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1.
Medicine (Baltimore) ; 100(5): e23171, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592817

RESUMO

BACKGROUND: Vibegron is a new ß3-adrenergic receptor agonist which has been demonstrated for the treatment of overactive bladder (OAB). We carried out meta-analysis to evaluate the efficiency of vibegron vs antimuscarinic monotherapy for treating OAB. METHODS: Randomized controlled trials (RCTs) of Vibegron vs antimuscarinic monotherapy for OAB were searched systematically by using EMBASE, MEDLINE, and the Cochrane Controlled Trials Register. The RevMan version 5.3.0. was used to analysis the data. RESULTS: Three RCTs involving a total of 1751 patients were studied in the Systematic review and Meta-analysis. Efficacy end points: the mean number of micturitions episodes/d (P = .16); the mean number of urgency episodes/d (P = .05); mean number of urgency incontinence episodes/d (P = .11) and mean number of incontinence episodes/d (P = .14) indicated that vibegron and antimuscarinic had no significant differences in terms of OAB treatment. Mean volume voided/micturition showed a distinct difference in the two groups (P = .009). With regard to dry mouth and drug related treatment-emergent adverse event (TEAE), vibegron showed better tolerance than antimuscarinic. Serious adverse event (SAE) and discontinuations due to adverse event (AE) did not show a significant difference between the two groups. CONCLUSIONS: The therapeutic effect of vibegron is similar to that of antimuscarinic, but vibegron does not increase the risk of AE.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Pirimidinonas/uso terapêutico , Pirrolidinas/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Humanos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
JAMA ; 324(22): 2301-2317, Dec. 3, 2020.
Artigo em Inglês | BIGG - guias GRADE | ID: biblio-1146633

RESUMO

Asthma is a major public health problem worldwide and is associated with excess morbidity, mortality, and economic costs associated with lost productivity. The National Asthma Education and Prevention Program has released the 2020 Asthma Guideline Update with updated evidence-based recommendations for treatment of patients with asthma. To report updated recommendations for 6 topics for clinical management of adolescents and adults with asthma: (1) intermittent inhaled corticosteroids (ICSs); (2) add-on long-acting muscarinic antagonists; (3) fractional exhaled nitric oxide; (4) indoor allergen mitigation; (5) immunotherapy; and (6) bronchial thermoplasty. The National Heart, Lung, and Blood Advisory Council chose 6 topics to update the 2007 asthma guidelines based on results from a 2014 needs assessment. The Agency for Healthcare Research and Quality conducted systematic reviews of these 6 topics based on literature searches up to March-April 2017. Reviews were updated through October 2018 and used by an expert panel (n = 19) that included asthma content experts, primary care clinicians, dissemination and implementation experts, and health policy experts to develop 19 new recommendations using the GRADE method. The 17 recommendations for individuals aged 12 years or older are reported in this Special Communication. From 20 572 identified references, 475 were included in the 6 systematic reviews to form the evidence basis for these recommendations. Compared with the 2007 guideline, there was no recommended change in step 1 (intermittent asthma) therapy (as-needed short-acting ß2-agonists [SABAs] for rescue therapy). In step 2 (mild persistent asthma), either daily low-dose ICS plus as-needed SABA therapy or as-needed concomitant ICS and SABA therapy are recommended. Formoterol in combination with an ICS in a single inhaler (single maintenance and reliever therapy) is recommended as the preferred therapy for moderate persistent asthma in step 3 (low-dose ICS-formoterol therapy) and step 4 (medium-dose ICS-formoterol therapy) for both daily and as-needed therapy. A short-term increase in the ICS dose alone for worsening of asthma symptoms is not recommended. Add-on long-acting muscarinic antagonists are recommended in individuals whose asthma is not controlled by ICS-formoterol therapy for step 5 (moderate-severe persistent asthma). Fractional exhaled nitric oxide testing is recommended to assist in diagnosis and monitoring of symptoms, but not alone to diagnose or monitor asthma. Allergen mitigation is recommended only in individuals with exposure and relevant sensitivity or symptoms. When used, allergen mitigation should be allergen specific and include multiple allergen-specific mitigation strategies. Subcutaneous immunotherapy is recommended as an adjunct to standard pharmacotherapy for individuals with symptoms and sensitization to specific allergens. Sublingual immunotherapy is not recommended specifically for asthma. Bronchial thermoplasty is not recommended as part of standard care; if used, it should be part of an ongoing research effort. Asthma is a common disease with substantial human and economic costs globally. Although there is no cure or established means of prevention, effective treatment is available. Use of the recommendations in the 2020 Asthma Guideline Update should improve the health of individuals with asthma.


