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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 311: 123986, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38335587

RESUMO

Tolterodine tartrate (TTD) was the first antimuscarinic medication developed exclusively for the treatment of overactive bladder syndrome and was approved by the FDA in 1998. As a result of the drug's extensive utilization within the local community following its authorization, there is a pressing need to develop and validate a spectrofluorometric method that is economically efficient, easily reproducible, environmentally sustainable, and possesses high sensitivity. The developed approach relies on enhancing the fluorescence intensity of TTD to reach a level 720 % higher than its initial value, achieved through the application of an aqueous sodium dodecyl sulfate (SDS) solution. A strong correlation was observed with a correlation coefficient of 0.9998 between the concentration of TTD and the fluorescence intensity within the range of 25.0-500.0 ng mL-1. This approach could be employed to quantify TTD in its pure form and to examine pharmaceutical tablets for the purposes of verifying uniform content. Additionally, it was utilized for the evaluation of TTD concentrations in spiked human plasma.


Assuntos
Bexiga Urinária Hiperativa , Humanos , Tartarato de Tolterodina , Bexiga Urinária Hiperativa/tratamento farmacológico , Espectrometria de Fluorescência/métodos , Antagonistas Muscarínicos/uso terapêutico , Dodecilsulfato de Sódio
2.
J Biochem Mol Toxicol ; 38(1): e23517, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37702107

RESUMO

Bacterial endotoxin lipopolysaccharide (LPS)-induced inflammatory response and ferroptosis play an important role in urinary tract infections. Tolterodine has been used as a urinary tract antispasmodic and anticholinergic agent. However, the effects of Tolterodine against LPS-induced insults in human bladder epithelial cells (hBECs) have not been reported before. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays to determine the cell viability, reactive oxygen species (ROS) and malondialdehyde level detection were used to determine the level of oxidative stress, enzyme-linked immunosorbent assay and Western blot analysis were used to detect the protein level. In the current study, we found that Tolterodine ameliorated LPS-induced production of ROS and lipid oxidation in hBECs. Interestingly, Tolterodine inhibited the production of interleukin 6, interleukin-1ß, and tumor necrosis factor α. Also, Tolterodine reduced the levels of Fe2+ and suppressed ferroptosis by reducing the levels of glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2, and acyl-CoA synthetase long-chain family member 4 in LPS-challenged bladder epithelial cells. Mechanistically, it was shown that Tolterodine restored the nuclear factor E2-related factor 2 (Nrf2)/nuclear factor-κB signaling. Importantly, inhibition of Nrf2 with its specific inhibitor ML385 abolished the protective effects of Tolterodine in the inflammatory response and ferroptosis, suggesting that the effects of Tolterodine are mediated by Nrf2. Based on these findings, we conclude that Tolterodine might serve as a promising agent for the treatment of LPS-induced bladder inflammation.


Assuntos
Ferroptose , Lipopolissacarídeos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Lipopolissacarídeos/toxicidade , Tartarato de Tolterodina , Fator 2 Relacionado a NF-E2/metabolismo , Bexiga Urinária/metabolismo , Células Epiteliais/metabolismo
3.
Int Braz J Urol ; 49(5): 535-563, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37506033

RESUMO

bladder based on a systematic review and network meta-analysis approach. METHODS: Pubmed, Embase, Web of Science, and the Cochrane Register of Clinical Trials databases were systematically searched. The search time frame was from database creation to June 2, 2022. Randomized controlled double-blind trials of oral medication for overactive bladder were screened against the protocol's entry criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 software. RESULT: A total of 60 randomized controlled double-blind clinical trials were included involving 50,333 subjects. Solifenacin 10mg was the most effective in mean daily micturitions and incontinence episodes, solifenacin 5/10mg in mean daily urinary urgency episodes and nocturia episodes, fesoterodine 8mg in urgency incontinence episodes/d and oxybutynin 5mg in voided volume/micturition. In terms of safety, solifenacin 5mg, ER-tolterodine 4mg, mirabegron, vibegron and ER-oxybutynin 10mg all showed a better incidence of dry mouth, fesoterodine 4mg, ER-oxybutynin 10mg, tolterodine 2mg, and vibegron in the incidence of constipation. Compared to placebo, imidafenacin 0.1mg showed a significantly increased incidence in hypertension, solifenacin 10mg in urinary tract infection, fesoterodine 4/8mg and darifenacin 15mg in headache. CONCLUSION: Solifenacin showed better efficacy. For safety, most anticholinergic drugs were more likely to cause dry mouth and constipation, lower doses were better tolerated. The choice of drugs should be tailored to the patient's specific situation to find the best balance between efficacy and safety.


