Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization

Purpose: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II–IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization. Method: This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett’s correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety. Results: Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups. Conclusion: Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines

The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study

Aims: Progressive aortic stiffening eventually leads to left ventricular (LV) hypertrophy and heart failure if left untreated. Anti-hypertensive agents have been shown to reverse this to some extent. The effects of sacubitril/valsartan (LCZ696), a dual-action angiotensin receptor blocker (ARB), and neprilysin inhibitor, on arterial stiffness and LV remodelling have not been investigated. Methods and results: This was a randomized, multi-centre, double-blind, double-dummy, active-controlled, parallel group, study to compare the effects on cardiovascular remodelling of sacubitril/valsartan with those of olmesartan in patients with hypertension and elevated pulse pressure. Magnetic resonance imaging scans were used to assess LV mass and local aortic distensibility, at baseline and at 12 and 52 weeks after initiation of treatment. Central pulse and systolic pressure were determined using a SphymoCor® XCEL device at each time point. A total of 114 patients were included, with 57 in each treatment group. The mean age was 59.8 years, and 67.5% were male. Demographic characteristics did not vary between the two sets of patients. Left ventricular mass index decreased to a greater extent in the sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (−6.36 vs. −2.32 g/m2; P = 0.039) and from baseline to 52 weeks (−6.83 vs. −3.55 g/m2; P = 0.029). These differences remained significant after adjustment for systolic blood pressure (SBP) at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively) and similar signals (though formally non-significant) were observed after adjusting for changes in SBP (P = 0.0612 and P = 0.0529, respectively). There were no significant differences in local distensibility changes from baseline to 12 or 52 weeks between the two groups; however, there was a larger reduction in central pulse pressure for the sacubitril/valsartan group compared to the olmesartan group (P = 0.010). Conclusion: Since LV mass change correlates with cardiovascular prognosis, the greater reductions in LV mass indicate valuable advantages of sacubitril/valsartan compared to olmesartan. The finding that LV mass index decrease might be to some extent independent of SBP suggests that the effect of the dual-acting agent may go beyond those due to its BP-lowering ability

Sacubitril/valsartan:beyond natriuretic peptides

Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to potentially beneficial physiological effects. The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system (RAAS) by blocking the angiotensin II receptor. It has been shown to improve mortality and hospitalisation outcomes in patients with HF due to left ventricular systolic dysfunction. The key advantage of sacubitril/valsartan has been perceived to be its ability to augment BNP, while its other effects have largely been overlooked. This article highlights the important effects of sacubitril/valsartan, beyond just the augmentation of BNP. First we discuss how NPS physiology differs between healthy individuals and those with HF by looking at mechanisms like the overwhelming effects of RAAS on the NPS, natriuretic peptide receptor desensitisation and absolute natriuretic deficiency. Secondly, this review explores other hormones that are augmented by sacubitril/valsartan such as, bradykinin, substance-P and adrenomedullin that may contribute to the efficacy of sacubitril/valsartan in HF. We also discuss concerns that sacubitril/valsartan may interfere with amyloid β homeostasis with potential implications on Alzheimer’s disease and macular degeneration. Finally, we explore the concept of ‘auto-inhibition’ which is a recently described observation that humans have innate NEP inhibitory capability when natriuretic peptide levels rise above a threshold. There is speculation that auto-inhibition may provide a surge of natriuretic and other vasoactive peptides to rapidly reverse decompensation. We contend that by pre-emptively inhibiting NEP, sacubitril/valsartan is inducing this surge earlier during decompensation, resulting in the better outcomes observed

Visinin-like protein 1 regulates natriuretic peptide receptor B in the heart

Accumulating evidence indicates that Visinin-like protein-1 (VILIP-1), a member of the family of neuronal calcium sensor proteins (NCS), modulates a variety of processes in extra-neuronal tissues. In this study, we describe VILIP-1 expression in the human heart, rat cardiomyocytes, and H9c2 cells, and demonstrate that VILIP-1 regulates the cell surface localization of natriuretic peptide receptor B (NPR-B). In preparations from failing hearts, we observed VILIP-1 downregulation and reduced NPR-B signalling. In conclusion, VILIP-1 deficiency may be responsible for the reduced efficiency of the natriuretic peptide system in cardiac hypertrophy and heart failure and may therefore serve as pharmacological target

