Essential Nutrients:  Background Information

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Overview of Essential Fatty Acids

Edited by David F. Horrobin
1982 Eden Press Inc.
This book is out of print.  The following is taken from Chapter 1.

Clinical Uses Of Essential Fatty Acids

David F. Horrobin


Polyunsaturated fatty acids (PUFAs) are fatty acids which have two or more double bonds linking carbon atoms in the molecule (1). On the whole they tend to be found in liquid form, unless they are complexed with other fats. Not all liquid fats are rich in PUFAs. Coconut oil and palm oil largely consist of saturated fats while olive oil contains large amounts of the mono-unsaturated oleic acid.


Essential fatty acids (EFAs) are dietary factors which were discovered at the University of Minnesota by George and Mildred Burr in 1929. Like vitamins EFAs cannot be made by the body but must be taken in with the food (1, 2). All EFAs are PUFAs, but most PUFAs are not EFAs (3, 4). In order to act as an EFA, highly specific chemical structures are required. There are two series of EFAs, the n6 derived from cis-linoleic acid, and the n3 derived from alpha-linolenic acid. The numbers indicate the position of the first double bond from the omega end of the molecule. The n6 series seems to be considerably more important but the n3 series are now beginning to be intensively investigated with particular reference to their roles in cardiovascular function and in the brain.

Like certain vitamins, cis-linoleic acid and alpha-linolenic acid have no biological activity of their own, apart from being oxidized to provide energy. If they are to function as EFAs, they require specific biochemical transformation within the body. The reaction sequences are shown in figure 1. The exact functions of each of the fatty acids in the sequence are by no means fully known. It is known that unless cis-linoleic acid can be converted to gamma-linolenic acid (GLA), it has no biological activity as an EFA (5)  

Figure 1


The two series of EFAs, the n3 and the n6 series are not interchange-able in animals. However the enzymes which metabolize the n6 and the n3 series seem to be identical. There are considerable species differences between EFA metabolism which will be discussed in later sections. In particular, delta-5-desaturase activity is high in rats and mice but low in humans and guinea pigs (13).

EFAs are important for two quite different reasons. First they are constituents of all membranes in all tissues of the body. They play a vital role in determining the biological properties of all these membranes. It is therefore not surprising that EFA deficiency leads to profound disturbances in all tissues (1, 2).

Second, EFAs are the precursors of a group of highly reactive, short-lived molecules, the prostaglandins (PGs) and leukotrienes (LTs). These substances serve a wide variety of functions and each cell type produces a specific pattern of PGs and LTs. There are over fifty types of PGs and LTs and related molecules known and new ones are discovered every year. There are powerful mechanisms within cells for degrading PGs and LTs and almost all PGs are removed from the blood during a single passage through the lungs. The main actions of these substances therefore seem to be as local messengers which regulate the activity of the tissues in which they are produced (6, 7).

The PGs and LTs have an almost incredible variety of effects, some highly desirable and some harmful. Three of the EFAs can act as precursors for PGs, dihomogammalinolenic acid (DGLA) and arachidonic acid (AA) of the n6 series and eicosapentaenoic acid (EPA) of the n3 series. DGLA cannot give rise to LTs and the PGs it leads to are either neutral or, like PGE1, very desirable in their actions. PGE 1 is an activator of cyclic AMP formation, an inhibitor of platelet aggregation, a vasodilator, an inhibitor of inflammatory reactions and an activator of T lymphocyte function (7).

AA, in contrast, produces a very mixed bag of substances. Unlike DGLA it can give rise to LTs which are very pro-inflammatory. Some of the PGs it leads to such as PG12 (prostacyclin) have desirable effects such as inhibition of platelet aggregation and vasodilatation. Others, such as thromboxane A2 (TXA2, a substance closely related to PGs) and PGF2a have largely undesirable effects such as promo-tion of vasospasm, thrombosis and inflammation. The PGs and thromboxanes are formed from AA by a cyclo-oxygenase enzyme system while the leukotrienes are formed by a lipoxygenase enzyme system (figure 2) (7, 8).

Figure 2

Arachidonic acid products are found in abundance wherever any form of inflammation is taking place. In order for these products to be formed, AA must first be released from membrane stores and converted to a free form. The free AA can then be converted either to leukotrienes and related compounds or to prostaglandins and related compounds. Aspirin and other non-steroidal anti-inflammatory drugs inhibit inflammation by blocking the cyclo-oxygenase only. If LTs are important in a reaction, as they seem to be in asthma for example, aspirin and related drugs may leave more free AA to be converted to LTs and so provoke an exacerbation. This appears to be the mechanism behind aspirin-induced asthma. Steroids are much more potent anti-inflammatories than the aspirin-like compounds because they block the release of arachidonic acid and so inhibit the formation of both PGs and LTs. PGE1 has a steroid-like action in blocking AA mobilisation ( 9, 10). At present less is known about selective inhibitors of the lipoxygenase pathway. Vitamin E is one such inhibitor (145). Another is a hydroxy acid which can be formed from DGLA (11). DGLA derivatives therefore inhibit the formation of inflammatory substances from AA in two quite distinct ways. This has led to the proposal that there is a negative feedback balance between DGLA and AA, with adequate amounts of DGLA and its products being required to control inflammation (10).