Assuntos
Humanos , Adolescente , Adulto , Asma/prevenção & controle , Administração dos Cuidados ao Paciente/organização & administração , Alérgenos/uso terapêutico , Dessensibilização Imunológica , Corticosteroides/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Termoplastia Brônquica , Óxido Nítrico/uso terapêutico
5.
Arch. esp. urol. (Ed. impr.) ; 73(6): 509-522, jul.-ago. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-195926

RESUMO

OBJETIVO: Evaluar si la menor tasa de abandonos del tratamiento de la vejiga hiperactiva (VH) con mirabegrón podría generar ahorros para el Sistema Nacional de Salud (SNS) y ganancia de años de vida ajustados por calidad (AVACs), en comparación con los fármacos antimuscarínicos (AM) (tolterodina, fesoterodina, oxibutinina, solifenacina). MÉTODOS: Modelo probabilístico (simulación de Monte Carlo de segundo orden) en una cohorte hipotética de 1.000 pacientes con VH y un horizonte temporal de 1 año. Las tasas de abandono/persistencia del tratamiento con mirabegrón y AM se obtuvieron de un estudio observacional español en 1.798 pacientes. Los costes unitarios (€ 2018) y la pérdida de utilidades ligada al abandono del tratamiento se obtuvieron de precios públicos españoles y de la literatura, respectivamente. RESULTADOS: En cada paciente tratado con mirabegrón se duplica la tasa de persistencia en comparación con los AM, ganándose anualmente 0,0151 ±0,0007 AVACs, frente a AM. Con mirabegrón se generaría un ahorro anual por paciente de 80,74 ± 4,61 € en comparación con los AM, con una probabilidad de ahorro del 100%. La sustitución hipotética de los AM por mirabegrón, generaría en el plazo de 1 año un ahorro para el SNS de 6,6 millones de euros (IC 95%3,9-10,1 millones de euros) y se ganarían 1.238 AVAC (IC95% 731; 1.885 AVAC). CONCLUSIONES: El modelo probabilístico muestra una mayor persistencia en pacientes tratados con mirabegrón en comparación con los AM, generando un impacto positivo sobre la calidad de vida de los pacientes así como ahorros para el SNS


OBJECTIVE: To evaluate whether the lower dropout rate of the treatment of overactive bladder (OAB) with mirabegron could generate cost savings to the National Health System (NHS) and lead to quality-adjusted life years (QALYs) gains, compared to the most commonly prescribed antimuscarinics (AM) in Spain (tolterodine, fesoterodine, oxybutynin, solifenacin). METHODS: A probabilistic model (second order Monte Carlo simulation) in a hypothetical cohort of 1,000 patients with OAB and a time horizon of 1 year was carried out. Discontinuation and persistence rates for both mirabegron and AM were obtained from a Spanish observational study in 1798 patients. Unit costs (€ 2018) and utility loss associated with treatment discontinuation were obtained from Spanish public prices and literature, respectively. RESULTS: Persistence rates in patients treated with mirabegron were twice as high compared to AM, leading to a QALY gain of 0.0151 ± 0.0007 per year. Treatment with mirabegron could generate savings of 80.74 ± 4.61 € per patient per year compared to AM, assuming 100% probability of saving. The hypothetical substitution of AM treatment for mirabegron could potentially generate savings of 6.6 million euros (95% CI 3.9-10.1 million euros) to the NHS and 1,238 QALYs gains (CI 95% 731; 1,885 QALYs) within a period of 1 year. CONCLUSIONS: The probabilistic model presented showed a greater persistence in patients treated with mirabegron compared to AM, leading to a positive impact in patients quality of life, as well cost savings to the NHS in Spain


Assuntos
Humanos , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/economia , Agonistas de Receptores Adrenérgicos beta 3/economia , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Antagonistas Muscarínicos/economia , Antagonistas Muscarínicos/uso terapêutico , Qualidade de Vida , Método de Monte Carlo , Acetanilidas/economia , Acetanilidas/uso terapêutico , Tiazóis/economia , Tiazóis/uso terapêutico , Recusa do Paciente ao Tratamento , Espanha , Fatores de Tempo
6.
Arch Esp Urol ; 73(6): 509-522, 2020 Jul.
Artigo em Espanhol | MEDLINE | ID: mdl-32633246

RESUMO

OBJECTIVE: To evaluate whether the lower dropout rate of the treatment of overactive bladde r(OAB) with mirabegron could generate cost savings to the National Health System (NHS) and lead to quality-adjusted life years (QALYs) gains, compared to the most commonly prescribed antimuscarinics (AM) in Spain (tolterodine, fesoterodine, oxybutynin, solifenacin). METHODS: A probabilistic model (second order Monte Carlo simulation) in a hypothetical cohort of 1,000 patients with OAB and a time horizon of 1 year was carried out. Discontinuation and persistence rates for both mirabegron and AM were obtained from a Spanish observational study in 1798 patients. Unit costs (€ 2018) and utility loss associated with treatment discontinuation were obtained from Spanish public prices and literature, respectively. RESULTS: Persistence rates in patients treated with mirabegron were twice as high compared to AM, leading to a QALY gain of 0.0151 ± 0.0007 per year. Treatment with mirabegron could generate savings of 80.74 ±4.61 € per patient per year compared to AM, assuming 100% probability of saving. The hypothetical substitution of AM treatment for mirabegron could potentially generate savings of 6.6 million euros (95% CI 3.9-10.1 million euros) to the NHS and 1,238 QALYs gains (CI95%731; 1,885 QALYs) within a period of 1 year. CONCLUSIONS: The probabilistic model presented showed a greater persistence in patients treated with mirabegron compared to AM, leading to a positive impactin patients quality of life, as well cost savings to the NHS in Spain.


