Search Results (48)

Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder affecting an estimated 1.36 billion people worldwide. It is associated with excessive daytime sleepiness, impaired quality of life, cardiovascular and cerebrovascular disease, and increased all-cause mortality, and is a substantial economic burden. Although positive airway pressure (PAP) remains the gold-standard therapy, its effectiveness is limited by suboptimal tolerance and adherence, leading to interest in pharmacological alternatives. Among emerging options, AD109, a combination of the selective noradrenergic reuptake inhibitor atomoxetine (75 mg) and the antimuscarinic aroxybutynin (2.5 mg), taken once daily, represents a mechanistically targeted approach that acts on the neuromuscular roots of OSA. Preclinical work demonstrated that pharyngeal dilator tone is suppressed in sleep through withdrawal of noradrenergic excitation and active muscarinic inhibition at the hypoglossal motor nucleus, providing the rationale for combining a noradrenergic agent with an antimuscarinic to augment hypoglossal motor output and preserve upper-airway patency. Building on a series of smaller precursor trials of noradrenergic–antimuscarinic combinations, AD109 has demonstrated consistent efficacy across phase 2 and two large phase 3 trials (SynAIRgy and LunAIRo), with meaningful reductions in the apnea–hypopnea index, improvements in nocturnal oxygenation, and a generally favorable tolerability profile. These findings position AD109 as a promising oral option, particularly for adults with mild to severe OSA who cannot tolerate or decline PAP. However, its effect on long-term cardiovascular, neurocognitive, and mortality outcomes remains to be established. This commentary reviews the mechanism of action and clinical trial evidence for AD109 and related combinations. Full article

Background: Concurrent use of acetylcholinesterase inhibitors (AChEIs) and medicines with anticholinergic activity is a clinically important medication safety concern in dementia care because these medicines may pharmacologically oppose dementia treatment and increase the risk of avoidable harm. This review systematically synthesised evidence on the prevalence, patterns, predictors and clinical consequences of concurrent use of anticholinergic and anti-dementia drugs (ADDs) in older adults with dementia. Methods: A PRISMA-informed systematic review was conducted employing Ovid MEDLINE, Embase and PsycINFO from January 2010 to April 2026. Observational studies were eligible if they included older adults with dementia and reported concurrent exposure to at least one anticholinergic medicine and an ADD, defined as AChEIs and/or memantine. Study quality was appraised using the Newcastle–Ottawa Scale. Results: Twenty-eight studies were included, spanning community, outpatient memory-clinic, acute hospital, long-term care and population-based settings. Two distinct exposure constructs were identified: (1) temporal co-prescribing and (2) cumulative anticholinergic burden among ADD users. Reported prevalence varied markedly according to the exposure definition and setting. Concurrent use was lowest in studies limited to bladder antimuscarinic overlap, generally around 5–13%,but increased to 20–45% when broader anticholinergic definitions were used. In long-term care and institutional cohorts, concurrent exposure reached 61–67%. Recurring predictors included polypharmacy, fragmented care or multiple prescribers, urinary symptoms, behavioural and psychological symptoms of dementia, Parkinson’s disease and non-geriatric prescribing. One large population-based study reported that high anticholinergic burden was associated with treatment modification of AChEIs (aHR 1.12), delirium (aHR 1.52), and two-year mortality (aHR 1.23). Additional studies reported associations with longer hospital stays or readmission. Conclusions: Concurrent use of anticholinergic medicines and ADDs is a common, clinically important and potentially modifiable medication-safety problem in dementia care. Full article

