Omega-3 Fatty Acid Ethyl Esters Research Articles

Effect of omega-3 fatty acid ethyl esters on postprandial arterial elasticity in patients with familial hypercholesterolemia

Impaired arterial elasticity reflects increased risk of atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH). Treatment with omega-3 fatty acid ethyl esters (ω-3FAEEs) in FH patients has been shown to improve postprandial triglyceride-rich lipoprotein (TRL) metabolism, including TRL-apolipoprotein(a) [TRL-apo(a)]. Whether ω-3FAEE intervention also improves postprandial arterial elasticity in FH has not been demonstrated. We carried out an 8-week open-label, randomized, crossover trial to test the effect of ω-3FAEEs (4g/day) on postprandial arterial elasticity in 20FH subjects following ingestion of an oral fat load. Fasting and postprandial large (C1) and small (C2) artery elasticity at 4 and 6h were measured by pulse contour analysis of the radial artery. The area under-the-curves (AUCs) (0-6h) for C1, C2, plasma triglycerides and TRL-apo(a) were determined using the trapezium rule. Compared with no treatment, ω-3FAEEs significantly increased fasting (+9%, P<0.05) and postprandial C1 at 4h (+13%, P<0.05) and at 6h (+10%, P<0.05), with improvement in the postprandial C1 AUC (+10%, P<0.01). ω-3FAEEs also decreased postprandial triglyceride and TRL-apo(a) AUCs (-17% and-19%, respectively, P<0.05). ω-3FAEEs had no significant effect on fasting and postprandial C2. The change in C1 AUC was inversely associated with the changes in the AUC of triglycerides (r=-0.609, P<0.01) and TRL-apo(a) (r=-0.490, P<0.05). High-dose ω-3FAEEs improves postprandial large artery elasticity in adults with FH. Reduction in postprandial TRL-apo(a) with ω-3FAEEs may contribute to the improvement in large artery elasticity. However, our findings need to be confirmed in a larger population. https://www. com/NCT01577056.

Marine-Derived Compounds Applied in Cardiovascular Diseases: Submerged Medicinal Industry

Cardiovascular diseases (CVDs) are among the most impactful illnesses globally. Currently, the available therapeutic option has several side effects, including hypotension, bradycardia, arrhythmia, and alteration in different ion concentrations. Recently, bioactive compounds from natural sources, including plants, microorganisms, and marine creatures, have gained a lot of interest. Marine sources serve as reservoirs for new bioactive metabolites with various pharmacological activities. The marine-derived compound such as omega-3 acid ethyl esters, xyloketal B, asperlin, and saringosterol showed promising results in several CVDs. The present review focuses on marine-derived compounds' cardioprotective potential for hypertension, ischemic heart disease, myocardial infarction, and atherosclerosis. In addition to therapeutic alternatives, the current use of marine-derived components, the future trajectory, and restrictions are also reviewed.

Effect of omega-3 ethyl esters on the triglyceride-rich lipoprotein response to endotoxin challenge in healthy young men

Oxylipins are produced enzymatically from polyunsaturated fatty acids, are abundant in triglyceride-rich lipoproteins (TGRLs), and mediate inflammatory processes. Inflammation elevates TGRL concentrations, but it is unknown if the fatty acid and oxylipin compositions change. In this study, we investigated the effect of prescription ω-3 acid ethyl esters (P-OM3; 3.4 g/d EPA + DHA) on the lipid response to an endotoxin challenge (lipopolysaccharide; 0.6 ng/kg body weight). Healthy young men (N = 17) were assigned 8–12 weeks of P-OM3 and olive oil control in a randomized order crossover study. Following each treatment period, subjects received endotoxin challenge, and the time-dependent TGRL composition was observed. Postchallenge, arachidonic acid was 16% [95% CI: 4%, 28%] lower than baseline at 8 h with control. P-OM3 increased TGRL ω-3 fatty acids (EPA 24% [15%, 34%]; DHA 14% [5%, 24%]). The timing of ω-6 oxylipin responses differed by class; arachidonic acid-derived alcohols peaked at 2 h, while linoleic acid-derived alcohols peaked at 4 h (pint = 0.006). P-OM3 increased EPA alcohols by 161% [68%, 305%] and DHA epoxides by 178% [47%, 427%] at 4 h compared to control. In conclusion, this study shows that TGRL fatty acid and oxylipin composition changes following endotoxin challenge. P-OM3 alters the TGRL response to endotoxin challenge by increasing availability of ω-3 oxylipins for resolution of the inflammatory response.

