RESUMO
BACKGROUND: This phase 3 trial assessed AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis against symptomatic coronavirus disease 2019 (COVID-19). METHODS: Adults without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2-infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab) or placebo. Primary end points were safety and first post-dose SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR)-positive symptomatic COVID-19 event before day 183. RESULTS: A total of 1121 participants were randomized and dosed (AZD7442, n = 749; placebo, n = 372). Median (range) follow-up was 49 (5-115) and 48 (20-113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162 of 749 (21.6%) and 111 of 372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR-positive symptomatic COVID-19 occurred in 23 of 749 (3.1%) and 17 of 372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction, 33.3%; 95% confidence interval [CI], -25.9 to 64.7; P = .21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR-negative (n = 974, 87%) or missing an RT-PCR result (n = 99, 9%) at baseline, AZD7442 reduced RT-PCR-positive symptomatic COVID-19 by 73.2% (95% CI, 27.1 to 90.1) vs placebo. CONCLUSIONS: This study did not meet the primary efficacy end point of post-exposure prevention of symptomatic COVID-19. However, analysis of participants who were SARS-CoV-2 RT-PCR-negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19. Clinical Trials Registration. NCT04625972.
Assuntos
COVID-19 , Adulto , Humanos , COVID-19/prevenção & controle , SARS-CoV-2 , Profilaxia Pós-Exposição , Vacinas contra COVID-19RESUMO
Acetylcholinesterase (AChE) is one of the classical targets in the treatment of Alzheimer's disease (AD). Inhibition of AChE slows down the hydrolysis of acetycholine and increases choline levels, improving the cognitive function. The achieved success of plant-based natural drugs acting as AChE inhibitors, such as galantamine (GAL) from Galanthus genus and huperzine A from Huperzia serrate (approved drug in China), in the treatment of AD, and the fact that natural compounds (NCs) are considered as safer and less toxic compared to synthetic drugs, led us to screen the available NCs (almost 150,000) in the ZINC12 database for AChE inhibitory activity. The compounds were screened virtually by molecular docking, filtered for suitable ADME properties, and 32 ligands from 23 structural groups were selected. The stability of the complexes was estimated via 1 µs molecular dynamics simulation. Ten compounds formed stable complexes with the enzyme and had a vendor and a reasonable price per mg. They were tested for AChE inhibitory and antioxidant activity. Five compounds showed weak AChE inhibition and three of them exhibited high antioxidant activity.
Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Inibidores da Colinesterase/química , Galantamina/farmacologia , Humanos , Simulação de Acoplamento MolecularRESUMO
BACKGROUND: In patients with mild asthma, as-needed use of an inhaled glucocorticoid plus a fast-acting ß2-agonist may be an alternative to conventional treatment strategies. METHODS: We conducted a 52-week, double-blind trial involving patients 12 years of age or older with mild asthma. Patients were randomly assigned to one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide-formoterol (200 µg of budesonide and 6 µg of formoterol) used as needed (budesonide-formoterol group), or twice-daily budesonide (200 µg) plus terbutaline used as needed (budesonide maintenance group). The primary objective was to investigate the superiority of as-needed budesonide-formoterol to as-needed terbutaline with regard to electronically recorded weeks with well-controlled asthma. RESULTS: A total of 3849 patients underwent randomization, and 3836 (1277 in the terbutaline group, 1277 in the budesonide-formoterol group, and 1282 in the budesonide maintenance group) were included in the full analysis and safety data sets. With respect to the mean percentage of weeks with well-controlled asthma per patient, budesonide-formoterol was superior to terbutaline (34.4% vs. 31.1% of weeks; odds ratio, 1.14; 95% confidence interval [CI], 1.00 to 1.30; P=0.046) but inferior to budesonide maintenance therapy (34.4% and 44.4%, respectively; odds ratio, 0.64; 95% CI, 0.57 to 0.73). The annual rate of severe exacerbations was 0.20 with terbutaline, 0.07 with budesonide-formoterol, and 0.09 with budesonide maintenance therapy; the rate ratio was 0.36 (95% CI, 0.27 to 0.49) for budesonide-formoterol versus terbutaline and 0.83 (95% CI, 0.59 to 1.16) for budesonide-formoterol versus budesonide maintenance therapy. The rate of adherence in the budesonide maintenance group was 78.9%. The median metered daily dose of inhaled glucocorticoid in the budesonide-formoterol group (57 µg) was 17% of the dose in the budesonide maintenance group (340 µg). CONCLUSIONS: In patients with mild asthma, as-needed budesonide-formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide-formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy. (Funded by AstraZeneca; SYGMA 1 ClinicalTrials.gov number, NCT02149199 .).
