Oleum Oenotherae Biennis is the fixed oil obtained from the seeds of Oenothera biennis L. (Onagraceae).
Oenothera communis Léveillé, Oenothera graveolens Gilib., Onagra biennis Scop., Onagra vulgaris Spach. (1).
Selected vernacular names
Enotera, evening primrose, hhashyshat el hhimar, king’s cureall, la belle de nuit, ligetszépeolaj, mematsuyoigusa, Nachtkerzenöl, onagre, raghan-e gole magrebi, teunisbloem (1-7).
Indigenous to Europe and is naturalized in North America (7, 8).
A biennial or occasionally an annual, up to 1.25 m high. Thick yellowish conical root produces compressed rosettes of obtuse basal leaves, from which arise much-branched reddish, rough stems; stems bear alternate, lanceolate to ovate, entire, 4 cm long, short petioled leaves. Flowers very fragrant, 3-5 cm in diameter, yellow, erect on spikes, 4-petalled; open in the evening and wilt after 1 night. Seed pods contain many small reddish-brown seeds. Plant hybridizes easily (2, 9).
Plant material of interest: fixed oil obtained from the seeds
A light-amber liquid.
Odourless; taste: oily.
General identity tests
Standard methods for analysis of fatty acids (1, 9).
Tests for specific microorganisms and microbial contamination limits are as described in the WHO guidelines on quality control methods for medicinal plants (10).
Refractive index: 1.476-1.480 (5).
Specific gravity: 0.920-0.930 (5).
The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (11). For other pesticides, see the European pharmacopoeia (11), and the WHO guidelines on quality control methods for medicinal plants (10) and pesticide residues (12).
For maximum limits and analysis of heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (10).
Where applicable, consult the WHO guidelines on quality control methods for medicinal plants (10) for the analysis of radioactive isotopes.
Other purity tests
Foreign organic matter acid values to be established in accordance with national requirements.
Concentration limits of linoleic acid (cis-linoleic acid) and γ-linolenic acid (cis-γ-linolenic acid) need to be established. However, based on literature data, values of not less than 60% and 7%, respectively, may be considered. A gas chromatography method is available for quantitative analysis (13).
Major chemical constituents
The major constituents are linoleic acid (cis-linoleic acid) (65-80%), γ-linolenic acid (cis-γ-linolenic acid) (8-14%), oleic acid (6-11%), palmitic acid (7-10%) and stearic acid (1.5-3.5%). Other constituents include sterols and triterpene alcohols (1, 3, 6, 14, 15). The structures of linoleic acid and γ-linolenic acid are presented below.
Uses supported by clinical data
Internally for symptomatic treatment of atopic eczema (2, 16-21), diabetic neuropathy (22, 23), and mastalgia (24-26). Clinical evidence for its use in the treatment of rheumatoid arthritis (27-30) is conflicting, as are the results of trials in women with premenstrual syndrome (31-35). Further well-designed clinical trials are needed to clarify these data. The results from clinical trials do not support the use of Oleum Oenotherae Biennis for the treatment of climacteric symptoms or psoriasis (36, 37).
Uses described in pharmacopoeias and in traditional systems of medicine
Topical use for the treatment of minor bruises and wounds (2).
Uses described in folk medicine, not supported by experimental or clinical data
Taken internally for the treatment of asthma, coughs, gastrointestinal disorders, pain and whooping cough (2, 9, 38).
Oleum Oenotherae Biennis was added to the diet (1 g/kg body weight, for 5 days) of guinea-pigs sensitized to ovalbumin prior to sequential allergen inhalation challenges. Treatment with the fixed oil reduced the severity of bronchial reactions following allergen challenge; the reactions were less severe in the animals challenged 80 minutes after treatment (86% reduction) than in those challenged after 10 minutes (33% reduction) (39).
Effects on cholesterol and triglyceride levels
Administration of the fixed oil to rabbits (15% of a high-cholesterol diet) for 6 weeks reduced total serum cholesterol and triglyceride levels, and increased high-density lipoprotein levels (40). A decrease in cholesterol and triglyceride levels in plasma and liver was observed in rats fed a diet containing the fixed oil (10% of a high-cholesterol diet) for 5 weeks (41). The fixed oil also increased the levels of high-density lipoprotein, IgG and leukocytes in the serum of mice fed a regular diet containing 10% fixed oil for 6 weeks (42). Levels of total serum cholesterol and very-low-density lipoprotein were consistently lower in rats fed a high-cholesterol diet supplemented with 10% fixed oil for 13 weeks, after having been fed a regular diet for 8 weeks (since birth) (43).