Assuntos
Antagonistas Muscarínicos , Qualidade de Vida , Bexiga Urinária Hiperativa/tratamento farmacológico , Acetanilidas , Humanos , Modelos Estatísticos , Antagonistas Muscarínicos/uso terapêutico , Espanha , Tiazóis
7.
Adv Pharmacol ; 89: 311-356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616212

RESUMO

Conventional antidepressants typically require weeks of daily dosing to achieve full antidepressant response in antidepressant responders. A newly evolving group of compounds can engender more rapid response times in depressed patients. These drugs include the newly approved antidepressant (S)-ketamine (esketamine, Spravato). A seminal study by Furey and Drevets in 2006 showed antidepressant response in patients after only a few doses with the antimuscarinic drug scopolamine. Several clinical reports have generally confirmed scopolamine as a rapid-acting antidepressant. The data with scopolamine are consistent with the adrenergic/cholinergic hypothesis of mania/depression derived from clinical reports originating in the 1970s from Janowsky and colleagues. Additional support for a role for muscarinic receptors in mood disorders comes from the greater efficacy of conventional antidepressants that have relatively high levels of muscarinic receptor blocking actions (e.g., the tricyclic antidepressant amitriptyline vs the selective serotonin reuptake inhibitor fluoxetine). There appears to be appreciable overlap in the mechanisms of action of scopolamine and other rapid-acting antidepressants (ketamine) or putative rapid-acting agents (mGlu2/3 receptor antagonists) although gaps exist in the experimental literature. Current hypotheses regarding the mechanisms underlying the rapid antidepressant response to scopolamine posit an M1 receptor subtype-initiated cascade of biological events that involve the amplification of AMPA receptors. Consequent impact on brain-derived neurotrophic factor and mTor signaling pathways result in the induction of dendritic spines that enable augmented functional connectivity in brain areas regulating mood. Two major goals for research in this area focus on finding ways in which scopolamine might best be utilized for depressed patients and the discovery of alternative compounds that improve upon the efficacy and safety of scopolamine.


Assuntos
Antidepressivos/farmacologia , Receptores Muscarínicos/metabolismo , Animais , Antidepressivos/química , Antidepressivos/uso terapêutico , Colina/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Humanos , Antagonistas Muscarínicos/uso terapêutico
8.
Adv Pharmacol ; 89: 357-386, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616213

RESUMO

Scopolamine is a nonselective muscarinic antagonist that has shown relatively rapid antidepressant effects, although to date the results are from limited clinical studies. Scopolamine reportedly has downstream signaling effects thought to be linked to neuroplasticity within glutamatergic synapses and consequent antidepressant action. In psychiatry, clinically validated pathways are unusual and thus merit further research in an effort develop more effect medicines for patients with mood disorders. Thus, we are faced with a unique opportunity to build on the clinical observation associated with scopolamine through reverse translation to identify of targets that retain the clinical efficacy while reducing the side effect profile. This chapter reviews the clinical antidepressant findings with scopolamine, including discussion of differential response across patient subgroups, as well as a review of biomarkers that predict clinical outcome. The preclinical data associated with scopolamine also are reviewed and convey a vision for narrowing in on the therapeutic muscarinic receptor subtype(s) that support the antidepressant effects to guide the development of next generation antimuscarinic drug targets for depression.


Assuntos
Antidepressivos/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Escopolamina/uso terapêutico , Animais , Colina/antagonistas & inibidores , Depressão/tratamento farmacológico , Humanos , Escopolamina/efeitos adversos , Resultado do Tratamento
9.
Drugs Aging ; 37(8): 559-565, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32557178

RESUMO

Overactive bladder (OAB) and frailty are multidimensional syndromes, and the prevalence of both increases with age. Little evidence exists for a direct association between OAB and frailty, but urinary urgency may well be a precursor of frailty in older people. Frail older adults are no less deserving of treatment than fit older adults, and lifestyle, behavioral, and pharmacological interventions remain the primary options for treatment, with some evidence for efficacy. Data on onabotulinumtoxinA therapy or percutaneous tibial nerve stimulation in frail older adults are sparse. Frail older adults are often excluded from drug trials, but evidence is accumulating that antimuscarinics and, to a lesser extent, beta-adrenergic agonists are safe, well-tolerated, and effective in older adults. Cognitive impairment associated with frailty should not be used as justification for avoiding the use of antimuscarinics. More studies are required to better understand the association between OAB and frailty, as both are associated with poor outcomes and may be amenable to intervention. Drug trials for OAB treatments should be encouraged to include frail older adults, as this population is highly affected yet often excluded.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Idoso Fragilizado , Antagonistas Muscarínicos/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Idoso Fragilizado/psicologia , Fragilidade/psicologia , Humanos , Estilo de Vida , Masculino , Prevalência , Bexiga Urinária Hiperativa/epidemiologia , Bexiga Urinária Hiperativa/prevenção & controle , Bexiga Urinária Hiperativa/psicologia
10.
Medicine (Baltimore) ; 99(26): e20803, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590764

