °C/75% RH, and 40 °C/75% RH, and sampling were performed according to the International Council for Harmonisation (ICH) stability conditions. Assays were performed by HPLC and UV, and mass detection. Results: Degradation analysis revealed that temperature played a critical role in SLD degradation and the formation of its primary degradation products, dehydrosilodosin and impurity 1. Conclusions: AquaBa^® demonstrated superior protective properties compared to PVC/PVDC, preserving SLD content above 95% for over 12 months under 25 °C and 30 °C conditions while limiting the formation of degradation products. Nevertheless, impurity 1 exceeded its ICH Q3B (R2) specification limit (0.3%) after six months under all conditions tested, suggesting a critical interaction between SLD and excipients such as Capryol^® 90. Kinetic modeling confirmed first-order degradation kinetics for both dehydrosilodosin and impurity 1, with a faster degradation rate observed in PVC/PVDC blisters. These findings highlight the critical role of packaging in pharmaceutical stability. While AquaBa^® emerges as the preferred option for SLD soft capsules, formulation optimization remains necessary to limit impurity formation, extend shelf life, and ensure regulatory compliance. Full article

In left ventricular hypertrophy (LVH), the combined external administration of hydrogen sulfide (H₂S) and nitric oxide (NO) has been shown to reverse LVH by activating the endothelial nitric oxide synthase pathway (eNOS/NO), independent of the cystathionine γ-lyase (CSE/H₂S) pathway. Individually, both H₂S and NO have also been reported to significantly improve RCBP, restore renal excretory performance, and enhance α-adrenergic receptor responsiveness in rats. The induction of LVH was performed over a period of two weeks using drinking water with caffeine and isoprenaline. Five weeks later, the rats were fed with L-arginine (1.25 g/L) as a nitrogen oxide donor. Vascular reactions to methoxamine, phenylephrine, and noradrenaline were assessed in presences and absence of 5-methylurapidil (5-MeU), BMY7378, and chloroethylclonidine (CeC) and α1-adrenoceptor antagonists. In both the Control WKY and LVH-WKY groups, combined H₂S+NO therapy significantly (p < 0.05) upregulated the renal mRNA of CSE and eNOS when compared with untreated LVH rats. The treatment also markedly increased RCBP in LVH-H₂S+NO rats relative to LVH controls. Furthermore, H₂S+NO administration enhanced the activity of α_1A, α_1B, and α_1D adrenergic receptors in mediating renal vasoconstriction. Even under receptor blockade with high doses (HDs) of 5-MeU, CeC, and BMY 7378, renal vasoconstriction responses to adrenergic agonists like NA, PE, and ME in the LVH-H₂S+NO group remained comparable to those observed in the counterpart Control-H₂S+NO group. The findings of current study suggest that simultaneous exogenous administration of H₂S and NO donors improve renal cortical blood flow, support renal function, and augment α_1A, α_1B, and α_1D adrenergic receptor responsiveness to adrenergic agonists like NA, PE, and ME in LVH rats. This effect appears to rely primarily on the eNOS/NO pathway, with partial contribution from the CSE/H₂S pathway. Full article

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Because of its high potential for spreading and its limited response to treatment, UM remains a clinical challenge. Previous studies suggest that clinical adrenergic receptor (AR) antagonists might be effective in the treatment of UM. This study reports the antitumor activity of α-blocker in UM spheroids generated from α_1A- and α_2A-AR-positive UM cell lines. These cell lines were derived from primary tumors or hepatic metastases and differed in their genetic risk status for metastasis. Drug screening with UM spheroids revealed that prazosin and doxazosin dose-dependently reduced viability, whereas terazosin, alfuzosin, silodosin, tamsulosin, and phenoxybenzamine were found to be inefficient. Prazosin induced apoptosis, resulting in the disintegration of UM spheroid morphology and growth inhibition. Additionally, prazosin prevented UM spheroid cell outgrowth and long-term survival, indicating potential for tumor control. Like the selective α_1A-AR antagonist RS17053, prazosin inhibited the formation and growth of UM spheroids stimulated by the α_1-agonist phenylephrine. This suggests a tumor-preventive effect through the blockade of α_1A-AR. The present study highlights the responses of UM spheroids to α-AR antagonists and demonstrates that prazosin, doxazosin, or RS17053 may be a treatment option for preventing UM tumor recurrence or metastasis. Full article