Inhibition of platelet aggregation
Administration of the fixed oil to rats (5 ml/kg body weight) inhibited adenosine diphosphate-induced platelet aggregation ex vivo (14). However, in another study no effect on adenosine diphosphate-induced platelet aggregation ex vivo was observed in rats fed a diet containing the fixed oil (10% of diet) (41). Administration of the fixed oil to rabbits (15% of a high-cholesterol diet) reduced platelet hyperaggregation ex vivo (40).
Rats fed a diet containing 11% fixed oil for 7 weeks showed a decrease in the spontaneous development of hypertension (41, 44). However, the vascular response to the vasoconstrictor hormones norepinephrine, angiotensin II or the calcium channel blocker verapamil remained unchanged (44). In another study, however, intragastric administration of the fixed oil to rats (1 ml daily for 3 months) significantly reduced the vascular response to renin and angiotensin II (P < 0.05), and significantly increased the formation of vascular prostacyclinlike activity (P < 0.05), compared with control rats which received olive oil (14). Intragastric administration of the fixed oil to rats enhanced the hypotensive effects of dihydralazine, clonidine and captopril (45).
Administration of the fixed oil (147 nmol/hour via an osmotic pump for 8 weeks) to male rats fed a fat-free diet attenuated the cardiovascular responses (increased heart rate and blood pressure) to chronic isolation stress (46). Administration of γ-linolenic acid (0.4 mg/kg body weight/hour, via an osmotic pump for 8 weeks) also attenuated the cardiovascular responses to chronic isolation stress in male rats genetically predisposed to hypertension (47). Administration of the fixed oil to rats (9% of diet) decreased cardiac arrhythmias induced by ischaemia (48).
Intragastric administration of the fixed oil to rats (10 ml/kg body weight) inhibited gastric mucosal damage resulting from ulcers induced by pylorus ligation, non-steroidal anti-inflammatory drugs, and hypothermic restraint. The same dose of the fixed oil also protected gastric mucosa from damage by necrotizing agents (0.6 mol/l hydrochloric acid, 0.2 mol/l sodium hydroxide and 80% ethanol) (49).
Subcutaneous administration of the fixed oil to rats (4mg/kg body weight) suppressed adjuvant-induced arthritis when administered 1-15 days after adjuvant injection (50). Intragastric administration of the fixed oil (0.2ml/kg body weight) stimulated phagocytosis, T-lymphocyte production and natural killer cell activity in cyclophosphamide-induced immune suppression in mice (51). Daily topical application of the fixed oil (10%) to the skin of pigs for 6 weeks enhanced cell proliferation (52).
Administration of the fixed oil (10% of diet) to rats with streptozocin-induced diabetes corrected a decrease in nerve conduction velocity, but did not reduce the prolonged hypoxic time to conduction failure after 1 month of treatment. Capillary density of the endoneurium also increased. Treatment of the animals with flurbiprofen, a cyclooxygenase inhibitor, reduced the effect of the fixed oil (53). Intragastric administration of the fixed oil (1g/kg body weight) for 6 weeks to rats with streptozocin-induced diabetes improved conduction velocity in the sciatic motor nerve and increased sciatic endoneural blood flow (54). In another study, administration of the fixed oil (5% of diet) to rats with streptozocin-induced diabetes prevented the decrease in nerve conduction velocity without affecting the levels of nerve sorbitol, fructose and myoinositol, or the decrease in axonal transport of substance P (55).
Intragastric administration of the fixed oil (0.6 ml daily) to pregnant rats on days 4-8 of gestation significantly reduced the embryotoxic effects of ethanol (56).
