Diurnal rhythm of plasma EPA and DHA in healthy adults

Knowledge of the diurnal variation in circulating omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be an important consideration for the development of dosing protocols designed to optimise tissue delivery of these fatty acids. The objective of the current study was to examine the variation in plasma concentrations of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) over a 24-h period in healthy adults under eating and sleeping conditions generally approximate to a free-living environment. Twenty-one healthy participants aged 25–44 years took part in a single laboratory visit encompassing an overnight stay. EPA and DHA were measured in plasma samples collected every two hours from 22:00 until 22:00 the following day, with all meals being provided at conventional times. Cosinor analysis was used to estimate the diurnal variation in each fatty acid from pooled data across all participants. A significant diurnal variation in the pooled plasma concentrations of both fatty acids was detected. However, evidence of distinct rhythmicity was strongest for DHA. The timing of the peak concentration of DHA was 17:43 with a corresponding nadir at 05:43. In comparison, the observed acrophase for EPA was delayed by three hours, occurring at 20:41, with a nadir at 08:41. This is the first time that the diurnal variation in these important bioactive fatty acids has been described in a sample of healthy adults following a normal pattern of eating and sleeping. In the absence of any dietary intake of EPA and DHA, circulating levels of these fatty acids fall during the overnight period and reach their lowest point in the morning. Consumption of n-3 PUFAs at night time, which counteracts this pattern, may have functional significance

Supplementation with oil rich in eicosapentaenoic acid, but not in docosahexaenoic acid, improves global cognitive function in healthy, young adults: results from randomized controlled trials

Background Evidence regarding the effects of the omega-3 (ɷ-3) PUFAs (n–3 PUFAs) DHA and EPA on cognition is lacking. Objectives We investigated whether supplementation with oils rich in EPA or DHA improves cognition, prefrontal cortex (PFC) hemoglobin (Hb) oxygenation, and memory consolidation. Methods Healthy adults (n = 310; age range: 25–49 y) completed a 26-wk randomized controlled trial in which they consumed either 900 mg DHA/d and 270 mg EPA/d (DHA-rich oil), 360 mg DHA/d and 900 mg EPA/d (EPA-rich oil), or 3000 mg/d refined olive oil (placebo). Cognitive performance and memory consolidation were assessed via computerized cognitive test battery. PFC Hb oxygenation was measured using near infrared spectroscopy (NIRS). Results Both global accuracy and speed improved with EPA-rich oil compared with placebo and DHA-rich oil [EPA vs. placebo accuracy: estimated marginal mean (EMM) = 0.17 (95% CI: 0.09, 0.24) vs. EMM = 0.03 (95% CI = −0.04, 0.11); P = 0.044; EPA vs. placebo speed: EMM = −0.15 (95% CI: −0.22, −0.07) vs. EMM = 0.03 (95% CI: −0.05, 0.10); P = 0.003]. Accuracy of memory was improved with EPA compared with DHA [EMM = 0.66 (95% CI: 0.26, 1.06) vs. EMM = −0.08 (95% CI: −0.49, 0.33); P = 0.034]. Both EPA- and DHA-rich oils showed trends towards reduced PFC oxygenated Hb (oxy-Hb) compared with placebo [placebo: EMM = 27.36 µM (95% CI: 25.73, 28.98); DHA: EMM = 24.62 µM (95% CI: 22.75, 26.48); P = 0.060; EPA: EMM = 24.97 µM (95% CI: 23.35, 26.59); P = 0.082]. Conclusions EPA supplementation improved global cognitive function and was superior to the oil enriched with DHA. Interpreted within a neural efficiency framework, reduced PFC oxygenated Hb suggests that n–3 PUFAs may be associated with increased efficiency. These trials were registered in the clinical trials registry (https://clinicaltrials.gov/) as NCT03158545, NCT03592251, NCT02763514

Differential Effects of DHA- and EPA-Rich Oils on Sleep in Healthy Young Adults: A Randomized Controlled Trial

Emerging evidence suggests that adequate intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs), which include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), might be associated with better sleep quality. N-3 PUFAs, which must be acquired from dietary sources, are typically consumed at suboptimal levels in Western diets. Therefore, the current placebo-controlled, double-blind, randomized trial, investigated the effects of an oil rich in either DHA or EPA on sleep quality in healthy adults who habitually consumed low amounts of oily fish. Eighty-four participants aged 25–49 years completed the 26-week intervention trial. Compared to placebo, improvements in actigraphy sleep efficiency (p = 0.030) and latency (p = 0.026) were observed following the DHA-rich oil. However, these participants also reported feeling less energetic compared to the placebo (p = 0.041), and less rested (p = 0.017), and there was a trend towards feeling less ready to perform (p = 0.075) than those given EPA-rich oil. A trend towards improved sleep efficiency was identified in the EPA-rich group compared to placebo (p = 0.087), along with a significant decrease in both total time in bed (p = 0.032) and total sleep time (p = 0.019) compared to the DHA-rich oil. No significant effects of either treatment were identified for urinary excretion of the major melatonin metabolite 6-sulfatoxymelatonin. This study was the first to demonstrate some positive effects of dietary supplementation with n-3 PUFAs in healthy adult normal sleepers, and provides novel evidence showing the differential effects of n-3 PUFA supplements rich in either DHA or EPA. Further investigation into the mechanisms underpinning these observations including the effects of n-3 PUFAs on sleep architecture are required

