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Introduction: Heart failure (HF) is a syndrome increasing worldwide, and literature shows that the hospitalizations are associated with greater mortality rates. A patient-centered method combined with optimized medical treatment and palliative care may improve HF outcomes, and some advocate a multifaceted approach to achieve a perfect management of chronic HF (CHF)., Objective: The objective of this study was to present the study protocol of GENICA project which aims to optimize the ambulatory approach of CHF patients, and reduce their re-hospitalization, emergency readmission, and global death rate., Design: Prospective cohort including patients referred to HF consultation and collecting sociodemographic, clinical, and analytical variables among others. The outcomes will be mortality, re-hospitalization, and emergency readmission rates. The association between the independent variables and outcomes will be assessed by logistic regression. Comparison between GENICA patients and controls will be made by χ 2 test. Significance at p level of less than 0.05., Results: GENICA will offer a wide range of longitudinal data with evidence that will influence future healthcare of CHF patients at an ambulatory basis., Discussion: GENICA will provide practical evidence of real HF patient's profile and develop workable decision algorithms, which will influence future ambulatory care of CHF. HF patients will be safer at home and will keep stability for longer periods, consuming less health resources and slow the progression of the disease. Being a matched cohort, GENICA benefits from an accuracy similar to that of randomized controlled trials, without the need to perform a rigorous allocation of the intervention. Being prospective there's no problem about response bias., Conclusion: CHF should be approached with a multidisciplinary and multifaceted strategy privileging the outpatient setting, including home monitoring, and GENICA is the paramount protocol enabling this. GENICA may come to show health policy makers that the asset is not to divide and rule, but to converge strategies, therapies, and knowledge.

Introduction: Heart failure (HF) represents a huge financial and economic burden worldwide. Some authors advocate that remote monitoring should be implemented to improve HF management, but given its increasing incidence, as well as its morbidity and mortality, a question still remains: are we monitoring it properly? There is no shortage of literature on home monitoring devices, however, most of them are designed to monitor an unsuitable array of variables and, to the best of our knowledge, there are no large randomized studies about their impact on morbidity/mortality of HF patients., Objective: Description of a novel monitoring device., Methods: As a solution, we designed MONITORIA (MOnitoring NonInvasively To Overcome mortality Rates of heart Insufficiency on Ambulatory)., Results: This is a multimodal device that will provide real time monitoring of vital, electrophysiological, hemodynamic and chemical signs, transthoracic impedance, and physical activity levels. The device is meant to perform continuous analysis and transmission of all data. Significant alterations in a patient's variable will alert the attending physician and, in case of potentially life-threatening situations, the national emergency medical system. The MONITORIA device will, also, have a function that sends shocks or functions as a pacemaker to treat certain arrhythmias/blockades. This function can be activated the very first time the patient utilizes it, based on their risk of sudden cardiac death., Discussion/conclusions: MONITORIA is a promising device mostly because it is included in a follow-up program that takes into account a multi-perspective feature of HF development and is based on the real world patient, adapting innovations not to the disease but rather to the patients., (Copyright © 2021 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Heart failure (HF) is a multifactorial chronic syndrome with progressive increasing incidence causing a huge financial burden worldwide. Remote monitoring should, in theory, improve HF management, but given increasing morbidity and mortality, a question remains: are we monitoring it properly? Device-based home monitoring enables objective and continuous measurement of vital variables and non-invasive devices should be first choice for elderly patients. There is no shortage of literature on the subject, however, most studies were designed to monitor a single variable or class of variables that were not properly assembled and, to the best of our knowledge, there are no large randomized studies about their impact on HF patient management. To overcome this problem, we carefully selected the most critical possible HF decompensating factors to design MONITORIA, a non-invasive device for comprehensive HF home monitoring. MONITORIA stands for MOnitoring Non-Invasively To Overcome mortality Rates of heart Insufficiency on Ambulatory, and in this paper, which is part I of a series of three articles, we discuss the theoretical basis for its design. MONITORIA and its inherent follow-up strategy will optimize HF patient care as it is a promising device, which will essentially