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1.
Acta Neuropathol ; 147(1): 60, 2024 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-38526612

RESUMO

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.


Assuntos
Neuropatias Diabéticas , Antagonistas Muscarínicos , Animais , Humanos , Camundongos , Ratos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/patologia , Ácidos Mandélicos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Qualidade de Vida , Receptores Muscarínicos , Diabetes Mellitus Tipo 1
2.
Respir Res ; 25(1): 104, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38419021

RESUMO

BACKGROUND: Airway epithelial cells (AECs) are a major component of local airway immune responses. Direct effects of type 2 cytokines on AECs are implicated in type 2 asthma, which is driven by epithelial-derived cytokines and leads to airway obstruction. However, evidence suggests that restoring epithelial health may attenuate asthmatic features. METHODS: We investigated the effects of passive sensitisation on IL-5, NF-κB, HDAC-2, ACh, and ChAT in human bronchial epithelial cells (HBEpCs) and the effects of fluticasone furoate (FF) and umeclidinium (UME) alone and in combination on these responses. RESULTS: IL-5 and NF-κB levels were increased, and that of HDAC-2 reduced in sensitised HEBpCs. Pretreatment with FF reversed the effects of passive sensitisation by concentration-dependent reduction of IL-5, resulting in decreased NF-κB levels and restored HDAC-2 activity. Addition of UME enhanced these effects. Sensitized HEBpCs also exhibited higher ACh and ChAT levels. Pretreatment with UME significantly reduced ACh levels, and addition of FF caused a further small reduction. CONCLUSION: This study confirmed that passive sensitisation of AECs results in an inflammatory response with increased levels of IL-5 and NF-κB, reduced levels of HDAC-2, and higher levels of ACh and ChAT compared to normal cells. Combining FF and UME was found to be more effective in reducing IL-5, NF-κB, and ACh and restoring HDAC-2 compared to the individual components. This finding supports adding a LAMA to established ICS/LABA treatment in asthma and suggests the possibility of using an ICS/LAMA combination when needed.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Humanos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , NF-kappa B , Interleucina-5 , Asma/tratamento farmacológico , Corticosteroides/uso terapêutico , Administração por Inalação , Células Epiteliais , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
3.
BJU Int ; 133(1): 25-33, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37500569

RESUMO

OBJECTIVE: To evaluate the evidence regarding the therapeutic benefits and safety of oral detrusor relaxing agents (DRAs) in treating neurogenic detrusor overactivity (NDO). METHODS: A comprehensive search was performed on 1 September 2022. Two authors independently reviewed the articles to extract data using a pre-designed form. The meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A common-effect or random-effects model was used based on the heterogeneity among studies. Bayesian network meta-analysis (NMA) was further performed to make indirect comparisons of antimuscarinics and mirabegron. RESULTS: A total of 23 randomised controlled trials (RCTs) comprising 1697 patients were included in our analysis. Compared to placebo, the clinical benefits of oral DRAs, along with more adverse events (AEs), were demonstrated in the treatment of NDO. In the subgroup analysis, antimuscarinics significantly improved both urodynamic and bladder diary outcomes (including urinary incontinence episodes, urinary frequency, and residual volume), with a higher rate of AEs, such as xerostomia. Mirabegron improved some of the parameters and had fewer bothersome side-effects in patients with NDO. The NMA showed that none of the antimuscarinics or mirabegron was superior or inferior to the other. CONCLUSIONS: Detrusor relaxing agents are associated with improved outcomes in patients with NDO and our analysis has added new evidence regarding antimuscarinics. Evidence concerning mirabegron as first-line therapy for NDO is still limited. Well-designed RCTs are still required in this specific population.


Assuntos
Toxinas Botulínicas Tipo A , Bexiga Urinaria Neurogênica , Bexiga Urinária Hiperativa , Humanos , Bexiga Urinaria Neurogênica/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Metanálise em Rede , Toxinas Botulínicas Tipo A/efeitos adversos , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico , Urodinâmica , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Eur J Clin Pharmacol ; 80(6): 847-853, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38396308

