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BACKGROUND AND OBJECTIVE: Cases of appendicitis were identified in the pivotal randomized clinical trial on BNT162b2 mRNA vaccine and reported from coronavirus disease 2019 (COVID-19) vaccine pharmacovigilance systems. Three cohort studies and two self-controlled case series (SCCS) studies evaluating the association between mRNA vaccines and appendicitis reported discordant results. To address this uncertainty, the present study examines in a large population, with a SCCS design, the association between mRNA (BNT162b2 and mRNA-1273) and, for the first time, viral vector (ChAdOx1-S and Ad26.COV2-S) COVID-19 vaccines and acute appendicitis. METHODS: The SCCS study design was used to evaluate the association between COVID-19 vaccination and subsequent onset of acute appendicitis. The study was based on record linkage of health archives through TheShinISS application, a statistical tool that locally processes data from regional health care databases according to ad hoc, study-tailored and common data model. The study population included all vaccinated subjects ≥ 12 years old between 27 December 2020 and 30 September 2021. The acute appendicitis was identified through discharge diagnoses of hospital admissions or emergency department visits. Incident cases were defined as those who experienced a first event of acute appendicitis in the study period, excluding subjects with a diagnosis of appendicitis in the previous 5 years. Exposure was defined as the first or second dose of BNT162b2, mRNA-1273 and ChAdOx1-S and the single dose of Ad26.COV2-S. The risk interval was defined as 42 days from the first or second vaccination dose and divided into pre-specified risk subperiods; the reference period was the observation time outside the risk interval. Relative incidences (RI) and 95% confidence intervals (95% CI) were estimated with the SCCS method 'modified for event-dependent exposures', through unbiased estimating equations. The seasonal component was considered as a time-dependent covariate. RESULTS: In the 42-day risk interval 1285 incident cases of acute appendicitis occurred: 727 cases after the first dose and 558 cases after the second dose. In the main analysis, no increased risks of acute appendicitis were observed in subjects vaccinated with BNT162b, mRNA-1273, ChAdOx1-S and Ad26.COV2-S. The subgroup analyses by sex showed an increased risk in the 14-27 day risk interval, in males after the first dose of mRNA-1273 (RI of 1.71; 95% CI 1.08-2.70, p = 0.02) and in females after the single dose of Ad26.COV2-S (RI of 4.40; 95% CI 1.29-15.01, p = 0.02). CONCLUSIONS: There was no evidence of association of BNT162b, ChAdOx1-S, mRNA-1273 and Ad26.COV2-S with acute appendicitis in the general population. The results of the subgroup analyses by sex needs to be considered with caution. The multiplicity issue cannot be excluded being these hypotheses two of several hypotheses tested. In addition, relevant literature on the biological mechanism of the disease and evidence of similar effects with other vaccines or with the same vaccines are still lacking to provide strong support for a conclusion that there is an harmful effect in males and females with mRNA-1273 and Ad26.COV2-S.
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BACKGROUND: Recently published studies have reported association of COVID-19 vaccine ChAdOx1-S (Vaxzevria) with Guillain Barré Syndrome (GBS). Less is known about the safety of other COVID-19 vaccines with respect to GBS outcome. This study investigated the association of COVID-19 vaccines with GBS in more than 15 million persons aged ≥12 years in Italy. METHODS: Study population was all individuals aged ≥12 years who received at least one dose of COVID-19 vaccines, admitted to emergency care/hospital for GBS from 27 December 2020-30 September 2021 in Italy. Identification of GBS cases and receipt of at least one dose of mRNA-1273 (Elasomeran), BNT162b2 (Tozinameran), ChAdOx1-S (Vaxzevria) and Ad26.COV2.S (Janssen) through record linkage between regional health care and vaccination registries. Relative Incidence (RI) was estimated Self-controlled case series method adapted to event-dependent exposure using in the 42-day exposure risk period after each dose compared with other observation periods. RESULTS: Increased risk of GBS was found after first (RI = 6.83; 95% CI 2.14-21.85) and second dose (RI = 7.41; 2.35-23.38) of mRNA-1273 and first dose of ChAdOx1-S (RI = 6.52; 2.88-14.77). Analysis by age found an increased risk among those aged≥60 years after first (RI = 8.03; 2.08-31.03) and second dose (RI = 7.71; 2.38-24.97) of mRNA-1273. The first dose of ChAdOx1-S was associated with GBS in those aged 40-59 (RI = 4.50; 1.37-14.79) and in those aged ≥ 60 years (RI = 6.84; 2.56-18.28). CONCLUSIONS: mRNA-1273 and ChAdOx1-S vaccines were associated with an increased risk of GBS however this risk resulted in a small number of excess cases. Limitations were loss of GBS outpatient cases and imprecision of the estimates in the subgroup analysis due to a low number of events.
