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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
2.
Neurosci Lett ; 740: 135466, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152457

RESUMO

The sense of taste provides information regarding the nutrient content, safety or potential toxicity of an edible. This is accomplished via a combination of innate and learned taste preferences. In conditioned taste aversion (CTA), rats learn to avoid ingesting a taste that has previously been paired with gastric malaise. Recent evidence points to a role of cholinergic muscarinic signaling in the amygdala for the learning and storage of emotional memories. The present study tested the participation of muscarinic receptors in the amygdala during the formation of CTA by infusing the non-specific antagonist scopolamine into the basolateral or central subnuclei before or after conditioning, as well as before retrieval. Our data show that regardless of the site of infusion, pre-conditioning administration of scopolamine impaired CTA acquisition whereas post-conditioning infusion did not affect its storage. Also, infusions into the basolateral but not in the central amygdala before retrieval test partially reduced the expression of CTA. Our results indicate that muscarinic receptors activity is required for acquisition but not consolidation of CTA. In addition, our data add to recent evidence pointing to a role of cholinergic signaling in peri-hippocampal structures in the process of memory retrieval.


Assuntos
Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Receptores Muscarínicos/fisiologia , Transdução de Sinais/fisiologia , Paladar/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Emoções , Masculino , Consolidação da Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Microinjeções , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/fisiologia , Ratos , Ratos Wistar , Receptores Muscarínicos/efeitos dos fármacos , Escopolamina/administração & dosagem , Escopolamina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Paladar/efeitos dos fármacos
3.
Neurosci Lett ; 745: 135551, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33346074

RESUMO

BACKGROUND: Previous studies suggest that muscarinic cholinergic receptors might act upon the dopamine release in the mesolimbic system and alter drug-reinforcing values related to drug craving. AIMS: We examined the effects of systemic biperiden administration, a muscarinic cholinergic (M1/M4) receptor antagonist, on ethanol (dose of 2 g/Kg) conditioned place preference (CPP), neuronal activation, dopamine and its metabolites levels in the nucleus accumbens. METHODS: Thirty minutes before the ethanol-induced CPP test, mice received saline or biperiden at doses of 1.0, 5.0, or 10.0 mg/kg. The time spent in each compartment was recorded for 15 min. After the CPP protocol, animals were euthanized, and we investigated the activation of the nucleus accumbens by immunohistochemistry for Fos. We also quantified dopamine, homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens by high-performance liquid chromatography (HPLC). Additionally, the rotarod was employed to evaluate the effects of biperiden on motor coordination. RESULTS: Biperiden at different doses (1.0, 5.0, and 10.0 mg/kg) blocked the expression of ethanol-induced CPP. These biperiden doses increased the number of Fos-positive cells and the dopamine turnover in the nucleus accumbens. None of the doses affected the motor coordination evaluated by the rotarod. CONCLUSIONS: Our results show that biperiden can modulate the effect of alcohol reward, and its mechanism of action may involve a change in dopamine and cholinergic mesolimbic neurotransmission.


Assuntos
Biperideno/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Etanol/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Receptor Muscarínico M1/antagonistas & inibidores , Receptor Muscarínico M4/antagonistas & inibidores , Animais , Condicionamento Clássico/fisiologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Ácido Homovanílico/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M4/metabolismo
5.
Lancet Respir Med ; 8(11): 1106-1120, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32979987