RESUMO

INTRODUCTION: Long-acting muscarinic antagonists (LAMA) or beta-2 agonists (LABA) have been recommended for symptom control in group A COPD patients as a first-line bronchodilator treatment in GOLD guidelines. However, there is no mention of priority/superiority between the two treatment options. We aimed to compare the effectiveness of these treatments in this group. METHODS: The study cohort was formed of all subjects from six pulmonology clinics with an initial diagnosis of COPD who were new users of a LAMA or LABA from January 2020 to December 2021. Seventy-six group A COPD patients, in whom LABA or LAMA therapy had been started in the last 1 month as a first-line treatment, were included in our study. Participants were evaluated with spirometry, COPD Assessment Test (CAT), mMRC scale, and St. George Respiratory Questionnaire (SGRQ) for three times (baseline, 6-12th months). RESULTS: There were 76 group A COPD patients with LAMA (67.1%) and LABA (32.9%). The number of patients who improved in CAT score at the end of the first year was significantly higher in patients using LAMA than those using LABA (p = 0.022); the improvement at minimum clinically important difference (MCID) in CAT score of LAMA group at 1st year was also significant (p = 0.044). SGRQ total and impact scores were found to be statistically lower at 1st year compared to baseline in patients using LAMA (p = 0.010 and 0.006, respectively). Significant improvement was detected in CAT and SGRQ scores at the 6th month visit in the LAMA group having emphysema (p = 0.032 and 0.002, respectively). CONCLUSION: According to significant improvements in CAT and SGRQ score, LAMA may be preferred over LABA as a bronchodilator agent in group A COPD patients, especially in emphysema-dominant phenotype.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Masculino , Feminino , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/uso terapêutico , Idoso , Pessoa de Meia-Idade , Broncodilatadores/uso terapêutico , Broncodilatadores/administração & dosagem , Resultado do Tratamento , Espirometria , Agonistas Muscarínicos/uso terapêutico , Agonistas Muscarínicos/administração & dosagem , Preparações de Ação Retardada
5.
Dev Med Child Neurol ; 66(7): 910-918, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38214675

RESUMO

AIM: To investigate the efficacy, safety, and impact on quality of life (QoL) of an oral formulation of 320 µg/mL glycopyrronium designed for children. METHOD: A double-blind, placebo-controlled SALIVA (Sialanar plus orAl rehabiLitation against placebo plus oral rehabilitation for chIldren and adolescents with seVere sialorrhoeA and neurodisabilities) trial was conducted. Children (3-17 years) with neurodisabilities and severe sialorrhoea (modified Teachers Drooling Scale ≥6) were randomized to 320 µg/mL glycopyrronium or placebo, in addition to non-pharmacological standard care. RESULTS: Of 87 participants, 44 were aged 10 years or under and 43 had cerebral palsy. The primary endpoint, change in total Drooling Impact Scale (DIS) score from baseline to day 84, was significantly greater (improved) with 320 µg/mL glycopyrronium versus placebo (median [quartile 1, quartile 3] -29.5 [-44.5, 0] vs -1 [-16, 5]; p < 0.001), an effect also observed at day 28 (median - 25 vs -2; p < 0.01). Significant reduction in bibs/clothes used per day was seen with glycopyrronium versus placebo at day 84 (median - 2 vs 0; p < 0.01). Glycopyrronium significantly improved DIS items 9 and 10 related to the extent that drooling affects the child's and family's life (p ≤ 0.03). Adverse events were reported by 77.3% and 69.8% of children with glycopyrronium and placebo respectively; the most common treatment-related adverse event was constipation (20.5% and 16.3%). INTERPRETATION: The formulation of 320 µg/mL glycopyrronium significantly improved drooling and reduced its impact on QoL, with good tolerability in children with neurodisabilities. WHAT THIS PAPER ADDS: The formulation of 320 µg/mL glycopyrronium significantly improved Drooling Impact Scale score versus placebo at day 84. The formulation reduced the impact of drooling on the child's and family's quality of life. There were no safety or tolerability concerns with this specific formulation.


Assuntos
Glicopirrolato , Qualidade de Vida , Sialorreia , Humanos , Sialorreia/tratamento farmacológico , Sialorreia/etiologia , Criança , Glicopirrolato/uso terapêutico , Glicopirrolato/administração & dosagem , Método Duplo-Cego , Masculino , Feminino , Adolescente , Pré-Escolar , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/uso terapêutico , Paralisia Cerebral/complicações , Paralisia Cerebral/tratamento farmacológico , Resultado do Tratamento , Índice de Gravidade de Doença
6.
BMC Urol ; 24(1): 97, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664686

