PCL-based nanoparticles for doxorubicin-ezetimibe co-delivery: A combination therapy for prostate cancer using a drug repurposing strategy.

Introduction: Drug repurposing is an effective strategy for identifying the use of approved drugs for new therapeutic purposes. This strategy has received particular attention in the development of cancer chemotherapy. Considering that a growing body of evidence suggesting the cholesterol-lowering drug ezetimibe (EZ) may prevent the progression of prostate cancer, we investigated the effect of EZ alone and in combination with doxorubicin (DOX) on prostate cancer treatment. Methods: In this study, DOX and EZ were encapsulated within a PCL-based biodegradable nanoparticle. The physicochemical properties of drug containing nanoparticle based on PCL-PEG-PCL triblock copolymer (PCEC) have been exactly determined. The encapsulation efficiency and release behavior of DOX and EZ were also studied at two different pHs and temperatures. Results: The average size of nanoparticles (NPs) observed by field emission scanning electron microscopy (FE-SEM) was around 82±23.80 nm, 59.7±18.7 nm, and 67.6±23.8 nm for EZ@PCEC, DOX@PCEC, and DOX+EZ@PCEC NPs, respectively, which had a spherical morphology. In addition, DLS measurement showed a monomodal size distribution of around 319.9, 166.8, and 203 nm hydrodynamic diameters and negative zeta potential (-30.3, -6.14, and -43.8) mV for EZ@PCEC, DOX@PCEC, and DOX+EZ@PCEC NPs, respectively. The drugs were released from the NPs sustainably in a pH and temperature-dependent manner. Based on the MTT assay results, PCEC copolymer exhibited negligible cytotoxicity on the PC3 cell line. Therefore, PCEC was a biocompatible and suitable nano-vehicle for this study. The cytotoxicity of the DOX-EZ-loaded NPs on the PC3 cell line was higher than that of NPs loaded with single drugs. All the data confirmed the synergistic effect of EZ in combination with DOX as an anticancer drug. Furthermore, fluorescent microscopy and DAPI staining were performed to show the cellular uptake, and morphological changes-induced apoptosis of treated cells. Conclusion: Overall, the data from the experiments represented the successful preparation of the nanocarriers with high encapsulation efficacy. The designed nanocarriers could serve as an ideal candidate for combination therapy of cancer. The results corroborated each other and presented successful EZ and DOX formulations containing PCEC NPs and their efficiency in treating prostate cancer.

L-Ornithine-L-Aspartate and Intermittent Renal Replacement Therapy in Fulminant Hepatitis A: A Case Report

Hepatitis A is a common viral infection worldwide that is transmitted via the fecal-oral route. Since the introduction of an efficient vaccine, the incidence of infection has decreased but the number of cases has risen due to widespread community outbreaks among unimmunized individuals. Classic symptoms include fever, malaise, dark urine, and jaundice, and are more common in older children and adults. People are often most infectious 14 days prior to and 7 days following the onset of jaundice. We will discuss the case of a young male patient, diagnosed with acute hepatitis A, leading to fulminant hepatitis refractory to conventional therapy and the development of subsequent kidney injury. The medical treatment through the course of hospitalization was challenging and included the use of L-ornithine-L-aspartate and prolonged intermittent hemodialysis, leading to a remarkable outcome. Hepatitis A is usually self-limited and vaccine-preventable;supportive care is often sufficient for treatment, and chronic infection or chronic liver disease rarely develops. However, fulminant hepatitis, although rare, can be very challenging to manage as in the case of our patient.Copyright © 2023 The Author(s).

Optimizing lipid management-impact of the COVID 19 pandemic upon cardiovascular risk in England.

