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Original Research
Evaluation of the Effect of Neptune Krill Oil on Chronic
Inflammation and Arthritic Symptoms

Luisa Deutsch, MD, MSc
Department of Behavioral Science and Health Research, University Health Network Toronto, Sciopsis Inc. Evidence BasedNutraMedicine, Richmond Hill, Ontario, CANADA Key words: C-reactive protein, inflammation, omega-3, phospholipids, Neptune Krill Oil, NKO™, antioxidants
Objectives: a) To evaluate the effect of Neptune Krill Oil (NKO™) on C-reactive protein (CRP) on patients
with chronic inflammation and b) to evaluate the effectiveness of NKO™ on arthritic symptoms.
Methods: Randomized, double blind, placebo controlled study. Ninety patients were recruited with con-
firmed diagnosis of cardiovascular disease and/or rheumatoid arthritis and/or osteoarthritis and with increased levels of CRP (Ͼ1.0 mg/dl) upon three consecutive weekly blood analysis. Group A received NKO™ (300 mgdaily) and Group B received a placebo. CRP and Western Ontario and McMaster Universities (WOMAC) osteoarthritis score were measured at baseline and days 7, 14 and 30.
Results: After 7 days of treatment NKO™ reduced CRP by 19.3% compared to an increase by 15.7%
observed in the placebo group (p ϭ 0.049). After 14 and 30 days of treatment NKO™ further decreased CRPby 29.7% and 30.9% respectively (p Ͻ 0.001). The CRP levels of the placebo group increased to 32.1% after14 days and then decreased to 25.1% at day 30. The between group difference was statistically significant; p ϭ0.004 at day 14 and p ϭ 0.008 at day 30. NKO™ showed a significant reduction in all three WOMAC scores.
After 7 days of treatment NKO™, reduced pain scores by 28.9% (p ϭ 0.050), reduced stiffness by 20.3% (p ϭ0.001) and reduced functional impairment by 22.8% (p ϭ 0.008).
Conclusion: The results of the present study clearly indicate that NKO™ at a daily dose of 300 mg
significantly inhibits inflammation and reduces arthritic symptoms within a short treatment period of 7 and 14 INTRODUCTION
predictor of future cardiovascular risk [6]. CRP has been shownin several prospective, nested case-control studies to be asso- Inflammation is closely linked to the pathogenesis of ath- ciated with an increased risk of myocardial infarction [7–12], erosclerosis and joint disease and may be provoked by nonin- stroke [7,9,13,14], sudden death from cardiac causes [15], and fectious (e.g., injury, smoking, diabetes, obesity) as well as infectious sources. C-reactive protein (CRP), which is one of In arthritic joints CRP production reflects the release of the most useful biomarkers of inflammation, appears to be a proinflammatory cytokines, such as interleukins-1 and -6 (IL-1 central player in the harmful effects of systemic inflammation and IL-6) and tumor necrosis factor-alpha (TNF-␣), which are and an easy and inexpensive screening test to assess inflam- essential in the mechanism of cartilage degeneration [17–22].
mation-associated risk [1]. Unlike other markers of inflamma- CRP is significantly increased in patients with rheumatoid tion, CRP levels are stable over long periods, have no diurnal arthritis and slightly but significantly higher in patients with variation and can be measured inexpensively.
osteoarthritis than in matched controls [1,23–29]. CRP was also Current studies suggest that CRP is a strong predictor of found to increase in patients with knee osteoarthritis showing future cardiovascular events [2–5]. At all levels of estimated disease progression as well as in patients with rapidly destructive 10-year risk for events according to the Framingham risk score hip osteoarthritis [24 –29]. Contrary to erythrocyte sedimentation and at all levels of LDL cholesterol, CRP remained a strong rate (ESR), evidence has proven a strong association between CRP Address reprint requests to: Dr. Luisa Deutsch, Sciopsis Inc. Evidence Based NutraMedicine, 18 Corso Court, Richmond Hill, Ontario L4S 1H4, CANADA. Journal of the American College of Nutrition, Vol. 26, No. 1, 39–48 (2007)Published by the American College of Nutrition and level of clinical severity in patients with osteoarthritis of the Considering the continuously increasing evidence of ad- verse events related to the chronic use of non-steroidal anti- The results of human studies on the anti-inflammatory inflammatory drugs (NSAIDs), which represent the gold stan- properties of omega-6 and omega-3 fatty acids are contro- dard for the treatment of chronic inflammatory conditions, it is versial, varying from no effect to a beneficial effect [30 –34].
