Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer's Disease Drug Candidate.

Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer's disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile. Leucettinib-21's selectivity (analyzed by radiometric, fluorescence, interaction, thermal shift, residence time assays) reveals DYRK1A as the first target but also some "off-targets" which may contribute to the drug's biological effects. Leucettinib-21 was cocrystallized with CLK1 and modeled in the DYRK1A structure. Leucettinib-21 inhibits DYRK1A in cells (demonstrated by direct catalytic activity and phosphorylation levels of Thr286-cyclin D1 or Thr212-Tau). Leucettinib-21 corrects memory disorders in the Down syndrome mouse model Ts65Dn and is now entering safety/tolerance phase 1 clinical trials.

Bayesian Network Meta-analysis of Randomized Controlled Trials on the Efficacy of Antiarrhythmics in the Pharmacological Cardioversion of Paroxysmal Atrial Fibrillation.

PURPOSE: Since atrial fibrillation (AF) is one of the major arrhythmias managed in hospitals worldwide, it has a major impact on public health. The guidelines agree on the desirability of cardioverting paroxysmal AF episodes. This meta-analysis aims to answer the question of which antiarrhythmic agent is most effective in cardioverting a paroxysmal AF. MATERIALS AND METHODS: A systematic review and Bayesian network meta-analysis, searching MEDLINE, Embase, and CINAHL, were performed, including randomized controlled trials (RCTs) enrolling a population of unselected adult patients with a paroxysmal AF that compared at least two pharmacological regimes to restore the sinus rhythm or a cardioversion agent against a placebo. The main outcome was efficacy in restoring sinus rhythm. RESULTS: Sixty-one RCTs (7988 patients) were included in the quantitative analysis [deviance information criterion (DIC) 272.57; I2 = 3%]. Compared with the placebo, the association verapamil-quinidine shows the highest SUCRA rank score (87%), followed by antazoline (86%), vernakalant (85%), tedisamil at high dose (i.e., 0.6 mg/kg; 80%), amiodarone-ranolazine (80%), lidocaine (78%), dofetilide (77%), and intravenous flecainide (71%). Taking into account the degree of evidence of each individual comparison between pharmacological agents, we have drawn up a ranking of pharmacological agents from the most effective to the least effective. CONCLUSIONS: In comparing the antiarrhythmic agents used to restore sinus rhythm in the case of paroxysmal AF, vernakalant, amiodarone-ranolazine, flecainide, and ibutilide are the most effective medications. The verapamil-quinidine combination seems promising, though few RCTs have studied it. The incidence of side effects must be taken into account in the choice of antiarrhythmic in clinical practice. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2022, CRD42022369433 (Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369433 ).

Right Ventricular Dysfunction in Right Coronary Artery Infarction: A Primary PCI Registry Analysis.

Right ventricular involvement in inferior myocardial infarction (MI) was historically associated with a poor prognosis. However, few studies addressed the impact of right ventricular (RV) dysfunction in the primary percutaneous intervention (pPCI) era. Our aim was to assess the prognostic significance of RV dysfunction in right coronary artery (RCA) related MI treated with pPCI. METHODS: A total of 298 patients with a RCA related MI undergone pPCI between January 2011 and June 2015 were included. RV dysfunction was defined by a RV-FAC <35% at echocardiographic examination and further divided into mild (RV-FAC between 35 and 25%) and moderate-severe (RV-FAC <25%). RV function before discharge was reassessed in 95% of the study cohort. The primary endpoint was overall mortality. Median follow-up was 29 months. RESULTS: In RCA related MI, moderate-severe (HR 5.882, p = 0.002, 95% CI 1.882-18.385) but not mild RV dysfunction independently predicted lower survival at follow-up along with age (HR 1.104, p <0.001, CI 1.045-1.167). Importantly, patients recovering RV function at discharge showed a lower mortality (p = 0.001) vs patients with persistent moderate-severe RV dysfunction) that approached the risk of patients without RV dysfunction at presentation. CONCLUSION: In RCA related MI treated with pPCI, RV dysfunction was one of the strongest independent predictor of lower overall survival. However, patients with only transient RV dysfunction showed a better prognosis compared to patients who had persistent RV dysfunction. The focus on intensive support management of the RV in the first hours after pPCI may be important to overcome the acute phase and to promote RV recovery.