Assuntos
Bexiga Urinária Hiperativa , Xerostomia , Humanos , Bexiga Urinária Hiperativa/tratamento farmacológico , Succinato de Solifenacina/efeitos adversos , Tartarato de Tolterodina/uso terapêutico , Metanálise em Rede , Método Duplo-Cego , Constipação Intestinal/tratamento farmacológico , Xerostomia/tratamento farmacológico , Resultado do Tratamento , Antagonistas Muscarínicos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Urologiia ; (2): 66-72, 2023 May.
Artigo em Russo | MEDLINE | ID: mdl-37401707

RESUMO

PURPOSE: To assess the prescribing practices for overactive bladder (OAB) pharmacotherapy based on the prescription trend analysis across different specialties of India. METHOD: s: IQVIA (Quintiles and IMS Health) secondary sales audit (SSA), as well as a prescription audit for antimuscarinics and beta-3 adrenoceptor agonists (mirabegron) from 2014 to 2021, were analyzed. The data includes SSA data of various antimuscarinics like solifenacin, oxybutynin, tolterodine, darifenacin, trospium and mirabegron change in the prescription trend of antimuscarinics and mirabegron across different specialties; prescribers overlap analysis for solifenacin and mirabegron among Indian urologists were also analyzed. RESULTS: Urologists prescription rates of OAB drugs were 65% in 2016 and 54% in 2021. The rate of OAB medication prescription by non-urologist was highest from the surgeon (11%), followed by gynecologists (9%) and consultant physicians (8%) in 2021. In addition, among OAB medication prescription rates for antimuscarinics were 100% in 2016 and 58% in 2021 whereas for mirabegron, it was 0% in 2016 and 42% in 2021. Solifenacin was most frequently prescribed anticholinergics, followed by oxybutynin, tolterodine, darifenacin, and trospium. The proportion of prescribers of OAB medication among urologists was 38% in 2016 and 33% in 2021. Exclusive prescribers of solifenacin were 748 in 2018 and 739 in 2021 at the urologist, whereas for mirabegron, it was 961 in 2018 and 934 in 2021. The compound annual growth rate for prescription of the last 6 years (from 2016-2021) for solifenacin and mirabegron was -3% and 8% respectively. CONCLUSIONS: Urology remained a top prescribing specialty for OAB drugs, although prescription share increased at surgeon and consultant physician. OAB medicines prescriptions by urologists are shifting from leading antimuscarinic solifenacin to beta-agonist mirabegron. Data from this study will ultimately lead to the OAB medication preference by the specialist that could lead to more advanced OAB management.


Assuntos
Bexiga Urinária Hiperativa , Agentes Urológicos , Humanos , Bexiga Urinária Hiperativa/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Succinato de Solifenacina/uso terapêutico , Tartarato de Tolterodina/uso terapêutico , Acetanilidas/uso terapêutico , Prescrições , Agentes Urológicos/uso terapêutico
5.
Cochrane Database Syst Rev ; 5: CD003781, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-37160401

RESUMO

BACKGROUND: Around 16% of adults have symptoms of overactive bladder (OAB; urgency with frequency and/or urge incontinence), with prevalence increasing with age. Anticholinergic drugs are commonly used to treat this condition. This is an update of a Cochrane Review first published in 2002 and last updated in 2006. OBJECTIVES: To assess the effects of anticholinergic drugs compared with placebo or no treatment for treating overactive bladder syndrome in adults. SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 14 January 2020), and the reference lists of relevant articles. We updated this search on 3 May 2022, but these results have not yet been fully incorporated. SELECTION CRITERIA: We included randomised or quasi-randomised trials in adults with overactive bladder syndrome that compared an anticholinergic drug alone with placebo treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and extracted data from the included studies, including an assessment of the risk of bias. We assessed the certainty of the body of evidence using the GRADE approach. We processed data as described in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We included 104 studies, 71 of which were new or updated for this version of the review. Although 12 studies did not report the number of participants, there were 47,106 people in the remainder of the included studies. The majority of the studies had insufficient information to allow judgement of risk of bias and we judged them to be unclear for all domains. Nine anticholinergic drugs were included in these studies: darifenacin; fesoterodine; imidafenacin; oxybutynin; propantheline; propiverine; solifenacin; tolterodine and trospium. No studies were found that compared anticholinergic drugs to no treatment. At the end of the treatment period, anticholinergics may slightly increase condition-specific quality of life (mean difference (MD) 4.41 lower, 95% confidence interval (CI) 5.28 lower to 3.54 lower (scale range -100 to 0); 12 studies, 6804 participants; low-certainty evidence). Anticholinergics are probably better than placebo in terms of patient perception of cure or improvement (risk ratio (RR) 1.38, 95% CI 1.15 to 1.66; 9 studies, 8457 participants; moderate-certainty evidence), and the mean number of urgency episodes per 24-hour period (MD 0.85 lower, 95% CI 1.03 lower to 0.67 lower; 23 studies, 16,875 participants; moderate-certainty evidence). Compared to placebo, anticholinergics may result in an increase in dry mouth adverse events (RR 3.50, 95% CI 3.26 to 3.75; 66 studies, 38,368 participants; low-certainty evidence), and may result in an increased risk of urinary retention (RR 3.52, 95% CI 2.04 to 6.08; 17 studies, 7862 participants; low-certainty evidence). Taking anticholinergics may be more likely to lead to participants withdrawing from the studies due to adverse events (RR 1.37, 95% CI 1.21 to 1.56; 61 studies, 36,943 participants; low-certainty evidence). However, taking anticholinergics probably reduces the mean number of micturitions per 24-hour period compared to placebo (MD 0.85 lower, 95% CI 0.98 lower to 0.73 lower; 30 studies, 19,395 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: The use of anticholinergic drugs by people with overactive bladder syndrome results in important but modest improvements in symptoms compared with placebo treatment. In addition, recent studies suggest that this is generally associated with only modest improvement in quality of life. Adverse effects were higher with all anticholinergics compared with placebo. Withdrawals due to adverse effects were also higher for all anticholinergics except tolterodine. It is not known whether any benefits of anticholinergics are sustained during long-term treatment or after treatment stops.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Bexiga Urinária Hiperativa , Adulto , Humanos , Antagonistas Colinérgicos/efeitos adversos , Qualidade de Vida , Tartarato de Tolterodina , Bexiga Urinária Hiperativa/tratamento farmacológico , Revisões Sistemáticas como Assunto
6.
Value Health Reg Issues ; 37: 1-8, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37099838

