Early evidence of efficacy for orally administered SPM ...

Design and sampling

The design of this research was a single-arm, open-label clinical trial. The protocol and all study materials were reviewed and approved by the IRB of the National University of Natural Medicine (NUNM; MetaG SPM IRB, #091515-B) and registered on ClinicalTrials.gov as Influence of an Omega-3 SPM Supplement on Quality of Life (NCT02683850). The trial aimed to assess the impact of SPM Active™ softgel supplementation on quality of life in adults with moderate to severe chronic pain symptoms (as measured by the Patient Reported Outcomes Measurement Information System (PROMIS)-43 Profile—Pain Intensity subdomain).

Participants were recruited from the greater Portland, Oregon area using community-based flyers and advertisements. Information about the study was also available through the NUNM website. In addition, a network of community physicians was established for additional recruitment. Potential participants were screened over the telephone and referred to one of five clinical sites to determine eligibility.

Eligible candidates included adults 20–70 years of age, with a Body Mass Index of 19–40 kg/m2, that had no other significant medical problems, were able to maintain stable intake of therapeutic agents for at least 30 days, and were able to refrain from adding any therapeutic agents for the duration of the study. In addition, only participants suffering from moderate to severe chronic pain (i.e. an average pain score of greater than or equal to a 4 on the PROMIS-43 Profile—Pain Intensity subdomain) for at least 3 months were included in the study. Exclusion criteria were chosen to minimize the possibility of confounding the detection of changes in pain or inflammation, such as recent initiation of, or changes to, pain medications or other pain reduction therapies. In addition, women who were lactating, pregnant, or planning pregnancy at the time of screening or would be within the 6 months subsequent to screening, were excluded from study participation.

Intervention, packaging, and labeling

Study participants received 2 bottles of the intervention: SPM Active™ softgels (Metagenics, Inc., Gig Harbor, WA). The SPM Active™ softgel is a dietary supplement Generally Recognized As Safe (GRAS), commercialized by Metagenics Inc. The SPM Active™ softgels used in this study were manufactured by Solutex (https://www.solutex.es/; Parque Empresarial Omega Edificio Gamma Avenida de Barajas 24, 3ª 28109 Madrid, Spain). These softgels met or exceeded all quality control requirements, as well as all softgel production requirements for Good Manufacturing Practices (cGMP).

Each SPM Active™ softgel contained 250 mg of a marine lipid fraction (Lipinova®), standardized to 17-HDHA and 18-HEPE (Solutex, Spain) with demonstrated pro-resolving activity covered by the patent family PCT/US2013/040313.

For the purposes of this study, the softgels were packaged in unlabeled bottles with approximately 60 softgels per bottle. A product label was provided by the Helfgott Research Institute, which included instructions on use, as well as contact information for any questions that arose.

Participants were provided with written instructions at their Baseline visit and were instructed to take 3 softgels in the morning and 3 softgels in the evening. Participants were also provided with a study supplement log to record their daily intake of the softgels and record any questions or concerns that emerged. Participants returned the study supplement log and any unused study supplement softgels at the Week 2 and Week 4 study visits.

SPM Active™ dose titration occurred during the Week 2 study visit, based on the pain ratings obtained via REDCap reported within the 2 days prior to the visit. Participants who reported PROMIS-43-measured ‘pain intensity’ levels that had decreased by 2 points or more after 2 weeks had their dose decreased to 2 softgels in the morning and 2 softgels in the evening for weeks 3 and 4 of the study (N = 16). Participants who reported PROMIS-43-measured ‘pain intensity’ levels that had not changed, had only decreased by one point, or had increased, increased their dose to 4 softgels in the morning and 4 softgels in the evening for weeks 3 and 4 of the study (N = 28). The unused supplement bottle from the first 2 weeks was relabeled with the appropriate dosing and returned to participants for the last 2 weeks of the trial.

Study visits

The study participant visits were grouped into 2 categories: screening visit and study visits. Study visit one (Baseline) occurred directly after the screening visit. Clinical re-evaluations occurred every 2 weeks, as Week 2 and Week 4 study visits.

At the screening visit, medications and supplements were reviewed, as was participant health history. Eligibility was determined by administration of a standardized ninety-one point Adverse Event Monitoring form (participants were excluded if any item was determined to be Grade 3, ‘severe or medically significant but not immediately life-threatening’, or higher); the PROMIS-43 Profile–Pain Intensity subdomain; and BMI. After an informed consent consultation, eligible participants were enrolled in the study.