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Vacinas contra COVID-19 , COVID-19 , Síndrome de Guillain-Barré , Humanos , Vacina de mRNA-1273 contra 2019-nCoV , Ad26COVS1 , Vacina BNT162 , ChAdOx1 nCoV-19 , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/complicações , Vacinas contra COVID-19/efeitos adversos , Síndrome de Guillain-Barré/epidemiologia , Síndrome de Guillain-Barré/etiologia , Itália/epidemiologia , Vacinação/efeitos adversos , Vigilância de Produtos ComercializadosRESUMO
Millions of people have died because of the COVID-19 pandemic. The vaccination campaign helped tackle the pandemic and saved millions of lives. In a retrospective pharmacovigilance study, we explored the safety of the BNT162b2 (Comirnaty) vaccine among healthcare workers (HCWs) in a large Italian teaching hospital, and 2428 Adverse Events Reports (AERs) filed by HCWs after the administration of the first dose of vaccine were collected and analyzed, reporting the results quantitively and comparing them to the vaccine Summary of Product Characteristics (SPC). Spearman's correlation coefficients were computed to investigate the correlation among reported adverse effects, and recurrent clusters of symptoms were investigated through the Principal Component Analysis (PCA) and k-means Cluster Analysis. The BNT162b2 vaccine's safety profile was favorable, with predominant reports of early onset, mild, non-serious and short-term resolved symptoms. We observed higher than the expected frequency for various non-serious undesirable effects, especially among those listed and classified as less common in the SPC. Furthermore, we identified three clusters of adverse effects that were frequently reported together, defined by the presence/absence of fatigue, malaise, localized pain, chills, pyrexia, insomnia, nausea and injection site pain. Post-marketing pharmacovigilance activities, together with targeted public health interventions, can be valuable tools to promote vaccination and improve the control of the spread of the pandemic, especially in sensitive settings and populations such as hospitals and healthcare professionals.
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BACKGROUND: Myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccines administration have been reported, but their frequency is still uncertain in the younger population. This study investigated the association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines, BNT162b2, and mRNA-1273 and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years in Italy. METHODS AND FINDINGS: We conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Exposure risk period (0 to 21 days from the vaccination day, subdivided in 3 equal intervals) for first and second dose was compared with baseline period. The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose, age, sex, and vaccine product. Calendar period was included as time-varying confounder in the model. During the study period 2,861,809 persons aged 12 to 39 years received mRNA vaccines (2,405,759 BNT162b2; 456,050 mRNA-1273); 441 participants developed myocarditis/pericarditis (346 BNT162b2; 95 mRNA-1273). Within the 21-day risk interval, 114 myocarditis/pericarditis events occurred, the RI was 1.99 (1.30 to 3.05) after second dose of BNT162b2 and 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after first and second dose of mRNA-1273. During the [0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after first dose of mRNA-1273, with RI of 6.55 (2.73 to 15.72), and after second dose of BNT162b2 and mRNA-1273, with RIs of 3.39 (2.02 to 5.68) and 7.59 (3.26 to 17.65). The number of EC for second dose of mRNA-1273 was 5.5 per 100,000 vaccinated (3.0 to 7.9). The highest risk was observed in males, at [0 to 7) days after first and second dose of mRNA-1273 with RI of 12.28 (4.09 to 36.83) and RI of 11.91 (3.88 to 36.53); the number of EC after the second dose of mRNA-1273 was 8.8 (4.9 to 12.9). Among those aged 12 to 17 years, the RI was of 5.74 (1.52 to 21.72) after second dose of BNT162b2; for this age group, the number of events was insufficient for estimating RIs after mRNA-1273. Among those aged 18 to 29 years, the RIs were 7.58 (2.62 to 21.94) after first dose of mRNA-1273 and 4.02 (1.81 to 8.91) and 9.58 (3.32 to 27.58) after second dose of BNT162b2 and mRNA-1273; the numbers of EC were 3.4 (1.1 to 6.0) and 8.6 (4.4 to 12.6) after first and second dose of mRNA-1273. The main study limitations were that