Much less is known about derivatives of EPA. On the whole they seem to be much less potent than those of DGLA or AA and to be either neutral or positive in their effects. One important action of EPA is to compete with AA and so to prevent the conversion of AA to inflammatory metabolites (12).


In rats the delta-5-desaturase which converts DGLA to AA is highly active and so linoleic acid in the diet is rapidly converted to AA (13). It is perhaps unfortunate that rats are so extensively used for experiments on EFAs and PGs because EFA metabolism in humans is quite different. In adult humans DGLA is converted to AA only very slowly if at all (13). Guinea pigs are similar to humans in this respect and it may be significant that the immune and inflammatory systems of the guinea pig tend to be rather similar to those in humans.

Because of the low activity of the delta-5-desaturase, in humans the balance between 1 and 2 series PGs may be readily influenced by the diet. Linoleic acid, which gives rise to DGLA, comes mainly from vegetable sources although organ meats contain some. Arachidonic acid comes mainly from meat and some seafoods, shrimps being a particularly rich source. There is also arachidonic acid in some sea-weeds. On the whole, however, the diets of vegetarians are likely to contain primarily 1 series PG precursors while those of meat eaters contain both. Some of the health differences between meat eaters and vegetarians could be related to this.


Much less is known about this and what we do know has come from two unusual circumstances. In the 1950s, when much research was being done on artificial milk preparations for infants, some formula-tions were made in which EFA levels were far too low. The most striking observations in these infants were dry, scaly skin, eczema-like rashes, irritability and a substantial increase in calorie intake (16, 17). The infants fed these formulae had much larger appetites than contemporaries taking a normal EFA diet. Addition of EFAs to the formulae reduced appetite and caused rapid clearing of the skin.

In the 1970s, when fluids for total parenteral nutrition were being developed, the American Food and Drug Administration would not allow EFAs to be included. The result was a series of reports of acute EFA deficiency in adults, with skin rashes resembling psoriasis or eczema, failure of wound healing and irritability being prominent (18-21).


No specific work has been done on chronic EFA deficiency in either animals or humans. It is therefore not known what the long term effects of a partial EFA deficiency might be in either animals or humans.

However there are two classical ways of investigating what an essential nutrient does. The first is to deprive individuals of that nutrient and to watch what happens. The second is to administer an excess of the nutrient. If on giving an apparent excess of a nutrient, certain manifestations of disease disappear, then it is legitimate to conclude that those manifestations may have resulted from long term partial deficiency. Over the past 25 years, this second type of study has repeatedly been carried out using PUFAs as sources of EFAs. Doctors and authoritative national and international committees have repeatedly urged patients to take 10-15% of their total calorie intake in the form of EFAs. This is in contrast to the 1% of total calorie intake which is adequate to support normal growth and development of young animals (148, 149). Curiously, EFAs are the only nutrients which the medical profession consistently advises their patients to take in mega-doses. These mega-doses have been found to have desirable effects in a variety of conditions, notably cardiovascular problems, diabetes, breast and menstrual cycle problems and multiple sclerosis.

Another important development in relation to chronic EFA deficiency arises from the work of Brenner's group on aging and EFA metabolism (22-24). They have shown that in animals, the delta-6-desaturase enzyme which is required for the metabolism of both cis-linoleic acid and alpha-linolenic acid, is lost with aging: It disappears in the gonads first and later in the rest of the body. Loss of this enzyme means that aging animals inevitably become functionally deficient in EFAs. Even though they may be taking normal amounts of linoleic and alpha-linolenic acids in the diet, they cannot make use of these as functional EFAs.

As yet only a few studies in humans have addressed themselves to this problem (25-27). However these strongly suggest that the enzyme is lost or only partly functional in older humans. Administration of linoleic acid to older humans usually produces little change in DGLA. However administration of small amounts of gamma-linolenic acid, which by-passes the enzymes, leads to a 3-8 fold rise in DGLA in plasma and platelets (25, 26). If these findings are con-firmed, they mean that humans, as they become older, will also become functionally EFA deficient because of inability to metabolize the usual dietary sources of EFAs.