RESUMO

OBJECTIVES: This study aimed to estimate the cost-utility of effective interventions for enuresis treatment in children and adolescents and to calculate the incremental cost-utility ratio from the perspective of the Brazilian Unified Health System in a 1-year time horizon. METHODS: The economic analysis is in 7 stages: (1) survey of evidence of treatments for enuresis, (2) performing the network meta-analysis, (3) estimation of the probability of cure, (4) cost-utility analysis, (5) model sensitivity analysis, (6) analysis of acceptability of interventions by acceptability curve, and (7) monitoring the technological horizon. RESULTS: The association between desmopressin and oxybutynin is the therapeutic strategy with the highest probability of success in the treatment of enuresis in children and adolescents compared with placebo (relative risk [RR] 2.88; 95% confidence interval [CI] 1.65-5.04), followed by the combination therapy between desmopressin and tolterodine (RR 2.13; 95% CI 1.13-4.02), alarm (RR 1.59; 95% CI 1.14-2.23), and neurostimulation (RR 1.43; 95% CI 1.04-1.96). Combination therapy between desmopressin and tolterodine was the only 1 considered not to be cost-effective. Neurostimulation, alarm therapy, and therapy had the respective incremental cost-utility ratio values: R$5931.68, R$7982.92, and R$29 050.56/quality-adjusted life-years. CONCLUSION: Among the therapies that are on the borderline of efficiency, the combined therapy between desmopressin and oxybutynin presents the greatest incremental benefit at an incremental cost that is still feasible, given that it does not exceed the reference value of the cost-effectiveness threshold established in Brazil.


Assuntos
Desamino Arginina Vasopressina , Enurese , Humanos , Criança , Adolescente , Brasil , Desamino Arginina Vasopressina/uso terapêutico , Tartarato de Tolterodina
7.
Indian Pediatr ; 60(6): 447-451, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37078485

RESUMO

OBJECTIVE: To compare the efficacy of desmopressin plus tolterodine (D+T) with desmopressin plus indomethacin (D+I) for treating enuresis in children. DESIGN: Open-label randomized controlled trial. SETTING: Bandar Abbas Children's Hospital, a tertiary care children's hospital in Iran, from March 21, 2018, to March 21, 2019. PARTICIPANTS: 40 children older than five years with monosymp-tomatic and non-monosymptomatic primary enuresis resistant to desmopressin monotherapy. INTERVENTION: Patients were randomized to receive either D+T (60 µg sublingual desmopressin and 2 mg tolterodine) or D+I (60 µg sublingual desmopressin and 50 mg indomethacin) every night before bedtime for five months. OUTCOME: Reduction in the frequency of enuresis was evaluated at one, three, and five months, and response to treatment at five months. Drug reactions and complications were also noted. RESULTS: After adjustment for age, consistent incontinence from toilet training, and non-monosymptomatic enuresis, D+T was significantly more efficacious than D+I; mean (SD) percent in nocturnal enuresis reduction at 1 [58.86 (7.27)% vs 31.18 (3.85) %; P<0.001], 3 [69.78 (5.99) % vs 38.56 (3.31) %; P<0.000], and 5 [84.84(6.21) % vs 39.14 (3.63) %; P<0.001] months showing a large effect. At 5 months, complete response to treatment was only observed with D+T, while treatment failure was significantly higher with D+I (50% vs 20%; P=0.047). None of the patients in either group developed cutaneous drug reactions or central nervous system symptoms. CONCLUSION: Desmopressin plus tolterodine appears to be superior to desmopressin plus indomethacin for treating pediatric enuresis resistant to desmopressin.


Assuntos
Enurese Noturna , Criança , Humanos , Pré-Escolar , Enurese Noturna/tratamento farmacológico , Desamino Arginina Vasopressina/uso terapêutico , Indometacina/uso terapêutico , Tartarato de Tolterodina/uso terapêutico , Quimioterapia Combinada
8.
Trials ; 24(1): 287, 2023 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-37085880

RESUMO

BACKGROUND: Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women. METHODS: The TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function. DISCUSSION: The TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age. TRIAL REGISTRATION: ClinicalTrials.gov NCT05362292. Registered on May 5, 2022.