The Baseline study visit and subsequent study visits included administration of the Adverse Event Monitoring form, PROMIS-43 Profile, American Chronic Pain Association’s (ACPA) Quality of Life Scale, Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder scale (GAD-7), and Brief Pain Inventory long form (BPI). In order to reduce provider interference on participant responses, the administration of all research instruments was separated from clinical care and provider interaction through the use of a centralized REDCap-based survey sent to and completed by participants on their own (but according to the study timeline). A blood sample was taken at each visit to be analyzed for the biomarkers high-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate (ESR).

The Patient Global Impression of Change (PGIC) and the Patient Global Satisfaction Scale (PGSS) were administered at the Week 4 study visit only.

Outcome measures

Primary outcome measure

The primary outcome of the trial was health-related quality of life, measured by the PROMIS-43 instrument (primary measure) and the ACPA’s Quality of Life Scale (secondary measure).

PROMIS–43 Profile subdomains

The PROMIS-43 Profile consists of seven domains (Ability to Participate in Social Roles and Activities, Anxiety, Depression, Fatigue, Pain Interference, Physical Function, and Sleep Disturbance), with six questions per domain rated on a 5-point rating scale. Additionally, there is a 1-question Pain Intensity domain rated on an 11-point scale. The domains are assessed “over the past 7 days” except for the Physical Function domain, which has no specified time frame. A raw score is created from each subscale (except Pain Intensity) that makes up the Profile. Raw scores are translated into T-scores, which are reported as the final score for each participant. The PROMIS-43 Profile provides a standardized, reliable, and valid measure of Pain Interference, Pain Intensity, Physical Function, Fatigue, Sleep Disturbance, and Ability to Participate in Social Roles and Activities. The Dutch-Flemish PROMIS Pain Behavior item bank was found to have good cross-cultural validity, reliability and construct validity [17].

The subdomains used to assess quality of life as the primary outcome included Ability to Participate in Social Roles and Activities (shortened for purposes of this study to Social Function), Fatigue, and Sleep Disturbance. The subdomains of Anxiety, Depression, Pain Interference, and Physical Function, as well as Pain Intensity, were used in conjunction with additional standardized tools as exploratory outcomes, as described below.

American Chronic Pain Association’s quality of life scale

The ACPA’s Quality of Life Scale is a single item measure of function for people with chronic pain. Quality of Life is rated using an 11-point scale ranging from “Non-Functioning” to “Normal Quality of Life”. The ACPA Quality of Life scale was developed specifically as a measure of functioning for people with chronic pain. It has been used by thousands of medical professionals across the globe for many years and is used extensively by the US Department of Veterans Affairs. Wayne State University College of Nursing is currently using the scale in research of the maintenance and improvement of functional states in patients with chronic pain.

Exploratory outcome measures

Exploratory outcomes included: changes in depression and anxiety; pain relief; pain intensity; pain interference; physical function; patient satisfaction; patient impression of change in their condition; changes in inflammatory serum biomarkers; and adverse events. Changes in depression were measured by the PHQ-9 and the PROMIS-43 Profile–Depression subdomain, while changes in anxiety were measured by the GAD-7 scale and the PROMIS-43 Profile–Anxiety subdomain. Items in the BPI determined pain relief and pain quality. Pain intensity and pain interference were determined by the PROMIS-43 Profile subdomains of the same names, as well as several BPI items, as outlined below. Patient satisfaction and impression of change were determined using the PGSS and the PGIC. The biomarkers hs-CRP and ESR were used to assess changes in inflammation. A comprehensive case report form was used to determine changes in pain medication use. Adverse events were closely monitored and systematically collected. These tools are described in detail below.

Patient Health Questionnaire (PHQ-9)

The PHQ-9 is a self-administered depression scale based on the mood module from the PRIME-MD diagnostic instrument for common mental disorders. The PHQ-9 scores each of the nine DSM-IV criteria as “0” (not at all) to “3” (nearly every day), rated for the last 2 weeks—this provides a depression severity score based on a 0–21 continuous scale. The PHQ-9 is a validated instrument for detecting depression and monitoring its severity, and higher scores are associated with increasing levels of depression severity [18, 19]. The PHQ-9 final score is rated from No Depression to Severe Depression.