RESUMO

BACKGROUND: Early descriptions of patients admitted to hospital during the COVID-19 pandemic showed a lower prevalence of asthma and chronic obstructive pulmonary disease (COPD) than would be expected for an acute respiratory disease like COVID-19, leading to speculation that inhaled corticosteroids (ICSs) might protect against infection with severe acute respiratory syndrome coronavirus 2 or the development of serious sequelae. We assessed the association between ICS and COVID-19-related death among people with COPD or asthma using linked electronic health records (EHRs) in England, UK. METHODS: In this observational study, we analysed patient-level data for people with COPD or asthma from primary care EHRs linked with death data from the Office of National Statistics using the OpenSAFELY platform. The index date (start of follow-up) for both cohorts was March 1, 2020; follow-up lasted until May 6, 2020. For the COPD cohort, individuals were eligible if they were aged 35 years or older, had COPD, were a current or former smoker, and were prescribed an ICS or long-acting ß agonist plus long-acting muscarinic antagonist (LABA-LAMA) as combination therapy within the 4 months before the index date. For the asthma cohort, individuals were eligible if they were aged 18 years or older, had been diagnosed with asthma within 3 years of the index date, and were prescribed an ICS or short-acting ß agonist (SABA) only within the 4 months before the index date. We compared the outcome of COVID-19-related death between people prescribed an ICS and those prescribed alternative respiratory medications: ICSs versus LABA-LAMA for the COPD cohort, and low-dose or medium-dose and high-dose ICSs versus SABAs only in the asthma cohort. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the association between exposure categories and the outcome in each population, adjusted for age, sex, and all other prespecified covariates. We calculated e-values to quantify the effect of unmeasured confounding on our results. FINDINGS: We identified 148 557 people with COPD and 818 490 people with asthma who were given relevant respiratory medications in the 4 months before the index date. People with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA-LAMA combinations (adjusted HR 1·39 [95% CI 1·10-1·76]). Compared with those prescribed SABAs only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1·55 [1·10-2·18]), whereas those given a low or medium dose were not (1·14 [0·85-1·54]). Sensitivity analyses showed that the apparent harmful association we observed could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS that were not recorded in the database (e value lower 95% CI 1·43). INTERPRETATION: Our results do not support a major role for regular ICS use in protecting against COVID-19-related death among people with asthma or COPD. Observed increased risks of COVID-19-related death can be plausibly explained by unmeasured confounding due to disease severity. FUNDING: UK Medical Research Council.


Assuntos
Corticosteroides/administração & dosagem , Asma/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Pneumonia Viral/mortalidade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/complicações , Betacoronavirus , Estudos de Coortes , Registros Eletrônicos de Saúde , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Pandemias , Modelos de Riscos Proporcionais , Doença Pulmonar Obstrutiva Crônica/complicações , Análise de Regressão , Adulto Jovem
6.
Lancet Respir Med ; 8(10): 1000-1012, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32653074

RESUMO

BACKGROUND: Patients with asthma who are inadequately controlled on inhaled corticosteroid-long-acting ß2-adrenoceptor agonist (ICS-LABA) combinations might benefit from the addition of a long-acting muscarinic receptor antagonist. The aim of the IRIDIUM study was to assess the efficacy and safety of a once-daily, single-inhaler combination of mometasone furoate, indacaterol acetate, and glycopyrronium bromide (MF-IND-GLY) versus ICS-LABA in patients with inadequately controlled asthma. METHODS: In this 52-week, double-blind, double-dummy, parallel-group, active-controlled phase 3 study, patients were recruited from 415 sites across 41 countries. Patients aged 18 to 75 years with symptomatic asthma despite treatment with medium-dose or high-dose ICS-LABA, at least one exacerbation in the previous year, and a percentage of predicted FEV1 of less than 80% were included. Enrolled patients were randomly assigned (1:1:1:1:1) via interactive response technology to receive medium-dose or high-dose MF-IND-GLY (80 µg, 150 µg, 50 µg; 160 µg, 150 µg, 50 µg) or MF-IND (160 µg, 150 µg; 320 µg, 150 µg) once daily via Breezhaler, or high-dose fluticasone-salmeterol (FLU-SAL; 500 µg, 50 µg) twice daily via Diskus. The primary outcome was change from baseline in trough FEV1 with MF-IND-GLY versus MF-IND at week 26 in patients in the full analysis set, analysed by means of a mixed model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02571777, and is completed. FINDINGS: Between Dec 8, 2015, and Jun 14, 2019, 3092 of 4851 patients screened were randomly assigned (medium-dose MF-IND-GLY, n=620; high-dose MF-IND-GLY, n=619; medium-dose MF-IND, n=617; high-dose MF-IND, n=618; high-dose FLU-SAL, n=618). 2747 (88·8%) patients completed the 52-week treatment and 321 (10·4%) started but discontinued study treatment prematurely. Medium-dose MF-IND-GLY (treatment difference [Δ] 76 mL [95% CI 41-111]; p<0·001) and high-dose MF-IND-GLY (Δ 65 mL [31-99]; p<0·001) showed superior improvement in trough FEV1 versus corresponding doses of MF-IND at week 26. Improvements in trough FEV1 were greater for both medium-dose MF-IND-GLY (99 mL [64-133]; p<0·001) and high-dose MF-IND-GLY (119 mL [85-154]; p<0·001) than for high-dose FLU-SAL at week 26. Overall, the incidence of adverse events was balanced across the treatment groups. Seven deaths were reported (one with medium-dose MF-IND-GLY, two with high-dose MF-IND-GLY, and four with high-dose MF-IND) during the study; none of these deaths was considered by the investigators to be caused by study drugs or other study-related factors. INTERPRETATION: Once-daily, single-inhaler MF-IND-GLY improved lung function versus ICS-LABA combinations (MF-IND and FLU-SAL) in patients with inadequately controlled asthma. The safety profile was similar across treatment groups. MF-IND-GLY therefore constitutes a good treatment option in these patients. FUNDING: Novartis Pharmaceuticals.