imperative to research for more innovative and safer treatments A proposed competition between omega-3 and omega-6 [54 – 61]. The current study addresses the need for safer alter- fatty acids may be the reason for the observed discrepancies natives in the management of inflammation and arthritic dis- of the effects of n-3 fatty acids on cytokines [35]. Both ease and evaluates the hypotheses that Neptune Krill Oil is safe omega-3 and omega-6 fatty acids are substrates for the and effective for the reduction of inflammation as measured byserum CRP and the management of pain in patients with production of human eicosanoids and share the same en- arthritic disease. The objectives of the present study were a) to zymes for the synthesis of prostaglandins and leukotrienes.
evaluate the effect of NKO™ on CRP in patients with chronic Omega-3 fatty acids produce eicosanoids with fewer inflam- inflammation and b) to evaluate the effect of NKO™ on the matory properties than those derived from omega-6 fatty quality of life of patients with arthritic disease.
acids [36 –38]. Hence, a dominant ratio of dietary intake of omega-3 versus omega-6 fatty acids is critical to inflamma- MATERIALS AND METHODS
Neptune Krill Oil is extracted from Antarctic Krill (Ephau- sia Superba), a zooplankton at the bottom of the food chain.
Even though krill is the main food source for whales it remains the most abundant biomass on earth because of its high regen- Adult patients between 30 and 75 years with a confirmed eration properties. The krill used for Neptune Krill Oil is diagnosis of cardiovascular disease and/or rheumatoid arthritis harvested in the Antarctic Ocean where the worldwide harvest and/or osteoarthritis and with increased CRP levels at 1.0 mg/dlor more and a standard deviation not higher than 0.05 in three is less than 0.1% the allowed fishing quota. Being at the bottom consecutive weekly tests, who fulfilled the inclusion criteria of the food chain, having a very short lifespan of 1–2 years and and signed an informed consent form, were included in the living in the clean waters of the Antarctic Ocean, makes the study. Excluded from the study were patients who could not krill and thus Neptune Krill Oil naturally pure of heavy metals, restrain from consuming alcohol for the duration of the study, with a history of gastrointestinal perforation or hemorrhage or The oil is extracted by a patented cold vacuum extraction symptomatic peptic ulcer. Patients with seafood allergy, diabe- process that protects the biomass from exposure to heat, light or tes or concurrent medical disease or concomitant treatments oxygen. This protects the oil through-out its production and (including postmenopausal hormones) that could confound or maintains the original nutrients of krill intact. The result is a interfere with the outcome measures, as well as those taking concentrate of novel marine phospholipid carriers of eicosa- concomitant anticoagulants were not eligible for enrollment.
pentanoic (EPA) and docosahexanoic (DHA) fatty acids and Also excluded were patients with moderate or severe depres- potent antioxidants. The main antioxidants, astaxanthin and a sion or who were unable to respond to the study questionnaire.
novel flavonoid, similar to the 6,8-Di-C-glucosylluteolin, es- Women of childbearing age were required to have confirmed terify the EPA and DHA respectively. This provides a signif- use of adequate contraception since their last menses and to icant stability and antioxidant potency to the oil.
agree to continue this practice during the study.
Anecdotal data suggests that Neptune Krill Oil may be effective for the management of arthritic symptoms. Evidence Study Design
has shown that phospholipids, omega-3 fatty acids and astax- In this prospective randomized double blind clinical trial 90 anthin have direct or indirect anti-inflammatory properties patients who fulfilled the study criteria were recruited from the [9 –13,30 –53]. Phospholipids protect the cell membrane for practices of primary care physicians in Ontario, Canada. Pa- toxic injury [39]. Multiple studies have proven EPA and DHA tients were randomly assigned by a computer-generated sched- to trigger secretion of anti-inflammatory prostaglandins of ule into one of two groups. The first group (Group A) received the 3 series (PE , PI and thromboxane A ) and interleukin-6 NKO™ at a daily morning dose of 300 mg; the second group resulting in a decrease CRP and tumor necrosis factor (TNF) (Group B) received a neutral placebo. The NKO™ contained [30 –38,40 –53]. Astaxanthin inhibits the production of 17% EPA, 10% DHA and an omega-3 versus omega-6 ratio of proinflammatory prostaglandins (PGE2) and TNF [9 –13,41– 15 to 1. The placebo used was microcrystalline cellulose. Both 43]. A dietary supplement that contains a natural combina- the NKO™ and the placebo were administered in non-distin- tion of phospholipids, EPA, DHA and astaxanthin may offer guishable glycerin softgels. Compliance was tested by a count an alternative regimen for the management of chronic in- of softgels at each visit after 7, 14 and 30 days. All blood tests were taken at a central lab in the morning, between 7:00 and 10:00 am under fasting conditions for 8 hours. Blood sampling it was initially developed for the assessment of pain, stiffness and testing occurred weekly during the 3 week screening pe- and function of daily living in the elderly with osteoarthritis it riod, at baseline after the 1 week wash-out and at each fol- has recently been revised for younger and/or more active pa- low-up visit after 7, 14 and 30 days of treatment.