Generalized Anxiety Disorder scale (GAD-7)

The GAD-7 is a 7-item self-report instrument to assess generalized anxiety disorder in primary care patients. Items are rated for the last 2 weeks, using a 4-point rating scale from “1” (not at all) to “5” (nearly every day). A score of 10 or greater on the GAD-7 represents a cut point for identifying cases of generalized anxiety disorder, while cut points of 5, 10, and 15 might be interpreted as representing mild, moderate, and severe levels of anxiety on the GAD-7. There is an overall relationship between GAD-7 severity levels and disability scores, with higher mean disability values related to higher severity levels [20].

Brief Pain Inventory (BPI), long form

The BPI is a 32-item self-report questionnaire that examines pain severity/intensity and impairment caused by pain on emotional and physical functioning. The instrument consists of a series of 11-point numeric rating scales. 4 items measure pain intensity (pain now, average pain, worst pain, and least pain) using “0” (no pain) to “10” (pain as bad as you can imagine) as anchors. These scores are individually given as measures of pain. Seven items measure the level of interference with function caused by pain during the past week (general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life) with anchors of “0” (does not interfere) to “10” (completely interferes). A composite mean score of the seven items is given as a measure of pain interference.

The BPI also asks the patient to rate the quality of their pain (e.g. aching, throbbing, shooting, stabbing, etc.) and to rate the relief they feel from the current pain treatment. The BPI pain scale has been widely used and found to provide a reliable and valid measure of pain, pain interference, and improvements in pain over time across cultures and languages, and for purposes of this study, in chronic nonmalignant pain populations [21, 22].

PROMIS–43 Profile subdomains

This instrument is described in detail above (Primary Outcome Measure section). Pain Intensity and the subdomains of Anxiety, Depression, Physical Function, and Pain Interference were used as exploratory outcome measures. The Anxiety and Depression subdomains were used in conjunction with the GAD-7 and PHQ-9 to measure anxiety and depression. Pain Intensity and Pain Interference were used in conjunction with the BPI items to measure pain intensity and interference; Physical Function was used as an independent marker to determine changes in physical function.

Patient Global Impression of Change (PGIC)

The PGIC is a single-item rating of the participant’s impression of change in their condition with treatment on a 7-point scale that ranges from “very much improved” to “very much worse” with “no-change” as the midpoint. The PGIC has frequently been used as an indicator of meaningful change in response to treatments for chronic pain [23]. Consensus guidelines outline the PGIC measure as an important indicator of meaningful change in treatments for chronic pain [24, 25].

Patient Global Satisfaction Scale (PGSS)

The PGSS is a single-item rating by participants of their satisfaction with treatment on a 10-point scale that ranges from “very satisfied” to “not at all satisfied”.

High-Sensitivity C-Reactive Protein (hs-CRP)

CRP is an acute-phase protein released into the blood by the liver during inflammation and is a sensitive marker of low-grade systemic inflammation. Plasma CRP levels can increase dramatically after severe trauma, bacterial infection, inflammation, surgery, or neoplastic proliferation. Measurement of CRP has been used historically to assess activity of inflammatory disease and to monitor inflammatory processes. The hs-CRP test is a highly sensitive quantification of CRP that can be detected at a lower level than CRP [26].

Erythrocyte Sedimentation Rate (ESR)

ESR is a laboratory test for assessing inflammatory or the acute phase response. It is not diagnostic of any particular disease, but when elevated may indicate the presence of inflammation, infection, rheumatologic disease or neoplasm [27].

Multi-Systems Adverse Event Monitoring form

Adverse events were tracked and monitored using the Multi-Systems Adverse Event Monitoring form, a standardized, 91-point monitoring form that asks questions pertaining to the following organ systems: eyes/ears/nose/throat, gastrointestinal, neurological/ musculoskeletal, psychological/general, cardiopulmonary, skin, genitourinary, and whole body systems.

Data security and storage

This study used REDCap—a secure, web-based application that supports electronic data capture for research studies—for data storage and management. Data was exported from REDCap to either Excel or SPSS for analysis. All procedures conducted adhered to the Informed Consent and protocol, as approved by the MetaG SPM IRB.

