Search Results (13)

Pituitary cells are specialized cells located within the pituitary gland, a small, pea-sized gland situated at the base of the brain. Through the use of cellular electrophysiological techniques, the electrical properties of these cells have been revealed. This review paper aims to introduce the ion currents that are known to be functionally expressed in pituitary cells. These currents include a voltage-gated Na⁺ current (I_Na), erg-mediated K⁺ current (I_K(erg)), M-type K⁺ current (I_K(M)), hyperpolarization-activated cation current (I_h), and large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel. The biophysical characteristics of the respective ion current were described. Additionally, we also provide explanations for the effect of various drugs or compounds on each of these currents. GH₃-cell exposure to GV-58 can increase the magnitude of I_Na with a concurrent rise in the inactivation time constant of the current. The presence of esaxerenone, an antagonist of the aldosterone receptor, directly suppresses the magnitude of peak and late I_Na. Risperidone, an atypical antipsychotic agent, is effective at suppressing the I_K(erg) amplitude directly, and di(2-ethylhexyl)-phthalate suppressed I_K(erg). Solifenacin and kynurenic acid can interact with the K_M channel to stimulate I_K(M), while carisbamate and cannabidiol inhibit the I_h amplitude activated by sustained hyperpolarization. Moreover, the presence of either rufinamide or QO-40 can enhance the activity of single BK_Ca channels. To summarize, alterations in ion currents within native pituitary cells or pituitary tumor cells can influence their functional activity, particularly in processes like stimulus–secretion coupling. The effects of small-molecule modulators, as demonstrated here, bear significance in clinical, therapeutic, and toxicological contexts. Full article

The core subunits of the K_V7.2, K_V7.3, and K_V7.5 channels, encoded by the KCNQ2, KCNQ3, and KCNQ5 genes, are expressed across various cell types and play a key role in generating the M-type K⁺ current (I_K(M)). This current is characterized by an activation threshold at low voltages and displays slow activation and deactivation kinetics. Variations in the amplitude and gating kinetics of I_K(M) can significantly influence membrane excitability. Notably, I_K(M) demonstrates distinct voltage-dependent hysteresis when subjected to prolonged isosceles-triangular ramp pulses. In this review, we explore various small-molecule modulators that can either inhibit or enhance the amplitude of I_K(M), along with their perturbations on its gating kinetics and voltage-dependent hysteresis. The inhibitors of I_K(M) highlighted here include bisoprolol, brivaracetam, cannabidiol, nalbuphine, phenobarbital, and remdesivir. Conversely, compounds such as flupirtine, kynurenic acid, naringenin, QO-58, and solifenacin have been shown to enhance I_K(M). These modulators show potential as pharmacological or therapeutic strategies for treating certain disorders linked to gain-of-function or loss-of-function mutations in M-type K⁺ (K_V7x or KCNQx) channels. Full article

Background and Objectives: Ureteral stents are widely used in the field of urology but can cause varying degrees of side effects. This study utilized a network meta-analysis to evaluate stent-related discomfort (SRD) in patients with alpha-blockers (alfuzosin, tamsulosin, and silodosin), antimuscarinics (solifenacin), beta 3-agonists (mirabegron), and phosphodiesterase 5-inhibitors (tadalafil) versus a placebo. Materials and Methods: Relevant randomized controlled trials (RCTs) from 2006 to 2021 were identified from electronic databases, including PubMed, EMBASE, and the Cochrane Library. The following identifiers were included to assess the urinary symptom score (USS): participants (patients with ureteral stents), interventions (patients who took medication for stent discomfort), and outcomes (comparisons of the Ureteric Stent Symptoms Questionnaire (USSQ)). We also executed an independent quality assessment using the Scottish Intercollegiate Guidelines Network (SIGN). Results: A total of 16 RCTs were identified, and they included 1865 patients. Compared with the placebo, mirabegron (mean difference (MD): −3.87; 95% confidence interval (CI): −10.6–2.35), tadalafil (MD: −4.47; 95% CI: −10.8–1.63), and silodosin (MD: −4.02; 95% CI: −12–4.01) did not show significant differences to the placebo, whereas others did. Alfuzosin, mirabegron, silodosin, solifenacin, and tadalafil were not inferior to tamsulosin in terms of the USS using Bayesian analyses. In the random effect model, P-score tests showed that solifenacin possessed the highest P-score (p = 0.8484); tamsulosin was the second highest (p = 0.7054). As a result of the rank-probability test, solifenacin was also ranked highest in terms of USS, and tamsulosin was ranked second. Conclusions: Compared with the placebo, solifenacin, tamsulosin, and alfuzosin significantly decreased the USS. In our study, solifenacin may be considered the most effective medication for SRD. Full article

