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A study of evening primrose seed oil in atopic asthma
Prostaglandins Leukotrienes and Essential Fatty Acids (1989) 35. 69-72 0 Longman Group UK Ltd 1989
A Study Asthma
of Evening
Primrose
P. EBDEN, C. BEVAN, J. BANKS, A. FENNERTYAND
Seed Oil in Atopic
E. H. WALTERS
Department of Thoracic Medicine, Llandough Hospital, Penarth, South Glamorgan and MRC Pneumoconiosis Unit Penarth, South Glamorgan Address for correspondence:- Dr. P. Ebden Glenfield General Hospital, Groby Road, Leicester, LE3 9QP United Kingdom.
Abstract - It has shown recently that Evening Primrose Oil (Efamol) produces a significant clinical improvement in atopic eczema. Efamol contains gamma-linolenic acid which is a precursor to PGE, a more consistent bronchodilator than PGE2. We have conducted a double blind placebo controlled study in atopic asthmatics given Efamol for an eight week period looking at the control of asthma, including histamine challenge tests. We have found no effect on the asthma or challenge tests although Efamol produced an alteration in fattv acid profile. The oatients showed an abnormal fatty acid profile. We speculate that such fatty ac’id abnormalities could be important in the aetiology of asthma.
Introduction
itself a precursor of PGEi (3). This is a more consistent bronchodilator than PGE2, although the latter is normally more abundantly produced in human airways from arachidonic acid (4, 5).
A recent study by Wright and Burton (1) showed that oral Evening Primrose Seed Oil (Efamol) produced significant clinical improvement in 99 patients with atopic eczema. Manku and coworkers (2) showed in a similar group of patients that there was a deficit of plasma phospholipid gamma-linolenic acid, dihomogamma-linolenic acid and arachidonic acid. The administration of Efamol Evening Primrose Seed Oil (which contains B-9% gamma-linolenic acid) partially corrected their biochemical abnormalities. We have studied a group of atopic asthmatic patients to see whether Efamol has any effect on the control of asthma. An increase in gamma-linolenic acid could possibly be beneficial because it is a precursor of dihomogamma-linolenic acid,
Methods
Twelve (atopic) mild chronic asthmatic patients (4 male) were studied. Their mean age was 33 years (range 20-52). Informed consent was They were normally treated with obtained. inhaled bronchodilator and/or corticosteroids: one patient took inhaled broncholidator and inhaled sodium cromoglycate. They were allocated in random order to treatment with two Efamol capsules four times daily or similar placebo capsules for two eight week periods. 69
70
PROSTAGLANDINS
Each Efamol capsule contained 360 mg of linoleic acid and 45 mg of gamma-linolenic acid, and each placebo capsule contained 500 mg of liquid paraffin. Efamol is the seed oil from strains of the. evening primrose (Oenothera biennis) selected to produce oil of constant composition. Control of asthma was assessed by the patient recording the best of three peak expiratory flow rates using a Wright’s mini peak flow meter on rising and before retiring. The record was made at least four hours after use of inhaled bronchodilator. Symptom scores were recorded daily for activity, night symptoms, day wheeze and cough. All drugs were continued unchanged throughout the study period, apart from inhaled bronchodilators. The patients were allowed to use the latter according to need, and usage was recorded daily. At the end of each eight week period a histamine dose-response curve was constructed. The patients attended the laboratory at the same time of day for the study and were asked to avoid bronchodilators during the previous twelve hours. After sitting quietly for thirty minutes, baseline airways conductance (sGaw) was measured in a constant volume whole body plethysmoraph. The mean of the last seven of eight satisfactory recordings was taken, and baseline sGaw was taken as the mean of two such sets of recordings