adapt innovation not to the disease but rather to the patients., (Copyright © 2020 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers., Methods: Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers., Key Findings: Mean eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0-τ (in μmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio eslicarbazepine plasma exposure (μmol h/L) to ESL daily-dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively., Significance: ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss ) of eslicarbazepine and similar extent of plasma exposure (AUCss,0-τ ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Background: Etamicastat is a novel, potent, and reversible peripheral dopamine-β-hydroxylase inhibitor that has been administered orally at doses up to 600 mg once daily for 10 days to male healthy volunteers and appears to be well tolerated., Objective: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat., Material and Methods: A single-center, open-label, randomized, two-way crossover study in 12 healthy male subjects was performed. Subjects were administered a single dose of etamicastat 200 mg following either a standard high-fat and high-calorie content meal (test) or 10 hours of fasting (reference). The statistical method for testing the effect of food on the pharmacokinetic parameters of interest was based upon the 90% confidence interval (CI) for the test/reference geometric mean ratio (GMR). The parameters of interest were maximum plasma concentration (C(max)), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC(last)), and AUC from time zero to infinity (AUC(∞)). Bioequivalence was assumed when the 90% CI fell within the recommended acceptance interval (80, 125)., Results: Etamicastat C(max), AUC(last), and AUC(∞) were 229 ng/mL, 1856 ng · h/mL, and 2238 ng · h/mL, respectively, following etamicastat in the fasting, and 166 ng/mL, 1737 ng · h/mL, and 2119 ng · h/mL, respectively, following etamicastat in the fed condition. Etamicastat test/reference GMR was 72.27% (90% CI 64.98, 80.38) for C(max), 93.59% (90% CI 89.28, 98.11) for AUC(last), and 96.47% (90% CI 91.67, 101.53) for AUC(∞). Time to C(max) was prolonged by the presence of food (p < 0.001). The C(max), AUC(last), and AUC(∞) values of the inactive metabolite BIA 5-961 were 275 ng/mL, 1827 ng · h/mL, and 2009 ng · h/mL, respectively, in the fasting, and 172 ng/mL, 1450 ng · h/mL, and 1677 ng · h/mL, respectively, in the fed condition. BIA 5-961 test/reference GMR was 62.42% (90% CI 56.77, 68.63) for C(max), 79.41% (90% CI 56.77, 68.63) for AUC(last), and 83.47% (90% CI 76.62, 90.93) for AUC(∞). A total of six mild to moderate unspecific adverse events were reported by four subjects. There was no clinically significant abnormality in laboratory assessments., Conclusion: Etamicastat was well tolerated. The C(max) of etamicastat decreased 28% following oral administration of etamicastat in the presence of food, while AUC remained within the pre-defined acceptance interval. The delay in absorption and decrease in peak exposure of etamicastat is not clinically significant, and therefore etamicastat could be administered without regard to meals., Trial Registration: EudraCT No. 2007-006530-33.

Background: Activation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure. A strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of norepinephrine (noradrenaline) via inhibition of dopamine-β-hydroxylase (DβH)., Objective: To assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5-453), a new DβH inhibitor, following repeated dosing., Methods: A double-blind, randomized, placebo-controlled study was conducted in healthy young male volunteers. Participants received once-daily doses of placebo or etamicastat 25, 50, 100, 200, 400, or 600 mg, for 10 days., Results: Etamicastat underwent N-acetylation to its metabolite BIA 5-961. Etamicastat and BIA 5-961 maximum concentrations were achieved at 1-3 and 2-4 hours, respectively, after dosing. Elimination half-lives ranged from 18.1 to 25.7 hours for etamicastat and 6.7 to 22.5 hours for BIA 5-961. Both etamicastat and BIA 5-961 followed linear pharmacokinetics. The extent of systemic exposure to etamicastat and BIA 5-961 increased in an approximately dose-proportional manner, and steady-state plasma concentrations were attained up to 9 days of dosing. Etamicastat accumulated in plasma following repeated administration. The mean observed accumulation ratio was 1.3-1.9 for etamicastat and 1.3-1.6 for BIA 5-961. Approximately 40% of the etamicastat dose was recovered in urine in the form of parent compound and BIA 5-961. There was a high variability in pharmacokinetic parameters, attributable to different N-acetyltransferase-2 (NAT2) phenotype. Urinary excretion of norepinephrine decreased following repeated administration of etamicastat. Etamicastat was generally well tolerated. There was no serious adverse event or clinically significant abnormality in clinical laboratory tests, vital signs, or ECG parameters., Conclusion: Etamicastat was well tolerated. Etamicastat undergoes N-acetylation, which is markedly influenced by NAT2 phenotype. NAT2 genotyping could be a step toward personalized medicine for etamicastat., Trial Registration: EudraCT No. 2007-004142-33.