Cardiovascular and lipid-lowering effects of a marine lipoprotein extract in a high-fat diet-induced obesity mouse model.

Obesity is a major health challenge worldwide, with implications for diabetes, hypertension and cardiovascular disease (CVD). Regular consumption of dark-meat fish is linked to a lower incidence of CVD and associated metabolic disorders due to the presence of long-chain omega-3 fatty acid ethyl esters in fish oils. The aim of the present study was to determine whether a marine compound like a sardine lipoprotein extract (RCI-1502), regulates fat accumulation in the heart of a high-fat diet-induced (HFD) mouse model of obesity. To investigate its effects in the heart and liver, we conducted a randomized, 12-week placebo-controlled study in which we analyzed the expression of vascular inflammation markers, obesity biochemical patterns and related CVD pathologies. Male HFD-fed mice treated with a RCI-1502-supplemented diet showed reduced body weight, abdominal fat tissue and pericardial fat pad mass density without systemic toxicity. RCI-1502 significantly reduced triacylglyceride, low-density lipoprotein and total-cholesterol concentrations in serum, but increased HDL-cholesterol levels. Our data show that RCI-1502 is beneficial for reducing obesity associated with a long-term HFD, possibly by exerting a protective effect on lipidic homeostasis, indicated also by histopathological analysis. These results collectively indicate that RCI-1502 acts as a cardiovascular therapeutic nutraceutical agent, which modulates fat-induced inflammation and improves metabolic health.

Study protocol of the PROUD48 study comparing the effects of pemafibrate and omega-3 fatty acid ethyl esters on ApoB-48 in statin-treated patients with dyslipidaemia: a prospective, multicentre, open-label, randomised, parallel group trial in Japan

IntroductionThis study will compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl esters on fasting apolipoprotein B-48 (apoB-48), a surrogate marker reflecting postprandial hypertriglyceridaemia, which is a residual...

Phase II trial of moderate dose omega-3 acid ethyl esters for colorectal cancer prevention in patients with lynch syndrome (COLYNE).

TPS209 Background: Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome and is responsible for about 3% of newly diagnosed CRC. It is caused by germline mutations in one of the DNA mismatch repair (MMR) genes, and patients with LS carry a lifetime risk of CRC ranging between 10% and 70%. The role of inflammation in driving this malignant transformation is now well established and retrospective studies have revealed a potential chemo-preventative role for omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), possibly via inhibition of inflammatory pathways associated with the development of defective MMR CRC tumors. While patients with LS have the highest risk of developing CRC, the majority of chemoprevention trials are focused on sporadic CRC. Effective interventions to reduce the risk of developing CRC in this population are limited to close surveillance and surgical prophylaxis. There is an unmet need for safe, effective, and non-invasive chemo-preventive interventions in patients with LS. Methods: This pilot study is a single-arm, open-label, phase 2 clinical trial of omega-3 acid ethyl esters (generic Lovasa; 2 grams orally once daily) for adult patients (≥ 18 years of age) with confirmed LS (based on germline testing of the MMR genes panel: MLH1, MSH2, MSHS6, PMS2 or deletion in EPCAM gene). Patients who are not candidate for elective endoscopy and/or with prior history of right sided or pan-colectomy are excluded. Thirty-four patients are expected to enroll, with a primary objective to determine the feasibility (defined as 80% retention rate) of 12 months of treatment with 2 grams capsules of omega-3 acid ethyl esters daily. Secondary endpoints include safety and tolerability of the intervention. Correlative aims include pre and post treatment assessment of colon mucosal tissue proliferation (right sided colon specimens will be evaluated for markers of proliferation (Ki-67) and apoptosis (Caspase-3)), the effect of omega-3 acid ethyl esters on inflammatory markers in serum, urine and feces (PGE-2, COX-2, β-catenin levels, and EPA:AA ratios), and gene expression related to proliferation, apoptosis and cell survival in colon tissue (NF-κB/Wnt pathways). The impact of omega-3 acid ethyl esters on intestinal microbiota will also be assessed (16S rRNA-based profiling). Correlative Colon tissue, serum, urine and feces samples are collected at baseline and at 12 months. The study is actively enrolling with 20 patients enrolled at the time of submission. Clinical trial information: NCT03831698.

