Fish Oil Capsules: More Than Brain Food

There is growing evidence increased consumption of fish may be beneficial to health. Recent studies have found an association between consumption of fish oil and reduced risk of cardiovascular disease, as well as improvements in other health conditions, such as psoriasis and rheumatoid arthritis.

Most current research on the benefits of consuming more fish is directed at the effects derived from omega-3 fatty acids in many fish species. However, studies of human dietary preferences reveal up to one-half of the population may not like to eat fish. Of those who do eat fish, many prefer fish only when it is deep-fried, or consume non-fatty fish species, which are poorer sources of fish oil. This is one reason fish oil capsules have become popular as an alternative source of fish oil.

Support for the use of fish oil capsules primarily comes from three well-known epidemiological studies, two of which were carried on outside of the United States. One study, conducted in the Netherlands, suggested ingestion of as little as 35 grams of fish per day (a single one-half pound meal of fish per week) might help prevent coronary heart disease, possibly significantly reducing mortality due to cardiovascular disease in a 20 year follow up. Further, it has been suggested a regular diet of fish may decrease levels of plasma triglycerides, plasma cholesterol, low density lipoprotein-cholesterol (LOL) , and very low density lipoprotein-cholesterol (VLDL)

Conversely, two other epidemiological studies have shown no relationship between fish consumption and cardiovascular mortality. Yet it is important to note there is some conflicting evidence regarding the benefits of fish oil consumption on blood pressure and its relationship to the development of some types of cancer.

In general, fish oil capsules supply concentrations of Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DNA) . The EPA-DNA rich fish oil is generally sold in soft gelatin capsules. The gelatin provides an oxygen barrier which prevents the development of toxic lipid peroxides (e.g. malondialdehyde) . Liquid, non-encapsulated formulations generally do not have this protection, and therefore may contain some toxic lipid peroxides.

In most cases the fish oils come from cold water ocean fish. Encapsulated products contain fish oil, not fish liver oil. This distinction is important since fish liver oil contains fat-soluble vitamin A and vitamin D, which if taken excessively have the remote potential of being toxic. The literature contains reports of vitamin A and vitamin D toxicity when levels above 50,000 lU/day are consumed.

Fish Oil Capsules - Method Of Action

In general, dietary unsaturated fatty acids play an important role in reducing atherogenesis and thrombosis. Fish oils appear to reduce hyperlipidemia, while decreasing the production of the prothrombotic substance, thromboxane, by enhancing the production of the platelet antiaggregatory substance, pros tacyclin.

Through the combined vasodilatory effects of prostacyclin (Pgl-2 and Pgl-3), fish oils may improve peripheral circulation and thereby facilitate the reduction of very low density lipoprotein-cholesterol (VLDL) removal. This may be due to a specific alteration of cell membrane fluidity, while also altering the activities of membrane-bound enzymes. This can result in change in receptor activity, specificity and signal transduction.

Fish oils also depress the synthesis of hepatic fatty acids and triglycerides and secretion of very low density lipoprotein-cholesterol (VLDL) . One further benefit is fish oils displace arachidonic acid from tissue phospholipids, resulting in omega-3 essential fatty acid levels inhibiting thromboxane synthesis.

The effects of fish oils are very selective. Sicosapenteenoic acid (EPA) and Docosahexaenoic acid (DRA) components not only displace arachidonic acid and inhibit cyclo-oxygenase, but EPA becomes a substrate for cyclo-oxygenase when the peroxide tone is high and is converted to the potent antiaggregatory Pgl-3. It has been suggested these findings may explain the increased bleeding time and the decreased incidence of coronary artery disease which has been reported in Japanese with high fish consumption and in some Eskimos.

EPA- and DRA-rich fish oil has also been found to suppress production of inflammatory agents found in rheumatoid arthritis and psoriasis. The anti-inflammatory effect of the omega-3 fatty acids might be mediated in part by their inhibitory effect on production of interleukin-l and tumor necrosis factor, both principal mediators of inflammation. In cases of psoriasis vulgaris, fish oils produce symptomatic improvement by effecting changes in levels of the inflammatory Leukotriene compounds especially Leukotriene B4. This Leukotriene is a lipoxygenation product of the fatty acid arachidonic acid. The EPA in fish oil 'replaces' the arachidonic acid in phospholipids, leading to the formation of Leukotriene BS, rather than B4. Leukotriene B5 causes a much weaker inflammatory response. Neutrophils were isolated from the peripheral blood of patients given fish oil to treat their psoriasis. Patients whose symptoms improved with fish oil therapy had higher levels of Leukotriene BS than did those patients who showed no improvement.