RESUMO

RATIONALE: Voiding difficulty is more common in males, although it is not uncommon in females. Female voiding difficulty can be caused by iatrogenic, anatomic, and neurogenic factors, and specifically urethra stricture, impaired detrusor contractility, primary bladder neck obstruction, and detrusor-external sphincter dyssynergia. Labial adhesion is a rare cause of female voiding difficulty.The incidence of labial fusion has been reported to be 0.6% to 1.4% in children; however, the incidence in the elderly has yet to be fully elucidated. PATIENT CONCERNS: We present the case of a postmenopausal and sexually inactive 76-year-old female patient who had nearly total vaginal and urethral occlusion due to labial adhesion. She had no underlying diseases and came to our clinic with a 10-month history of voiding difficulty, postmicturition dribbling, and involuntary urinary leakage when getting up. DIAGNOSIS: A genital examination revealed nearly total fusion of the labia minor with only a 3-mm pinhole opening at the posterior end. INTERVENTIONS: Treatment included surgical separation, the local application of estrogen cream, and self-dilatation. She also received an antimuscarinic agent to treat overactive bladder secondary to bladder outlet obstruction which was caused by labial adhesion. OUTCOMES: No surgical complications occurred. Moreover, no labial adhesion or voiding dysfunction was found immediately after the surgery or after 6 months of follow-up. LESSONS SUBSECTIONS: Genital examinations are a basic but very important noninvasive skill for physicians. This case report highlights that genital examinations should be a priority for patients with gynecological or urological symptoms.


Assuntos
Estrogênios/administração & dosagem , Obstrução do Colo da Bexiga Urinária , Bexiga Urinária Hiperativa , Procedimentos Cirúrgicos Urogenitais/métodos , Doenças da Vulva , Idoso , Feminino , Humanos , Antagonistas Muscarínicos/uso terapêutico , Pós-Menopausa , Resultado do Tratamento , Uretra/patologia , Uretra/fisiopatologia , Obstrução do Colo da Bexiga Urinária/etiologia , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/cirurgia , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/etiologia , Micção , Cremes, Espumas e Géis Vaginais/administração & dosagem , Doenças da Vulva/complicações , Doenças da Vulva/diagnóstico , Doenças da Vulva/fisiopatologia , Doenças da Vulva/cirurgia
11.
Expert Opin Pharmacother ; 21(12): 1449-1454, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32452702

RESUMO

INTRODUCTION: Multiple Sclerosis (MS) manifests with a plethora of signs and symptoms affecting brain structures and spinal pathways. The multitude of lesions in MS patients makes difficult to establish the relative role of each of them to lower urinary tract symptoms (LUTS). Generally, the subcortical white-matter lesions result in detrusor overactivity, whilst lesions of the spinal cord result in the combined occurrence of detrusor overactivity and detrusor-sphincter dyssynergia (DSD). It has been estimated that 80-90% of patients with MS will suffer from some form of LUTS over the course of the disease. Among LUTS, the most reported is detrusor overactivity which includes urinary urgency, frequent urination, nocturia, and urge urinary incontinence. AREAS COVERED: The authors review the management of lower urinary tract symptoms in MS patients providing their expert opinions on the subject matter. EXPERT OPINION: LUTS affect the quality of life substantially and are associated with a significantly increased mortality. The adequate management is an important challenge for both patients and caregivers with a multidisciplinary approach likely necessary.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Canabinoides/uso terapêutico , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Toxinas Botulínicas Tipo A/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Canabinoides/administração & dosagem , Cateteres de Demora , Feminino , Humanos , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/etiologia , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Antagonistas Muscarínicos/administração & dosagem , Qualidade de Vida , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Estimulação Elétrica Nervosa Transcutânea , Infecções Urinárias/diagnóstico , Infecções Urinárias/etiologia , Urodinâmica
12.
J Pharmacol Exp Ther ; 374(1): 44-51, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32327528

RESUMO

Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M1 receptor-selective muscarinic antagonist pirenzepine when delivered by subcutaneous injection, oral gavage, or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of mice with streptozotocin-induced diabetes dose-dependently (0.1%-10.0%) prevented tactile allodynia, thermal hypoalgesia, and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia, whereas withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 day/wk. Similar local effects were noted with the nonselective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies. SIGNIFICANCE STATEMENT: Muscarinic antagonist pirenzepine alleviates diabetic peripheral neuropathy when applied topically in mice.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Administração Tópica , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/uso terapêutico , Doenças do Sistema Nervoso Periférico/complicações
13.
Neurol Clin ; 38(2): 379-396, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32279716