RESUMO

BACKGROUND: Overactive bladder is a common chronic urological disorder in children, liable to impact normal social activities, disrupt sleep and even impair self-esteem. We aimed to evaluate the efficacy and safety of solifenacin combined with biofeedback for paediatric overactive bladder. METHOD: Forty-five children with overactive bladder were enrolled and divided into three groups: 15 patients in Group A were treated with solifenacin, 15 cases in Group B with biofeedback, and the other 15 patients in Group C with the combination of solifenacin plus biofeedback. Each group was subdivided into the non-urge incontinence (non-UI) and urge incontinence (UI) groups. The remission rates were compared among the three groups at 2, 4, 8 and 12 weeks from the beginning of treatment. The side effects of solifenacin were recorded and followed up. RESULT: After 2 weeks since initial treatment, the complete response rates were 33.3% (5/15), 20.0% (3/15), and 53.3% (8/15) in the three groups. At 4 weeks, the complete remission rates were 46.7% (7/15), 33.3% (5/15), and 60.0% (9/15) respectively. Moreover, the complete remission rates of the UI groups were higher than the non-UI groups (p < 0.05). At 8 weeks, the complete response rates were 53.3% (8/15), 40.0% (6/15), and 67.7% (10/15). At 12 weeks, the complete response rates were 67.8% (10/15), 60.0% (9/15), and 86.7% (13/15). The complete response rates were higher and urodynamic parameters were improved obviously in group C than the other two groups (p < 0.05) during the follow-ups. The median voiding frequency decreased and median functional bladder capacity increased obviously in Group C after 4 weeks (p < 0.05). Dry mouth was observed in 2 patients (4.4%). 2 patients experienced constipation (4.4%), and neither case was severe. The symptoms of these four patients had relieved by reducing the dose of solifenacin. CONCLUSION: Solifenacin combined with biofeedback had good efficacy and compliance for children experiencing overactive bladder. It took only 2 weeks to achieve the complete response rate over 50%, especially for the improvement of UI symptoms.


Assuntos
Biorretroalimentação Psicológica , Succinato de Solifenacina , Bexiga Urinária Hiperativa , Humanos , Succinato de Solifenacina/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/terapia , Criança , Feminino , Masculino , Resultado do Tratamento , Terapia Combinada , Antagonistas Muscarínicos/uso terapêutico , Adolescente , Pré-Escolar
7.
Lung ; 202(2): 119-125, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38321329

RESUMO

PURPOSE: This study aimed to examine reports of cardiovascular adverse events (CV AEs) observed in the real-world during treatment with aclidinium, tiotropium, glycopyrronium, and umeclidinium alone or in combination with a LABA and, in the context of triple therapy, with the addition of an ICS, and submitted to the food and drug administration adverse event reporting system (FAERS). METHODS: A retrospective disproportionality analysis was conducted utilizing CV AE reports submitted to the FAERS from January 2020 to 30 September 2023. Disproportionality was measured by calculating the reporting odds ratio. RESULTS: Compared with ipratropium, tiotropium was associated with fewer reports of CV AEs. Compared with tiotropium, other LAMAs were more likely to be associated with reports of CV AEs. Combinations of glycopyrronium with indacaterol or formoterol and umeclidinium with vilanterol significantly reduced reports of CV AEs compared with the respective LAMA. The addition of an ICS to these combinations further reduced the risk of CV AE reports. CONCLUSION: Our study suggests that inhaled LAMAs are not free from cardiac AE risks. This risk may be more evident when the newer LAMAs are used, but it is generally significantly reduced when COPD patients are treated with dual bronchodilators or triple therapy. However, these results do not prove that LAMAs cause CV AEs, as FAERS data alone are not indicative of a drug's safety profile. Given the frequency with which COPD and cardiovascular disease co-exist, a large study in the general population could shed light on this very important issue.


Assuntos
Doenças Cardiovasculares , Doença Pulmonar Obstrutiva Crônica , Estados Unidos/epidemiologia , Humanos , Brometo de Tiotrópio/efeitos adversos , Glicopirrolato/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Estudos Retrospectivos , United States Food and Drug Administration , Agonistas de Receptores Adrenérgicos beta 2 , Combinação de Medicamentos , Antagonistas Muscarínicos/uso terapêutico , Broncodilatadores , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Receptores Muscarínicos/uso terapêutico , Administração por Inalação
8.
Am J Respir Crit Care Med ; 208(12): 1316-1327, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37812772

RESUMO

Rationale: Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs. Objectives: The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Methods: Phase II randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (www.clinicaltrials.gov identifier NCT05071612). Measurements and Main Results: Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the AD109 5/75 mg arm (-42.9%; both P < 0.0001 vs. placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%; P < 0.01 vs. placebo). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg (P < 0.05 vs. placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time (P < 0.05 vs. AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy. Conclusions: AD109 showed clinically meaningful improvement in OSA, suggesting that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).