Assuntos
Bexiga Urinária Hiperativa , Incontinência Urinária , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Tartarato de Tolterodina/efeitos adversos , Antagonistas Muscarínicos/efeitos adversos , Bexiga Urinária Hiperativa/diagnóstico , Qualidade de Vida , Estudos Prospectivos , Incontinência Urinária/diagnóstico , Incontinência Urinária/tratamento farmacológico , Antagonistas Colinérgicos/efeitos adversos , Agonistas Adrenérgicos/uso terapêutico , Resultado do Tratamento , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
9.
J Nepal Health Res Counc ; 20(3): 750-754, 2023 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-36974869

RESUMO

BACKGROUND: Solefinacin and Tolterodine are new generation antimuscarinics claimed to have bladder specific action and less adverse effect like dry mouth. The objective of the study was to compare the improvement in urinary symptoms among patients using solefinacin and tolterodine with overactive bladder symptoms. METHODS: A hospital based cross-sectional comparative study was done for one year duration. All patients with overactive bladder symptoms were included and in every alternate patient's solefinacin and tolterodine were given after taking note of baseline OAB symptoms, PPBC score and UPS score. Participants were followed up after one month and noted improvement in endpoint OAB symptoms. Comparison of baseline to end-point symptoms changes among each group of participants were analyzed for statistical significance. RESULTS: Among 101 participants included in the study, 49 participants were in solefinacin group and 52 participants were in tolterodine group. The end-point comparison of urgency symptoms were improved by 20.1±6.76 (mean ± SD) units in solefinacin group and by 17.0 ± 9.18 units in tolterodine group. Urgency perception score improved to 2.1±0.66 for patients under solefinacin and 2±0.73 for tolterodine. Patient perception of bladder condition (PPBC) showed improvement in solefinacin group by 3.2±1.26 units and in tolteradine by 2.8±1.54 units (p = 0.165). Comparing the patient's perception of treatment outcome, massive improvement was reported by 81.6% of those receiving Solefinacinand 65.4% receiving tolterodine, though not statistically significant ( p = 0.131). CONCLUSIONS: Solefinacin and Tolterodine showed improvement in urinary symptoms, UPS and PPBC. Both showed comparable efficacy without significant superiority over one another.


Assuntos
Doenças da Bexiga Urinária , Bexiga Urinária Hiperativa , Humanos , Tartarato de Tolterodina/uso terapêutico , Succinato de Solifenacina/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária Hiperativa/diagnóstico , Bexiga Urinária , Estudos Transversais , Fenilpropanolamina/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Cresóis/uso terapêutico , Nepal , Resultado do Tratamento , Percepção
10.
Chem Res Toxicol ; 36(3): 479-491, 2023 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-36795936

RESUMO

Tolterodine (TOL) is an antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency, and urge incontinence. During the clinical use of TOL, adverse events such as liver injury took place. The present study aimed at the investigation of the metabolic activation of TOL possibly associated with its hepatotoxicity. One GSH conjugate, two NAC conjugates, and two cysteine conjugates were found in both mouse and human liver microsomal incubations supplemented with TOL, GSH/NAC/cysteine, and NADPH. The detected conjugates suggest the production of a quinone methide intermediate. The same GSH conjugate was also observed in mouse primary hepatocytes and in the bile of rats receiving TOL. One of the urinary NAC conjugates was observed in rats administered TOL. One of the cysteine conjugates was found in a digestion mixture containing hepatic proteins from animals administered TOL. The observed protein modification was dose-dependent. CYP3A primarily catalyzes the metabolic activation of TOL. Ketoconazole (KTC) pretreatment reduced the generation of the GSH conjugate in mouse liver and cultured primary hepatocytes after TOL treatment. In addition, KTC reduced the susceptibility of primary hepatocytes to TOL cytotoxicity. The quinone methide metabolite may be involved in TOL-induced hepatotoxicity and cytotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Citocromo P-450 CYP3A , Humanos , Ratos , Camundongos , Animais , Ativação Metabólica , Citocromo P-450 CYP3A/metabolismo , Tartarato de Tolterodina/metabolismo , Cisteína/metabolismo , Cetoconazol/metabolismo , Microssomos Hepáticos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Glutationa/metabolismo
11.
Urogynecology (Phila) ; 29(1): 48-57, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36384907