RESUMO

Tardive dyskinesia (TD) is an iatrogenic condition that encompasses a wide phenomenological spectrum of movement disorders caused by exposure to dopamine receptor blocking agents (DRBAs). TD may cause troublesome or disabling symptoms that impair quality of life. Due to frequent, often inappropriate, use of DRBAs, TD prevalence rates among patients exposed to DRBAs continue to be high. The judicious use of DRBAs is key to the prevention of TD, reduction of disease burden, and achieving lasting remission. Dopamine-depleting vesicular monoamine transporter type 2 inhibitors are considered the treatment of choice of TD.


Assuntos
Discinesia Tardia/terapia , Antipsicóticos/uso terapêutico , Toxinas Botulínicas/uso terapêutico , Estimulação Encefálica Profunda/métodos , Eletroconvulsoterapia , Humanos , Antagonistas Muscarínicos/uso terapêutico , Fármacos Neuromusculares/uso terapêutico , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Triexifenidil/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
14.
Am J Respir Crit Care Med ; 201(9): e56-e69, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32283960

RESUMO

Background: This document provides clinical recommendations for the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). It represents a collaborative effort on the part of a panel of expert COPD clinicians and researchers along with a team of methodologists under the guidance of the American Thoracic Society.Methods: Comprehensive evidence syntheses were performed on all relevant studies that addressed the clinical questions and critical patient-centered outcomes agreed upon by the panel of experts. The evidence was appraised, rated, and graded, and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach.Results: After weighing the quality of evidence and balancing the desirable and undesirable effects, the guideline panel made the following recommendations: 1) a strong recommendation for the use of long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination therapy over LABA or LAMA monotherapy in patients with COPD and dyspnea or exercise intolerance; 2) a conditional recommendation for the use of triple therapy with inhaled corticosteroids (ICS)/LABA/LAMA over dual therapy with LABA/LAMA in patients with COPD and dyspnea or exercise intolerance who have experienced one or more exacerbations in the past year; 3) a conditional recommendation for ICS withdrawal for patients with COPD receiving triple therapy (ICS/LABA/LAMA) if the patient has had no exacerbations in the past year; 4) no recommendation for or against ICS as an additive therapy to long-acting bronchodilators in patients with COPD and blood eosinophilia, except for those patients with a history of one or more exacerbations in the past year requiring antibiotics or oral steroids or hospitalization, for whom ICS is conditionally recommended as an additive therapy; 5) a conditional recommendation against the use of maintenance oral corticosteroids in patients with COPD and a history of severe and frequent exacerbations; and 6) a conditional recommendation for opioid-based therapy in patients with COPD who experience advanced refractory dyspnea despite otherwise optimal therapy.Conclusions: The task force made recommendations regarding the pharmacologic treatment of COPD based on currently available evidence. Additional research in populations that are underrepresented in clinical trials is needed, including studies in patients with COPD 80 years of age and older, those with multiple chronic health conditions, and those with a codiagnosis of COPD and asthma.


Assuntos
Corticosteroides/normas , Agonistas de Receptores Adrenérgicos beta 2/normas , Broncodilatadores/normas , Quimioterapia Combinada/normas , Antagonistas Muscarínicos/normas , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Broncodilatadores/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/uso terapêutico , Guias de Prática Clínica como Assunto , Sociedades Médicas/normas , Estados Unidos
15.
Expert Opin Pharmacother ; 21(9): 997-1004, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32237914

RESUMO

INTRODUCTION: In chronic obstructive pulmonary disease (COPD), inhaled long-acting antimuscarinic agents (LAMA) are effective maintenance therapies used across all severity stages of the disease. Most of them are administered via dry powder inhalers, but these devices require a potent inspiratory flow which cannot be effectively achieved by patients with advanced disease. In such patients, inhaled therapy via nebulization might be an option. AREAS COVERED: Revefenacin is a LAMA that was specifically formulated for once daily nebulization and which was authorized by the FDA as a maintenance therapy for COPD. In phase II and III clinical studies discussed in this review, revefenacin demonstrated its rapid onset of action and sustained effect on lung function on both a short- and long-term basis. EXPERT OPINION: Nebulized revefenacin with once daily use does not require any particular effort of administration and hence can be used by patients with severe airways obstruction or by those having milder cognitive deficits. Further studies are needed, however, to better document the long-term cardiovascular safety and its ability to reduce the exacerbation rate.