Assuntos
Apneia Obstrutiva do Sono , Humanos , Cloridrato de Atomoxetina/uso terapêutico , Apneia Obstrutiva do Sono/tratamento farmacológico , Sono , Polissonografia , Fadiga , Pressão Positiva Contínua nas Vias Aéreas , Antagonistas Muscarínicos/uso terapêutico
9.
COPD ; 21(1): 2327345, 2024 12.
Artigo em Inglês | MEDLINE | ID: mdl-38509685

RESUMO

Type 2 diabetes is a frequent comorbidity in chronic obstructive pulmonary disease (COPD) patients, with the GOLD treatment recommendations asserting that the presence of diabetes be disregarded in the choice of treatment.In a cohort of COPD patients with frequent exacerbations, initiators of single-inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, adjusted by propensity score weighting and stratified by type 2 diabetes.The COPD cohort included 1,114 initiators of triple inhalers and 4,233 of dual bronchodilators (28% with type 2 diabetes). The adjusted hazard ratio (HR) of exacerbation with triple therapy was 1.04 (95% CI: 0.86-1.25) among COPD patients with type 2 diabetes and 0.74 (0.65-0.85) in those without. The incidence of severe pneumonia was elevated with triple therapy among patients with type 2 diabetes (HR 1.77; 1.14-2.75).Triple therapy in COPD is effective among those without, but not those with, type 2 diabetes. Future therapeutic trials in COPD should consider diabetes comorbidity.


Triple therapy for frequent COPD exacerbators is effective in patients without type 2 diabetes but not in those with type 2 diabetes. The impact of comorbidities should be considered in future COPD therapeutic trials.


Assuntos
Diabetes Mellitus Tipo 2 , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Broncodilatadores , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Administração por Inalação , Quimioterapia Combinada , Antagonistas Muscarínicos/uso terapêutico , Nebulizadores e Vaporizadores , Comorbidade
10.
Eur Respir J ; 62(2)2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37343975

RESUMO

BACKGROUND: Single-inhaler dual bronchodilators are now recommended as initial treatment of COPD for patients with multiple exacerbations or with moderate or severe dyspnoea. It is unclear whether there are differences in effectiveness among commonly used dual bronchodilators. METHODS: We identified a cohort of COPD patients, aged ≥40 years, treated during 2017-2020, from the UK Clinical Practice Research Datalink, a real-world practice setting. Inhaled corticosteroid-naïve patients initiating vilanterol-umeclidinium (VIL-UME) were compared with those initiating olodaterol-tiotropium (OLO-TIO) or indacaterol-glycopyrronium (IND-GLY) dual bronchodilators primarily on the incidence of moderate and severe COPD exacerbation over 1 year, and corresponding hazard ratios (HRs), after adjustment by propensity score weighting. RESULTS: The cohort included 15 224 initiators of VIL-UME, 5536 initiators of OLO-TIO and 5059 initiators of IND-GLY. The HR of a moderate or severe exacerbation with VIL-UME was 0.91 (95% CI 0.85-0.97) compared with OLO-TIO and 0.96 (95% CI 0.89-1.03) compared with IND-GLY. The risk of severe exacerbation was not different for VIL-UME when compared with OLO-TIO (HR 1.04, 95% CI 0.86-1.26) and IND-GLY (HR 1.05, 95% CI 0.86-1.28). All-cause mortality was lower with VIL-UME compared with IND-GLY (HR 0.82, 95% CI 0.68-0.98), but not compared with OLO-TIO (HR 0.87, 95% CI 0.72-1.04). CONCLUSION: In a real-world setting of COPD treatment, the three dual bronchodilator combinations were similarly effective on the risk of a severe exacerbation of COPD. However, the VIL-UME and IND-GLY combinations may confer slightly superior effectiveness than OLO-TIO on the risk of moderate or severe exacerbation. The potential lower mortality with VIL-UME warrants further investigation.


Assuntos
Broncodilatadores , Doença Pulmonar Obstrutiva Crônica , Humanos , Antagonistas Muscarínicos/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2 , Glicopirrolato , Nebulizadores e Vaporizadores , Combinação de Medicamentos , Administração por Inalação , Resultado do Tratamento
11.
Eur Respir J ; 62(2)2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37474159

RESUMO

Several current guidelines/strategies outline a treatment approach to asthma, which primarily consider the goals of improving lung function and quality of life and reducing symptoms and exacerbations. They suggest a strategy of stepping up or down treatment, depending on the patient's overall current asthma symptom control and future risk of exacerbation. While this stepwise approach is undeniably practical for daily practice, it does not always address the underlying mechanisms of this heterogeneous disease. In the last decade, there have been attempts to improve the treatment of severe asthma, such as the addition of a long-acting antimuscarinic agent to the traditional inhaled corticosteroid/long-acting ß2-agonist treatment and the introduction of therapies targeting key cytokines. However, despite such strategies several unmet needs in this population remain, motivating research to identify novel targets and develop improved therapeutic and/or preventative asthma treatments. Pending the availability of such therapies, it is essential to re-evaluate the current conventional "one-size-fits-all" approach to a more precise asthma management. Although challenging, identifying "treatable traits" that contribute to respiratory symptoms in individual patients with asthma may allow a more pragmatic approach to establish more personalised therapeutic goals.


