Antimuscarinic Agents Research Articles

Serum levels of prostate specific antigen, free PSA, [-2]proPSA, fPSA/tPSA ratio, Prostate Health Index, and glycosylation patterns of free PSA in patients with benign prostatic hyperplasia pharmacotherapy.

The medication used to treat benign prostate hyperplasia (BPH), a common condition in men over 50 years of age, can alter the levels of biomarkers used in prostate cancer detection. Commonly used medications for BPH include alpha-blockers, 5-alpha reductase inhibitors (5-ARIs), and muscarinic antagonists. We studied the impact of these drugs on total prostate-specific antigen (tPSA), free PSA (fPSA), [-2]proPSA, fPSA/tPSA ratio, and the Prostate Health Index (PHI), as well as novel potential biomarkers in the form of glycan composition of fPSA. Serum samples were collected from 564 males with BPH, with a mean age of 68.5 years. The samples were used to measure levels of tPSA, fPSA, and [-2]proPSA. The fPSA/tPSA and PHI were then calculated. The glycan composition of fPSA was analyzed using lectin-based glycoprofiling. Pharmacotherapy data was collected from the patients' medical records. Alpha-blocker monotherapy was associated with higher fPSA and fPSA/tPSA ratio, and decreased PHI. Levels of tPSA were not impacted. Alpha-blocker and 5-ARI dual therapy was associated with reduced levels of fPSA, [-2]proPSA, and PHI. Therapy combining alpha-blockers and antimuscarinic agents did not significantly influence biomarker levels apart from an increase in a Maackia amurensis lectin-recognized glycan originating in fPSA. BPH pharmacotherapy notably affects prostate cancer biomarkers. Recognizing the impact of pharmacotherapy is crucial for achieving an accurate diagnosis of prostate cancer and for planning treatment.

An Improved and Efficient Practical Process for the Synthesis of Enantiomerically Pure Solifenacin Succinate as an Antimuscarinic Agent

Background: Solifenacin succinate is an active pharmaceutical drug molecule that is extremely effective in treating overactive bladder symptoms, such as urine incontinence, urgency, and frequent urination. The free base is yellow oil, and the salt solifenacin succinate forms yellowish crystals that are extremely stable and effective. Solifenacin is a very active antagonist due to its potent muscarinic M3 receptor antagonist characteristics. Furthermore, solifenacin is effective in the treatment of bowel syndrome (IBS) by blocking M3 receptors and a broad spectrum of bowel dysfunction. Objective: The objective of this study was to develop a practical and highly efficient scalable synthesis of enantiomerically pure solifenacin as an antimuscarinic agent. Methods: In this work, the Zn(OTf)2 catalyst was used to develop a novel, environmentally benign, high-yielding, and robust protocol for the synthesis of enantiomerically pure solifenacin succinate. Results: The synthesis of enantiomerically pure solifenacin succinate was achieved in seven steps using commercially available phenylethylamine and benzoyl chloride as the starting materials. We carried out the reaction optimization by treatment of (S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)- carbonyl chloride and (R)-(-)-3-Quinuclidinolin in the presence of Zn(OTf)2 catalyst. Furthermore, the solifenacin-free base was treated with succinic acid to afford its corresponding salt. The highlight of this protocol is the use of 20 mol% Zn(OTf)2 catalyst for the first time. The readily available starting materials, robustness, easy operation, high yield, and low cost make the approach more attractive and highly applicable. Conclusion: In summary, we developed a novel Zn(OTf)2-catalysed environmentally benign, highyielding, and robust protocol for the synthesis of enantiomerically pure solifenacin succinate. The proposed strategy is highly cost-effective and avoids the use of hazardous and unsafe sensitive, strong bases as well as tedious work-up procedures. Effective synthesis was achieved using readily available starting materials and reagents. Thus, the protocol is highly efficient, compatible, and commercially viable for the synthesis of important solifenacin products.