Assuntos
Asma/tratamento farmacológico , Combinação Fluticasona-Salmeterol/administração & dosagem , Glicopirrolato/administração & dosagem , Indanos/administração & dosagem , Furoato de Mometasona/administração & dosagem , Quinolonas/administração & dosagem , Administração por Inalação , Adolescente , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Broncodilatadores/administração & dosagem , Criança , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Nebulizadores e Vaporizadores , Resultado do Tratamento , Adulto Jovem
7.
N Engl J Med ; 383(1): 35-48, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32579807

RESUMO

BACKGROUND: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking. METHODS: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 µg or 160 µg of budesonide], a LAMA [18 µg of glycopyrrolate], and a LABA [9.6 µg of formoterol]) or one of two dual therapies (18 µg of glycopyrrolate plus 9.6 µg of formoterol or 320 µg of budesonide plus 9.6 µg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only. RESULTS: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-µg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-µg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-µg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-µg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group. CONCLUSIONS: Triple therapy with twice-daily budesonide (at either the 160-µg or 320-µg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Budesonida/administração & dosagem , Fumarato de Formoterol/administração & dosagem , Glucocorticoides/administração & dosagem , Glicopirrolato/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Budesonida/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Fumarato de Formoterol/efeitos adversos , Glucocorticoides/efeitos adversos , Glicopirrolato/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/mortalidade
8.
BMJ Support Palliat Care ; 10(3): 343-349, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32546559

RESUMO

BACKGROUND: Anticipatory prescribing (AP) of injectable medications in advance of clinical need is established practice in community end-of-life care. Changes to prescribing guidelines and practice have been reported during the COVID-19 pandemic. AIMS AND OBJECTIVES: To investigate UK and Ireland clinicians' experiences concerning changes in AP during the COVID-19 pandemic and their recommendations for change. METHODS: Online survey of participants at previous AP national workshops, members of the Association for Palliative Medicine of Great Britain and Ireland and other professional organisations, with snowball sampling. RESULTS: Two hundred and sixty-one replies were received between 9 and 19 April 2020 from clinicians in community, hospice and hospital settings across all areas of the UK and Ireland. Changes to AP local guidance and practice were reported: route of administration (47%), drugs prescribed (38%), total quantities prescribed (35%), doses and ranges (29%). Concerns over shortages of nurses and doctors to administer subcutaneous injections led 37% to consider drug administration by family or social caregivers, often by buccal, sublingual and transdermal routes. Clinical contact and patient assessment were more often remote via telephone or video (63%). Recommendations for regulatory changes to permit drug repurposing and easier community access were made. CONCLUSIONS: The challenges of the COVID-19 pandemic for UK community palliative care has stimulated rapid innovation in AP. The extent to which these are implemented and their clinical efficacy need further examination.