Fish Oil Capsules - Therapeutic Approaches

Most fish oil capsules contain 300 or 500 milligrams of omega-3 fish oil per one gram capsule. Thus, patients therapeutically using fish oil at the levels discussed in this section, may require between 15 to 30 capsules to get the derived benefits described herein. This amount adds up to substantial calories in the total daily diet. Further, unless supplemented with vitamin E, there is a possibility of vitamin E deficiency developing from prolonged intake of high doses.

In a recent review of fish oil supplementation and coronary disease, it was concluded 10 capsules or 25 milliliters (1/2 teaspoon) of cod liver oil a day (providing 1.8 grams of EPA) appears 'to be safe over a long term.'

Caution should be taken when recommending fish oil supplementation to pregnant women, to individuals with known or suspected bleeding disorders or to persons taking aspirin therapeutically. These individuals should consult with their physician before beginning such supplementation.

Cancer

Eleven preliminary animal studies have reported favorable anticancer activity by fish oil. These studies were reviewed in 1987. Considerably more research is going on at this time. However, it remains premature to recommend fish oil as an anticancer substance until additional studies are completed in humans.

In 1989, researchers studying the effects of fish oil on human mammary carcinoma growth discovered an important role for fish oil in altering tumor sensitivity to anticancer drugs. In that study, tumor growth in mice fed fish oil and inoculated with human mammary cancer was reduced.

As had been shown in prior research, measurements of mice mitochondrial enzymes involved in lipid metabolism showed the fish oil consumption caused increased oxidation of the polyunsaturated fatty acids. This would result in inhibition of tumor growth due to increased oxidation of fatty acids in tumor tissue. The result of such changes is increased lipid peroxidation causing increased susceptibility of the tumor to any pro-oxidant antitumor drug. So when the mice in this study were given two anticancer drugs, doxorubicin or mitomycin C, tumor growth was significantly inhibited.

Additional evidence of fish oil?s potential inhibition of cancer growth comes from in vivo and in vitro work reported in 1989 examining the effect of EPA on metastasis of tumor cells. Researchers cultured malignant murine melanoma and human fibrosarcoma cells in a media supplemented with EPA. Production of collagenase IV by the tumor cells was significantly decreased. Collagenase IV is a critical substance found in cancer cells leading to metastatic activity. The same procedure was attempted with arachidonic acid metabolites without comparable results. These findings add further support to growing evidence indicating EPA may reduce the spontaneous metastases associated with some cancers, while also altering the progression of the cancer itself.

Cardiovascular disease

In general, dietary unsaturated fatty acids appear to reduce undesirable circulating fats (e.g. in hyperlipidemia) while decreasing the production of the prothrombotic substance thromboxane. In studies involving fish oil as an unsaturated fatty acid, data from clinical trials show a significant reduction of levels of very low density lipoprotein?cholesterol (VLDL) , plasma triglycerides, plasma cholesterol, and low density lipoprotein-cholesterol
(LDL).

These findings are important because they may explain the significant difference in mortality rate due to cardiovascular disease between certain Alaskan natives and mainland Americans. In an autopsy series of 339 Alaskan natives, Authaud found cardiovascular disease was a cause of death in only 35 (or 10.3%) of the cases, whereas it accounts for 50% for all deaths in the United States.

Recent evidence also suggests fish oil may prevent atherosclerosis in Rhesus monkeys and hyperlipidemic pigs, despite lack of improvement in serum cholesterol levels. These findings warrant consideration given the high mortality and morbidity associated with atherosclerosis.

For therapeutic dosages, intakes of 5 grams of fish oil a day may be advisable. However, there is sufficient evidence to consider fish oil supplementation, in the range of from 2 to 10 grams per day, for patients with elevated cholesterol (7.75 mmol/liter) or triglycerides (5.64 mmol/liter)

Kinsella has suggested for both prophylactic and therapeutic applications, the most benefit is derived from fish oil when total fat intake is lowered to least 30% of calories, saturated fatty acids to no more than 30% of total fat, and omega-S fatty acids (vegetable oils) to a maximum of 10%.