Assuntos
Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Budesonida/administração & dosagem , Fumarato de Formoterol/administração & dosagem , Terbutalina/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Idoso , Broncodilatadores/efeitos adversos , Budesonida/efeitos adversos , Criança , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol/efeitos adversos , Glucocorticoides/administração & dosagem , Humanos , Quimioterapia de Manutenção , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Inquéritos e Questionários , Terbutalina/efeitos adversos , Adulto JovemRESUMO
Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer's disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aß) oligomers and inhibits the formation of Aß plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/síntese química , Curcumina/química , Galantamina/síntese química , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Técnicas de Química Combinatória , Galantamina/química , Galantamina/farmacologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Networks of biological molecules are key to cellular function, governing processes ranging from signal cascade propagation to metabolic pathway regulation. Genetic duplication processes give rise to sets of regulatory proteins that have evolved from a common ancestor, leading to interactomes whose dysregulation is often associated with disease. A better understanding of the determinants of specificity at interfaces shared by functionally related proteins is crucial to the rational design of novel pharmacotherapeutic agents. To this end, a comprehensive data set of drug and drug-like binders was assembled for the Bcl-xL and Bcl-2 antiapoptotic proteins-archetypal examples of regulatory systems governed by evolutionarily conserved protein-protein interactions. These were first used to derive a two-dimensional quantitative structure-activity relationship (2D QSAR) model, predicting ligand specificity for these homologous proteins. The strengths and weaknesses of high-throughput 2D QSAR were then compared and contrasted to those of theoretically rigorous thermodynamic integration calculations performed on 14 complexes of Bcl-xL-specific, Bcl-2-specific, and potent dual binders bound to the Bcl-xL and Bcl-2 proteins. We demonstrate that free energy calculations provide an added layer of essential information, which traditional QSAR cannot capture. Moreover, we show that protein energetic responses to different ligands, expressed as per-residue energy values, can be used to fingerprint the protein-ligand interaction, extending the framework of four-dimensional molecular dynamics/quantitative structure-activity relationships (4D-MD/QSAR) toward the facilitation of future drug design strategies.
Assuntos
Apoptose , Simulação de Dinâmica Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína bcl-X/metabolismo , Ligantes , Ligação Proteica , Conformação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/química , Relação Quantitativa Estrutura-Atividade , Termodinâmica , Proteína bcl-X/químicaRESUMO
It is uncertain whether phenotypes of asthma and chronic obstructive pulmonary disease (COPD) vary between populations with different genetic and environmental characteristics. Here, our objective was to compare the phenotypes of airways disease in two separate populations.This was a cross-sectional observational study in adult populations from New Zealand and China. Participants aged 40-75â years who reported wheeze and breathlessness in the last 12â months were randomly selected from the general population and underwent detailed characterisation. Complete data for cluster analysis were available for 345 participants. Hierarchical cluster analysis was undertaken, based on 12 variables: forced expiratory volume in 1â s (FEV1), FEV1/forced vital capacity ratio, bronchodilator reversibility, peak expiratory flow variability, transfer coefficient of the lung for carbon monoxide, exhaled nitric oxide fraction, total IgE, C-reactive protein, age of symptom onset, body mass index, health status and cigarette smoke exposure.Cluster analysis of the combined dataset described five phenotypes: "severe late-onset asthma/COPD overlap group", "moderately severe early-onset asthma/COPD overlap group", "moderate to severe asthma group with type 2 predominant disease", and two groups with minimal airflow obstruction, differentiated by age of onset. Separate analyses by country showed similar patterns; however, a distinct obese/comorbid group was observed in the New Zealand population.Cluster analysis of adults with symptomatic airways disease suggests the presence of similar asthma/COPD overlap phenotypes within populations with different genetic and environmental characteristics, and an obese/comorbid phenotype in a Western population.