the outcome was not validated through review of clinical records, and there was an absence of information on the length of hospitalization and, thus, the severity of the outcome. CONCLUSIONS: This population-based study of about 3 millions of residents in Italy suggested that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years. According to our results, increased risk of myocarditis/pericarditis was associated with the second dose of BNT162b2 and both doses of mRNA-1273. The highest risks were observed in males of 12 to 39 years and in males and females 18 to 29 years vaccinated with mRNA-1273. The public health implication of these findings should be considered in the light of the proven mRNA vaccine effectiveness in preventing serious COVID-19 disease and death.
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Vacinas contra COVID-19 , COVID-19 , Miocardite , Pericardite , Vacina de mRNA-1273 contra 2019-nCoV , Adolescente , Adulto , Vacina BNT162 , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Criança , Feminino , Humanos , Itália/epidemiologia , Masculino , Miocardite/induzido quimicamente , Miocardite/epidemiologia , Pericardite/induzido quimicamente , Pericardite/epidemiologia , Vigilância de Produtos Comercializados , SARS-CoV-2 , Vacinação/efeitos adversos , Adulto JovemRESUMO
Health workers, especially those in patient-facing roles, had a significantly increased risk of COVID-19 infection, having serious outcomes, and risking spreading the virus to patients and staff. Vaccination campaign planning suggests allocating initial supplies of BNT162b2 vaccine to health workers given the importance of early protection to safeguard the continuity of care to patients. The aim of the study is to assess the effectiveness and safety of BNT162b2 vaccine among the health workers of Fondazione Policlinico Universitario Agostino Gemelli IRCCS (FPG). The retrospective cohort study was conducted among health staff working at the FPG. Vaccination data were collected from hospital records. The primary end points were vaccine effectiveness and safety. A total of 6649 health workers were included, of whom 5162 received injections. There were 14 cases of COVID-19 with onset at least 14 days after the second dose among vaccinated health workers and 45 cases among unvaccinated ones. BNT162b2 was 91.5% effective against COVID-19 (95% credible interval, 84.7% to 95.3%). The safety profile of BNT162b2 vaccine consisted of short-term, non-serious events. The promotion and boost of the COVID-19 vaccination campaign represents a key public health measure useful to curb the spread of the pandemic especially in vulnerable contexts, such as hospitals, where health workers carry out a paramount role for the entire community, and requires further protection with a possible booster dose in view of autumn-winter 2021.
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COVID-19 , Vacinas , Vacina BNT162 , Vacinas contra COVID-19 , Humanos , Programas de Imunização , Estudos Retrospectivos , SARS-CoV-2RESUMO
A 50-year-old man was admitted to the emergency department with abrupt massive epistaxis. An accurate anamnesis and physical evaluation could not reveal any other anomalies, while coagulation tests showed potentially life threatening prolonged prothrombin time, with activated partial thromboplastin and thrombin time, with fibrinogen and antithrombin III within limits. Despite the prompt pharmacological and compressive local treatment, bleeding continued and the patient was therefore hospitalized. Highly specific coagulation and toxicological testing-among others high-performance liquid chromatography assessment on plasma-were performed, leading to the unexpected identification of brodifacoum. Police and criminal justice authorities revealed the source of exposure to brodifacoum after several months of investigation, residing in his everyday life. Brodifacoum is a long-lasting anticoagulant, acting as a vitamin K antagonist, and belongs to the family of superwarfarins. Brodifacoum use is authorized as rodenticide in many countries worldwide, but has been reported as cause of severe coagulopathies in humans, both intentional or involuntary, even consumed as a contaminant of herbal drugs, such as cannabis. The original contribution of this case to the knowledges of human brodifacoum intoxication resides in the multidisciplinary approach and the collaborative interplay of clinical and toxicology experts as well as judicial authorities.