tients with knee injury and/or knee or hip osteoarthritis. It Patients were asked to stop use of all dietary supplements, provides a validated assessment of the patient’s functional especially those containing omega-6, foods containing a high capacity, specifically joint pain, stiffness and functional impair- content of omega-6 (corn, soy, safflower and sunflower oils ment [62–77]. The WOMAC osteoarthritis score has 3 sub- and sunflower seeds) and all analgesics (except acetamino- scales with 24 items; 5 items assessing pain, 2 items for phen) and anti-inflammatory medications for two weeks prior stiffness, and 17 items measuring physical function. It can be to initiation of the trial for washout purposes. Patients were self-administered in less than 5 minutes. The WOMAC can be allowed to take acetaminophen (650 mg caplets) as a rescue both scored separately for each subscale and together to give a analgesic medication, for severe pain throughout the trial. The composite score. The scale employed in this study to quantify maximum dose of acetaminophen allowed was as recom- patient global assessment of disease activity was the Likert mended by the manufacturer; 1–2 capsules every 8 hours. All scale; a 5-point scale in which 0 represents the best outcome patients were instructed to keep a diary of their acetaminophen and 4 the worst. Minimal clinically significant change is con- consumption and report it at their next scheduled visit.
sidered a decrease of 0.4 mm on each item in the three sub- Ninety patients were recruited, 45 per group, of whom 44 scales [71–77]. In order to avoid environmental or other bias, patients in the NKO™ group and 43 patients in the placebo all patients responded to the WOMAC in the physician’s office group completed 30 days of treatment. Two patients withdrew from the study, one per group, after a minor accident thatrequired additional analgesic treatment. One patient on placebo Statistical Design
withdrew for personal reasons. The mean age of patients in theNKO™ group was 54.6 (14.8) years and 55.3 (14.3) years in A sample size of 90 patients (45 patients per group) pro- the placebo group. There were 25 (55.6%) male patients in the vided 80% power to detect a CRP reduction of 10% from NKO™ group and 22 (48.9%) in the placebo group.
baseline to 14 days. Within group differences reflecting In Group A and B respectively, 5 and 7 patients were changes over time for the same patient were assessed for diagnosed only with atherosclerosis, 18 and 16 patients only statistical significance with the Paired Student’s t-test. Between with osteoarthritis, 10 and 12 patients only with rheumatoid group differences were assessed with planned comparisons of arthritis and 12 and 10 patients with cardiovascular disease and one way analysis of variance. Statistical significance was set at osteoarthritis. Overall, in the NKO™ and placebo group re- p Ͻ 0.05. Values are presented as mean Ϯ standard deviation.
spectively, 17 and 17 patients were diagnosed with cardiovas-cular disease, 30 and 26 with osteoarthritis and 10 and 12 withrheumatoid arthritis.
At baseline, there was no significant difference between Outcome Measures
groups with regards to concomitant medications (p ϭ 0.987), During the screening period, in order to avoid the inclusion CRP levels (p ϭ 0.087) and the three WOMAC scores (pain Ϫ of patients with acute inflammation, the primary efficacy pa- p ϭ 0.539, stiffness Ϫ p ϭ 0.104, functional impairment Ϫ p ϭ rameter, C-reactive protein, was measured weekly for three 0.105). Patients on NKO™ reduced their consumption of res- consecutive weeks. Patients who maintained a CRP of at least cue medications between baseline and 30 days by 31.6% and 1 mg/dl, without fluctuations higher than 0.05 mg, were blindly significantly less consumption than patients on placebo, who randomized in their group and after the washout period initiated reduced their acetaminophen intake by 5.9% (p ϭ 0.012).
their respective treatment, either NKO™ or placebo. CRP was After 7 days of treatment NKO™ reduced mean (SD) CRP further tested after 7, 14 and 30 days of treatment.
by 19.3% (1.1) compared to an increase by 15.7% (1.9) ob- At baseline as well as at each of the three follow-up visits, served in the placebo group. The difference between the two patients with arthritic disease were asked to complete the groups was statistically significant (p ϭ 0.049). NKO™ further Western Ontario and McMaster Universities (WOMAC) ar- decreased CRP after 14 and 30 days of treatment by 29.7% thritic pain assessment questionnaire. The Western Ontario and (0.9) and 30.9% (1.0) respectively. The CRP levels of the McMaster (WOMAC) University osteoarthritis score is a 24- placebo group increased by 32.1% (1.9) after 14 days and then item questionnaire completed by the patient and focusing on decreased to 25.1% (1.1) at day 30. The within group decrease joint pain, stiffness and loss of function related to osteoarthritis of mean (SD) CRP by NKO™ through the three testing periods of the knee and hip [62–77]. The WOMAC is used extensively was statistically significant (p ϭ 0.001). Contrary the CRP in in clinical trials for the evaluation of the effect of investiga- the within placebo group increased significantly (p ϭ 0.028).
tional products on the treatment of osteoarthritis. Even though The between group difference in all three testing days was JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION Table 1. C-Reactive Protein (CRP) mg/dl by Group and Visit
Table 2. WOMAC Pain Scores by Group and Visit*
* 0 represents the best outcome and 4 the worst.
statistically significant; p ϭ 0.049 at 7 days, p ϭ 0.004 at day DISCUSSION
14 and p ϭ 0.008 at day 30 (Table 1).