Use of Guideline Directed Lipid Lowering Therapy among Patients with Diabetes without ASCVD in a Large Cardiology Practice

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Patients with diabetes mellitus (DM) are considered high-risk for ASCVD. Current guidelines recommend a moderate to high-intensity statin for the primary prevention of ASCVD in adult patients with DM and once on a maximally tolerated statin icosapent ethyl if with multiple risk factors and elevated triglycerides. <h3>Objective/Purpose</h3> To assess adherence with these guidelines among cardiologists in a single large cardiology practice. <h3>Methods</h3> We identified 8,834 patients (age > 20) with DM and no history of ASCVD who had at least one office visit between December 2019 and November 2020. Patient characteristics, laboratory data and medications were extracted from their electronic health record (EHR). <h3>Results</h3> The mean age was 67.8 +/- 12.1 years, 50.4% were female and 70.1% were white. In total 1,707 (19.3%) were on no statin therapy, 472 (7.9%) on low intensity statin, and 6,645 (75.3%) on guideline directed statin therapy (moderate to high intensity). Among patients aged 40 to 75, 74.2% were on guideline directed statin therapy. Of the 8,834 patients: 7,213 (81.6%) had an LDL-C in their EHR, of which 1,541 (21.4%) had an LDL-C > 100 mg/dL. Of patients with an LDL-C > 100 mg/dL, only 145 (9.4%) were on either ezetimibe or a bile acid sequestrant. In total 7,194 patients had a triglyceride level in their EHR, of which 2,583 (30.8%) had elevated triglycerides (> 150 mg/dL). In patients with elevated triglycerides, 66.7% were on no triglyceride lowering medication, 10.6% were on a fibrate, 10.4% on over-the-counter fish oil, 5.8% on omega-3 fatty acid ethyl ester, 5.5% on icosapent ethyl (6.1% for triglycerides > 150 and LDL-C < 100 mg/dL), and 1.0% on niacin. <h3>Conclusions</h3> Over one-fourth of patients with DM without ASCVD in a large cardiology practice are on no statin or on a lower than guideline directed statin intensity and over 1 in 5 have an LDL-C > 100 mg/dL. High triglycerides are common, often not treated and when treated the most common medications are a fibrate or over-the-counter fish oil. The use of icosapent ethyl is low. There is a need to identify strategies to improve the delivery of guideline directed lipid-lowering therapy to reduce residual ASCVD risk in those with DM.

Analysis of the impact on the health care budget and consumers of the use of the preparation of omega-3 acid ethyl esters90 in the treatment of patients with atherogenic dyslipidemia.

Aim To evaluate economic results of using omega-3 acid ethyl esters 90 for primary prevention of cardiovascular catastrophes in patients with residual hypertriglyceridemia (HTG).Material and methods The economic evaluation of using the medicine omega-3 acid ethyl esters 90 in the system of drug provision of the population of the Russian Federation was performed by analyzing the effect on the budget using a pharmacoeconomic model developed with the Microsoft Office Excel 2016 software. The effect of omega-3 acid ethyl esters 90 was evaluated in 555 643 patients with residual HGT (Moscow). The study lasted for one year. Results of the meta-analysis by A.A. Bernasconi et al. (2020) were used as a source of efficacy data. The following direct and indirect medical expenses for treatment of cardiovascular complications of residual HTG were taken into account in this study: expenses for drug therapy; expenses for therapy and rehabilitation for nonfatal complications; expenses for fatal outcomes; state support for disability; foregone per capita gross domestic product resulting from losses of earnings due to temporary incapacity to labor by people of work-able age; and salary payments for temporary incapacity to work.Results Using omega-3 acid ethyl esters 90 in 555 643 patients with residual HTG will allow preventing 1 437 fatal ischemic cardiovascular complications (including 564 deaths from ischemic heart disease and 1 128 cases of myocardial infarction (MI), including 558 fatal cases of MI). Furthermore, the difference in expenses compared to the high-dose statin treatment alone will be 359 252 253 rubles or 0.32 %.Conclusion The results of this comprehensive pharmacoeconomical study showed that the use of omega-3 acid ethyl esters 90 in patients with residual HGT is an economically preferrable strategy compared to high-dose statin treatment alone and does not influence significantly the budgetary expenses as a part of the State Guarantee of Free Medical Care to the Citizens of the Russian Federation (increase in expenses by 0.32 % compared to the current practice). At the same time, the use of omega-3 acid ethyl esters 90 results in a 10% decrease in the number of fatal ischemic cardiovascular complications.