Design and Evaluation of Inorganic/Organic Hybrid Bio-composite for Site-Specific Oral Delivery of Darifenacin

Benign hyperplasia (BHP) is a common disorder that affects men over the age of 60 years. Transurethral resection of the prostate (TURP) is the gold standard for operative treatment, but a range of drugs are also available to improve quality of life and to reduce BHP-associated urinary tract infections and complications. Darifenacin, an anti-muscarinic agent, has been found effective for relieving symptoms of overactive bladder associated with BHP, but the drug has poor solubility and bioavailability, which are major challenges in product development. An inorganic/organic bio-composite with gastric pH-resistant property was synthesized for the targeted oral delivery of Darifenacin to the lower gastrointestinal tract (GIT). This development was accomplished through co-precipitation of calcium carbonate in quince seed-based mucilage. The FTIR, XRD, DSC, and TGA results showed good drug-polymer compatibility, and the SEM images showed calcite formation in the quince hydrogel system. After 72 h, the drug release of 34% and 75% were observed in acidic (0.1N HCl) and 6.8 pH phosphate buffer, respectively. A restricted/less drug was permeated through gastric membrane (21.8%) as compared to permeation through intestinal membrane (65%.) The developed composite showed significant reduction in testosterone-induced prostatic hyperplasia (2.39 ± 0.12***) as compared to untreated diseased animal group. No sign of organ toxicity was observed against all the developed composites. In this study, we developed an inorganic–organic composite system that is highly biocompatible and effective for targeting the lower GIT, thereby avoiding the first-pass metabolism of darifenacin.Graphical

Predictors of the effectiveness of initial therapy with antimuscarinic agents in children with neurogenic urination disorders

BACKGROUND: Almost a third of patients with neurogenic urinary disorders have a refractory nature to therapy with antimuscarinic agents. The aim of the current trial was to identify predictors of the effectiveness of initial therapy with antimuscarinic agents in children with neurogenic urination disorders. For this, a comprehensive analysis of clinical parameters and video urodynamic findings in children was made. AIM: The purpose of this study was to identify predictors of the successful initial therapy with M-anticholinergic preparations in children with neurogenic urinary disorders. For this, results of a comprehensive analysis of initial clinical and video urodynamic parameters were used.. METHODS: A prospective longitudinal cohort study involved 62 patients, aged 1.8–18 years, with neurogenic urination. In addition to the standard examination, all patients underwent a video urodynamic examination at Laborite Delphis UDS-600 device with parallel cystography at Siemens X-ray C-arc (Siemens, Germany). By the obtained results, 52 out of 62 patients were prescribed antimuscarinic agents as the first line therapy. Therapy effectiveness was assessed in 3 months. Analysed parameters were age, presence/absence of self-catheterization, as well as presence/absence of vesicoureteral reflux (VUR) revealed at conventional retrograde urethrocystography and/or video urodynamic examination. RESULTS: The multivariate regression analysis demonstrated that the risk of ineffective antimuscarinic therapy increases by 75,6% in patients with VUR revealed at retrograde uretrocystography, regardless of patient's age and self-catheterization (OR=0.244; 95% CI=0.063-0.937; p=0.040) and by 89.8% (OR=0.102; 95% CI=0.019-0.554; p=0.008) when VUR is detected at video urodynamic examination. Unlike patients with a positive effect (n=24; 50%), 24 patients (50%) who had no response to antimuscarinic therapy were younger (median age 8 years); they also were self-catheterized and had VUR revealed at video urodynamic examination. Outcomes of the prescribed therapy were not associated with other video urodynamic parameters. The identified significant predictors (age, self-catheterization and VUR at video urodynamic examination) have allowed to develop a model for predicting antimuscarinic therapy effectiveness before its administration. This model can promote a rational selection of patients for antimuscarinic therapy, as the first line therapy, with a high probability of positive outcome in 84.9% of patients. CONCLUSION: When prescribing antimuscarinic agents, patient's age, self-catheterization, VUR revealed at retrograde urethrocystography and video urodynamic examination should be taken into account. Predictors of effective antimuscarinic therapy in children with neurogenic urinary disorders, which increase the likelihood of successful outcomes, are patient's age (over 12 years), no self-catheterization and no VUR at video urodynamic examination. Patients younger than 12 years, with self-catheterization and VUR are less likely to respond to antimuscarinic therapy.

Update on Overactive Bladder Therapeutic Options.