Assuntos
Benzamidas/uso terapêutico , Carbamatos/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Benzamidas/farmacocinética , Benzamidas/farmacologia , Carbamatos/farmacocinética , Carbamatos/farmacologia , Humanos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia
16.
Am J Respir Crit Care Med ; 201(12): 1508-1516, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32162970

RESUMO

Rationale: The IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations. Five hundred seventy-four patients were censored in the original analysis owing to incomplete vital status information.Objectives: Report ACM and impact of stepping down therapy, following collection of additional vital status data.Methods: Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg following a run-in on their COPD therapies. Time to ACM was prespecified. Additional vital status data collection and subsequent analyses were performed post hoc.Measurements and Main Results: We report vital status data for 99.6% of the intention-to-treat population (n = 10,355), documenting 98 (2.36%) deaths on FF/UMEC/VI, 109 (2.64%) on FF/VI, and 66 (3.19%) on UMEC/VI. For FF/UMEC/VI, the hazard ratio for death was 0.72 (95% confidence interval, 0.53-0.99; P = 0.042) versus UMEC/VI and 0.89 (95% confidence interval, 0.67-1.16; P = 0.387) versus FF/VI. Independent adjudication confirmed lower rates of cardiovascular and respiratory death and death associated with the patient's COPD.Conclusions: In this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Androstadienos/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Clorobenzenos/uso terapêutico , Glucocorticoides/uso terapêutico , Mortalidade , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/uso terapêutico , Administração por Inalação , Idoso , Causas de Morte , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença
17.
Monaldi Arch Chest Dis ; 90(1)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32072800

RESUMO

To date treatment protocols in Respiratory and or Internal departments across Italy for treatment of chronic obstructive pulmonary disease (COPD) patients at hospital admission with relapse due to exacerbation do not find adequate support in current guidelines. Here we describe the results of a recent clinical audit, including a systematic review of practices reported in literature and an open discussion comparing these to current real-life procedures. The process was dived into two 8-hour-audits 3 months apart in order to allow work on the field in between meeting and involved 13 participants (3 nurses, 1 physiotherapist, 2 internists and 7 pulmonologists). This document reports the opinions of the experts and their consensus, leading to a bundle of multidisciplinary statements on the use of inhaled drugs for hospitalized COPD patients. Recommendations and topics addressed include: i) monitoring and diagnosis during the first 24 h after admission; ii) treatment algorithm and options (i.e., short and long acting bronchodilators); iii) bronchodilator dosages when switching device or using spacer; iv) flow measurement systems for shifting to LABA+LAMA within 48 h; v) when nebulizers are recommended; vi) use of SMI to deliver LABA+LAMA when patient needs SABA <3 times/day independently from flow limitation; vii) use of DPI and pre-dosed MDI to deliver LABA+LAMA or TRIPLE when patient needs SABA <3 times/day, with inspiratory flow > 30 litres/min; viii) contraindication to use DPI; ix) continuation of LABA-LAMA when patient is already on therapy; x) possible LABA-LAMA dosage increase; xi) use of SABA and/or SAMA in addition to LABA+LABA; xii) use of SABA+SAMA restricted to real need; xiii) reconciliation of drugs in presence of comorbidities; xiv) check of knowledge and skills on inhalation therapy; xv) discharge bundle; xvi) use of MDI and SMI in tracheostomized patients in spontaneous and ventilated breathing.


Assuntos
Broncodilatadores/administração & dosagem , Auditoria Clínica/métodos , Nebulizadores e Vaporizadores/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/uso terapêutico , Idoso de 80 Anos ou mais , Broncodilatadores/uso terapêutico , Progressão da Doença , Quimioterapia Combinada , Hospitalização/estatística & dados numéricos , Humanos , Itália/epidemiologia , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/uso terapêutico , Equipe de Assistência ao Paciente/estatística & dados numéricos
18.
Toxicol Lett ; 325: 67-76, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017982

RESUMO

Racemic 3-quinuclidinyl-α-methoxydiphenylacetate (MB266) was synthesised. Its activity at muscarinic acetylcholine receptors (mAChRs), and muscle and neuronal nicotinic acetylcholine receptors (nAChRs), was compared to that of atropine and racemic 3-quinucidinyl benzilate (QNB) using a functional assay based on agonist-induced elevation of intracellular calcium ion concentration in CN21, Chinese Hamster Ovary (CHO) and SHSY5Y human cell lines. MB266 acted as an antagonist at acetylcholine receptors, displaying 18-fold selectivity for mAChR versus nAChR (compared to the 15,200-fold selectivity observed for QNB). Thus O-methylation of QNB reduced the affinity for mAChR antagonism and increased the relative potency at both muscle and neuronal nAChRs. Despite MB266 having a pharmacological profile potentially useful for the treatment of anticholinesterase poisoning, its administration did not improve the neuromuscular function in a soman-poisoned guinea-pig diaphragm preparation pretreated with the organophosphorus nerve agent soman. Consideration should be given to exploring the potential of MB266 for possible anticonvulsant action in vitro as part of a multi-targeted ligand approach.