An abundant biliary fatty acid metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides

Background and Aims: Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here we identify in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increase to concentrations similar to those of steroidal bile acids. We aimed to determine physiological function of this metabolite.

Microalgal feedstock for the production of omega-3 fatty acid ethyl esters and ɛ-polylysine

Microalgal omega-3 fatty acids are considered as an efficient alternative for fish-based omega-3 fatty acids. Ethyl esters derived from omega-3 fatty acids are being considered as the drug for hypertriglyceridemia. In this study, omega-3 fatty acids rich Chlorella sp. was utilized for the transesterification for the ethyl ester production using a potassium carbonate alkaline catalyst. At the optimized conditions of transesterification, 86.2% ethyl ester yield was achieved with solvent to algae ratio (20 mL/g), water addition (45 %), catalyst (4 %), temperature (75°C), and reaction time (60 min). Additionally, the acid-hydrolysed spent biomass was used for the production of ɛ-polylysine by fermentation using Streptomyces sp. as fermentative organism. The maximum yield of 1.78 g/L was achieved after 90 h fermentation. This study established a biorefinery approach where two highly valuable compounds could be produced from the Chlorella sp. by transesterification followed by fermentation.

An abundant biliary metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides.

Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified, despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here, we identified in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increased to concentrations similar to those of steroidal bile acids. The biliary docosahexaenoic acid-containing (DHA-containing) NAT C22:6 NAT was increased in human and mouse plasma after dietary omega-3 fatty acid supplementation and potently inhibited intestinal triacylglycerol hydrolysis and lipid absorption. Supporting this observation, genetic elevation of endogenous NAT levels in mice impaired lipid absorption, whereas selective augmentation of C22:6 NAT levels protected against hypertriglyceridemia and fatty liver. When administered pharmacologically, C22:6 NAT accumulated in bile and reduced high-fat diet-induced, but not sucrose-induced, hepatic lipid accumulation in mice, suggesting that C22:6 NAT is a negative feedback mediator that limits excess intestinal lipid absorption. Thus, biliary omega-3 NATs may contribute to the hypotriglyceridemic mechanism of action of fish oil and could influence the design of more potent omega-3 fatty acid-based therapeutics.

Sustainable Synthesis of Omega-3 Fatty Acid Ethyl Esters from Monkfish Liver Oil

The search for economic and sustainable sources of polyunsaturated fatty acids (PUFAs) within the framework of the circular economy is encouraged by their proven beneficial effects on health. The extraction of monkfish liver oil (MLO) for the synthesis of omega-3 ethyl esters was performed to evaluate two blending systems and four green solvents in this work. Moreover, the potential solubility of the MLO in green solvents was studied using the predictive simulation software COnductor-like Screening MOdel for Realistic Solvents (COSMO-RS). The production of ethyl esters was performed by one or two-step reactions. Novozym 435, two resting cells (Aspergillus flavus and Rhizopus oryzae) obtained in our laboratory and a mix of them were used as biocatalysts in a solvent-free system. The yields for Novozym 435, R. oryzae and A. flavus in the one-step esterification were 63, 61 and 46%, respectively. The hydrolysis step in the two-step reaction led to 83, 88 and 93% of free fatty acids (FFA) for Novozym 435, R. oryzae and A. flavus, respectively. However, Novozym 435 showed the highest yield in the esterification step (85%), followed by R. oryzae (65%) and A. flavus (41%). Moreover, selectivity of polyunsaturated fatty acids of R. oryzae lipase was evidenced as it slightly esterified docosahexaenoic acid (DHA) in all the esterification reactions tested.

Abstract 13318: Omega-3 Ethyl Esters and Atrial Fibrillation or Flutter in Patients With Coronary Artery Disease: Results From a Randomized Trial