Millions of Americans are burdened by overactive bladder (OAB) syndrome and the psychogenic and economic hardships that accompany it. Several theories attempt to explain OAB as a neurogenic dysfunction, myogenic dysfunction, urothelial dysfunction, or decreased expression of a channel protein secondary to bladder outlet obstruction. Given that the etiology of OAB is a working theory, the management of OAB is also an evolving subject matter in medicine. There are uncertainties surrounding the pathophysiology of OAB, the strength of a clinical diagnosis, and accurate reporting because of the disease's stigma and decreased use of health care. This is a narrative review that used PubMed, Google Scholar, Medline, and ScienceDirect to review literature on current and future OAB therapies. Currently, first-line treatment for OAB is behavioral therapy that uses lifestyle modifications, bladder-control techniques, and psychotherapy. Second-line therapy includes antimuscarinic agents or beta 3 adrenergic agonists, and studies have shown that combination therapy with antimuscarinics and beta 3 adrenergic agonists provides even greater efficacy than monotherapy. Third-line therapies discussed include onabotulinumtoxinA, posterior tibial nerve stimulation, and sacral neuromodulation. OnabotulinumtoxinA has been FDA-approved as a nonpharmaceutical treatment option for refractory OAB with minimal side effects restricted to the urinary tract. Posterior tibial nerve modulation and sacral neuromodulation are successful in treating refractory OAB, but the costs and complication rates make them high-risk procedures. Therefore, surgical intervention should be a last resort. Estrogen therapy is effective in alleviating urinary incontinence in postmenopausal women, consistent with the association between estrogen deficiency and genitourinary syndrome. Potassium channel activators, voltage-gated calcium channel blockers, and phosphodiesterase inhibitors look to be promising options for the future of OAB management. As new therapies are developed, individuals with OAB can better personalize their treatment to maximize their quality of life and cost-effective care.

Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment.

Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.

Chitosan-based buccal mucoadhesive bilayer tablets enhance the bioavailability of tizanidine hydrochloride by bypassing the first-pass metabolism

Tizanidine hydrochloride (TZN) is an antimuscarinic agent used in the treatment of pain-related spasms, multiple sclerosis, and stroke-related spasticity. It has low oral bioavailability (40 %) due to excessive first-pass metabolism in the liver. The aim of this project was to enhance the systemic bioavailability of TZN by developing buccal mucoadhesive bilayer tablet formulations using chitosan salts with molecular weights of 136 kDa (7 cP) and 169 kDa (10 cP). Structural characterisation of chitosans and their salts was performed by FTIR, 1H NMR, DSC, TGA, and XRD analyses. Soluble chitosan salts, chitosan glutamate and chitosan chloride, for the adhesive layer, and insoluble ethyl cellulose for the impermeable backing layer were selected as polymers to fabricate the buccal tablets by direct compression method. The tablets containing TZN demonstrated high swelling and good mucoadhesion characteristics as well as released all the drug within 8 h. While TC10, formulated with 10 cP chitosan chloride, showed the highest swelling properties, TG10, prepared with 10 cP chitosan glutamate, exhibited the highest mucoadhesion. Chitosan glutamate tablets (TG7 and TG10) demonstrated better mucoadhesive characteristics and stability than chitosan chloride ones (TC7 and TC10) in the buccal medium based on the results of swelling and drug release studies. The permeability studies performed by Franz diffusion cell demonstrated that the amount of TZN passing through the bovine buccal mucosa was between 13.4 and 14.4 %. Stability studies conducted at 5 ± 2 °C, 25 ± 2 °C and 40 ± 2 °C for 6 months showed that no changes in the content uniformity and pH were observed. The in vivo comparative bioavailability studies in female New Zealand rabbits were performed and TZN-containing buccal mucoadhesive bilayer tablets fabricated with both chloride (TC10) and glutamate (TG10) salts of chitosan demonstrated three times higher bioavailability than the commercial TZN product (Sirdalud® oral tablet) administered by the gastrointestinal route.

Does diphenhydramine exert a sex-dependent effect on sudomotor responses during exertional heat stress?