taken five minutes apart. Increasing concentrations of histamine disphosphate were inhaled via a Wright nebuliser driven by compressed air at 20 lbs/sq inch (137.9 kPa). Concentrations of histamine ranged from 0.05 mg/ml to 10 mg/ml given in approximately doubling concentration until a fall of sGaw of approximately 60% had occurred. Each dose consisted of ten *tidal breaths timed by a metronome set at eighteen beats per minutes. Increasing doses were given at three minute intervals. sGaw was measured between 1.5 and 3 minutes following each administered dose, the recorded value being the mean of the last of six of seven technically satisfactory recordings. Induced bronchoconstriction is quickly reversed by salbutamol inhalation on completion of the study. The regression line of the descending part of each cumulative histamine log dose response curve was calculated for values with a 15% or more fall in sGaw. The doses which represented a 20% and 35% in sGaw from baseline values (log DzO and log D35 respectively) were deter-
LEUKOTRlENES
AND ESSENTIAL
FA7TY
ACIDS
mined for each patient and D2’ was taken on an index of airways sensitivity. Baseline sGaw, log D20, log DJ~ and slope of the regression line before and after treatment were compared using Student’s t test, as were the sum of the daily symptom scores, bronchodilator usage and mean PEFR for the last two weeks of each eight week period. At the start of the study and at the end of each eight week period venous blood samples were taken into lithium heparin tubes, centrifuged at 2000 rpm and plasma stored at -20 “C until analysis was performed as described by Manku (2) for fatty acids in the plasma phospholipids. Results
There was no effect of Efamol capsules on the control of asthma. There was no statistically significant difference in the mean morning or evening peak expiratory flow rates for the last fourteen days of each treatment period. There was no statistically significant difference for a similar period in the symptoms score or daily inhaled bronchodilator usage. Similarly there was no statistically significant difference in the histamine challenge value (baseline, slope, log &O
or
log
W.
The results are tabulated in Table 1. Comparisons were made using Student’s t test. The results of the plasma phospholipid fatty acid analyses are shown in Table 2 before and after treatment with Efamol. No side effects were noted from treatment with Efamol. Table 1 Comparison of Results for Last 14 Days Treatment with Evening Primrose Oil Compared to Placebo (n-12). Each Value shows the Mean -t- SD. For Details of Measurements see the Methods
Section. Evening Oil
Primrose
Placebo
370.4 5 118.0
368.66 + 111.8
Daily no of puffs of bronchodilator
4.27 + 393
3.55 f 3.75
Baseline Saw kPa-’ -’
1.09 t 0.58
1.27 + 0.49
Mean morning peak expiratory flow rate l/min
Log Dx,
-0.49 + 0.51
0.68 f 0.60
J-og D,, Slope kPa-’ _’
-0.16 + 0.50
-0.36 + 0.60
-0.63 f 0.36
-0.66 f 0.36
71
EVENING PRIMROSE SEED OIL IN ATOPIC ASTHMA
Table 2
Level of Fatty Acids in Total Plasma Phospholipids Study Asthmatics
Linoleic acid Gammalinolenic acid Dihomogammalinolenic acid Arachidonic acid Adrenic acid Alpha-linolenic acid Eicosapentaenoic acid Docasahexaenoic acid Oleic acid Palmitic acid Stearic acid
Normal’
Baseline
After
18:2n-6 18:3n-6
21.24 + 2.81 0.16 + 0.12
23.24 z!z 3.84 0.16 + 0.30*
22.86 + 3.73 0.40 f 0.37”
20:3n-6
3.06 + 0.60
20:4n-6 22:4n-6 22:5n-6 18:3n-3
11.36 0.73 1.12 0.27
+ ? I! f
1.67 0.26 0.67 0.53
2.94 + 0.61** 9.13 0.15 0.07 0.44
?I f i 2
1.40 0.24 0.15 0.12
Efamol
3.70 f 0.65** 9.69 + 1.35 0.21 + 0.23 0.097 + 0.21 0.32 i 0.15
20:5n-3
1.01 + 0.36
1.25 f 0.21
I.20 + 0.17
22:.5n-3 22:6n-3
O.Y3 I? 0.27 3.54 + 0.89
1.22 ?I 0.45 3.81 f 0.79
1.12 f 0.39 3.79 + 0.93
18: ln-9 16:O 18:0
13.50 + 2.20 25.81 rt 1.69 Il.61 a 1.32
12.52 + 1.23 27.44 z!z 1.48 13.14 ?I I.05
12.21 f 1.08 27.28 f 1.69 13.15 f 2.15