ST-elevation myocardial infarction with reduced left ventricular ejection fraction: Insights into persisting left ventricular dysfunction. A pPCI-registry analysis.

Primary percutaneous coronary intervention (pPCI) largely reduced the rate of left ventricular (LV) dysfunction after ST-segment elevation acute myocardial infarction (STEMI). Though LV recovery begins early following revascularization, the optimal timing for re-assessment of LV function is still unclear. We sought to assess the proportion and timing of LV recovery in STEMI patients presenting with LV dysfunction treated by pPCI and to identify possible early predictors of adverse LV remodeling. STEMI patients with LV ejection fraction (LVEF ≤40%) at presentation treated by pPCI from 2007 to 2013 were included whether they had an available 3-step LVEF assessment (<24h post-pPCI, discharge and follow-up). Primary endpoint was LVEF ≤35% at follow-up. At a median time of 3months, 43 out of 154 patients (28%) had LVEF ≤35%. In patients with persistent LV dysfunction, LVEF was lower at admission and increased less during hospitalization (from 31±6 to 35±4% Vs 35±5 to 43±8% for patients with 3-months LVEF >35%, p<0.001). Independent predictors of 3-months LVEF ≤35% were creatinine at admission, peak troponin I and LVEF. Of note, LVEF re-assessment at discharge (median time 6days, IQR 4-9) showed an increased accuracy to predict 3-months LV dysfunction compared to LVEF at admission (AUC 0.80, 95% CI 0.72-0.88 vs AUC 0.69, 95% CI 0.58-0.79 respectively, p=0.03). In most of patients presenting with STEMI and LV dysfunction, a significant LV recovery can be observed early following pPCI. LVEF measurement at discharge indeed emerged as the best indicator of late persistence of severe LV dysfunction.

[Clinical experience with ferric carboxymaltose in non-dialysis chronic kidney disease]. / Ferro carbossimaltosio nella malattia renale cronica non dialitica: una iniziale esperienza clinica.

BACKGROUND: Patients with non-dialysis-dependent chronic kidney disease (ND-CKD) often show anemia and iron deficiency despite oral iron supplementation caused by poor iron absorption, intolerance and non-compliance. METHODS: We prospectively followed seven adult patients with ND-CKD (eGFR <60 ml/min/1.73m2), anemia (Hb<11 g/dl or treatment with ESA), iron deficiency (TSAT<20% and/or ferritin<100 ng/mL) and intolerant or non-responders to oral iron supplementation. Patients received ferric carboxymaltose (FCM) (single dose of 500 mg iv) eventually followed by further doses if iron deficiency persisted. Hemoglobin, ferritin, TSAT and ESA doses were recorded at baseline and after 2, 4, 8, 12, 16, 20 and 24 weeks. RESULTS: After 2 weeks of FCM, ferritin increased from 5348 to 222154 ng/mL (P<0.05) and remained steady thereafter. The increase of TSAT from baseline (115%) was more gradual being significant from week 4 (198%) up to week 24 (2412%). During the study, patients received on average 2.31.0 injections of FCM, to the amount of 1143440 mg. Hb levels remained stable throughout the study, despite a significant reduction of ESA dosage (from 3426 g/week at baseline to 1116 and 1710 g/week, after 4 and 24 weeks, respectively). On average, the ESA dose saving was 2024 g/week. Even considering the higher cost of FCM, ESA dose reduction allowed shortening overall costs by 673/patient during the 24 weeks of study. CONCLUSION: In ND-CKD patients, FCM is effective in correcting iron deficiency and associated with stable Hb levels and significant decrease of ESA dosage. This allows a marked reduction of costs for anemia correction.

