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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
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.
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.
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
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
predictor of future cardiovascular risk . 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 , 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 . 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. E-mail:firstname.lastname@example.org
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 . 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-
), 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
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 . 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
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-
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
groups with regards to concomitant medications (p
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-
ϭ 0.539, stiffness Ϫ p
ϭ 0.104, functional impairment Ϫ p
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
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
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
C-Reactive Protein (CRP) mg/dl by Group and Visit
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
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
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
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
ϭ 0.001) and functional impairment (p
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
Change in WOMAC Pain Scores/100 by Group and Visit*
* 0 represents the best outcome and 4 the worst.
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 . 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
Change in WOMAC Stiffness Scores/100 by Group and Visit*
* 0 represents the best outcome and 4 the worst.
WOMAC Functional Impairment Scores by Group and Visit*
* 0 represents the best outcome and 4 the worst.
Change in WOMAC Functional Impairment Scores/100 by Group and Visit*
* 0 represents the best outcome and 4 the worst.
production of PGE2 and TNF-. This study suggests that astax-
anthin may have an anti-inflammatory effect and may be a
promising agent for the treatment of inflammation .
1. Johansen JS, Stoltenberg M, Hansen M, Florescu A, Horslev-
The present study confirms the results of previous research
Petersen K, Lorenzen I, Price PA: Serum YKL-40 concentrations
demonstrating the anti-inflammatory effects of EPA and DHA and
in patients with rheumatoid arthritis: relation to disease activity.
of a dominant omega-3 versus omega-6 ratio [30 –38,40,44 –53].
2. Roberts WL, Moulton L, Law TC, Farrow G, Cooper-Anderson M,
Simopoulos has shown that omega-3 fatty acids lower CRP more
Savory J, Rifai N: Evaluation of nine automated high-sensitivity
so than any other nutrient, which accounts for decreasing the risk
C-reactive protein methods: implications for clinical and epidemi-
for coronary heart disease . Human and animal studies have
ological applications. Clin Chem 47:418–425, 2001.
provided evidence that dietary intake of omega-3 fatty acids mod-
3. Ockene IS, Matthews CE, Rifai N, Ridker PM, Reed G, Stanek E:
ifies inflammatory and immune reactions. This makes making
Variability and classification accuracy of serial high-sensitivity
omega-3 fatty acids potential therapeutic agents for inflammatory
C-reactive protein measurements in healthy adults. Clin Chem
A possible explanation for the increase of CRP observed in
4. Meier-Ewert HK, Ridker PM, Rifai N, Price N, Dinges DF, Mull-
the placebo group is the interruption of all anti-inflammatory
ington JM: Absence of diurnal variation of C-reactive protein
levels in healthy human subjects. Clin Chem 47:426–430, 2001.
regimens one week prior and for the duration of the trial. Since
5. Rifai N, Buring JE, Lee IM, Manson JE, Ridker PM: Is C-reactive
the patients enrolled suffered from a chronic inflammatory
protein specific for vascular disease in women? Ann Intern Med
condition with chronically high CRP, the cessation of all anti-
inflammatory treatment may have triggered the increased pro-
6. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR: Comparison of
C-reactive protein and low-density lipoprotein cholesterol levels in
The significant reduction of pain shown in the WOMAC
the prediction of first cardiovascular events. New Engl J Med
pain score is also demonstrated the significantly lower con-
sumption of NSAIDs by the group of patients treated with
7. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH:
NKO™. This finding becomes even more significant if we
Inflammation, aspirin, and the risk of cardiovascular disease in
consider the nephrotoxicity of NSAIDs mainly among patients
apparently healthy men. New Engl J Med 336:973–979, 1997.
8. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman
M, Meilahn EN, Kuller LH: Relationship of C-reactive protein to
The results of the present study validate the potent anti-
risk of cardiovascular disease in the elderly: results from the
inflammatory properties of NKO™ and reinforce the potential
Cardiovascular Health Study and the Rural Health Promotion
mechanism of action. The CRP reduction induced by NKO™
Project. Arterioscler Thromb Vasc Biol 17:1121–1127, 1997.
demonstrates that NKO™ is a safe and effective alternative for
9. Ridker PM, Hennekens CH, Buring JE, Rifai N: C-reactive protein
the treatment of inflammation, particularly with all the recently
and other markers of inflammation in the prediction of cardiovas-
proven adverse events of the most widely used NSAIDs. Fur-
cular disease in women. N Engl J Med 342:836–843, 2000.
