Obesity is associated with endothelial dysfunction related to decreased NO bioavailability, increased endothelin 1 vasoconstrictor activity, and decreased circulating ghrelin. Therefore, we tested ...whether exogenous ghrelin may have benefits to improve the balance between endothelin 1 and NO in patients with obesity-related metabolic syndrome. Vasoactive actions of endothelin 1 and NO were assessed in 8 patients with metabolic syndrome and 8 matched controls by evaluating forearm blood flow responses (strain-gauge plethysmography) to intra-arterial infusion of BQ-123 (endothelin A receptor antagonist; 10 nmol/min), followed by N-monomethyl-l-arginine (NO synthase inhibitor; 4 μmol/min), before and after infusion of ghrelin (200 ng/min). In the absence of ghrelin, the vasodilator response to BQ-123 was greater in patients than in controls (P<0.001), whereas infusion of N-monomethyl-l-arginine induced smaller vasoconstriction in patients than in controls (P=0.006). Importantly, exogenous ghrelin decreased the vasodilator response to BQ-123 (P=0.007 versus saline) and enhanced the magnitude of changes in forearm blood flow induced by N-monomethyl-l-arginine (P=0.003) in patients but not in controls (both P>0.05). The favorable effect of ghrelin on endothelin A–dependent vasoconstriction was likely related to the stimulation of NO production, because no change in the vascular effect of BQ-123 was observed after ghrelin (P=0.44) in 5 patients with metabolic syndrome during continuous infusion of the NO donor sodium nitroprusside (0.2 μg/min). In patients with metabolic syndrome, ghrelin has benefits to normalize the balance between vasoconstrictor (endothelin 1) and vasodilating (NO) mediators, thus suggesting that this peptide has important peripheral actions to preserve vascular homeostasis in humans.
BackgroundPatients with obesity-related metabolic syndrome (MetS) have endothelial dysfunction due to decrease nitric oxide (NO) availability and increased endothelin (ET)-1-mediated vasoconstrictor ...tone. Given the prognostic significance of endothelial dysfunction, these abnormalities may be involved in the increased risk of cardiovascular mortality of these patients. Whether patients with metabolically healthy obesity (MHO), in whom those metabolic abnormalities that define the MetS are not present, have similar impairment of endothelial function is unknown.MethodsForearm blood flow (FBF) responses were measured by strain-gauge plethysmography during intra-arterial infusion of graded-doses of acetylcholine (ACh; an endothelial-dependent vasodilator) and sodium nitroprusside (SNP; an endothelium-independent vasodilator), and/or during selective antagonism of ETA receptors by BQ-123 (10 nmol/min for 60 minutes) in lean subjects (n=56) and in obese patients (n=119), with either MHO (n=34) or the MetS (n=85).ResultsACh and SNP caused vasodilation in both obese and lean participants (all P<0.001 vs. baseline). The response, however, 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 the MetS (P<0.001), whereas the responsiveness to SNP was equally impaired in both groups (P=0.45); this suggests higher degree of endothelial dysfunction in the MetS, but similar impairment of smooth muscle reactivity in MHO and the MetS. As expected, BQ-123 increased FBF in obese (P<0001 vs. baseline), but not in lean participants, hence the FBF response to ETA receptor blockade was higher in both obese groups than in controls (both P<0.001). In keeping with the ACh results, the FBF response to BQ-123 was significantly higher in patients with the MetS than in those with MHO (P=0.007).ConclusionsPatients with MHO have abnormal vascular reactivity, albeit their endothelial dysfunction is less pronounced than in patients with the MetS. These findings indicate that obesity per se is associated with some degree of vascular damage independently of those metabolic abnormalities underlying the MetS.
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.
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 M
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.
Introduction:
In December 2020, the Italian Medicines Agency (AIFA) in collaboration with the Italian Regional Centers of Pharmacovigilance evaluated four individual case safety reports (ICSRs) ...reporting obinutuzumab and non-overt disseminated intravascular coagulation (DIC) as a new possible signal. In this study, we described the process of signal management for obinutuzumab-associated non-overt DIC.
Methods:
In accordance with the Guideline on Good Pharmacovigilance Practices Module IX, we described the process of the Italian and European Union signal management process in five steps: signal detection, signal validation, signal confirmation, signal analysis, and prioritization and signal assessment.
