Olinical Investigator

Clin Investig (1992) 70:167-171

Clinical Pharmacology Overview

© Springer-Verlag 1992

Treatment of atopic eczema with evening primrose oil: rationale and clinical results M.J. Kerscher and H.C. Korting Dermatologische Klinik und Poliklinik der Ludwig-Maximilians Universitfit Miinchen

Summary. Recently a defect in the function of the enzyme delta-6-desaturase has been discussed as a major factor in the development of atopic eczema. Delta-6-desaturase is responsible for the conversion of linoleic acid to gamma linolenic acid. Several plants, including evening primrose, are known to be fairly rich in gamma linolenic acid. Hence, substitution of gamma linolenic acid in patients prone to developing atopic eczema seems like a feasible concept. During the last few years different clinical trials have been performed. Controlled trials following a parallel study design showed marked improvement in atopic eczema. Patients treated with the drug showed less inflammation, dryness, scaling and overall severity compared to controls. Although these findings have been supported by meta-analysis, there is still conflicting evidence in trials based on a crossover design alone, demonstrating a decrease in itching. At present, evening primrose oil in doses used for the treatment of atopic eczema is considered safe. However, still more trials addressing both efficacy and safety are needed to made a final decision. Key words: Atopic eczema - 6-6-Desaturase - yLinolenic acid - Prostaglandin E 1 - Evening primrose oil

Defect of delta-6-desaturase (D6D) as biochemical basis for atopy

As early as in 1933 Hansen first reported low levels of essential fatty acids (EFA) in the blood of paAbbreviations: AA=arachidonic acid; D5D=6-5-desaturase;

D6D=g-6-desaturase; DGLA=dihomogammalinolenic acid; EPO=evening primrose oil; EFA=essential fatty acids; GLA = ~,-linolenic acid; LA = linoleic acid; PGE = prostaglandin E

tients with atopic eczema, especially in children, and changes in the fatty acid composition of their serum lipids [17]. Manku and others have analysed the fatty acid composition of plasma phospholipids from patients with atopic eczema and found lower levels of 7-1inolenic acid (GLA), dihomogammalinolenic acid (DGLA), and arachidonic acid (AA), but a higher level of eis-linolenic acid than in healthy volunteers [8, 27, 41]. The characteristic feature of the abnormality seems to be an increase in linolenic acid and a decrease of arachidonic acid and other metabolites of linoleic acid (LA). This suggested a defect in the function of the ~-6-desaturase (D6D) enzyme [27, 28]. A deficiency of prostaglandin E 1 (PGE 1) is thought to be the result of the reduced D6D activity. Earlier, Melnik and Plewig proposed a new hypothesis for the pathogenesis of atopy [31] which links the well-known alterations in cell-mediated and humoral immunity, the disturbances of mediator metabolism, and the increased disposition of atopic skin to inflammation to a common underlying deficiency in the production of PGE 1, which in part results from a reduced D6D activity. Lack of PGE 1 and effect on the epidermis

DGLA and AA (Fig. 1), both normally found in small amounts in epidermal phospholipids, are precursors of PGE 1 and PGE 2, which are very important for the maturation and differentiation of lymphocytes in the thymus and for the activation of T-suppressor lymphocytes in the peripheral immune system [13-15, 38]. PGE 1 is found in the thymus and has thymus hormone-like actions in promoting T-lymphocyte maturation and function [1, 20, 47]. A reduced D6D activity in newborns could explain an inadequate formation of GLA and its metabolites, notably PGE 1. In fact, new-

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PATHWAYS OF THE MATABOLISM OF THE n 6 EFA

I LA

18 : 2n6 I

I

D6D

GLA

18 : 3n6 I

I

ELONGASE

t DGLA D5D

20 : 3n6 t CYC/OXYGENASE

I

CYCLOXYGENASE

Fig. 1. Linoleic acid at first is converted to GLA by D6D; subsequently, an active elongase converts GLA to DGLA, the precursor of AA and PGE 1/2

borns with a defect in D6D have low levels of GLA and its metabolites [30, 41]. This has two consequences relevant to the immune system. First, EFA are necessary for the maintenance of normal epithelial impermeability, and second, a functional deficiency will lead to a deficit in T-suppressor cell function followed by an increased immunoglobulin E (IgE) synthesis [30, 31]. Strannegard et al. reported a significant correlation between an increased concentration of IgE and linolenic acid in cord blood, caused by the deficient D6D [41]. Furthermore, PGE I affected the mediator metabolism by an intracellular increase in cAMP concentration, which inhibits histamine liberation [5, 16, 38]. The most important effects of reduced PGE 1 precursors on skin physiology are the decrease in production of PGE I and the increase in liberating mediators from leukocytes, mast cells, and basophils - a characteristic feature of atopic diathesis [10, 18, 37]. Furthermore, histamine liberated by degranulation of mast cells has immunosuppressive effects by inhibition of the function of immunocompetent cells [35]. These mechanisms may induce a vicious circle in the immunodeficient skin of patients with atopy [30, 31]. PGE 2 also binds

to specific receptors and activates T-suppressor lymphocytes by the induction of adenylate cyclase. This leads to the formation of interleukin 2, to the proliferation of mitogen-stimulated T-cells, and to the suppression of antibodies stimulated by B-lymphocytes [13, 15, 34]. Therefore, in atopics patients the lack of PGE 1 and 2 is responsible for the inhibition of inflammatory responses and T-cell proliferation [30].