Introduction: The first-generation H1 antihistamine diphenhydramine hydrochloride (DPH) is a potent antimuscarinic agent which may compromise sweat output during heat stress. DPH consumption prior to exertional heat stress could further suppress the sweating response in females due to their lower postjunctional cholinergic sensitivity of the sweat glands relative to males. Objective and Hypothesis: The purpose of the present study was to test the hypothesis that DPH would reduce sweating to a greater extent in females relative to males due to differences in cholinergic sensitivity at the sweat gland. Methods: Equal groups (10 per group) of males (24±3 y; 82.6±10.1 kg; 182±5 cm) and females (22±3 y, 67.7±7.8 kg, 171±6 cm) completed two experimental trials presented in a randomized double-blind fashion. Upon arrival to lab, participants consumed either i) a placebo (PLA) pill or ii) 50 mg DPH and then rested in a room maintained at ~29.5°C & 35% RH for 2 hours before conducting a 60-minute treadmill march at a fixed rate of heat production relative to body surface area (~245 W/m2). Rectal temperature (Trec), local sweat rate of the forearm (LSR), and whole body sweat loss (WBSL) were measured. Sex-segregated analysis was conducted for each outcome variable as the difference between PLA and DPH. Results: Baseline Trec did not differ within sex between PLA and DPH (males: -0.10±0.26°C; females: -0.05±0.33°C, P=0.70), however a higher absolute baseline Trec was observed in females compared to males (P=0.006). In comparison to PLA, DPH did not exert a sex-dependent effect on ΔTrec following 60-min of exercise (males: 0.04±0.11°C; females: 0.02±0.37°C, P=0.90). No sex-dependent effect on the onset of sweating was observed between DPH and PLA (males: -0.4±2.6 min; females: 0.6±2.4 min, P=0.34). DPH did not exert a sex-dependent effect on LSR at steady-state (males: 0.03±0.25 mg/cm2/min; females: -0.01±0.21 mg/cm2/min, P=0.71). Lastly, no sex-dependent effect on WBSL was observed between PLA and DPH (males: 14±34 g; females: 6±43 g, P=0.98). Conclusion: Current evidence suggests that sex does not independently modulate the sweating response during exertional heat stress following the consumption of 50 mg of DPH. This research is supported by Dr. Ravanelli’s Research Seed Grant from the Centre for Research in Occupational Safety & Health, and Dr. Ravanelli’s Natural Sciences and Engineering Research Council of Canada Discovery Grant (PIN#2022-05096). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Retrospective Study on Prescription Pattern on the Management of Chronic Obstructive Pulmonary Disease (COPD)

Background: COPD is a disease caused by chronic bronchitis, emphysema, or combination of both conditions. As per the Global Burden of Disease 2017 prediction, COPD is the second leading cause of death in Nepal, the fourth leading cause of premature death and the third cause for disability-adjusted life years (DALYs) in Nepal. The prevalence of COPD in Nepal was 11.7%. If current situation prevails, the burden of COPD might increase continuously in the nation. Hence, the findings from this study might provide baseline information to medical and paramedical students and other researchers to conduct further study in similar area. Objectives: The study was done to assess the prescription pattern for management of COPD in multispecialty hospital of Nepal. Method: A retrospective study was conducted at 100 bedded multispecialty hospital located at Lalitpur, Nepal. A total of 200 inpatient records, from Baishak 2075 to Chaitra 2078 were reviewed and data was collected as per the objectives and analysed by using SPSS version 16 and MS Excel 2013. Result: Out of 200 COPD patients studied, female patients (58%) were higher than male patients and maximum patients (42.5%) were from the age group 70-79. The most common symptom was shortness of breath (77.5%) followed by cough (50%) and fever (33.5%) Hypertension (38.5%) was the most frequent co morbidity seen among COPD patients followed by corpulmonale (20%) and diabetes mellitus type II (19%). Doxophylline was the most prescribed methylxanthines during hospitalization (47.5%) and discharge (51%) as well. Among inhalers, Tiotropium bromide and combination of Salbutamol and Fluticasone (52.5%) was prescribed most to the hospitalised patients. Hydrocortisone (68.5%) was the most prescribed corticosteroids during hospitalization where as Prednisolone (49.5%) was the most prescribed corticosteroids during discharge. 85.5% of patients were prescribed Ipratropium bromide for nebulisation in hospitalised patients. Pantoprazole (55.5%) was the most prescribed proton pump inhibitors followed by Rabeprazole (34%). Maximum patients (103) preferred Rotacap than metered dose inhaler (MDI) and dry powder inhaler (DPI). Azithromycin (52.5%) was most frequently prescribed antibiotics during hospitalization followed by ceftriaxone (85%), whereas among discharge patients, Cefpodoxime (35%) was most frequently prescribed antibiotics followed by Azithromycin (32%). The drugs prescribed with generic name were 31.31% and from essential drug list (EDL) was 37.72 %. Conclusion: The prescription pattern of COPD was studied and found that Doxophylline, Tiotropium bromide, Hydrocortisone and Azithromycin were most prescribed methylxanthnes, antimuscarinic agents, corticosteroids and antibiotics respectively. The findings from the study showed that prescribing drugs with generic name and from EDL was low so prioritization on prescribing drugs by generic name and EDL needs to be encouraged.