Assuntos
Asma/epidemiologia , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Idoso , Asma/fisiopatologia , Broncodilatadores/uso terapêutico , China , Análise por Conglomerados , Comorbidade , Estudos Transversais , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Obesidade/epidemiologia , Fenótipo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Capacidade VitalRESUMO
Leiomyomas of the Fallopian tubes are rare and their correct diagnosis is extremely difficult. Usually they are incidental findings seen at autopsy or unrelated surgical procedures: A 34-year-old woman presented with lower abdominal pain. Transvaginal ultrasound revealed a solid 7 cm extrauterine mass. Both ovaries are normal. Our preoperative diagnosis was torsion of the fallopian tube due intratubal leiomyoma. Laparoscopic surgery was performed and the leiomyoma was found to have originated from the isthmus of the right Fallopian tube. Laparoscopic myomectomy was performed with preservation of the ramus tubarius dextra. The histological examination concluded to a leiomyoma with ischemic changes. We report a case of torsion of a tubal leiomyoma, which was successfully managed laparoscopically.
Assuntos
Neoplasias das Tubas Uterinas/cirurgia , Tubas Uterinas/cirurgia , Leiomioma/cirurgia , Dor Abdominal , Adulto , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/patologia , Feminino , Humanos , Laparoscopia , Leiomioma/patologiaRESUMO
Laparoscopic myomectomy and total laparoscopic hysterectomy are challenging surgical procedures for gynecologists, which can result in great blood loss. Most of the conversions to laparotomy happened because of intraoperative bleeding. Blocking uterine perfusion during,, Class II" laparoscopic procedures is valuable and feasible for the management of our patients. We present our modification of uterine artery identification and clipping.
Assuntos
Laparoscopia/métodos , Artéria Uterina , Miomectomia Uterina/métodos , Útero/cirurgia , Feminino , Humanos , Histerectomia/métodos , Artéria Uterina/cirurgia , Útero/irrigação sanguíneaRESUMO
Uterine myoma is the most frequent benign tumor of female organs. Intraligamentary myomas in the broad ligament are rare. We present a case of 50 years old patient with 22 cm intraligamentary myoma with cystic degeneration, who is referred to the Gynecological Department of Ob/Gyn Hospital "Dr. Shterev" with complains of severe pain. This case is interesting for its rareness and diagnostic dilemma, because degenerative myomas can imitate malignant mass. Total laparoscopic hysterectomy with ablastic vaginal morcellation of the specimen in endobag was performed. The patient was discharged from the clinic next day.
Assuntos
Laparoscopia , Leiomioma/cirurgia , Neoplasias Uterinas/cirurgia , Útero/cirurgia , Feminino , Humanos , Histerectomia , Leiomioma/patologia , Pessoa de Meia-Idade , Miomectomia Uterina , Neoplasias Uterinas/patologia , Útero/patologiaRESUMO
Genuine urinary stress incontinence (GUSI) is defined by the International Continence Society (ICS) as involuntary loss of urine coincident with increased intra-abdominal pressure in the absence of a detrusor contraction or an over-distended bladder. If the patient demonstrates a cystocele secondary to a paravaginal defect, a paravaginal defect repair should be performed before the colposuspension. The laparoscopic retropubic colposuspension gained popularity because of its reported advantages of improved visualization, shorter hospital stay, faster recovery and decreased blood loss. A review of our experience revealed 11 of 24 patients had a Burch urethropexy and paravaginal repair and 13 of 24 a Burch urethropexy alone. Average operative time was 80 min, estimated blood loss of less than 50 ml and hospital stays less than 48 h.
Assuntos
Colposcopia , Laparoscopia , Incontinência Urinária por Estresse/complicações , Incontinência Urinária por Estresse/cirurgia , Procedimentos Cirúrgicos Urológicos , Perda Sanguínea Cirúrgica , Colposcopia/métodos , Feminino , Humanos , Laparoscopia/métodos , Tempo de Internação , Procedimentos Cirúrgicos Urológicos/métodos , Vagina/patologia , Vagina/cirurgiaRESUMO
Lymphadenectomy has traditionally been performed using large incisions during laparotomy. Since the initial report by Dargent and colleagues in the late 1980s, laparoscopic lymphadenectomy has been utilized in the management of gynecologic malignancies. After Dargent's description of the first pelvic lymphadenectomy performed laparoscopically, Nezhat et al. described the first para-aortic lymphadenectomy performed laparoscopically forcancer of the uterine cervix. Many raports since have described the safety and effectiveness of laparoscopic lymphadenectomy for gynecologic malignancies.
