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Among patients with heart failure and a reduced ejection fraction, those who received the cardiac myosin activator omecamtiv mecarbil had a lower incidence of a composite of heart-failure events or cardiovascular death at a median of 22 months than those who received placebo.

Every late autumn, fluttering poplar leaves scatter throughout the campus and city streets. In this work, poplar leaves were used as the raw material, while H[sub.3]PO[sub.4] and KOH were used as activators and urea was used as the nitrogen source to prepare biomass based-activated carbons (ACs) to capture CO[sub.2]. The pore structures, functional groups and morphology, and desorption performance of the prepared ACs were characterized; the CO[sub.2] adsorption, regeneration, and kinetics were also evaluated. The results showed that H[sub.3]PO[sub.4] and urea obviously promoted the development of pore structures and pyrrole nitrogen (N–5), while KOH and urea were more conductive to the formation of hydroxyl (–OH) and ether (C–O) functional groups. At optimal operating conditions, the CO[sub.2] adsorption capacity of H[sub.3]PO[sub.4]– and KOH–activated poplar leaves after urea treatment reached 4.07 and 3.85 mmol/g, respectively, at room temperature; both showed stable regenerative behaviour after ten adsorption–desorption cycles.

Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. Cytokinetics Inc.

Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512. From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18–32, p<0·0001), stroke volume 3·6 mL (0·5–6·7, p=0·0217), left ventricular end-systolic diameter −1·8 mm (−2·9 to −0·6, p=0·0027), left ventricular end-diastolic diameter −1·3 mm, (−2·3 to 0·3, p=0·0128), heart rate −3·0 beats per min (−5·1 to −0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma −970 pg/mL (−1672 to −268, p=0·0069). The frequency of adverse clinical events did not differ between groups. Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. Amgen.

The serotonin-receptor modulator pimavanserin reduces psychosis in patients with Parkinson’s disease. In a randomized discontinuation trial involving patients with psychosis related to several types of dementia, the frequency of relapse over a period of 26 weeks was 13% with pimavanserin and 28% with placebo.

Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223. The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect ( r 2=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. Cytokinetics Inc.

PurposeExcessive tachycardia in resuscitated septic shock patients can impair hemodynamics and worsen patient outcome. We investigated whether heart rate (HR) control can be achieved without increased vasopressor requirements using the titratable highly selective, ultra-short-acting β1-blocker landiolol.MethodsThis randomized, open-label, controlled trial was conducted at 20 sites in 7 European countries from 2018 to 2022 and investigated the efficacy and safety of landiolol in adult patients with septic shock and persistent tachycardia. Patients were randomly assigned to receive either landiolol along with standard treatment (n = 99) or standard treatment alone (n = 101). The combined primary endpoint was HR response (i.e., HR within the range of 80−94 beats per minute) and its maintenance without increasing vasopressor requirements during the first 24 h after treatment start. Key secondary endpoints were 28-day mortality and adverse events.ResultsOut of 196 included septic shock patients, 98 received standard treatment combined with landiolol and 98 standard treatment alone. A significantly larger proportion of patients met the combined primary endpoint in the landiolol group than in the control group (39.8% [39/98] vs. 23.5% [23/98]), with a between-group difference of 16.5% (95% confidence interval [CI]: 3.4–28.8%; p = 0.013). There were no statistically significant differences between study groups in tested secondary outcomes and adverse events.ConclusionThe ultra-short-acting beta-blocker landiolol was effective in reducing and maintaining HR without increasing vasopressor requirements after 24 h in patients with septic shock and persistent tachycardia. There were no differences in adverse events and clinical outcomes such as 28-day mortality vs. standard of care. The results of this study, in the context of previous trials, do not support a treatment strategy of stringent HR reduction (< 95 bpm) in an unselected septic shock population with persistent tachycardia. Further investigations are needed to identify septic shock patient phenotypes that benefit clinically from HR control.

Information on the homogeneity and distribution of .sup.13 carbon (.sup.13 C) and nitrogen (.sup.15 N) labeling in winter wheat (Triticum aestivum L.) is limited. We conducted a dual labeling experiment to evaluate the variability of .sup.13 C and .sup.15 N enrichment in aboveground parts of labeled winter wheat plants. Labeling with .sup.13 C and .sup.15 N was performed on non-nitrogen fertilized (-N) and nitrogen fertilized (+N, 250 kg N ha.sup.-1 ) plants at the elongation and grain filling stages. Aboveground parts of wheat were destructively sampled at 28 days after labeling. As winter wheat growth progressed, [delta].sup.13 C values of wheat ears increased significantly, whereas those of leaves and stems decreased significantly. At the elongation stage, N addition tended to reduce the aboveground [delta].sup.13 C values through dilution of C uptake. At the two stages, upper (newly developed) leaves were more highly enriched with .sup.13 C compared with that of lower (aged) leaves. Variability between individual wheat plants and among pots at the grain filling stage was smaller than that at the elongation stage, especially for the -N treatment. Compared with those of .sup.13 C labeling, differences in .sup.15 N excess between aboveground components (leaves and stems) under .sup.15 N labeling conditions were much smaller. We conclude that non-N fertilization and labeling at the grain filling stage may produce more uniformly .sup.13 C-labeled wheat materials, whereas the materials were more highly .sup.13 C-enriched at the elongation stage, although the [delta].sup.13 C values were more variable. The .sup.15 N-enriched straw tissues via urea fertilization were more uniformly labeled at the grain filling stage compared with that at the elongation stage.

Purpose The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective β1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. Materials and methods We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. Findings Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol ( p  < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. Implications Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. Trial registration NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7

The urea cycle is a metabolic pathway for the disposal of excess nitrogen, which arises primarily as ammonia. Nitrogen is essential for growth and life-maintenance, but excessive ammonia leads to life-threatening conditions. The urea cycle disorders (UCDs) comprise diseases presenting with hyperammonemia that arise in either the neonatal period (about 50% of cases) or later. Congenital defects of the enzymes or transporters of the urea cycle cause the disease. This cycle utilizes five enzymes, two of which, carbamoylphosphate synthetase 1 and ornithine transcarbamylase are present in the mitochondrial matrix, whereas the others (argininosuccinate synthetase, argininosuccinate lyase and arginase 1) are present in the cytoplasm. In addition, N-acetylglutamate synthase and at least two transporter proteins are essential to urea cycle function. Severity and age of onset depend on residual enzyme or transporter function and are related to the respective gene mutations. The strategy for therapy is to prevent the irreversible toxicity of high-ammonia exposure to the brain. The pathogenesis and natural course are poorly understood because of the rarity of the disease, so an international registry system and novel clinical trials are much needed. We review here the current concepts of the pathogenesis, diagnostics, including genetics and treatment of UCDs.