MECHANISM OF ACTION
EFFICAS FOR ASTHMA INHIBITS THE 5-LO ENZYME AND REDUCES SYNTHESIS OF LEUKOTRIENES
Excess production of leukotrienes promotes the inappropriate response to harmless antigenic substances that characterizes allergy. Leukotrienes are:fatty acid-derived inflammatory mediators that play a significant role in the pathophysiology of allergic diseases, including asthma, atopic dermatitis, and allergic rhinitis derived from the fatty acid arachidonic acid (AA), which is concentrated in the membrane phospholipids of blood cells
synthesized by circulating immune cells in response to a stimulus such as allergen exposure.
The dietary fatty acids, EPA and GLA, in Efficas Care and their metabolites are incorporated into phospholipids in the membranes of immune system cells. Once released from the cell membrane in response to a stimulus such as allergen exposure, these fatty acids block the conversion of arachidonic acid to leukotrienes by inhibiting the action of the 5-lipoxygenase enzyme (5-LO). Through this dietary mechanism of action Efficas for Asthma is suitable for use in multiple allergic diseases. It has been determined through medical evaluation that in order to blunt the overproduction of leukotrienes, individuals with allergic disorders have a unique need for higher levels of these fatty acids than can be obtained in a normal diet. The same stimulus that releases AA from membranes will release other highly unsaturated fatty acids, including DGLA and EPA. These free fatty acids impact the leukotriene pathway in two ways: direct inhibition of 5-LO, and competitive inhibition of series 4 leukotriene synthesis. Inhibition of the first enzyme in the pathway, 5-LO, reduces levels of all the leukotrienes (27).
ACTION OF THE GLA METABOLITES, DGLA AND 15-HETRE ON LEUKOTRIENE SYNTHESIS
When released from membranes, DGLA may act directly as an inhibitor of 5-LO. DGLA decreased leukotriene LTB4 production by human mononuclear leukocytes in vitro in a dose-dependent manner (28). Alternatively, DGLA can be further oxidized to produce a more potent 5-LO inhibitor. DGLA is not a substrate for 5-LO, but instead is converted by 15-LO to 15-OH-DGLA (aka 15-HETrE). 15-HETrE blocks conversion of AA to LTA4 by direct inhibition of 5-LO (29) and is a stronger inhibitor of LTB4 production than is DGLA (50x).
Inhibition of 5-LO activity in human neutrophils ex vivo has also been demonstrated in cells supplemented with GLA or DGLA (31).
Neutrophils metabolize DGLA to 15-HETrE (31). Reduced production of LTB4 by isolated neutrophils in response to 2 dietary levels of GLA supplementation has been documented in healthy humans (32, 33). Borage oil (at 480 mg or 1.5 g GLA/day) suppressed production by human neutrophils of LTB4 46% and 65%, respectively, compared to olive oil (33). At the higher dose of borage oil, 1.5 g GLA/day, the level of AA was increased in neutrophil phospholipids1. A dose response to GLA was demonstrated, but the effect was not linear. In a separate study, borage oil providing 0.75 g GLA per day did not significantly reduce leukotriene production, but 1.5 g GLA per day was very effective after 2 weeks of dosing (17), although AA levels were also significantly increased.
IMPACT OF EPA ON AA LEVELS IN MEMBRANES AND LEUKOTRIENE SYNTHESIS
Dietary EPA (provided in fish oil) has been demonstrated in multiple studies to actively reduce levels of AA in membrane phospholipids (30, 34, 35, 36). Further, EPA inhibits the enzyme delta-5 desaturase that would otherwise produce AA from DGLA (3, 37), so that higher doses of GLA can be provided safely in a medical food as long as EPA is also provided in sufficient quantity.
Finally, in contrast to DGLA, EPA is a substrate for 5-LO, and thus competes with AA for the enzyme’s active sites (35). Not only are the total amounts of 4-series leukotrienes reduced, but the kinetics of production are slowed (35). 5-series leukotrienes are produced from the action of 5-LO on EPA, but these have much reduced bronchoconstricting activity compared to LTC4, LTD4 and LTE4 (38).
Asthmatics that produced 5-series leukotrienes in response to EPA (fish oil) supplementation had improved respiratory function (39). Subjective assessments of asthma symptoms also were reported to improve with fish oil supplementation (40). Omega-3 supplementation also significantly reduced cough in atopic children (41). Up to 90% of asthmatics experience bronchoconstriction in response to exercise (42). High dose fish oil supplementation significantly reduced production of cysteinyl leukotrienes and significantly improved post-exercise pulmonary function in elite athletes with exercise-induced bronchoconstriction (EIB) (42).
1 In the absence of sufficient dietary EPA, high doses of GLA can lead to increased AA in membrane phospholipids. Thus, it is very important to include EPA in the formulation of EFFICAS CARE.
IMPACT OF GLA IN COMBINATION WITH EPA ON AA LEVELS IN MEMBRANES AND LEUKOTRIENE SYNTHESIS
Multiple clinical studies demonstrate the impact of the medical food, Efficas Care, on leukotrienes. When GLA and EPA are provided together in the proper amounts and ratios, leukotrienes synthesis is inhibited and arachidonic acid levels are controlled (3, 17, 18).
For further details on the mechanism of action for Efficas Care please see the Efficas for Asthma Monograph.
THE MEDICAL FOOD EFFICAS FOR ASTHMA, CONTAINING A PROPRIETARY MIXTURE OF GLA AND EPA, REDUCES LEUKOTRIENES AND AVOIDS ARACHIDONIC ACID ACCUMULATION.
Efficas for Asthma alters the pool of fatty acids (AA, EPA, GLA, DGLA). When allergic stimuli or other triggers are present, AA, DGLA and EPA are released from immune cell membranes. DGLA and the DGLA metabolite, 15-HETrE, inhibit the 5-lipoxygenase enzyme (5-LO) which is essential for leukotriene production. EPA is a competitive inhibitor of 5-LO and also prevents the metabolism of DGLA to AA by inhibiting the delta-5 desaturase enzyme. Through these nutrient-based actions, Efficas for Asthma is suitable for use in multiple allergic diseases.