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4-Hidroxicumarinas/intoxicação , Acidentes , Anticoagulantes/intoxicação , Epistaxe/etiologia , Medicina Legal , Rodenticidas/intoxicação , 4-Hidroxicumarinas/sangue , Anticoagulantes/sangue , Cromatografia Líquida de Alta Pressão , Homicídio , Humanos , Masculino , Pessoa de Meia-Idade , Rodenticidas/sangueRESUMO
A sensor array based on heterojunctions between semiconducting organic layers and single walled carbon nanotube (SWCNT) films is produced to explore applications in breathomics, the molecular analysis of exhaled breath. The array is exposed to gas/volatiles relevant to specific diseases (ammonia, ethanol, acetone, 2-propanol, sodium hypochlorite, benzene, hydrogen sulfide, and nitrogen dioxide). Then, to evaluate its capability to operate with real relevant biological samples the array is exposed to human breath exhaled from healthy subjects. Finally, to provide a proof of concept of its diagnostic potential, the array is exposed to exhaled breath samples collected from subjects with chronic obstructive pulmonary disease (COPD), an airway chronic inflammatory disease not yet investigated with CNT-based sensor arrays, and breathprints are compared with those obtained from of healthy subjects. Principal component analysis shows that the sensor array is able to detect various target gas/volatiles with a clear fingerprint on a 2D subspace, is suitable for breath profiling in exhaled human breath, and is able to distinguish subjects with COPD from healthy subjects based on their breathprints. This classification ability is further improved by selecting the most responsive sensors to nitrogen dioxide, a potential biomarker of COPD.
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Biomarcadores , Testes Respiratórios , Doença Pulmonar Obstrutiva Crônica , Expiração , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , SemicondutoresAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/etiologia , Linfoma Folicular/complicações , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cloridrato de Bendamustina/farmacologia , Feminino , Humanos , Linfoma Folicular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab/farmacologiaRESUMO
The aim of this proof-of-concept, pilot study was the evaluation of the effects of steroid administration and suspension of an inhaled corticosteroid (ICS)-long-acting ß2-agonist (LABA) extrafine fixed dose combination (FDC) on metabolomic fingerprints in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized that a comprehensive metabolomics approach discriminates across inhaled pharmacotherapies and that their effects on metabolomic signatures depend on the biological fluids analyzed. We performed metabolomics via nuclear magnetic resonance (NMR) spectroscopy in exhaled breath condensate (EBC), sputum supernatants, serum, and urine. Fourteen patients suffering from COPD who were on regular inhaled fluticasone propionate/salmeterol therapy (visit 1) were consecutively treated with 2-week beclomethasone dipropionate/formoterol (visit 2), 4-week formoterol alone (visit 3), and 4-week beclomethasone/formoterol (visit 4). The comprehensive NMR-based metabolomics approach showed differences across all pharmacotherapies and that different biofluids provided orthogonal information. Serum formate was lower at visits 1 versus 3 (P = 0.03), EBC formate was higher at visit 1 versus 4 (P = 0.03), and urinary 1-methyl-nicotinamide was lower at 3 versus 4 visit (P = 0.002). NMR-based metabolomics of different biofluids distinguishes across inhaled pharmacotherapies, provides complementary information on the effects of an extrafine ICS/LABA FDC on metabolic fingerprints in COPD patients, and might be useful for elucidating the ICS mechanism of action.