Assuntos
Antídotos/farmacologia , Antídotos/uso terapêutico , Inibidores da Colinesterase/envenenamento , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Agentes Neurotóxicos/envenenamento , Antagonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/uso terapêutico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Antídotos/síntese química , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Diafragma/efeitos dos fármacos , Cobaias , Humanos , Técnicas In Vitro , Masculino , Antagonistas Muscarínicos/síntese química , Músculo Esquelético/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Antagonistas Nicotínicos/síntese química , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Soman/envenenamento
19.
Drug Ther Bull ; 58(2): 25-29, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32001450

RESUMO

Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.


Assuntos
Alarmes Clínicos , Desamino Arginina Vasopressina/uso terapêutico , Enurese Noturna/tratamento farmacológico , Fatores Etários , Antidepressivos Tricíclicos/uso terapêutico , Comorbidade , Humanos , Antagonistas Muscarínicos/uso terapêutico , Enurese Noturna/terapia
20.
Brasília; CONITEC; fev. 2020.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1121203

RESUMO

INTRODUÇÃO: A bexiga neurogênica é um termo aplicado ao mau funcionamento da bexiga urinária e do esfíncter urinário, devido à disfunção neurológica que resulta de trauma, doença ou lesão interna ou externa. Alguns pacientes com disfunção neurogênica do trato urinário inferior apresentam sintomas que se relacionam com o armazenamento prejudicado de urina, como o aumento da frequência de micção, urgência urinária e incontinência urinária. PERGUNTA: Qual a eficácia e a segurança da oxibutinina, tolterodina, solifenacina e darifenacina para disfunção de armazenamento em pacientes adultos com bexiga neurogênica? TECNOLOGIAS: Antimuscarínicos (oxibutinina, tolderodina, solifenacina e darifenacina). EVIDÊNCIAS CIENTÍFICAS: Para a pergunta sobre a eficácia e segurança dos antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) foram recuperadas 868 referências por meio das estratégias de busca, das quais cinco foram incluídos, sendo todos ECR. Os principais desfechos de eficácia avaliados pelos estudos incluídos foram: capacidade máxima da bexiga, número de episódios de incontinência diária, número de cateterizações diárias, Incontinence Quality of Life (I-QoL) e escore Patient Perception of Bladder Condition (PPBC). Além dos desfechos de eficácia, foram avaliados os eventos adversos. Um estudo evidenciou que a oxibutina intravesical promoveu maior ganho em volume cistométrico que a oxibutinina oral (aumento médio (DP) de 116,6 (27,5) e 18,1 (27,5) mL, respectivamente para oxibutinina vesical e oral ­ p = 0,009). Ademais, um outro estudo evidenciou que a solifenacina, nas dosagens de 5 e 10 mg, e a oxibutinina, na dose de 15 mg, proporcionaram aumento significativo no volume cistométrico em relação ao placebo (aumento médio (DP) de 77,8 (115,4) mL, 134,2 (124,7) mL, e 134,2 (124,7) mL, respectivamente para solifenacina 5 mg, solifenacina 10 mg e oxibutinina de 15 mg ­ p<0,01 para todas as comparações versus placebo). Dois estudos compararam a tolterodina versus placebo, para o desfecho volume cistométrico. Um dos estudos não exibiu diferença entre os grupos. O outro mostrou efeito dose resposta para a tolterodina, sendo a dose de 4 mg a mais eficaz em relação ao placebo (p=0,009). Para o desfecho número de episódios de incontinência/dia, após quatro semanas, a oxibutinina 15 mg apresentou uma redução média (DP) de ­2,71 (2,84) episódios de incontinência/dia, enquanto o grupo que recebeu solifenacina 10 mg apresentou redução de ­0,57 (2,29) episódios de IU/dia (p<0,01), após quatro semanas. Outro estudo, que comparou a oxibutinina à tolterodina, ambas em dose personalizada (média de 8,4 mg/dia para tolterodina e 12,5 mg/dia para a oxibutinina), não mostrou diferença significante entre as terapias, para qualquer um dos desfechos de eficácia avaliados. O desfecho primário de qualidade de vida (I-QoL), apenas apresentou resultados de comparação para a oxibutinina, quando em formulação vesical versus oral. Nesse caso, não houve diferença estatisticamente significativa (p = 0,730). Para além dessa comparação, os desfechos de qualidade de vida (I-QoL) e funcionalidade (PPBC), não apresentaram resultados de comparação para qualquer outro estudo avaliado. Ademais, mesmo para o desfecho de redução de episódios de IU, existe dúvida em relação à significância clínica do resultado, haja vista que a redução média de episódios foi < 2 para a maioria dos estudos, diante de um cenário basal de 2-5 episódios/dia. A qualidade metodológica dos estudos foi baixa e não existem comparações diretas que englobem os quatro antimuscarínicos considerados (darifenacina, oxibutinina, tolterodina e solifenacina). AVALIAÇÃO ECONÔMICA: Os estudos avaliados neste relatório não incluíram a análise da darifenacina. Além disso, não existe um estudo