NC100668, A NEW TRACER FOR IMAGING OF VENOUS THROMBOEMBOLISM: DISPOSITION AND METABOLISM IN RATS

ABSTRACT: The NC100668 consists of a 13-amino acid peptide, N-terminally blocked with an acetyl group containing an iodinated tyrosine and coupled to a Tc-chelator (NC100194) via the C-terminal glycine. Using the common three-letter abbreviations for amino acids, the structure of NC100668 is Acetyl-Asn-Gln-Glu-Gln-Val-Ser-ProTyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194, where NC100194 is represented by the chemical formula -NH-CH 2 -CH 2 -N(CH 2 -CH 2 -NH-C(CH 3 ) 2 -C(CH 3 )ϭN-OH) 2 . The detailed structure is shown in 99m Tc-NC100668 is being developed as a diagnostic radiopharmaceutical for imaging of venous thromboembolism, which is a major health problem with an estimated average annual incidence in the United States exceeding 1 per 1000 Diagnostic radiopharmaceuticals are radioactive substances that are administered to patients. Many of these agents are labeled with the ␥-emitter 99m Tc, which has a half-life of 6.02 h doi:10.1124/dmd.105.006239. ABBREVIATIONS: NC100668, Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194; NC100194, -NH-CH 2 -CH 2 -N(CH 2 -CH 2 -NH-C(CH 3 ) 2 -C(CH 3 )ϭN-OH) 2 ; Fmoc, 9-fluorenyloxycarbonyl; Boc, butyl oxy carbonyl; PyBOP, benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate; DMF, dimethylformamide; TFA, trifluoroacetic acid; MS, mass spectrometry; HPLC, high-performance liquid chromatography; QWBA, quantitative whole-body autoradiography; SAC, self-absorption coefficient; % ID, percentage of injected dose; LC-MS, liquid chromatography-mass spectrometry; MS/MS, tandem mass spectrometry

A novel self-micro-emulsifying delivery system enhances enrichment of eicosapentaenoic acid and docosahexaenoic acid after single and repeated dosings in healthy adults in a randomized trial

Background A self-micro-emulsifying delivery system (SMEDS) promotes spontaneous emulsification of omega-3 (n–3) ethyl esters (EEs) into microdroplets in the stomach. Objective The objective was to compare the effect of SMEDS preparations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) EEs with standard EEs on EPA and DHA concentrations in the bloodstream after a single dose and repeated daily dosing. Methods Eighty healthy subjects aged 18–65 y were randomly assigned to SMEDS-EPA or EE-EPA (both providing more EPA than DHA) or SMEDS-DHA or EE-DHA (both providing more DHA than EPA). They consumed a single dose (1.23–1.33 g EPA+DHA) without a meal, and EPA and DHA were measured in plasma over the following 24 h. Participants continued to take a single dose each morning before breakfast for 12 wk. EPA and DHA were measured in fasting plasma, mononuclear cells (MNCs), and RBCs. Results EPA and DHA were higher in plasma in the 24 h after a single dose of SMEDS-EPA or SMEDS-DHA than after consuming the comparator EE (P < 0.001 for both). Compared with the EE form, repeated daily dosing of the SMEDS formulations for 12 wk resulted in higher concentrations of EPA and DHA in plasma (P = 0.086 and 0.005, respectively), MNCs (P < 0.001 and 0.020, respectively), and RBCs (both P < 0.001). The omega-3 index increased over 12 wk from 5.1 ± 0.9 to 7.9 ± 0.9 in the SMEDS-EPA group, from 5.3 ± 1.1 to 9.0 ± 1.2 in the SMEDS-DHA group, from 4.8 ± 0.8 to 6.4 ± 0.9 in the EE-EPA group, and from 5.2 ± 0.9 to 7.2 ± 1.0 in the EE-DHA group (all P < 0.001). The omega-3 index was higher with SMEDS than with the comparator EE at 12 wk (both P < 0.001). Conclusions Compared with standard EEs, a SMEDS results in greater incorporation of EPA and DHA into blood pools after a single dose and with repeated daily dosing in healthy adults. A SMEDS enhances delivery of bioactive ω-3 fatty acids. This trial was registered at www.isrctn.com as ISRCTN96459690

A novel omega-3 glyceride mixture enhances enrichment of eicosapentaenoic acid and docosahexaenoic acid after single dosing in healthy older adults: results from a double-blind crossover trial