Effect of norepinephrine reuptake inhibitors combined with antimuscarinic agents vs monotherapy for OSA: a systematic review and meta-analysis.

Randomized controlled trials have shown that combining norepinephrine reuptake inhibitors and antimuscarinics can ameliorate the severity of obstructive sleep apnea. This article explores whether the effectiveness and safety of combining norepinephrine reuptake inhibitors with antimuscarinic agents surpass monotherapy for treating obstructive sleep apnea. We searched randomized controlled trials including adult patients with obstructive sleep apnea who received combination therapy and monotherapy in 8 databases from inception until April 5, 2023 and evaluated the studies' quality and conducted a meta-analysis and systematic review. The primary outcome was the apnea-hypopnea index. Secondary outcome measures included loop gain, hypoxic burden, oxygen desaturation index, and ventilation at low ventilatory drive, among other indicators. We assessed the quality of the studies using Cochrane Methods criteria. We identified 4 randomized controlled trials for systematic review and 2 for meta-analysis. The results of the meta-analysis showed that norepinephrine reuptake inhibitors combined with antimuscarinic agents in patients with obstructive sleep apnea prolonged total sleep time by a mean of 28.20 minutes [95% confidence interval (5.78, 50.61), P = .01] and increased sleep efficiency by 4.73% [95% confidence interval (0.50, 8.97), P = .03] compared with norepinephrine reuptake inhibitors alone. Other indices and adverse events were of no statistical significance. The systematic reviews revealed that norepinephrine reuptake inhibitors combined with antimuscarinics may be superior to monotherapy in improving apnea-hypopnea index and endotypic traits. This evaluation demonstrated the potential advantages of combining norepinephrine reuptake inhibitors plus antimuscarinics for treating OSA compared with norepinephrine reuptake inhibitors alone and revealed no statistically significant difference in drug safety. Wang J, Ye Y, Shang Z, etal. Effect of norepinephrine reuptake inhibitors combined with antimuscarinic agents vs monotherapy for OSA: a systematic review and meta-analysis. J Clin Sleep Med. 2024;20(8):1363-1372.

(178) Climacturia: Emerging Type of Urinary Incontinence, Its Prevalence, Risk Factors, and Management: A Systematic Review and Prevalence Meta-analysis