The delta-6-desaturase (D6D) enzyme is absolutely vital to an under-standing of the EFAs since it is a gatekeeper for both the n6 and the n3 series (figure 1). It converts cis-linoleic acid to gamma-linolenic acid (GLA), and alpha-linolenic acid to 18:4 n3. For over 20 years Brenner has conducted a systematic investigation of the behaviour of this enzyme. His findings and those of other groups are as follows (22, 31, 32):

1.   Saturated fats inhibit the activity of the enzyme.
2.   Trans fatty acids formed by the processing of vegetable oils inhibit the enzyme.
3.   In diabetic animals the activity of the enzyme is low (28).
4.   Alcohol inhibits the enzyme (29).
5.   Aging leads to loss of enzyme activity.
6.   Adrenaline inhibits the enzyme, an effect mediated by beta-receptors since 
      it can be abolished by beta blockade. This is a neglected potential site of 
      action of beta-blockers in cardio-vascular disease.
7.   Starvation inhibits the enzyme, but a restricted calorie intake may increase
      enzyme activity three fold (150) .
8.   Glucocorticoids inhibit the enzyme.
9.   A very low protein diet inhibits the enzyme whereas a very high protein 
      diet activates it.
10. Administration of glucose to normal animals inhibits the enzyme.
11. Oncogenic viruses and ionizing radiation inhibit the enzyme (30).

It is thus apparent that a large number of agents which are known to have profound effects on health (e.g. alcohol, diabetes, calorie restriction, catecholamines, beta-blockers, glucose) also have major effects on the D6D and so regulate the availability of EFAs to the body. The effects of these agents on the D6D are rarely considered when their sites of action are being explored.