thermore, this study demonstrates a significant improvement in
10. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A,
Hutchinson WL, Pepys MB: C-reactive protein, a sensitive marker
all 3 WOMAC scores among the 30 and 10 patients on NKO™
of inflammation, predicts future risk of coronary heart disease in
as compared to the 26 and 12 patients on placebo who were
initially healthy middle-aged men: results from the MONICA
diagnosed with osteoarthritis and rheumatoid arthritis. No ad-
(Monitoring Trends and Determinants in Cardiovascular Disease)
verse events were reported making NKO™ safe for human
Augsburg Cohort Study, 1984 to 1992. Circulation 99:237–242,
11. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby
P, Gallimore JR, Pepys MB: Low grade inflammation and coro-
nary heart disease: prospective study and updated meta-analyses.
12. Mendall MA, Strachan DP, Butland BK, Ballam L, Morris J,
Sweetnam PM, Elwood PC: C-reactive protein: relation to total
The results of the present study indicate that NKO™ at a
mortality, cardiovascular mortality and cardiovascular risk factors
daily dose of 300 mg may within a short time to reaction (7–14
in men. Eur Heart J 21:1584–1590, 2000.
days) significantly inhibit inflammation by reducing CRP as
13. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H,
well as significantly alleviate symptoms caused by osteoarthri-
Massaro JM, D’Agostino RB, Franzblau C, Wilson PW: Plasma
tis and rheumatoid arthritis. Further research is required to
concentration of C-reactive protein and risk of ischemic stroke and
better understand the mechanism of action and to compare the
transient ischemic attack: the Framingham Study. Stroke 32:2575–
effects of NKO with other anti-inflammatory agents presently
14. Ford ES, Giles WH: Serum C-reactive protein and self-reported
stroke: findings from the Third National Health and Nutrition
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
Examination Survey. Arterioscler Thromb Vasc Biol 20:1052–
Effect of eicosapentaenoic acid and docosahexaenoic acid on ox-
idative stress and inflammatory markers in treated-hypertensive
15. Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM: Prospective
type 2 diabetic subjects. Free Radic Biol Med 35:772–781, 2003.
study of C-reactive protein, homocysteine, and plasma lipid levels
31. Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Willett WC,
as predictors of sudden cardiac death. Circulation 105:2595–2599,
Rimm EB: Habitual Dietary Intake of n-3 and n-6 Fatty Acids in
Relation to Inflammatory Markers Among US Men and Women.
16. Ridker PM, Stampfer MJ, Rifai N: Novel risk factors for systemic
atherosclerosis: a comparison of C-reactive protein, fibrinogen,
32. James MJ, Gibson RA, Cleland LG: Dietary polyunsaturated fatty
homocysteine, lipoprotein(a), and standard cholesterol screening
acids and inflammatory mediator production. Am J Clin Nutr
as predictors of peripheral arterial disease. JAMA 285:2481–2485,
33. Calder PC: N-3 polyunsaturated fatty acids, inflammation and
17. Otterness IG, Bliven ML, Downs JT, Natoli EJ, Hanson DC:
immunity: pouring oil on troubled waters or another fishy tale?
Inhibition of interleukin-1 synthesis by tenidap: a new drug for
arthritis. Cytokine 3:227–228, 1991.
34. Pasceri V, Cheng JS, Willerson JT, Yeh ET, Chang J: Modulation
18. Sipe JD, Bartle MN, Loose LD: Modification of the proinflamma-
of C-reactive protein-mediated monocyte chemoattractant pro-
tory cytokine production by the antirheumatic agents tenidap and
tein-1 induction in human endothelial cells by anti-atherosclerosis
naproxen. J Immunol 148:480–484, 1992.
drugs. Circulation 103:2531–2534, 2001.
19. Loose LD, de Oliveira R, Sipe JD, Franzblau C, Shanahan WR: A
35. Krauss RM, Eckel RH, Howard B, Appel LJ, Daniels SR, Deck-
possible systemic component of osteoarthritis: elevated concentra-
elbaum RJ, Erdman JW Jr, Kris-Etherton P, Goldberg IJ, Kotchen
tions (by ELISA) of C reactive protein in serum of OA patients and
TA, Lichtenstein AH, Mitch WE, Mullis R, Robinson K, Wylie-
modulation by tenidap. Arthritis Rheum 39(Suppl):S166, 1996.