A meta-analysis of nine placebo-controlled clinical trials (four parallel studies and five with crossover design) of Oleum Oenotherae Biennis in the symptomatic treatment of 311 patients with atopic eczema concluded that the fixed oil was more effective than placebo (20). However, two double-blind, placebocontrolled studies that were not included in the meta-analysis, one crossover trial of 123 patients (2-4 g for children, 6-8 g for adults, daily for 4 weeks) (57), and one parallel trial of 102 patients (dosage not stated) (58), reported negative results. In another double-blind, placebo-controlled study, the efficacy of the fixed oil in the treatment of 39 patients with chronic dermatitis of the hands was assessed. Patients received 6 g fixed oil or placebo daily for 16 weeks. Improvements were observed in both groups, but there was no significant difference between the two groups (59). A randomized double-blind, placebocontrolled crossover trial of 99 patients assessed the efficacy of oral administration of the fixed oil for symptomatic treatment of atopic eczema. Patients treated with 2-4 g fixed oil daily for 12 weeks showed a 30-45% improvement in the overall severity of the eczema, including a significant decrease in itching and scaling (P < 0.002), as compared with those that received the placebo (21). Similar results were reported in a multicentre study (60). In a double-blind, parallel trial, oral administration of 430 mg oil daily to 37 patients with psoriasis resulted in no significant improvement in symptoms (37).
A double-blind, placebo-controlled study tested two doses of the fixed oil in the treatment of 51 children with atopic dermatitis. Patients were treated for 8 weeks with either a placebo, the fixed oil, or a combination of 50% placebo and 50% fixed oil (daily dose of 0.5 g/kg body weight, for all treatments). A significant improvement in the overall severity of the clinical symptoms was observed in patients treated with the fixed oil alone (P = 0.046). This treatment also increased the concentration of omega-6 fatty acids in the erythrocyte cell membranes (17). In a study without controls, oral administration of the fixed oil (3 g) to 12 children daily for 4-20 weeks improved the symptoms of atopic eczema (2, 16, 18). In a double-blind, placebo-controlled, parallel trial, 58 children with atopic dermatitis were treated daily with either placebo or the fixed oil (2-4 g) for 16 weeks. Plasma concentrations of essential fatty acids increased in the group treated with the fixed oil. Symptomatic improvements occurred in both groups, but there was no significant difference between the two treatments (61). The major difficulty with this study was the use of a placebo containing sun- flower oil, which has a similar spectrum of essential fatty acids to the fixed oil.
The serum concentration of eight fatty acids over time was measured after oral administration of the fixed oil to six healthy volunteers. Six capsules of the fixed oil (500 mg each) were administered in both the morning and evening. The fatty acid concentrations in the serum were determined after each administration of the fixed oil as their methyl esters by gas chromatography-mass spectrometry. After administration of the fixed oil, γ-linolenic acid showed an absorption-elimination pattern, and its area under the curve at 24 hours and maximum concentration (Cmax) were significantly increased over baseline values. The half-life of γ-linolenic acid was shorter after the evening dose (2.7 hours) than after the morning treatment (4.4 hours). Serum levels of dihomo-γ-linolenic acid and arachidonic acid did not increase after administration of the fixed oil (62).
Four clinical trials have assessed the efficacy of the fixed oil for the treatment of rheumatoid arthritis in small numbers of patients (27-30). Three of the trials were unable to establish a significant benefit of using the fixed oil (27, 28).
A 12-week prospective trial involving 20 patients with rheumatoid arthritis assessed the effects of the fixed oil (4.8 ml, equivalent to 360 mg γ-linolenic acid, daily). Prior to the study, all patients discontinued their pharmacological treatments (at least 4 weeks before the start) and non-steroidal anti-inflammatory drugs (4 days before the start). In addition to the fixed oil, patients received vitamin E daily and a product containing zinc, ascorbic acid, niacin and pyridoxine. The symptoms of rheumatoid arthritis, such as joint tenderness, swollen joints, morning stiffness and pain, were assessed at the beginning of the trial and at 2-week intervals during treatment. Although three patients reported improvements in symptoms during treatment, the study concluded that there was no significant impact on the symptoms of rheumatoid arthritis (27). Another 12-week prospective study involving 20 patients with rheumatoid arthritis assessed the efficacy of 20 ml fixed oil daily (equivalent to 750mg γ-linolenic acid daily) (28). The placebo group received olive oil (20 ml daily). All patients discontinued anti-inflammatory medications 7-10 days prior to the study. Although the plasma concentrations of prostaglandin E2 decreased in four of the patients treated with the fixed oil, no statistically significant changes in symptoms were observed in either group (27). The third study was a 6-month, prospective, double-blind, placebo-controlled clinical trial involving 40 patients with rheumatoid arthritis and upper gastrointestinal lesions associated with the use of non-steroidal anti-inflammatory drugs. Nineteen patients received 6 g fixed oil and 120mg vitamin E daily, while 21 patients in the placebo group received olive oil (6 g daily). Although all patients continued to take non-steroidal antiinflammatory drugs, three in each group reduced their dosage by one tablet per day. The results of this trial showed a significant reduction in morning stiffness in patients receiving the fixed oil after 3 months of therapy, which was also seen after 6 months of treatment. A significant reduction (P = 0.04) in pain and articular index was seen only in patients treated with olive oil (29).
