Going Beyond Ceramides in Moisturizers: The Role of Natural Moisturizing Factors.

Xerosis is experienced by almost everyone at some time in their lives and the foundation of management of dry skin (both consumer- and healthcare professional--directed) rests on the use of moisturizers. Given the wide range of available moisturizers, counseling patients about selecting the optimum moisturizer for their individual situation relies on knowledge of ingredients and formulations. Traditionally, the main focus for many moisturizers centered on the core functional and structural role of ceramides within the epidermal barrier.  However, while a key aspect of transepidermal water loss and other skin barrier functions, components other than ceramides are equally essential in increasing moisturization. The skin's natural moisturizing factors (NMFs) are a complex mixture of water-attracting compounds such as amino acids, urea, lactate, pyrrolidone carboxylic acid (PCA), and electrolytes which play a fundamental role in preserving physiologic function by regulating the water content of the stratum corneum. By facilitating water retention, NMFs contribute significantly to the suppleness, elasticity, normal desquamation, and overall integrity of the skin barrier. Incorporation of NMFs into moisturizers addresses critical deficiencies in the skin's moisture balance that exist in xerotic and atopic skin, and in many skin disorders, mitigating signs and symptoms associated with xerosis and promoting optimal skin health. The biochemical composition of NMFs and the intricate interplay with epidermal homeostasis translate to a central role in moisturizers used for prophylactic and therapeutic management of various dry skin conditions, beyond ceramides alone. J Drugs Dermatol. 2024;23(6):466-471.     doi:10.36849/JDD.8358.

Persistent effects of the orexin-1 receptor antagonist SB-334867 on naloxone precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine dependent rats.

AIM OF THE STUDY: In this study, we investigated the effect of long-term administration of orexin receptor 1 (OXR1) antagonist on naloxone-precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine-dependent rats. MATERIALS AND METHODS: Wistar rats received subcutaneous (s.c.) injections of morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. In chronic groups, the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle, was injected repetitively from postnatal day 1 (PND1)-PND23 and then for the following seven days before each morphine injection. Meanwhile, in acute groups, SB-334867, or its vehicle, was administered before each morphine injection. In groups of rats that were designated for withdrawal experiments, naloxone (2.5 mg/kg, i.p.) was administered after the last injection of morphine. In the formalin-induced pain, the effect of OXR1 inhibition on the antinociceptive effects of morphine was measured by injecting formalin after the final morphine injection. RESULTS: Animals that received long-term SB-334867 administration before morphine injection demonstrated a significant reduction in chewing, defecation, diarrhea, grooming, teeth chattering, wet-dog shake, and writhing. Inhibiting OXR1 for a long time increased formalin-induced nociceptive behaviors in interphase and phase II of the formalin-induced pain. CONCLUSIONS: Our results indicated that the inhibition of OXR1 significantly reduces the development of morphine dependence and behavioral signs elicited by the administration of naloxone in morphine-dependent rats. Furthermore, the prolonged blockade of OXR1 might be involved in formalin-induced nociceptive behaviors.

Pharmacokinetics, Disposition, and Biotransformation of [14C]Omecamtiv Mecarbil in Healthy Male Subjects after a Single Intravenous or Oral Dose.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that is currently in clinical development for the treatment of heart failure. The absorption and disposition of [14C]OM (60 µCi) were studied after a single intravenous infusion (35 mg over 1 hour) or oral solution dose (35 mg) in 14 healthy male subjects. Mean recovery of the administered [14C]OM dose was 85.1% and 86.5% over 336 hours for the intravenous and oral routes, respectively. After intravenous dosing, 47.8% and 37.3% of the dose was recovered in urine and feces, respectively; after oral dosing, 48.6% and 38.0% was recovered in urine and feces, respectively. Unchanged OM accounted for a minor percentage of radioactivity in urine (mean 7.7% of dose) and feces (mean 4.1% of dose) across all subjects. The major metabolites recovered in urine and feces were M3 (decarbamoylation product) and sequential metabolite M4 (lactam of M3), which accounted for means of 26.5% and 11.6% of the administered dose, respectively. The CYP4 family of enzymes was primarily responsible for the formation of M3 based on in vitro studies. Other metabolic pathways accounted for 14.9% of the administered dose. In pooled plasma, OM, M3, and M4 accounted for 83.8%, 6.0%, and 3.3% of the total [14C]OM-related materials. No other plasma metabolites constituted more than 3% of the administered dose. The bioavailability for OM solution was 93.5% after rapid and extensive absorption. SIGNIFICANCE STATEMENT: This study characterized the absorption and disposition of OM, a novel small molecule being developed for the treatment of heart failure. OM was primarily cleared through metabolism by the CYP4 family through oxidative cleavage of a terminal carbamate moiety that resembles hydrolysis.