Rosett J, St Jeor S, Suttie J, Tribble DL, Bazzarre TL: AHA
20. Loose LD, Sipe JD, Kirby DS, Kraska AR, Weiner ES, Shanahan
Dietary Guidelines: revision 2000: A statement for healthcare
WR, Leeming MR, Farrow P, Stack CB, Ting N: Reduction of
professionals from the Nutrition Committee of the American Heart
acute-phase proteins with tenidap, a cytokine modulating antirheu-
Association. Circulation 102:2284–2299, 2000.
matic drug. Br J Rheumatol 32(Suppl 3):19–25, 1993.
36. Paschos GK, Rallidis LS, Liakos GK, Panagiotakos D, Anastasia-
21. Johansen JS, Baslund B, Garbasch C, Hansen M, Lorenzen I, Price
dis G, Votteas V, Zampelas A: Background diet influences the
PA: YKL-40 in giant cells and macrophages from patients with
anti-inflammatory effect of alpha-linolenic acid in dyslipidaemic
giant cell arteritis. Arthritis Rheum 42:2624–2630, 1999.
subjects. Br J Nutr 92:649–655, 2004.
22. Johansen JS, Moller S, Price PA, Bendtsen F, Junge J, Garbarsch
37. Zampelas A, Paschos G, Rallidis L, Yiannakouris N: Linoleic acid
C, Henriksen JH: Plasma YKL-40: a new potential marker of
to alpha-linolenic acid ratio. From clinical trials to inflammatory
fibrosis in patients with alcoholic cirrhosis? Scand J Gastroenterol
markers of coronary artery disease. World Rev Nutr Diet 92:92–
23. Spector TD, Hart DJ, Nandra D, Doyle DV, Mackillop N, Galli-
38. Rallidis LS, Paschos G, Liakos GK, Velissaridou AH, Anastasiadis
more JR, Pepys MB: Low-level increases in serum C reactive
G, Zampelas A: Dietary alpha-linolenic acid decreases C-reactive
protein are present in early osteoarthritis of the knee and predict
protein, serum amyloid A and interleukin-6 in dyslipidaemic pa-
progressive disease. Arthritis Rheum 40:723–727, 1997.
tients. Atherosclerosis 167:237–242, 2003.
24. Conrozier Th, Carkier M-C, Mathieu P: Serum levels of YKL-40
39. Hirata F, Axelrod J: Phospholipid methylation and biological sig-
and C reactive protein in patients with hip osteoarthritis and
nal transmission. Science 209:1082–1090, 1980.
healthy subjects: a cross sectional study. Ann Rheum Dis 59:828–
40. Vanderhoek JY, Bryant RW, Bailey JM: Inhibition of leukotriene
biosynthesis by the leukocyte product 15-hydroxy-5,8,11,13-
25. Conrozier T, Chappuis-Cellier C, Richard M, Mathieu P, Richard
eicosatetraenoic acid. J Biol Chem 255:10064–10066, 1980.
S, Vignon E: Increased serum-C-reactive protein levels by immu-
41. Naguib YM: Antioxidant activities of astaxanthin and related caro-
nonephelometry in patients with rapidly destructive osteoarthritis.
tenoids. J Agric Food Chem 48:1150–1154, 2000.
Rev Rhum Engl Ed 65:759–765, 1998.
42. Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren
26. Wolfe F: The C reactive protein but not erythrocyte sedimentation
K, van Leeuwen PA: Flavonoids: a review of probable mecha-
rate is associated with clinical severity in patients with osteoar-
nisms of action and potential applications. Am J Clin Nutr 74:418–
thritis of the knee or hip. J Rheumatol 24:1486–1488, 1997.
27. Johansen JS, Jensen HS, Price PA: A new biochemical marker for
43. Kazuhiro O, Kenji S, Satoshi K: Effects of astaxanthin on lipopo-
joint injury. Analysis of YKL-40 in serum and synovial fluid. Br J
lysaccharide-induced inflammation in vitro and in vivo. Invest
Ophthalmol Vis Sci 44:2694–2701, 2003.
28. Hakala BE, White C, Recklies AD: Human cartilage gp-39, a
44. Horrobin DF: The role of essential fatty acids and prostaglandins
major secretory product of articular chondrocytes and synovial
in the premenstrual syndrome. J Reprod Med 28:465–468, 1983.
cells, is a mammalian member of chitinase protein family. J Biol
45. Simopoulos AP: Omega-3 fatty acids in health and disease and in
growth and development. Am J Clin Nutr 54:438–463, 1991.