Nephroprotection with saxagliptin.

The nephroprotective effect of the new anti-diabetic drugs acting on incretin system is suggested by preclinical studies. However, no study evaluating kidney effects of these drugs as primary outcome on the long term has been conducted in patients followed in diabetes centers. We designed a pilot observational study involving two diabetes clinics to evaluate the effect of prolonged treatment with saxagliptin on renal function in type 2 diabetics. Patients were enrolled if treated for at least 12 months with saxagliptin without concurrent changes to anti-hypertensive and lipid-lowering therapy. Primary outcome was to evaluate the effect of saxagliptin on albuminuria and estimated glomerular filtration rate (eGFR). Secondary outcomes were the effects of treatment on common clinical and laboratory parameters. Sixty-three patients were enrolled. After 12 months of treatment with saxagliptin, albuminuria declined from a mean (95%CI) of 39 (25-52) to 22 (14-30) mg/l (P<0.001), and the prevalence of increased albuminuria (>20 mg/L) diminished by 27% versus baseline. The anti-albuminuric effect was independent of glycemic and blood pressure control. The eGFR remained unchanged after treatment in the presence of decreased glycated hemoglobin (from 7.1 to 6.7%). Therefore, this pilot study suggests that saxagliptin treatment in diabetic patients at high renal risk is associated with a reduction in albuminuria and GFR stability. Prospective trials are required to confirm the potential nephroprotective effects of saxagliptin.

Contrast-induced nephropathy in patients undergoing primary percutaneous coronary intervention without acute left ventricular ejection fraction impairment.

The prognostic relevance of direct contrast toxicity in patients treated with primary percutaneous coronary intervention remains unclear, owing to the confounding hemodynamic effect of acute left ventricular ejection fraction (LVEF) impairment on kidney function estimation. In the present study, 644 consecutive patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention were prospectively enrolled. Contrast-induced nephropathy (CIN) was defined as an increase in serum creatinine >25% or a decrease in the estimated glomerular filtration rate (eGFR) <25% from baseline in the first 72 hours. The primary end point of the study was major adverse cardiovascular events at 1 year (composite of death, myocardial infarction, target lesion revascularization, and bleeding). Among the global population, the interaction between the LVEF and eGFR at admission to define CIN was statistically significant (p <0.001). When only the 385 patients without acute LVEF impairment (i.e., those with LVEF ≥40%) were considered, 27 (7%) developed postprocedural CIN that was associated with increased major adverse cardiovascular events rate at 1 year of clinical follow-up (38% vs 9%; p <0.001). On adjusted Cox multivariate analysis, CIN was an independent predictor of worse outcomes, both when defined according to creatinine (hazard ratio 3.81, 95% confidence interval 1.71 to 8.48, p = 0.001) or eGFR (hazard ratio 3.77, 95% confidence interval 1.53 to 9.28, p = 0.004) variations. In conclusion, in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, LVEF has a significant interaction with eGFR. When only patients without acute LVEF impairment were considered, CIN confirmed its negative prognostic effect on the 1-year clinical outcomes.

Serum double monoclonal components and hematological malignancies: only a casual association? Review of 34 cases.

A double monoclonal component (MC) detected in the serum and/or urine represents a very rare occurrence (2-6% of monoclonal gammopathies). In this study, we report 34 patients with double serum MCs, focusing on the associated diseases. The diagnosis was made using high-resolution serum protein electrophoresis and immunofixation. Of the 1214 patients with monoclonal gammopathies, 49 had a double MC but only 34 (2.8%) were included in our study. A double MC was associated with hematological malignancies in 20/34 cases. Based on our experience, a double MC is more often associated with other diseases, especially an oncohematological one.

Reversal of angiodysplasia-derived anemia after transcatheter aortic valve implantation.