Introduction: Statins have led to significant reductions in cardiovascular disease (CVD) events; however, a high level of residual cardiovascular risk remains. The REDUCE-IT trial showed additional benefit with icosapent ethyl to statins in reducing CVD morbidity and mortality. However, the safety of omega-3 ethyl esters with regards to atrial fibrillation (Afib) in patients with coronary artery disease (CAD) remains unclear. Hypothesis: We hypothesize that omega-3 ethyl esters may influence the risk of Afib or flutter in patients with CAD. Methods: In total, 285 CAD patients on statins were randomized to high dose omega-3 ethyl esters (1.86 g of Eicosapentaenoic acid [EPA] and 1.5 g of Docosahexaenoic acid [DHA]) or no omega-3 for 30 months. The incidence and recurrence of Afib or flutter was compared in those on EPA/DHA plus statin to statin alone (control). Results: A total of 240 patients were included in the analysis and no difference in baseline characteristics was observed (Table A). In total, 19 patients were in Afib or flutter during the trial: 12 in EPA/DHA and 7 in control (9.5% vs. 6.1%, respectively, p=0.33). The incidence of new onset Afib or flutter within 30 months was 7.2% and 4.9% in patients receiving omega-3 ethyl esters compared to controls, respectively (p=0.48). No significant difference in recurrence of Afib occurred among patients with a history of paroxysmal Afib receiving omega-3 ethyl esters compared to control (26.7% vs. 16.7%, respectively, p=0.53) (Table B). Conclusions: EPA/DHA did not increase the incidence of Afib or flutter in patients with established CAD. Further studies are warranted to better understand the effects of omega-3 ethyl esters on the cardiac conduction system.

Optimisation of omega-3 concentration and sensory analysis of chia oil

The objective of this study was to obtain concentrated α-linolenic acid ethyl esters from chia oil with values of chemical indicators permitted by current legislation for edible oils and its sensory quality was determined. In the transesterification reaction, sodium hydroxide catalyst concentration and alcohol: oil molar ratios were studied. The model of transesterification with artificial neural networks showed an optimum at a catalyst concentration of 0.387 gNaOH/100goil and a 12.7:1 alcohol: oil molar ratio. The urea complexation was carried out at weight ratios urea: omega-3 fatty acid ethyl esters of 0.5:1, crystallisation at −10 °C for 24 h. Molecular distillation was carried out in one and two stages, where the best results were provided by using one stage, a distillation temperature of 85 °C and pressure of 1.579 × 10−5 atm. The combination of transesterification, urea complexation and molecular distillation allowed obtaining an increase of 24.50 % of omega -3 fatty acids ethyl esters in the final product. This product contains 781.35 g/ kg omega-3, and values of free fatty acids and peroxide of 0.693 % and 1.052 meqO2/kg, respectively. Chia oil presents the higher values of nutty and cream flavour (positive attributes), and turbidity. In the final product these attributes diminishes considerably.

Elective carotid stenting after urgent best medical treatment suppresses recurrent stroke in patients with symptomatic carotid artery severe stenosis

ObjectiveUrgent carotid endarterectomy and carotid artery stenting (CAS) for symptomatic advanced carotid artery stenosis is controversial because carry risks of hemorrhagic and thromboembolic complications. As treatments for preventing recurrent stroke have recently advanced, this study evaluated whether elective CAS with urgent best medical therapy reduces recurrent stroke for symptomatic severe carotid artery stenosis. Patients and methodsA total of 131 consecutive patients who underwent CAS for severe stenosis of the carotid artery between 2013–2017 were divided into acute ischemic minor stroke (AIMS) and Asymptomatic groups. The AIMS group comprised 59 patients presenting with minor stroke who underwent elective CAS with oral dual antiplatelet therapy, statin therapy, and add-on oral omega-3 fatty acid ethyl esters from 4 weeks before CAS. The Asymptomatic group comprised 72 patients treated with best medical therapy for 4 weeks before CAS. ResultsNo recurrent ischemic stroke was observed under urgent best medical treatment before elective CAS in the AIMS group. Although the frequency of vulnerable plaque and degree of stenosis were much higher in the AIMS group, no significant differences were seen in perioperative complications. Baseline serum eicosapentaenoic acid (EPA) levels and EPA/ arachidonic acid (AA) were significantly lower in the AIMS group (p = 0.04, 0.04, respectively) and serum EPA/AA was significantly increased a day before CAS and 3 months after CAS compared with baseline. ConclusionUrgent best medical treatment reduces recurrent stroke and facilitates safe elective CAS in patients with symptomatic and severe carotid artery stenosis.