1. Mead JF, Fulco AJ. The Unsaturated and Polyunsaturated Fatty Acids in Health and Disease. CC Thomas, Springfield, 1976.
2. Holman RT. Essential fatty acid deficiency. Progress in the Chemistry of Fats and Other Lipids (ed RT Holman). Pergamon Press, New York, 275-348, 1966.
3. Sinclair HM. Dietary fats and coronary heart disease. Lancet 1: 414-5, 1980.
4. Sinclair HM. Prevention of coronary heart disease: the role of
essential fatty acids. Postgrad Med J 56: 579-84, 1980.
5. Frankel TL, Rivers JPW. The nutritional and metabolic impact
of gamma-linolenic acid on cats deprived of animal lipid. Br J
Nutr 39: 227-31, 1978.
6. Horton EW. The prostaglandins. Springer Verlag, Berlin, New York, 1972.
7. Horrobin DF. Prostaglandins: Physiology, Pharmacology and Clinical Significance. Eden Press, Montreal, Churchill Living-stone, Edinburgh, 1978.
8. Ford-Hutchinson AW. Leukotrienes and neutrophil function: a review. J Roy Soc Med 74: 831-4, 1981.
9. Minkes M, Stanford N, Chi MMY et al. Cyclic adenosine mono-phosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions. J Clin Invest 59: 449-54, 1977.
10. Horrobin DF. Regulation of prostaglandin biosynthesis: negative feedback mechanisms and the selective control of forma-tion of 1 and 2 series prostaglandins: relevance to inflammation and immunity. Med Hypotheses 6: 687-709, 1980.
11. Vanderhoek JY, Bryant RW, Bailey JM. Inhibition of leukotriene biosynthesis by 15-hydroxy-eicosanoids. International Symposium on Leukotrienes and Other Lipoxygenase Products. Florence, abstract book, 94, 1981.
12. Lands WEM, Byrnes MJ. The influence of ambient peroxides on the conversion of eicosapentaenoic acid to prostaglandins. Progr Lipid Res 20: 287-90, 1982.
13. Stone KJ, Willis AL, Hart M et al. The metabolism of dihomogammalinolenic acid in man. Lipids 14: 174-80, 1979.
15. Sinclair HM. Essential fatty acids and the skin. Br Med Bull 14: 258-61, 1958.
16. Hansen AE. Role of unsaturated dietary fat in infant nutrition. Am J Public Health 47: 1367-70, 1957.
17. Hansen AE, Haggard ME, Boelsche AN et al. Essential fatty acids in human nutrition. J Nutr 60: 565-76, 1958.
18. Paulsrud JR, Pensler L, Whitten OF et al. Essential fatty acid deficiency in infants induced by fat-free intravenous feeding.
Am J Clin Nutr 25: 897-904, 1972.
19. Fleming CR, Smith LM, Hodges RE. Essential fatty acid deficiency in adults receiving total parenteral nutrition. Am J Clin Nutr 29: 976-83, 1976.
20. McCarthy DM, May RJ, Maher M et al. Trace metal and essential fatty acid deficiency during total parenteral nutrition. Am J Dig Dis 23: 1009-16, 1978.
21. Riella MC, Broviac JW, Wells M et al. Essential fatty acid deficiency in human adults during total parenteral nutrition. Ann Intern Med 83: 786-9, 1975.
22. Brenner RR. Nutritional and hormonal factors influencing desaturation of essential fatty acids. Progr Lipid Res 20: 41-8, 1982.
23. Peluffo RR, Ayala S, Brenner RR. Metabolism of fatty acids of the linoleic acid series in the testicles of diabetic rats. Am J Physiol 218: 669-73, 1970.
24. Ayala S, Gaspar G, Brenner RR et al. Fate of linoleic, arachidonic and docosatetraenoic acids in rat testicles. J Lipid Res 14: 296-305, 1973.
25. Darcet P, Mendy F et al. Effect of a diet enriched with gamma-linolenic acid on PUFA metabolism and platelet aggregation in elderly men. Ann Nutr Aliment 34: 277-90, 1980.
26. Weber PC. Effects of evening primrose oil on platelet and plasma lipids and on platelet aggregation in middle-aged men and women. In preparation.
27. Horrobin DF. Loss of delta-6-desaturase activity as a key factor in aging. Med Hypotheses 7: 1219-28, 1981.
28. Poisson JP, Lemarchal P, Blond JP et al. Influence of alloxan diabetes on the conversion of linoleic and gamma-linolenic acids to arachidonic acid in the rat in vivo. Diabete Metab 4: 39-45, 1978.
29. Reitz RC, Wang L, Schilling RJ et al. Effects of ethanol ingestion on the unsaturated fatty acids from various tissues. Progr Lipid Res 20: 209-13, 1982.
30. Bailey JM. Lipid metabolism in cultured cells. Lipid Metabolism in Mammals (ed F Snyder). Plenum Press, New York, 2: 352, 1977.
31. Brenner RR. The oxidative desaturation of unsaturated fatty acids in animals. Molec Cell Biochem 3: 41-52, 1974.
32. Brenner RR. Metabolism of endogenous substrates by microsomes. Drug Metab Rev 6: 155-212, 1977.
33. Gibson RA, Kneebone GM. Fatty acid composition of human
colostrum and mature breast milk. Am J Clin Nutr 34: 252-7, 1981.
34. Enig MG. Fatty acid composition of selected food items with emphasis on trans octadecenoate and trans octadecedienoate. Thesis, University of Maryland, 1981.