BACKGROUND: We sought to understand the impact of the COVID-19 pandemic on lipid-lowering therapy prescribing as a potential cause of the excess cardiovascular mortality seen post-pandemic in England. We examined temporal changes over 3 years in the prescribing of high-intensity and non-high-intensity statin therapy and ezetimibe. SOURCES OF DATA: We utilized data available via the National Health Service (NHS) Business Services Authority (NHSBSA) Information Services Data Warehouse, extracting 3 monthly data from October 2018 to December 2021 on high- and low-intensity statin and ezetimibe prescribing, (commencement, cessation or continuation) through each time period of study and those before, and after, the period of interest. AREAS OF AGREEMENT: Optimizing lipid management is a key component of the NHS Long Term Plan ambition to reduce deaths from cardiovascular disease, stroke and dementia. AREAS OF CONTROVERSY: The COVID-19 pandemic and associated lockdown have seen a significant reduction in prescribing of lipid-lowering therapies. If cardiovascular risk is not to worsen in the forthcoming years, urgent action is needed to ensure that the impact of the pandemic upon optimization of cholesterol and the historical undertreatment of cholesterol is reversed and improved. AREAS TIMELY FOR DEVELOPING RESEARCH: Prescription data available via NHSBSA can support our understanding of the implications of policy and behaviour and highlight the impact of guidelines in practise. GROWING POINTS: Understanding the impact of the COVID-19 pandemic upon cholesterol management and the opportunities for newer lipid-lowering therapies delivered using a population health approach have the potential to enhance lipid-lowering and improve cardiovascular mortality and morbidity and reduce health inequalities.

Trends in Lipid-Lowering Prescriptions by Statin Intensity - United States, 2017-202

Introduction: Almost 30% of US adults have elevated low-density lipid cholesterol (LDL-C) increasing their risk of atherosclerotic cardiovascular disease (ASCVD). The 2018 American College of Cardiology/American Heart Association Multisociety Cholesterol Guideline recommends maximally tolerated statin for those at increased ASCVD risk and add-on therapies (ezetimibe and PCSK9 inhibitors) for those at very high risk with LDL-C>=70 mg/dl, but prescription fill trends are unknown. Method(s): Using the IQVIA Total Patient Tracker database (covering ~93% of outpatient retail prescriptions in the US) from Q1 2017-Q1 2022, we determined counts of patients who filled low-, moderate-, or high-intensity statins alone and with ezetimibe or PCSK9 inhibitors. Overall percent change and joinpoint regression were used to assess trends. Result(s): From Q1 2017-Q1 2022, patients filling any statin intensity increased 25% with the greatest increase in high-intensity statins (64.1%). Concurrent fills of high-intensity statin and ezetimibe rose 210%, with an increase in slope by Q2 2019 for all statin intensities (p<0.001, Figure A). Patients filling a PCSK9 inhibitor and all statin intensities increased over the study period (2124% for high-intensity), with increases in slope in Q2 2019 and continued increase in fills but less sharp rise in Q1 2020 (p<0.001, Figure B). Conclusion(s): Increasing prescription fills of high-intensity statins and add-on ezetimibe and PCSK9 inhibitors indicate uptake of guideline-concordant lipid-lowering therapies for cardiovascular disease prevention. There is need for continuity of PCSK9 inhibitor therapy which may have been disrupted during COVID-19. (Figure Presented).

Impact of the COVID-19 pandemic on cardiovascular heart disease medication use: time-series analysis of England's prescription data during the COVID-19 pandemic (January 2019 to October 2020).

