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What is known and objective Sacubitril/valsartan ( LCZ696) has been recently approved for the treatment of heart failure ( HF) patients with reduced ejection fraction. Several HF patients receive statins as co-medication. Methods Because clearance of statins is meditated via OATP1B1/1B3, the inhibition potential of these transporters by LCZ696 analytes was evaluated in vitro. Furthermore, an open-label, fixed-sequence clinical study was conducted to determine the effect of LCZ696 on the exposure of simvastatin and its active metabolite simvastatin acid. In this clinical study, 26 healthy subjects received simvastatin 40 mg alone or in combination with LCZ696 or after 1 or 2 h of LCZ696 dosing. Results and discussion Although no significant inhibition by LBQ657 (an active metabolite of sacubitril) and valsartan was observed, sacubitril inhibited OATP1B1 and OATP1B3 in vitro, with IC50 of 1·91 and 3·81 μ m, respectively. Upon co-administration of simvastatin with LCZ696, the Cmax of simvastatin and simvastatin acid decreased by 7% and 13%, respectively. When administered 1 h after LCZ696 dosing, the corresponding Cmax of simvastatin and simvastatin acid decreased by 16% and 4%, respectively. When administered 2 h after LCZ696 dosing, the Cmax of simvastatin decreased by 33% and that of simvastatin acid increased by 16%. However, no notable changes were observed in the AUCs of simvastatin or simvastatin acid upon co-administration or time-separated administration with LCZ696. No notable impact of simvastatin co-administration was observed on the pharmacokinetics of LCZ696 analytes. LCZ696 and simvastatin were generally well tolerated when administered alone or in combination. What is new and conclusions Overall, the results of this study suggest that although sacubitril inhibited OATP1B1 and OATP1B3 in vitro, it does not translate into any clinically relevant in vivo effect. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study is to compare mask leak and delivered ventilation during Neopuff (NP) mask ventilation in two modes: (i) with NP pressure dial hidden and resuscitator watching chest wall (CW) rise with, (ii) CW movement hidden and resuscitator watching NP pressure dial. Methods: Thirty-six participants gave mask ventilation to a modified manikin designed to measure mask leak and delivered ventilation for two minutes in each mode randomly assigned. Paired t-tests were used to analyse differences in mean values. Linear regression was used to determine the association of mask leak with delivered ventilation. Results: Of 7277 inflations analysed, 3621 were observing chest wall mode (CWM) and 3656 observing NP mode (NPM). Mask leak was similar between the groups; 31.6% for CWM and 31.5% (p = 0.56) for NPM. There were no significant differences in airways pressures and expired tidal volumes (TVe) between modes. Mask leak was strongly associated with TVe (R = −0.86 p < 0.0001) and with peak inspiratory pressure (PIP) (R = −0.51 p < 0.0001). TVe was associated with PIP (R = 0.51 p < 0.0001). Conclusion: This study provides reassurance that NP mask leak is not greater when resuscitators watch the NP pressure dial. Mask leak is related to TVe. Mask ventilation training with manikins should include tidal volume measurements. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study is to assess the effects of an intravenous 10 mg/kg loading dose of caffeine base in cerebral oxygenation, cerebral Doppler blood flow velocity and cardiac output in preterm infants. Methods: Preterm neonates <34 weeks gestation were investigated at 1 and 4 h following the loading dose of caffeine using Doppler cerebral sonography, cardiac echocardiography and cerebral spatially resolved near-infrared spectroscopy. Results: Forty infants were studied with a mean gestational age (mean ± standard deviation) of 27.7 (±2.5) weeks, birth weight of 1155 (±431) g and a postnatal age of 2.8 (±2.2) days. Mean Anterior Cerebral Artery peak and time average mean blood flow velocity fell significantly by 14% and 17.7%, respectively at 1 h post-caffeine loading dose, which recovered partially by 4 h. Cerebral Tissue Oxygenation Index fell from pre-dose levels by 9.5% at 1 h with partial recovery to 4.9% reduced at 4 h post-dose. There were no significant changes in left or right ventricular output, transcutaneous oxygen saturation, transcutaneous PCO2 or total vascular resistance. Conclusions: A loading dose of 10 mg/kg caffeine base resulted in significant reduction at 1 h post-dose in cerebral oxygenation and cerebral blood flow velocity with partial recovery at 4 h. [ABSTRACT FROM AUTHOR]

