De novo design of bioactive phenol and chromone derivatives for inhibitors of Spike glycoprotein of SARS-CoV-2 in silico.

This work presents the synthesis of 12 phenol and chromone derivatives, prepared by the analogs, and the possibility of conducting an in silico study of its derivatives as a therapeutic alternative to combat the SARS-CoV-2, pathogen responsible for COVID-19 pandemic, using its S-glycoprotein as a macromolecular target. After the initial screening for the ranking of the products, it was chosen which structure presented the best energy bond with the target. As a result, derivative 4 was submitted to a molecular growth study using artificial intelligence, where 8436 initial structures were obtained that passed through the interaction filters and similarity to the active glycoprotein pocket through the MolAICal computational package. Thus, 557 Hits with active configuration were generated, which is very promising compared to the BLA reference link for inhibiting the biological target. Molecular dynamics also simulated these compounds to verify their stability within the active protein site to seek new therapeutic propositions to fight against the pandemic. The Hit 48 and 250 are the most active compounds against SARS-CoV-2. In summary, the results show that the Hit 250 would be more active than the natural compound, which could be further developed for further testing against SARS-CoV-2. The study employs the de novo approach to design new drugs, combining artificial intelligence and molecular dynamics simulations to create efficient molecular structures. This research aims to contribute to the development of effective therapeutic strategies against the pandemic.

Efficacy and Safety of PCSK9 Inhibitors in Hypercholesterolemia Associated With Refractory Nephrotic Syndrome.

INTRODUCTION: Treatment of hypercholesterolemia in refractory nephrotic syndrome remains a therapeutic challenge. There is not enough evidence supporting the efficacy of statins, and these drugs can be associated with an increased incidence of adverse effects. Herein we summarize our clinical experience with 12 patients suffering from refractory nephrotic syndrome with associated vascular disease and uncontrolled hypercholesterolemia despite treatment with statins who were treated with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors. METHODS: Twelve adult patients with primary nephrotic syndrome refractory to multiple lines of immunosuppressive treatment who suffered from clinical atheromatous vascular disease were treated with PCSK9 inhibitors according to the prescription guidelines for secondary prevention of cardiovascular events. Eight patients with refractory nephrotic syndrome without vascular disease treated with atorvastatin comprised the control group. RESULTS: Four weeks after treatment with PCSK9 inhibitors, a statistically significant decrease in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels was observed without significant changes in serum albumin levels or proteinuria. The mean LDL-C decrease was 36.8% ± 4.9% mmol/L at 4 weeks and remained unchanged throughout the follow-up period. In the control group, there were no significant changes in the levels of total cholesterol or LDL-C during the follow-up period. At the diagnosis of nephrotic syndrome, plasma PCSK9 levels were 334 ± 40 ng/mL and correlated significantly with serum LDL-C levels (r = 0.49, P = 0.023). Six months after starting treatment with PCSK9 inhibitors, plasma PCSK9 levels were significantly reduced to values of 190 ± 36 ng/mL (P = 0.001) with a mean relative reduction of 42.3% ± 12.6%. No local adverse effects were seen at the injection site and no significant changes were seen in the levels of transaminase, creatine phosphokinase, or aldolase. CONCLUSION: PCSK9 inhibitors may be an effective and safe alternative for the treatment of hypercholesterolemia associated with refractory nephrotic syndrome.

[Selective cholesterol absorption inhibition as a new prospect in treatment of hypercholesterolemia]. / Inhibición selectiva de la absorción de colesterol: una nueva perspectiva en el tratamiento de la hipercolesterolemia.

Ezetimibe is the first of a new class of lipid-lowering drugs, the 2-azetidinones, which selectively inhibits the absorption of intestinal cholesterol. Ezetimibe's mechanism of action complements that of cholesterol synthesis inhibitors. Ezetimibe as monotherapy or in combination with statins significantly decreases plasma cLDL levels. As monotherapy, ezetimibe is well tolerated with a side-effect profile similar to placebo, whereas in combination with statins no differences in the incidence of myopathy, rhabdomyolysis or elevated liver enzymes are reported.

Inhibición selectiva de la absorción de colesterol: una nueva perspectiva en el tratamiento de la hipercolesterolemia / Selective cholesterol absorption inhibition as a new prospect in treatment of hypercholesterolemia

La ezetimiba es el primer fármaco de una nueva clase de agentes hipolipemiantes, las 2-azetidionas, que actúan selectivamente inhibiendo la absorción intestinal de colesterol. Este mecanismo es complementario al de los inhibidores de la síntesis de colesterol. Tanto en monoterapia como coadministrada con estatinas, contribuye de forma eficaz a la reducción de la concentración plasmática de colesterol unido a lipoproteínas de baja densidad. En monoterapia, la ezetimiba ha demostrado una buena tolerancia con un porcentaje de reacciones adversas similar a placebo, mientras que coadministrada con estatinas no se observó un aumento de la incidencia de miopatía, rabdomiólisis ni elevación de las enzimas hepáticas

Ezetimibe is the first of a new class of lipid-lowering drugs, the 2-azetidinones, which selectively inhibits the absorption of intestinal cholesterol. Ezetimibe's mechanism of action complements that of cholesterol synthesis inhibitors. Ezetimibe as monotherapy or in combination with statins significantly decreases plasma cLDL levels. As monotherapy, ezetimibe is well tolerated with a side-effect profile similar to placebo, whereas in combination with statins no differences in the incidence of myopathy, rhabdomyolysis or elevated liver enzymes are reported

Effects of hypolipidemic treatment on serum markers of vascular inflammation in dyslipidemic men.