Assuntos
Neoplasias do Endométrio/diagnóstico , Endométrio/patologia , Laparoscopia , Excisão de Linfonodo , Linfonodos/cirurgia , Pelve/cirurgia , Feminino , Humanos , Laparoscopia/métodos , Excisão de Linfonodo/métodosRESUMO
OBJECTIVE: To evaluate the differences in the intraoperative blood loss during laparoscopic myomectomy with or without uterine artery clipping (UAC). METHODS: From January 2013 to April 2015, we enrolled prospectively 119 women with symptomatic intramural myomas who were scheduled to undergo laparoscopic myomectomy (37 with UAC (study group) and 82 without (control group)). RESULTS: Characteristics of the myomas, operating time, duration of hospital stay and blood loss were comparable between the two groups. The average operating time and blood loss were 75 +/- 11 minutes and 100 +/- 20 ml for the experimental group and 60 +/- 9 minutes and 178 +/- 56 ml for the control group respectively statistically significant. CONCLUSION: Concurrent UAC during laparoscopic myomectomy reduces the intraoperative blood loss and the frequency of excessive bleeding. This study demonstrated the superiority of laparoscopic uterine artery ligation combined with myomectomy in treatment of symptomatic myomas.
Assuntos
Perda Sanguínea Cirúrgica , Laparoscopia/métodos , Leiomioma/cirurgia , Artéria Uterina/cirurgia , Miomectomia Uterina/métodos , Neoplasias Uterinas/cirurgia , Útero/cirurgia , Adulto , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Duração da Cirurgia , Miomectomia Uterina/efeitos adversosRESUMO
Uterine leiomyomas are one of the most common benign smooth muscle tumors in women, with a prevalence of 20 to 40% in women over the age of 35 years. Fifty percent of them may necessitate treatment, because of bleeding, pelvic pain and infertility. Laparoscopic myomectomy is one of the treatment options. The major concern of myomectomy either by open procedure or by laparoscopy is the bleeding encountered during the operation. One of the methods to reduce the intraoperative blood loss and to prevent excessive bleeding is the clipping of both uterine arteries and aa. ovaricae.
Assuntos
Leiomioma/cirurgia , Artéria Uterina/cirurgia , Miomectomia Uterina/métodos , Neoplasias Uterinas/cirurgia , Útero/cirurgia , Perda Sanguínea Cirúrgica , Feminino , Humanos , Laparoscopia/métodosRESUMO
A great number operative techniques for correction of retroverted uterus are reported in the last years. The aim of these different methods is correction of the retroversion of the uterus, which is connected with pelvic congestion and symptomatic relief. We present a clinical case of 26 years old patient with one Caesarean section. The lady complains of chronic pelvic pain, dispareunia and dismenorrhea. The US exam shows an uterus in strong retroversion position. We restored the anatomic position of the uterus using laparoscopic anterior ligementopexy.
Assuntos
Doenças Uterinas/cirurgia , Útero/cirurgia , Adulto , Cesárea , Dismenorreia/complicações , Feminino , Humanos , Laparoscopia/métodos , Dor Pélvica/complicações , Resultado do Tratamento , Doenças Uterinas/complicações , Doenças Uterinas/patologia , Útero/patologiaRESUMO
BACKGROUND AND OBJECTIVE: To evaluate the efficacy and tolerability of budesonide/formoterol as maintenance and reliever therapy versus budesonide/formoterol maintenance plus terbutaline in adults with persistent asthma not adequately controlled with inhaled corticosteroid (ICS) therapy alone. METHODS: In this 12-month, randomized, double-blind, parallel-group, phase III study (NCT00839800), patients (age ≥ 16 years; receiving maintenance ICS; ≥ 1 severe exacerbation in the 12 months prior to study entry) were randomized to either budesonide/formoterol 160/4.5 µg 1 inhalation twice daily plus budesonide/formoterol 160/4.5 µg as-needed or budesonide/formoterol 160/4.5 µg 1 inhalation twice daily plus terbutaline 0.4 mg as-needed for 12 months. PRIMARY OUTCOME: time to first severe asthma exacerbation; secondary outcomes included: lung function, asthma symptom variables and tolerability. RESULTS: Two thousand and ninety-one patients were randomized: 170 (16%) receiving budesonide/formoterol maintenance and reliever therapy experienced 259 severe exacerbations versus 229 patients (22%) receiving budesonide/formoterol plus terbutaline who experienced 363 severe exacerbations. Budesonide/formoterol maintenance and reliever therapy prolonged the time to first severe exacerbation versus budesonide/formoterol plus terbutaline (P = 0.0007) and reduced the instantaneous risk of an exacerbation by 30% (hazard ratio 0.70, 95% confidence interval 0.57-0.85, P = 0.0003). Times to first oral steroid use, first hospitalization and first emergency room treatment were all significantly prolonged in the budesonide/formoterol maintenance and reliever group versus budesonide/formoterol plus terbutaline. Both treatment groups were well tolerated. CONCLUSIONS: Budesonide/formoterol maintenance and reliever therapy provided more effective asthma control, including a prolonged time to first severe asthma exacerbation, than budesonide/formoterol plus terbutaline and was well tolerated. Budesonide/formoterol maintenance and reliever therapy also improved lung function and asthma symptoms.