Assuntos
Antiasmáticos , Asma , Humanos , Qualidade de Vida , Quimioterapia Combinada , Asma/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Corticosteroides/uso terapêutico , Administração por Inalação , Antiasmáticos/uso terapêutico
12.
J Urol ; 209(2): 314-324, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36395428

RESUMO

PURPOSE: We evaluate the efficacy and safety of combining antimuscarinics with alpha-blockers to treat storage symptoms in men with benign prostatic hyperplasia. MATERIALS AND METHODS: Searches were carried out on PubMed, MEDLINE, EMBASE, and Cochrane databases to identify randomized, placebo-controlled trials published before February 15, 2022, assessing the efficacy or safety of antimuscarinics in men with benign prostatic hyperplasia treated with alpha-blockers. Further meta-analyses were performed using standardized mean difference and risk ratio. RESULTS: A total of 12 randomized trials were included in the systematic review. The meta-analysis showed no impact of antimuscarinics on the number of urgencies per day (SMD -0.23 [95%CI: -0.64; -0.17]; P = .21). However, the use of antimuscarinics was associated with a small reduction of micturition episodes per day (SMD -0.19 [95%CI: -0.37; -0.01]; P = .045). With regard to side effects, post-void residual increased slightly in patients treated with antimuscarinics (SMD 0.26 [95%CI: 0.15; 0.37]; P < .01). In addition, there was a higher risk of acute urinary retention (RR 3.26 [95%CI: 1.35; 7.86]; P = .02), dry mouth (RR 3.43 [95%CI: 1.86; 6.32]; P < .001), and constipation (RR 2.92 [95%CI: 1.48; 5.73]; P < .001) with the use of antimuscarinics. Finally, the risk of treatment interruption due to adverse events was higher for the patients treated with antimuscarinics (RR 1.74 [95%CI: 1.27; 2.38]; P < .01). CONCLUSIONS: The addition of antimuscarinics to alpha-blockers was not associated with a substantial reduction in urgencies and micturition episodes in benign prostatic hyperplasia patients with storage symptoms. In addition, the toxicity profile was not in favor of antimuscarinic use in these patients.


Assuntos
Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Masculino , Humanos , Antagonistas Muscarínicos/uso terapêutico , Hiperplasia Prostática/complicações , Hiperplasia Prostática/tratamento farmacológico , Sintomas do Trato Urinário Inferior/complicações , Quimioterapia Combinada , Antagonistas Adrenérgicos alfa/uso terapêutico , Resultado do Tratamento
13.
World J Urol ; 41(5): 1373-1379, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36971826

RESUMO

PURPOSE: Abnormalities in autonomic function are associated with an overactive bladder (OAB). Heart rate variability is generally used as the sole assessment of autonomic activity; however, we utilized neuECG, a novel method of recording skin electrical signals, to assess autonomic nervous function in healthy controls and patients with OAB before and after treatment. METHODS: The prospective sample included 52 participants: 23 patients newly diagnosed with OAB and 29 controls. Autonomic function was assessed in all participants in the morning using neuECG, which analyzed the average skin sympathetic nerve activity (aSKNA) and electrocardiogram simultaneously. All patients with OAB were administered antimuscarinics; urodynamic parameters were assessed before treatments; autonomic and bladder functions using validated questionnaires for OAB symptoms were evaluated before and after OAB treatment. RESULTS: Patients with OAB had significantly higher baseline aSKNA (p = 0.003), lower standard deviation of the normal-to-normal beat intervals, lower root mean square of the successive differences, lower high-frequency, and higher low-frequency than did controls. Baseline aSKNA had the highest value in predicting OAB (AUROC = 0.783, p < 0.001). The aSKNA was negatively correlated with first desire and normal desire in urodynamic studies (both p = 0.025) and was significantly decreased after treatment at rest, stress, and recovery phases, as compared to those before treatment (p = 0.046, 0.017, and 0.017, respectively). CONCLUSION: Sympathetic activity increased significantly in patients with OAB compared to that in healthy controls, and decreased significantly post-treatment. Higher aSKNA is associated with decreased bladder volume at which voiding is desired. SKNA may be a potential biomarker for diagnosing OAB.