Assuntos
Cuidadores , Vias de Administração de Medicamentos , Cuidados Paliativos/métodos , Padrões de Prática Médica/estatística & dados numéricos , Assistência Terminal/métodos , Administração Bucal , Administração Sublingual , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos Opioides/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Fentanila/administração & dosagem , Clínicos Gerais , Cuidados Paliativos na Terminalidade da Vida/métodos , Hospitais para Doentes Terminais , Humanos , Hipnóticos e Sedativos/administração & dosagem , Irlanda/epidemiologia , Lorazepam/administração & dosagem , Metotrimeprazina/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Enfermeiras Especialistas , Medicina Paliativa , Pandemias , Médicos , Pneumonia Viral/epidemiologia , Guias de Prática Clínica como Assunto , Inquéritos e Questionários , Telemedicina/métodos , Adesivo Transdérmico , Reino Unido/epidemiologia
9.
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
11.
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
12.
Arch. bronconeumol. (Ed. impr.) ; 56(4): 242-248, abr. 2020. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-194742

RESUMO

La aparición de la denominada triple terapia inhalada mediante la combinación de un agonista ß2 de acción prolongada (LABA), un anticolinérgico de acción prolongada (LAMA) y un corticoide inhalado (ICS) en una combinación a dosis fijas (CDF) en un solo dispositivo de inhalación ha supuesto un cambio en el uso de este tratamiento. A pesar de que los ensayos clínicos nos aportan una idea de la eficacia y la seguridad de estas CDF, su aplicación a la clínica diaria puede presentar retos para el clínico sobre dos escenarios concretos. En pacientes que ya están recibiendo una triple terapia en dispositivos distintos el cambio a una CDF podría suponer beneficios en cuanto a disminución de errores críticos en el manejo de los inhaladores, mayor adherencia al tratamiento y menor coste, manteniendo la misma eficacia clínica. En pacientes que no están recibiendo una triple terapia en dispositivos distintos y que necesiten un cambio en el tratamiento, la CDF de triple terapia presenta beneficios mostrados en los ensayos clínicos. Aunque las diferencias metodológicas entre ensayos desaconsejan comparaciones directas, los resultados clínicos muestran una buena eficacia, pero también una considerable variabilidad y un número de resultados clínicos aún por explorar. En el futuro deberán desarrollarse ensayos que completen los datos de eficacia clínica, estudios en vida real que informen de su efectividad y trabajos encaminados a descubrir el perfil de paciente que presenta una mayor respuesta terapéutica a cada CDF, con el objeto de avanzar en el tratamiento personalizado


The emergence of a fixed-dose combination (FDC) of a long-acting ß2-agonists (LABAS), a long-acting anticholinergic agent (LAMA), and an inhaled corticosteroid (ICS) in a single inhalation device has changed the approach to inhaled therapy. Although clinical trials describe the efficacy and safety of these FDCs, their use in daily clinical practice can present challenges for the clinician in two specific scenarios. In patients who are already receiving triple therapy via different devices, switching to FDCs could confer benefits by reducing critical errors in the management of inhalers, improving therapeutic adherence, and lowering costs, while maintaining the same clinical efficacy. In patients who are not receiving triple therapy in different devices and who require a change in treatment, triple therapy FDC has shown benefits in clinical trials. Although methodological differences among the trials advise against direct comparison, clinical results show good efficacy, but also considerable variability, and a number of clinical outcomes have yet to be explored. In the future, trials must be developed to complete clinical efficacy data. Real-world efficacy trials are needed, and studies must be designed to determine the profile of patients who present a greater therapeutic response to each FDC in order to pave to way towards more personalized treatment


Assuntos
Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Corticosteroides/administração & dosagem , Agonistas Adrenérgicos beta/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Protocolos Clínicos
13.
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
14.
Int Braz J Urol ; 46(2): 185-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32022506