Background and Objectives: Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet((R)) CR 200/50) in healthy subjects (n = 16)., Methods: This was a randomized, double-blind, placebo-controlled, four-way crossover study in healthy subjects, with at least 5 days of washout between treatment periods., Results: There was a dose-dependent and significant increase in levodopa extent of exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) without a significant change in peak exposure (maximum plasma concentration; [C(max)]). Using placebo as a reference, levodopa geometric mean ratios (GMRs) and 90% CIs following nebicapone 50 mg, 100 mg and 200 mg were, respectively, 1.13 (0.98, 1.30), 1.04 (0.90, 1.19) and 1.10 (0.96, 1.27) for C(max) and 1.26 (1.16, 1.34), 1.37 (1.27, 1.75) and 1.47 (1.42, 1.65) for AUC(infinity). For 3-O-methyldopa (3-OMD), the GMRs and 90% CIs were, respectively, 0.61 (0.55, 0.67), 0.45 (0.41, 0.50) and 0.33 (0.30, 0.36) for C(max) and 0.69 (0.61, 0.78), 0.53 (0.41, 0.61) and 0.41 (0.37, 0.47) for AUC(infinity). Nebicapone dose dependently and significantly decreased COMT activity. Maximum COMT inhibition occurred at 1.5-2.4 hours post-dose and ranged from 56% to 73% with nebicapone 50 mg and 200 mg, respectively. There was a good correlation between plasma concentrations of nebicapone and inhibition of S-COMT activity. Treatments were well tolerated., Conclusion: Following concomitant administration with levodopa/carbidopa CR 200 mg/50 mg, single doses of nebicapone 50 mg, 100 mg and 200 mg significantly and dose-dependently inhibited S-COMT activity, increased systemic exposure to levodopa, and reduced 3-OMD formation.

Objective: To investigate the effect of food on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel antagonist., Material and Methods: Single-centre, open-label, randomised, two-way crossover study in 12 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 14 days or more. In each of the study periods subjects were administered a single dose of eslicarbazepine acetate 800 mg following either a standard high-fat content meal or 10 hours of fasting., Results: Eslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (C(max)) in fed (test) and fasting (reference) conditions were, respectively, 12.8 +/- 1.8 microg/mL and 11.3 +/- 1.9 microg/mL, and the areas under the plasma concentration time curve from 0 to infinity (AUC(infinity)) were, respectively, 242.5 +/- 32.1 microg.h/mL and 243.6 +/- 31.1 microg.h/mL (arithmetic mean +/- SD). The point estimate (PE) and 90% confidence interval (90% CI) of the test/reference C(max )geometric mean ratio were 1.14 and 1.04, 1.25, respectively; for the AUC(infinity) ratio, the PE and 90% CI were 1.00 and 0.95, 1.04, respectively. Bioavailability of eslicarbazepine acetate administered in fed and fasting conditions was similar and bioequivalence is accepted for both AUC(infinity) and C(max) because the 90% CI lies within the acceptance range of 0.80-1.25. No statistically significant differences were found in time of occurrence of C(max)., Conclusion: The presence of food had no significant effect on the pharmacokinetics of eslicarbazepine acetate and therefore this new voltage-gated sodium channel antagonist may be administered without regard to meals.