Fish oil seems to have hypotensive effects ranging from small (with 5 grams per day) to substantial (6 grams per day) . Yetiv has speculated fish oil depresses vascular reactivity to hormones involved in hypertension. Yetiv suggested fish oil acted by increasing vasodilatory prostaglandin?s Pgl-2 and Pgl-3, and this increase accounted for the observed reduction in blood pressure.

To test this hypothesis, a study was conducted to examined the ability of fish oil to lower blood pressure in men with mild essential hypertension. One group received 10 ml. of fish oil (3 grams of omega-3 fatty acids) , a second group 50 ml. of fish oil (15 grams) , a third group 50 ml. safflower oil (39 grams of omega-S fatty acids) and a fourth group 50 ml. of a mixture of coconut, olive and safflower oils. The latter group represented the approximate amount of fatty acids consumed in the average American diet (39% saturated fat, 46% monounsaturated fat, and 15% polyunsaturated fat) . Males who received the highest dose of fish oil (50 ml. equal to 9 grams of EPA and 6 grams of OHA) had an average reduction of 6.5mm Hg in systolic pressure and a 4.4mm Hg in diastolic pressure. Hone of the other three groups, including the 10 ml. fish oil group, saw this kind of reduction. The study did not find the expected association between the formation of Pgl-2 and Pgl-3 and a sustained reduction in blood pressure.
This indicates vasodilatory prostaglandin?s are not the primary mediators of blood pressure reduction by fish oil. What those mediators are remains unknown to date.

Lupus (Systemic Lupus Erythematosus)

SLE is a generalized connective tissue disorder tending to affect middle-aged females. It is characterized by skin eruptions, neurological manifestations, lymphadenopathy, fever and other symptoms, in addition, to a range of abnormal immunological phenomena, including hypocomplementemia and hypergammaglobulinemia.

In 1989, the first controlled study of fish oil?s effects on SLE was reported. Prior to then a number of anecdotal reports suggested improvement of some patients following fish oil supplementation. The early clinical attempts were based on animal studies using inbred mice strains, which were criticized because of questionable generalization to human SLE patients.

The 1989 study tested 6 grams of EPA or 6 grams of OHA daily for five weeks in 12 patients having SLE. Thereafter, patients were taken off supplementation and continued without supplementation for a five week washout period. Then patients were returned to supplementation for another five weeks, but this time given 18 grams of EPA or DHA per day. At the higher EPA/DHA levels (18 grams a day) there was a 38% decrease in triglycerides, a 39% decrease in very low density lipoproteins (VLDL) cholesterol, and a 28% increase in high density lipoproteins (HDL)

Overall this resulted in significant improvements in inflammatory and artherosclerotic processes typically seen in SLE patients. These findings suggest some beneficial effects from fish oil supplementation. However, possible long-term benefits from fish oil supplementation in SLE patients have still not been studied. The first clinical trial of the benefits of fish oil?s EPA in the alleviation of the symptoms of osteoarthritis was reported in 1989. Patients were given ibuprofen, an aspirin-like analgesic, with either 10 milliliters of EPA a day or placebo for six months. Patients assessed the level of pain and interference they experienced in everyday activity. The average scores for these indexes ?were strikingly lower in the EPA (group) than the placebo group.? However, the differences were not as statistically significant as the researchers had hoped, meaning additional studies are suggested. This is the first report of fish oil being of benefit to patients with osteoarthritis.

Fish Oil Capsules - Toxicity Factors

Of particular concern has been the reports of prolonged bleeding time in populations having a proportionately high intake of fish. Several studies have shown this effect appears to be dose-dependent, although collagen-induced platelet aggregation is not inhibited. Many studies have shown fish oil supplements prolong bleeding time, inhibit platelet aggregation, and decrease Thromboxane 2 production. However, the concept of prolonged bleeding time is significant or potentially life-threatening is under review.

Foran has pointed out there are some associated risks, in general, from increased consumption of fish. Some fish may be contaminated from industrial effluents and toxins. Many of these toxins are known to increase the risk of cancer. Animal experiments have demonstrated eating such contaminated fish as infrequently as once a week may increase the risk of developing cancer, in addition, to its risk to pregnant mothers and infants.