Assuntos
Bexiga Urinária Hiperativa , Humanos , Estudos Prospectivos , Micção/fisiologia , Antagonistas Muscarínicos/uso terapêutico , Biomarcadores , Urodinâmica
14.
Neurourol Urodyn ; 42(5): 1080-1087, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36975140

RESUMO

OBJECTIVES: Antimuscarinic medications are the first-line treatments for overactive bladder, the most common form of bladder dysfunction. Their primary action is thought to block detrusor muscarinic receptors. It is unclear, however, if these therapeutics have actions on other tissues within the lower urinary tract. This study assessed whether clinical antimuscarinics have a functional impact on urothelium with lamina propria (U&LP) tissue. METHODS: Strips of porcine detrusor and U&LP were mounted in carbogen-gassed Krebs-bicarbonate solution at 37°C. The tissues were paired with carbachol-response curves performed in the absence or presence of each antimuscarinic. pEC50 values for each curve were analyzed and estimated affinities calculated. RESULTS: Both detrusor and U&LP tissues contracted with muscarinic receptor stimulation, which was inhibited by commonly used antimuscarinics. In detrusor samples (p < 0.001 for all), right parallel shifts from the control were observed in response to oxybutynin (1 µM), solifenacin (1 µM), tolterodine (1 µM), darifenacin (100 nM), trospium (100 nM) and fesoterodine (100 nM). This shift was consistent in U&LP samples, with no significant differences between the two layers. CONCLUSIONS: The data suggests that clinical antimuscarinics are as effective at inhibiting tonic contractions of the U&LP as they are on detrusor, presenting the U&LP as an alternate target of these medications in the treatment of lower urinary tract symptoms.


Assuntos
Antagonistas Muscarínicos , Bexiga Urinária Hiperativa , Animais , Suínos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Bexiga Urinária , Urotélio , Bexiga Urinária Hiperativa/tratamento farmacológico , Receptores Muscarínicos , Músculo Liso , Mucosa , Contração Muscular
15.
Neurourol Urodyn ; 42(7): 1491-1498, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37395464

RESUMO

INTRODUCTION AND OBJECTIVES: Medical treatments for overactive bladder (OAB) have proven efficacy in controlled trials. However, 1-year treatment persistence is reported to be as low as 25% for anticholinergics and 40% for ß3 agonists. Real-world data on treatment continuation and treatment sequence is limited. Therefore, we aimed to study treatment persistence trends in women initiated on OAB medications. MATERIALS AND METHODS: We used advanced data-mining techniques to query the largest regional provider's medication purchase database, dispensing for patients, for all women initiating OAB pharmacotherapy between 2010 and 2020. Treatment persistence was measured as days in which the patient was in possession of medication and nonpersistence was defined as prescription nonrefilling for 90 days. We employed a Sankey diagram to explore trends in OAB medication acquisition and treatment sequence. We compared treatment persistence using Kaplan-Meier survival curves and pairwise log-rank analysis. RESULTS: Here, 46 079 women made 791 681 unique claims of OAB medications. Only 39% of the patients tried more than one OAB formulation, including dose change. The overall persistence rate for all drugs was 55% in 30 days, 46% in 90 days, and 37% per year. The persistence rate for Mirabegron at 30 days was 54%, 42% at 90 days, and 17% at 1 year. Overall, persistence rates were unchanged when stratifying by the time Mirabegron insurance acceptance into coverage (p > 0.05). CONCLUSIONS: Real-world OAB pharmacotherapy persistence rates are lower than previously reported. The introduction of Mirabegron did not seem to improve these rates or affect the treatment sequence.


Assuntos
Bexiga Urinária Hiperativa , Agentes Urológicos , Humanos , Feminino , Bexiga Urinária Hiperativa/tratamento farmacológico , Estudos Retrospectivos , Antagonistas Muscarínicos/uso terapêutico , Acetanilidas/uso terapêutico , Prescrições , Resultado do Tratamento , Agentes Urológicos/uso terapêutico
16.
Eur J Clin Pharmacol ; 79(10): 1321-1332, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37507595