35. Keys A, Aravanis C, van Buchem FSP et al. The diet and all causes of death rate in the seven countries study. Lancet 2: 58-61, 1981.
36. Kannel WB. Meaning of the downward trend in cardiovascular mortality. JAMA 247: 877-80, 1982.
37. Lancet editorial. Why the American decline in coronary heart disease? Lancet 1: 183-4, 1980.
38. Katan MB, Beynen AC. Linoleic acid consumption and coro-
nary heart disease in the USA and UK. Lancet 2:371, 1981.
39. Oliver MF. Fats and atheroma. Br Med J 1: 889-90, 1979.
40. Oliver MF. Cholesterol, coronaries, clofibrate and death. New
Eng J Med 299: 1360-2, 1978.
41. Yaari S, Goldbourt U, Even-Zohar S et al. Association of serum high density lipoprotein and total cholesterol with total, cardio-vascular and cancer mortality in a 7 year prospective study of 10,000 men. Lancet 1:1011-4, 1981.
42. Rose G, Shipley MJ. Plasma lipids and mortality: a source of error. Lancet 1: 523-5, 1980.
43. Bronte-Stewart B. The effect of dietary fats on blood lipids and their relation to ischaemic heart disease. Br Med Bull 14: 243-52, 1958.
44. Wilson WS, Hulley SB, Burrows MI et al. Serial lipid and lipoprotein responses to the American Heart Association fat-controlled diet. Am J Med 51: 491, 1971.
45. Turpeinen O. Effect of cholesterol-lowering diet on mortality from coronary heart disease and other causes. Circulation 59: 1-7, 1979.
46. Hoffmann P, Taube C, Ponicke K et al. Influence of linoleic acid content of the diet on arterial pressure of salt-loaded rats. Acta Biol Med Germ 37: 863, 1978.
47. Macdonald MC, Kline RL, Mogenson GJ. Dietary linoleic acid and salt-induced hypertension. Canad J Physiol 59: 872-5, 1981.
48. Hoffmann P, Taube C, Forster W. Augmented acute hypo-
tensive effect of dihydralazine and clonidine after linoleic acid
rich diet in normotensive conscious rats. Prostaglandins Med,
in press.
50. Rao RH, Rao UB, Srikantia SG. Effect of polyunsaturate-rich vegetable oils on blood pressure in essential hypertension. Clin Exper Hypertension 3: 27-38, 1981.
51. Comberg HU, Heyden S, Hames CG et al. Hypotensive effect of dietary prostaglandin precursors in hypertensive man. Prostaglandins 15: 193, 1978.
52. Jacono JM, Judd JT, Marshall MW et al. The role of dietary essential fatty acids and prostaglandins in reducing blood pressure. Progr Lipid Res 20: 349-64, 1982.
53. Judd JT, Marshall MW, Canary J. Effects of diets varying in fat and P/S ratio on blood pressure and blood lipids in adult men. Progr Lipid Res 20: 571-4, 1982.
54. Hornstra G. Dietary fats and arterial thrombosis: effects and mechanism of action. Progr Biochem Pharmacol 13: 326, 1977.
55. Fleischman AT, Bierenbaum MJ, Justice DD et al. Titrating dietary linoleate to in vivo platelet function in man. Am J Clin Nutr 28: 601-5, 1975.
56. Fisher JM, Donegan D, Leon H et al. Effects of prostaglandins and their precursors in some tests of hemostatic function. Progr Lipid Res 20: 799-806, 1982.
57. Malinow MR. The reversibility of atheroma. Circulation 64: 1-3, 1981.
58. Oliver MF. Serum cholesterol: the knave of hearts and the joker. Lancet 2: 1090-5, 1981.
59. Christie SBM, Conway N, Pearson HES. Observations on the performance of a standard exercise test by claudicants taking gamma-linolenic acid. J Atheroscler Res 8: 83-90, 1968.
60. Olsson AG, Thyresson N. Healing of ischaemic ulcers by intra-venous prostaglandin El in a woman with thromboangitis obliterans. Acta Derm Vener 58: 467-72, 1978.
61. Kyle V, Parr G, Salisbury R et al. Vasospastic disease, cold stress and prostaglandin E. Br Med J 2: 1549, 1981.
62. Bierenbaum ML, Oudhof JH. Platelet hyperaggregability in acute coronary disease managed with PGE1. International Prostaglandin Conference,Washington, abstract book, 10, May, 10, 1979.
63. Oster P, Arab L, Schellenberg B et al. Blood pressure and adipose tissue linoleic acid. Res Exp Med 175: 287-91, 1979.
64. Vaddadi KS, Horrobin DF. Weight loss produced by evening primrose oil administration in normal and schizophrenic individuals. IRCS J Med Sci 7: 52, 1979.
65. Lowndes R, Mansel RE. The effects of evening primrose oil
administration on the serum lipids of normal and obese patients. International Efamol Conference, November 1981, London, England.
66. Mir MA. A possible mechanism for the effect of evening prim-rose oil (Efamol) in obesity. International Efamol Conference, November 1981, London, England.
67. Munro JF. A placebo controlled trial of evening primrose oil (Efamol) in the treatment of human obesity. International Efamol Conference, November 1979, London, England.