BACKGROUND: Management of high blood pressure (BP) typically requires adherence to medication regimes. However, it is known that the COVID-19 pandemic both interrupted access to some routine prescriptions and changed some patient health behaviours. AIM: This study, therefore, retrospectively investigated prescription reimbursement of cardiovascular (CVD) medicines as a proxy measure for patient adherence and access to medicines during the pandemic. METHODS: A cohort study of all primary care patients in England prescribed CVD medicines. The exposure was to the global pandemic. Prescriptions were compared before and after the pandemic's onset. Statistical variation was the outcome of interest. RESULTS: Descriptive statistics show changes to monthly prescriptions, with wide confidence intervals indicating varying underlying practice. Analysis of variance reveals statistically significant differences for bendroflumethiazide, potassium-sparing diuretics, nicorandil, ezetimibe, ivabradine, ranolazine, colesevelam and midodrine. After the pandemic began (March-October 2020), negative parameters are observed for ACE inhibitors, beta-blockers, calcium channel blockers, statins, antiplatelet, antithrombotics, ARBs, loop diuretics, doxazosin, bendroflumethiazide, nitrates and indapamide, indicating decelerating monthly prescription items (statistically significant declines of calcium channel blockers, antithrombotic, adrenoreceptor blockers and diuretics) of CVD medicines within the general population. Many data points are not statistically significant, but fluctuations remain clinically important for the large population of patients taking these medications. CONCLUSION: A concerning decline in uptake of CVD therapies for chronic heart disease was observed. Accessible screening and treatment alongside financial relief on prescription levies are needed. A video abstract is (4 min 51 s) available: https://bit.ly/39gvEHi.

Cholesterol-lowering drugs for high-risk hypercholesterolemia patients with COVID-19 while on Paxlovid™ therapy.

Paxlovid™ is a promising antiviral oral medication for patients at a high risk of a severe form of COVID-19. Regarding COVID-19 patients who have hypercholesterolemia and are at high or very high risk for an acute atherothrombotic cardiovascular event, we are highlighting patients with heterozygous familial hypercholesterolemia as an example of severe hypercholesterolemia. Unfortunately, the concomitant use of Paxlovid and a statin, which is highly dependent on cytochrome P4507A (CYP3A) for clearance, may result in significant drug interactions. Since an abrupt withdrawal of statin use may cause serious negative rebound effects on the cardiovascular system, it is essential to continue statin treatment also during the 5-day Paxlovid treatment period. During Paxlovid treatment, simvastatin and lovastatin need to be substituted with another statin, such as pravastatin or fluvastatin, while a reduction of the dose of atorvastatin and rosuvastatin is recommended.

Ezetimibe Evaluation as a Treatment of Hyperlipidemia in Patients with Covid-19: A Case Report

The current coronavirus disease known as (COVID-19) which has been declared by the World Health Organization (WHO) in December 2019 as a global health emergency and then after as a pandemic, represents a big challenge to all healthcare systems worldwide specially for managing the infection among patients who are hospitalized, acutely ill or elderly. The death rate caused by COVID-19 is not predictable but is increased by many factors including age, dyslipidemia, diabetes mellitus, obesity, and cardiovascular disorders. Since a lot of patients with these conditions are under lipid-lowering therapy, we carried out this case report study to understand the effectiveness, safety, and potential interactions between Ezetimibe, and patients with acute COVID-19 infection. In this study, the lipid profile, kidney functions, and glycated hemoglobin has been measured baseline and then after 25 days for patient with hyperlipidemia and suffers from acute COVID-19 infection. Serum cholesterol level, HDL, LDL and HDL risk factor were decreased in COVID case by 17%, 10%, 21%, and 7%, respectively. Interestingly, we observed a considerable increase in triglycerides concentration by 13.5%. These findings reveal that Sars-CoV-2 might be a factor interacting with hyperlipidemia-reducing therapy, and lower ezetimibe efficacy. However, larger cohort studies are required to confirm these findings.