Results:
In the signal detection phase, four cases of obinutuzumab-associated non-overt DIC met the criteria for signal definition (ROR 213.6 and IC025 77). In the signal validation phase, both the Italian and European databases of spontaneously reported adverse drug reactions were investigated with supporting evidence from medical literature. Four patients (two men and two women aged 67–77) were in treatment with obinutuzumab for chronic lymphocytic leukemia, and they developed a subclinical DIC within 24 h from the administration of the drug. The DIC spontaneously resolved in all cases. Three more ICSRs were reported in the EudraVigilance database. The medical literature provided poor evidence of the possible association between obinutuzumab and DIC. The signal was subsequently validated, first by AIFA and then by EMA. The signal was confirmed by the Pharmacovigilance Risk Assessment Committee (PRAC) Rapporteur in the “signal confirmation” phase, and it entered “signal analysis and prioritization” and “signal assessment”. In these phases, the PRAC assessed and confirmed DIC as a possible adverse reaction to obinutuzumab. Finally, the Summary of Product characteristics was updated with this new risk.
Conclusion:
Despite the intrinsic difficulties linked to the nature of the event itself, the process of signal detection and the issuing of the risk minimization measures by the Italian Medicines Agency as part of the EU procedures have proven to be efficient.
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.
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Obese patients have vascular dysfunction related to impaired nitric oxide (NO)-dependent vasodilation and increased endothelin (ET)-1 activity. Obestatin is a gastrointestinal peptide ...with favorable metabolic actions linked to obesity and diabetes; it has also been shown to exert cardiovascular benefits in experimental models by producing vascular relaxation via specific activation of endothelium-dependent NO signaling. Here we tested the hypothesis that obestatin might have advantageous impacts on the NO pathway and the ET-1 system in patients with central obesity. To this purpose, forearm blood flow responses to intra-arterial infusion of graded doses of exogenous obestatin (0.2; 0.4; 0.8; 1,6; 3.2 nmol/min, each dose given for 5 min) were assessed in lean subjects (n=5) and in patients with central obesity (n=14), during the concurrent infusion of saline and after NO inhibition by L-NMMA (4 μmol/min for 15 min). In another group of obese patients (n=10), vascular responses to selective blockade of ET
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receptors (BQ-123, 10 nmol/min for 60 min) were measured in the absence and the presence of obestatin (0.8 nmol/min). In lean subjects, before NO synthase inhibition obestatin resulted in a progressive increase in forearm flow (60% at the highest dose; P<0.001 vs. baseline); obestatin-induced vasodilation, however, was completely abolished by L-NMMA (P<0.001 vs. saline). Similarly, in obese patients obestatin induced a significant vasodilation (45%; P<0.001 vs. baseline), which was blunted by L-NMMA (16%; P<0.01 vs. saline). Before obestatin, in obese patients ET
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receptor blockade resulted in a marked vasodilation (39% flow increase at 60 min; P<0.001 vs. baseline), which was totally abrogated in the presence of obestatin (P<0.001 vs. absence). In conclusion, obestatin produces vasorelaxation in healthy humans via specific activation of endothelium-dependent NO signaling. This beneficial effect of obestatin is preserved in obese arteries, where it is associated with inhibition of ET-1 signaling. These actions of obestatin, therefore, may be important in the normal regulation of vascular function and are clearly relevant to obesity, a condition characterized by increased prevalence of hypertension and cardiovascular complications.
Electronic noses (e-noses), artificial sensor systems generally consisting of chemical sensor arrays for the detection of volatile compound profiles, have potential applications in respiratory ...medicine. We assessed within-day and between-day repeatability of an e-nose made from 32 sensors in patients with stable chronic obstructive pulmonary disease (COPD). We also compared between-day repeatability of an e-nose, fraction of exhaled nitric oxide (FENO) and pulmonary function testing. Within-day and between-day repeatability for the e-nose was assessed in two breath samples collected 30 min and seven days apart, respectively. Repeatability was expressed as an intraclass correlation coefficient (ICC). All sensors had ICC above 0.5, a value that is considered acceptable for repeatability. Regarding within-day repeatability, ICC ranged from 0.75 to 0.84 (mean = 0.80 ± 0.004). Sensors 6 and 19 were the most reproducible sensors (both, ICC = 0.84). Regarding between-day repeatability, ICC ranged from 0.57 to 0.76 (mean = 0.68 ± 0.01). Sensor 19 was the most reproducible sensor (ICC = 0.76). Within-day e-nose repeatability was greater than between-day repeatability (P < 0.0001). Between-day repeatability of FENO (ICC = 0.91) and spirometry (ICC range = 0.94-0.98) was greater than that of e-nose (mean ICC = 0.68). In patients with stable COPD, the e-nose used in this study has acceptable within-day and between-day repeatability which varies between different sensors.
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