Values are mean percentages of the total fatty acids present * SD. a. from Manku M S, Horrobin D F. Huang T S and Morse N. Lipids I# 906-908. Comparison of before and after Efamol using t test. *p
Discussion It was our original intention
to study asthmatic patients to see whether Efamol, which contains 9% gamma-linolenic acid, could improve asthmatic control. The metabolic pathway of the relevant fatty acids is shown in the figure. It has been shown in atopic eczematous patients that there is a deficiency of gamma-linolenic acid and subsequent metabolites which can be partially corrected using Efamol, with subsequent improvement of the eczema. One of these metabolites is dihomogamma-linolenic acid which is a precursor to PGEr. Since PGEr is a more effective airways smooth muscle relaxant than the more naturally occurring PGEz it Metabolic
pathways
linoleic delta-6-desaturase gamma linolenic elongation dihomogammalinolenic delta-5-desaturase arachidonic elongation adrenic delta-4-desaturase Figure
of the n-6 and n-6 182 1 l8:3 1 20:3 4 PGE, 20:4 1 PG2 22:4 series I 22:s
n-3 fatty acids n-3 18:3 alphalinolenic J l8:4 I 20:4 i 20:5 eicosapentaenoic 1 22:5 4 22:6 decosahexaenoic
seemed reasonable to propose that Efamol should have positive benefit in atopic asthmatic patients. Our study shows that there is no benefit from eight weeks treatment at an Efamol dosage of two capsules four times a day (a sufficient dose to produce improvement in eczematous patients). We have used both objective measurements of peak expiratory flow rate, daily bronchodilator usage and histamine challenge testing as well as subjective responses. The fatty acid data show that Evening Primrose Oil had significant effects on gamma-linolenic acid levels and its subsequent metabolite dihomogamma-linolenic acid. Despite having these metabolic effects there was no response in improvement of asthma control. The atopic asthmatics do seem to show reductions in arachidonic acid, adrenic acid (22: 4n-6) and 22: 5-r-6 as compared to previously published normal values. This might indicate abnormal metabolism of n-6 essential fatty acids. A direct statistical comparison with controls is not possible as they are not age and sex matched, although differences in fatty acid levels with sex and age are very small. The n-3 series appears not to be affected but this is not surprising since it is preferentially metabolised by the same enzymes which metabolise the n-6 series. The failure of Efamol to raise concen-
72
PROSTAGLANDINS
trations of arachidonic acid is interesting. it suggests that dihomogamma-linolenic acid is-only slowly converted to arachidonic acid in humans with asthma and that the aim of increasing the ratio of 1 series PG precursors to 2 series PG precursors is feasible. Further work is required to elucidate the roles of EFAs in asthma and to test possible effects of higher doses of gammalinolenic acid, and/or longer periods of treatment.
LEUKOTRIENES
AND ESSENTIAL FA’ITY ACIDS
References 1 Wright W, Burton J L. Oral evening primrose seed oil improves atopic eczema. Lancet ii; 1120-1122, 1982. D F, Morse N, Kyte V, Jenkins K. Prostaglandins Leukotr Med 9; 615-628. 1982. Chaud M, Franchi A M, Gimeno M F. Gimeno A L. 3. Gamma-linolenic acid improves the constancy of contractions in uteri from spayed rats and is metabolized to prostaglandin E, but not to bisenoic prostanoids. Prostaglandins 35: 95-106. 1988. 4. Gardiner P J, Collier H 0 J. Receptors for E and F prostaglandins in airways. Adv Prostaglandin Thromboxane Res 7; 1003-8, 1980. 5. Karim S M M, Sandler M, Williams E D. Distribution of prostaglandins in human tissues. Br J Pharmacol Chemother 31; 340-4. 1967. 2. Manku M S, Horrobin
A Study Asthma
of Evening
Primrose
P. EBDEN, C. BEVAN, J. BANKS, A. FENNERTYAND
Seed Oil in Atopic
E. H. WALTERS
Department of Thoracic Medicine, Llandough Hospital, Penarth, South Glamorgan and MRC Pneumoconiosis Unit Penarth, South Glamorgan Address for correspondence:- Dr. P. Ebden Glenfield General Hospital, Groby Road, Leicester, LE3 9QP United Kingdom.