Abstract Introduction Climacturia is an emerging type of urinary incontinence which occurs immediately following orgasm. Both men and women may suffer from climacturia in equivocal rates. This phenomenon is becoming more problematic as it impacts physiological and psychosexual aspect of well-being and quality of life. While awareness of climacturia becomes evident, studies are inadequate to support evidenced-based management in primary and urologic care settings. Objective This study aimed to conduct a systematic review and prevalence meta-analysis of climacturia and investigate its risk factors and evidenced-based management. Methods A systematic review of 24 articles were conducted following PRISMA 2020 guidelines. The PubMed, CINAHL, and Cochrane Library database were searched using the word “climacturia” and phrase “orgasm associated urinary incontinence” respectively. Search limiters applied included literature written in English from year of inception to 2022. Title and abstract reviews were conducted on 78 articles. Articles which did not discuss climacturia, duplicates, and previous systematic reviews were excluded after full article review. Results The review accounts a total of N = 7798 subjects which are composed of N = 7629 (97.83%) males and N = 169 (2.17%) females with age range of 18 to 80 years old. A total of N = 2, 039 (26%) participants are with climacturia, N = 87 or 4.26% are females and N = 1, 931 or 95.74% are males. The risk factors associated with climacturia include sexually active male, history of prostate cancer after prostatectomy within 12 months of surgery or radiation therapy, increased Body Mass Index (BMI), erectile dysfunction (ED), increased urethral width, presence of urinary incontinence, pain-associated orgasm and loss of penile length after pelvic surgery, use of aides to obtain an erection, and increased incontinence scores for men. For women, the risk factors are high scores of female sexual function index (FSFI) and detrusor overactivity. The management for females is limited to pharmacologic therapy with use of antimuscarinic agents. While, behavioral therapy, pharmacologic regimen, pelvic floor muscle training (PFMT), surgery (sling procedure) are the management options for affected men. Conclusions Climacturia affects males more than females, however, the evidence to support the efficacy of treatment options for both sexes are equally inadequate. Primary care and Advanced Practice Providers in primary and urologic care settings are at best position to query patients for the presence of and manage climacturia in timely manner. Further research is needed to increase evidence supporting effective management of climacturia for both men and women. Disclosure No.

Pharmacological interventions for the treatment of obstructive sleep apnea syndrome.

Obstructive Sleep Apnea Syndrome (OSAS) affects 13-33% of males and 6-9% of females globally and poses significant treatment challenges, including poor adherence to Continuous Positive Airway Pressure (CPAP) and residual excessive sleepiness (RES). This review aims to elucidate the emerging interest in pharmacological treatments for OSAS, focusing on recent advancements in this area. A thorough analysis of extensive clinical trials involving various drugs, including selective dopamine reuptake inhibitors, selective norepinephrine inhibitors, combined antimuscarinic agents, and orexin agonists, was conducted. These trials focused on ameliorating respiratory metrics and enhancing sleep quality in individuals affected by OSAS. The studied pharmacological agents showed potential in improving primary outcomes, notably the apnea-hypopnea index (AHI) and the Epworth sleepiness scale (ESS). These improvements suggest enhanced sleep quality and symptom management in OSAS patients. With a deeper understanding of OSAS, pharmacological interventions are emerging as a promising direction for its effective management. This review provides a comprehensive overview of the current state of drug research in OSAS, highlighting the potential of these treatments in addressing the disorder's complex challenges.

Adreno-Muscarinic Synergy of Contractile Responses From Human Hyperplastic Prostate.

Adreno-muscarinic synergy, a supra-additional contractile response to simultaneous application of α-adrenoreceptor and muscarinic receptor agonists, is a feature of several lower urinary tract regions that have dual sympathetic and parasympathetic innervation. We tested the hypothesis that synergy is also a feature of prostate tissue obtained from men with benign prostatic enlargement. Isolated tissue strips were dissected from prostate 'chips', collected after transurethral prostate resection procedures for in vitro experiments, to measure isometric tension at 36°C. Added separately to the superfusate, phenylephrine and carbachol generated contractions with mean pEC50 (-log10EC50) values of 5.36 and 5.58, respectively, although phenylephrine maximal responses were about six-fold greater. In the presence of carbachol, the mean phenylephrine pEC50 was significantly increased to 5.84 and maximal response increased by 28%; overall, a significant synergistic response was demonstrated. The synergistic response was reduced by muscarinic receptor antagonists, most potently by the M3-selective agent 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide), and less so by M2 and M1-selective inhibitors gallamine and pirenzepine, but with an overall profile indicating M3/M2 mediation of the synergistic response. The magnitude of the synergistic response was variable between prostate chips that provided isolated preparations suggesting regional heterogenicity, although their zonal origin could not be determined. These experiments show that adreno-muscarinic contractile synergy is a feature of human hyperplastic prostate tissue. This has implications for the use of a combination therapy of α-blockers and anti-muscarinic agent to relieve secondary symptoms associated with benign prostatic hyperplasia, at least in men who can tolerate antimuscarinics without a risk of retention.