The potential adverse effects of long?term fish oil supplementation are unknown. However this is also true of all other oils, such as vegetable oils and most hypolipidemic drugs currently prescribed.

Fish Oil Capsules - Research Briefs

-Atherosclerosis ?This randomized clinical trial tested whether fish oil supplements can improve human coronary atherosclerosis.

Epidemiological studies of populations whose intake of oily fish is high, as well as laboratory studies of the effects of the polyunsaturated fatty acids in fish oil, support the hypothesis that fish oil is antiatherogenic.

Mean minimal diameter of artherosclerotic coronary arteries decreased by 0.104 and 0.138 mm in the fish oil and control groups, respectively (p = 0.6 between groups), and percent stenosis increased by 2.4% and 2.6%, respectively (p = 0.8). Confidence intervals exclude improvement by fish oil treatment of > 0.17 mm, or > 2.6%.

Fish oil treatment for 2 years does not promote major favorable changes in the diameter of artherosclerotic coronary arteries.

Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. Sacks-FM; Stone-PH; Gibson-CM; Silverman-DI; Rosner-B; Pasternak-RC. J-Am-Coll-Cardiol 1995 Jun; 25(7) 1492-8.

-Myocardial infarction-

Evaluated whether increased intake of fish oils (Eicosapentaenoic and Docosahexaenoic acids) might reduce the risk of coronary heart disease.

Observational and clinical studies have suggested that increased intake of fish oils, as reflected in plasma levels of fish oils, may reduce the risk of myocardial infarction.

14,916 participants in the Physicians? Health Study with a sample of plasma before randomization. Each participant with myocardial infarction occurring during the first 5 years of follow-up was matched by smoking status and age with a randomly chosen control participant who had not developed coronary heart disease.

There was a lack of association between fish oil levels and the incidence of myocardial infarction.

Results indicated no beneficial effect of increased fish oil consumption on the incidence of a first myocardial infarction.

A prospective study of plasma fish oil levels and incidence of myocardial infarction in U.S. male physicians. Guallar-E; Hennekens-CH; Sacks-FM; Willett-WC; Stampfer-MJ. J-Am-Coll-Cardiol. 1995 Feb; 25(2); 387-94.



