Postmarketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12 to 39 years in Italy: A multi-database, self-controlled case series study.

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.

NMR-Based Metabolomics for the Assessment of Inhaled Pharmacotherapy in Chronic Obstructive Pulmonary Disease Patients.

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.

Vasodilator responses and endothelin-dependent vasoconstriction in metabolically healthy obesity and the metabolic syndrome.

Patients with metabolically healthy obesity (MHO) do not present the cluster of metabolic abnormalities that define the metabolic syndrome (MetS). Whether MHO is associated with lower impairment of vasoreactivity than the MetS is unknown. For this purpose, forearm blood flow (FBF) responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and/or the selective endothelin type A (ETA) receptor blocker BQ-123 in 119 obese individuals with MHO (n = 34) or with the MetS (n = 85) and in healthy lean controls (n = 56). ACh and SNP caused a significant vasodilation in both obese and lean participants (all P < 0.001). However, the response to both agents was significantly lower in the obese than in the control group (both P < 0.001). Among the obese participants, the reactivity to ACh was higher in MHO than in MetS patients, whereas the responsiveness to SNP was equally impaired in both groups (P = 0.45). Infusion of BQ-123 significantly increased FBF in obese patients (P < 0001), but not in the lean participants; hence, FBF following ETA receptor blockade was higher in both obese groups than in controls (both P < 0.001). FBF response to BQ-123 was significantly higher in patients with the MetS than in those with MHO (P = 0.007). In conclusion, patients with MHO have abnormal vascular reactivity, although their endothelial dysfunction is less pronounced than in patients with the MetS. These findings indicate that obesity is associated with vascular damage independent of those metabolic abnormalities underlying the MetS.

Phenylephrine eye drops in pediatric patients undergoing ophthalmic surgery: incidence, presentation, and management of complications during general anesthesia.

BACKGROUND: Phenylephrine eye drops are widely used as mydriatic agent to reach the posterior segment of the eye. In literature, many reports suggest a systemic absorption of this agent as a source of severe adverse drug reactions. Hence, we reviewed our experience with topical phenylephrine in ophthalmic surgery. METHODS: In May 2006, following US guidelines publication, a standard operating procedure was issued in our operating rooms to standardize the use of phenylephrine eye drops in our practice. Two years later, after the occurrence of a cluster of serious adverse drug reactions in infants undergoing surgery, a review of phenylephrine safety and systemic complications incidence was performed. RESULTS: We observed 451 pediatric patients, and 187 met the inclusions criteria: Among them, 4 experienced hemodynamic complications due to phenylephrine eye drops. The incidence of major complications was 2.1%. CONCLUSIONS: Two different patterns of side effects occurred. The first one was a cardiovascular derangement with severe hypertension and heart rate alterations; the other one involved exclusively pulmonary circuit causing early edema. These clinical manifestations, their duration, and treatment responses are all explainable by alfa1-adrenergic action of phenylephrine. This hypothetic pathogenesis has been confirmed also by the usefulness of direct vasodilators (anesthetic agents) and by the negative outcome occurred in the past with the use of beta-blockers.

Post-marketing active surveillance of Guillain Barré Syndrome following COVID-19 vaccination in persons aged ≥12 years in Italy: A multi-database self-controlled case series study.

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.

The electronic nose in respiratory medicine.

Several volatile organic compounds have been identified in exhaled breath in healthy subjects and patients with respiratory diseases by gas chromatography/mass spectrometry. Identification of selective patterns of volatile organic compounds in exhaled breath could be used as a biomarker of inflammatory lung diseases. An electronic nose (e-nose) is an artificial sensor system that generally consists of an array of chemical sensors for detection of volatile organic compound profiles (breathprints) and an algorithm for pattern recognition. E-noses are handheld, portable devices that provide immediate results. E-noses discriminate between patients with respiratory disease, including asthma, COPD and lung cancer, and healthy control subjects, and also among patients with different respiratory diseases. E-nose breathprints are associated with airway inflammation activity. In combination with other 'omics' platforms, e-nose technology might contribute to the identification of new surrogate markers of pulmonary inflammation and subphenotypes of patients with respiratory diseases, provide a molecular basis to a personalized pharmacological treatment, and facilitate the development of new drugs.

BNT162b2 COVID-19 Vaccine Safety among Healthcare Workers of a Tertiary Hospital in Italy.

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.

Rho-kinase inhibition improves vasodilator responsiveness during hyperinsulinemia in the metabolic syndrome.