RESUMO

OBJECTIVE: To evaluate the effects of solifenacin, darifenacin, and propiverine on nasal-, subfoveal-, temporal choroidal thicknesses (NCT, SFCT, TCT), intraocular pressure (IOP) and pupil diameter (PD). MATERIALS AND METHODS: Patients with overactive bladder (OAB) diagnosed according to The International Continence Society were administered with solifenacin, darifenacin or propiverine on a daily basis between November 2017 and May 2018. NCT, SFCT, TCT, IOP, and PD of these patients were measured and compared as initial, fourth and twelfth weeks. RESULTS: A total of 165 patients (330 eyes) with OAB were evaluated. Solifenacin (n=140) signifi cantly reduced IOP from 17.30±2.72 mmHg to 16.67±2.56 mmHg (p=0.006) and 16.57±2.41 mmHg (p=0.002), at the fourth and twelfth weeks, respectively. Darifenacin (n=110) signifi cantly reduced NCT from 258.70±23.96 µm to 257.51±22.66 µm (p=0.002) and 255.36±19.69 µm (p=0.038), at the fourth and twelfth weeks, respectively. Propiverine (n=80) signifi cantly increased PD from 4.04±0.48 mm to 4.08±0.44 mm (p=0.009) and 4.09±0.45 mm (p=0.001), at the fourth and twelfth weeks, respectively. CONCLUSION: These findings can help to decide appropriate anticholinergic drug choice in OAB patients. We finally suggest further well-designed randomized prospective studies with a larger population to evaluate the anticholinergic-related complications in eyes.


Assuntos
Benzilatos/efeitos adversos , Benzofuranos/efeitos adversos , Corioide/efeitos dos fármacos , Pressão Intraocular/efeitos dos fármacos , Antagonistas Muscarínicos/efeitos adversos , Pupila/efeitos dos fármacos , Pirrolidinas/efeitos adversos , Succinato de Solifenacina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzilatos/administração & dosagem , Benzofuranos/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Estudos Prospectivos , Pirrolidinas/administração & dosagem , Succinato de Solifenacina/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Adulto Jovem
15.
Expert Opin Drug Metab Toxicol ; 16(2): 143-148, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31958237

RESUMO

Introduction: There is solid evidence that in patients with poorly controlled severe asthma despite the use of ICS and LABA, the addition of LAMAs, such as tiotropium, significantly increases the time to the first severe exacerbation and provides a modest but sustained bronchodilation. However, only a very limited number of pharmacokinetic studies with these agents have been performed in asthmatic patients.Areas covered: The pharmacokinetic profile of inhaled tiotropium, umeclidinium and glycopyrronium in healthy volunteers and that of inhaled tiotropium and umeclidinium in asthmatic patients have been reviewed.Expert opinion: In asthmatic patients, LAMAs are rapidly absorbed into the systemic compartment and demonstrate bi-exponential elimination (rapidly declining plasma concentrations followed by slow apparent terminal elimination). Apparently, the severity of asthma does not change the pharmacokinetics of LAMAs. The limited information available is focused on the plasma pharmacokinetic profile of these drugs and, consequently, although suitable for establishing a systemic safety profile, it does not tell us much about possible therapeutic efficacy of LAMAs in asthmatics because quantification of systemic plasma values is neither at the airways, which are their site of action nor representative of their transport to this site.


Assuntos
Asma/tratamento farmacológico , Antagonistas Muscarínicos/administração & dosagem , Receptor Muscarínico M3/antagonistas & inibidores , Administração por Inalação , Antiasmáticos/administração & dosagem , Antiasmáticos/farmacocinética , Antiasmáticos/farmacologia , Asma/fisiopatologia , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Broncodilatadores/farmacologia , Humanos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M3/metabolismo , Índice de Gravidade de Doença
16.
Expert Rev Clin Pharmacol ; 13(2): 103-113, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31951778