RESUMO

IMPORTANCE: The international phase 3 EMPOWUR trial demonstrated efficacy and safety of vibegron, a newer ß 3 -adrenergic receptor agonist, in adults with overactive bladder (OAB). Women are disproportionately affected by OAB, especially those with bothersome symptoms, such as urge urinary incontinence (UUI). OBJECTIVE: This subgroup analysis from EMPOWUR assessed efficacy and safety of vibegron in women. STUDY DESIGN: In EMPOWUR, patients with OAB were randomized 5:5:4 to 12 weeks of treatment with once-daily vibegron 75 mg, placebo, or tolterodine 4-mg extended release. Efficacy end points included change from baseline at week 12 in mean daily number of micturitions, UUI episodes, and urgency episodes. Safety was assessed through adverse events (AEs). RESULTS: Of the patients included in the analysis, 1286 (84.9%) were women (vibegron, n = 463; placebo, n = 459; tolterodine, n = 364). At week 12, women receiving vibegron showed significant reductions (95% confidence intervals of least squares mean differences does not include 0) from baseline versus placebo in mean daily micturitions, UUI episodes, and urgency episodes, with least squares mean differences (95% confidence intervals) of -0.5 (-0.8 to -0.2), -0.7 (-1.0 to -0.4), and -0.8 (-1.3 to -0.4), respectively. Treatment-emergent AE incidence was similar with vibegron (39%) and placebo (35%); the most common AE with incidence higher with vibegron (4.3%) than placebo (2.6%) was headache. CONCLUSIONS: In this subgroup analysis, women receiving vibegron showed significant reductions in key efficacy end points versus placebo and favorable safety profile, consistent with the overall results from EMPOWUR, suggesting that vibegron is efficacious and safe for the treatment of OAB in this patient population.


Assuntos
Bexiga Urinária Hiperativa , Adulto , Humanos , Feminino , Masculino , Bexiga Urinária Hiperativa/tratamento farmacológico , Tartarato de Tolterodina/efeitos adversos , Resultado do Tratamento , Pirimidinonas , Incontinência Urinária de Urgência/induzido quimicamente
12.
Sci Rep ; 12(1): 17905, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36289427

RESUMO

To summarize the differences in urodynamic outcomes between oral antimuscarinic drugs and OnabotulinumtoxinA, and finding a therapy that maintains good urodynamics in neurogenic detrusor overactivity (NDO). We conducted a literature search of EMBASE and PubMed, with the language limited to English. In the analysis, all of the published randomized trials of OnabotulinumtoxinA or antimuscarinic drugs used to treat NDO were found and the results were finally obtained through Bayesian model analysis. A total of 12 RCTs and 2208 patients were included. OnabotulinumtoxinA 300U was superior to other drugs in terms of MCC, volume at IDC, and Pdetmax endpoints. OnabotulinumtoxinA 200U was more effective on the urodynamic endpoint of BC than other drugs or doses of OnabotulinumtoxinA. According to the MCC urodynamic results, oxybutynin, solifenacin 10 mg, and tolterodine 4 mg also had positive effects. OnabotulinumtoxinA 300U, 200U and 100U were better in improving the urodynamic results of NDO, and the current evidence also shows that selective injection of onabotulinumtoxinA can effectively improve the urodynamic results.


Assuntos
Toxinas Botulínicas Tipo A , Bexiga Urinaria Neurogênica , Bexiga Urinária Hiperativa , Humanos , Urodinâmica , Antagonistas Muscarínicos/uso terapêutico , Antagonistas Muscarínicos/farmacologia , Bexiga Urinaria Neurogênica/tratamento farmacológico , Succinato de Solifenacina/farmacologia , Succinato de Solifenacina/uso terapêutico , Metanálise em Rede , Tartarato de Tolterodina/farmacologia , Teorema de Bayes , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico
13.
Expert Rev Pharmacoecon Outcomes Res ; 22(8): 1187-1198, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36172806

RESUMO

BACKGROUND: Overactive bladder (OAB) is defined as urinary urgency, usually with urinary frequency and nocturia. . The current treatment for OAB includes conservative management, surgery, and pharmacotherapy. Mirabegron is a new drug acting by the ß3-adrenoceptor agonism. This study aimed to review the cost-effectiveness of mirabegron in the treatment of OAB. AREAS COVERED: We searched published articles in electronic search databases. Ten studies were included in the qualitative analysis. Various antimuscarinics, including oxybutynin, fesoterodine, tolterodine, darifenacin, and trospium were compared with mirabegron. The results were evaluated and compared according to the quality-adjusted life-years (QALY), cost/year, and incremental cost-effectiveness ratio (ICER). Of the ten studies in only three, mirabegron was not a cost-effective strategy. In seven cases, mirabegron was cost-effective. EXPERT OPINION: The cost-effectiveness of mirabegron was variable in different regions; however, most of the studies show the cost-effectiveness of mirabegron. Our study illustrates that mirabegron's ICER in comparison with its comparators is below the willingness to pay threshold even in the countries with low GDP/Capita. Our proposal for future economic studies for OAB pharmacotherapy is to compare different doses, formulations, and administration forms in a real-world context.