Objectives: Silodosin, a selective α1A-adrenoceptor antagonist, is used to treat lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to interindividual variability in its efficacy and safety. This study aimed to investigate the influence of CYP3A4, CYP3A5, UGT2B7, and ABCB1 polymorphisms on silodosin pharmacokinetics, efficacy, and safety in Russian patients with BPH. Methods: A prospective observational study included 103 Russian male patients with moderate-to-severe LUTS (IPSS > 8) due to BPH, treated with silodosin (8 mg daily) for 8 weeks. Genotyping for CYP3A4*1B, CYP3A4*22, CYP3A5*3, UGT2B7 (rs73823859, rs7439366, and rs7668282), and ABCB1 (rs4148738, rs1045642, rs2032582, and rs1128503) was performed using real-time PCR. The silodosin minimum steady-state plasma concentration (Css min) was measured via HPLC-MS. Efficacy was evaluated by the International Prostate Symptom Score (IPSS), quality of life scale, maximum urinary flow rate (Qmax), residual urine volume (RUV), and prostate volume at the baseline and week 8. Adverse drug reactions (ADRs) were recorded. Results: CYP3A4*22 CT carriers (n = 6) exhibited higher Css min (17.59 ± 2.98 vs. 9.0 ± 10.47 ng/mL, p = 0.049) but less absolute IPSS improvement (p < 0.05), likely due to higher baseline symptom severity. However, the change in IPSS (ΔIPSS_1–4) from the baseline to week 8 did not differ significantly (−5.78 ± 5.29 vs. −6.0 ± 4.54, p = 0.939). CYP3A5*3 GG homozygotes (n = 96) showed greater ΔIPSS_1–4 improvement (−6.25 ± 4.60 vs. 0.0 ± 9.53, p = 0.042) and a lower IPSS at day 28 (7.64 ± 4.50 vs. 20.0 ± 6.55, p < 0.001). UGT2B7 rs7439366 TT carriers (n = 34) had an improved Qmax (ΔQmax_1–4 5.4 vs. 3.3 and 2.0 mL/s for CC and CT, p = 0.041). ABCB1 1236C>T TT homozygotes (n = 25) showed a trend toward reduced RUV (p = 0.053). No polymorphisms were associated with adverse drug reactions (15 events in 42 patients, 35.7%). Conclusions: Genetic polymorphisms CYP3A4*22, CYP3A5*3, and UGT2B7 rs7439366 may modulate silodosin pharmacokinetics and efficacy parameters in BPH patients but not safety. Larger-scale studies are warranted to validate these initial findings. Full article

β-adrenoceptors (BARs) are involved in vascular endothelial growth factor (VEGF) production during retinal neovascularization. Here, using human retinal endothelial and Müller cells (hRECs and MIO-M1, respectively), we evaluated the effects exerted by hypoxia on BARs, hypoxia-inducible factor-1α subunit (HIF-1α) and VEGF, as well as the involvement of BAR3 and nitric oxide synthase (NOS) enzymes in hypoxia-induced VEGF production. We altered oxygen availability through a hypoxic incubator. BARs, HIF-1 α and VEGF levels were evaluated. Cells were treated with the BAR3 antagonist SR59230A, different NOS inhibitors or the NO donor SNAP. The influence of the BAR3/NOS axis on hypoxic VEGF production was assessed. Hypoxia upregulated BAR3, HIF-1α and VEGF in hRECs and MIO-M1 cells. SR59230A counteracted hypoxia-dependent VEGF increase in both cell lines, exerting no effect on HIF-1α upregulation. Treatments with NOS inhibitors prevented the hypoxia-dependent VEGF increase, while SNAP abrogated the effect of SR59230A in reducing hypoxia-induced VEGF upregulation. The present results corroborate the hypothesis that in the hypoxic retina, BAR3 influence on VEGF production is mediated by NO and suggest that, at least in endothelial and Müller cells, BAR3 activity is necessary to allow the HIF-1-mediated VEGF upregulation. Full article

