To evaluate the incidence of periprocedural creatine kinase-MB (CK-MB) release and its impact on longterm mortality in contemporary percutaneous coronary intervention (PCI) at a tertiary referral ...center.
Retrospective analysis of 4,958 patients undergoing PCI with deployment of at least 1 stent at our center between January 1, 2003 and December 31, 2005. Patients admitted with acute ST-elevation myocardial infarction or cardiogenic shock (n = 617), and patients with no available CK-MB levels (n = 477) were excluded, leaving 3,864 patients for analysis. The outcome measure was all-cause mortality obtained from the National Strategic Tracing Service with patients followed up to June 30, 2006 (mean follow up 22 months). The association between CK-MB level and mortality was examined using Cox proportional hazards analysis.
CK-MB elevation above the upper limit of normal (ULN) was detected in 29.4% patients. A total of 127 deaths were observed during follow up. By multivariate analysis, periprocedural CK-MB was independently associated with an increased risk of death (adjusted hazard ratio for every 10 units: 1.09; 95% CI: 1.05-1.12; p < 0.001). The relationship between the level of CK-MB and mortality was further examined by applying strata of CK-MB levels to the multivariate analysis (adjusted hazard ratio: 1.30, 1.76 and 2.26 for CK-MB levels of 1-3, 3-5 and > 5 the ULN, respectively).
In the current era of PCI, periprocedural myonecrosis, evidenced by CK-MB elevation, is common and is associated with less favorable long-term mortality.
Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets ...for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (
) through structure-guided optimization of our previously published isoindolinone lead (
). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.
Valvular endocarditis after percutaneous coronary intervention is unusual. We report a new case of mitral valve endocarditis after stent implantation to a saphenous vein graft.
Aim:
To conduct a systematic review and meta-analysis on retrograde wiring in chronic total occlusions (CTOs) with focus on its safety and feasibility.
Methods and Results:
We searched publications ...from 1990 to December 2013 in PubMed, Ovid, EMBASE, and the Cochrane database inserting a number of terms relating to the collateral circulation of the heart in CTOs. A total of 18 case series (n range17-462) with a total of 2280 CTO revascularization attempts fulfilled criteria for a study of retrograde wiring of collateral channels in CTOs. There were no randomized studies comparing a primary antegrade with a primary retrograde approach. Procedural CTO revascularization rates ranged from 67% to 90.6% with a large proportion having previously failed an “antegrade” approach. The septal perforator collaterals and epicardial channels were used in 73.2% (n = 1670) and 21.7% (n = 495) of cases. Although collateral/coronary perforation was not infrequent (n = 90, 5%), serious acute complications were uncommon; in the combined population 18 cases of cardiac tamponade (0.8%) and 3 deaths (0.1%). Septal perforating wiring (79.3%) was significantly more likely to be successful compared to epicardial coronary artery wiring (72.5%) when chosen by the operator as a route of retrograde access to the CTO body (relative risk 1.11 95% confidence interval: 1.02-1.20; P = .013).
Conclusion:
Successful retrograde wiring of collateral channels in selected patients undertaken by “CTO dedicated” operators can significantly enhance the chances of revascularization of complex CTOs with a low risk of acute serious complications. Septal perforator channels are significantly more likely to be successfully retrogradely wired compared to epicardial vessels when either is selected, by reference to their anatomical suitability by the operator, as a route of access.
A series of pyrrolidine amino nitrile DPP1 inhibitors have been developed and characterized. The S2 pocket structure–activity relationship for these compounds shows significant gains in potency for ...DPP1 from interacting further with target residues and a network of water molecules in the binding pocket. Herein we describe the X-ray crystal structures of several of these compounds alongside an analysis of factors influencing the inhibitory potency toward DPP1 of which stabilization of the water network, demonstrated using Grand Canonical Monte Carlo simulations and free energy calculations, is attributed as a main factor.
The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by ...activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
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