Assuntos
Acetanilidas , Bexiga Urinária Hiperativa , Humanos , Análise Custo-Benefício , Acetanilidas/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Tartarato de Tolterodina/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Resultado do Tratamento
14.
J Cardiovasc Pharmacol ; 80(5): 679-689, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35881423

RESUMO

ABSTRACT: Tolterodine is a first-line antimuscarinic drug used to treat overactive bladder. Adverse cardiac effects including tachycardia and palpitations have been observed, presumably because of its inhibition of the human ether-à-go-go-related gene (hERG) K + channel. However, the molecular mechanism of hERG channel inhibition by tolterodine is largely unclear. In this study, we performed molecular docking to identify potential binding sites of tolterodine in hERG channel, and two-microelectrode voltage-clamp to record the currents of hERG and its mutants expressed in Xenopus oocytes. The results of computational modeling demonstrated that phenylalanine at position 656 (F656) and tyrosine at position 652 (Y652) on the S6 helix of hERG channel are the most favorable binding residues of tolterodine, which was validated by electrophysiological recordings on Y652A and F656A hERG mutants. The Y652A and F656A mutations decreased inhibitory potency of tolterodine 345-fold and 126-fold, respectively. The Y652A mutation significantly altered the voltage dependence of channel inhibition by tolterodine. For both the wild-type and the mutant channels, tolterodine reduced the currents in a time-dependent manner, and the blockade occurred with the channel activated. Tolterodine did not interfere with hERG channel deactivation, whereas channel inactivation greatly impaired its blocking effect. The inhibition of hERG channel by tolterodine is independent of its action on muscarinic acetylcholine receptors. In conclusion, tolterodine is an open-state blocker of hERG K + channel with nanomolar potency. Y652 and F656, 2 aromatic residues on the inner S6 helix, are responsible for the high-affinity binding of tolterodine to hERG channel.


Assuntos
Canais de Potássio Éter-A-Go-Go , Bloqueadores dos Canais de Potássio , Humanos , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/química , Bloqueadores dos Canais de Potássio/farmacologia , Tartarato de Tolterodina/farmacologia , Simulação de Acoplamento Molecular , Mutação , Éteres , Relação Dose-Resposta a Droga
15.
Minerva Urol Nephrol ; 74(6): 761-779, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35708534

RESUMO

BACKGROUND: Antimuscarinic (AM) and beta-3-agonist (B3A) treatment are the standard first-line pharmacological treatment used to manage overactive bladder (OAB) patients. Aim of our study was to analyze real-life data of adverse events related to AMs and B3A reported on Eudra-Vigilance (EV) Database. METHODS: EV database is the system for managing and analyzing information on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area (EEA). We recorded the number of AEs for antimuscarinic and beta-3-agonist per category and severity until January 2021. RESULTS: Overall, 2313 AEs were reported for oxybutinin, 5129 for solifenacin, 2483 for tolterodine, 3523 for fesoterodine, 787 for trospium, 621 for propiverine and 7213 for mirabegron. Urinary retention was higher for fesoterodine (43%) and tolterodine (23%) when compared to solifenacin (10%), mirabegron (11%) and oxybutinin (4%). Cognitive disorder was uncommon for all the analyzed drugs analyzed. Regarding anticolinergic AEs: vision blurred, dry mouth and constipation were higher for AMs when compared to mirabegron. Their prevalence was higher in female patients. Mirabegron presented a higher risk of hypertension (7%) when compared to oxybutinin (2%, P<0.01), solifenacin (2%, P<0.01), tolterodine (2%, P<0.01) and fesoterodine (1%, P<0.01); the rate of hypertension was higher in females (63%) than males (29%) (P<0.01). The risk of acute urinary retention was also significantly higher (15% vs. 10%, P<0.01) in older patients (>85 years). CONCLUSIONS: Real life data is consistent with registry studies regarding the rate of AEs related to antimuscarinic and beta-3-agonist. However some differences were observed. Female patients present higher rates of AEs when compared to male patients. The risk of acute urinary retention was particularly evident in the octogenarians.


Assuntos
Hipertensão , Bexiga Urinária Hiperativa , Retenção Urinária , Idoso de 80 Anos ou mais , Humanos , Masculino , Feminino , Idoso , Antagonistas Muscarínicos/efeitos adversos , Succinato de Solifenacina/efeitos adversos , Tartarato de Tolterodina/efeitos adversos , Retenção Urinária/induzido quimicamente , Retenção Urinária/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/epidemiologia , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico
16.
Int J Clin Pract ; 2022: 6475014, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685566