RESUMO

OBJECTIVES: This study aimed to quantitatively compare the efficacy and safety of long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) and LABA/inhaled corticosteroid (ICS) fixed-dose combinations (FDCs) in preventing moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: A literature search was performed using public databases. The time course characteristics of the probability of a moderate or severe exacerbation in stable COPD patients treated with LABA/LAMA and LABA/ICS FDCs were described by the parametric survival function. A random-effects model in a single-arm meta-analysis was used to analyze the incidence of serious adverse events (SAEs) and pneumonia. RESULTS: Twenty studies including 23,955 participants were included. The proportion of participants with a history of COPD exacerbation (%) in the previous year and the postbronchodilator forced expiratory volume in the first second (FEV1) (%predicted) were important factors affecting drug efficacy. After adjusting the above factors to median levels of 100% and 45.5%, respectively, the moderate or severe exacerbation rates at 52 weeks for olodaterol/tiotropium, formoterol/budesonide, indacaterol/glycopyrronium, formoterol/glycopyrronium, vilanterol/fluticasone, salmeterol/fluticasone, and vilanterol/umeclidinium were 38.3%, 41.0%, 42.6%, 47.0%, 47.5%, 47.9%, and 53.0%, respectively. In terms of safety, significant differences were observed among drugs containing different LABA/LAMA FDCs. CONCLUSIONS: This study showed that not all LABA/LAMA FDCs were superior to LABA/ICS FDCs in safety and in preventing moderate or severe exacerbations in patients with stable COPD, providing important quantitative information for COPD-related guidelines.


Assuntos
Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica , Humanos , Administração por Inalação , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Combinação de Medicamentos , Fluticasona/uso terapêutico , Fumarato de Formoterol/uso terapêutico , Glicopirrolato/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
17.
J Asthma ; 60(9): 1633-1645, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36964764

RESUMO

OBJECTIVE: To review the evidence for the use of open-inhaler (inhaled corticosteroid [ICS] plus long-acting ß2-agonist [LABA] with separate add-on long-acting muscarinic antagonist [LAMA]) versus single-inhaler triple therapy (ICS/LABA/LAMA combination) and the merits of add-on LAMA to ICS/LABA in patients with uncontrolled asthma. DATA SOURCES: Original research articles were identified from PubMed using the search term "triple therapy asthma." Information was also retrieved from the ClinicalTrials.gov website. STUDY SELECTIONS: Articles detailing the use of add-on LAMA to ICS plus LABA (open-inhaler triple therapy), and closed triple therapy compared with ICS plus LABA dual therapy, addressing patient symptoms, exacerbations, and health-related quality of life. RESULTS: Open-inhaler triple therapy was associated with a significantly reduced incidence of hospitalizations and emergency department visits and a decrease in ICS dose, oral corticosteroids use, and antibiotics use. Exacerbations and acute respiratory events were also reduced. Single-inhaler triple therapy showed a greater improvement in lung function, asthma control, and health status and was noninferior to open-inhaler triple therapy for Asthma Quality of Life Questionnaire scores. Single-inhaler triple therapy may also lead to improved therapy adherence. CONCLUSION: Add-on LAMA to ICS plus LABA (open- or single-inhaler triple therapy) improves the response in patients who remain symptomatic and provides a reasonable alternative to ICS dose escalation in treatment-refractory patients.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Humanos , Asma/tratamento farmacológico , Asma/induzido quimicamente , Antagonistas Muscarínicos/uso terapêutico , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Qualidade de Vida , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2 , Nebulizadores e Vaporizadores , Quimioterapia Combinada , Corticosteroides
18.
Bioorg Chem ; 131: 106308, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36516520

RESUMO

Muscarine acetylcholine receptors (mAChRs) regulate a variety of central and peripheral physiological functions and emerge as important therapeutic targets for a number of diseases including chronic obstructive pulmonary disease (COPD). Inspired by two active natural products, we designed and synthesized a series of 2-(2,2-diarylethyl)-cyclamine derivatives for screening M3 mAChR antagonists. On this skeleton, the structural units including N heterocycle, aryl groups and its substituents on aryl were examined and resulted in a clear structure-activity relationships on the M3 mAChR. In general, these 2-(2,2-diarylethyl)-cyclamine derivatives exhibited good to excellent M3 antagonistic potency and receptor selectivity. The most active 5b-C1 had an IC50 value of 3 nM and the most of compound 6 displayed inactivity against histamine H1 receptor closely related to M3. In in vitro and in vivo evaluations of tracheo-relaxation function, some compounds even showed comparable activity to tiotropium bromide, a known blockbuster drug for COPD. Such excellent properties made these novel compounds potential candidates for COPD drug development.