68. Kinsell LW, Michaels GD, Partridge JW et al. Effect upon serum cholesterol and phospholipids of diets containing large amounts of vegetable fat. J Clin Nutr 1: 224-31, 1953.
69. Brenner RR, Peluffo RO, Mercuri 0 et al. Effect of arachidonic acid in the alloxan diabetic rat. Am J Physiol 215: 63-9, 1968.
70. Haessler HA, Crawford JD. Insulin-like inhibition of lipolysis and stimulation of lipogenesis by prostaglandin El. J Clin Invest 46: 1065, 1967.
71. Lambert B, Jacquemin C. Synergic effect of insulin and prostaglandin El on stimulated lipolysis. Prostaglandins Med 5: 375-82, 1980.
72. Houtsmuller AJ, van Hal-Ferwerda J, Zahan KJ et al. Favour-able influences of linoleic acid on the progression of diabetic micro and macro-angiopathy. Nutr Metab 24: Suppl 1: 105-118, 1980.
73. Pudelkewicz C, Seufert J, Holman RT. Requirements of the
female rat for linoleic and linolenic acids. J Nutr 64: 138, 1968.
74. Dickerson JW. Nutrition and breast cancer. J Hum Nutr 33:
17-23, 1979.
75. Goolamali SK, Shuster S. A sebotrophic stimulus in benign and malignant breast disease. Lancet 1: 428-9, 1975.
76. Horrobin DF. Cellular basis of prolactin action. Med Hypo-theses 5: 599-620, 1979.
77. Pashby NL, Mansel RE, Preece PE et al. A clinical trial of evening primrose oil (Efamol) in mastalgia. British Surgical Re-search Society, Cardiff, July 1981.
78. Brush MG. Evening primrose oil (Efamol) in the treatment of the premenstrual syndrome. International Efamol Conference, November 1981, London, England.
79. Zurier RB, Quagliata F. Effect of prostaglandin El on adjuvant arthritis. Nature 234: 304-5, 1971.
80. Zurier RB, Damjanov I, Sayadoff DM et al. Prostaglandin El treatment of NZB/W mice. Prevention of glomerulonephritis.
Arthritis Rheum 20: 1449, 1979.
81. Fantone JC, Kunkel SL, Ward PA et al. Suppression by prostaglandin El of vascular permeability induced by vasoactive inflammatory mediators. J Immunol 125: 2591-6, 1980.
82. Fantone JC, Kunkel SL, Ward PA. Suppression of human polymorphonuclear function after intravenous infusion of prostaglandin El. Prostaglandins Med 7: 198-202, 1981.
83. Karim SMM, Sandler M, Williams ED. Distribution of prostaglandins in human tissues. Br J Pharmacol 31: 340-4, 1967.
84. Horrobin DF, Manku MS, Oka M et al. The nutritional regulation of T lymphocyte function. Med Hypotheses 5: 969-85, 1979.
85. Prickett JD, Robinson DR, Steinberg AD. Dietary enrichment with the polyunsaturated fatty acid, eicosapentaenoic acid, prevents proteinuria and prolongs survival in NZB/W mice. J Clin Invest 68: 556-9, 1981.
86. Kunkel SL, Ogawa H, Ward PA et al. Suppression of chronic inflammation by evening primrose oil. Progr Lipid Res 20: 885-8, 1982.
87. Karmali RA, Hanrahan R, Volkman A et al. Prostaglandins and essential fatty acids in regulation of autoimmunity and development of antibodies to DNA in NZB/W mice. Progr Lipid Res 20: 655-61, 1982.
88. McCormick JN, Neill WA, Sim AK. Immunosuppressive effect of linoleic acid. Lancet 2: 508, 1977.
89. Horrobin DF, Campbell A. Sjogren's syndrome and the sicca syndrome: the role of prostaglandin El deficiency. Treatment with essential fatty acids and vitamin C. Med Hypotheses 6: 225-32, 1980.
90. Horrobin DF, Campbell A, McEwen CG. Treatment of the sicca syndrome and Sjogren's syndrome with essential fatty acids, pyridoxine and vitamin C. Progr Lipid Res 20: 253-4, 1982.
91. McEwen CG. Management of dry eye syndrome with evening primrose oil (Efamol). International Efamol Conference, November 1981, London, England.
92. McKendry RJR. Treatment of Sjogren's syndrome with essential fatty acids, pyridoxine and vitamin C. Prostaglandins Med, in press, 1982.
93. Faber HK, Roberts DB. Studies in infantile allergic eczema: serum lipids with special reference to saturation of the fatty acids. J Pediatr 6: 490, 1935.
94. Cornbleet T. Use of maize oil (unsaturated fatty acids) in the
treatment of eczema. Arch Dermat Syph 31: 224-6, 1935.
95. Ginsberg JE, Bernstein C. Effect of oils containing unsaturated
fatty acids on patients with dermatitis. Arch Dermat Syph 36:
1033, 1937.
96. Finnerud CW, Kesler RL, Wiese HF. Ingestion of lard in the treatment of eczema and allied dermatoses. Arch Dermat Syph 44: 849-61, 1941.
97. Lovell CR, Burton JL, Horrobin DF. Treatment of atopic
eczema with evening primrose oil. Lancet 1: 278, 1981.
98. Wright S, Burton JL. A controlled trial of the treatment of
atopic eczema in children with evening primrose oil (Efamol).
Lancet, November 1982
99. Wright S, Burton JL. A controlled trial of the treatment of atopic eczema in adults with evening primrose oil (Efamol). p'73, this Symposium.