Blockade of orexin receptors in the ventral tegmental area reduced the extinction period of the lateral hypothalamic-induced conditioned place preference in rats.

The orexinergic connection between the lateral hypothalamus (LH) and the ventral tegmental area (VTA) is involved in modulating the reward circuit. The conditioned place preference (CPP) can be induced by microinjection of carbachol, a cholinergic agonist, into the LH. The current research was conducted to understand whether intra-VTA orexin receptors (OXRs) could influence the duration of the extinction period or maintenance of the intra-LH carbachol-induced CPP. To this end, the rats unilaterally received intra-LH carbachol (250 nM) within a 3-day conditioning period. Animals that have already passed the conditioning test were unilaterally administered by intra-VTA microinjection of SB334867, an OX1R antagonist, or TCS OX2 29, an OX2R antagonist during the extinction phase of the LH stimulation-induced CPP. For the first time, our data indicated that daily intra-VTA administration of either SB334867 (30 nM) or TCS OX2 29 (10 and 30 nM) during the extinction period decreased the maintenance of intra-LH carbachol-induced CPP. In conclusion, OXRs in the VTA play crucial roles in the maintenance of reward processes.

Formaldehyde 2% is not a useful means of detecting allergy to formaldehyde releasers- results of the ESSCA network, 2015-2018.

BACKGROUND: Studies suggest that patch testing with formaldehyde releasers (FRs) gives significant additional information to formaldehyde 1% aq. and should be considered for addition to the European baseline series (EBS). It is not known if this is also true for formaldehyde 2% aq. OBJECTIVES: To determine the frequency of sensitization to formaldehyde 2% aq. and co-reactivity with FRs. To establish whether there is justification for including FRs in the EBS. MATERIALS AND METHODS: A 4-year, multi-center retrospective analysis of patients with positive patch test reactions to formaldehyde 2% aq. and five FRs. RESULTS: A maximum of 15 067 patients were tested to formaldehyde 2% aq. and at least one FR. The percentage of isolated reactions to FR, without co-reactivity to, formaldehyde 2% aq. for each FR were: 46.8% for quarternium-15 1% pet.; 67.4% imidazolidinyl urea 2% pet.; 64% diazolidinyl urea 2% pet.; 83.3% 1,3-dimethylol-5, 5-dimethyl hydantoin (DMDM) hydantoin 2% pet. and 96.3% 2-bromo-2-nitropropane-1,3-diol 0.5% pet. This demonstrates that co-reactivity varies between FRs and formaldehyde, from being virtually non-existent in 2-bromo-2-nitropropane-1,3-diol 0.5% pet. (Cohen's kappa: 0, 95% confidence interval [CI] -0.02 to 0.02)], to only weak concordance for quaternium-15 [Cohen's kappa: 0.22, 95%CI 0.16 to 0.28)], where Cohen's kappa value of 1 would indicate full concordance. CONCLUSIONS: Formaldehyde 2% aq. is an inadequate screen for contact allergy to the formaldehyde releasers, which should be considered for inclusion in any series dependant on the frequency of reactions to and relevance of each individual allergen.

Efficacy and Safety of Early Intravenous Landiolol on Myocardial Salvage in Patients with ST-segment Elevation Myocardial Infarction before Primary Percutaneous Coronary Intervention: A Randomized Study.

Early treatment with an oral ß-blocker is recommended in patients with a ST-segment-elevation myocardial infarction (STEMI). In this multicenter study, we evaluated the effects of a continuous administration of landiolol, an ultrashort-acting ß-blocker, before primary percutaneous coronary intervention (PCI) on myocardial salvage and its safety in STEMI patients. A total of 47 Japanese patients with anterior or lateral STEMI undergoing a primary PCI within 12 h of symptom onset were randomized to receive intravenous landiolol (started at 3 µg/min/kg dose and continued to a total of 50 mg; n=23) or not (control; n=24). Patients with Killip class III or more were excluded. The primary outcome was the myocardial salvage index on cardiac magnetic resonance imaging (MRI) performed 5-7 days after the PCI. Cardiac MRI was performed in 35 patients (74%). The myocardial salvage index in the landiolol group was significantly greater than that in the control group (44.4±14.6% vs. 31.7±18.9%, respectively; p=0.04). There were no significant differences in adverse events at 24 h between the landiolol and control groups. A continuous administration of landiolol before a primary PCI may increase the degree of myocardial salvage without additional hemodynamic adverse effects within the first 24 h after STEMI.