BACKGROUND: The purpose of our study was to assess the effect of hypolipidemiant drugs on serum markers of vascular inflammation (E-Selectin, VCAM-1 and MCP-1) in dyslipidemic men without cardiovascular disease. MATERIAL/METHODS: 84 dyslipidemic men were consecutively recruited from the Lipid Unit of a tertiary hospital. The patients were placed on statins (n=44) or fibrates (n=22), depending on the lipid profile, for 4 months. In the control group (n=18), a hypolipidemiant diet alone was indicated. RESULTS: Baseline levels of VCAM-1 and MCP-1 were not correlated with the lipid profile. By contrast, baseline E-Selectin levels correlated directly with glucose and triglyceride levels, and negatively with HDL-C. In multiple regression analysis, HDL-C and glucose concentrations independently influenced E-selectin levels. After treatment, we observed a significant decrease of E-Selectin levels in patients treated with statins, and the changes in E-Selectin levels were inversely associated with HDL-C variations. We did not observe any changes in VCAM-1 levels after the treatment regime we used. Regarding MCP-1, a significant increase was detected in the patients receiving fibrates. In addition, the percentage increment of MCP-1 was higher in patients treated with gemfibrozil than in patients who received bezafibrate. CONCLUSIONS: We observed a reduction in E-Selectin levels after statin therapy. This finding was associated with increased HDL-C. Fibrates, especially gemfibrozil, increased MCP-1 concentrations. This deleterious effect was unrelated to changes in lipid profile, and may help explain why fibrates have less impact than statins in reducing cardiovascular disease.

Atorvastatin versus Bezafibrate in Mixed Hyperlipidaemia : Randomised Clinical Trial of Efficacy and Safety (the ATOMIX Study).

OBJECTIVE: Combined hyperlipidaemia is a common and highly atherogenic lipid phenotype with multiple lipoprotein abnormalities that are difficult to normalise with single-drug therapy. The ATOMIX multicentre, controlled clinical trial compared the efficacy and safety of atorvastatin and bezafibrate in patients with diet-resistant combined hyperlipidaemia. PATIENTS AND STUDY DESIGN: Following a 6-week placebo run-in period, 138 patients received atorvastatin 10mg or bezafibrate 400mg once daily in a randomised, double-blind, placebo-controlled trial. To meet predefined low-density lipoprotein-cholesterol (LDL-C) target levels, atorvastatin dosages were increased to 20mg or 40mg once daily after 8 and 16 weeks, respectively. RESULTS: After 52 weeks, atorvastatin achieved greater reductions in LDL-C than bezafibrate (percentage decrease 35 vs 5; p < 0.0001), while bezafibrate achieved greater reductions in triglyceride than atorvastatin (percentage decrease 33 vs 21; p < 0.05) and greater increases in high-density lipoprotein-cholesterol (HDL-C) [percentage increase 28 vs 17; p < 0.01 ]. Target LDL-C levels (according to global risk) were attained in 62% of atorvastatin recipients and 6% of bezafibrate recipients, and triglyceride levels <200 mg/dL were achieved in 52% and 60% of patients, respectively. In patients with normal baseline HDL-C, bezafibrate was superior to atorvastatin for raising HDL-C, while in those with baseline HDL-C <35 mg/dL, the two drugs raised HDL-C to a similar extent after adjustment for baseline values. Both drugs were well tolerated. CONCLUSION: The results show that atorvastatin has an overall better efficacy than bezafibrate in concomitantly reaching LDL-C and triglyceride target levels in combined hyperlipidaemia, thus supporting its use as monotherapy in patients with this lipid phenotype.

Effect of atorvastatin and bezafibrate on plasma levels of C-reactive protein in combined (mixed) hyperlipidemia.

C-reactive protein (CRP) is a non-specific but sensitive marker of underlying systemic inflammation. High CRP plasma levels correlate with risk for future cardiovascular events. The present study evaluated the effects of atorvastatin (10-40 mg) and bezafibrate (400 mg) on CRP concentrations after 6 and 12 months of treatment in 103 patients with combined (mixed) hyperlipidemia. The number of cardiovascular risk factors present in a given patient was associated with baseline CRP levels. After 6 months and 1 year, atorvastatin treatment was associated with significant (P<0.001) decreases from baseline of CRP concentrations by 29 and 43%, respectively, while bezafibrate-treated patients showed non-significant reductions of 2.3 and 14.6%, respectively (P=0.056 and 0.005 for the respective differences between the two treatment arms at 6 months and 1 year). The magnitude of change in CRP after 1 year was directly related to baseline CRP levels. Covariance analysis showed that CRP decreases in the atorvastatin group were unrelated to total cholesterol and LDL cholesterol reductions; however, they were directly related to triglyceride changes (r=0.28, P=0.047) and inversely related to HDL cholesterol changes (r=-0.28, P=0.045). A model including baseline CRP values and treatment effect showed that atorvastatin use was a significant predictor of change in CRP levels over time (beta=0.82, P=0.023). These results suggest a potential anti-atherosclerotic additional benefit of atorvastatin in patients at a risk of cardiovascular disease.