Current lipid-lowering approach and LDL target achievement in very high-risk patients: in-hospital results of a high-volume primary percutaneous coronary intervention tertiary center

Background: Low-density lipoprotein-cholesterol (LDL-C) is a well-accepted causal risk factor for atherothrombotic cardiovascular disease. Several randomized controlled trials and meta-analyses have shown that lipid-lowering therapies reduce cardiovascular events and have a positive effect in reducing vulnerable plaques. In particular, the recommended target for LDL-C has become more and more stringent, moving to 1.4 mmol/l (55 mg/dl) for very high-risk patients. According to the 2019 ESC/EAS Guidelines, the current paradigm for lipid management favors a stepwise approach consisting of early initiation of high-intensity statin, followed by subsequent addition of ezetimibe, and ultimately a consideration of PCSK9 inhibitor treatment if LDL-C levels remain elevated. Methods: We recruited 307 patients admitted for acute coronary syndrome (ACS) during the COVID-19 pandemic from March 2020 to December 2020. Baseline LDL-C concentration and prescribed hypolipemiant treatment at hospital admission and discharge were registered. Therefore, we included all consecutive patients identified as very-high cardiovascular risk, according to 2019 ESC guidelines. We stratified our population through variables independently associated with non-attainment of LDL-cholesterol such as hypertension, diabetes, peripheral arterial disease, clinical manifestations of ACS, number of main vessels treated, and complexity of the atherosclerotic disease. Results: 274 patients were included. Mean age was 69,9 years (SD 11,4), 20,8%were women, 23,7%had diabetes, 16,4%had PAD and 32,1 % suffered from valvular disease, mainly with mitral regurgitation or aortic stenosis no more than mild or moderate. Of 25.1% with a previous history of acute myocardial infarction, the 33,3% of whom didn't have statin therapy pre-ACS index (p =0,001). At admission, medium cholesterol levels of patients that underwent previous coronary revascularization (25,5% of the total population) were 84,21 ± 31,2 mg/dL, not in range according to both 2016 and 2019 ESC guidelines. At discharge, 77,37 % of all the patients included received only statin therapy VS 22,63% with statin plus ezetimibe. In the subpopulation of patients with recurring ACS events with LDL pre-admission > 100 mg/dL,despite high dose statin, only 25% of this population were discharged adding ezetimibe (VS 75% who kept on the treatment of high dose statin without up-titration). Conclusions: Management of dyslipidemia is frequently suboptimal and the gap between guidelines and clinical practice for lipid management across Europe has been exacerbated by the 2019 guidelines. A greater utilization of non-statin lipid-lowering therapies is likely needed to reach the LDL-C optimal target. A correct stratification of the risk class would help to identify, in a personalized perspective of treatment, patients at very high risk that would take advantage of more aggressive therapy to reach the lowest target of LDL-C ('the lower is better'). (Figure Presented).

Managing hyperlipidaemia in patients with COVID-19 and during its pandemic: An expert panel position statement from HEART UK.

The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations. Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrants, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen. There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests.

[Lipid treatment in the period COVID-19]. / Tratamiento hipolipemiante en la era COVID-19.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic has shown that cardiovascular diseases carry a higher risk of mortality. Doubts have been raised regarding lipid therapy in these patients. The objectives are to analyze the efficacy and safety of lipid lowering therapy in patients with COVID-19. MATERIAL AND METHODS: A review of the scientific literature was conducted in PubMed, CDC Reports, NIH, and NCBI SARS-CoV-2 using the keywords: COVID-2, statins, ezetimibe, PCSK9 inhibitors, hypercholesterolemia, and hypolipidemic drugs. RESULTS: The statins should continue to use patients with COVID-19 based on their efficacy, safety, immunosuppressive effects, anti-inflammatory availability and accessibility. Depending on the cardiovascular risk levels of these patients, the use of high potency statins and/or ezetimibe and/or iPCSK9 may be necessary in patients with high and very high cardiovascular risk. Patients treated with iPCSK9 should continue treatment for its beneficial effects in preventing cardiovascular disease. Patients with familial hypercholesterolemia and COVID-19 are especially vulnerable to cardiovascular disease and should continue to receive severe lipid lowering therapy. CONCLUSIONS: In patients with COVID-19, the majority of baseline CVDs are of atherosclerotic origin, with the worst prediction for patients with high risk and very high risk of CVD. In these patients, intensive treatment with statins and/or fixed combination with ezetimibe and/or iPCSK9 plays a fundamental role.