PHARMACOTHERAPY OF OVERACTIVE BLADDER: A 10 YEARS SYSTEMATIC REVIEW

Background: OAB is a stigmatized condition that significantly affects quality of life. The current first-line pharmacological approach to treating OAB involves various medications, primarily antimuscarinic agents and adrenoceptor agonist. This study aims to provide a 10 year systematic review of pharmacological approach in OAB treatment. Methods: This systematic review adhered to the PRISMA 2020 standards and included full-text English literature published between 2014 and 2024. Exclusion criteria involved editorials, review articles from the same journal, and submissions lacking a DOI. Literature was gathered from online sources such as PubMed and SagePub. Result: Our search in PubMed yielded 997 articles, while SagePub produced 357 articles. Focusing on the last 10 years (2014-2024), PubMed had 667 articles and SagePub had 160 articles. Ultimately we selected 5 papers that met our criteria, 3 from PubMed and 2 from SagePub. Conclusion: Due to the the improvements in urgency, frequency, and incontinence as well as fewer treatment-related adverse events, adrenoceptor agonist mirabegron is recommended as the first-line treatment for OAB.

Predicting muscarinic receptor occupancy in human bladder mucosa from urinary concentrations of antimuscarinic agents for overactive bladder

To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive bladder. The calculated mean plasma or serum unbound steady state concentrations were 0.06–11 nM in clinical dosages of five antimuscarinic agents. Urinary concentrations calculated from the mean plasma or serum and renal clearance ranged between 19 nM and 2 μM, which were >10-fold higher than the Ki values for bladder muscarinic receptors excluding propiverine. Bladder mucosal muscarinic receptor occupancy estimated from the urinary concentrations and the Ki values was >90 % at a steady state in clinical dosages of five antimuscarinic agents. The bladder muscarinic receptor occupancy was higher than that in the parotid gland calculated based on the mean plasma or serum unbound concentrations and Ki values for muscarinic receptors in the parotid gland. These results suggest that sufficient and selective muscarinic receptor occupancy by antimuscarinic agents, to exert pharmacological effects, in the bladder mucosa can be predicted using urinary concentrations.

Myopia Control Combination to Slow The Progression of Myopia

Myopia is the most common refractive eye disorder in the world. Myopia is characterized by the inability of the eye to focus light on the retina, resulting in blurred distance vision. The purpose of this study is to understand the effectiveness of various methods or combinations of myopia control that can be used to slow or prevent the progression of myopia. This study used the Systematic Literature Review research method. The data collection technique in this study was carried out by literature study by exploring scientific journals, articles, books, and related publications contained in recognized databases, such as PubMed, Google Scholar, Scopus, and so on. The data that has been collected is analyzed through three stages, namely data reduction, data presentation and conclusion drawing. The results showed that the combination of controls to slow myopia include orthokeratology, environmental modification, low-level red-light therapy, antimuscarinic agents, increasing outdoor time and combination therapy.

A comparative study of atropine and atropine plus pralidoxime in the management of organo-phosphorous poisoning

Background: Poisoning with organophosphorus compounds (OP) is a common problem throughout the world particularly in developing countries. Standard treatment involves resuscitation, administration of the anti-muscarinic agent atropine, an acetylcholinesterase reactivator (pralidoxime) and assisted ventilation if necessary. In this study we compared the efficacy of add-on pralidoxime therapy over therapy with atropine alone in OP poisoning. Methods: The study included 103 patients, out of 103 OP poisoning cases, 54 patients received both atropine and PAM (group A) and 49 received only atropine (group B). Main outcome parameters of the study were total hospital stay and mortality. The data was compared using ‘t’ test while mortality was compared using Fisher’s exact test. Data was tabulated, analysed, reviewed and evaluated. Results: There was no difference in duration of hospital stay between the two group. The mean hospital stay in group A was 3.71±1.92 days and in group B was 3.14±2.01 days (p value >0.05). No difference in mortality was seen between the two group. Out of 54 in group A, 8 died and in group B out of 49, 7 died (p value >0.05). Importantly cost burden is very high in the pralidoxime added group. Conclusions: There is no significant difference in use of atropine alone or atropine-pralidoxime combination in terms of morbidity and mortality in OP poisoning rather the later incurs more economic burden which may not be practicable in poor countries like India. However, a larger multicentric prospective study needs to be conducted, to be able to draw a definitive conclusion.

