RESUMO
Background: Anti-obesity medications (AOMs) have historically had limited weight-loss efficacy. However, newer glucagon-like peptide-1 receptor agonist (GLP-1 RA)-based therapies seem to be more effective, including dual agonists of GLP-1R and the glucagon receptor (GCGR) or glucose-dependent insulinotropic polypeptide receptor. Objective: To explore healthcare professionals' (HCPs) experience in obesity treatment and their understanding of agonists of GCGR, glucose-dependent insulinotropic polypeptide (GIP) RA, and GLP-1 RA. Methods: This cross-sectional online survey of HCPs prescribing AOMs was conducted in the United States in 2023 with a questionnaire designed to evaluate prescribing behavior and understanding of GCGR, GIP RA, and GLP-1 RA. Results: The 785 respondents (251 primary-care physicians [PCPs], 263 endocrinologists, and 271 advanced practice providers [APPs]) reported 55% of their patients had obesity (body mass index ≥30 kg/m2 or ≥27 with weight-related complications) and recommended AOMs to 49% overall, significantly more endocrinologists (57% of patients, p < 0.0005) than PCPs (43%) or APPs (46%). The greatest barriers to treatment were medication cost/lack of insurance (mean 4.2 on 1-5 scale [no barrier-extreme barrier]), low patient engagement/adherence (3.3), and inadequate time/staff (3.1). Metformin was the type 2 diabetes (T2D) medication most commonly prescribed to treat obesity in T2D patients (92.5% of respondents). Most HCPs (65%) were very/extremely familiar with GLP-1 RA, but only 30% with GIP RA and 16% with GCGR. Most HCPs expected dual GCGR/GLP-1 RA to benefit many obesity-related conditions; however, only a minority of HCPs perceived that they would benefit non-cardiometabolic complications of obesity. Conclusions: Among HCPs prescribing AOMs, gaps exist in the management of people living with obesity as <50% are prescribed AOMs. Barriers to treatment indicate a need to improve access to AOMs. HCPs were less familiar with GCGR or GIP RA than GLP-1 RA but expect dual GCGR/GLP-1 RA may offer additional benefits, potentially addressing treatment barriers and access. Thus, there is a need for greater education among HCPs regarding the mechanism of action and therapeutic effects of GCGR agonists, and dual GCGR/GLP-1 RA, so that the full range of obesity-related complications can be effectively treated.
RESUMO
For optimal drug delivery, dry powder inhalers (DPIs) depend on the patient's peak inspiratory flow (PIF) and the internal resistance of the device to create turbulent energy and disaggregate the powder. A suboptimal PIF may lead to ineffective drug inhalation into the lungs. Our objective was to report the prevalence of suboptimal PIF in patients with COPD hospitalized for any reason using 1 or more DPIs. In this real-world, observational, singlesite, retrospective study, PIF was measured for each DPI using the In-Check™ DIAL set to match the resistance of the DPI used by each patient. PIFs <60 and <30L/min were considered suboptimal for low to medium-high- and high-resistance DPIs, respectively. At initial hospitalization, the prevalence of suboptimal PIF was 44.6% in 829 patients (mean age, 71.7 years; 56.8% female); 21.2% were measured during admission for a COPD exacerbation. Suboptimal PIF percentages were 61.0% (38.1±9.5L/min [mean±standard deviation (SD)]) across low to medium-high-resistance DPIs and 17.2% (20.7±4.2L/min) for high-resistance DPIs. Overall, 190/829 patients had 1 or more 30-day all-cause readmission with 253 corresponding PIF measurements. For readmissions, suboptimal PIFs were observed in 49.5% (94/190) of patients. Suboptimal PIF percentages were 65.4% (38.4±9.2L/min) for low to medium-high-resistance DPIs and 19.8% (22.4±3.3L/min) for high-resistance DPIs. As the overall prevalence of suboptimal PIFs in hospitalized patients with COPD varied according to the specific internal resistance of the DPI, these findings may have clinical implications for inhaler selection.