RESUMO

Background: Overactive bladder (OAB) is characterized by urgency and frequency with (OAB wet) or without (OAB dry) urge urinary incontinence (UUI). In the phase 3 EMPOWUR trial, vibegron-a selective ß 3-adrenergic receptor agonist for the treatment of OAB-significantly improved daily number of urgency episodes and micturitions vs. placebo (P < 0.01). These post hoc analyses aimed to compare the efficacy of vibegron vs. placebo in OAB dry and wet populations. Methods: Patients were randomly assigned 5:5:4 to receive once-daily vibegron 75 mg, placebo, or tolterodine 4 mg extended release, respectively, for 12 weeks. Baseline criteria for OAB dry included an average of ≥8 micturitions, ≥3 urgency episodes, and <1 UUI episode per diary day and for OAB wet included an average of ≥8 micturitions and ≥1 UUI episode per diary day. Change from baseline in mean daily number of urgency episodes and micturitions was assessed in both populations. Results: Of the 1463 patients included in the full analysis set, 336 (23%) had OAB dry (vibegron, N = 123; placebo, N = 115; and tolterodine, N = 98), and 1127 (77%) had OAB wet (vibegron, N = 403; placebo, N = 405; and tolterodine, N = 319). Vibegron was associated with significant reductions (95% CIs of the least squares mean differences [LSMD] does not include 0) from baseline at week 12 vs. placebo in mean daily urgency episodes for the dry (LSMD [95% CI], ‒1.0 [‒2.0, ‒0.1]) and wet (‒0.6 [‒1.0, ‒0.1]) populations. Vibegron was associated with significant reductions from baseline at week 12 vs. placebo in mean daily micturitions for the dry (LSMD [95% CI], ‒0.8 [‒1.5, ‒ 0.1]) and wet (‒0.5 [‒0.8, ‒0.1]) populations. There were no significant differences in either outcome between tolterodine and placebo for either the dry or wet populations in this study. Conclusions: In this subgroup analysis from the EMPOWUR trial, vibegron was associated with significant reductions compared with placebo in urgency episodes and micturitions in both the OAB dry and wet populations, suggesting that vibegron is similarly efficacious for these endpoints in patients with and without UUI. This trial is registered with NCT03492281.


Assuntos
Bexiga Urinária Hiperativa , Método Duplo-Cego , Humanos , Pirimidinonas , Pirrolidinas , Tartarato de Tolterodina/uso terapêutico , Resultado do Tratamento , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária de Urgência
17.
Female Pelvic Med Reconstr Surg ; 28(7): 429-435, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35536677

RESUMO

IMPORTANCE: Clinical data on the use of overactive bladder (OAB) medications are limited by the physician interpretation of adverse effects rather than those that are patient reported. OBJECTIVE: The aim of the study was to evaluate the association between OAB medications and adverse drug events (ADEs) through the self-reporting U.S. Food and Drug Administration Adverse Event Report System database. STUDY DESIGN: The U.S. Food and Drug Administration Adverse Event Report System (FAERS) database was queried from 2004 to 2019. Adverse drug events were recategorized. Disproportionality analysis was used to detect the risk signals for each OAB medication and ADEs. χ 2 values were calculated to assess the association between ADEs and dosage. RESULTS: A total number of 14,102 reports were identified. The most frequently reported OAB medications were mirabegron (35%), transdermal oxybutynin (27%), and solifenacin (25%). Neuropsychiatric (NP) ADEs were highest with tolterodine and fesoterodine usage (16% and 15.6%, respectively) and transdermal oxybutynin had the lowest (6.5%). Increasing the dose of tolterodine or fesoterodine was not associated with increased NP ADEs. Oxybutynin had the highest risk of affect/mood disorder, agitation, and balance/movement disorder; however, it had the lowest risk of headache/migraine compared with all OAB medications. Mirabegron compared with all other OAB medications had the lowest risk of affect/mood disorder and agitation; however, it had the highest risk of headache and migraines. CONCLUSIONS: The FAERS database not only is a repository of ADEs but also may represent evolving prescribing habits for OAB medications. Transdermal oxybutynin had the lowest NP ADEs and may be appropriate for selected individuals.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Bexiga Urinária Hiperativa , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Cefaleia/induzido quimicamente , Cefaleia/tratamento farmacológico , Humanos , Antagonistas Muscarínicos , Tartarato de Tolterodina , Bexiga Urinária Hiperativa/diagnóstico , Bexiga Urinária Hiperativa/tratamento farmacológico
18.
Int Urogynecol J ; 33(7): 2031-2036, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35445808

RESUMO

INTRODUCTION AND HYPOTHESIS: Obstructive sleep apnea syndrome is associated with urological symptoms, including overactive bladder (OAB). This study aims to determine whether combined tolterodine and CPAP therapies are more effective for patients with OSAS than CPAP treatment only. METHODS: Women who underwent polysomnography test and were diagnosed with moderate-to-severe OSAS with apnea-hypopnea index (AHI) were included in the study. Data were collected on AHI, OAB awareness-8-item tool (OAB-V8), incontinence questionnaire-urinary incontinence short form (ICIQ-UI-SF), total daily urine volume (DUV), and the Benefit, satisfaction with treatment and willingness (BSW) tool. Eligible patients were randomized to receive either CPAP treatment only or combined CPAP and tolterodine treatment for 3 months. RESULTS: Among 103 participants, a total of 60 were included. Patients in both treatment arms showed significant improvements in OAB-V8, ICIQ-UI-SF, and total DUV compared to their baseline. The mean OAB-V8 was 15.7 at baseline and 5.6 at 3 months for the combined treatment arm and 16.6 and 7.6 at 3 months for the CPAP group only (mean baseline-adjusted between-group difference -1.1 [95% CI, -12.3 to -7.4]; p < 0.001). The improvement in the mean ICIQ-UI-SF was also statistically more significant in the combined therapy group than in the CPAP only arm (mean baseline-adjusted between-group difference -3.27 [95% CI, -4.6 to -1.59]; p < 0.001). No statistical significance was found in the improvement of total DUV between the groups. CONCLUSIONS: In this study, combined use of tolterodine with CPAP provides beneficial effects to CPAP treatment only regarding OAB symptoms. Further research is required to confirm these findings in a large cohort.