A significant benefit of the fixed oil was seen in a double-blind, placebocontrolled study which assessed the efficacy of the fixed oil, alone or in combination with fish oil, for the treatment of rheumatoid arthritis in 34 patients taking non-steroidal anti-inflammatory drugs. Following 12 months of treatment, a significant subjective improvement was observed in patients receiving either the fixed oil (540 mg daily) or the fixed oil and fish oil (450mg and 240mg daily, respectively), as compared with the placebo group. In addition, these patients had markedly reduced their intake of non-steroidal antiinflammatory drugs (30).
A review of four clinical studies (three with crossover design) reported improvements in the symptoms of premenstrual syndrome (PMS) following treatment with the fixed oil (31-33). One of these, a double-blind, placebo-controlled crossover study, assessed the efficacy of the fixed oil in women with PMS. After 8 weeks, improvements were seen in all the major clinical symptoms of PMS in both groups. Symptoms improved by 60% in patients treated with the fixed oil and by 40% in the placebo group. Irritability and depression were notably improved in the group treated with the fixed oil (31). In a study without controls, 196 women with PMS received two capsules of the fixed oil (500 mg each) twice daily during the luteal phase of the menstrual cycle. The women scored their symptoms during the cycle before treatment and for two cycles after treatment. During the two cycles after treatment, irritability decreased by 77%, depression by 74%, breast tenderness and pain by 76%, headache by 71% and ankle swelling by 63%. These improvements were highly significant (P < 0.001) (31). Another study without controls assessed the efficacy of the fixed oil in 68 women with severe PMS, who had failed to respond to at least one other therapeutic regime. Patients were treated with a graduated dosage of the fixed oil, starting with two 500 mg capsules twice daily in the luteal phase only, going up to four capsules twice daily during the whole cycle if there was no response to treatment. Total remission of symptoms was seen in 61% of patients; 23% had partial remission. Of the 36 women who had also experienced breast pain as part of PMS, 26 had total relief from breast pain, five had partial relief and five showed no improvement (33).
More recent reviews (63, 64) have assessed the clinical trials: seven placebocontrolled trials were identified, only five of which were randomized. Five of the seven trials (three of which were randomized) reported improvements in the symptoms of PMS. However, two of the best-performed studies, both randomized, double-blind, placebo-controlled crossover studies, failed to show any beneficial effects of the fixed oil (34, 35). In one study, 27 women with PMS received 12 capsules of the fixed oil (500 mg each) or placebo daily. Treatment with the fixed oil did not reduce either the magnitude or the cyclicity of symptoms (34). The other study of 38 women with PMS found no difference between the fixed oil (6 g daily for six cycles) and placebo in alleviating symptoms (35).
In a study without controls of 19 women with PMS, patients were treated with four capsules of the fixed oil (500 mg each) twice daily for five cycles. A reduction in the scores of individual symptoms (irritability, swollen abdomen, breast discomfort, depression, anxiety, fatigue and general oedema) and total PMS scores was observed after one cycle, and improvements continued over all five cycles (65). The clinical and biochemical effects of the fixed oil were investigated in 30 women with severe, incapacitating PMS. The patients were treated with 3 g fixed oil or placebo daily, beginning on day 15 of the cycle until the next menstrual period. Treatment with the fixed oil alleviated PMS symptoms, as compared with treatment with the placebo. No changes were found in the plasma levels of 6-keto-prostaglandin F1α, follicle-stimulating hormone, luteinizing hormone, prolactin, progesterone, estradiol or testosterone (66).
The effect of the fixed oil on mastalgia, one of the symptoms of PMS, was assessed in a randomized, double-blind, placebo-controlled crossover study. Seventy-three women were treated with the fixed oil or placebo for 3 months. In patients with both cyclical and non-cyclical mastalgia, treatment with the fixed oil significantly reduced breast pain and tenderness (P < 0.02-0.05) (25). Another double-blind, placebo-controlled clinical trial assessed the efficacy of the fixed oil in 42 women with cyclic breast pain and tenderness. Patients were treated with eight capsules (500 mg each) daily for 12 weeks. The fixed oil was significantly more effective than placebo in reducing nodularity, breast tenderness and irritability, as well as promoting a feeling of well-being (P < 0.05) (67).