100. Schwartz JH, Bennett B. The differential effect of acetyl-salicylic acid on in vitro aggregation of platelets from normal, asthmatic and aspirin-sensitive individuals. Int Arch Allergy Appl Immunol 45: 899-904, 1973.
101. Byrom NA, Timlin DM. Immune status in atopic eczema: a survey. Br J Dermatol 100: 491-8, 1979.
102. Swank RL. Multiple sclerosis: a correlation of its incidence with dietary fat. Am J Med Sci 220: 421-30, 1950.
103. Sinclair H. Deficiency of essential fatty acids. Lancet 1: 381, 1956.
104. Hughes D, Keith AB, Mertin J et al. Linoleic acid therapy in severe experimental allergic encephalomyelitis in the guinea pig. Clin Exp Immunol 40: 523-31, 1980.
105. Stackpoole A, Mertin J. The effect of prostaglandin precursors on in vivo models of cell-mediated immunity. Progr Lipid Res 20: 649-54, 1982.
106. Mertin J, Stackpoole A. Suppression by essential fatty acids of experimental allergic encephalomyelitis is abolished by indomethacin. Prostaglandins Med 1: 283-91, 1978.
107. Field EJ, Joyce G. Effect of prolonged ingestion of gamma-
linolenate by MS patients. Eur Neurol 17: 67-76, 1978.
108. Field EJ. Multiple sclerosis: treatment and prophylaxis. J Roy
Soc Med 72: 487-8, 1979.
109. Seaman GVF, Swank RL, Tamblyn CH et al. Simplified red cell electrophoretic mobility test for multiple sclerosis. Lancet 1: 1138-9, 1979.
110. Sanders H, Thompson RHS, Wright HP, Zilkha KJ. Further studies on platelet adhesiveness and serum cholesteryl linoleate levels multiple sclerosis. J Neurol Neurosurg Psych 31: 321-5, 1968.
111. Wolfgram F, Myers L, Ellison G et al. Serum linoleic acid in multiple sclerosis. Neurology 25: 786-8, 1975.
112. Horrobin DF. Multiple sclerosis: the rational basis for treatment with colchicine and evening primrose oil. Med Hypo-theses 5: 365-78, 1979.
113. Horrobin DF, Lieb J. A biochemical basis for the actions of
lithium on behaviour and immunity: relapsing and remitting disorders for inflammation and immunity such as multiple sclerosis or recurrent herpes as manic-depression of the immune system. Med Hypotheses 7: 891-905, 1981.
114. Swank RL. Multiple sclerosis: twenty years on a low fat diet. Arch Neurol 23: 460, 1970.
115. Millar JHD, Zilkha KJ, Longman MJS et al. Double blind trial of linoleate supplementation of the diet in multiple sclerosis. Br Med J 1: 765-70, 1973.
116. Bates D, Fawcett PRW, Shaw DA et al. Polyunsaturated fatty acids in treatment of acute remitting multiple sclerosis. Br Med J 2: 1390-1, 1978.
117. Paty DW, Cousin HK, Read S et al. Linoleic acid in multiple sclerosis. Failure to show any therapeutic benefit. Acta Neurol Scand 58: 53, 1978.
118. Crawford MA, Stevens P. A study on essential fatty acids and multiple sclerosis. Progr Lipid Res 20: 255-8, 1982.
119. Dworkin RH. Linoleic acid and multiple sclerosis. Lancet 1: 1153-4, 1981.
120. Gozzo SD, D'Udine B. Diet deprived of essential fatty acids affects brain myelination. Neurosci Lett 7: 267-75, 1978.
121. Horrobin DF, Ally Al, Karmali RA et al. Prostaglandins and schizophrenia: further discussion of the evidence. Psychol Med 8: 430-8, 1978.
122. Horrobin DF. Schizophrenia: reconciliation of the dopamine, prostaglandin and opioid concepts and role of the pineal. Lancet 1: 529-31, 1979.
123. Hedqvist P. Basic mechanisms of prostaglandin action on autonomic neurotransmission. Ann Rev Pharmacol Toxicol 17: 259-79, 1977.
124. Borda E, Agostini M de C, Gimeno MF et al. Selective stimulation of PGE1 synthesis by soterenol in the isolated vas deferens
is mediated by alpha adrenoreceptors. Prostaglandins Med, in press, 1982.
125. Manku MS, Oka M, Horrobin DF. Differential regulation of the formation of prostaglandins and related substances from arachidonic acid and from dihomogammalinolenic acid. 1. Effects of ethyl alcohol. Prostaglandins Med 3: 119-28, 1979.
126. George FR, Collins AC. Prostaglandin synthesis inhibitors antagonize the depressant effects of ethanol. Pharmacol Biochem Behav 10: 865-9, 1979.
127. Rotrosen J, Segarnick DJ, Cordaso DM. Interactions between essential fatty acids and prostaglandins in the control of the withdrawal syndrome in alcohol-addicted mice. Submitted for publication. See p175, this symposium.
128. Abdulla YH, Hamadah K. Effect of ADP on PGE formation in blood platelets from patients with depression, mania and schizophrenia. Br J Psychiatry 127: 591-5, 1975.
129. Horrobin DF, Manku MS. Possible role of prostaglandin El in the affective disorders and alcoholism. Br Med J 1: 1363-6, 1980.