We analyze data indicating that a set of currently marketed FDA/EMA-approved drugs used to treat parkinsonism, extrapyramidal side effects of antipsychotic drugs, or overactive bladder may have the potential to slow the growth of glioblastoma; diffuse midline glioma, H3K27-altered (DMG); and a particular form of DMG growing in the pons of children, diffuse intrinsic pontine glioma (DIPG). These gliomas are typically associated with poor prognosis. Clinical trials evaluating conventional chemotherapeutic drugs have failed to improve DIPG survival. Our analysis of the biochemistry and physiology of DMG and DIPG concludes that neuronal acetylcholinergic agonisms at muscarinic receptors M1 and M3 on primitive oligodendrocyte precursor cells (OPCs) are trophic, growth-stimulating factors in DMG/DIPG growth. A set of muscarinic receptor inhibitors—benztropine, biperiden, and trihexyphenidyl—is used clinically to treat Parkinson’s disease or the parkinsonian side effects from antipsychotic medicines. Another muscarinic inhibitor, oxybutynin, is used to treat overactive bladder. All four drugs may impose dose-related side effects inherent to muscarinic receptor inhibition, such as xerostomia, asthenia, and mild cognitive impairment. We recount the evidence for the inhibition of OPC proliferation and migration mediated by these four M1/M3 inhibitors and report details on the rationale for selecting oxybutynin as the primary candidate for adjuvant therapy in DMG/DIPG. We chose oxybutynin as the first choice to study in DMG and DIPG compared to other antimuscarinic drugs based on its (i) high brain-tissue concentration, (ii) relatively stronger M3 inhibition, (iii) lower side-effect propensity than scopolamine, (iv) wide availability, and (v) the absence of H1 antihistamine or dopaminergic effects. Given the rapidly fatal nature of DMG and DIPG, the potential of oxybutynin for growth slowing may outweigh the associated risks and mild side-effect burdens. Full article

Older adults with multiple diseases are likely to be prescribed multiple medications including anticholinergic agents, which are frequently prescribed to manage conditions such as overactive bladder and chronic obstructive pulmonary disease and Parkinson’s disease. Overactive bladder (OAB) has been the subject of increased disease awareness and is a common and significant cause of reduced quality of life, particularly in the elderly. The selective β₃ adrenoceptor agonist, mirabegron was developed for the pharmacological treatment of OAB. Mirabegron has been shown to exert off-target effects on various functional proteins such as muscarinic receptors in rat tissues. This agent may relax the detrusor muscle by activating β₃ adrenoceptors and also antagonizing muscarinic receptors. Mirabegron and antimuscarinics exerted additive effects on muscarinic receptor binding and relaxant responses of cholinergic contractions of the detrusor muscle. Mirabegron excreted in human urine appears to directly attenuate muscarinic receptor-mediated functions in the bladder. Combination therapy of mirabegron and solifenacin in patients with OAB may enhance not only their therapeutic effects on OAB, but also increase the risk of anticholinergic adverse effects. Therefore, the safety of concomitant use of mirabegron and other drugs such as antimuscarinics for elderly patients needs to be carefully considered. Full article

Background: Mixed urinary incontinence (MUI), particularly the urge-predominant subtype, involves both stress urinary incontinence (SUI) and urge urinary incontinence (UUI), posing a therapeutic challenge. Duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI), enhances urethral tone, while tolterodine, an antimuscarinic agent, reduces detrusor overactivity. Their combination may offer synergistic benefits. Aim: The aim of this study was to evaluate the efficacy of duloxetine and tolterodine combination therapy in urge-predominant MUI and identify factors influencing treatment success. Method: A retrospective study was conducted on 106 patients (mean age: 56.45 years) with urge-predominant MUI treated with duloxetine (40 mg twice daily) and tolterodine (4 mg once daily) for 12 weeks. Treatment outcomes were evaluated using the overactive bladder symptom score (OABSS), International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), 24 h pad test, and Clinical Global Impression Scale (CGI). Univariate and multivariate regression analyses were performed to determine predictors of success. Results: Significant improvements were observed: OABSS decreased from 11.08 to 6.95, ICIQ-SF decreased from 15.69 to 8.84, and pad use decreased from 3.58 to 0.73/day (all p 0.0001). Bladder capacity increased from 315.09 mL to 436.32 mL. Baseline ICIQ-SF scores were independent predictors of success (odds ratio [OR] = 2.919, p = 0.001). Patient satisfaction reached 77.4%, with mild side effects (constipation and dizziness) in 14 patients. Conclusions: Duloxetine and tolterodine combination therapy significantly improved symptoms and quality of life in urge-predominant MUI. Baseline ICIQ-SF scores may predict treatment success. Further prospective studies are needed. 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

