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68 (0.87-2.48), P  less then  .0001; 2.40 (1.68-3.12), P  less then  .0001; 2.23 (1.48-2.99), P  less then  .0001; and 2.80 (2.03-3.58), P  less then  .0001, respectively. Per 1-unit increase in log-transformed ARR, the multivariable-adjusted odds ratio (95% CI) for conventional, 24-hour, sustained and masked hypertension was 1.70 (1.17-2.28), P = .0004; 1.29 (1.06-1.56), P = .01; 1.82 (1.33-2.49), P = .002; and 1.14 (0.94-1.38), P = .20, respectively. CONCLUSIONS In young adults, ARR was strongly associated with conventional and ambulatory BP. Our data suggest that an aldosterone-driven phenomenon occurs very early in the development of hypertension. BACKGROUND Data regarding emergency department (ED) assessment of acute chest pain (CP) and incidence of myocardial infarction (MI) among adult congenital heart disease (ACHD) patients, relative to the non-congenital population, is lacking. OBJECTIVES To describe MI risk in ACHD patients presenting to the ED with chest pain and to compare clinical characteristics, diagnostic testing patterns, and outcomes to controls. METHODS We retrospectively identified a cohort of ACHD patients presenting with acute CP and matched them with non-ACHD controls at a large tertiary-level ED during the period 1998-2018. RESULTS The congenital and control cohorts comprised 297 patients respectively. While MI was less common among ACHD patients (5.2%) than controls (19.7%), P = .01, arrhythmia (14% vs 6%, P  less then  .001) and acute heart failure (3% vs 0.3%, P = .02) were more often the cause of symptoms. Despite more often presenting with non-anginal CP (81% vs 66%, P  less then  .001) and having fewer CAD risk factors (P = .03), ACHD patients underwent more frequent stress testing (22% vs 14%, P  less then  .001) and underwent invasive coronary angiography with equal frequency (7% vs 8%, P = .99). The trend of greater diagnostic scrutiny for acute coronary disease, in the absence of increased risk, strongly correlated with degree of congenital complexity. Both CP character and HEART Score reliably predicted MI for ACHD patients and controls (both P  less then  .001). CONCLUSION MI is an uncommon cause of CP among ACHD patients presenting to the ED and occurs less frequently than seen in the general population. Established MI predictors, CP character and HEART Score, can reliably identify MI in ACHD patients. BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality worldwide. Exercise intolerance is the main symptom of HFpEF and is associated with a poor quality of life and increased mortality. Currently, there are no approved medications for the treatment of HFpEF. Praliciguat (IW-1973), a novel soluble guanylate cyclase stimulator that may help restore deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine 3',5'-monophosphate signaling, is being investigated for the treatment of patients with HFpEF. Temsirolimus METHODS CAPACITY HFpEF is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacy of praliciguat over 12 weeks in approximately 184 patients with HFpEF. Eligible patients must have evidence supporting clinical HFpEF and at least 2 of the following 4 conditions associated with NO deficiency diabetes/prediabetes, hypertension, obesity, and age >70 years. The primary efficacy end point is the change from baseline in peak VO2 by cardiopulmonary exercise test (CPET). Secondary end points include the change from baseline in 6-minute walk test distance and the change in ventilatory efficiency on CPET, as well as number of CPET responders. Other exploratory end points include changes in echocardiographic parameters, New York Heart Association functional classification, cardiac events, blood and urine biomarkers pathophysiologically relevant to heart failure, and patient-reported outcomes including Kansas City Cardiomyopathy Questionnaire. CONCLUSIONS The CAPACITY HFpEF trial will provide data on short-term safety and efficacy of praliciguat on peak exercise capacity, as well as multiple secondary end points of submaximal functional capacity, patient-reported outcomes, and biomarkers. NADPH-oxidases (NOXs) purposefully produce reactive-oxygen-species (ROS) and are found in most kingdoms of life. The seven human NOXs are each characterized by a specific expression profile and a fine regulation to spatio-temporally tune ROS concentration in cells and tissues. One of the best known roles for NOXs is in host protection against pathogens but ROS themselves are important second messengers involved in tissue regeneration and the modulation of pathways that induce and sustain cell proliferation. As such, NOXs are attractive pharmacological targets in immunomodulation, fibrosis and cancer. We have studied an extensive number of available NOX inhibitors, with the specific aim to identify bona fide ligands versus ROS-scavenging molecules. Accordingly, we have established a comprehensive platform of biochemical and biophysical assays. Most of the investigated small molecules revealed ROS-scavenging and/or assay-interfering properties to various degrees. A few