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus and a leading cause of blindness in the working-age population. Current pharmacological treatments counteract DR’s later stages without targeting the earlier disease phases. Using computational approaches, our group previously identified the α1D and α2C adrenoceptors (α1DR and α2CR) as new putative drug targets for DR. Therefore, the aim of this work was to validate the role of these receptors in an in vitro model of DR, i.e., retinal pigmented epithelial cells (ARPE-19) challenged with high glucose (HG, 50 mM). We examined the effects of selective α1DR and α2CR agonists and antagonists on hyperglycemia-induced mitochondrial dysfunction and blood retinal barrier breakdown. Seahorse XFe was employed to assess the oxygen consumption rate and extracellular acidification rate. The integrity of the ARPE-19 barrier was evaluated through transepithelial electrical resistance measurements and a sodium fluorescein permeability test. α1DR pharmacological modulation through the α1DR antagonist BMY 7378 (0.1–1 µM, 24 h), but not α2CR, significantly attenuated HG-induced mitochondrial dysfunction. BMY 7378 (0.1–1 µM, 48 h) also prevented HG-mediated damage to retinal epithelial integrity. In contrast, the α1DR agonist phenylephrine (1–10 μM, 24 h) further reduced ARPE-19 mitochondrial activity compared to HG, indicating that α1D activation is directly implicated in DR-mediated mitochondrial dysfunction. In conclusion, the current in vitro study validated α1DR as a pharmacological target for DR. Full article

Purpose: This study aimed to compare the effects of the phytoestrogens resveratrol (RES) and genistein (GEN) on the contractility of isolated uterine smooth muscle from rats, focusing on both spontaneous and stimulated contractions, and to investigate the underlying mechanisms. Methods: Uterine strips were suspended vertically in perfusion chambers containing Kreb’s solution, various concentrations of RES and GEN were added to the ex vivo uterine strips, and contractions were measured before and after incubation with RES or GEN. Results: (1) Both RES and GEN inhibited K⁺-induced contractions in a dose-dependent manner; the β/β₂-adrenoceptor antagonist propranolol (PRO), ICI118551, the ATP-dependent K⁺ channel blocker glibenclamide (HB-419) and the NO synthase inhibitor N-nitro-L-arginine (L-NNA) diminished the inhibitory effects of RES and GEN on K⁺-induced contractions. (2) RES and GEN also dose-dependently inhibited PGF_2α-induced uterine contractions. (3) The inhibitory effects of RES and GEN were observed in spontaneous contractile activities as well; PRO, ICI118551, HB-419 and L-NNA attenuated the inhibitory effects of RES and GEN on the spontaneous contractions of isolated uterine muscle strips. (4) RES and GEN significantly decreased the cumulative concentration response of Ca²⁺ and shifted the Ca²⁺ cumulative concentration–response curves to the right in high-K⁺ Ca²⁺-free Kreb’s solution. (5) RES and GEN markedly reduced the first phasic contraction induced by oxytocin, acetylcholine, and prostaglandin F_2α but did not alter the second phasic contraction caused by CaCl₂ in Ca²⁺-free Kreb’s solution. Conclusions: RES and GEN can directly inhibit both spontaneous and activated contractions of isolated uterine smooth muscle. The mechanisms underlying the inhibitory effects of RES and GEN likely involve β adrenergic receptor activation, reduced Ca²⁺ influx and release, the activation of ATP-dependent K⁺ channels and increased NO production. Full article

Background: The purpose of the study was to determine whether the use of β-adrenoceptor antagonists (β-blockers) can affect metalloproteinase 2 (MMP-2) and its tissue inhibitor (TIMP-2) in patients with chronic kidney disease (CKD) on conservative treatment. Methods: The circulating MMP-2/TIMP-2 system, proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the marker of oxidative stress—Cu/Zn superoxide dismutase (Cu/Zn SOD)—were measured in 23 CKD patients treated with β-blockers [β-blockers (+)] and in 27 CKD patients not receiving the above medication [β-blockers (−)]. Results: The levels of MMP-2, TIMP-2, and IL-6 were significantly lower in the β-blockers (+) than in the β-blockers (−) group, whereas Cu/Zn SOD concentrations were not affected by β-blocker use. There was a strong, independent association between MMP-2 and TIMP-2 in both analyzed patient groups. In the β-blockers (+) group, MMP-2 levels were indirectly related to the signs of inflammation, whereas in the β-blockers (−) group, the alterations in the MMP-2/TIMP-2 system were associated with the oxidative stress marker and CKD etiology. Conclusions: This study is the first to suggest that the use of β-blockers was associated with the reduction in IL-6 and the MMP-2/TIMP-2 system in CKD, providing a pharmacological rationale for the use of β-blockers to reduce inflammation and abnormal vascular remodeling in CKD. Full article