que avalie os antimuscarínicos versus um comparador em comum e, mesmo que fosse estabelecida a comparação indireta entre eles, o desfecho primordial, que avalia a qualidade de vida, não está presente em todos os estudos incluídos. O estudo que permitiria o maior número de comparações seria o de Amarenco et al. 2015, pois incluiu a solifenacina em 5 e 10 mg, além da oxibutinina e o placebo. No entanto, o estudo não forneceu o valor da diferença entre os braços, quanto ao ganho em qualidade de vida (I-QoL), entre início e fim do estudo. Realizamos os testes estatísticos para essa diferença não relatada e vimos que todas, sem exceção, foram não significativas. Sendo assim, devido ao alto risco de viés do estudo de Amarenco et al. 2015, à falta de estudos que avaliassem a darifenacina e à ausência do desfecho I-QoL em alguns estudos, não seria plausível realizar uma análise econômica utilizando desfechos substitutos ou não significativos (estatística e clinicamente). AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário adotou a perspectiva do SUS e um horizonte temporal de cinco anos (2020-2024). O custo dos tratamentos medicamentosos limitou-se ao valor de aquisição dos medicamentos, (oxibutinina, tolterodina, solifenacina, darifenacina e mirabegrona) obtidos do Banco de Preços em Saúde. Dada a ausência de dados específicos para indivíduos com bexiga neurogênica, foram consideradas as quatro principais causas de bexiga neurogênica: doença de Parkinson (DP), esclerose múltipla (EM), acidente vascular cerebral (AVC) e danos na coluna vertebral (DCV). As porcentagens de uso dos agentes antimuscarínicos foram obtidas de uma publicação do Sistema de Saúde Inglês (NHS). Com isso, a estimativa de impacto orçamentário neste cenário decorrente da incorporação dos antimuscarínicos e mirabegrona seria de R$ 2.095.249.966,02 bilhões no primeiro ano de incorporação. Após cinco anos de incorporação esse valor seria de R$ 10.679.375.762,42 bilhões de reais. Cenários alternativos foram elaborados, considerando a incorporação de apenas um dos medicamentos. Nestes cenários as estimativas de impacto orçamentário, decorrentes da incorporação de cada um dos antimuscarínicos e mirabegrona, após cinco anos de incorporação, variaram de R$ 3.486.573.869,54 a R$ 20.415.826.991,67 bilhões de reais, sendo a oxibutinina e a tolterodina, respectivamente, os cenários de menor e maior custo. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: foram realizadas buscas no ClinicalTrials.gov e Cortellis™, a fim de localizar potenciais medicamentos para o tratamento de pacientes adultos com bexiga neurogênica. Não foram encontrados medicamentos nas fases de desenvolvimento clínico, contudo foi detectado a fesoterodina em estudo para pacientes pediátricos com incontinência urinária de causa neurológica. CONSIDERAÇÕES GERAIS: Os antimuscarínicos disponíveis atualmente no Brasil são: oxibutinina, tolterodina, solifenacina e darifenacina. No entanto, há pouca evidência científica sobre a eficácia e segurança desses medicamentos e qual seria o ideal para o tratamento de disfunção de armazenamento em pacientes neurogênicos adultos. A qualidade metodológica dos estudos encontrados foi baixa e não existem comparações diretas que englobem os quatro antimuscarínicos aqui considerados (darifenacina, oxibutinina, tolterodina e solifenacina). RECOMENDAÇÃO PRELIMINAR: pelo exposto, a Conitec, em sua 82ª reunião ordinária, no dia 09 de outubro de 2019, recomendou a não incorporação no SUS dos antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) para o tratamento da bexiga neurogênica. Além do aspecto financeiro, considerou-se, primordialmente, a ausência de benefício clínico significante e baixa qualidade da evidência analisada. CONSULTA PÚBLICA: Foram recebidas nove contribuições de experiência ou opinião, sendo sete discordantes da recomendação preliminar, uma não discordou nem concordou e uma foi excluída por não ter conteúdo analisável. A Conitec entendeu que não houve argumentação suficiente para alterara sua recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 85º reunião ordinária, no dia 04 de fevereiro de 2020, deliberaram, por unanimidade, por recomendar a não incorporação no SUS dos antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) para o tratamento da disfunção de armazenamento em pacientes com bexiga neurogênica. DECISÃO: não incorporar os antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) para o tratamento da disfunção de armazenamento em pacientes com bexiga neurogênica, no âmbito do Sistema Único de Saúde - SUS, conforme a Portaria nº 9, publicada no Diário Oficial da União nº 49, seção 1, página 187, em 12 de março de 2020.


Assuntos
Humanos , Parassimpatolíticos/uso terapêutico , Bexiga Urinaria Neurogênica/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Tartarato de Tolterodina/uso terapêutico , Succinato de Solifenacina/uso terapêutico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
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