RESUMO

Introduction: Treatment options for COPD have evolved rapidly in the last decade and inhaled bronchodilators have largely supplanted the use of oral bronchodilators because of their increased efficacy and excellent safety with topical delivery to the lung. Recently added to the therapeutic armamentarium are fixed-dose combinations (FDC) of two long acting bronchodilators. LAMAs (long acting muscarinic antagonists) and LABAs (long acting beta agonists) are the main classes available and use different pathways to effectively produce bronchial smooth muscle relaxation.Areas covered: The most recent inhaled FDC LAMA/LABA to come to market is Aclidinium Bromide and Formoterol Fumarate. We searched databases of PubMed, Cochrane Library, and manufacturers' websites and retrieved all the randomized-controlled trials (RCTs) conducted with these drugs up to September 2019.Expert opinion: It is likely that FDCs will become the core of our COPD pharmacotherapy for all but the mildest COPD patients. These individual drugs have excellent efficacy and safety records for the maintenance treatment of COPD. Studies have demonstrated that twice daily treatment with aclidinium/formoterol resulted in significant improvement in lung function and an improved exercise tolerance when compared to placebo. Adverse effects are within the range of what is seen with other LAMA/LABA combinations.


Assuntos
Fumarato de Formoterol/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacologia , Combinação de Medicamentos , Fumarato de Formoterol/efeitos adversos , Fumarato de Formoterol/farmacologia , Humanos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Tropanos/efeitos adversos , Tropanos/farmacologia
17.
Expert Opin Drug Metab Toxicol ; 16(2): 103-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918590

RESUMO

Introduction: Overactive bladder (OAB) has a heterogeneous presentation that varies between individuals and by gender. Treatment with antimuscarinic medications is standard first line pharmacotherapy for most patients with OAB. However, gender specific differences in the pharmacokinetics and pharmacodynamics of antimuscarinic therapy are often overlooked and not discussed.Areas covered: This review will explore differences by gender between the presentation and treatment of OAB. We will discuss the differences between sexes in terms of lower urinary tract anatomy, muscarinic receptors, and hormone variation. The effect of antimuscarinics on males and females as well as adherence and persistence patterns will be reviewed in order to fully review all available literature on the gender specific pharmacokinetic and pharmacodynamic considerations for antimuscarinic use in the treatment of OAB.Expert opinion: Despite extensive research into various antimuscarinic formulations and therapeutic regimens for the treatment of OAB, identification of gender specific pharmacokinetic and pharmacodynamics considerations remains scant. As our knowledge and understanding of OAB, muscarinic receptors, and antimuscarinic medications evolve, we will hopefully be better able to understand and implement gender-specific and genomic-sprecific treatment regimens and considerations for improved clinical outcomes.


Assuntos
Antagonistas Muscarínicos/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Animais , Feminino , Humanos , Masculino , Adesão à Medicação , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Fatores Sexuais , Bexiga Urinária Hiperativa/fisiopatologia
18.
J Clin Psychopharmacol ; 40(1): 30-37, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31834098

RESUMO

PURPOSE/BACKGROUND: Biperiden is a muscarinic antagonist that produces memory impairments without impairing attention or motor functions in healthy subjects. It has been suggested that a biperiden-induced memory deficit could model age- and dementia-related memory impairments. The goal of the current study was to determine the dose- and time-dependent effects of biperiden on cognition in healthy volunteers. METHODS/PROCEDURES: Twenty-one healthy volunteers participated in a placebo-controlled, 3-way, crossover study. After a baseline test, cognitive performance was tested at 3 time points after a single dose of biperiden 2 or 4 mg, or placebo. Episodic memory was measured using a 15-word verbal learning task (VLT). Furthermore, n-back tasks, a sustained attention to response task and a reaction time task were used, as well as subjective alertness and a side effects questionnaire. In addition, blood serum values and physiological measures were taken. FINDINGS/RESULTS: Biperiden decreased the number of words recalled in immediate and delayed recall of the VLT 90 minutes after drug intake. A dose-dependent impairment was found for the delayed recall, whereas the immediate recall was equally impaired by the 2 doses. Biperiden did not affect the performance on the VLT 4 hours after administration. Performance in the n-back task and the sustained attention to response task were not affected by biperiden at any time point. Both doses were well tolerated as reported side effects were mild at Tmax and were minimal at the other time points. IMPLICATIONS/CONCLUSIONS: Biperiden exerts effects on episodic memory without negatively affecting other cognitive performance and behavioral measures that were assessed in this study. The data provide further evidence that biperiden has selective effects on cognition, even after a high dose.