Switchability and minimal effect of food on pharmacokinetics of modified release tablet strengths of omecamtiv mecarbil, a cardiac myosin activator.

Omecamtiv mecarbil (OM) is a cardiac myosin activator in clinical development for the treatment of heart failure. The effect of food on the pharmacokinetics (PK) of 25, 37.5, and 50 mg strength modified release (MR) tablets and the bioequivalence of two 25 mg tablets versus one 50 mg MR tablet were evaluated in two open-label, randomized, cross-over studies in healthy subjects. Subjects received two 25 mg tablets or one 50 mg OM MR tablet under fed or fasted states in Study 1 (n = 39), and single oral doses of 25 and 37.5 mg OM MR tablets and to assess its relative bioavailability to the 25 mg MR tablet, a 25 mg oral solution under fed or fasted states in Study 2 (n = 34). The area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax ) of 25, 37.5, or 50 mg OM MR tablets were approximately 13%-22% higher and 31%-40% higher, respectively, when taken with food. The two 25 mg and one 50 mg OM MR tablets were bioequivalent (90% confidence intervals) of the geometric mean ratios for Cmax and AUC of OM were within 0.8-1.25 under the fasted or fed state. OM was well tolerated and all treatment-emergent events were mild in severity and resolved by the end of the study. In conclusion, these studies demonstrated that the effect of food on the PK of OM was minimal at all three studied strengths of the MR tablets, and two 25 mg MR tablets may be switched for one 50 mg MR tablet (EudraCT Number: 2019-003683-44).

Discovery of DS68702229 as a Potent, Orally Available NAMPT (Nicotinamide Phosphoribosyltransferase) Activator.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the nicotinamide adenine dinucleotide (NAD+) salvage pathway. Because NAD+ plays a pivotal role in energy metabolism and boosting NAD+ has positive effects on metabolic regulation, activation of NAMPT is an attractive therapeutic approach for the treatment of various diseases, including type 2 diabetes and obesity. Herein we report the discovery of 1-(2-phenyl-1,3-benzoxazol-6-yl)-3-(pyridin-4-ylmethyl)urea 12c (DS68702229), which was identified as a potent NAMPT activator. Compound 12c activated NAMPT, increased cellular NAD+ levels, and exhibited an excellent pharmacokinetic profile in mice after oral administration. Oral administration of compound 12c to high-fat diet-induced obese mice decreased body weight. These observations indicate that compound 12c is a promising anti-obesity drug candidate.

A novel technique to evaluate nail softening effects of different urea formulations.

Urea has been incorporated into several topical ungual formulations to hydrate and soften the nail plate. In this study, we employed various characterization techniques (visual observation, scanning electron microscopy, measurement of thickness, transonychial water loss, nail electrical resistance, and mechanical study) to investigate the effect of urea concentration on the hydration of bovine hoof membranes - an in vitro model of infected human nails. We obtained inconsistent results in the thickness, transonychial water loss, nail electrical resistance, and scanning electron microscopy studies. In the mechanical study using a modified Texture Analyzer method, we reported an inverse and linear correlation between urea concentrations in the formulations and the force required to puncture the treated membrane (R2 = 0.9582, n ≥ 8). As the urea concentration decreased from 4x to 2x, 1x, and 0x % w/w, the puncture force increased significantly from 0.47 ± 0.07 to 0.77 ± 0.07, 0.91 ± 0.09, and 1.33 ± 0.26 N, respectively (p < 0.05). Thus, urea provided a positive softening effect on the membranes and the puncture force could indicate the urea level in topical formulations. In this study, we provided a novel, efficient, and reliable tool to evaluate the hydration level and physical properties of bovine hoof membranes.

Glycogen synthase kinase 3ß as a potential therapeutic target in synovial sarcoma and fibrosarcoma.

Soft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi-pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3ß, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3ß in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3ß (tyrosine 216-phosphorylated) was higher in synovial sarcoma (SYO-1, HS-SY-II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3ß activity by pharmacological agents (AR-A014418, SB-216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis. These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3ß inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3ß in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3ß as a new and promising therapeutic target for these STS types.