Abstract - It has shown recently that Evening Primrose Oil (Efamol) produces a significant clinical improvement in atopic eczema. Efamol contains gamma-linolenic acid which is a precursor to PGE, a more consistent bronchodilator than PGE2. We have conducted a double blind placebo controlled study in atopic asthmatics given Efamol for an eight week period looking at the control of asthma, including histamine challenge tests. We have found no effect on the asthma or challenge tests although Efamol produced an alteration in fattv acid profile. The oatients showed an abnormal fatty acid profile. We speculate that such fatty ac’id abnormalities could be important in the aetiology of asthma.
Introduction
itself a precursor of PGEi (3). This is a more consistent bronchodilator than PGE2, although the latter is normally more abundantly produced in human airways from arachidonic acid (4, 5).
A recent study by Wright and Burton (1) showed that oral Evening Primrose Seed Oil (Efamol) produced significant clinical improvement in 99 patients with atopic eczema. Manku and coworkers (2) showed in a similar group of patients that there was a deficit of plasma phospholipid gamma-linolenic acid, dihomogamma-linolenic acid and arachidonic acid. The administration of Efamol Evening Primrose Seed Oil (which contains B-9% gamma-linolenic acid) partially corrected their biochemical abnormalities. We have studied a group of atopic asthmatic patients to see whether Efamol has any effect on the control of asthma. An increase in gamma-linolenic acid could possibly be beneficial because it is a precursor of dihomogamma-linolenic acid,
Methods
Twelve (atopic) mild chronic asthmatic patients (4 male) were studied. Their mean age was 33 years (range 20-52). Informed consent was They were normally treated with obtained. inhaled bronchodilator and/or corticosteroids: one patient took inhaled broncholidator and inhaled sodium cromoglycate. They were allocated in random order to treatment with two Efamol capsules four times daily or similar placebo capsules for two eight week periods. 69
70
PROSTAGLANDINS
Each Efamol capsule contained 360 mg of linoleic acid and 45 mg of gamma-linolenic acid, and each placebo capsule contained 500 mg of liquid paraffin. Efamol is the seed oil from strains of the. evening primrose (Oenothera biennis) selected to produce oil of constant composition. Control of asthma was assessed by the patient recording the best of three peak expiratory flow rates using a Wright’s mini peak flow meter on rising and before retiring. The record was made at least four hours after use of inhaled bronchodilator. Symptom scores were recorded daily for activity, night symptoms, day wheeze and cough. All drugs were continued unchanged throughout the study period, apart from inhaled bronchodilators. The patients were allowed to use the latter according to need, and usage was recorded daily. At the end of each eight week period a histamine dose-response curve was constructed. The patients attended the laboratory at the same time of day for the study and were asked to avoid bronchodilators during the previous twelve hours. After sitting quietly for thirty minutes, baseline airways conductance (sGaw) was measured in a constant volume whole body plethysmoraph. The mean of the last seven of eight satisfactory recordings was taken, and baseline sGaw was taken as the mean of two such sets of recordings taken five minutes apart. Increasing concentrations of histamine disphosphate were inhaled via a Wright nebuliser driven by compressed air at 20 lbs/sq inch (137.9 kPa). Concentrations of histamine ranged from 0.05 mg/ml to 10 mg/ml given in approximately