References

1. Abmed, A & B Holub Alteration and recovery of bleeding times, platelet aggregation and fatty acid composition of individual phospholipids in platelets of human subjects receiving a supplement of cod?liver oil. Lipids. 1984. 19; 617?624.
2. Arthaud, JR. Cause of death in 339 Alaskan natives as determined by autopsy. Arch Pathol Lab Med. 1970. 90; 433?438.
3. Bakker, D., B. Haberstroh, D. Philbrick, et al. Triglyceride lowering in nephrotic syndrome patients consuming a fish oil concentrate. Mutr Res. , 1989. 9(1); 27-34.
4. Ejerve, KS. , L. Thoresen & S. Brsting. Linseed and cod liver oil induce rapid growth in a
5. 7-year old girl with omega-3 fatty acid deficiency. J Parenter Enteral Mutr.1988.12(5);521?525.
6. Borgeson, C. , L. Pardini, R. Pardini, et al. Effects of dietary fish oil on human mammary carcinoma and on lipid-metabolizing enzymes. Lipids, 1989. 24; 290-295.
7. Bradlow, BA., H. Chetty, J. van der Westhuyzen, et al. The effects of a mixed fish diet on platelet function, fatty acids and serum lipids. Thromb Res. 1983. 29; 561-568.
8. Brox, Killie, Funnes, et al. The effect of cod-liver oil and corn oil on platelets and vessel wall in man. Thromb Haemost. , 1981. 46; 604-611.
9. Clark, W., A. Parbtami, B. Holub, et al. Omega-3 fatty acid dietary supplementation in lupus nephritis. Kidney Int. 1989. 35; 368.
10. Croft, K. , L. Beilin, R. Vandongen. The effect of dietary fish oil on platelet metabolism of 14-C arachidonic acid. Thromb Res. 1986. 42; 99-194.
11. Curb, J.D. & D.M. Reed. Fish consumption and mortality from coronary heart disease. New Eng J Med. 1985. 313; 821.
12. Davis, H.R. , R.T. Bridenstine, D. Vesselinovitch, et al. Fish oil inhibits development of atherosclerosis in rhesus monkeys. Atherosclerosis. 1987. 7; 441-449.
13. DiCiacomo, R. , J. Kremer, D. Shah. Fish-oil dietary supplementation in patients with Raynaud?s phenomenon: a double-blind controlled, prospective study. Am J Med. 1989. 86; 158-164.
14. Endres, S. , R. Ghorbani, V.E. Kelley, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. New Eng J Med. 1989. 320(5); 265-271.
15. Foran, J.A. , B.S. Glenn & B. Silverman. Increased fish consumption may be risky. JAMA. 1989. 262(1); 28.
16. Foran, JA. , M. Cox & D. Croxton. Sport fish consumption advisories and projected cancer risks in the Great Lakes basin. AJPH. 1989. 79.
17. Foran, JA. & D. VanderPloeg. Consumption advisories for sport fish in the Great Lakes basin. J Great Lakes Res. 1989.
18. Goodnight, S.H. , W.S. Harris, & W.E. Connor. The effects of dietary w3 fatty acids on platelet composition and function in man - A prospective, controlled trial. Blood. 1981. 58; 880-885.
19. Gudbjarnason, J. & J. Hallgrimmson. The role of myocardial membrane lipids in the development of cardiac necrosis. Acta Med Scand Suppl. 1976. 587; 17-27.
20. Herold, P.M. £ JE. Kinsella. Fish oil consumption and decreased risk of cardiovascular disease - a comparison of findings from animal and human feeding trials. Am J Clin Nutr. 1986.43; 566?598.
21. Hirai, A., T. Terano, T. Hamazaki, et al. The effects of the oral administration of fish oil concentrate on the release and the metabolism of [l4CJarachidonic acid and [14CJ eicosapentaenoic acid by human platelet. Thromb Res. 1982. 28; 285-298.
22. Hollander, Hong, Kirkpatrick, et al. Differential effects of fish oil supplements on atherosclerosis. Circulation, 1987. 76 Suppl 4. 1245.
23. Hutchinson. Fish liver oil vs. fish oil. Can Med Assoc J. 1988. 139;1037.
24. Isseroff, R.R. Fish again for dinner! The role of fish and other dietary oils in the therapy of skin disease. J Am Aca Dermatol. 1988. 19; p 1073.
25. Karmali, R.A. Fatty acids: inhibition. AJCN. 1987. 45; 225-229.
26. Kinsella, JE. Effects of polyunsaturated fatty acids on factors related to cardiovascular disease. Am J Cardiol. 1987. 60; 23G-32G.
27. Knapp, H. & G. Fitzergerald. The antihypertensive effects of fish oils: a controlled study of polyunsaturated fatty acid supplements in essential hypertension. Mew Eng J Med. 1989. 320(16); 1037?1043.
28. Knapp, H., I. Reilly, P. Alessand.rini, et al. In vivo indexes of platelet and vascular function during fish oil administration in patients with atherosclerosis. N Eng J Med. 1986. 314; 937?942.
29. Kragballe, K. & K. Fogh. A low-fat diet supplemented with dietary fish oil (Max-EPA) results in improvement of psoriasis and in formation of leukotriene BS. Acts Derm Venereol. 1989. 69(1); 23?28.