The Impact of Polypharmacy on Management of Lower Urinary Tract Symptoms in Parkinson'sDisease.

Lower urinary tract (LUT) symptoms are a common presentation of autonomic dysfunction in Parkinson's disease (PD). Symptoms significantly impact quality of life and are associated with worsening of motor symptoms and increased risk for falls. Different medical co-morbidities can often contribute to LUT symptoms, and a thorough evaluation therefore becomes essential. The effects of medications used for Parkinson's disease and other co-existing medical co-morbidities on LUT symptoms is often underestimated. Treatment options include behavioural therapy, oral agents such as antimuscarinic and beta-3 receptor agonist agents, botulinum toxin and neuromodulation. The first-line oral agents cause adverse effects that may exacerbate pre-existing Parkinson's disease-related symptoms. Furthermore, these oral agents can interact with other medications used in Parkinson's disease, and the challenges posed by interactions on pharmacological effects and metabolism are discussed. Knowledge about drug interactions can help in effective management of such patients and mitigate the risks for developing adverse effects.

A preliminary study of the effects of an antimuscarinic agent on anxious behaviors and white matter microarchitecture in nonhuman primates.

Myelination subserves efficient neuronal communication, and alterations in white matter (WM) microstructure have been implicated in numerous psychiatric disorders, including pathological anxiety. Recent work in rodents suggests that muscarinic antagonists may enhance myelination with behavioral benefits; however, the neural and behavioral effects of muscarinic antagonists have yet to be explored in non-human primates (NHP). Here, as a potentially translatable therapeutic strategy for human pathological anxiety, we present data from a first-in-primate study exploring the effects of the muscarinic receptor antagonist solifenacin on anxious behaviors and WM microstructure. 12 preadolescent rhesus macaques (6 vehicle control, 6 experimental; 8F, 4M) were included in a pre-test/post-test between-group study design. The experimental group received solifenacin succinate for ~60 days. Subjects underwent pre- and post-assessments of: 1) anxious temperament (AT)-related behaviors in the potentially threatening no-eye-contact (NEC) paradigm (30-min); and 2) WM and regional brain metabolism imaging metrics, including diffusion tensor imaging (DTI), quantitative relaxometry (QR), and FDG-PET. In relation to anxiety-related behaviors expressed during the NEC, significant Group (vehicle control vs. solifenacin) by Session (pre vs. post) interactions were found for freezing, cooing, and locomotion. Compared to vehicle controls, solifenacin-treated subjects exhibited effects consistent with reduced anxiety, specifically decreased freezing duration, increased locomotion duration, and increased cooing frequency. Furthermore, the Group-by-Session-by-Sex interaction indicated that these effects occurred predominantly in the males. Exploratory whole-brain voxelwise analyses of post-minus-pre differences in DTI, QR, and FDG-PET metrics revealed some solifenacin-related changes in WM microstructure and brain metabolism. These findings in NHPs support the further investigation of the utility of antimuscarinic agents in targeting WM microstructure as a means to treat pathological anxiety.

Triple inhaled therapy for asthma in Canada

A significant number of patients with asthma have poor control on their current inhaled therapies, typically a combination of inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic bronchodilators (LABA). Adding a long-acting antimuscarinic agent (LAMA) has been shown to improve asthma control and the availability of triple therapy formulations (ICS/LABA/LAMA) in a single inhaler device or single inhaler triple therapy (SITT) mitigates the adherence concerns associated with use of multiple inhaler devices. Here, we provide an overview of the pivotal data concerning the use of triple asthma therapy in patients with poor control on ICS-LABA treatment, and present our expert approach to their application in the routine clinical management of such patients as well the appropriate sequencing of initiating triple therapy and seeking a referral for consideration of more advanced therapies.