SAT-569 Management of Severe Gestational Hypertriglyceridemia

Background: Severe gestational hypertriglyceridemia is a dangerous and life threatening illness. Management can be difficult due to the limited data on safety of medical therapy during pregnancy. We present a case of severe gestational hypertriglyceridemia.Case Presentation: A 29 year old woman, G4P2012 at 23w3d, with a past medical history of gestational diabetes, nontoxic thyroid nodule, and hypertriglyceridemia presented to the emergency room for abdominal pain and nausea. She has no known family history of lipid disorders. Her last pregnancy was complicated by acute pancreatitis due to hypertriglyceridemia. Between pregnancies, her triglyceride level was >900 mg/dL and gemfibrozil therapy was advised, however reported nonadherence. In current pregnancy and after counseling, she was prescribed omega-3 acid ethyl esters (Lovaza) 2 grams twice a day and referred to maternal fetal medicine. Triglyceride level on admission was 3640 mg/dL, and she admitted to poor adherence to Lovaza. Liver function tests were within normal limits. She was started on an insulin drip, as well omega-3 fatty acids 4g daily. However, the triglyceride level remained elevated despite 72 hours on the insulin drip and it was subsequently discontinued. Plasmapheresis was discussed but deferred given no evidence of pancreatitis. Gemfibrozil 600mg twice a day was added to the omega-3 fatty acids which were titrated up to 2g three times a day. On her day of discharge, her triglyceride level was 2200 mg/dL and abdominal pain had resolved. She was maintained on gemfibrozil and Omega-3 fatty acids, with plans to increase them by 1g per week to reach a goal of 10g per day with a goal triglyceride level <1000mg/dL. Pre-gestational diabetes was tightly controlled with insulin. She was also seen by the nutritionist for counseling of a low fat diet and was followed very closely as an outpatient. Although the omega-3 fatty acids were titrated to 8g per day, the triglyceride level remained ~2000mg/dL. She remained asymptomatic and delivered a healthy baby boy weighing 3446 grams at 36 weeks 4 days, with no complications. She continues follow up with endocrinology with triglycerides 6 months later being 1618 mg/dl.Conclusion: We present a patient with severe gestational hypertriglyceridemia with a known history of pancreatitis. Due to the rarity of this condition, there is limited data on the safety of treatments for hypertriglyceridemia in pregnant women. This case demonstrates the use of gemfibrizol is appropriate when the hypertriglyceridemia threatens the health of the mother and baby. Further studies are needed to establish efficacy and safety of the use of these treatments in pregnant patients.

Omega-3 fatty acid ethyl esters improve low-density lipoprotein subclasses without increasing low-density lipoprotein-cholesterol levels: A phase 4, randomized study

Background and aimsWe aimed to investigate blood lipid and lipoprotein profiles in patients with dyslipidemia receiving hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) after 8 weeks of omega-3 fatty acid ethyl esters (Omega-3) treatment, using high-performance liquid chromatography with highly-sensitive gel filtration columns. MethodsIn this phase 4, randomized, open-label study, patients with dyslipidemia receiving statins were randomized 1:1 to Omega-3 treatment (oral Omega-3 2 g twice daily) or Control (no Omega-3). Primary endpoint was change in mean particle size of low-density lipoprotein (LDL) and small dense LDL (cholesterol monitoring) in the specific 20-lipoprotein fraction assay. Secondary endpoints included changes in lipids, apolipoproteins, and lipoprotein concentrations in fasting blood. Changes were compared between treatments using analysis of covariance, adjusted by baseline fasting triglycerides and age. ResultsFifty-three patients were randomized (Omega-3, n = 24; Control, n = 29). The difference in LDL particle size between Omega-3 and Control groups was significant at week 8 (p = 0.0040). Differences in least squares mean change in concentration from baseline to week 8 between Omega-3 and Control groups were significant for total cholesterol (p = 0.0009), LDL-C (p = 0.0442), non-high-density lipoprotein cholesterol (p = 0.0009), and remnant lipoprotein-cholesterol (p = 0.0396). Differences were significant for apolipoproteins AI, AII, B, B-48, B-100, CII, CIII, and CII/III, but not apolipoprotein E. ConclusionsSignificant increases in LDL particle sizes and significant decreases in blood lipid, lipoprotein and apolipoprotein concentrations were observed with Omega-3 compared with Control. Omega-3 may improve blood lipid profile and increase LDL particle size, resulting in an anti-atherogenic profile.

A self-emulsifying Omega-3 ethyl ester formulation (AquaCelle) significantly improves eicosapentaenoic and docosahexaenoic acid bioavailability in healthy adults.

