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Omega-3 cont'd

Docosahexaenoic Acid (DHA) is an omega-3 highly unsaturated fatty acid that may be biosynthesized from eicosapentaenoic acid (EPA) or obtained directly through oils from oily fish such as salmon, herring, mackerel, anchovies and sardines, or in cod liver oil. Only 4% to 9% of the PUFA omega-3 alpha-linolenic acid is converted to the HUFA omega-3 DHA.41,42 The benefits of DHA may, for the most part be attributed towards its ability to improve cell membrane functions and cellular signaling. DHA is greater than that of EPA in increasing plasma membrane fluidity of vascular endothelial cells.85 The greater effect of DHA may be due to its ability to influence functions of membrane-bound proteins such as receptors, ion channels, and various enzymes, which may affect downstream signaling pathways after receptor stimulation or expression of ion channel proteins.86 The improved cellular signaling may be why DHA appears to have unique beneficial effects on cardiovascular health and may be effective in preventing or treating senile dementia, depression and certain visual dysfunction and other conditions.87 Cardiovascular benefits attributed to consumption of omega-3 rich fish oil may be due to the effects of DHA in specific applications. It appears that supplemented DHA has a greater ability to reduce ambulatory blood pressure and heart rate in mildly hyperlipidemic men than does EPA.10,45,44,50 This may be because men have a relatively lower ability to convert alpha-linolenic acid to docosahexaenoic acid.31 In both genders, DHA may be a more effective anti-thrombotic agent than EPA.88 DHA increases LDL particle size in type 2 diabetic patients, which decreases the susceptibility of LDL to glycation and oxidation and lower the progression of endothelial dysfunction in type 2 diabetic patients.89 The increased activity of membrane-bound enzymes and transporters induced by DHA and the concomitant increase in lipid fluidity may be one of the mechanisms involved in DHA-induced clearance of plasma cholesterol.90 Alzheimer’s patients with DHA in the top quartile have a 47% lower risk of developing dementia than those in the bottom quartile.76 Increased intake of DHA can correct the DHA deficiency seen in Alzheimer’s patients.77 Supplementation restores brain DHA levels, enhances learning and memory tasks in aged animals, and significantly reduces beta amyloid, plaques, and tau in transgenic AD models.91 Depressive disorders may be due to relative deficiency of docosahexaenoic acid, the principal omega-3 fatty acid in brain gray matter, which has neurotrophic and neuroprotective properties. DHA deficiency may increase vulnerability to neuronal atrophy in the prefrontal cortex of patients with affective disorders, such as unipolar and bipolar depression.92 It is believe that DHA deficiency may increase vulnerability to recurrent affective disorders because the prefrontal cortex modulates multiple limbic structures involved in affective regulation. Attention-deficit/hyperactivity disorder (ADHD) is a pervasive neurobehavioral disorder affecting approximately 5% of children and adolescents and 3% of adults. The prefrontal cortex (PFC) may play the most critical role in the expression of ADHD.93 When healthy boys aged (8-10 y/o) received DHA at a dosage of 400 or 1200 mg/day for eight weeks, erythrocyte membrane DHA composition increased by 47% (low does or 70% high-dose). The erythrocyte DHA composition was positively correlated with dorsolateral prefrontal cortex activation and with alterations in functional activity in cortical attention networks during sustained attention in healthy boys.94 A double blind study in patients with ADHD revealed a statistically significant improvement based on parent reports, with a subgroup also showing significant improvement based on clinical assessment.95 Metabolism of omega-3 fatty acids may be impaired in individuals with ADHD, who may require higher intake of omega-3 fatty acids.96 Visual processing and optimal retinal function are dependent on DHA content to maintain membrane fluidity and permeability, and the associated enzyme and transport activities.97 Inadequate tissue levels of DHA is associated with alterations in retinal function. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction enhancing activation of membrane bound retinal proteins and possibly by supporting rhodopsin regeneration. Visual processing deficits have been ameliorated with DHA supplementation in some cases.98 Rheumatoid arthritis patients taking dietary supplements of fish oil exhibit improvements in clinical parameters of disease activity from baseline, including the number of tender joints, and these improvements are associated with significant decreases in levels of IL-1 beta from baseline. Some patients who take fish oil are able to discontinue NSAIDs without experiencing a disease flare.99

For individuals not consuming fish rich in omega-3 fatty acids twice a week, encapsulated fish oils provide an option. In spite of the fact that they are two very different matrixes, consuming 1 to 2 encapsulated fish oils on a daily bases was effective as eating oily fish twice a week. In a comparative study the total daily average was 95 mg of EPA and 390 mg of DHA. Whether omega-3 fatty acids are consumed from oil-rich fish or fish-oil capsules on a regular bases for 16 weeks, there was no difference in the effect on the major long-chain omega-3 fatty acids. As such, encapsulated fish oils have a bioavailability similar to oily fish.100 As expected, daily intake of encapsulated fish oils resulted in fewer fluctuations than consuming oily fish twice a week. The frequency of fishy aftertaste was higher in persons taking the capsules than in those eating oily fish. The fishy after taste is most often considered “mildly unpleasant.” The unpleasant taste may be diminished by taking the fish before meals with a large glass of water 30 minutes before meals, to diminish stomach retention time, based on clinical experience. Enteric-coated fish oil can be beneficial for both decreasing the unpleasant after taste and as therapeutic intervention for patients with inflammatory bowel disease. Enteric-coated fish oil increases remission, and decreases relapse in both adult and children with Crohn’s disease.101,102 All subjects taking the enteric-coated fish oil also attained higher levels of EPA and DHA demonstrated by RBC fatty acid analysis.103