A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma.

Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A "3 + 3" dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.

Amino Acid-Based Poly(ester urea)s as a Matrix for Extended Release of Entecavir.

The use of polymers as excipients for drug delivery has afforded stable formulations that reliably control the release of active pharmaceutical ingredients (APIs). While many materials are available and used, few polymers exhibit the numerous advantages, including amorphous characteristics, noninflammatory properties, and resorbable degradation products, like those of poly(ester urea)s (PEUs). Furthermore, stability issues that arise in various APIs can make formulation optimization difficult. Herein, a series of PEUs were synthesized that vary by the fraction of l-phenylalanine monomer incorporated into the copolymerization. The various PEUs and entecavir monohydrate were dry-mixed at different weight percentages (15, 30, and 50%). Filaments of the PEU formulations were extruded and analyzed quantitatively for drug loading and content uniformity by using µ-CT and UPLC analysis. Drug dissolution profiles from filament segments were monitored over a 4-week period and ultimately showed that the controlled release of entecavir was influenced by the incorporation of the l-phenylalanine within the polymer.

The contribution of orexin receptors within the ventral tegmental area to modulation of antinociception induced by chemical stimulation of the lateral hypothalamus in the animal model of orofacial pain in the rats.

Involvement of the ventral tegmental area (VTA) and the lateral hypothalamus (LH) in the modulation of formalin-induced nociception is well documented. In this study, we investigated the role of orexin 1 (OX1) and orexin 2 (OX2) receptors within the VTA in modulation of the LH-induced antinociception during both phases of orofacial formalin test. Male adult Wistar rats weighing 230-250 g were unilaterally implanted with two stainless steel guide cannulae in the VTA and LH. In two separate supergroups, animals received SB334867 (OX1 receptor antagonist) or TCS OX2 29 (OX2 receptor antagonist), at the doses of 3, 10, and 30 nM/rat into the VTA before intra-LH microinjection of carbachol (250 nM/rat) as a nonselective cholinergic receptor agonist for chemical stimulation of orexinergic neurons in this region. Rats were subcutaneously injected with 1% formalin (50 µl; s) into the orofacial region, 5 min after intra-LH microinjection of carbachol or saline. The blockade of both orexin receptors in the VTA reduced intra-LH carbachol-induced antinociception. However, this effect was greater during the late phases of the orofacial formalin test. The blockade of the OX1 but not OX2 receptors in the VTA affect the pain-related behaviors during the early phase, and also, the contribution of OX2 receptor to modulate the LH-induced antinociceptive responses was greater than OX1 receptor during the late phase of orofacial formalin test. The results indicated the neural pathway projected from the LH to the VTA contributes to the modulation of formalin-induced orofacial pain. Orexinergic drugs might be considered as therapeutic agents for inflammatory pain treatment.

Urea supplementation in rumen and post-rumen for cattle fed a low-quality tropical forage.

We evaluated the differences between the supplementation of urea in rumen and/or abomasum on forage digestion, N metabolism and urea kinetics in cattle fed a low-quality tropical forage. Five Nellore heifers were fitted with rumen and abomasum fistulas and assigned to a Latin square design. The treatments were control, continuous infusion of urea in the abomasum (AC), continuous infusion of urea in the rumen, a pulse dose of urea in the rumen every 12 h (PR) and a combination of PR and AC. The control exhibited the lowest (P < 0·10) faecal and urinary N losses, which were, overall, increased by supplementation. The highest urinary N losses (P < 0·10) were observed when urea was either totally or partially supplied as a ruminal pulse dose. The rumen N balance was negative for the control and when urea was totally supplied in the abomasum. The greatest microbial N production (P < 0·10) was obtained when urea was partially or totally supplied in the abomasum. Urea supplementation increased (P < 0·10) the amount of urea recycled to the gastrointestinal tract and the amount of urea-N returned to the ornithine cycle. The greatest (P < 0·10) amounts of urea-N used for anabolism were observed when urea was totally and continuously infused in the abomasum. The continuous abomasal infusion also resulted in the highest (P < 0·10) assimilation of microbial N from recycling. The continuous releasing of urea throughout day either in the rumen or abomasum is able to improve N accretion in the animal body, despite mechanism responsible for that being different.

Alterations in the Endophyte-Enriched Root-Associated Microbiome of Rice Receiving Growth-Promoting Treatments of Urea Fertilizer and Rhizobium Biofertilizer.