Peroral treatment with evening primrose oil: bypass of the D6D defect Figure I shows the pathways of the metabolism of the n 6 essential fatty acids. The epidermis can synthesize tetraenoic eicosanoids from arachidonic acid via the cyclooxygenase and lipooxygenase pathways. AA is derived from dietary linoleic acid by an alternating sequence of D6D, chain elongation, and D5D in which new double bonds are created and a two carbon unit is added to the fatty acid chain. At first, however, linoleic acid is converted to GLA by D6D which is lacking in atopic eczema. Subsequently, an active elongase converts GLA to DGLA, the precursor of 20:4n-6 [6, 7, 37, 44]. When studying the fatty acids of the plasma phospholipids, the levels of GLA, DGLA, and AA were lower in patients with atopic eczema, whereas the level of linoleic acid was higher than in healthy control persons. This suggested defective functioning of the D6D enzyme [27, 28]. Therefore, peroral treatment with GLA may increase the levels of D6D metabolites of linoleic acid and may improve the clinical symptoms of atopic eczema. Some plants containing GLA are known. Evening primrose oil, for example, is obtained from the seeds of a hybridized variety of evening primrose (Oenothera biennis) and consists of 8.9% GLA, 74.7% LA, 6.8% palmitic acid, 7.7% oleic acid, and 1.9% stearinic acid [6]. Other plant products containing small amounts of GLA are ribes seed [32] and seed of the black-currant [42].

Therapeutic results of peroral application of evening primrose oil In the 1930s and 1940s several investigators found dietary supplementation with essential fatty acids to be of therapeutic value in atopic eczema [17]. Furthermore, good therapeutic results were claimed for the addition of high doses of linoleic acid-rich oils to the diet of persons with atopic eczema, but the advent of topical glucocorticoids made an end to this dietary form of treatment of atopic eczema. Due to the increasing awareness

169 of the unwanted side effects of topical glucocorticoids, the possible role of unsaturated fatty acids in the pathogenesis of eczema became of interest again and is currently being extensively investigated [31]. In 1981, Lovell et al. reported preliminary observations suggesting a modest but significant improvement of atopic eczema in both the doctor's and the patient's own assessment [25]. Up to now, a variety of studies on the effect of evening primrose oil (EPO) in patients with atopic eczema have been performed. Two studies, however, showed only a small or no improvement after peroral treatment [2, 40]. Topical treatment with EPO initially showed no significant clinical improvement of atopic eczema [26]. In the other controlled trials with a parallel or cross-over study design, peroral treatment with EPO markedly improved atopic eczema. The eczema was assessed by the degree of inflammation, dryness, scaling, and overall severity. For statistical evaluation, 9 of the studies 4 with parallel study design, 5 with cross-over study design - were summarized in a meta-analysis [33]. All trials with parallel study design showed a marked improvement of atopic eczema (p< 0.0001) as judged from the degree of inflammation, dryness, scaling, and overall severity. No clear-cut improvement - apart from the itch symptom could be demonstrated in trials following a crossover study design. In some trials, plasma levels of D G L A and AA were determined in addition to clinical evaluations. When measuring plasma phospholipids, a positive correlation was found between the clinical improvement of eczema and an increase in D G L A and AA [33].

Safety of peroral evening primrose oil In none of the clinical studies were unwanted effects of EPO observed. This is consistent with the chronic toxicity and carcinogenicity studies of EPO in rats, mice, and dogs [1 I, 12]. The carcinogenicity study revealed no significant differences in tumor incidence between untreated animals and ones dosed with different, excessively high doses of EPO. These results do not provide any support for the hypothesis that linoleic acid initiates or promotes the development of tumors in rats and mice [12]. EPO has been thoroughly subjected to toxicity evaluations as required for a new drug. EPO in doses higher than those likely to be taken as nutritional supplement and those now proposed for medicinal use, i.e., 480 mg/day (doses up to 2.5 ml/kg daily in rats and 5 ml/kg daily in dogs) did not produce any important adverse effects when compared with corn oil as control [11]. Ad-

ministration of EPO as a nutritional supplement is considered as safe as the administration of corn oil [11].