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1–15) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7–9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α₁-adrenergic receptors (α₁-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α₁-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α_1A and α_1B, was conducted. Selected compounds were tested for their activity towards two α₁-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC₅₀ < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α_1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α_1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin. Full article

Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors antagonists are antihypertensive agents that exert mild beneficial effects on the metabolic profile in hypertensive patients. However, they are no longer used as a first-line therapy for hypertension based on Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) outcomes. Later studies have shown that quinazoline-based α1-adrenolytics (prazosin, doxazosin) induce apoptosis; however, this effect was independent of α1-adrenoceptor blockade and was associated with the presence of quinazoline moiety. Recent studies showed that α1-adrenoceptors antagonists may reduce mortality in COVID-19 patients due to anti-inflammatory properties. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted anti-inflammatory, antihypertensive properties and reduced insulin resistance and visceral adiposity. In this study, we aimed to evaluate the effect of fructose consumption and treatment with α1-adrenoceptor antagonists of different classes (MH-76 and prazosin) on liver tissue of fructose-fed rats. Livers were collected from four groups (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical and histopathological studies. Both α1-adrenolytics reduced macrovesicular steatosis and triglycerides content of liver tissue and improved its antioxidant capacity. Treatment with MH-76, contrary to prazosin, reduced leucocytes infiltration as well as decreased elevated IL-6 and leptin concentrations. Moreover, the MH-76 hepatotoxicity in hepatoma HepG2 cells was less than that of prazosin. The use of α1-adrenolytics with anti-inflammatory properties may be an interesting option for treatment of hypertension with metabolic complications. Full article

Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (α1, α2, β1, β2, and β3) and renal denervation on atherosclerosis. All five types of adrenoceptors are present in arterial blood vessels. α1 blockers inhibit atherosclerosis but increase the risk of heart failure while α2 agonism may protect against atherosclerosis and newer generations of β blockers and β3 agonists are promising therapies against atherosclerosis; however, new randomized controlled trials are warranted to investigate the effectiveness of these therapies in atherosclerosis inhibition and cardiovascular risk reduction in the future. The role of renal denervation in atherosclerosis inhibition in humans is yet to be established. Full article

The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore if [¹¹C]yohimbine, a selective antagonist radioligand of the α2 adrenoceptors, may be used to assess in vivo changes in synaptic noradrenaline during acute pharmacological challenges. Anesthetised Göttingen minipigs were positioned in a head holder in a PET/CT device. Microdialysis probes were placed in the thalamus, striatum and cortex and dialysis samples were collected every 10 min. Three 90 min [¹¹C]yohimbine scans were acquired: at baseline and at two timepoints after the administration of amphetamine (1–10 mg/kg), a non-specific releaser of dopamine and noradrenaline, or nisoxetine (1 mg/kg), a specific noradrenaline transporter inhibitor. [¹¹C]yohimbine volumes of distribution (V_T) were obtained using the Logan kinetic model. Both challenges induced a significant decrease in yohimbine V_T, with time courses reflecting their different mechanisms of action. Dialysis samples revealed a significant increase in noradrenaline extracellular concentrations after challenge and an inverse correlation with changes in yohimbine V_T. These data suggest that [¹¹C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges. Full article