29. Nyirkos P, Golds EE: Human synovial cells secrete a 39 kD
46. Drevon CA: Marine oils and their effects. Nutr Rev 50:38–45,
protein similar to a bovine mammary protein expressed during the
non-lactating period. Biochem J 268:265–268, 1993.
47. Hansen HS: Dietary essential fatty acids and in vivo
30. Mori TA, Woodman RJ, Burke V, Puddey IB, Croft KD, Beilin LJ:
production in mammals. World Rev Nutr Diet 42:102–134, 1983.
48. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van
Ontario and McMaster Universities (WOMAC) Osteoarthritis In-
der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC:
dex in Italian patients with osteoarthritis of the knee. Osteoarthritis
The effect of dietary supplementation with n-3 polyunsaturated
fatty acids on the synthesis of interleukin-1 and tumor necrosis
63. Jinks C, Jordan K, Croft P: Measuring the population impact of
factor by mononuclear cells. New Engl J Med 320:265–271, 1989.
knee pain and disability with the Western Ontario and McMaster
49. Hansen HS, Olsen SF: Dietary (n-3)-fatty acids, prostaglandins and
Universities Osteoarthritis Index (WOMAC). Pain 100:55–64,
prolonged gestation in humans. Prog Clin Biol Res 282:305–317,
64. Angst F, Aeschlimann A, Steiner W, Stucki G: Responsiveness of
50. Lee TH, Mencia-Huerta JM, Shih C, Corey EJ, Lewis RA, Austen
the WOMAC osteoarthritis index as compared with the SF-36 in
KF: Effects of exogenous arachidonic, eicosapentaenoic and do-
patients with osteoarthritis of the legs undergoing a comprehensive
cosahexaenoic acids on the generation of 5-lipoxygenase pathway
rehabilitation intervention. Ann Rheum Dis 60:834–840, 2001.
products by ionophore-activated human neutrophils. J Clin Invest
65. Bellamy N, Kirwan J, Boers M, Brooks P, Strand V, Tugwell P,
Altman R, Brandt K, Dougados M, Lequesne M: Recommenda-
51. Deutch B: Menstrual pain in Danish women correlated with low
tions for a core set of outcome measures for future phase III
n-3 polyunsaturated fatty acid intake. Eur J Clin Nutr 49:508–516,
clinical trials in knee, hip, and hand osteoarthritis. Consensus
development at OMERACT III. J Rheumatol 24:799–802, 1997.
52. Deutch B: Painful menstruation and low intake of n-3 fatty acids.
66. Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD: Knee
Ugeskr Laeger 158:4195–4198, 1996.
Injury and Osteoarthritis Outcome Score (KOOS)—development
53. Harel Z, Biro FM, Kottenhahn RK, Rosenthal SL: Supplementa-
of a self-administered outcome measure. J Orthop Sports Phys
tion with omega-3 polyunsaturated fatty acids in the management
of dysmenorrhea in adolescents. Am J Obstet Gynecol 174:1335–
67. Mazzuca SA, Brandt KD, Katz BP, Dittus RS, Freund DA, Lubitz
R, Hawker G, Eckert G: Comparison of general internists, family
54. Hutchison R: COX-2 selective NSAIDs. Am J Nurs 104:16, 2004.
physicians, and rheumatologists managing patients with symptoms
55. Barton LL: Nonsteroidal anti-inflammatory drugs and invasive
of osteoarthritis of the knee. Arthritis Care Res 10:289–299, 1997.
staphylococcal infections: the cart or the horse? Pediatrics 115:
68. Martin DP, Engelberg R, Agel J, Swiontkowski MF: Comparison
of the musculoskeletal function assessment questionnaire with the
56. Sudbo J, Lee JJ, Lippman SM, Mork J, Sagen S, Flatner N,
short form-36, the Western Ontario and McMaster Universities
Ristimaki A, Sudbo A, Mao L, Zhou X, Kildal W, Evensen JF,
Osteoarthritis Index, and the Sickness Impact Profile health-status
Reith A, Dannenberg AJ: Non-steroidal anti-inflammatory drugs
measures. J Bone Joint Surg 79-A:1323–1335, 1997.