In patients with the metabolic syndrome (MetS), the facilitatory effect of insulin on forearm vasodilator responsiveness to different stimuli is impaired. Whether the RhoA/Rho kinase (ROCK) pathway is involved in this abnormality is unknown. We tested the hypotheses that, in MetS patients, ROCK inhibition with fasudil restores insulin-stimulated vasodilator reactivity and that oxidative stress plays a role in this mechanism. Endothelium-dependent and -independent forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were assessed in MetS patients (n = 8) and healthy controls (n = 5) before and after the addition of fasudil (200 µg/min) to an intra-arterial infusion of insulin (0.1 mU/kg/min). In MetS patients (n = 5), fasudil was also infused without hyperinsulinemia. The possible involvement of oxidative stress in the effect of fasudil during hyperinsulinemia was investigated in MetS patients (n = 5) by infusing vitamin C (25 mg/min). In MetS patients, compared with saline, fasudil enhanced endothelium-dependent and -independent vasodilator responses during insulin infusion (P < 0.001 and P = 0.008, respectively), but not in the absence of hyperinsulinemia (P = 0.25 and P = 0.13, respectively). By contrast, fasudil did not affect vasoreactivity to ACh and SNP during hyperinsulinemia in controls (P = 0.11 and P = 0.56, respectively). In MetS patients, fasudil added to insulin and vitamin C did not further enhance vasodilation to ACh and SNP (P = 0.15 and P = 0.43, respectively). In the forearm circulation of patients with the MetS, ROCK inhibition by fasudil improves endothelium-dependent and -independent vasodilator responsiveness during hyperinsulinemia; increased oxidative stress seems to be involved in the pathophysiology of this phenomenon.

Evaluation of the Effectiveness and Safety of the BNT162b2 COVID-19 Vaccine in the Vaccination Campaign among the Health Workers of Fondazione Policlinico Universitario Agostino Gemelli IRCCS.

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.

Generalized impairment of vasodilator reactivity during hyperinsulinemia in patients with obesity-related metabolic syndrome.

Defective insulin-dependent vasodilation might contribute importantly to metabolic and vascular abnormalities of the metabolic syndrome (MetS). However, despite extensive investigation, the precise mechanisms involved in insulin's vasoactive effects have not been fully elucidated. Therefore, this study sought to better characterize insulin's physiological actions on vascular reactivity and their potential derangement in the MetS. Forearm blood flow responses to graded doses of acetylcholine, sodium nitroprusside, and verapamil were assessed by strain-gauge plethysmography in patients with obesity-related MetS (n = 20) and in matched controls (n = 18) before and after intra-arterial infusion of insulin (0.2 mU·kg(-1)·min(-1)). Possible involvement of increased oxidative stress in the impaired insulin-stimulated vasodilator responsiveness of patients with MetS (n = 12) was also investigated using vitamin C (25 mg/min). In control subjects, significant potentiation of the vasodilator responses to acetylcholine, nitroprusside, and verapamil was observed after insulin infusion (all P < 0.05). However, no significant change in vasodilator reactivity to either of these drugs was observed following hyperinsulinemia in patients with MetS (all P > 0.05). Interestingly, administration of vitamin C to patients with MetS during hyperinsulinemia significantly enhanced the vasodilator responsiveness to acetylcholine, nitroprusside, and verapamil (all P < 0.05 vs. hyperinsulinemia alone). In conclusion, insulin exerts a generalized facilitatory action on vasodilator reactivity, and this effect is impaired in patients with MetS likely because of increased oxidative stress. Given the importance of vasodilator reactivity in affecting glucose disposal and vascular homeostasis, this defect may then contribute to the development of metabolic and vascular complications in insulin-resistant states.

Sudden nasal bleeding and brodifacoum: A case of accidental exposure or attempted homicide?

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.

Development of a Sensing Array for Human Breath Analysis Based on SWCNT Layers Functionalized with Semiconductor Organic Molecules.

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.

Converse regulatory functions of estrogen receptor-alpha and -beta subtypes expressed in hypothalamic gonadotropin-releasing hormone neurons.