Assuntos
Biperideno/efeitos adversos , Cognição/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Memória Episódica , Antagonistas Muscarínicos/efeitos adversos , Aprendizagem Verbal/efeitos dos fármacos , Adolescente , Adulto , Atenção/efeitos dos fármacos , Biperideno/administração & dosagem , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/psicologia , Antagonistas Muscarínicos/administração & dosagem , Tempo de Reação/efeitos dos fármacos , Fatores de Tempo , Adulto Jovem
19.
Int J Clin Pharmacol Ther ; 58(3): 155-165, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31724530

RESUMO

PURPOSE: (R,R)-penehyclidine fumarate (R2PHF) is a highly selective muscarinic receptor antagonist used to suppress glandular secretions before general anesthesia or tracheal intubation and to treat organophosphorus poisoning. This is the first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of R2PHF in healthy subjects. MATERIALS AND METHODS: In this single-center, double-blind, randomized study, 23 subjects received escalation doses of R2PHF (0.0625 mg, 0.25 mg, 0.50 mg, and 1.0 mg), 4 received the parent drug penehyclidine hydrochloride (PHC, 1.0 mg) as a reference, and 4 received a placebo. The pharmacokinetic parameters of R2PHF were determined. Tolerability was assessed based on adverse events and clinical laboratory tests. RESULTS: Single doses of 0.0625 mg, 0.25 mg, and 0.50 mg R2PHF were well-tolerated by healthy subjects. Delirium was set as the termination outcome and appeared in 1 case receiving 1.0 mg. For this reason, the escalation experiment was cut off. The mean half-life (T1/2) ranged from 30.57 to 32.27 hours. CONCLUSION: R2PHF was safe and well-tolerated at doses ranging from 0.0625 to 0.50 mg. A single administration of 0.50 mg was determined to be the maximum tolerated dose of R2PHF. Further pharmacodynamics, safety, and efficacy testing is required to advance R2PHF to the next stage of clinical development and application.


Assuntos
Fumaratos/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Quinuclidinas/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fumaratos/farmacocinética , Humanos , Infusões Intravenosas , Masculino , Antagonistas Muscarínicos/farmacocinética , Quinuclidinas/farmacocinética , Adulto Jovem
20.
J Pharmacol Sci ; 142(2): 50-59, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31818640

RESUMO

Cholinergic neurons play an important role in the higher functions of the brain, such as the memory, cognition, and nociception. However, the exact mechanism behind how the stimulation of all the muscarinic M1 receptors in the entire brain results in the alleviation of partial sciatic nerve ligation (PSNL)-induced mechanical hypersensitivity has not been investigated. Thus, we examined which subtype of GABA receptor was involved in the alleviation of PSNL-induce mechanical hypersensitivity produced by an intracerebroventricular administration of a muscarinic M1 receptor agonist, McN-A-343. Administering a GABAA receptor antagonist, bicuculline, resulted in no changes to the McN-A-343-induced anti-hypersensitivity in PSNL mice whereas a GABAB receptor antagonist, CGP35348, dose-dependently inhibited the anti-hypersensitivity. Furthermore, CGP35348 increased mechanical hypersensitivity in naïve mice, and the hypersensitivity was blocked by NMDA receptor antagonists, MK-801 and D-AP5. Additionally, muscarinic M1 receptors colocalized with GABAB1 receptors and an NMDA receptor subunit, GluN2A, in a large region of the brain. Consequently, these results suggest that the activation of muscarinic M1 receptors in the entire brain reduces nerve injury-induced mechanical hypersensitivity via the GABAB receptors, and the activation of the GABAB receptors regulates glutamatergic transmission via NMDA receptors.


Assuntos
Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/administração & dosagem , Agonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Receptor Muscarínico M1/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/metabolismo , Animais , Bicuculina/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Camundongos , Antagonistas Muscarínicos/metabolismo , Receptor Muscarínico M1/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Nervo Isquiático/efeitos dos fármacos , Estresse Mecânico
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