Assuntos
Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica , Humanos , Antagonistas Muscarínicos/uso terapêutico , Derivados da Escopolamina/química , Derivados da Escopolamina/uso terapêutico , Receptor Muscarínico M3 , Brometo de Tiotrópio/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
19.
Int Urogynecol J ; 34(6): 1271-1277, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36422657

RESUMO

INTRODUCTION AND HYPOTHESIS: Representatives of two classes of oral medication are often used to treat urgency urinary incontinence (UUI): solifenacin, an M3-receptor-selective antimuscarinic, and mirabegron, a beta-3 agonist. Two previous asynchronous drug-specific studies suggested different interactions between these medications and the urobiome despite identical methodologies, including recruitment, sample procurement, medication dose escalation strategy, determination of 12-week responders versus nonresponders, and data collection. This analysis compares data from these two studies using a uniform analytic approach. METHODS: Urine was collected aseptically via transurethral catheter from consenting participants for subsequent processing by the Expanded Quantitative Urine Culture (EQUC) protocol in two cohorts (n=50 and n=47) that were demographically similar. Species accumulation curves were generated to compare the total number of unique species detected. Indices that measure richness, evenness, and/or abundance were used to compare alpha (within sample) diversity. The Bray-Curtis Dissimilarity Index was used to determine between sample (beta) diversity. RESULTS: The majority of the 40 species detected in the pre-treatment urobiomes were detected in both cohorts. Both pre-treatment urobiomes were substantially similar in species richness, evenness, and diversity. Differences in pre-treatment urobiomes were associated with treatment response for solifenacin-treated participants only. In contrast, the pre-treatment urobiomes of mirabegron-treated participants were not associated with treatment response. Changes in the post-treatment urobiomes were detected in both cohorts with an increase in richness for both solifenacin (5-mg dose only) and mirabegron. CONCLUSIONS: Pre-treatment urobiome characteristics were associated with treatment response in participants treated with solifenacin, but not mirabegron. Differences exist in urobiome response after treatment with two medications that have known differences in mechanism of action.


Assuntos
Bexiga Urinária Hiperativa , Incontinência Urinária , Adulto , Feminino , Humanos , Acetanilidas/uso terapêutico , Quimioterapia Combinada , Antagonistas Muscarínicos/uso terapêutico , Succinato de Solifenacina/uso terapêutico , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária/tratamento farmacológico
20.
BMC Urol ; 23(1): 64, 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-37095473

RESUMO

BACKGROUND: Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective ß3-adrenergic receptor agonist approved in the US in December 2020, demonstrated efficacy in reducing symptoms of OAB and was safe and well tolerated in the 12-week EMPOWUR trial and its 40-week, double-blind extension trial. The goal of the COMPOSUR study is to evaluate vibegron in a real-world setting to assess patient treatment satisfaction, tolerability, safety, duration of treatment, and persistence. METHODS: This is a 12-month, prospective, observational, real-world study, with an optional 12-month extension to 24 months, in the US assessing adults ≥ 18 years old starting a new course of vibegron. Patients must be previously diagnosed with OAB with or without UUI, symptomatic for ≥ 3 months before enrollment, and receive prior treatment with an anticholinergic, with mirabegron, or with a combination of an anticholinergic and mirabegron. Enrollment is performed by the investigator following exclusion and inclusion criteria guided by US product labeling, reinforcing a real-world approach. Patients complete the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q) monthly and the OAB Questionnaire short form (OAB-q-SF) and Work Productivity and Activity Impairment Questionnaire (WPAI:US) at baseline and monthly for 12 months. Patients are followed up via phone call, in-person visits, or telehealth (ie, virtual) visits. The primary endpoint is patient treatment satisfaction as determined by the OAB-SAT-q satisfaction domain score. Secondary endpoints include percent positive responses to individual OAB-SAT-q questions, additional OAB-SAT-q domain scores, and safety. Exploratory endpoints include adherence and persistence. DISCUSSION: OAB leads to a significant decrease in quality of life, as well as impairment of work activities and productivity. Persistence with OAB treatments can be challenging, often due to lack of efficacy and adverse effects. COMPOSUR is the first study to provide long-term, prospective, pragmatic treatment data for vibegron in the US and the resultant effect on quality of life among patients with OAB in a real-world clinical setting. Trial registration ClinicalTrials.gov identifier: NCT05067478; registered: October 5, 2021.


Assuntos
Bexiga Urinária Hiperativa , Adulto , Humanos , Adolescente , Bexiga Urinária Hiperativa/tratamento farmacológico , Qualidade de Vida , Estudos Prospectivos , Resultado do Tratamento , Acetanilidas/uso terapêutico , Método Duplo-Cego , Antagonistas Colinérgicos/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico
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