and the risk of oral cancer: a nested case-control study. Lancet
69. Bellamy N, Kean WF, Buchanan WW, Gerecz-Simon E, Campbell
J: Double blind randomized controlled trial of sodium meclofe-
57. Reijman M, Bierma-Zeinstra SM, Pols HA, Koes BW, Stricker
namate (Meclomen) and diclofenac sodium (Voltaren): postvali-
BH, Hazes JM: Is there an association between the use of different
dation reapplication of the WOMAC Osteoarthritis Index. J Rheu-
types of nonsteroidal antiinflammatory drugs and radiologic pro-
gression of osteoarthritis? The Rotterdam Study. Arthritis Rheum
70. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW:
Validation study of WOMAC: a health status instrument for mea-
58. Messerli FH, Sichrovsky T: Does the pro-hypertensive effect of
suring clinically important patient relevant outcomes to antirheu-
cyclooxygenase-2 inhibitors account for the increased risk in car-
matic drug therapy in patients with osteoarthritis of the hip or knee.
diovascular disease? Am J Cardiol 96:872–873, 2005.
59. Bennett JS, Daugherty A, Herrington D, Greenland P, Roberts H,
71. Kreibich DN, Vaz M, Bourne RB, Rorabeck CH, Kim P, Hardie R,
Taubert KA: The use of nonsteroidal anti-inflammatory drugs
Kramer J, Kirkley A: What is the best way of assessing outcome
(NSAIDs): a science advisory from the American Heart Associa-
after total knee replacement? Clin Orthop 331:221–225, 1996.
tion. Circulation 111:1713–1716, 2005.
72. Barr S, Bellamy N, Buchanan WW, Chalmers A, Ford PM, Kean
60. Sowers JR, White WB, Pitt B, Whelton A, Simon LS, Winer N,
WF, Kraag GR, Gerecz-Simon E, Campbell J: A comparative
Kivitz A, van Ingen H, Brabant T, Fort JG, Celecoxib Rofecoxib
study of signal versus aggregate methods of outcome measurement
Efficacy and Safety in Comorbidities Evaluation Trial (CRES-
based on the WOMAC Osteoarthritis Index. J Rheumatol 21:2106–
CENT) Investigators: The effects of cyclooxygenase-2 inhibitors
and nonsteroidal anti-inflammatory therapy on 24-hour blood pres-
73. Laupacis A, Bourne R, Rorabeck C, Feeny D, Wong C, Tugwell P,
sure in patients with hypertension, osteoarthritis, and type 2 dia-
Leslie K, Bullas R: The effect of elective total hip replacement on
betes mellitus. Arch Intern Med 165:161–168, 2005.
health-related quality of life. J Bone Joint Surg 75-A:1619–1626,
61. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R,
Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien
74. Slemenda C, Brandt KD, Heilman DK, Mazzuca S, Braunstein
TK, Schnitzer TJ, VIGOR Study Group: Comparison of upper
EM, Katz BP, Wolinsky FD: Quadriceps weakness and osteoar-
gastrointestinal toxicity of rofecoxib and naproxen in patients with
thritis of the knee. Ann Intern Med 127:97–104, 1997.
rheumatoid arthritis. New Engl J Med 343:1520–1528, 2003.
75. Stucki G, Sangha O, Stucki S, Michel BA, Tyndall A, Dick W,
62. Salaffi F, Leardini G, Canesi B, Mannoni A, Fioravanti A, Capo-
Theiler R: Comparison of the WOMAC (Western Ontario and
rali R, Lapadula G, Punzi L, GOnorthrosis and Quality Of Life
McMaster Universities) osteoarthritis index and a self-report for-
Assessment (GOQOLA): Reliability and validity of the Western
mat of the self-administered Lequesne-Algofunctional index in
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
patients with knee and hip osteoarthritis. Osteoarthritis Cartilage
77. Bellamy N: “WOMAC Osteoarthritis Index: A User’s Guide.”
London, Ontario: McMaster University, 1995.
76. McGrory BJ, Harris WH: Can the Western Ontario and McMaster
Universities (WOMAC) Osteoarthritis Index be used to evaluate
different hip joints in the same patient? J Arthroplasty 11:841–844,
Received April 30, 2005; revision accepted September 12,
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PATIENT INFORMATION Ropinirole Hydrochloride Tablets If you have Restless Legs Syndrome (RLS, also known as Ekbom Syndrome), read the following Read this information completely before you start taking ropinirole hydrochloride tablets . Read the information each time you get more medicine. There may be new information. This leaflet provides a summary about ropinirole hydrochloride