Direct pharmacokinetic/pharmacodynamic relationships for otamixaban were investigated after rising doses in healthy subjects using mixed-effect modeling. Activated partial thromboplastin time, prothrombin time, dilute prothrombin time, and Russell's viper venom-induced clotting time (RVVT) related linearly, whereas Heptest clotting time (HCT) followed a sigmoidal E(max) model. The pharmacokinetic/pharmacodynamic response (slope) and their corresponding interindividual variability (seconds per ng/mL, [% coefficient of variation]) were 0.263 (29%) for Russell's viper venom-induced clotting time, 0.117 (10%) for dilute prothrombin time, 0.058 (19%) for activated partial thromboplastin time, and 0.021 (11%) for prothrombin time. For Heptest clotting time, the parameter estimates with their corresponding interindividual variability (% coefficient of variation) were 71 ng/mL (30%) for EC(50), 186 seconds (64%) for E(max), and 17 seconds (16%) for E(0). The model predicted otamixaban plasma concentrations to double the clotting times that were close to those observed. These pharmacokinetic/pharmacodynamic relationships, together with the predictable pharmacokinetics, allowed the anticoagulant effect at given doses of otamixaban to be foreseen in healthy subjects. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of otamixaban was investigated in healthy male subjects over a wide range of intravenous doses, with duration of administration varying between 1-minute infusions (bolus dose) and 24-hour infusions, using noncompartmental and multicompartmental methods. A global compartmental analysis (2 and 3 compartments) generated a single set of pharmacokinetic parameters, regardless of infusion rate and duration, and took into account the 30% decrease in clearance and volume of distribution observed over the dose range. The 2-compartment model was retained to predict bolus plus 3-hour-infusion doses of otamixaban for future phase (2/3) studies. Otamixaban exhibited in healthy subjects several interesting pharmacokinetic features in view of its potential therapeutic use in coronary thrombosis: a rapid plasma distribution and elimination, a well-described dose-exposure relationship, a low intersubject variability in plasma exposure, and a mixed renal and biliary excretion with constant renal clearance. [ABSTRACT FROM AUTHOR]

Aim: Estimation of end-tidal carbon dioxide (EtCO 2 ) with capnography can guide mask ventilation in infants born at less than 30 weeks of gestation. Chemical-sensitive colorimetric devices to detect CO 2 are widely used at resuscitation. We aimed to quantify EtCO 2 in the first breaths following initiation of mask ventilation at birth and correlated need for endotracheal intubation., Methods: Infants <30 weeks gestation receiving mask ventilation were randomised into two groups of mask-hold technique (one-person vs. two-person). Data on EtCO 2 in the first 30 breaths, time to achieve 5 mmHg, 10 mmHg and 15 mmHg CO 2 using a respiratory function monitor was determined., Results: Twenty-five infants with a mean gestation of 27.3 (±3 weeks) and mean birth weight 920.4 (±188.3 g) were analysed. The median EtCO 2 was 5.6 mmHg in the first 10 breaths, whereas it was 12.6 mmHg for 11-20 breaths and 18 mmHg for 21-30 breaths. There was no significant difference in maximum median EtCO 2 for the first 20 breaths, although EtCO 2 was significantly lower in infants who were intubated (32.0 vs. 15.0, p = 0.018)., Conclusion: EtCO 2 monitoring in infants <30 weeks gestation at birth is feasible and reflective of alveolar ventilation. EtCO 2 may help guide ventilation of preterm infants at birth., (© 2022 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TR LIK066 :TR PCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TR LIK066 :TR PCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TR LIK066 :TR PCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TR LIK066 :TR PCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TR LIK066 :TR PCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To investigate the glucosuric, renal and haemodynamic effects of licogliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, in patients with chronic kidney disease (CKD)., Methods: This multiple-dose, parallel-group, phase II mechanistic study randomized 53 participants (aged 18-78 years, body mass index ≤ 50 kg/m 2 ) with varying degrees of CKD or normal renal function to treatment with licogliflozin (50 mg once daily) or placebo for 7 days. The effects of licogliflozin on 24-h urinary glucose excretion (UGE 24 ), renal function, haemodynamics, pharmacokinetics and safety were assessed., Results: Licogliflozin treatment for 7 days significantly (p < .01) increased UGE 24 from baseline in participants with normal renal function (adjusted mean change: 41.8 [33.6, 49.9] g) or with mild (32.6 [24.1, 41.0] g), moderate A (35.7 [28.6, 42.9] g) or moderate B (20.3 [13.1, 27.5] g) CKD, but not in severe (6.2 [-0.71, 13.18] g) CKD. Licogliflozin reduced urinary electrolytes (sodium, potassium and chloride), blood pressure and urinary volume to varying extents among different groups. Significant increases in renin (p < .05), angiotensin II (p < .05) and aldosterone (p < .01) levels were observed. Adverse events were generally mild, and most commonly included diarrhoea (94%), flatulence (68%) and abdominal pain (21%)., Conclusion: Licogliflozin treatment results in significantly increased UGE and favourable changes in urinary electrolytes and haemodynamics in patients with varying degrees of CKD (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m 2 )., (© 2021 John Wiley & Sons Ltd.)