doubling concentration until a fall of sGaw of approximately 60% had occurred. Each dose consisted of ten *tidal breaths timed by a metronome set at eighteen beats per minutes. Increasing doses were given at three minute intervals. sGaw was measured between 1.5 and 3 minutes following each administered dose, the recorded value being the mean of the last of six of seven technically satisfactory recordings. Induced bronchoconstriction is quickly reversed by salbutamol inhalation on completion of the study. The regression line of the descending part of each cumulative histamine log dose response curve was calculated for values with a 15% or more fall in sGaw. The doses which represented a 20% and 35% in sGaw from baseline values (log DzO and log D35 respectively) were deter-
LEUKOTRlENES
AND ESSENTIAL
FA7TY
ACIDS
mined for each patient and D2’ was taken on an index of airways sensitivity. Baseline sGaw, log D20, log DJ~ and slope of the regression line before and after treatment were compared using Student’s t test, as were the sum of the daily symptom scores, bronchodilator usage and mean PEFR for the last two weeks of each eight week period. At the start of the study and at the end of each eight week period venous blood samples were taken into lithium heparin tubes, centrifuged at 2000 rpm and plasma stored at -20 “C until analysis was performed as described by Manku (2) for fatty acids in the plasma phospholipids. Results
There was no effect of Efamol capsules on the control of asthma. There was no statistically significant difference in the mean morning or evening peak expiratory flow rates for the last fourteen days of each treatment period. There was no statistically significant difference for a similar period in the symptoms score or daily inhaled bronchodilator usage. Similarly there was no statistically significant difference in the histamine challenge value (baseline, slope, log &O
or
log
W.
The results are tabulated in Table 1. Comparisons were made using Student’s t test. The results of the plasma phospholipid fatty acid analyses are shown in Table 2 before and after treatment with Efamol. No side effects were noted from treatment with Efamol. Table 1 Comparison of Results for Last 14 Days Treatment with Evening Primrose Oil Compared to Placebo (n-12). Each Value shows the Mean -t- SD. For Details of Measurements see the Methods
Section. Evening Oil
Primrose
Placebo
370.4 5 118.0
368.66 + 111.8
Daily no of puffs of bronchodilator
4.27 + 393
3.55 f 3.75
Baseline Saw kPa-’ -’
1.09 t 0.58
1.27 + 0.49
Mean morning peak expiratory flow rate l/min
Log Dx,
-0.49 + 0.51
0.68 f 0.60
J-og D,, Slope kPa-’ _’
-0.16 + 0.50
-0.36 + 0.60
-0.63 f 0.36
-0.66 f 0.36
71
EVENING PRIMROSE SEED OIL IN ATOPIC ASTHMA
Table 2
Level of Fatty Acids in Total Plasma Phospholipids Study Asthmatics
Linoleic acid Gammalinolenic acid Dihomogammalinolenic acid Arachidonic acid Adrenic acid Alpha-linolenic acid Eicosapentaenoic acid Docasahexaenoic acid Oleic acid Palmitic acid Stearic acid
Normal’
Baseline
After
18:2n-6 18:3n-6
21.24 + 2.81 0.16 + 0.12
23.24 z!z 3.84 0.16 + 0.30*
22.86 + 3.73 0.40 f 0.37”
20:3n-6
3.06 + 0.60
20:4n-6 22:4n-6 22:5n-6 18:3n-3
11.36 0.73 1.12 0.27
+ ? I! f
1.67 0.26 0.67 0.53
2.94 + 0.61** 9.13 0.15 0.07 0.44
?I f i 2
1.40 0.24 0.15 0.12
Efamol
3.70 f 0.65** 9.69 + 1.35 0.21 + 0.23 0.097 + 0.21 0.32 i 0.15
20:5n-3
1.01 + 0.36
1.25 f 0.21
I.20 + 0.17
22:.5n-3 22:6n-3
O.Y3 I? 0.27 3.54 + 0.89
1.22 ?I 0.45 3.81 f 0.79
1.12 f 0.39 3.79 + 0.93
18: ln-9 16:O 18:0
13.50 + 2.20 25.81 rt 1.69 Il.61 a 1.32
12.52 + 1.23 27.44 z!z 1.48 13.14 ?I I.05
12.21 f 1.08 27.28 f 1.69 13.15 f 2.15
