The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that ...should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
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•A novel class of fluorobenzohomoadamantanamine‒chlorotacrine hybrids was synthesized.•The hybrids are up to 44-fold more potent than 6-chlorotacrine for hAChE inhibition.•The hybrids are up to 24-fold more potent than 6-chlorotacrine for hBChE inhibition.•The hybrids are up to 2-fold more potent than memantine for NMDA antagonism.•Most of the hybrids are brain permeable, according to the PAMPA-BBB assay.
Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. Multivessel (MV) SCAD is a challenging clinical presentation that might be associated to a worse prognosis ...compared with patients with single-vessel (SV) involvement.
The Spanish multicentre nationwide prospective SCAD registry included 389 consecutive patients. Patients were classified, according to the number of affected vessels, in SV or MV SCAD. Major adverse events (MAE) were analyzed during hospital stay and major cardiac or cerebrovascular adverse events (MACCE) at long-term clinical follow-up.
A total of 41 patients (10.5%) presented MV SCAD. These patients had more frequently a previous history of hypothyroidism (22% vs 11%, p = 0.04) and anxiety disorder (32% vs 16%, p = 0.01). MV SCAD patients presented more often as non-ST segment elevation myocardial infarction (73% vs 52%, p = 0.01) and showed less frequently type 1 angiographic lesions (12% vs 21%, p = 0.04). An impaired initial Thrombolysis In Myocardial Infarction (TIMI) flow 0–1 was less frequent (14% vs 29%, p < 0.01) in MV SCAD. In both groups, most patients were treated conservatively (71% vs 79%, p = NS). No differences were found regarding in-hospital MAE or MACCE at late follow-up (median 29 ± 11 months). However, the rate of stroke was higher in MV SCAD patients, both in-hospital (2.4% vs 0%, p < 0.01) and at follow-up (5.1% vs 0.6%, p = 0.01).
Patients with MV SCAD have some distinctive clinical and angiographic features. Although composite clinical outcomes, in-hospital and at long-term follow-up, were similar to those seen in patients with SV SCAD, stroke rate was significantly higher in patients with MV SCAD.
•MV SCAD patients showed a different clinical and angiographic profile when compared with SV SCAD patients.•There were no significant differences in combined clinical events, in-hospital MAE and follow up MACCE, between groups.•Peripartum status was more frequent among patients with MV SCAD.•MV SCAD patients presented a higher risk of stroke, both during admission and at long-term follow up.
Autologous adipose tissue-derived mesenchymal stem cells (ATMSCs) therapy is a promising strategy to improve post-myocardial infarction outcomes. In a porcine model of acute myocardial infarction, we ...studied the long-term effects and the mechanisms involved in allogeneic ATMSCs administration on myocardial performance.
Thirty-eight pigs underwent 50 minutes of coronary occlusion; the study was completed in 33 pigs. After reperfusion, allogeneic ATMSCs or culture medium (vehicle) were intracoronarily administered. Follow-ups were performed at short (2 days after acute myocardial infarction vehicle-treated, n=10; ATMSCs-treated, n=9) or long term (60 days after acute myocardial infarction vehicle-treated, n=7; ATMSCs-treated, n=7). At short term, infarcted myocardium analysis showed reduced apoptosis in the ATMSCs-treated animals (48.6±6% versus 55.9±5.7% in vehicle;
=0.017); enhancement of the reparative process with up-regulated vascular endothelial growth factor, granulocyte macrophage colony-stimulating factor, and stromal-derived factor-1α gene expression; and increased M2 macrophages (67.2±10% versus 54.7±10.2% in vehicle;
=0.016). In long-term groups, increase in myocardial perfusion at the anterior infarct border was observed both on day-7 and day-60 cardiac magnetic resonance studies in ATMSCs-treated animals, compared to vehicle (87.9±28.7 versus 57.4±17.7 mL/min per gram at 7 days;
=0.034 and 99±22.6 versus 43.3±14.7 22.6 mL/min per gram at 60 days;
=0.0001, respectively). At day 60, higher vascular density was detected at the border zone in the ATMSCs-treated animals (118±18 versus 92.4±24.3 vessels/mm
in vehicle;
=0.045). Cardiac magnetic resonance-measured left ventricular ejection fraction of left ventricular volumes was not different between groups at any time point.
In this porcine acute myocardial infarction model, allogeneic ATMSCs-based therapy was associated with increased cardioprotective and reparative mechanisms and with better cardiac magnetic resonance-measured perfusion. No effect on left ventricular volumes or ejection fraction was observed.
Right ventricle (RV) dysfunction is a main determinant of morbidity and mortality in postcapillary pulmonary hypertension (PH). However, currently there are not available therapies. Since reduced ...nitric oxide (NO) availability and cyclic guanylate monophosphate (cGMP) levels are central in this disease, therapies targeting the NO pathway might have a beneficial effect on RV performance. In this regard, sildenafil has shown contradictory results. Our objective was to evaluate the effect of sildenafil on RV performance in an experimental pig model of postcapillary PH induced by a fixed banding of the venous pulmonary confluent. Animals were evaluated by right heart catheterization and cardiac magnetic resonance before randomization and after 8 weeks on sildenafil (n = 8) or placebo (n = 8), and myocardial tissues were analyzed with histology and molecular biology. At the end of the study, animals receiving sildenafil showed better RV performance as compared with those on placebo (improvement in RV ejection fraction of 7.3% ± 5.8% versus −0.6% ± 5.0%, P= 0.021) associated with less apoptotic cells and gene expression related with reduced oxidative stress and increased anti-inflammatory activity in the myocardium. No differences were observed in pulmonary hemodynamics. In conclusion, in a translational large animal model of chronic postcapillary PH, sildenafil improved RV systolic function independently of afterload. Further research with pharmacological approaches able to manipulate the NO-cGMP axis are needed to confirm this potential cardioprotective effect.