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Doença Pulmonar Obstrutiva Crônica , Corticosteroides/uso terapêutico , Quimioterapia Combinada , Fumarato de Formoterol/uso terapêutico , Humanos , Espectroscopia de Ressonância Magnética , Metabolômica , Projetos Piloto , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
15-F2t-Isoprostane, a reliable biomarker of oxidative stress, has been found elevated in exhaled breath condensate (EBC), a non-invasive technique for sampling of airway secretions, in patients with cystic fibrosis (CF). Azithromycin has antioxidant properties in experimental models of CF, but its effects on oxidative stress in CF patients are largely unknown. Primary objective of this pilot, proof-of-concept, prospective, parallel group, pharmacological study, was investigating the potential antioxidant effects of azithromycin in CF patients as reflected by EBC 15-F2t-isoprostane. Secondary objectives included studying the effect of azithromycin on EBC and serum metabolic profiles, and on serum 15-F2t-isoprostane. In CF patients who were on maintenance treatment with oral vitamin E (200 UI once daily), treatment with oral azithromycin (250 or 500 mg depending on body weight) plus vitamin E (400 UI once daily) (group A) (n = 24) or oral vitamin E alone (400 UI once daily) (group B) (n = 21) was not associated with changes in EBC 15-F2t-isoprostane concentrations compared with baseline values after 8-weeks treatment or 2 weeks after treatment suspension. There was no between-group difference in post-treatment EBC 15-F2t-isoprostane. Likewise, no within- or between-group differences in serum 15-F2t-isoprostane concentrations were observed in either study group. NMR spectroscopy-based metabolomics of EBC shows that suspension of both azithromycin plus vitamin E and vitamin E alone has a striking effect on metabolic profiles in EBC. Between-group comparisons show that EBC metabolite distribution after treatment and 2 weeks after treatment suspension is different. Quantitative differences in ethanol, saturated fatty acids, acetate, acetoin/acetone, and methanol are responsible for these differences. Our study was unable to show antioxidant effect of azithromycin as add-on treatment with doubling the dose of oral vitamin E as reflected by 15-F2t-isoprostane concentrations in EBC. Add-on therapy with azithromycin itself does not induce EBC metabolite changes, but its suspension is associated with EBC metabolic profiles that are different from those observed after vitamin E suspension. The pathophysiological and therapeutic implications of these findings in patients with stable CF are unknown and require further research. Preliminary data suggest that EBC NMR-based metabolomics might be used for assessing the effects of pharmacological treatment suspension in stable CF patients.
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Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting ß2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics. Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 µg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 µg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 µg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 µg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured. Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25-75% and FEV1/FVC (P = 0.008-0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01). Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42.
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INTRODUCTION: Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.
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Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/administração & dosagem , Administração por Inalação , Animais , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacologia , Preparações de Ação Retardada , Desenvolvimento de Medicamentos/métodos , Humanos , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tropanos/efeitos adversos , Tropanos/farmacologiaRESUMO
Maintenance pharmacological treatment for stable chronic obstructive pulmonary disease (COPD) is based on inhaled drugs, including long-acting muscarinic receptor antagonists (LAMA), long-acting ß2-adrenoceptor agonists (LABA) and inhaled corticosteroids (ICS). Inhaled pharmacological treatment can improve patients' daily symptoms and reduce decline of pulmonary function and acute exacerbation rate. Treatment with all three inhaled drug classes is reserved for selected, more severe, patients with COPD when symptoms are not sufficiently controlled by dual LABA/LAMA therapy and exacerbations are frequent. This review focuses on the role of single-inhaler triple therapy with once-daily fluticasone furoate/umeclidinium/vilanterol fixed-dose combination, which is in phase III clinical development for maintenance treatment of severe-to-very severe COPD. In this review, we summarize evidence providing the rationale for its use in COPD and discuss the gaps to be filled in this pharmacotherapeutic area.