Values are mean percentages of the total fatty acids present * SD. a. from Manku M S, Horrobin D F. Huang T S and Morse N. Lipids I# 906-908. Comparison of before and after Efamol using t test. *p
Discussion It was our original intention
to study asthmatic patients to see whether Efamol, which contains 9% gamma-linolenic acid, could improve asthmatic control. The metabolic pathway of the relevant fatty acids is shown in the figure. It has been shown in atopic eczematous patients that there is a deficiency of gamma-linolenic acid and subsequent metabolites which can be partially corrected using Efamol, with subsequent improvement of the eczema. One of these metabolites is dihomogamma-linolenic acid which is a precursor to PGEr. Since PGEr is a more effective airways smooth muscle relaxant than the more naturally occurring PGEz it Metabolic
pathways
linoleic delta-6-desaturase gamma linolenic elongation dihomogammalinolenic delta-5-desaturase arachidonic elongation adrenic delta-4-desaturase Figure
of the n-6 and n-6 182 1 l8:3 1 20:3 4 PGE, 20:4 1 PG2 22:4 series I 22:s
n-3 fatty acids n-3 18:3 alphalinolenic J l8:4 I 20:4 i 20:5 eicosapentaenoic 1 22:5 4 22:6 decosahexaenoic
seemed reasonable to propose that Efamol should have positive benefit in atopic asthmatic patients. Our study shows that there is no benefit from eight weeks treatment at an Efamol dosage of two capsules four times a day (a sufficient dose to produce improvement in eczematous patients). We have used both objective measurements of peak expiratory flow rate, daily bronchodilator usage and histamine challenge testing as well as subjective responses. The fatty acid data show that Evening Primrose Oil had significant effects on gamma-linolenic acid levels and its subsequent metabolite dihomogamma-linolenic acid. Despite having these metabolic effects there was no response in improvement of asthma control. The atopic asthmatics do seem to show reductions in arachidonic acid, adrenic acid (22: 4n-6) and 22: 5-r-6 as compared to previously published normal values. This might indicate abnormal metabolism of n-6 essential fatty acids. A direct statistical comparison with controls is not possible as they are not age and sex matched, although differences in fatty acid levels with sex and age are very small. The n-3 series appears not to be affected but this is not surprising since it is preferentially metabolised by the same enzymes which metabolise the n-6 series. The failure of Efamol to raise concen-
72
PROSTAGLANDINS
trations of arachidonic acid is interesting. it suggests that dihomogamma-linolenic acid is-only slowly converted to arachidonic acid in humans with asthma and that the aim of increasing the ratio of 1 series PG precursors to 2 series PG precursors is feasible. Further work is required to elucidate the roles of EFAs in asthma and to test possible effects of higher doses of gammalinolenic acid, and/or longer periods of treatment.
LEUKOTRIENES
AND ESSENTIAL FA’ITY ACIDS
References 1 Wright W, Burton J L. Oral evening primrose seed oil improves atopic eczema. Lancet ii; 1120-1122, 1982. D F, Morse N, Kyte V, Jenkins K. Prostaglandins Leukotr Med 9; 615-628. 1982. Chaud M, Franchi A M, Gimeno M F. Gimeno A L. 3. Gamma-linolenic acid improves the constancy of contractions in uteri from spayed rats and is metabolized to prostaglandin E, but not to bisenoic prostanoids. Prostaglandins 35: 95-106. 1988. 4. Gardiner P J, Collier H 0 J. Receptors for E and F prostaglandins in airways. Adv Prostaglandin Thromboxane Res 7; 1003-8, 1980. 5. Karim S M M, Sandler M, Williams E D. Distribution of prostaglandins in human tissues. Br J Pharmacol Chemother 31; 340-4. 1967. 2. Manku M S, Horrobin