A review of the randomized trials and studies without controls involving 291 women with severe persistent mastalgia was performed. Patients were treated with either the fixed oil (six capsules of 500mg), bromocriptine (5mg) or danazol (200 mg) daily for 3-6 months. In patients with cyclical mastalgia, good responses were obtained in 45% of patients treated with the fixed oil, in 47% treated with bromocriptine and in 70% treated with danazol. The response rate in patients with non-cyclical mastalgia was 27%, 20% and 31%, respectively. Adverse reactions were reported in 2% of patients treated with the fixed oil, in 33% of patients treated with bromocriptine and in 22% of those treated with danazol (26). A review of 17 years of drug treatment at a mastalgia clinic described the efficacy of daily administration of danazol (200 mg), bromocriptine (5 mg) and the fixed oil (six capsules of 500 mg) in 414 patients (324 with cyclical and 90 with non-cyclical mastalgia). Treatment with danazol was most effective (in 79% of patients); the fixed oil and bromocriptine were effective in 58% and 54% of patients, respectively. However, the rates of adverse reactions were higher in patients treated with danazol and bromocriptine (30% and 35%, respectively) than in those treated with the fixed oil (4%) (24).
Dietary supplementation with the fixed oil was associated with a clinical, neurophysiological and quantitative sensory improvement in 22 male and female patients with diabetic polyneuropathy (22). After a preliminary trial in 22 patients with diabetes, positive effects were also reported in many neurological and neurophysiological parameters in a parallel double-blind study of 111 male and female patients with mild diabetic neuropathy (23).
Oral administration of the fixed oil to male patients with diabetes and healthy male volunteers (20 g, enriched with vitamin E) daily for 1 week enhanced erythropoiesis and changed the serum fatty acid profiles in both groups. Inhibition of platelet-activating factor 4 and plasma β-thromboglobulin was also observed in both groups (68).
The efficacy of the fixed oil was evaluated in a randomized, double-blind, placebo-controlled study of 35 women with hot flushes. The women were treated with either four capsules of the fixed oil (500 mg each, supplemented with 10 mg natural vitamin E) or placebo twice daily for 6 months. No significant improvement in menopausal flushing was observed in women treated with the oil, as compared with the placebo (36).
Uraemic skin disorders
The effects of oral administration of the fixed oil on plasma fatty acid concentrations and the symptoms of uraemic skin disorders (dryness, pruritus and erythema) were evaluated in a double-blind study of haemodialysis patients.
Patients treated with the fixed oil (2 g daily) for 6 weeks showed a significant increase in plasma dihomo-γ-linolenic acid (P < 0.05) and a significant decrease in uraemic pruritus (P < 0.05) (69).
No information available.
Oleum Oenotherae Biennis may precipitate symptoms of undiagnosed temporal lobe epilepsy, particularly in schizophrenic patients or patients taking epileptogenic drugs such as phenothiazines (70-72).
Oleum Oenotherae Biennis should be used with caution in patients with a history of epilepsy, particularly those with schizophrenia, or those taking epileptogenic drugs such as phenothiazines (19, 70).
Oleum Oenotherae Biennis inhibited platelet aggregation in animals (14, 40) and inhibited platelet-activating factor in humans (68). Therefore, patients taking anticoagulant drugs in conjunction with the fixed oil should be closely monitored.
No information available on general precautions or precautions concerning drug and laboratory test interactions; carcinogenesis, mutagenesis, impairment of fertility; teratogenic and non-teratogenic effects in pregnancy; nursing mothers; or paediatric use. Therefore, Oleum Oenotherae Biennis should not be administered during pregnancy or lactation or to children without medical supervision.
Headaches, nausea, loose stools and diarrhoea following treatment with Oleum Oenotherae Biennis have been reported (2). Administration of the fixed oil precipitated symptoms of undiagnosed temporal lobe epilepsy in schizophrenic patients taking epileptogenic drugs, in particular phenothiazines (72).
Fixed oil, neat or in capsule form (1, 13). Store in a well-filled, airtight glass container, protected from heat and light.
(Unless otherwise indicated)
Daily dosage: 320-480 mg fixed oil (calculated as γ-linolenic acid) in divided doses for atopic eczema, and 240-320 mg in divided doses for mastalgia (19).
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