Introduction: The application of double-J ureteral stents in urology is widespread, but their use is often accompanied by complications and bothersome symptoms, affecting patients’ quality of life (QoL). While various medications have been tested for alleviating the symptoms associated with double-J stents, consensus on their effectiveness remains elusive. This study aims to investigate the effectiveness of tamsulosin, solifenacin, mirabegron, desloratadine, and combination therapy using a Romanian-adapted version of the Ureteral Stent Symptom Questionnaire (USSQ). Materials and Methods: A prospective, observational, randomised trial was conducted at the Urology and Renal Transplant Clinic of Dr. “C.I. Parhon” Clinical Hospital in Iasi between 1 January 2022 and 1 August 2023. Three hundred twenty seven patients who underwent their first double-J stent insertion were evaluated with the Romanian-adapted USSQ at baseline and 30 days post-insertion. Patients were randomly divided into six groups based on the prescribed medications: control, tamsulosin, mirabegron, solifenacin, desloratadine, and combination therapy. Results: The data suggest a significant reduction in symptoms in patients who received medication compared with the control group. Furthermore, the combined medication of solifenacin 10 mg and tamsulosin 0.4 mg was particularly effective in reducing pain with statistical significance compared to the control group (p = 0.001). The highest mean scores for urinary symptom severity were observed in the control group (12.37 ± 6.82), and the lowest was in the mirabegron group (9.94 ± 5.82). The individuals who received a daily dose of 50 mg of mirabegron saw the most notable influence on their job. Conclusions: While no single medication emerged as a “miracle drug” for managing symptoms related to double-J stent insertion, the combination therapy of solifenacin and tamsulosin is the most promising option for improving symptoms related to double-J stent insertion and QoL. Additional extensive research is required to validate these initial results. Full article

Solifenacin (SFC) is a potent muscarinic antagonist that effectively reduces bladder muscle contraction, thereby alleviating symptoms such as frequency of micturition and urgency. Oxidation of SFC leads to the formation of impurities like Impurity K. Effective analysis and control of this impurity is crucial for ensuring compliance with regulatory standards and safeguarding patient health. To address these challenges, we propose a novel one-step synthesis of Impurity K from SFC. Impurity K was synthesized using cerium(IV) ammonium nitrate (CAN) in water/acetonitrile as the solvent. Additionally, we describe a new HPLC-MS method for the detection of Impurity K in solifenacin succinate tablets. Full article

Solifenacin, a selective muscarinic receptor antagonist, is one of the best-tolerated and most effective medicines that relieve storage symptoms in patients with an overactive bladder (OAB). However, the persistence of solifenacin in daily clinical practice remains far below that reported in clinical trials. This study aimed to analyze the adherence of patients to the therapy and the reasons for solifenacin discontinuation and non-regular use in OAB patients managed by urologists. Data concerning non-compliance and the discontinuation of solifenacin, along with the reasons, were collected during two consecutive visits for 64,049 OAB outpatients. Over the two visits, 81.6% of the patients continued therapy, and 88.6% were taking solifenacin regularly. An age ≥ 75 yrs., the male sex, a rural or small-city dwelling, and a prescription of ≥10 mg predicted therapy continuation. The female sex, a higher education, a short or long duration of an OAB, and a non-idiopathic OAB predicted regular use. The persistence of nycturia and urinary incontinence during therapy predicted both discontinuation and non-regular use. Dissatisfaction with therapy was the most frequent reason for discontinuation. In conclusion, an initial prescription of solifenacin at a low dose reduces the chance of OAB symptom improvement and results in more frequent discontinuation. A high rate of discontinuation related to dissatisfaction suggests unrealistic expectations for OAB patients and insufficient education by urologists. Full article

Infusions of Valeriana pilosa are commonly used in Peruvian folk medicine for treating gastrointestinal disorders. This study aimed to investigate the spasmolytic and antispasmodic effects of Valeriana pilosa essential oil (VPEO) on rat ileum. The basal tone of ileal sections decreased in response to accumulative concentrations of VPEO. Moreover, ileal sections precontracted with acetylcholine (ACh), potassium chloride (KCl), or barium chloride (BaCl₂) were relaxed in response to VPEO by a mechanism that depended on atropine, hyoscine butylbromide, solifenacin, and verapamil, but not glibenclamide. The results showed that VPEO produced a relaxant effect by inhibiting muscarinic receptors and blocking calcium channels, with no apparent effect on the opening of potassium channels. In addition, molecular docking was employed to evaluate VPEO constituents that could inhibit intestinal contractile activity. The study showed that α-cubebene, β-patchoulene, β-bourbonene, β-caryophyllene, α-guaiene, γ-muurolene, valencene, eremophyllene, and δ-cadinene displayed the highest docking scores on muscarinic acetylcholine receptors and voltage-gated calcium channels, which may antagonize M₂ and/or M₃ muscarinic acetylcholine receptors and block voltage-gated calcium channels. In summary, VPEO has both spasmolytic and antispasmodic effects. It may block muscarinic receptors and calcium channels, thus providing a scientific basis for its traditional use for gastrointestinal disorders. Full article