Pre-emulsification of an oil mixture prior to ingestion increases the absorption of longer chain highly unsaturated fatty acids (especially eicosapentaenoic acid and docosahexaenoic acid) but does not affect absorption of shorter chain less saturated fatty acids, suggesting that pre-emulsification of fish oils may be a useful means of boosting absorption of these beneficial fatty acids.104 It has also been observed that bioavailability of omega-3 fatty acids is significantly increased when EPA & DHA are incorporated into an emulsion.105 A new delivery system consisting of a microemulsion of DHA and EPA in a proprietary chewable gelatin matrix has been shown to significantly increase the absorption of EPA and DHA. This enhanced absorption was evidenced by the change from baseline of the plasma concentrations of EPA and DHA based on 26 hour area under curve (AUC), and by 26 hour maximum concentration (Cmax) when compared to fish oil triglycerides delivered in softgel capsules. The chewable gelatin matrix resulted in increased AUC of EPA by an additional 44.9% compared to fish oil delivered in softgel capsules and an increased Cmax of EPA by an additional 100.4% compared to fish oil delivered in softgel capsules. For DHA alone, the increase in AUC for DHA was not statistically significant when compared to fish oil delivered in softgel capsules, but the Cmax for DHA was statistically greater, with the increased Cmax of DHA an additional 115.8% greater compared to fish oil delivered in softgel capsules. For EPA & DHA delivered together, the bioavailability of EPA+DHA delivered within a gelatin matrix is significantly increased by 43.3% compared to fish oil delivered in softgel capsules triglycerides based on (AUC) data. When Cmax data is analyzed, the bioavailability of EPA+DHA delivered within a gelatin matrix is greater by 105.6% when compared to fish oil delivered in softgel capsules.106

Omega-3 fatty acids may also be used as an adjuvant to drug therapies to work synergistically, potentiate the effects, or decreasing toxicity of drug therapies. Hypertensive therapy in which fish oil was used with propranolol was more effective than propranolol or fish oil alone.107 The combined administration of fish oil and nifedipine possesses favorable anti-hypertensive and metabolic properties in hypertensive males with elevated lipid levels.108 Rheumatoid arthritis patients consuming n-3 dietary supplements were able to lower or discontinue their background doses of nonsteroidal anti-inflammatory drugs such as indomethacin or disease-modifying anti-rheumatic drugs.109,110 Some patients who take fish oil are able to discontinue NSAIDs without experiencing a disease flare.99 Hyperlipidemia treated with fish oil in addition to statin therapy, such as pravastatin or simvastatin may be preferable to multiple drug combinations for the treatment of combined hyperlipidaemia, in individuals with prior coronary events.111,112 Since HMG-CoA reductase inhibitors may increase the synthesis of metabolites from arachidonic acid in patients with hyperlipidemia the addition of fish oil is more effective for the prevention of coronary heart disease than HMG-CoA reductase inhibitors alone.113,114 Other conditions in which omega-3 fatty acids have been shown to have synergistic effects with drugs include depression115,116, Alzheimer’s disease117, cancer118,119,120 and Crohn’s disease.121,122,123 Noting that omega-3 fatty acids play a dominant role in inflammation as well as receptor function, there is evidence that their use will extend into mainstream medical care, including hospitalized and surgical patients.124 A recent study of 182 patients found that high-dose fish oil is safe in combination with aspirin and clopidogrel and does not increase the risk of bleeding compared with that seen with aspirin and clopidogrel alone.125 An earlier study of 260 patients taking 4 g fish-oil concentrate per day and either aspirin (300 mg/day) or warfarin (INR goal: 2.5-4.2), noted that no excess of bleeding episodes could be attributed to the use of fish oil given in addition to either aspirin or warfarin, and that no long-term effects by fish oil on parameters of coagulation and fibrinolysis were seen.126 Concerns about the putative bleeding risks associated with omega-3 supplementation may be relieved as ongoing research continues.

Patients taking higher dosages of omega-3 fatty acids for longer time intervals have the more pronounced clinical benefits than patients taking lower dosages associated with protection of function. As little as 20 mg/kg/day of omega-3 PUFA is necessary to reduces mortality due to coronary heart disease127, and as little as 11 mg/kg/day is needed to maintain DHA levels in liver and brain phospholipids.128 However, higher dosages are more effective for restoring lost function. Based on human studies, the therapeutic dosage, based on body weight, for autoimmune inflammatory diseases such as rheumatoid arthritis is at least 30 mg/kg/day of fish oil for 6 to 8 months.129 Increasing the dosage to 40 mg/kg/day improves clinical outcomes in less than four months.130 In another study, patients ingesting 54 mg/kg EPA and 36 mg/kg DHA per day had significant clinical improvement in 12 weeks compared to patients taking 27 mg/kg (EPA) and 18 mg/kg (DHA) per day, who saw similar improvement after 24 weeks. Dosages may vary based upon clinical condition. An increase in tissue DHA levels in cystic fibrosis patients aged 14 to 43 can be achieved by supplementing for six weeks with 70 mg/kg/d DHA.131 Alpha-linolenic acid (ALA) dosages cited in the literature range from 1.2 to 4.1 grams per day.132,133,134,135,136

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