Assuntos
Asma/tratamento farmacológico , Asma/fisiopatologia , Broncodilatadores/uso terapêutico , Budesonida/uso terapêutico , Etanolaminas/uso terapêutico , Terbutalina/uso terapêutico , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Adulto , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacologia , Budesonida/administração & dosagem , Budesonida/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Etanolaminas/administração & dosagem , Etanolaminas/farmacologia , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Fumarato de Formoterol , Humanos , Estudos Longitudinais , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Terbutalina/administração & dosagem , Terbutalina/farmacologia , Falha de Tratamento , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON). METHODS: We conducted an international multicenter retrospective study evaluating the outcomes of ON following PLEX. Outcomes were compared to raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset. RESULTS: A total of 395 ON attack treated with PLEX from 317 patients were evaluated. The median age was 37 years (range 9-75), and 71% were female. Causes of ON included multiple sclerosis (108), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (92), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (75), seronegative-NMOSD (34), idiopathic (83), and other (3). Median time from onset of vision loss to PLEX was 2.6 weeks (interquartile range [IQR], 1.4-4.0). Median visual acuity (VA) at the time of PLEX was count fingers (IQR, 20/200-hand motion), and median final VA was 20/25 (IQR, 20/20-20/60) with no differences among etiologies except MOGAD-ON, which had better outcomes. In 81 (20.5%) ON attacks, the final VA was 20/200 or worse. Patients with poor outcomes were older (P = .002), had worse VA at the time of PLEX (P < .001), and longer delay to PLEX (P < .001). In comparison with the ONTT subset with severe corticosteroid-unresponsive ON, a final VA of worse than 20/40 occurred in 6 of 50 (12%) PLEX-treated ON vs 7 of 19 (37%) from the ONTT treated with intravenous methylprednisolone without PLEX (P = .04). CONCLUSION: Most ON attacks improved with PLEX, and outcomes were better than attacks with similar severity in the ONTT. The presence of severe vision loss at nadir, older age, and longer delay to PLEX predicted a worse outcome whereas MOGAD-ON had a more favorable prognosis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Assuntos
Neuromielite Óptica , Neurite Óptica , Humanos , Feminino , Masculino , Troca Plasmática , Estudos Retrospectivos , Glicoproteína Mielina-Oligodendrócito , Neurite Óptica/terapia , Transtornos da Visão/terapia , AutoanticorposRESUMO
RATIONALE: Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), and there is currently no satisfactory therapy to treat people with COPD. We have previously shown that granulocyte/macrophage colony-stimulating factor (GM-CSF) regulates lung innate immunity to LPS through Akt/Erk activation of nuclear factor-kappaB and activator protein (AP)-1. OBJECTIVES: The aim of this study was to determine whether neutralization of GM-CSF can inhibit cigarette smoke-induced lung inflammation in vivo. METHODS: Male BALB/c mice were exposed to cigarette smoke generated from 9 cigarettes per day for 4 days. Mice were treated intranasally with 100 microg 22E9 (anti-GM-CSF mAb) and isotype control antibody on Days 2 and 4, 1 hour before cigarette smoke or sham exposure. On the fifth day mice were killed, and the lungs were lavaged with PBS and then harvested for genomic and proteomic analysis. MEASUREMENTS AND MAIN RESULTS: Cigarette smoke-exposed mice treated with anti-GM-CSF mAb had significantly less BALF macrophages and neutrophils, whole lung TNF-alpha, macrophage inflammatory protein (MIP)-2, and matrix metalloproteinase (MMP)-12 mRNA expression and lost less weight compared with smoke-exposed mice treated with isotype control. In contrast, smoke-induced increases in MMP-9 and net gelatinase activity were unaffected by treatment with anti-GM-CSF. In addition, neutralization of GM-CSF did not affect the phagocytic function of alveolar macrophages. CONCLUSIONS: GM-CSF is a key mediator in smoke-induced airways inflammation, and its neutralization may have therapeutic implications in diseases such as COPD.