We designed a bioequivalent tablet form of solifenacin succinate (SOL) with an improved storage stability using a direct compression (DC) technique. An optimal direct compressed tablet (DCT) containing an active substance (10 mg), lactose monohydrate, and silicified microcrystalline cellulose as diluents, crospovidone as a disintegrant, and hydrophilic fumed silica as an anti-coning agent was constructed by evaluating the drug content uniformity, mechanical properties, and in vitro dissolution. The physicochemical and mechanical properties of the DCT were as follows: drug content 100.1 ± 0.7%, disintegration time of 6.7 min, over 95% release within 30 min in dissolution media (pH 1.2, 4.0, 6.8, and distilled water), hardness > 107.8 N, and friability ~0.11%. The SOL-loaded tablet fabricated via DC showed an improved stability at 40 °C and RH 75%, exhibiting markedly reduced degradation products compared to those fabricated using ethanol or water-based wet granulation or a marketed product (Vesicare^®, Astellas Pharma). Moreover, in a bioequivalence study in healthy subjects (n = 24), the optimized DCT offered a pharmacokinetic profile comparable to that of the marketed product, with no statistical differences in the pharmacokinetic parameters. The 90% CIs for the geometric mean ratios of the test to the reference formulation for the area under the curve and the maximum drug concentration in plasma were 0.98–1.05 and 0.98–1.07, respectively, and satisfied the FDA regulatory criteria for bioequivalence. Thus, we conclude that DCT is a beneficial oral dosage form of SOL with an improved chemical stability. Full article

Background and Objectives: pseudo urgency syndrome among patients with mixed incontinence (MUI) causes and the corresponding treatment strategies is explored. Materials and Methods: A total of 40 patients with MUI are treated with transobturator tape (TOT) and/or solifenacin succinate. Further, 30 patients with simple stress urinary incontinence (SUI) that were treated with transobturator tape (TOT) from the period of December 2018 to August 2020 are retrospectively analyzed; then, their clinical characteristics and therapeutic effects were summarized and analyzed. Results: The effective rates of SUI symptoms in MUI and simple SUI groups were 85% and 90%, respectively; further, the difference was noted as not statistically significant (P > 0.05). Among the 40 patients with MUI, 12 patients had unstable bladder contraction, and the other 28 patients showed normal bladder compliance. The treatment effectiveness rates of SUI symptoms in patients with unstable bladder contraction and normal bladder compliance were 83.3% and 85.7%, respectively; further, no significant difference was noted (P > 0.05). However, the effective rates of urge urinary incontinence (UUI) were 50% and 85.7%, respectively, however the difference was noted as statistically significant (P < 0.05). Conclusions: Most of the UUI symptoms in MUI patients may be “pseudo urgency syndrome” caused by the worry about the leakage of urine, rather than a real sense of UUI that is caused by excessive bladder excitement. Direct surgical treatment in patients with MUI can improve the symptoms of urinary incontinence, and the effect is more obvious in patients with urinary frequency who have normal bladder compliance according to urodynamics. Full article

Background: The occurrence of postoperative urinary incontinence (UI) remains a problem for patients undergoing robot-assisted radical prostatectomy (RARP). Non-surgical interventions (NSI) in addition to intraoperative techniques and patient behavioral changes have been proposed to improve urinary continence (UC) recovery after RARP. However, to date, the real clinical impact of postoperative NSI remains not well characterized. Materials and Methods: We performed a Systematic Review in April 2021, using Allied and Complementary Medicine (AMED), Embase, and MEDLINE according to the PRISMA recommendations and using the Population, Intervention, Comparator and Outcome (PICO) criteria. Primary outcome of interest was the impact of NSI on UC recovery rate and time to achieve UC after RARP. Secondary outcomes of interest were the assessment of patient adherence to NSI, risk factors associated with UI, and correlation between postoperative NSI and sexual activity recovery. Results: A total of 2758 articles were screened, and 8 full texts including 1146 patients were identified (3 randomized controlled trials, 3 prospective single-arm trials, and 2 retrospective series). Postoperative NSI of interest included pelvic floor muscle training (PFMT) (n = 6 studies) and administration of oral medications (solifenacin) (n = 2 studies). PFMT appeared to increase UC rates and to accelerate time to achieve UC in the early postoperative period. Similarly, solifenacin provided higher rates of UC recovery and contributed to a certain degree of symptomatic relief. There was a great variability regarding NSI features and data reporting among studies. Major limitations were the small sample sizes and the short follow-up. Conclusion: Postoperative NSI to manage UI after RARP include PFMT and solifenacin administration. Both seem to modestly improve early UC recovery. Nonetheless, evidence supporting their routinely use is still weak and lacks appropriate follow-up to evaluate possible benefits on long-term UC recovery. Full article