We aim to assess the effect of Cavacurmin^® on prostate volume (PV), lower urinary tract symptoms (LUTS) and micturition parameters in men after 1 year of therapy. From September 2020 to October 2021, data from 20 men with LUTS/benign prostatic hyperplasia and PV ≥40 mL who were on therapy with α1-adrenoceptor antagonists plus Cavacurmin^® were retrospectively compared with 20 men on only α1-adrenoceptor antagonists. Patients were evaluated at baseline and after 1 year using the International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA), maximum urinary flow (Qmax) and PV. A Mann–Whitney U-test and Chi-square were used to assess the difference between the two groups. A comparison of paired data was performed with the Wilcoxon signed-rank test. Statistical significance was set at p-value < 0.05. There was no statistically significant difference in baseline characteristics between the two groups. At the 1-year follow-up, PV [55.0 (15.0) vs. 62.5 (18.0) mL, p = 0.04)], PSA [2.5 (1.5) ng/mL vs. 3.05 (2.7) vs. p = 0.009] and IPSS [13.5 (3.75) vs. 18 (9.25) p = 0.009] were significantly lower in the Cavacurmin^® group. Qmax was significantly higher in the Cavacurmin^® group [15.85 (2.9) vs. 14.5 (4.2), p = 0.022]. PV was reduced to 2 (5.75) mL in the Cavacurmin^® group from baseline, while it increased to 12 (6.75) mL in the α1-adrenoceptor antagonists group (p < 0.001). PSA decreased in the Cavacurmin^® group [−0.45 (0.55) ng/mL], whereas it increased in the α1-adrenoceptor antagonists group [0.5 (0.30) ng/mL, p < 0.001]. In conclusion, one-year Cavacurmin^® therapy was able to block prostate growth with a concomitant decrease in PSA value from baseline. The association of Cavacurmin^® with α1-adrenoceptor antagonists had a more beneficial effect compared to patients on α1-adrenoceptor antagonists alone but this needs further larger studies to be confirmed, particularly in the long-term. Full article

Background: Pharmacological treatment of benign prostatic hyperplasia (BPH)/benign prostatic obstruction (BPO)-associated lower urinary tract symptoms (LUTS) aims at improving patients’ quality of life by managing urinary symptoms and preventing complications and disease progression. However, continuous use of drugs to treat BPH/BPO-associated LUTS decreases over time. The aim of this retrospective observational study was to describe use of α1-adrenoceptor antagonists (ABs) and steroid 5α-reductase inhibitors (5ARIs) by adult (age ≥ 40 years) men in the ASL TO4, a Local Health Authority in the northern area of the city of Turin (Italy). Methods: Persistence measures were adopted as a robust, informative, and feasible way to understand medication-taking behavior and to assess patient compliance. Results: A total of 4309 men (median age 71 years) were enrolled. Monotherapy was the treatment option prescribed to the largest part of the study population. However, ≥two drugs were prescribed to a substantial proportion of men (23%). Men prescribed alfuzosin or dutasteride had significantly greater persistence, which decreased over time. Conclusions: Unmet needs and areas of intervention for healthcare systems aimed at improving the use of drugs for BHP/BPO-associated LUTS in the ASL TO4 Regione Piemonte were identified. Full article

Classically, the effects elicited by corticosteroids (CS) are mediated by the binding and activation of cytosolic glucocorticoid receptors (GR). However, several of the non-genomic effects of CS seem to be mediated by putative non-classic membrane receptors characterized by pharmacological properties that are different from those of classic cytosolic GR. Since pre-clinical findings suggest that inhaled CS (ICS) may also regulate the bronchial contractile tone via putative CS membrane-associate receptors, the aim of this review was to systematically report and discuss the impact of CS on human airway smooth muscle (ASM) contractility and airway hyperresponsiveness (AHR). Current evidence indicates that CS have significant genomic/non-genomic beneficial effects on human ASM contractility and AHR, regardless of their anti-inflammatory effects. CS are effective in reducing either the expression, synthesis or activity of α-actin, CD38, inositol phosphate, myosin light chain kinase, and ras homolog family member A in response to several pro-contractile stimuli; overall these effects are mediated by the genomic action of CS. Moreover, CS elicited a strong bronchorelaxant effect via the rapid activation of the Gsα–cyclic-adenosine-monophosphate–protein-kinase-A pathway in hyperresponsive airways. The possibility of modulating the dose of the ICS in a triple ICS/long-acting β₂-adrenoceptor agonist/long-acting muscarinic antagonist fixed-dose combination supports the use of a Triple MAintenance and Reliever Therapy (TriMART) in those asthmatic patients at Step 3–5 who may benefit from a sustained bronchodilation and have been suffering from an increased parasympathetic tone. Full article