30. Kremer, J.M. , J. Bigauoetter, A. Michalek, et al. Effects of manipulation of dietary fatty acids on clinical manifestations of rheumatoid arthritis. Lancet. 1985. I; 184-187.
31. Kromann, N. & A. Green. Epidemiological studies in the Upernavik District Greenland. Acta Med Scand. 1980. 208; 401?406.
32. Kromhout D. , E.B. Bosachieter & C.L. Coulander. The inverse relation between fish consumption and 20-year mortality from heart disease. New Eng J Med. 1985. 312; 1205-1209.
33. Lands WEM. , Culp, B.R. , Hirsi, A. , et al. Relationship of thromboxane generation to the aggregation of platelets from humans - Effects of eicosapentaenoic acid. Prostaglandins. 1985. 30; 819?825.
34. Lorenz, R. , U. Spengler, S. Fisher, et al. Platelet function, thromboxane formation and blood pressure control during supplementation of the Western diet with cod liver oil. Circulation 1983; 67; 504?511.
35. Neutze, J.M. & MB. Starling. Fish oils and coronary heart disease. New Zealand Med J. 1986. 99; 583?585.
36. Norell, SE. , A. Ahlbom, M. Feychting, et al. Fish consumption and mortality from coronary heart disease. Br Med J. 1986. 293; 426.
37. Reich, R. , L. Royce & G. Martin. Eicosapentaenoic acid reduces the invasive and metastatic activities of malignant tumor cells. Biochem Biophy Res Comm. 1989. 160; 559-564.
38. Rickett, J. , D. Robinson & A. Steinberg. Effects of dietary enrichment with eicosapentoenoic acid upon autoimmune nephritis in female NZBXNZW/F1 mice. Arthritis Rheumatism. 1983. 26(2);133?139.
39. Rudin, D. The dominant disease of modernized societies as omega-3 essential fatty acid deficiency syndrome: substrate beriberi. Med Hypothesis. 1982. 8(1); 17-47.
40. Ruiter, A. , A. Jongbloed, C. van Gent, et al. Influence of dietary mackeral oil on the condition of organs and on the blood lipid composition in the young growing pig. AJCN. 1978. 31; 2159?2166.
41. Rylance,P.B. , M.P. Gordge, R. Saynor, et al. Fish oil modifies lipids and reduces platelet aggregability in hemodialysis patients. Nephron. 1986. 43; 196-202.
42. Sacks-FM et al: Controlled trial of fish oil for regression of human coronary atherosclerosis. MARP Research Group.. J-Am-Coll-Cardiol. 1995 Jun; 25(7): 1492-8.
43. Sanders T.A.B. , F. Roshanai. The influence of different types of w3 polyunsaturated fatty acids on blood lipids and platelet function in healthy volunteers. Clin Sci. 1983. 64; 91-99.
44. Sanders, T.A.B. & NC. Hochland. A comparison of the influence on plasma lipids and platelet function of supplements of w3 and w6 polyunsaturated fatty acids. Br J Nutr. 1983. 50;521?529.
45. Schimke, E. , R. Hildebrandt, J. Beitz, et al. Influence of a cod liver oil diet in diabetics type I on fatty acid patterns and platelet aggregation. Biomed Biochim Acts. 1984. 43; S351?S353.
46. Siess, W. , P. Roth, B. Scherer, et al. Platelet-membrane fatty acids, platelet aggregation, and thromboxane formation during a mackerel diet. Lancet. 1980. 1; 441-444.
47. Singer, P., M. Wirth, S. Volgt, at al. Clinical studies on lipid and blood pressure lowering effect of eicosapentaenoic acid-rich diet. Biomed Biochim Acta. 1984. 43; S421-S425.
48. Shekella, R.B. , 0. Paul, AM. Shyrock, at al. Fish consumption and mortality from coronary heart diseae. New England J Med. 1985. 313: 820.
49. Srivastava, K.C. Docosahexaenoic acid (C22:6w3) and linoleic acid are anti-aggregatory and alter arachidonic acid metabolism in human platelets. Prostaglandins Leukotrienes Med. 1985. 17; 319?327.
50. Stammers, T., B. Sibbald & P. Freeling. Fish oil in osteoarthritis. Lancet. 1989. II; 503.
51. Thorngren, M. & A. Gustafson. Effects of 11?week increase in dietary eicosapentaenoic acid on bleeding time, lipid, and platelet aggregation. Lancet. 1981. 2; 1190-1194.
52. Vollset, SE., I. Heuch & E. Bjelke. Fish consumption and mortality from coronary heart disease. Hew Eng J Med. 1985. 313; 820?821.
53. Vorhees, J.J. Leukotrienes and other lypoxygenase products in the pathogenesis and therapy of psoriasis and other dermatoses. Arch Dermatol. 1983. 119(7) ; 541-547.
54. Von Schacky, C. , S. Fischer, P.C. Weber. Long-term effects of dietary marine w3 acids upon plasma and cellular lipids, platelet function, and eicosonoid formation in humans. J Clin Invest. 1985. 76; 1626?1631.
55. Weiner, B., I. Ockene, P. Levine, et al. Inhibition of atherosclerosis by cod-liver oil in a hyperlipidemic swine model. New Eng J Med. 1986. 315; 841-846.
56. Yetiv, J. Clinical applications of fish oils. JAMA. 1988 260(5); 665-670.