Background: Mixed urinary incontinence (MUI) has always represented a major therapeutic challenge and the management of this type of incontinence is often complicated by uncertain outcomes. Surgical options include interventions targeting both stress urinary incontinence (SUI) and urge urinary incontinence (UUI), although there are no international published guidelines that dictate whether it is better to start with surgical management to address the SUI or UUI component after the failure of conservative treatment. The aim of the present study is to evaluate the effectiveness of the Macroplastique (MPQ) procedure on overactive bladder (OAB) symptoms in women with MUI with a minimum follow-up of 1 year. Methods: A retrospective analysis of prospectively collected data was performed in two tertiary reference centers. We enrolled all women complaining of symptoms of SUI and OAB, dry or wet, with a urodynamically confirmed diagnosis of MUI [urodynamic stress incontinence (USI) with detrusor overactivity (DO)], who took a previous ineffective antimuscarinic treatment and underwent the MPQ procedure. We considered as objectively cured women who did not leak urine during the stress test and with a 1 h pad-test negative, while International Consultation on Incontinence Questionnaire–Short Form (ICIQ-SF), ICIQ-OAB, Patient Global Impression of Improvement (PGI-I) scale, and a Visual Analogue Scale (VAS) were used to assess subjective outcomes. Results: A total of forty-six patients who met the inclusion criteria and who underwent the MPQ procedure were considered for the analysis. At the 1-year mark of follow-up, 72% of patients were objectively cured at stress test and 65% were objectively cured at pad-test, while 72% of women declared themselves subjectively cured. OAB symptoms significantly improved after MPQ and a complete resolution of OAB was recorded in 35% of patients. Conclusions: This study demonstrated that MPQ is a safe and effective option for the treatment of female MUI. Furthermore, MPQ significantly improves the symptoms of OAB and is able to completely cure this condition in a relevant percentage of women with MUI when pharmacological treatment fails. Full article

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (C_max/DW)), elimination (terminal half-life (T_1/2) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and C_max/DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and C_max/DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T_1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, C_max, and CL/F of 5-HMT, which should be confirmed in other studies. Full article

Obstructive sleep apnea (OSA) is a prevalent pathology with current modalities of treatment including continuous positive airway pressure (CPAP), surgery, weight loss, hypoglossal nerve stimulation, and pharmacotherapy. While CPAP is the current standard treatment for OSA, lack of tolerance and side effects necessitate alternative modalities of treatment. Various pharmacologic agents exist with mechanisms that may target OSA. Early trials have demonstrated efficacy of noradrenergic-antimuscarinic combinations to stimulate the airway, promote pharyngeal muscle tone, and prevent airway collapse. These agents, which we discuss in detail, have demonstrated significant reductions in apnea-hypopnea index (AHI) and lowest oxygen saturations based on preliminary studies. Glucagon-like peptide 1 receptor agonists (GLP-1RA), which stimulate endogenous insulin, reducing glucagon release, and decreasing gastric emptying, have shown positive results for OSA patients through weight loss with reductions in AHI. In this narrative review article, we highlight the mechanisms, current data, and future potential for multiple drug classes, including respiratory stimulants and GLP-1RAs. Full article

The participation of butyrylcholinesterase (BChE) in the degradation of atropine has been recurrently addressed for more than 70 years. However, no conclusive answer has been provided for the human enzyme so far. In the present work, a steady-state kinetic analysis performed by spectrophotometry showed that highly purified human plasma BChE tetramer slowly hydrolyzes atropine at pH 7.0 and 25 °C. The affinity of atropine for the enzyme is weak, and the observed kinetic rates versus the atropine concentration was of the first order: the maximum atropine concentration in essays was much less than K_m. Thus, the bimolecular rate constant was found to be k_cat/K_m = 7.7 × 10⁴ M⁻¹ min⁻¹. Rough estimates of catalytic parameters provided slow k_cat < 40 min⁻¹ and high K_m = 0.3–3.3 mM. Then, using a specific organophosphoryl agent, echothiophate, the time-dependent irreversible inhibition profiles of BChE for hydrolysis of atropine and the standard substrate butyrylthiocholine (BTC) were investigated. This established that both substrates are hydrolyzed at the same site, i.e., S198, as for all substrates of this enzyme. Lastly, molecular docking provided evidence that both atropine isomers bind to the active center of BChE. However, free energy perturbations yielded by the Bennett Acceptance Ratio method suggest that the L-atropine isomer is the most reactive enantiomer. In conclusion, the results provided evidence that plasma BChE slowly hydrolyzes atropine but should have no significant role in its metabolism under current conditions of medical use and even under administration of the highest possible doses of this antimuscarinic drug. Full article