Estradiol (E(2)) acts as a potent feedback molecule between the ovary and hypothalamic GnRH neurons, and exerts both positive and negative regulatory actions on GnRH synthesis and secretion. However, the extent to which these actions are mediated by estrogen receptors (ERs) expressed in GnRH neurons has been controversial. In this study, Single-cell RT-PCR revealed the expression of both ERalpha and ERbeta isoforms in cultured fetal and adult rat hypothalamic GnRH neurons. Both ERalpha and ERbeta or individual ERs were expressed in 94% of cultured fetal GnRH neurons. In adult female rats at diestrus, 68% of GnRH neurons expressed ERs, followed by 54% in estrus and 19% in proestrus. Expression of individual ERs was found in 24% of adult male GnRH neurons. ERalpha exerted marked G(i)-mediated inhibitory effects on spontaneous action potential (AP) firing, cAMP production, and pulsatile GnRH secretion, indicating its capacity for negative regulation of GnRH neuronal function. In contrast, increased E(2) concentration and ERbeta agonists increase the rate of AP firing, GnRH secretion, and cAMP production, consistent with ERbeta-dependent positive regulation of GnRH secretion. Consonant with the coupling of ERalpha to pertussis toxin-sensitive G(i/o) proteins, E(2) also activates G protein-activated inwardly rectifying potassium channels, decreasing membrane excitability and slowing the firing of spontaneous APs in hypothalamic GnRH neurons. These findings demonstrate that the dual actions of E(2) on GnRH neuronal membrane excitability, cAMP production, and GnRH secretion are mediated by the dose-dependent activation of ERalpha and ERbeta expressed in hypothalamic GnRH neurons.

Heme oxygenase expression and activity in immortalized hypothalamic neurons GT1-7.

Heme oxygenase (HO), the main enzyme deputed to heme metabolism, has been identified as two main isoforms called HO-1 and HO-2. HO-1 is inducible and plays a main role in the cellular oxidant/antioxidant balance whereas HO-2 is constitutive and involved in the physiological metabolism of heme. However, it is noteworthy to mention that HO contribute to the regulation of the hypothalamic release of neuropeptides such as corticotrophin-releasing hormone and arginine-vasopressin and could modulate the pulsatile release of gonadotropin releasing hormone (GnRH). GT1-7 cells are immortalized hypothalamic neurons and a valuable tool to evaluate hypothalamic neuroendocrine control of reproduction. The aim of this work was to investigate and characterize the presence of HO isoforms in the GT1-7 hypothalamic neurons. Hemin, a well-known inducer of HO-1, significantly increased HO activity, whereas dexamethasone did not modify HO-2 activity. Moreover, hemin and DEX, in combination, did not have any additive effect on HO activity in GT1-7 neurons. Furthermore, basal HO-1 immunoreactivity identified in GT1-7 cells, was significantly up-regulated by hemin. Conversely, no HO-2 immunoreactivity was detected. Taken together, these results suggest the presence of functional HO-1 in GT1-7 immortalized hypothalamic neurons and open new avenues about the use of this cell line for the study of HO modulation of GnRH secretion and reproduction.

Expression of a functional g protein-coupled receptor 54-kisspeptin autoregulatory system in hypothalamic gonadotropin-releasing hormone neurons.

The G protein-coupled receptor 54 (GPR54) and its endogenous ligand, kisspeptin, are essential for activation and regulation of the hypothalamic-pituitary-gonadal axis. Analysis of RNA extracts from individually identified hypothalamic GnRH neurons with primers for GnRH, kisspeptin-1, and GPR54 revealed expression of all three gene products. Also, constitutive and GnRH agonist-induced bioluminescence resonance energy transfer between Renilla luciferase-tagged GnRH receptor and GPR54 tagged with green fluorescent protein, expressed in human embryonic kidney 293 cells, revealed heterooligomerization of the two receptors. Whole cell patch-clamp recordings from identified GnRH neurons showed initial depolarizing effects of kisspeptin on membrane potential, followed by increased action potential firing. In perifusion studies, treatment of GT1-7 neuronal cells with kisspeptin-10 increased GnRH peak amplitude and duration. The production and secretion of kisspeptin in cultured hypothalamic neurons and GT1-7 cells were detected by a specific RIA and was significantly reduced by treatment with GnRH. The expression of kisspeptin and GPR54 mRNAs in identified hypothalamic GnRH neurons, as well as kisspeptin secretion, indicate that kisspeptins may act as paracrine and/or autocrine regulators of the GnRH neuron. Stimulation of GnRH secretion by kisspeptin and the opposing effects of GnRH on kisspeptin secretion indicate that GnRH receptor/GnRH and GPR54/kisspeptin autoregulatory systems are integrated by negative feedback to regulate GnRH and kisspeptin secretion from GnRH neurons.

Single-inhaler triple therapy utilizing the once-daily combination of fluticasone furoate, umeclidinium and vilanterol in the management of COPD: the current evidence base and future prospects.

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.

Favorable Vascular Actions of Angiotensin-(1-7) in Human Obesity.

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.