Impact of Chlorine on the Internal Transition Rates and Excited States of the Thermally Delayed Activated Fluorescence Molecule 3CzClIPN

We analyze internal transition rates and the singlet-triplet energy gap of the thermally activated delayed fluorescence (TADF) molecule 3CzClIPN, which recently was introduced as an efficient photocatalyst. Distribution and origin of the non-monoexponential decays, which are commonly observed in TADF films, are revealed by analysis of transient fluorescence with an inverse Laplace transform. A numerically robust global rate fit routine, which extracts all relevant TADF parameters by modeling the complete set of data, is introduced. To compare and verify the results, all methods are also applied to the well-known 4CzIPN. The influence of the molecular matrix is discussed by embedding low concentrations of TADF molecules in polystyrene films. Finally, quantum chemical calculations are compared to the experimental results to demonstrate that the chlorine atom increases the charge transfer character of the relevant states, resulting in a reduction of the singlet-triplet energy gap

Isavuconazole shortens the QTc interval

Isavuconazole is a novel antifungal drug approved for the treatment of adults with invasive aspergillosis and mucormycosis. While azoles as a class effect are known to prolong QTc interval, clinical trials have shown that isavuconazole administration may cause shortening in a dose-related manner. Here, we assessed the effects of isavuconazole on the length of QTc interval. The objective of the study was to describe changes in the QTc interval induced by isavuconazole treatment. A total of 26 adult patients from 7 hospitals were included. Patients received isavuconazole for the treatment of invasive fungal infection and, in 1 case, for prophylaxis due to QTc prolongation under fluconazole. Twelve-channel electrocardiograms (ECGs) were performed before and during treatment. Out of 26 patients, 24 showed shortening of QTc interval. In patients with QTc shortening, QTc during isavuconazole treatment showed a mean decrease of 7.4&nbsp;\ub1&nbsp;5.8% (36.5&nbsp;\ub1&nbsp;38.8&nbsp;ms, range 7-202; P&nbsp;=.004), compared to pre-isavuconazole ECG. One patient with available long-term follow-up showed further decrease in QTc on days 55 and 110. Apart from 1 case report, these are the first data outside controlled clinical trials showing QTc shortening. Knowledge about cardiac effects of isavuconazole will serve to better manage the use of concomitant medications

Measuring the acute effect of insulin infusion on ATP turnover rate in human skeletal muscle using phosphorus-31 magnetic resonance saturation transfer spectroscopy

Mitochondrial dysfunction has been proposed to underlie the insulin resistance of type 2 diabetes. However, the relative time course of insulin action in stimulating ATP turnover rate and glucose uptake in skeletal muscle has not been examined. These two parameters were measured in young healthy subjects using the 31P MRS saturation transfer method in conjunction with the euglycaemic hyperinsulinaemic clamp technique respectively. Glucose infusion rate rose rapidly from 0 to 2.90 ± 0.11 mg/kgffm/min during the first 10 min of insulin infusion and further to 6.17 ± 0.57 mg/kgffm/min between 15 and 45 min. In contrast, baseline ATP turnover rate was 9.0 ± 0.4 µmol/g/min of muscle and did not change during the first 45 min of insulin infusion. Between 50 and 80 minutes ATP turnover rate increased by 8% and remained steady to 150 minutes (9.7 ± 0.5 µmol/g/min of muscle, p = 0.03 vs baseline). The in vivo time course of insulin stimulation of skeletal muscle ATP turnover rate is not consistent with a rate limiting effect upon the initiation of insulin-stimulated glycogen synthesis. Copyright © 2010 John Wiley & Sons, Ltd

Role of T198 Modification in the Regulation of p27Kip1 Protein Stability and Function

The tumor suppressor gene p27Kip1 plays a fundamental role in human cancer progression. Its expression and/or functions are altered in almost all the different tumor histotype analyzed so far. Recently, it has been demonstrated that the tumor suppression function of p27 resides not only in the ability to inhibit Cyclins/CDKs complexes through its N-terminal domain but also in the capacity to modulate cell motility through its C-terminal portion. Particular interest has been raised by the last amino-acid, (Threonine 198) in the regulation of both protein stability and cell motility