Solifenacin (Vesicare^®, SOL), known to be a member of isoquinolines, is a muscarinic antagonist that has anticholinergic effect, and it has been beneficial in treating urinary incontinence and neurogenic detrusor overactivity. However, the information regarding the effects of SOL on membrane ionic currents is largely uncertain, despite its clinically wide use in patients with those disorders. In this study, the whole-cell current recordings revealed that upon membrane depolarization in pituitary GH₃ cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K⁺ current (I_K(M)) with effective EC₅₀ value of 0.34 μM. The activation time constant of I_K(M) was concurrently shortened in the SOL presence, hence yielding the K_D value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of I_K(M) was shifted along the voltage axis to the left with no change in the gating charge of the current. Upon an isosceles-triangular ramp pulse, the hysteretic area of I_K(M) was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated I_K(M); however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in I_K(M) amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K⁺ (K_M) channels with no change in the single channel conductance; the mean open time of the channel became lengthened. In whole-cell current-clamp recordings, the SOL application reduced the firing of action potentials (APs) in GH₃ cells; however, either subsequent addition of TRH or linopirdine was able to reverse SOL-mediated decrease in AP firing. In hippocampal mHippoE-14 neurons, the I_K(M) was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with K_M channels and hence in stimulating I_K(M) in electrically excitable cells, and this noticeable action appears to be independent of its antagonistic activity on the canonical binding to muscarinic receptors expressed in GH₃ or mHippoE-14 cells. Full article

Enzymes are biocatalysts. In this study, a novel biocatalyst consisting of magnetic combined cross-linked enzyme aggregates (combi-CLEAs) of 3-quinuclidinone reductase (QNR) and glucose dehydrogenase (GDH) for enantioselective synthesis of (R)-3-quinuclidinolwith regeneration of cofactors in situ was developed. The magnetic combi-CLEAs were fabricated with the use of ammonium sulfate as a precipitant and glutaraldehyde as a cross-linker for direct immobilization of QNR and GDH from E. coli BL(21) cell lysates onto amino-functionalized Fe₃O₄ nanoparticles. The physicochemical properties of the magnetic combi-CLEAs were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and magnetic measurements. Field emission scanning electron microscope (FE-SEM) images revealed a spherical structure with numerous pores which facilitate the movement of the substrates and coenzymes. Moreover, the magnetic combi-CLEAs exhibited improved operational and thermal stability, enhanced catalytic performance for transformation of 3-quinuclidinone (33 g/L) into (R)-3-quinuclidinol in 100% conversion yield and 100% enantiomeric excess (ee) after 3 h of reaction. The activity of the biocatalysts was preserved about 80% after 70 days storage and retained more than 40% of its initial activity after ten cycles. These results demonstrated that the magnetic combi-CLEAs, as cost-effective and environmentally friendly biocatalysts, were suitable for application in synthesis of (R)-3-quinuclidinol essential for the production of solifenacin and aclidinium with better performance than those currently available. Full article

Objective: To evaluate the cost-effectiveness of solifenacin 5 mg/day versus other oral antimuscarinic agents used for overactive bladder (OAB) from a UK National Health Service (NHS) perspective. Study design: In a Markov model, hypothetical patients received solifenacin 5 mg/day or a comparator antimuscarinic, after which they could switch to an alternative antimuscarinic. The model estimated incremental cost-effectiveness ratios (ICER), expressed as cost per quality-adjusted life year (QALY) over a 5-year period. Results: Solifenacin 5 mg/day was the dominant treatment strategy (i.e., less costly and more effective) versus tolterodine extended-release (ER) 4 mg/day, fesoterodine 4 and 8 mg/day, oxybutynin ER 10 mg/day and solifenacin 10 mg/day, and was cost-effective (i.e., ICERs below the £30,000 per QALY threshold generally applied in the NHS) versus oxybutynin immediate release (IR) 10 mg/day, tolterodine IR 4 mg/day and trospium chloride 60 mg/day. The probability of solifenacin 5 mg/day being dominant/cost-effective at a willingness-to-pay threshold of £30,000 per QALY was 57–98%. Conclusions: Solifenacin 5 mg/day appears to be a cost-effective strategy for the treatment of OAB over a 5-year timeframe compared with other oral antimuscarinic agents in the UK. These findings are important for decision-makers considering the economic implications of selecting treatments for OAB. Full article