Application of intelligent formulation design has the ability to address the poor bioavailability and improve the fasted state bioavailability of fish oils. In this study we assessed the ability of a self-emulsifying drug delivery system (SEDDS), AquaCelle®, as an additive to enhance the oral absorption of Omega-3 ethyl esters (EE) in healthy subjects under low-fat diet conditions. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) EE were formulated with AquaCelle®. A single dose (680mg dose of oil containing 272mg of EPA EE and 204mg of DHA EE), randomized, double-blind, study measured uptake of EPA and DHA over 24h in healthy adults. Participants were randomized into two groups, receiving either the SEDDS AquaCelle® fish oil formulation or the unformulated fish oil EE as control. The AquaCelle® fish oil EE formulation demonstrated instant and complete emulsification on addition to water to produce an emulsion with an average diameter of 43μm, compared to the oil alone which did not emulsify. The study revealed a significant difference in absorption (Cmax and AUC0-24h) between the AquaCelle® group and the control group. The AquaCelle® group was capable of increasing maximum plasma concentrations and absorption (AUC0-24h) of total Omega-3 (EPA + DHA) 3.7- and 7.1-fold, respectively, compared to the control. Formulating Omega-3 EE with a SEDSS concentrate (AquaCelle®) demonstrated a significant improvement in the oral absorption of Omega-3 fatty acids without requiring a high-fat meal.

THE DOSE DEPENDENT EFFECTS OF OMEGA-3 FATTY ACID ETHYL ESTERS ON QT DISPERSION AND CORRECTED QT DISPERSION IN HYPERTENSIVE PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY

Objective:Left ventricular hypertrophy (LVH) leads to arrhythmia such as atrial fibrillation, ventricular arrhythmias and known risk factor of sudden cardiac death. Recent study suggests that Omega-3 fatty acid ethyl esters have anti-arrhythmic effects and reduce sudden cardiac death among survivor

Effects of Long Chain Omega-3 Fatty Acid Supplementation on the Lipoprotein Oxylipin Response to an Inflammatory Challenge in Humans (P08-127-19)

Abstract Objectives Oxylipins are derived from polyunsaturated fatty acids (PUFAs) and mediate inflammatory responses, but the time-dependent response of oxylipins to an acute inflammatory challenge in humans is unknown. Although omega-3 acid ethyl esters (O3EEs) reduce plasma triglycerides, it is unclear whether they alter the response of oxylipins in triglyceride rich lipoproteins (TGRLs). We investigated the effect of 3.4 g/d O3EEs on the oxylipin response to an inflammatory challenge. Methods Healthy young men (N = 16) received either placebo or 3.4 g/d O3EEs for 8–12 weeks in a crossover study design. After each treatment period, subjects underwent a low-dose endotoxin challenge (0.6 ng lipopolysaccharide (LPS)/kg body weight). Plasma samples were collected at baseline and 1, 2, 4, 8, 24, 48, 72, and 168 hours after LPS injection. TGRLs were separated from plasma, and esterified oxylipins were hydrolyzed and quantified by LC-MS/MS. Changes over time were assessed by the use of mixed models with repeated measures. Data is reported as mean (95% CI). Results The peak total oxylipin response occurred at 4 hours after LPS injection, with the exception of hydroxyeicosatetraenoic acids (HETEs). Regardless of treatment, the peak concentration of HETEs occurred at 2 hours. This timing differed from that of hydroxyoctadecadienoic acids (HODEs), which peaked at 4 hours (P = 0.004). Of the omega-3 derived oxylipins, O3EE treatment significantly increased hydroxyeicosapentaenoic acids (HEPEs) by 356% (133%, 792%), hydroxydocosahexaenoic acids (HDoHEs) by 172% (34%, 452%), and epoxydocosapentaeinoic acids (EpDPEs) by 316% (76%, 887%) compared to placebo at 4 hours after LPS challenge (P &lt; 0.007). Additionally, O3EE treatment also significantly altered the timing of the HEPE response (pinteraction = 0.004). Conclusions The time-dependent TGRL oxylipin response to inflammatory challenge differs according to oxylipin class, and the timing and magnitude of the response can be altered by O3EE treatment. This is may be a molecular explanation of the anti-inflammatory and pro-resolving effects of O3EEs. Funding Sources Pronova BioPharma; Penn State Clinical &amp; Translational Research Institute, NIH/NCATS Grant # UL1 TR000127; Penn State College of Health and Human Development. Supporting Tables, Images and/or Graphs