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Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Androstadienos/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Glucocorticoides/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Androstadienos/efeitos adversos , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Combinação de Medicamentos , Medicina Baseada em Evidências , Glucocorticoides/efeitos adversos , Humanos , Pulmão/fisiopatologia , Antagonistas Muscarínicos/efeitos adversos , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinuclidinas/efeitos adversos , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Obese patients have vascular dysfunction related to impaired insulin-stimulated vasodilation and increased endothelin-1-mediated vasoconstriction. In contrast to the harmful vascular actions of angiotensin (Ang) II, the angiotensin-converting enzyme 2 product Ang-(1-7) has shown to exert cardiovascular and metabolic benefits in experimental models through stimulation of the Mas receptor. We, therefore, examined the effects of exogenous Ang-(1-7) on vasodilator tone and endothelin-1-dependent vasoconstriction in obese patients. Intra-arterial infusion of Ang-(1-7) (10 nmol/min) resulted in significant increase in unstimulated forearm flow (P=0.03), an effect that was not affected by the Mas receptor antagonist A779 (10 nmol/min; P>0.05). In the absence of hyperinsulinemia, however, forearm flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during Ang-(1-7) administration compared with saline (both P>0.05). During infusion of regular insulin (0.15 mU/kg per minute), by contrast, endothelium-dependent vasodilator response to acetylcholine was significantly enhanced by Ang-(1-7) (P=0.04 versus saline), whereas endothelium-independent response to sodium nitroprusside was not modified (P=0.91). Finally, Ang-(1-7) decreased the vasodilator response to endothelin A receptor blockade (BQ-123; 10 nmol/min) compared with saline (6±1% versus 93±17%; P<0.001); nitric oxide inhibition by l-N-monomethylarginine (4 µmol/min) during concurrent endothelin A antagonism resulted in similar vasoconstriction in the absence or presence of Ang-(1-7 Ang-(1-7) (P=0.69). Our findings indicate that in obese patients Ang-(1-7) has favorable effects not only to improve insulin-stimulated endothelium-dependent vasodilation but also to blunt endothelin-1-dependent vasoconstrictor tone. These findings provide support for targeting Ang-(1-7) to counteract the hemodynamic abnormalities of human obesity.
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Angiotensina I/metabolismo , Endotelina-1/metabolismo , Insulina , Obesidade , Fragmentos de Peptídeos/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasoconstrição , Vasodilatação , Adulto , Feminino , Antebraço/irrigação sanguínea , Humanos , Insulina/metabolismo , Insulina/farmacocinética , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/fisiopatologia , Receptor de Endotelina A/metabolismo , Fluxo Sanguíneo Regional/fisiologia , Estatística como Assunto , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologiaRESUMO
Patients with central obesity have impaired insulin-stimulated vasodilation and increased ET-1 (endothelin 1) vasoconstriction, which may contribute to insulin resistance and vascular damage. Apelin enhances insulin sensitivity and glucose disposal but also acts as a nitric oxide (NO)-dependent vasodilator and a counter-regulator of AT1 (angiotensin [Ang] II type 1) receptor-induced vasoconstriction. We, therefore, examined the effects of exogenous (Pyr1)apelin on NO-mediated vasodilation and Ang II- or ET-1-dependent vasoconstrictor tone in obese patients. In the absence of hyperinsulinemia, forearm blood flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during saline or apelin administration (both P>0.05). During intra-arterial infusion of regular insulin, however, apelin enhanced the vasodilation induced by both acetylcholine and nitroprusside (both P<0.05). Interestingly, the vasodilator effect of concurrent blockade of AT1 (telmisartan) and AT2 (PD 123,319) receptors was blunted by apelin (3±5% versus 32±9%; P<0.05). Similarly, during apelin administration, blockade of ETA receptors (BQ-123) resulted in lower vasodilator response than during saline (23±10% versus 65±12%; P<0.05). NO synthase inhibition by L-NMMA (l-N-monometylarginine) during the concurrent blockade of either Ang II or ETA receptors resulted in similar vasoconstriction in the absence or presence of apelin (P>0.05). In conclusion, in patients with central obesity, apelin has favorable effects not only to improve insulin-stimulated endothelium-dependent and endothelium-independent vasodilator responses but also to blunt Ang II- and ET-1-dependent vasoconstriction by a mechanism not involving NO. Taken together, our results suggest that targeting the apelin system might favorably impact some hemodynamic abnormalities of insulin-resistant states like obesity.