Systemic sclerosis (SSc) is a multifaceted connective tissue disease whose aetiology remains largely unknown. Autoimmunity is thought to play a pivotal role in the development of the disease, but the direct pathogenic role of SSc-specific autoantibodies remains to be established. The recent discovery of functional antibodies targeting G-protein-coupled receptors (GPCRs), whose presence has been demonstrated in different autoimmune conditions, has shed some light on SSc pathogenesis. These antibodies bind to GPCRs expressed on immune and non-immune cells as their endogenous ligands, exerting either a stimulatory or inhibitory effect on corresponding intracellular pathways. Growing evidence suggests that, in SSc, the presence of anti-GPCRs antibodies correlates with specific clinical manifestations. Autoantibodies targeting endothelin receptor type A (ETAR) and angiotensin type 1 receptor (AT1R) are associated with severe vasculopathic SSc-related manifestations, while anti-C-X-C motif chemokine receptors (CXCR) antibodies seem to be predictive of interstitial lung involvement; anti-muscarinic-3 acetylcholine receptor (M3R) antibodies have been found in patients with severe gastrointestinal involvement and anti-protease-activated receptor 1 (PAR1) antibodies have been detected in patients experiencing scleroderma renal crisis. This review aims to clarify the potential pathogenetic significance of GPCR-targeting autoantibodies in SSc, focusing on their associations with the different clinical manifestations of scleroderma. An extensive examination of functional autoimmunity targeting GPCRs might provide valuable insights into the underlying pathogenetic mechanisms of SSc, thus enabling the development of novel therapeutic strategies tailored to target GPCR-mediated pathways. Full article

Background and Objectives: Until now, overactive bladder (OAB) with or without urge urinary incontinence (UUI) has been treated mainly in two ways: with behavioral methods and patient education, or using antimuscarinic drugs and/or beta-3 adrenergic receptor agonists. Unfortunately, these drugs may cause side effects in some women or are insufficiently effective, so patients abandon them. Therefore, in this pilot study, radiofrequency was evaluated as a new option in the treatment of OAB and UUI. Materials and Methods: Nineteen patients were enrolled in this pilot study using radiofrequency (RF), where the level of OAB and UUI was assessed using the validated ICIQ-OAB questionnaire. RF was applied four times for 20 min, once a week. Two weeks after treatment, the level of OAB and UUI was reassessed and processed statistically and the treatment effect evaluated. Results: Using the ICIQ-OAB, the severity of OAB and UUI was assessed: 0–3 mild symptoms; 4–7 moderate symptoms; 8–11 severe symptoms; 12–16 very severe symptoms. Before treatment, 10.5% of patients had mild symptoms, 21.1% moderate symptoms, 63.2% severe symptoms and 5.3% very severe symptoms. After treatment, 42.9% had mild symptoms, 50% moderate symptoms and 7% severe OAB and UUI symptoms. All four main symptoms—frequency, nocturia, urgency and incontinence—decreased statistically significantly, with the best results being found in urgency (p = 0.002). Conclusions: Based on this pilot study, RF seems a very promising method in the treatment of OAB and UUI. To extend our initial findings, it is necessary to perform a prospective, randomized and placebo-controlled study in order to obtain reliable results and to determine for how long one set of treatment maintains the results obtained immediately after the end of that treatment. In this way, we may determine how often the treatment needs to be repeated, if necessary, and when. Full article