We examined the bacterial endophyte-enriched root-associated microbiome within rice (Oryza sativa) 55 days after growth in soil with and without urea fertilizer and/or biofertilization with a growth-promotive bacterial strain (Rhizobium leguminosarum bv. trifolii E11). After treatment to deplete rhizosphere/rhizoplane communities, washed roots were macerated and their endophyte-enriched communities were analyzed by 16S ribosomal DNA 454 amplicon pyrosequencing. This analysis clustered 99,990 valid sequence reads into 1105 operational taxonomic units (OTUs) with 97% sequence identity, 133 of which represented a consolidated core assemblage representing 12.04% of the fully detected OTU richness. Taxonomic affiliations indicated Proteobacteria as the most abundant phylum (especially α- and γ-Proteobacteria classes), followed by Firmicutes, Bacteroidetes, Verrucomicrobia, Actinobacteria, and several other phyla. Dominant genera included Rheinheimera, unclassified Rhodospirillaceae, Pseudomonas, Asticcacaulis, Sphingomonas, and Rhizobium. Several OTUs had close taxonomic affiliation to genera of diazotrophic rhizobacteria, including Rhizobium, unclassified Rhizobiales, Azospirillum, Azoarcus, unclassified Rhizobiaceae, Bradyrhizobium, Azonexus, Mesorhizobium, Devosia, Azovibrio, Azospira, Azomonas, and Azotobacter. The endophyte-enriched microbiome was restructured within roots receiving growth-promoting treatments. Compared to the untreated control, endophyte-enriched communities receiving urea and/or biofertilizer treatments were significantly reduced in OTU richness and relative read abundances. Several unique OTUs were enriched in each of the treatment communities. These alterations in structure of root-associated communities suggest dynamic interactions in the host plant microbiome, some of which may influence the well-documented positive synergistic impact of rhizobial biofertilizer inoculation plus low doses of urea-N fertilizer on growth promotion of rice, considered as one of the world's most important food crops.

Elevated blood urea nitrogen alters the transcriptome of equine embryos.

High blood urea nitrogen (BUN) in cows and ewes has a negative effect on embryo development; however, no comparable studies have been published in mares. The aims of the present study were to evaluate the effects of high BUN on blastocoele fluid, systemic progesterone and Day 14 equine embryos. When a follicle with a mean (±s.e.m.) diameter of 25±3mm was detected, mares were administered urea (0.4g kg-1) with sweet feed and molasses (n=9) or sweet feed and molasses alone (control; n=10). Blood samples were collected every other day. Mares were subjected to AI and the day ovulation was detected was designated as Day 0. Embryos were collected on Day 14 (urea-treated, n=5 embryos; control, n=7 embryos). There was an increase in systemic BUN in the urea-treated group compared with control (P<0.05), with no difference in progesterone concentrations. There were no differences between the two groups in embryo recovery or embryo size. Urea concentrations in the blastocoele fluid tended to be higher in the urea-treated mares, with a strong correlation with plasma BUN. However, there was no difference in the osmolality or pH of the blastocoele fluid between the two groups. Differentially expressed genes in Day 14 embryos from urea-treated mares analysed by RNA sequencing were involved in neurological development, urea transport, vascular remodelling and adhesion. In conclusion, oral urea treatment in mares increased BUN and induced transcriptome changes in Day 14 equine embryos of genes important in normal embryo development.

Randomized controlled trial of landiolol, a short-acting beta-1 adrenergic receptor blocker, illustrating changes in high-molecular weight adiponectin levels after elective percutaneous coronary intervention.

Adiponectin (APN) has cardioprotective properties and bisoprolol has been reported to increase myocardial APN expression and reduce myocardial damage. Administration of landiolol, which has a higher cardio-selectivity and shorter half-life than bisoprolol, during the percutaneous coronary intervention (PCI) may increase serum APN and high-molecular weight (HMW)-APN, an active form of APN, in patients with stable angina pectoris (SAP). We recruited 70 patients with SAP and randomized them to intravenous landiolol during PCI (N = 35) or control group (N = 35). The primary endpoint was serum APN and HMW-APN level 3 days after PCI. There was no difference in the primary endpoint between the landiolol and control groups (8.93 ± 5.24 vs. 10.18 ± 5.81 µg/mL, p = 0.35 and 3.36 ± 2.75 vs. 4.28 ± 3.13 µg/mL, p = 0.20) for APN and HMW-APN levels, respectively. APN and HMW-APN level were significantly decreased 1 day after PCI [-0.55 ± 0.92 µg/mL (9.87-9.32 µg/mL), p < 0.001 and -0.20 ± 0.45 µg/mL (3.89-3.69 µg/mL), p < 0.001, respectively]. Additionally, the absolute change in HMW-APN was significantly smaller in the landiolol group compared to the control group (-0.08 ± 0.27 vs. -0.31 ± 0.55 µg/mL, p = 0.031). Multiple linear regression analysis showed that use of landiolol was an independent predictor of change in HMW-APN (ß = 0.276, p = 0.014). Serum APN and HMW-APN level 3 days after PCI were similar between patients treated with and without landiolol. APN and HMW-APN decreased 1 day after PCI in the SAP and landiolol mitigated decrease in HMW-APN.

Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke.

Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin's prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state. OM slowed the actin-induced powerstroke, despite a twofold increase in the rate constant for actin-activated phosphate release, the biochemical step in myosin's ATPase cycle associated with force generation and the conversion of chemical energy into mechanical work. We conclude that OM alters the energetics of cardiac myosin's mechanical cycle, causing the powerstroke to occur after myosin weakly binds to actin and releases phosphate. We discuss the physiological implications for these changes.

Successful Combination of Landiolol and Levosimendan in Patients with Decompensated Heart Failure.

Tachycardia and supraventricular tachyarrhythmias often impair cardiovascular capacity in patients with decompensated heart failure (dHF) treated with inotropes. Normalization of heart rhythm or rate typically improves diastolic filling and stroke volume (SV). Thus, isochronal administration of an ultra-short-acting and highly selective ß1-blockers, such as landiolol, along with inotropic calcium-sensitizer medications, such as levosimendan, could benefit patients with dHF.We present a case series of three patients with severe dHF and low ejection fraction who were successfully treated with a combination of landiolol and levosimendan. The co-administration of landiolol and levosimendan was well tolerated, improved cardiac function, normalized SV, and enabled the reduction of norepinephrine dosing in all patients. Additionally, the combination improved the vectorcardiographic spatial QRS-T angle and decreased the corrected QT interval. All patients were successfully discharged from the intensive care unit (ICU).A combination of levosimendan and landiolol was safe and well-tolerated. This combination may be a new option for successful treatment of patients with acute dHF complicated by sinus or supraventricular tachycardias.

Hippocampal orexin receptor blocking prevented the stress induced social learning and memory deficits.

Stress as a homeostatic challenge leads to the malfunction of learning and memory processes, namely social learning and memory. The orexin system is involved in stress responses through connections to the hypothalamic-pituitary axis (HPA). In addition, the hippocampus, a structure vulnerable to stress-induced changes, expresses orexin receptors 1 and 2 (OXr1 and OXr2) in various sub-regions. The present study is aimed at assessing the effects of hippocampal orexin receptor blockade on social learning and memory impairments and anxiety development following stress. Male Wistar rats (220-250 g) underwent cannula implantation in the hippocampus. Acute (two mild electric shocks, 5.5 mA) and chronic stresses (ten days of restraint, 6 h daily) were applied with or without injection of orexin receptor antagonists (SB-334867 or TCS OX 29). Sociability and social novelty in animals were assessed in a three-chamber social maze at the end of stress application. Anxiety and exploratory behavior of animals were then examined, with 20 min intervals, using the open field (OF) and elevated plus maze (EPM) tests, respectively. Cisterna Magna cerebro-spinal fluid (CSF) was drained, before sacrifice, for orexin (OX) assay and trunk blood was collected to measure the plasma corticosterone (CRT). Neither the acute nor the chronic stress could affect the sociability. The acute but not chronic stress prevented the animal from sniffing the familiar caged rat in the novelty session, a response which was reversed following the blockade of both OXRs. Furthermore, acute but not chronic stress, led to increased anxiety and immobility behavior which were both impeded by blocking the orexin receptor (OXR). Conversely, OX content in CSF increased due to chronic restraint stress, an effect that was reversed by orexin blockade. Finally, elevated plasma CRT was recorded in response to both acute and chronic stresses. The observed increase in plasma CRT in chronically-stressed rats was abolished following inhibition of OXRs, however a similar effect was not seen in the acute-stress group. Our results identify hippocampal OXRs as potential candidates capable of preventing acute stress-induced impairments of social novelty and anxiety behavior, and chronic stress-induced plasma CRT and CSF orexin, changes. OXR manipulation may improve adaptation to stress pathophysiology.