Analysis

All 3 time points (Baseline, Week 2 study visit, and Week 4 study visit) for the primary and exploratory outcome measures were initially analyzed using linear mixed modeling, followed by pairwise T-tests between Baseline and Week 2, then Baseline and Week 4, for each outcome measure. For all analyses, statistical significance was set at p = 0.05. Where applicable, the raw scores from each outcome measure (primary and exploratory) were translated into T-scores at Baseline, Week 2, and Week 4. These T-scores were then reported as the final score for each patient. Results were reported as “per protocol” analyses, without imputation of missing data, due to the need to determine efficacy.

All but one of the PROMIS-43 data sets, as well as the summary BPI interference score data set, were found to have reasonably normal T-score distributions; non-parametric testing confirmed these results. However, all other questionnaire data sets exhibited non-parametric distributions—this was likely due to the relatively small scales with which these tools are scored. Thus, these data sets were retested using Wilcoxon’s Signed-Rank test or Friedman’s test.

The distribution of hs-CRP showed rightward skew, but this was largely corrected with a log-transformation. All analyses of hs-CRP therefore used T-tests of the log-transformed variable. The distribution of ESR showed a more severe skew that could not be remedied by any standard transformation; therefore, results were verified using the same non-parametric tests listed above.

The PGIC and the PGSS were asked only at one time point (study visit 3); thus, no formal comparisons were performed and only frequency data was reported.

Sample size and statistical power

This study was powered to detect clinically significant changes in the Physical Function or Fatigue subscales of the PROMIS-43 or in the ACPA QOL Scale. Earlier work on the indicated PROMIS-43 subdomains indicates that minimally significant differences between groups are generally in the range of 4–6 points on a T-scale, corresponding to a standardized effect size of d = 0.4–0.6 [28]. For within-group changes over time, which tend to show larger effects, these estimates should be conservative; and we therefore calculated power to detect an effect of d = 0.5. For the ACPA, less information is available, but we calculated power to find a change of one point; and for an 11-point scale, we reasonably estimated the standard deviation at 2 points. Assuming a correlation of r = 0.5 between pre- and post-treatment measures, this again yielded an effect size of d = 0.5. Finally, using a paired t-test design with a two-sided α = 0.05, we calculated that with 40 participants, we would have 87% power to detect an effect size of d = 0.5 in any of the primary outcome measures. With 20% attrition (32 participants for analysis), we would still retain 78% power. Note that, although the referenced effect sizes are for Physical Function and Fatigue, PROMIS-43 T-scales are scored to have equal means and standard deviations, and we would expect similar power estimates on all subdomains. All power calculations were made using G*Power v.3.1.9.2 [29].

Chronic inflammation is connected to degenerative aging.

This has prompted scientists to coin the term “inflammaging” to describe this destructive process.1

Recent discoveries shed light on our understanding of inflammaging.2

Research shows that resolution of inflammation may be as important as inhibition of inflammation in the fight against age-related disorders.

The field of inflammation resolution is generating increasing interest.

This led scientists to identify compounds that help resolve inflammation. They are named:

Specialized pro-resolving mediators (SPMs)

Increasing SPM levels in preclinical models yields compelling findings.3

Clinical trials are currently recruiting participants and publishing results.4

How SPMs Resolve Inflammation

Specialized pro-resolving mediators are derived from polyunsaturated fatty acids, predominantly found in fish.3

In response to certain conditions, such as inflammation, small amounts of omega-3 fatty acids are converted to even more beneficial compounds: SPMs.3

Chronic inflammatory conditions such as inflammaging, have been associated with lower concentrations of SPMs in the body.5

SPMs resolve inflammation by three mechanisms:6-8

• Removing dead and dying cells through a process in which macrophage immune cells engulf and digest dying or dead cells. This helps clean up the aftermath of inflammatory cascades.
• Restoring inflammation balance by decreasing pro-inflammatory mediators, while increasing compounds that have anti-inflammatory activity.
• Renewing damaged tissue by promoting cellular regeneration.

These benefits promise to help prevent many chronic aging disorders including deposition of plaque in the arteries (atherosclerosis).9

Inflamed Arteries

Inflammation is a key player in the development of heart disease.

Atherosclerosis is partially driven by an imbalance between pro-inflammatory and inflammation-resolving mechanisms in the artery inner walls.9

Atherosclerosis can begin when LDL cholesterol (the “bad” cholesterol) particles get trapped inside the endothelium (lining of the arteries).