Spontaneous coronary artery dissection (SCAD) is a relatively infrequent cause of acute coronary syndrome. Clinical features, angiographic findings, management, and outcomes of SCAD patients who ...present reduced left ventricular ejection fraction (LVEF) remain unknown.
The Spanish multicentre prospective SCAD registry (NCT03607981), included 389 consecutive patients with SCAD. In 348 of these patients, LVEF could be assessed by echocardiography during the index admission. Characteristics and outcomes of patients with preserved LVEF (LVEF ≥50%, n = 295, 85%) were compared with those with reduced LVEF (LVEF <50%, n = 53, 15%). Mean age was 54 years and 90% of patients in both groups were women. The most frequent clinical presentation in patients with reduced LVEF was ST-segment elevation myocardial infarction (STEMI) (62% vs. 36%, P < 0.001), especially anterior STEMI. Proximal coronary segment and multi-segment involvement were also significantly more frequent in these patients. No differences were found on initial revascularization between groups. Patients with reduced LVEF significantly received more often neurohormonal antagonist therapy, and less frequently aspirin. In-hospital events were more frequent in these patients (13% vs. 5%, P = 0.01), with higher rates of death, cardiogenic shock, ventricular arrhythmia, and stroke. During a median follow-up of 28 months, the occurrence of a combined adverse event did not statistically differ between the two groups (19% vs. 12%, P = 0.13). However, patients with reduced LVEF had higher mortality (9% vs. 0.7%, P < 0.001) and readmission rates for heart failure (HF) (4% vs. 0.3%, P = 0.01).
Patients with SCAD and reduced LVEF show differences in clinical characteristics and angiographic findings compared with SCAD patients with preserved LVEF. Although these patients receive specific medications at discharge, they had higher mortality and readmission rates for HF during follow-up.
Beta-3 adrenergic receptor (β3AR) agonists have been shown to produce vasodilation and prevention of ventricular remodeling in different conditions. Given that these biological functions are critical ...in pulmonary hypertension (PH), we aimed to demonstrate a beneficial effect of β3AR agonists in PH. An experimental study in pigs (
n
= 34) with chronic PH created by pulmonary vein banding was designed to evaluate the acute hemodynamic effect and the long-term effect of β3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of β3AR mRNA and the vasodilator response of β3AR agonists in pulmonary arteries. Single intravenous administration of the β3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different β3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of −2.0 Wood units/m
2
for BRL37344 vs. +1.5 for vehicle,
p
= 0.04; and −1.8 Wood units/m
2
for mirabegron vs. +1.6 for vehicle,
p
= 0.002) associated with a significant improvement in magnetic resonance-measured RV performance. Histological markers of pulmonary vascular proliferation (p27 and Ki67) were significantly attenuated in β3AR agonists-treated pigs. β3AR was expressed in human pulmonary arteries and β3AR agonists produced vasodilatation. β3AR agonists produced a significant reduction in PVR and improved RV performance in experimental PH, emerging as a potential novel approach for treating patients with chronic PH.
Patients with coronary total occlusions are at especially high risk for restenosis and new revascularizations. Sirolimus-eluting stents dramatically improved the clinical outcome of this subset of ...patients in randomized trials, but other drug-eluting stents, mainly the everolimus-eluting stent (currently the most frequently used stent), have not yet been evaluated in patients with coronary total occlusions. The objective was to compare the second-generation everolimus-eluting stent with the first-generation sirolimus-eluting stent in patients with coronary total occlusions.
A total of 207 patients with coronary total occlusions and estimated time since occlusion >2 weeks were randomized to everolimus- or sirolimus-eluting stent. The primary end point was in-stent late loss at 9-month angiographic follow-up (noninferiority trial). Clinical follow-up was performed at 1 and 12 months. In-stent late loss at 9 months was 0.29±0.60 versus 0.13±0.69 mm in patients allocated to sirolimus- and everolimus-eluting stent, respectively. The observed difference in in-stent late loss between both groups was -0.16 mm (95% confidence interval, 0.04 to -0.36 mm; P for noninferiority <0.01). The rate of binary angiographic restenosis was 10.8% and 9.1% in patients allocated to sirolimus- and everolimus-eluting stent, respectively (P=0.709), whereas the rate of vessel reocclusion was 3.2% and 1.1%, respectively (P=0.339). At 12 months, the rate of major adverse events was 15.9% versus 11.1% with sirolimus- and everolimus-eluting stent, respectively (P=0.335), and probable or definitive stent thrombosis occurred in 3.0% and 0.0% of patients, respectively (P=0.075).
In patients with coronary total occlusions, everolimus-eluting stent is as effective as sirolimus-eluting stent.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00793221.
The Target Absorbers for Neutrals (TANs) represent one of the most radioactive regions in the Large Hadron Collider. Seven 40cm long fused silica rods with different dopant specifications, ...manufactured by Heraeus, were irradiated in one of the TANs located around the ATLAS experiment by the Beam RAte of Neutrals (BRAN) detector group. This campaign took place during Run 2 p＋p data taking, which occurred between 2016 and 2018. This paper reports a complete characterization of optical transmission per unit length of irradiated fused silica materials as a function of wavelength (240 nm–1500 nm), dose (up to 18 MGy), and level of OH and H2 dopants introduced in the manufacturing process. The dose delivered to the rods was estimated using Monte Carlo simulations performed by the CERN FLUKA team.
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