7-Methoxy-1-naphthaleneacetic acid ethyl ester

Systemic Bioavailability and Dose Proportionality of Omega-3 Administered in Free Fatty Acid Form Compared With Ethyl Ester Form: Results of a Phase 1 Study in Healthy Volunteers.[Pubmed:28116646]

Eur J Drug Metab Pharmacokinet. 2017 Oct;42(5):815-825.

BACKGROUND: Omega-3 carboxylic acids (OM3-CA) contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in free fatty acid form. Per gram, OM3-CA includes approximately half as much EPA as icosapent ethyl (IPE), an ethyl ester formulation of EPA. OBJECTIVE: The study aim was to assess systemic EPA and EPA + DHA exposures and plasma lipid parameters following multiple OM3-CA or IPE doses under low-fat dietary conditions, and dose proportionality after OM3-CA administration. METHODS: In this phase 1, two-cohort, open-label study (N = 114), participants following the Therapeutic Lifestyle Changes diet received either OM3-CA 2 g once daily for 10 days then OM3-CA 4 g once daily for 10 days, or IPE 2 g twice daily for 20 days. Exposure was considered similar if the 90% confidence intervals (CIs) of geometric least-squares mean (LSM) ratios for key pharmacokinetic parameters were within 80-125%. RESULTS: Baseline-adjusted steady-state EPA exposure was similar after dosing with OM3-CA 4 g/day versus IPE 4 g/day (LSM ratio, area under the concentration-time curve from time 0 to 24 h: 93.9%; 90% CI 85.6, 103.0). Combined molar-equivalent EPA + DHA exposure was 30.6% higher following OM3-CA 4 g/day than IPE 4 g/day. EPA and DHA exposure increased approximately proportionally with OM3-CA dose (2-4 g/day). Changes from baseline in lipid parameters were similar in the two cohorts. CONCLUSION: EPA exposure from OM3-CA and IPE was similar under low-fat dietary conditions, despite OM3-CA containing only approximately half as much EPA as IPE. EPA and DHA exposure from OM3-CA increased proportionally with dose.

A Novel omega-3 Acid Ethyl Ester Formulation Incorporating Advanced Lipid Technologies(TM) (ALT((R))) Improves Docosahexaenoic Acid and Eicosapentaenoic Acid Bioavailability Compared with Lovaza((R)).[Pubmed:28189364]

Clin Ther. 2017 Mar;39(3):581-591.

PURPOSE: The US Food and Drug Administration has approved several highly purified omega-3 fatty acid prescription drugs for the treatment of severe hypertriglyceridemia. These differ in the amounts and forms of docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). This study compared the bioavailability of SC401 (1530 mg EPA-ethyl esters [EEs] and DHA-EEs plus Advanced Lipid Technologies() [ALT(dagger)], a proprietary lipid-delivery platform to improve absorption), with. Lovaza(double dagger) (3600 mg omega-3, primarily EPA-EEs and DHA-EEs) under low-fat feeding conditions. METHODS: This was a Phase I, randomized, open-label, single-dose, 2-way crossover study in healthy participants housed from day -3 to day 2 in each treatment period. Blood samples for pharmacokinetic measurements were collected before and after dosing, and safety profile and tolerability were assessed. FINDINGS: In unadjusted analyses, SC401 had 5% lower Cmax and approximately the same AUC0-last of EPA + DHA total lipids compared with Lovaza. When adjusted for baseline, SC401 had ~6% higher Cmax and 18% higher AUC0-last for EPA + DHA total lipids, and dose- and baseline-adjusted analyses found that SC401 had ~149% higher Cmax and 178% higher AUC0-last than Lovaza for EPA + DHA total lipids. The Tmax was also substantially longer with Lovaza (~10 hours) than with SC401 (~6 hours). IMPLICATIONS: These results indicate that SC401, an omega-3 acid EE formulation containing ALT(dagger) achieved high bioavailability of EPA and DHA, at a lower dose (1530 mg) than Lovaza (3600 mg), under low-fat feeding conditions.

Bioequivalence Demonstration for Omega-3 Acid Ethyl Ester Formulations: Rationale for Modification of Current Guidance.[Pubmed:28189365]

Clin Ther. 2017 Mar;39(3):652-658.

The US Food and Drug Administration (FDA) draft guidance for establishing bioequivalence (BE) of omega-3 acid ethyl esters (containing both eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters), used to treat severe hypertriglyceridemia, recommends the conduct of 2 studies: one with participants in the fasting state and one with participants in the fed state. For the fasting study, the primary measures of BE are baseline-adjusted EPA and DHA levels in total plasma lipids. For the fed study, the primary measures of BE are EPA and DHA ethyl esters in plasma. This guidance differs from that established for icosapent ethyl (EPA ethyl esters) in which the primary measure of BE is baseline-adjusted total EPA in plasma lipids for both the fasting and fed states. The FDA guidance for omega-3 acid ethyl esters is not supported by their physiologic characteristics and triglyceride-lowering mechanisms because EPA and DHA ethyl esters are best characterized as pro-drugs. This article presents an argument for amending the FDA draft guidance for omega-3 acid ethyl esters to use baseline-adjusted EPA and DHA in total plasma lipids as the primary measures of BE for both fasting and fed conditions. This change would harmonize the approaches for demonstration of BE for omega-3 acid ethyl esters and icosapent ethyl (EPA ethyl esters) products for future development programs and is the most physiologically rational approach to BE testing.

Analysis of the herbicidal mechanism of 4-hydroxy-3-methoxy cinnamic acid ethyl ester using iTRAQ and real-time PCR.[Pubmed:28242453]

J Proteomics. 2017 Apr 21;159:47-53.

Absolute quantitation (iTRAQ) is the latest development in the new quantitative proteomics technology for high-throughput identification and quantitation of proteins. The mechanisms underlying the 4-hydroxy-3-methoxy cinnamic acid ethyl ester treatment in Arabidopsis thaliana was investigated. Deficiency-induced changes in the protein profile of A. thaliana caused by this compound were analyzed using iTRAQ and quantitative real-time PCR. A total of 2909 proteins were quantified, of which 49 and 34 proteins were upregulated and downregulated, respectively, in the experimental plants compared with the controls. Treatment results showed that numerous proteins were involved in photosystemII, energy metabolism, and cell structure formation. Based on the upregulated and downregulated proteins, high amount of AT4G21280 protein acted on the oxygen-evolving enhancer protein 3-1, while low amount of AT1G10340 protein affected the catabolic process of the photosystemII-associated light-harvesting complex II. We selected these proteins to preliminarily verify the expression of proteins using quantitative real-time PCR to provide a reliable basis for further studies after proteomics analysis. Results show that the combined use of iTRAQ and quantitative real-time PCR provides an effective method to study proteins, leading to the determination of a new herbicide mechanism.