Aim: To evaluate cerebral autoregulation changes in preterm infants receiving a loading dose of caffeine base., Methods: In a cohort of 30 preterm infants, we extracted measures of cerebral autoregulation using time and frequency domain techniques to determine the correlation between mean arterial pressure (MAP) and tissue oxygenation index (TOI) signals. These measures included the cerebral oximetry index (COx), cross-correlation and coherence measures, and were extracted prior to caffeine loading and in the 2 hours following administration of 10 mg/kg caffeine base., Results: We observed acute reductions in time domain correlation measures, including the cerebral oximetry index (linear mixed model coefficient -0.093, standard error 0.04; p = 0.028) and the detrended cross-correlation coefficient (ρ 5 coefficient -0.13, standard error 0.055; p = 0.025). These reductions suggested an acute improvement in cerebral autoregulation. Features from detrended cross-correlation analysis also showed greater discriminative value than other methods in identifying changes prior to and following caffeine administration., Conclusion: We observed a reduced correlation between MAP and TOI from near-infrared spectroscopy following caffeine administration. These findings suggest an acute enhanced capacity for cerebral autoregulation following a loading dose of caffeine in preterm infants, contributing to our understanding of the physiological impact of caffeine therapy., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: To evaluate the acute effect of intravenous caffeine on heart rate and blood pressure variability in preterm infants., Methods: We extracted and compared linear and nonlinear features of heart rate and blood pressure variability at two time points: prior to and in the two hours following a loading dose of 10 mg/kg caffeine base., Results: We studied 31 preterm infants with arterial blood pressure data and 25 with electrocardiogram data, and compared extracted features prior to and following caffeine administration. We observed a reduction in both scaling exponents (α 1 , α 2 ) of mean arterial pressure from detrended fluctuation analysis and an increase in the ratio of short- (SD1) and long-term (SD2) variability from Poincare analysis (SD1/SD2). Heart rate variability analyses showed a reduction in α 1 (mean (SD) of 0.92 (0.21) to 0.86 (0.21), p < 0.01), consistent with increased vagal tone. Following caffeine, beat-to-beat pulse pressure variability (SD) also increased (2.1 (0.64) to 2.5 (0.65) mmHg, p < 0.01)., Conclusion: This study highlights potential elevation in autonomic nervous system responsiveness following caffeine administration reflected in both heart rate and blood pressure systems. The observed increase in pulse pressure variability may have implications for caffeine administration to infants with potentially impaired cerebral autoregulation., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aims: LCZ696 (angiotensin receptor neprilysin inhibitor) is a novel drug developed for the treatment of heart failure with reduced ejection fraction. Neprilysin is one of multiple enzymes degrading amyloid-β (Aβ). Its inhibition may increase Aβ levels. The potential exists that treatment of LCZ696, through the inhibition of neprilysin by LBQ657 (an LCZ696 metabolite), may result in accumulation of Aβ. The aim of this study was to assess the blood-brain-barrier penetration of LBQ657 and the potential effects of LCZ696 on cerebrospinal fluid (CSF) concentrations of Aβ isoforms in healthy human volunteers., Methods: In a double-blind, randomized, parallel group, placebo-controlled study, healthy subjects received once daily LCZ696 (400 mg, n = 21) or placebo (n = 22) for 14 days., Results: LCZ696 had no significant effect on CSF AUEC(0,36 h) of the aggregable Aβ species 1-42 or 1-40 compared with placebo (estimated treatment ratios 0.98 [95% CI 0.73, 1.34; P = 0.919] and 1.05 [95% CI 0.82, 1.34; P = 0.702], respectively). A 42% increase in CSF AUEC(0,36 h) of soluble Aβ 1-38 was observed (estimated treatment ratio 1.42 [95% CI 1.05, 1.91; P = 0.023]). CSF levels of LBQ657 and CSF Aβ 1-42, 1-40, and 1-38 concentrations were not related (r(2) values 0.022, 0.010, and 0.008, respectively)., Conclusions: LCZ696 did not cause changes in CSF levels of aggregable Aβ isoforms (1-42 and 1-40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin. The clinical relevance of the increase in soluble CSF Aβ 1-38 is currently unknown., (© 2015 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Aim: To determine changes in respiratory mechanics when chest compressions are added to mask ventilation, as recommended by the International Liaison Committee on Resuscitation (ILCOR) guidelines for newborn infants., Methods: Using a Laerdal Advanced Life Support leak-free baby manikin and a 240-mL self-inflating bag, 58 neonatal staff members were randomly paired to provide mask ventilation, followed by mask ventilation with chest compressions with a 1:3 ratio, for two minutes each. A Florian respiratory function monitor was used to measure respiratory mechanics, including mask leak., Results: The addition of chest compressions to mask ventilation led to a significant reduction in inflation rate, from 63.9 to 32.9 breaths per minute (p < 0.0001), mean airway pressure reduced from 7.6 to 4.9 cm H2 O (p < 0.001), minute ventilation reduced from 770 to 451 mL/kg/min (p < 0.0001), and there was a significant increase in paired mask leak of 6.8% (p < 0.0001)., Conclusion: Adding chest compressions to mask ventilation, in accordance with the ILCOR guidelines, in a manikin model is associated with a significant reduction in delivered ventilation and increase in mask leak. If similar findings occur in human infants needing an escalation in resuscitation, there is a potential risk of either delay in recovery or inadequate response to resuscitation., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)