Macrophages enter the endothelium to clear out these oxidized LDL particles. If there is a lack of pro-resolving mediators, these macrophages will change into foam cells.9

This is a dangerous state that generally results in the foam cells dying and releasing their contents, creating an even greater pro-inflammatory environment.9

SPMs come into play here by initiating the removal of dead cells and foam cells through a process called efferocytosis.

If these cells are not removed, they contribute to plaque progression, which leads to atherosclerosis that endangers the heart, kidneys, and brain.9,10

How SPMs Differ from Omega-3s

The process of converting omega-3 fatty acids into SPMs requires several steps in the body.

When one eats cold water fish or takes fish oil supplements, tiny amounts may be converted to pro-resolving mediators (SPMs).

To meaningfully resolve inflammaging, higher amounts of standardized SPMs are often required beyond what can be obtained with fish oil.

Preclinical Research on SPM Precursors

In preclinical studies, SPMs and SPM precursors have been shown to have a variety of biological benefits.

Studies in mice have demonstrated impressive resolution benefits in a variety of disease models using the SPM precursor 18-HEPE.

SPM precursors enable formation of specialized pro-resolving mediators (SPMs) in the body.

One study involved a rodent model that mimics some of the complications related to cardiovascular disease. Following surgery, researchers injected mice with the SPM precursor 18-HEPE every three days.12

The mice that received 18-HEPE were significantly shielded from damaging complications brought on by the surgical procedure.

Another study used a mouse model of melanoma metastasis. Researchers pretreated mouse melanoma cells with the SPM precursor 18-HEPE while controls were not treated.

Healthy mice were then administered the SPM precursor 18-HEPE-treated melanoma cells and received additional 18-HEPE injections every other day. The SPM precursor-treated mice had significantly less formation of tumor colonies compared to controls.13

Another group of researchers found that treatment with the SPM precursor 17-HDHA was able to reverse pain behavior in two rat models of osteoarthritis.14

The Science Behind Specialized Pro-Resolving Mediators (SPMs)

SPM precursors are predominantly derived from the omega-3 fatty acids EPA and DHA.

But obtaining meaningful potencies of SPMs requires a series of complex metabolic processes that are often lacking in aging individuals.

The omega-3 fatty acid precursors needed to produce SPMs in the body include:11

• 18-HEPE (18-hydroxyeicosapentaenoic acid)
• 17-HDHA (17-hydroxydocosahexaenoic acid)
• 14-HDHA (14-hydroxydocosahexaenoic acid).

These precursors listed above are then converted into the following specialized pro-resolving mediators (SPMs):

• Resolvins
• Protectins
• Maresins

These make up the bulk of the SPMs that target inflammation through the three steps of removing, restoring and renewing.

New Human Trial of SPM Precursors

A human trial of SPM precursors was published in January 2020 and showed remarkable results.

In this study, 22 healthy volunteers aged 19 to 37 were randomized. One group received an enriched fish oil supplement containing omega-3 PUFAs plus a combination of SPM precursors, including 18-HEPE, 17-HDHA, and 14-HDHA. The other group received a placebo.18

Researchers separated the participants into different dosing groups and performed a series of tests. They were able to conclude that the SPM precursors:

• Significantly increased cell surface proteins involved in reversing inflammation and platelet aggregation (which leads to harmful clotting) caused by the addition of a pro-inflammatory stimulus in the drawn blood of the patients.
• Increased clearance of Staphylococcus aureus and E. coli, by immune cells, which was highest at the final measurement, after 24 hours.
• Decreased platelet activation, a central part of the process that leads to a blood clot, in association with an increased level of resolvins.
• Increased the expression of genes linked to immune responses, recruitment of immune cells that fight infection and other diseases, and cellular metabolism in peripheral blood cells.

Omega-3s Help Resolve Inflammation

Because the original sources of SPMs are primarily the omega-3 fatty acids EPA and DHA, increasing the intake of these healthy fats will assist in resolving inflammation.19-21

In a recent clinical trial, researchers showed that in response to a pro-inflammatory stimulus, EPA and DHA intake leads to the formation of more SPMs.21

For five months, participants were given either EPA and DHA or a placebo daily, before receiving a pro-inflammatory stimulus. Blood was collected daily for five days after receiving the stimulus.

By the fifth day, the group that received the EPA and DHA had 229% higher SPM levels than the placebo group. The levels of systemic inflammation, as measured by C-reactive protein, were significantly lower in the EPA/DHA treatment group compared to placebo.