compounds, however, were also demonstrated to directly engage one or more NOX enzymes. Diphenylene iodonium was found to react with the NOXs' flavin and heme prosthetic groups to form stable adducts. We also discovered that two compounds, VAS2870 and VAS3947, inhibit NOXs through the covalent alkylation of a cysteine residue. Importantly, the amino acid involved in covalent binding was found to reside in the dehydrogenase domain, where the nicotinamide ring of NADPH is bound. This work can serve as a springboard to guide further development of bona fide ligands with either agonistic or antagonistic properties toward NOXs. Adenylate cyclases (ACs), play a critical role in the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP). Studies have indicated that adenylyl cyclase type 2 (AC2) is potential drug target for many diseases, however, up to now, there is no AC2-selective agonist reported. In this research, docking-based virtual screening with the combination of cell-based biological assays have been performed for discovering novel potent and selective AC2 agonists. Virtual screening disclosed a novel hit compound 8 as an AC2 agonist with EC50 value of 8.10 μM on recombinant human hAC2 + HEK293 cells. The SAR (structure activity relationship) based on the derivatives of compound 8 was further explored on recombinant AC2 cells and compound 73 was found to be the most active agonist with the EC50 of 90 nM, which is 160-fold more potent than the reported agonist Forskolin and could selectively activate AC2 to inhibit the expression of Interleukin-6. The discovery of a new class of AC2-selective agonists would provide a novel chemical probe to study the physiological function of AC2. Since the discovery and early characterization of the histamine H3 receptor (H3R) in the 1980's, predominantly imidazole-based agonists were presented to the scientific community such as Nα-methylhistamine (Nα-MeHA) or (R)-α-methylhistamine ((R)α-MeHA). Whereas therapeutic applications have been prompted for H3R agonists such as treatment of pain, asthma and obesity, several drawbacks associated with imidazole-containing ligands makes the search for new agonists for this receptor demanding. Accordingly, high interest arose after publication of several pyrrolidindione-based, highly affine H3R agonists within this journal that avoid the imidazole moiety and thus, presenting a novel type of potential pharmacophores (Ghoshal, Anirban et al., 2018). In our present study performed in two independent laboratories, we further evaluated the exposed lead-compound (EC50 = 0.1 nM) of the previous research project with regards to pharmacological behavior at H3R. Thereby, no binding affinity was observed in neither [3H]Nα-MeHA nor bodilisant displacement assays that contradicts the previously published activity. Additional functional exploration employing GTPγ[35S], cAMP-accumulation assay and cAMP response element (CRE)-driven reporter gene assays exhibited slight partial agonist properties of such pyrrolidindiones but acting apart from the reported concentration range. We conclude, that the previously reported actions of such pyrrolidindiones result from an overestimation based on the method of measurement and thus, we cast doubt on the new pharmacophores with H3R agonist activity. Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant. A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT6Rs and 5-HT7Rs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonami in the treatment of BPSD. Tariquidar derivatives have been described as potent and selective ABCG2 inhibitors. However, their susceptibility to hydrolysis limits their applicability. The current study comprises the synthesis and characterization of novel tariquidar-related inhibitors, obtained by bioisosteric replacement of the labile moieties in our previous tariquidar analog UR-ME22-1 (9). CuAAC ("click" reaction) gave convenient access to a triazole core as a substitute for the labile amide group and the labile ester moiety was replaced by different acyl groups in a Sugasawa reaction. A stability assay proved the enhancement of the stability in blood plasma. Compounds UR-MB108 (57) and UR-MB136 (59) inhibited ABCG2 in a Hoechst 33342 transport assay with an IC50 value of about 80 nM and belong to the most potent ABCG2 inhibitors described so far. Compound 57 was highly selective, whereas its PEGylated analog 59 showed some potency at ABCB1. Both 57 and 59 produced an ABCG2 ATPase-depressing effect which is in agreement with our precedent cryo-EM study identifying 59 as an ATPase inhibitor that exerts its effect via locking the inward-facing conformation. Thermostabilization of ABCG2 by 57 and 59 can be taken as a hint to comparable binding to ABCG2. As reference substances, compounds 57 and 59 allow additional mechanistic studies on ABCG2 inhibition. Due to their stability in blood plasma, they are also applicable in vivo. The highly specific inhibitor 57 is suited for PET labeling, helping to further elucidate the (patho)physiological role of ABCG2, e.g. at the BBB.
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