Assuntos
Anticorpos Neutralizantes/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Pneumonia/prevenção & controle , Fumar/imunologia , Animais , Imunidade Inata , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/imunologiaRESUMO
Research Summary: We administered a survey experiment to a national sample of 1068 U.S. adults in April 2020 to determine the factors that shape support for various policing tactics in the midst of the COVID-19 pandemic. Respondents were sharply divided in their views about pandemic policing tactics and were least supportive of policies that might limit public access to officers or reduce crime deterrence. Information about the health risks to officers, but not to inmates, significantly increased support for "precautionary" policing, but not for "social distance" policing. The information effect was modest, but may be larger if the information came from official sources and/or was communicated on multiple occasions. Other factors that are associated with attitudes toward pandemic policing include perceptions of procedural justice, altruistic fear, racial resentment, and authoritarianism. Policy Implications: When considered together with other evidence, one clear takeaway from our study is that the public values police patrols and wants officers on call, even during pandemics. Another is that people who believe the police are procedurally just are more willing to trust officers in times of crisis and to empower them to enforce new laws, such as social distancing ordinances. Our results thus support continued procedural justice training for officers. A third takeaway is that agencies must proactively communicate with the public about the risks their officers face when responding to public health crises or natural disasters, in addition to how they propose to mitigate those risks. They must also be amenable to adjusting in response to community feedback.
RESUMO
BACKGROUND: Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta2-agonists, similar to the reduction with maintenance budesonide. OBJECTIVE: This post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents. METHODS: SYGMA 1 and 2 were 52-week, double-blind studies (NCT022149199; NCT02224157) in patients 12 years or older with mild asthma. Patients were randomized to twice-daily placebo + as-needed BUD-FORM 200/6 µg, twice-daily BUD 200 µg + as-needed terbutaline (BUD maintenance), or twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to <18 years). RESULTS: Severe exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P = .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P = .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to <14 years was significantly greater with as-needed BUD-FORM (4.8 cm) versus BUD maintenance (3.9 cm) (pooled: P < .046), and was similar between as-needed BUD-FORM (4.5 cm) and as-needed terbutaline (4.1 cm) (SYGMA 1: P = .500). No new or unexpected safety concerns were identified. CONCLUSIONS: In adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment.
Assuntos
Asma , Budesonida , Administração por Inalação , Adolescente , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Budesonida/uso terapêutico , Combinação Budesonida e Fumarato de Formoterol/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Fumarato de Formoterol/uso terapêutico , Humanos , Terbutalina/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: Budesonide-formoterol taken as needed is an emerging treatment for mild asthma. OBJECTIVE: We used data from the SYGMA studies to assess the safety of As-needed budesonide-formoterol compared with As-needed terbutaline and compared with maintenance budesonide. METHODS: SYGMA 1 and 2 were 52-week, double-blind, parallel-group studies in patients aged ≥ 12 years with physician-assessed mild asthma. Patients were randomized to As-needed budesonide-formoterol 200/6 µg, twice-daily budesonide 200 µg as maintenance plus As-needed terbutaline 0.5 mg, and As-needed terbutaline 0.5 mg (SYGMA 1 only). Adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs (DAEs), and study-defined asthma-related discontinuations from corresponding treatment groups in both studies were pooled. SYGMA 1 data were used for comparisons with As-needed terbutaline alone. RESULTS: The pooled analysis included 3366 patients in the As-needed budesonide-formoterol group and 3369 in the budesonide maintenance group, with AEs in 40.8% and 42.5% of patients, respectively. Common AEs included viral upper respiratory tract infection (viral URTI) and URTI. SAE, DAE, and asthma-related discontinuation rates were similar with As-needed budesonide-formoterol and maintenance budesonide. Potential local and systemic corticosteroid class effects were reported in ≤ 1% of patients for each budesonide-containing regimen. In SYGMA 1, AEs were more common in the As-needed terbutaline (n = 1277) than As-needed budesonide-formoterol (n = 1277) groups (42.7 vs. 38.0%), as were DAEs (2.9 vs. 0.8%) and asthma-related discontinuations (1.6 vs. 0.3%). CONCLUSIONS: Budesonide-formoterol anti-inflammatory reliever therapy is generally well-tolerated in patients with mild asthma and has a safety profile similar to that of daily budesonide. No new safety signals were identified. CLINICALTRIAL. GOV IDENTIFIERS: NCT02149199 (SYGMA 1) and NCT02224157 (SYGMA 2).