RESUMO
The Advancing the Patient Experience (APEX) in Chronic Obstructive Pulmonary Disease (COPD) registry (https://www.apexcopd.org/) is the first primary care health system-based COPD registry in the United States. While its ultimate goal is to improve the care of patients diagnosed with COPD, the registry is also designed to describe real-life experiences of people with COPD, track key outcomes longitudinally, and assess the effectiveness of interventions. It will retrospectively and prospectively collect information from 3000 patients enrolled in 5 health care organizations. Information will be obtained from electronic health records, and from extended annual and brief questionnaires completed by patients before clinic visits. Core variables to be collected into the APEX COPD registry were agreed on by Delphi consensus and fall into 3 domains: demographics, COPD monitoring, and treatment. Main strengths of the registry include: 1) its size and scope (in terms of patient numbers, geographic spread and use of multiple information sources including patient-reported information); 2) collection of variables which are clinically relevant and practical to collect within primary care; 3) use of electronic data capture systems to ensure high-quality data and minimization of data-entry requirements; 4) inclusion of clinical, database development, management and communication experts; 5) regular sharing of key findings, both at international/national congresses and in peer-reviewed publications; and 6) a robust organizational structure to ensure continuance of the registry, and that research outputs are ethical, relevant and continue to bring value to both patients and physicians.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Qualidade de Vida , Humanos , Avaliação de Resultados da Assistência ao Paciente , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/terapia , Sistema de Registros , Estudos RetrospectivosRESUMO
Selective activation of the NPY2 receptor to suppress appetite provides an approach to obesity management. Selective NPY2 PEGylated peptide agonists are described that consist of a peptide core corresponding to residues 25-36 of PYY and a nonpeptidic moiety at the peptide N-terminus that contributes to in vitro potency and in vivo efficacy and provides a PEGylation site. The lead peptide elicits a dose-dependent reduction of food intake in lean mice and of food intake, body weight, and fat mass in DIO mice.
Assuntos
Fármacos Antiobesidade/síntese química , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Oligopeptídeos/síntese química , Peptídeo YY/química , Polietilenoglicóis/química , Receptores de Neuropeptídeo Y/agonistas , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , AMP Cíclico/biossíntese , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Peptídeo YY/farmacologia , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
Selective activation of the neuropeptide Y (NPY)2 receptor to suppress appetite provides a promising approach to obesity management. A selective NPY2 polyethylene glycol-conjugated (PEGylated) peptide agonist is described that consists of a peptide core corresponding to residues 13 to 36 of human peptide YY (PYY) and a nonpeptidic moiety (2-mercaptonicotinic acid) at the peptide N terminus that is derivatized with 20-kDa monomethoxypolyethylene glycol. The PEGylated peptide elicits a dose-dependent reduction in food intake in lean C57BL/6 mice and Wistar rats that persists for 72 and 48 h, respectively. The effect on food intake in lean C57BL/6 mice is blocked by the selective NPY2 antagonist BIIE0246 (N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide formate). A dose-dependent reduction in body weight in diet-induced obese (DIO) mice is seen following daily dosing for 14 days. The reduction in body weight is sustained following dosing for 40 days, and it is accompanied by an increase in plasma adiponectin. Improvements in glucose disposal and in plasma insulin and glucose levels that are risk factors for type II diabetes are observed following once-daily subcutaneous dosing in DIO mice. The results provide evidence from two animal species that the long-acting selective NPY2 peptide agonist has potential for obesity management.
Assuntos
Depressores do Apetite/farmacologia , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Glucose/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptídeo YY/farmacologia , Polietilenoglicóis/farmacologia , Receptores de Neuropeptídeo Y/agonistas , Adiponectina/sangue , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Benzazepinas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives (e.g., 3 and 4) were synthesized as novel melatoninergic ligands with significantly lower vasoconstrictive activity in vitro in the rat tail artery. Binding affinity assays were performed on cloned human MT1 and MT2 receptors stably expressed in NIH3T3 cells.
Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Melatonina/agonistas , Vasoconstritores/química , Vasoconstritores/farmacologia , Animais , Benzofuranos/síntese química , Clonagem Molecular , Humanos , Ligantes , Melatonina/farmacologia , Camundongos , Estrutura Molecular , Células NIH 3T3 , Ligação Proteica/efeitos dos fármacos , Ratos , Receptor MT1 de Melatonina/efeitos dos fármacos , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/efeitos dos fármacos , Receptor MT2 de Melatonina/metabolismo , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/síntese químicaRESUMO
A novel series of benzoxazole derivatives was synthesized and evaluated as melatoninergic ligands. The binding affinity of these compounds for human MT(1) and MT(2) receptors was determined using 2-[(125)I]-iodomelatonin as the radioligand. The results of the SAR studies in this series led to the identification of compound 28, which exhibited better MT(1) and MT(2) receptor affinities than melatonin itself. This work also established the benzoxazole nucleus as a melatoninergic pharmacophore, which served as an isosteric replacement to the previously established alkoxyaryl core.