The researchers repeated this testing using slight variations with their methods. Results consistently showed that EPA and DHA intake increases the level of SPMs in response to a pro-inflammatory stimulus.

This is great news for those who eat lots of cold-water fish and/or take high-potency fish oil supplements. Those with potential inflammaging issues may want to supplement with SPM Precursors:

• 18-HEPE
• 17-HDHA
• 14-HDHA

What you need to know

SPM Precursors + Omega-3s

Resolve

Inflammation

• Chronic inflammation is a major risk factor in aging, age-related disease, and degenerative disorders.
• Scientists have identified compounds that resolve inflammation, called specialized pro-resolving mediators (SPMs).
• SPMs are mostly derived from the omega-3 fatty acids EPA and DHA, which are primarily found in fish. A recent clinical trial showed that supplementation with a marine oil enriched with SPM precursors increases SPM levels and helps resolve inflammation.
• Another clinical trial showed that supplementation with omega-3s also increased SPMs in the body and helped lower levels of the inflammatory marker C-reactive protein.

Preclinical Research on SPMs

Preclinical data demonstrate promising results from the direct use of specialized pro-resolving mediators (SPMs).

In one study, researchers tested the effects of an SPM resolvin on mice that had obesity-associated osteoarthritis. The treatment was injected into the animals’ joints. The results showed a significant reduction in pro-inflammatory macrophage infiltration into the soft tissue surrounding the joints (synovium), reduced severity of synovium inflammation, and prevention of cartilage degradation.15

A review of preclinical studies concluded that SPMs may be an effective treatment for gum disease (periodontitis). These studies showed that topical application of a resolvin and a lipoxin (an omega-6-derived SPM) to inflamed periodontal tissue results in a significant prevention of tooth loss compared to the control group.16

A mouse study showed that injections with the SPM maresin reduced inflammation-induced neuropathic pain.17

Summary

Chronic inflammation is so strongly correlated with age that scientists describe it as inflammaging.1

For decades, researchers have been studying how to better inhibit inflammation. They are now also beginning to understand the importance of resolving inflammation.

An abundance of preclinical data has demonstrated substantial potential benefits of having higher levels of specialized pro-resolving mediators (SPMs) or SPM precursors.

Polyunsaturated fatty acids, particularly the omega-3 class, can be made into SPMs in your body. However, taking SPM precursors directly may be more effective.

Those concerned about chronic inflammation and persistently elevated inflammatory markers (like C-reactive protein and interleukin-6) may want to add a multi-SPM formula to their intake of omega-3 fatty acids.

Several clinical trials on SPM precursors are underway, with some completed and some still recruiting participants.4

Life Extension® is also now recruiting generally healthy people for a clinical trial. If you are in the Fort Lauderdale area and are interested in participating, please call 1-866-517-4536.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

Weight Loss Increases SPMs

In a recent study, researchers discovered that weight loss leads to a significant increase in the formation of SPMs.22

The researchers selected 42 patients with metabolic syndrome and took blood samples of their neutrophils, which are a short-lived type of white blood cell that eliminates pathogens.23 The researchers then stimulated the neutrophils and measured the release of SPMs to use for comparison after the intervention.

Patients were randomly selected to go through either a weight loss program (treatment) or a weight stabilization program (control).

After 16 weeks, the researchers again took blood samples of their neutrophils and provided stimulation to measure the amount of SPM release.

At the end of the trial, the SPM release from the neutrophils of the patients in the control group was unchanged compared to baseline.

The weight loss group had significantly elevated SPM release compared to baseline. Compared to the control group, weight loss led to a 2-fold increase the release of the SPM E-series resolvin.

References

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18. Souza PR, Marques RM, Gomez EA, et al. Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study. Circ Res. 2020 Jan 3;126(1):75-90.
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20. Barden AE, Shinde S, Burke V, et al. The effect of n-3 fatty acids and coenzyme Q10 supplementation on neutrophil leukotrienes, mediators of inflammation resolution and myeloperoxidase in chronic kidney disease. Prostaglandins Other Lipid Mediat. 2018 May; 136:1-8.
21. Norris PC, Skulas-Ray AC, Riley I, et al. Identification of specialized pro-resolving mediator clusters from healthy adults after intravenous low-dose endotoxin and omega-3 supplementation: a methodological validation. Sci Rep. 2018 Dec 21;8(1):18050.
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