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Anexinas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Obesidade/fisiopatologia , Vasodilatação/efeitos dos fármacos , Acetilcolina/farmacologia , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Apelina , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Feminino , Antebraço/irrigação sanguínea , Humanos , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Piridinas/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Telmisartan , ômega-N-Metilarginina/farmacologiaRESUMO
Obese patients have impaired vasodilator reactivity and increased endothelin 1 (ET-1)-mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)-dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1-dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating doses of obestatin resulted in a progressive increase in blood flow from baseline (both P < 0.001). This vasodilation was predominantly mediated by enhanced NO activity, because NG-monomethyl-l-arginine markedly blunted the flow response to obestatin in both groups (both P < 0.05 vs. saline). In obese subjects, antagonism of ETA receptors by BQ-123 increased forearm flow during saline (P < 0.001) but did not induce additional vasodilation (P > 0.05) during obestatin. Circulating obestatin levels were not different between lean and obese participants (P = 0.41). Our findings indicate that obestatin causes NO-dependent vasodilation in the human circulation. This effect is preserved in obesity, where it is accompanied by reduced ET-1-mediated vasoconstriction. These latter observations make obestatin a promising target for vascular prevention in obesity and diabetes.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Grelina/farmacologia , Obesidade Abdominal , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-1 , Inibidores Enzimáticos/farmacologia , Feminino , Antebraço/irrigação sanguínea , Humanos , Masculino , Óxido Nítrico/metabolismo , Peptídeos Cíclicos/farmacologia , ômega-N-Metilarginina/farmacologiaRESUMO
INTRODUCTION: Dupilumab (REGN668/SAR231893), produced by a collaboration between Regeneron and Sanofi, is a monoclonal antibody currently in phase III for moderate-to-severe asthma. Dupilumab is directed against the α-subunit of the interleukin (IL)-4 receptor and blocks the IL-4 and IL-13 signal transduction. Areas covered: Pathophysiological role of IL-4 and IL-13 in asthma; mechanism of action of dupilumab; pharmacology of IL-4 receptor; phase I and phase II studies with dupilumab; regulatory affairs. Expert opinion: Patients with severe asthma who are not sufficiently controlled with standard-of-care represent the target asthma population for dupilumab. If confirmed, efficacy of dupilumab in both eosinophilic and non-eosinophilic severe asthma phenotype might represent an advantage over approved biologics for asthma, including omalizumab, mepolizumab, and reslizumab. Head-to-head studies to compare dupilumab versus other biologics with different mechanism of action are required. Pediatric studies with dupilumab are currently lacking and should be undertaken to assess efficacy and safety of this drug in children with severe asthma. The lack of preclinical data and published results of the completed four phase I studies precludes a complete assessment of the pharmacological profile of dupilumab. Dupilumab seems to be generally well tolerated, but large studies are required to establish its long-term safety and tolerability.
Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Antiasmáticos/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Asma/fisiopatologia , Humanos , Interleucina-13/imunologia , Interleucina-4/imunologia , Índice de Gravidade de DoençaRESUMO
Combining individual drugs in a single inhaler is the most convenient way to deliver triple therapy. A long-acting muscarinic receptor antagonist (LAMA) added to an inhaled corticosteroid (ICS)/long-acting ß2-adrenoceptor agonist (LABA) fixed-dose combination (FDC) can improve efficacy of pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). New inhaled ICS/LABA/LAMA FDCs, including fluticasone furoate/vilanterol/umeclidinium, budesonide/formoterol/glycopyrronium and beclometasone/formoterol/glycopyrronium, are in Phase III of clinical development for COPD. Triple inhaled therapy might be particularly useful in patients with severe to very severe COPD, above all in those with peripheral blood or sputum eosinophilia, asthma-COPD overlap syndrome (ACOS) or frequent exacerbators. Future prospective studies should assess efficacy and safety of triple ICS/LABA/LAMA therapy in selected COPD phenotypes.