130. Horrobin DF. A biochemical basis for alcoholism and for alcohol-induced damage including the fetal alcohol syndrome and cirrhosis: interference with essential fatty acid and prostaglandin metabolism. Med Hypotheses 6: 929-42, 1980.
131. Wilson DE, Engel J, Wong R. Prostaglandin El prevents alcohol-induced fatty liver. Clin Res 21: 829, 1973.
132. Varma PK, Persaud TVN. Protection against ethanol-induced embryonic damage by gamma-linolenic acid and linoleic acid. Prostaglandins Med, 8:641-5, 1982.
133. Wender PH, Reimherr FW, Wood DR. Attention deficit disorder (minimal brain dysfunction) in adults. Arch Gen Psych 38: 449-56, 1981.
134. Colquhoun V, Bunday S. A lack of essential fatty acids as a possible cause of hyperactivity in children. Med Hypotheses 7: 681-6, 1981.
135. Mathe AA, Sedvall G, Wiesel FA et al. Increased content of immunoreactive prostaglandin E in cerebrospinal fluid of patients with schizophrenia. Lancet 1: 16-17, 1980.
136. Horrobin DF. Prostaglandins and schizophrenia. Lancet 1: 706-7, 1980.
137. Horrobin DF, Manku MS, Oka M et al. The role of a prostaglandin El deficiency in schizophrenia: interactions with dopamine and opiates. The Biological Basis of Schizophrenia,
ed G Hemmings, Wiley, Chichester, 2: 1-15, 1981.
138. Obi FO, Nwanze EAC. Fatty acid profiles in mental disease. 1. Linolenate variations in schizophrenia. J Neurol Sci 43: 447-54, 1979.
139. Vaddadi KS. Penicillin and essential fatty acid supplementation in schizophrenia. Prostaglandins Med 2: 77-80, 1979.
140. Chouinard G, Horrobin DF, Annable L. An antipsychotic action of penicillin in schizophrenia. IRCS J Med Sci 6: 187, 1978.
141. Parmigiani P. Evening primrose oil and captopril in schizophrenia. International Efamol Conference, November 1981, London, England.
142. Vaddadi KS. The use of gamma-linolenic acid and linoleic acid to differentiate between temporal lobe epilepsy and schizophrenia. Prostaglandins Med 6: 375-9, 1981.
143. Hitzemann RJ, Garver DL. Abnormalities in membrane lipids associated with deficiencies in lithium counterflow. Society Biol Psychiatry, New Orleans, June 1981.
144. Huang YS, Cunnane SC, Horrobin DF et al. Most biological effects of zinc deficiency corrected by gamma-linolenic acid but not by linoleic acid. Atherosclerosis 41: 193-207, 1982.
145. Panganamala RV, Miller JS, Gwebu ET et al. Differential effects of vitamin E and other anti-oxidants on prostaglandin synthetase, platelet aggregation and lipoxidase. Prostaglandins 14: 261-71, 1977.
146. Vanderhoek JY, Bryant RW, Bailey JM. Inhibition of leukotriene biosynthesis by 15-hydroxy-eicosanoids. International Symposium on Leukotrienes, Florence, abstract book, 94, June 1981.
147. Hassam AG, Willis AL, Denton JP et al. The effect of an essential fatty acid deficient diet on the levels of prostaglandins and and their fatty acid precursors in the rabbit brain. Lipids 14: 78-80, 1979.
148. WHO/FAO. Dietary Fats and Oils in Human Nutrition. Report of an Expert Consultation. UN Food and Agriculture Organisation, Rome, 1977.
149. Lewis B. Dietary prevention of ischaemic heart disease—a policy for the 80s. Br Med J 2: 177-80, 1980.
150. Faas FH, Carter WJ. Altered fatty acid desaturation and micro-somal fatty acid composition in the streptozotocin diabetic rat. Lipds 15: 953-61, 1980.
151. Hill EC, Johnson SB, Holman RT. Intensification of essential fatty acid deficiency by dietary trans fatty acids. J Nutr 109:
1759, 1979.
152. Anderson JT, Grande F, Keys A. Effect on serum cholesterol in man of fatty acids produced by hydrogenation of corn oil. Fed Proc 20: 96, 1961.
153. Huttner JJ, Gwebu EG, Panganamala RV et al. Fatty acids and their prostaglandin derivatives: inhibitors of proliferation in aortic smooth muscle. Science 197: 289-91, 1977.
154. Lagarde M, Berciaud P, Burtin M et al. Refractoriness of diabetic platelets to inhibitory prostaglandins. Prostaglandins Med 7: 341-8, 1981.
155. Lagarde M, Dechavanne M, Rigaud M, Durand J. Basal level of human platelet prostaglandins: PGE1 is more elevated than PGE2. Prostaglandins 17: 685-91, 1979.
156. Horrobin DF. Multiple sclerosis: the rational basis for treatment with colchicine and evening primrose oil. Med Hypo-theses 5: 365-78, 1979.
157. Horrobin DF, Botez T, Botez MI. Polyunsaturated fatty acids and colchicine in multiple sclerosis. Br Med J 1: 199-200, 1979.
158. Rotrosen J, Mandio D, Segarnick D et al. Ethanol and prostaglandin El: biochemical and behavioural interactions. Life Sci 26: 1867-76, 1980.
159. Glen AIM. Evaluation of dietary supplementation with essential fatty acids in the management of alcohol dependent patients. Efamol International Conference, London, England, November 1981.