Lexicomp
Dr. Wynn

Dr. Richard L. Wynn is Professor of Pharmacology at the University of Maryland Dental School. He holds a BS degree in pharmacy and a PhD degree in pharmacology. More »He chaired the Department of Pharmacology at the University of Maryland Dental School from 1980 to 1995. He is the lead author of the Drug Information Handbook for Dentistry, co-author of many other dental drug publications, author of over 300 refereed scientific journal articles, consultant to the Academy of General Dentistry, featured columnist, and a featured speaker presenting more than 500 courses in continuing dental education. One of his primary interests continues to be keeping dental professionals informed of all aspects of drug use in dental practice.

I'll have the fish, with an aspirin on the side: Attacking inflammation with combined aspirin and omega-3s

Neutrophils are first to arrive at tissue sites undergoing an acute inflammatory response and play a protective role in host defense. But, excessive accumulation of these neutrophils in tissues leads to an increase in inflammatory response, prolongation of the signs of inflammation, and tissue damage. The family of fatty acid molecules called resolvins serve as a signal to our bodies use to start shutting down this type of inflammation. Resolvins are produced in the body from dietary omega-3 fatty acids. Aspirin helps trigger production of one type of resolvin from these omega-3s called aspirin-triggered resolvin D3.

Aspirin is well known to inactivate cyclo-oxygenase type I enzyme (COX-1 enzyme), blocking the synthesis of inflammatory prostaglandins and thromboxane. Aspirin's action within cells that possess cyclo-oxygenase type 2 (COX-2) is different. Unlike COX-1 inhibition, in which COX-1 activity is shut down completely by aspirin, COX-2 is modified by aspirin to produce the D3 resolvin from docosahexaenoic acid (DHA) precursor, specifically in macrophages, eosinophils and neutrophils.

A study out of University of Southern California and Harvard Medical School showed that omega-3 fatty acids DHA and EPA are required as the precursors, or "building blocks," to create the signal to attenuate inflammation. The researchers synthesized several resolvins to identify the molecular structure of the aspirin-sensitive one, and they showed that it can reduce skin and abdominal tissue inflammation in mice. Specifically, the group determined the chemical structure of one DHA-derived resolvin known simply as D3 and the aspirin-triggered resolvin D3. The aspirin-triggered D3 potently regulated neutrophils and other mediators, reducing peritonitis and dermal inflammation in mice. The D3 blocked human neutrophil transmigration, and it enhanced macrophage phagocytosis. These observations were described in the context of beneficial effects of taking dietary DHA and EPA along with aspirin. The researchers are now developing aspirin-triggered resolving congeners that could act as anti-inflammatory drug leads.

The full report is found at:

Dalli, J., et al. "Resolvin D3 and aspirin-triggered resolving D3 are potent immunoresolvents." Chemistry & Biology 2013; 20(2): 188-201.

There also appears to be a group of resolvins of an E series generated from omega-3 fatty acids that modulate inflammation and that may be increased in their formation by low-dose aspirin. In a study out of London looking at the efficacy of resolvins as anti-arthritic agents, a cohort of 20 healthy individuals was recruited in order to assess plasma levels of resolvins following 3 weeks of omega-3 supplementation. The D-series resolvins were detected in physiological active levels, and the biosynthesis of the D series can be enhanced by aspirin. Also the study described an E series of resolvins that could be enzymatically generated via a pathway initiated by aspirin modulation of COX-2 enzyme. A resolvin labeled as E-1 was measured in bioactive concentrations in the plasma of healthy volunteers 4 hours after taking a fish oil supplement containing 1 gram EPA and 0.8 gram DHA followed by low-dose (162 mg) aspirin. This E-series resolvin, like the D series, also exhibits anti-inflammatory properties. This London report commented that omega-3 fatty acids are known to alleviate joint stiffness and pain in rheumatoid arthritis patients. The report went on the describe resolvins as anti-inflammatory agents that offer new avenues for developing therapeutics for inflammatory conditions such as rheumatoid arthritis.

The complete report is found at:

Norling, L.V. and Perretti, M. "The role of omega-3 derived resolvins in arthritis." Curr Opin Pharmacol, 2013; In Press.

The Dental Study

The dental clinical study was out of Mansoura, Egypt, and Goldman School of Dental Medicine, Boston University. The introduction to the study commented that host modulatory therapy has emerged as a treatment for periodontal disease. This therapy aims to reduce tissue destruction by modifying destructive aspects of the host response. Omega-3 fatty acids, including DHA and EPA, are known to have therapeutic anti-inflammatory and protective actions in inflammatory diseases, including periodontitis. Work by other investigators has demonstrated that omega-3 fatty acids serve as substrates for enzymatic conversion to a novel series of lipid mediators named resolvins and protectins. Resolvins and protectins have been shown to exhibit protective actions in experimental colitis, peritonitis, brain ischemia and periodontitis. The authors then cited studies showing that DHA and EPA in the presence of aspirin undergo metabolism to resolvins, which are anti-inflammatory. Resolvins have been shown to prevent inflammation in a variety of animal models. The study goal hypothesized that omega-3 fatty acids, when taken with aspirin, will exert measurable protective and anti-inflammatory actions through the production of resolvins and perhaps other endogenous mediators.

For their methods, 80 healthy subjects (40 in each group) with advanced chronic periodontitis were enrolled in Mansoura, Egypt, in a parallel design, double-blind clinical study. The control group was treated with initial therapy of scaling and root planning (SRP), followed by a daily placebo. The omega-3 fatty acid group was treated with initial therapy of SRP, followed by dietary supplement of fish oil (900 mg DHA + EPA) and 81 mg aspirin daily. Saliva samples were obtained from all patients at baseline and 3 and 6 months for evaluation of receptor activator of nuclear factor - kappa beta ligand (RANKL) and matrix metalloproteinase-8 (MMP-8). Plaque and gingival indices, bleeding on probing, probing depths and attachment levels were recorded at the same time points. Subjects came to the clinic every 4 weeks during the course of the experiment (26 weeks) to replenish their medication.

Study Results

There was a significant reduction in probing depths and a significant attachment gain after 3 and 6 months in the fish oil / aspirin group compared to both baseline and the placebo control group. Salivary RANKL and MMP-8 levels showed significant reductions in the fish oil / aspirin group in response to treatment at 3 and 6 months and compared to the control group at 6 months. Supplementation with fish oil and aspirin combination resulted in a significant shift in the frequency of pockets with probing depths < 4 mm.

Discussion

The report described successful adjunctive use of dietary omega-3 fatty acids plus aspirin supplementation in humans as an adjunct to non-surgical treatment of periodontitis. In this clinical proof of concept study, 900 mg of DHA + EPA in a fish oil dietary supplement administered daily in conjunction with 81 mg aspirin tablets for 6 months significantly improved the outcome of standard scaling and root planning using probing depths and clinical attachment levels and standard indices as outcome measures.

The salivary markers of bone resorption (RANKL) and inflammation (MMP-8) were significantly reduced in the dietary supplement group. This reduction in these two biomarkers correlated well with clinical improvement after SRP, and their reduction was enhanced by dietary supplementation with omega-3 plus aspirin, again which correlated well with enhanced clinical improvement.

The authors suggested that the anti-inflammatory effects observed in the study were due to the production of resolvins of the D series and resolvins of an E series, which were enhanced by aspirin.

The full report of the dental study can be found at:

El-Sharkawy, H., et al. "Adjunctive treatment of chronic periodontitis and daily dietary supplementation with omerga-3 fatty acids and low-dose aspirin." J Periodontol 2010; Nov., 81(11): 1635-43.