Assuntos
Apneia Obstrutiva do Sono , Bexiga Urinária Hiperativa , Incontinência Urinária , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Polissonografia , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/terapia , Tartarato de Tolterodina/uso terapêutico , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico
19.
Female Pelvic Med Reconstr Surg ; 28(3): e49-e54, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35272333

RESUMO

IMPORTANCE: Antimuscarinic medications are often discontinued, and there is a paucity of data regarding patient experience of medications within this class. OBJECTIVE: The objective of this study is to qualitatively explore patient experience of antimuscarinic medications used for overactive bladder using reviews on Drugs.com. STUDY DESIGN: We examined reviews prior to February 2, 2020 (available since 2008) for oral antimuscarinic medications. User content was reviewed qualitatively via inductive content analysis. Investigators coded third-party impressions, categorizing each review as positive, mostly positive, mostly negative, or negative. The prevalence of side effects, themes, and impressions are described, with comparisons by drug using χ2, Mann-Whitney U, and Kruskal-Wallis tests, as appropriate. Correlation between ordinal and categorical variables was performed using Tau and Spearman correlation coefficients, respectively. RESULTS: We analyzed 469 user reviews. 68.2% reported symptom improvement. The most common side effects were dry mouth (29%) and fatigue (10.7%). Fewer neurologic side effects were reported in the solifenacin (13.9%) and trospium (none) groups (P = 0.009). Tolterodine and trospium immediate release had lower rates of ears, nose, and throat side effects (22.5% and 26.2%, respectively, P = 0.001.) Analysis of themes suggested 2 domains driving overall satisfaction: improvement and side effects. Improvement was associated with a positive satisfaction score (ρ = 0.64, P < 0.001) and gestalt impression (ρ = 0.74, P < 0.001). The factors that most negatively affected these measures were persistent symptoms followed by gastrointestinal side effects (P < 0.001). CONCLUSIONS: Our data suggest important differences within this class of medication both in terms of side effects and patient satisfaction. Furthermore, symptom improvement is the leading factor for patient satisfaction, whereas gastrointestinal side effects are associated with dissatisfaction.


Assuntos
Antagonistas Muscarínicos , Bexiga Urinária Hiperativa , Feminino , Humanos , Masculino , Antagonistas Muscarínicos/efeitos adversos , Avaliação de Resultados da Assistência ao Paciente , Succinato de Solifenacina/efeitos adversos , Tartarato de Tolterodina , Bexiga Urinária Hiperativa/tratamento farmacológico
20.
Eur J Clin Pharmacol ; 78(6): 897-906, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35218404

RESUMO

OBJECTIVE: Catheter-related bladder discomfort (CRBD) is a common complication of intraoperative urinary catheterization. Various studies have evaluated the efficacy of different interventions in postoperative CRBD. The present review was performed to assess the efficacy of these interventions. METHODS: PubMed, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) databases were systematically searched to identify randomized controlled trials (RCTs) investigating the efficacy of different drugs for the prevention of postoperative CRBD. This review evaluated the incidence and severity of CRBD after different interventions at 0, 1, 2, and 6 h postoperatively. RESULTS: Forty-five studies including 31 different drugs were analyzed. Eleven drugs were investigated in more than two RCTs, of which dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and pudendal nerve block (PNB) generally showed significantly higher efficacy than controls postoperatively. Solifenacin only showed significant efficacy compared with the control at 0 h, and intravenous lidocaine only showed significant efficacy compared with the control at 6 h. There were insufficient trials to draw conclusions regarding atropine, butylscopolamine, chlorpheniramine, clonidine, darifenacin, diphenhydramine, glycopyrrolate, intravesical bupivacaine, ketamine-haloperidol, pethidine-haloperidol, ketorolac, lidocaine-prilocaine cream, magnesium, hyoscine n-butyl bromide, oxycodone, paracetamol, parecoxib, trospium, resiniferatoxin, or amikacin. However, all but pethidine-haloperidol and chlorpheniramine showed some efficacy at various time points compared with controls. CONCLUSION: This review suggests that dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and PNB are effective in preventing postoperative CRBD. Considering the efficacy and adverse effects of all drugs, dexmedetomidine and gabapentin were ranked best.


Assuntos
Dexmedetomidina , Ketamina , Nefopam , Tramadol , Clorfeniramina/farmacologia , Clorfeniramina/uso terapêutico , Dexmedetomidina/uso terapêutico , Gabapentina/farmacologia , Gabapentina/uso terapêutico , Haloperidol/uso terapêutico , Humanos , Lidocaína , Meperidina/farmacologia , Meperidina/uso terapêutico , Nefopam/farmacologia , Nefopam/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Pregabalina/farmacologia , Tartarato de Tolterodina/farmacologia , Tartarato de Tolterodina/uso terapêutico , Tramadol/uso terapêutico , Bexiga Urinária/cirurgia , Cateteres Urinários/efeitos adversos
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