The development of new drugs or drug candidates based on the phenothiazine system (10H-dibenzo-[b,e]-1,4-thiazine) is a promising approach in view of the diverse biological activity of this tricyclic system, which is present in traditional drugs (chlorpromazine, thioridazine, trifluoperazine, and trifluopromazine) with antipsychotropic, antihistamine and antimuscarinic activities. In practical medicine, these drugs are used as antagonists of dopamine and other neurotransmitter receptors for the treatment of schizophrenia and bipolar disorders. Ongoing studies on the synthesis and biological screening of various phenothiazine derivatives in recent years have revealed other important biological effects of these compounds, among which their antitumor effects are of great interest. This work reports the synthesis of a novel N-substituted phenothiazine analog bearing a mitochondria-directed cationic group (E)-4-(1H-indol-3-ylvinyl)-pyridinium (F16) linked to the nitrogen atom of the phenothiazine core by a butane bridge. The lipophilic cationic F16 fragment was used as a means to enhance transmembrane transport and selective delivery of the hybrid molecule into the mitochondria of cancer cells. In tests on the BT474 breast cancer cell line, the phenothiazine-F16 hybrid demonstrated significant cytotoxic activity. The cytotoxic effect of the compound was noticeable at a concentration of 5 μM and further increased dose-dependently, leading to complete tumor cell death at a concentration of 50 μM (IC₅₀ 3.3 μM). The F16-derivative of phenotzine showed marked mitochondrial targeting. In experiments on isolated rat liver mitochondria, the tested agent, already at a concentration of 5 μM, significantly decreased the membrane potential of succinate-energized organelles. Increasing the concentration of the phenothiazine hybrid to 20 μM resulted in complete dissipation of the potential. The obtained result of antitumor activity against BT-474 cell culture and significant effect on the reduction of mitochondrial membrane potential allows us to consider phenothiazine-F16 hybrid as a new promising antitumor drug. Full article

We question whether bradyphrenia, slowing of cognitive processing not explained by depression or a global cognitive assessment, is a nosological entity in idiopathic parkinsonism (IP). The time taken to break contact of an index finger with a touch-sensitive plate was measured, with and without a warning in the alerting signal as to which side the imperative would indicate, in 77 people diagnosed with IP and in 124 people without an IP diagnosis. The ability to utilise a warning, measured by the difference between log_e-transformed reaction times (unwarned minus warned), was termed ‘cognitive efficiency’. It was approximately normally distributed. A questionnaire on self- and partner perception of proband’s bradyphrenia was applied. A multivariable model showed that those prescribed levodopa were less cognitively efficient (mean −5.2 (CI −9.5, −1.0)% per 300 mg/day, p = 0.02), but those prescribed the anti-muscarinic trihexyphenidyl were more efficient (14.7 (0.2, 31.3)% per 4 mg/day, p < 0.05) and those prescribed monoamine oxidase-B inhibitor (MAOBI) tended to be more efficient (8.3 (0.0, 17.4)%, p = 0.07). The variance in efficiency was greater within IP (F-test, p = 0.01 adjusted for any demographic covariates: coefficient of variation, with and without IP, 0.68 and 0.46, respectively), but not so after adjustment for anti-parkinsonian medication (p = 0.13: coefficient of variation 0.62). The within-participant follow-up time, a median of 4.8 (interquartile range 3.1, 5.5) years (101 participants), did not influence efficiency, irrespective of IP status. Perception of bradyphrenia did not usefully predict efficiency. We conclude that both bradyphrenia and ‘tachyphrenia’ in IP appear to have iatrogenic components, of clinically important size, related to the dose of antiparkinsonian medication. Levodopa is the most commonly prescribed first-line medication: co-prescribing a MAOBI may circumvent its associated bradyphrenia. The previously reported greater efficiency associated with (low-dose) anti-muscarinic was confirmed. Full article

Major depressive disorder is one of the most severe mental disorders. It strongly impairs daily functioning, and, in extreme cases, it can lead to suicide. Although different treatment options are available for patients with depression, there is an ongoing search for novel therapeutic agents, such as scopolamine (also known as hyoscine), that would offer higher efficacy, a more rapid onset of action, and a more favorable safety profile. The aim of our study was to review the current clinical evidence regarding the use of scopolamine, a promising therapeutic option in the treatment of depression. A systematic literature search was performed using PubMed, Embase, and CENTRAL databases up to 5 June 2023. We included randomized placebo-controlled or head-to-head clinical trials that compared the clinical efficacy and safety of scopolamine in the treatment of major depressive disorder. Two reviewers independently conducted the search and study selection and rated the risk of bias for each study. Four randomized controlled trials were identified in the systematic review. The included studies investigated the use of scopolamine administered as an oral, intramuscular, or intravenous drug, alone or in combination with other antidepressants. The results indicated that scopolamine exerts antidepressant effects of varying intensity. We show that not all studies confirmed a statistically and clinically significant reduction of depressive symptoms vs. placebo. A broader perspective on scopolamine use in antidepressant treatment should be confirmed in subsequent large randomized controlled trials assessing both effectiveness and safety. Therefore, studies directly comparing the effectiveness of scopolamine depending on the route of administration are required. Full article