Prevention of atopy by peroral treatment with GLA In comparative clinical trials peroral treatment with EPO containing G L A has led to an improvement of atopic eczema, in particular itch, by bypassing the D6D defect. Increased levels of D C L A and AA have been associated with an improvement of atopic eczema. Furthermore, a significant decrease of the pathologically increased ratio of Thelper cells/T-suppressor cells has been observed. Therefore, a new therapeutic approach for the prevention of manifestations of atopy in newborns with positive atopic diathesis may consist of the peroral application of GLA immediately after birth to influence the maturation of the immune system [30, 31]. Moreover, peroral treatment with EPO during pregnancy and the lactation period has been discussed as regards the increased levels of linoleic acid and decreased levels of GLA, DCLA, and AA in women with atopy [30, 31]. Perorally given EPO before and after birth, during the maturation of the thymus, may compensate for the lack of lymphocytic PGE receptors and D6D. This may help to prevent atopic disorders.

Open questions A multicenter trial with an uniform study design still seems advisable, because so far all clinical trials, even the multicenter study [33], are limited by differences in the study design. Differences in peroral doses of EPO, treatment periods, and evaluation criteria make a definite judgement and comparisons difficult. Up to now, the first examination by a physician was after 3-4 weeks. Thus, the onset of activity has not yet been established. Moreover, the dose-response relationship for EPO has still to be determined. All trials demonstrated the difficulties in substantiating the therapeutic response on the basis of clinical parameters alone. This is all the more true in patients with atopic eczema as placebo effects also have to be taken into account. Therefore, objective quantifiable criteria for the examination of the skin have to be established, e.g., by addressing skin thickness using high-frequency ultrasound, skin roughness with profilometry, and the cutaneous microflora with the detergent scrub technique. In conclusion, a multicenter, placebo-controlled trial with parallel study design and with uniform doses of EPO over a defined period of

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time is needed. Additional topical therapy should be the same in each patient. Evaluation of the effects has to be based on frequent assessment, in particular during the first months, including bioengineering and microbiological procedures. Control examinations should be combined with blood sampling for determination of EFA in plasma phospholipids every 2 weeks. Lipid analysis should focus on EFA, in particular D G L A and AA. This would allow us to link clinical changes to biochemical ones. Moreover, patient compliance would thus be monitored. Lastly, other changes, especially increases in serum cholesterol and neutral lipids levels should be looked at to define the potential scope of unfavourable changes in the blood. References 1. Bach MA, Bach JF (1974) Effects of prostaglandins and indomethacin on rosette-forming lymphocytes: interaction with thymic hormone. In : Robinson H J, Vane JR (eds) Prostaglandin synthetase inhibitors. Raven Press, New York, pp 241-248 2. Bamford JTM, Gibson RW, Renier CM (1985) Atopic eczema unresponsive to evening primrose oil (linolenic and gamma linolenic acids). J Am Acad Dermatol 3:959-965 3. Biagi PL, Bordoni A, Masi M, Ricci G, Fanelli C, Patrizi A, Ceccolini E (1988) A long-term study on the use of evening primrose oil (Efamol) in atopic children. Drugs Exp Clin Res 14:285-290 4. Bordoni A, Biagi PL, Masi M, Ricci G, Fanelli C, Patrizi A, Ceccolini E (1987) Evening primrose oil (Efamol) in the treatment of children with atopic eczema. Drugs Exper Clin Res 14:291-297 5. Bourne HR, Lichtenstein LM, Melmon KL (1972) Pharmacologic control of allergic histamine release in vitro: evidence for an inhibitory role of 3' Y-adenosine monophosphate in human leukocytes. J Immunol 108:695-705 6. Brenner RR (1974) The oxidative desaturation of unsaturated fatty acids in animals. Mol Cell Biochem 3:41-52 7. Brenner RR (1977) Metabolism of endogenous substrates by microsomes. Drug Metab Rev 6:155-212 8. Brown WR, Hansen AE (1937) Arachidonic and linoleic acid of the serum in normal and eczematous human subjects. Proc Soc Exp Biol Med 36:113-117 9. Burton JL (1989) Dietary fatty acids and inflammatory skin disease. Lancet I: 27-31 10. Cheng DS, Hanifin JM (1986) Atopic dermatitis. In: Thiers BH, Dobson RL (eds) Pathogenesis of skin disease. Churchill Livingstone, New York, pp 13-23 11. Everett D J, Greenough R J, Perry CJ, MacDonald P, Bayliss P (1988) Chronic toxicity studies of Efamol evening primrose oil in rats and dogs. Med Sci Res 16:863-864 12. Everett DJ, Perry CJ, Bayliss P (1988) Carcinogenicity studies on Efamol evening primrose oil in rats and mice. Med Sci Res 16:865-866 13. Fischer A, Le Deist F, Durandy A (1985) Separation of a population of human T-lymphocytes that bind prostaglandin E 2 and exert a suppressor activity. J Immunol 134:815819 14. Goldstein G, Scheid M, Hammerling U, Boyse EA, Schlesinger DH, Niall HD (1975) Isolation of a polypeptide that has lymphocyte differentiating properties and is probably

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Received: August 14, 1991 Accepted : November 22, 1991

Priv. Doz. Dr. H.C. Korting Dermatologische Klinik und Poliklinik der Universitfit Miinchen Frauenlobstrasse 9-11 W-8000 Miinchen 2, FRG