Assuntos
Benzoxazóis/síntese química , Benzoxazóis/metabolismo , Melatonina/química , Melatonina/fisiologia , Receptores de Melatonina/fisiologia , Desenho de Fármacos , Humanos , Ligantes , Melatonina/metabolismo , Ligação ProteicaRESUMO
N-[2-[2-(4-Phenylbutyl)benzofuran-4-yl]cyclopropylmethyl]acetamide 3a was synthesized as an orally bioavailable agonist at MT1 and MT2 melatonin receptors with significantly low vasoconstrictive activity.
Assuntos
Acetamidas/farmacocinética , Benzofuranos/farmacocinética , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Acetamidas/síntese química , Acetamidas/toxicidade , Administração Oral , Animais , Benzofuranos/síntese química , Benzofuranos/toxicidade , Disponibilidade Biológica , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/biossíntese , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Células NIH 3T3 , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
Optimization of a benzyl piperazine pharmacophore produced N-acyl-4-indanyl-piperazines that bind with high affinity to melatonergic MT(2) receptors. (R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamide fumarate (13) is a water soluble, selective MT(2) agonist, which produces advances in circadian phase in rats at doses of 1-56 mg/kg that are no different from those of melatonin at 1 mg/kg. Unlike melatonin, 13 produced only weak contractile effects in rat tail artery.
Assuntos
Piperazinas/síntese química , Piperazinas/farmacologia , Receptores de Superfície Celular/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Células 3T3 , Adenilil Ciclases/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Piperazinas/metabolismo , Ratos , Ratos Long-Evans , Receptores de Superfície Celular/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de MelatoninaRESUMO
A series of benzoxazole derivatives was synthesized and evaluated as melatoninergic ligands. The binding affinity of these compounds for human MT(1) and MT(2) receptors was determined using 2-[(125)I]-iodomelatonin as the radioligand. From this series of benzoxazole derivatives, compounds 14 and 17 were identified as melatonin receptor agonists.
Assuntos
Benzoxazóis/síntese química , Receptores de Melatonina/agonistas , Benzoxazóis/farmacologia , Sítios de Ligação , Linhagem Celular , Desenho de Fármacos , Humanos , Ligantes , Melatonina/análogos & derivados , Melatonina/metabolismo , Ensaio Radioligante , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Melatonina/metabolismo , Relação Estrutura-AtividadeRESUMO
A new 5-HT(1A) silent antagonist 14 (5-HT(1A) IC(50)=2.2 nM) antagonizes the effects of agonists on reciprocal forepaw treading behavior, on neuronal firing in the rat dorsal raphé, and on 5-HT(1A) release in the raphé and hippocampus. While 14 alone was inactive in the social interaction paradigm, it completely reversed the social interaction activity of the serotonergic compounds (buspirone, 1, and 2).
Assuntos
Receptores Pré-Sinápticos/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacologia , Química Encefálica/efeitos dos fármacos , Buspirona/farmacologia , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Relações Interpessoais , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of fluoren-9-yl ethyl amides (2) were synthesized and evaluated for human melatonin MT(1) and MT(2) receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide (2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT(1) and MT(2) receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.
Assuntos
Fenômenos Cronobiológicos/fisiologia , Fluorenos/química , Melatonina/metabolismo , Amidas/síntese química , Amidas/farmacologia , Animais , Sítios de Ligação , Relação Dose-Resposta a Droga , Humanos , Camundongos , Células NIH 3T3 , Ensaio Radioligante , Ratos , Receptores de Melatonina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of chiral heterocyclic aminopyrrolidine derivatives was synthesized as novel melatoninergic ligands. Binding affinity assays were performed on cloned human MT(1) and MT(2) receptors, stably expressed in NIH3T3 cells. Compound 16 was identified as an orally bioavailable agonist at MT(1) and MT(2) melatonin receptors with low vasoconstrictive activity.