Tables 2–7 present the effects of NKO™ on the 3 Non-steroidal anti-inflammatory agents (NSAIDs) are the WOMAC osteoarthritis scores compared to placebo, from most commonly prescribed agents for inflammatory conditions.
baseline to 30 days. NKO™ showed a significant reduction NSAIDs are drugs with analgesic, antipyretic and anti-inflam- in all three WOMAC scores. NKO™ reduced pain signifi- matory effects. Most NSAIDs, such as aspirin, ibuprofen and cantly more than placebo in all three follow-up visits; p ϭ naproxen act as non-selective inhibitors of cyclooxygenase— 0.050 at visit 1 (day 7), p ϭ 0.049 at visit 2 (day 14) and p ϭ they inhibit both the cyclooxygenase-1 (COX-1) and cycloox- 0.011 at visit 3 (day 30). Similar effects were observed with ygenase-2 (COX-2) isoenzymes, whereas COX-2 inhibitors the stiffness and functional impairment scores. In all three selectively inhibit the cyclooxygenase-2 isoenzyme. The main follow-up visits the between group differences in change of advantage of NSAIDs is that, unlike opioids, they do not stiffness (p ϭ 0.001) and functional impairment (p ϭ 0.005) produce sedation, respiratory depression, or addiction. Certain were statistically significant (Tables 4 –7). No adverse NSAIDs have become accepted as relatively safe, resulting in events were reported during the 30 days of treatment with the rescheduling of these agents, e.g. ibuprofen, to allow avail- ability over-the-counter. However, recent evidence suggests an Table 3. Change in WOMAC Pain Scores/100 by Group and Visit*
* 0 represents the best outcome and 4 the worst.
Table 4. WOMAC Stiffness Scores by Group and Visit*
* 0 represents the best outcome and 4 the worst.
association between COX-2 inhibitor exposure and cardiovas- of the lipoxygenase pathways. The significantly dominant ome- cular risk. Considering that small increases in ambulatory and ga-3 to omega-6 ratio (15:1) in Neptune Krill Oil may partially clinic systolic blood pressure in patients with hypertension and explain the anti-inflammatory effects observed in this trial. The type II diabetes are associated with substantial increases in the balance of polyunsaturated (essential) fatty acids in the body is risk of cardiovascular morbidity, the use of these medications critical for the maintenance of healthy cell membranes and has been restricted to the lowest effective dose for the shortest hormone regulation. During the last decades, the American diet possible duration of treatment [54 – 61].
has shifted to much higher levels of omega-6 and less omega-3 Neptune Krill Oil is a rich source of unique phospholipid fatty acid intake. Long-chain omega-6 such as arachidonic acid, carriers of omega-3 fatty acids, eicosapentanoic acid (EPA) and predominating in the phospholipids of cell membranes can docosahexanoic acid (DHA), esterified on antioxidants, as encourage the production of pro-inflammatory type-2 prosta- astaxanthin and a novel flavonoid. Phospholipids are important glandins (PGE2), while omega-3 fatty acids promote the pro- in protecting membranes from toxic injury and free radical duction of anti-inflammatory prostaglandins [1,2]. An addi- attack [39]. The composition of phospholipids in Neptune Krill tional factor is the naturally occurring astaxanthin in NKO™ Oil appears to be optimal to offer such protection. The unrav- which may also actively contribute in its anti-inflammatory eling of the exact mechanism of action is a multifactorial potency. A recent study by Ohgami K. et al demonstrates that project which is still ongoing. We speculate that it is based on astaxanthin inhibits nitric oxide production through inhibiting the blockage of leukotriene formation by interfering at the level the activity of inducible nitric oxide synthase (NOS), and JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION Table 5. Change in WOMAC Stiffness Scores/100 by Group and Visit*
* 0 represents the best outcome and 4 the worst.
Table 6. WOMAC Functional Impairment Scores by Group and Visit*
* 0 represents the best outcome and 4 the worst.
Table 7. Change in WOMAC Functional Impairment Scores/100 by Group and Visit*
* 0 represents the best outcome and 4 the worst.
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