Aortic valve stenosis associated with angiodysplasia (Heyde's syndrome) and consequent anemia had previously been reported to benefit from surgical aortic valve replacement. In this clinical case an 89-year-old patient with chronic angiodysplasia-derived anemia, characterized by acute phases of active gastrointestinal bleeding experienced a normalization of hemoglobin values after a trans-catheter aortic valve implantation (TAVI) of a self-expandable aortic valve prosthesis (CoreValve, Medtronic Inc., Minneapolis, MN, USA). This is the first, to our knowledge, reported clinical case of remission of angiodysplasia-derived anemia after TAVI.

[Treatment of acute high-risk pulmonary embolism]. / Trattamento dell'embolia polmonare acuta ad alto rischio.

At present, high-risk pulmonary embolism represents a cardiovascular emergency burdened with high in-hospital mortality and characterized by acute right ventricular dysfunction and hemodynamic impairment. In addition to circulatory support and anticoagulation, thrombolytic therapy has become the cornerstone of the treatment in patients presenting with this condition. Despite the recommendations, a consistent proportion of patients does not currently receive thrombolytic therapy. Although performed in a limited number of patients, transcatheter and surgical embolectomy procedures are an alternative or synergistic therapeutic strategy to thrombolysis, enabling a prompt resolution of right ventricular volume overload. In this review, data from the literature are discussed with the aim of defining an algorithm for the treatment of high-risk patients.

Echocardiographic evaluation of systolic and mean pulmonary artery pressure in the follow-up of patients with pulmonary hypertension.

AIMS: To identify a correction of the modified Bernoulli formula used to estimate systolic and mean pulmonary artery pressure [sPAP and mPAP; respectively: sPAP = 4 × TRv (tricuspid regurgitation velocity)(2)+ RAP (right atrial pressure); and mPAP = 0.61sPAP + 2], applicable in the follow-up of pulmonary hypertension (PH) patients. METHODS AND RESULTS: From January 1979 to December 2009, 60 patients with precapillary (class I and IV) and 'out of proportion' PH were consecutively enrolled in the PH Registry of Trieste. All patients underwent both echocardiographic and right heart catheter evaluation. We used a simple-linear-regression method in order to compare sPAP and mPAP Doppler-estimated values with the respective right-heart catheterization invasive variables. The comparison of the estimated with the traditional modified Bernoulli formula echo-Doppler data and the effective invasive values confirmed a significant association between them (for sPAP P< 0.001; for mPAP P= 0.006). Simple-linear-regression-derived formulas were sPAP = 1.07 × (4TRv(2)+ RAP) + 7.4 (1) and mPAP = 1.1 × (0.61sPAP + 2) + 2.5 (2). These regression-corrected formulas were validated in an external population of PH patients. CONCLUSION: Our data suggest that formulas (1) and (2) could be more reliable with respect to the traditional modified Bernoulli equation, when estimating echocardiographically sPAP and mPAP in patients with PH confirmed by right-heart catheterization.

[Amino acid loss during dialysis treatment]. / Perdita di aminoacidi nel corso di terapia emodialitica extracorporea.

Protein-calorie malnutrition is a widespread complication in hemodialysis (HD) patients and is associated with increased mortality. The pathogenesis of malnutrition is multifactorial. Intradialytic amino acid (AA) loss is considered one of the cofactors in the complex mechanisms that lead to malnutrition in HD patients. It has been documented that in each dialysis session there is a 6-8 gram loss of AA into the dialysate, which worsens with the use of high-flux membranes. The intradialytic AA loss is variably compensated by reduction of liver synthesis and increased AA release from muscle stores. In malnourished HD patients the serum AA concentration, especially branched-chain AA (BCAA), is correlated with nutritional status and anorexia, whereas BCAA supplementation improves the nutritional parameters and increases appetite. Further studies are necessary to clarify the role of alterations of AA metabolism in the pathogenesis of malnutrition and the potential beneficial effects of BCAA supplementation or alternative treatments in malnourished patients.