A glyceride mix of mono, di, and triglycerides increases solubilisation and enhances emulsification of omega-3 (ω-3) fatty acid (FA) containing lipids in the stomach. This allows for better access of digestive enzymes, pivotal for the release of bioactive ω-3 FA.The objective was to compare the effect of a glyceride formulation and an ethyl ester (EE) formulation of EPA+DHA on concentrations of EPA and DHA in plasma following single dosing.We conducted a double-blind crossover trial in which twenty healthy adults aged 50-70 y consumed a single dose (2.8 g EPA+DHA) of each EPA+DHA formulation without a meal in random order separated by a two-week wash out period. EPA and DHA were measured in plasma total lipid over the following 12 h.EPA and DHA in plasma total lipid increased over 12 h with both formulations. A 10 x greater Δ concentration of EPA, 3 x greater Δ concentration of DHA, and 5 x greater Δ concentration of EPA+DHA was seen with the glyceride-EPA+DHA. The time at which the maximal concentrations of ω-3 FA occurred was 4 h earlier for EPA, 1 h earlier for DHA, and 2 h earlier for EPA+DHA when consuming glyceride-EPA+DHA.A mix of mono, di, and triglycerides results in greater and faster incorporation of EPA and DHA into blood plasma lipid in the absence of a fatty meal. This may provide benefit to individuals on a low fat diet or with digestive impairments and could result in greater efficacy in clinical trials using ω-3 FA

Icosabutate for the treatment of very high triglycerides: A placebo-controlled, randomized, double-blind, 12-week clinical trial

Icosabutate is a structurally enhanced omega-3 fatty acid molecule developed with the aim of achieving improved triglyceride (TG)-lowering efficacy, increased potency, and preserved safety compared with conventional prescription omega-3 fatty acid. To evaluate the efficacy and safety of icosabutate 600 mg once daily in patients with very high TGs. After a 6-8 week run-in period, men and women with TG levels ≥ 500 mg/dL and ≤ 1500 mg/dL were randomized to double-blind treatment with placebo or icosabutate 600 mg for 12 weeks. The primary end point was % change from baseline in TGs at 12 weeks. A total of 87 subjects were randomized. At baseline, median TG (interquartile range) levels were 611 (543-878) and 688 (596-892) mg/dL, and the median change after 12 weeks of treatment was -51% and -17%, respectively, for a placebo-corrected change of -33% (P < .001). Adjusted for placebo, icosabutate significantly reduced very low-density lipoprotein cholesterol (-36%, P < .001), remnant lipoprotein cholesterol (-34%, P < .001), apolipoprotein (Apo) C-III (-35%, P < .001), trended toward reduced non-high-density lipoprotein cholesterol (-7%, P = .064); significantly increased high-density lipoprotein cholesterol (18%, P < .001) and low-density lipoprotein cholesterol (28%, P < .001), with a trend of an increased lipoprotein (a; 10%, P = .054). No changes were observed in total cholesterol, apolipoprotein B, or apolipoprotein A1. Fasting plasma glucose was unchanged, whereas fasting plasma insulin was reduced (P = .001) with icosabutate. Icosabutate was generally well tolerated. Treatment with icosabutate once daily significantly reduced TG, very low-density lipoprotein cholesterol, and Apo C-III levels in patients with very high TG levels. This trial was registered at www.clinicaltrials.gov as NCT0189351

Supplementation with oil rich in eicosapentaenoic acid, but not in docosahexaenoic acid, improves global cognitive function in healthy, young adults: results from randomized controlled trials

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Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia

To evaluate the efficacy and safety of icosabutate, an oral, once-daily, first-in-class medication, in reducing non-high-density lipoprotein cholesterol (non-HDL-C) in patients with persistent hypertriglyceridemia despite statin therapy. The study was designed to randomly assign 140 patients with fasting triglyceride levels ≥200 but <500 mg/dl on a stable dose of statin therapy to receive either masked icosabutate 600 mg once daily or a control for 12 weeks. The primary end point was a percentage change in non-HDL-C from baseline to 12 weeks. With icosabutate, non-HDL-C levels were reduced (-9.2%) when compared with the control (-0.4%) for a between-group difference of -7.4% (p = 0.02). Compared with the control, icosabutate reduced triglycerides (-27.0%, p < 0.001), very- low-density lipoprotein (VLDL) cholesterol (-31.5%, p < 0.001) and apolipoprotein C-III (-22.5%, p < 0.001). LDL-C levels did not change (0.5%, p = 0.87). HDL-C (10.2%, p < 0.001) was increased. After 113 subjects had been randomized, the study was terminated due to a partial clinical hold imposed by US regulators after observing QT prolongation at supratherapeutic doses of icosabutate in a dog study. In this study, adverse events were balanced between treatment arms, and there were no discontinuations due to adverse events. Icosabutate was efficacious in lowering non-HDL-C and other biomarkers of cardiovascular risk and was generally well tolerate