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<th colspan="13"><p><strong>Appendix C</strong></p>
<p><strong>Intervention Trials Published 1992-2000 with Omega-3 Fatty
Acids (EPA and DHA) Including a Measure of Vascular Inflammation in the
Protocol</strong></p>
<p><strong>[Shaded rows indicate beneficial effect of Omega-3 Fatty
Acids (EPA and DHA)]</strong></p></th>
</tr>
<tr class="odd">
<th><strong>Reference</strong></th>
<th colspan="2"><strong>Objective</strong></th>
<th colspan="2"><strong>Study design</strong></th>
<th colspan="2"><strong>Duration</strong></th>
<th colspan="2"><strong>Intake</strong></th>
<th colspan="2"><strong>Subjects</strong></th>
<th colspan="2"><strong>Results</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><p>Abe, et. al.</p>
<p>1998</p>
<p>Aterioscler Thromb Vasc Biol.</p>
<p>1998;18:723-31</p>
<p>[U.S.]</p></td>
<td colspan="2">To examine the relationship between hypertriglyceridemia
dyslipidemia (high triglycerides/low HDL) and levels of soluble cell
adhesion molecules (sCAMs) and other risk factors.</td>
<td colspan="2">Randomized, placebo controlled</td>
<td colspan="2"><p>6 weeks</p>
<p>Initial dietary phase (AHA Step I Diet) lasted 6 weeks for all
subjects prior to tx.</p>
<p>After 6 weeks of the placebo-controlled study, the study was
extended. 31 subjects, including those who had been randomized to
placebo, received 4 g/d of Omacor for 28 weeks (7 months; n = 28) or 52
weeks (12 months; n = 9).</p></td>
<td colspan="2"><p>4 g/d Omacor (a highly purified formulation of the
ethyl esters of n-3 FAs: specific levels of EPA/DHA not specified).</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td colspan="2"><p>59 subjects total (33 males and 26 females)</p>
<p>39 subjects (22 males and 17 females) with hypertriglyceridemia
(serum triglycerides <u>&gt;</u>500 mg/dl but <u>&lt;</u>2000 mg/dl)</p>
<p>20 subjects (11 males and 9 females) with normolipidemic levels</p>
<p>(LDL levels &lt;160 mg/dl and fasting triglyceride &lt;150 mg/dl</p>
<p>Three groups:</p>
<p>1) Placebo hypertriglyceridemia control group (n = 20)</p>
<p>2) Omacor hypertriglyceridemia tx. Group</p>
<p>( n = 19)</p>
<p>3) Normolipidemic control group</p>
<p>(n = 20)</p>
<p>AHA Step I Diet maintained during 6-week treatment period.</p>
<p>Two subjects (of 41) were not included in the analysis for the
following reasons: 1 subject in the Omacor group was not available for
the follow-up period and one subject in the placebo group did not have
specimen available for assessment of sCAMs.</p></td>
<td colspan="2"><p><u>Soluble intercellular adhesion molecule-1
(sICAM-1):</u> Remained unchanged and similar in the Omacor and placebo
group. Long-term administration of Omacor (&gt; 6 months; n = 27) led to
a significant in levels of sICAM-1 (9%; p = 0.02).</p>
<p><u>Soluble vascular cell adhesion molecule-1 (sVCAM-1)</u>: Remained
unchanged and similar in the Omacor and placebo group.</p>
<p>Percent changes in sCAMs were not associated with % changes in TG, TC
or HDL.</p>
<p>Additional data on effects of recombinant soluble vascular cell
adhesion (rsVCAM-1) on THP-1 (a human acute monocytic leukemia-derived
cell line) and peripheral blood monocyte adhesion to human umbilical
vein endothelial cells (HUVEC) stimulated with IL-1 for 24 hours under
flow conditions are not reported here.</p></td>
</tr>
<tr class="even">
<td><p>Almdahl et al. 1993</p>
<p><em>Scand J Thor Cardiovasc</em> 1993;27:81-86</p>
<p>[Norway]</p></td>
<td colspan="2">To explore the possibility of monocyte and platelet
trapping during reperfusion after cold cardioplegic arrest and to
determine if pretreatment with n-3 FAs would modify these behavior.</td>
<td colspan="2">Randomized, double-blind, placebo-controlled trial.</td>
<td colspan="2">6 weeks</td>
<td colspan="2"><p>5.04 g/d EPA + DHA as ethyl esters (3.15 g/d EPA,
1.89 g/ DHA; K-85 capsules) (n-3 group)</p>
<p>placebo: corn oil</p>
<p>Compliance:</p>
<p>Serum FA analysis.</p></td>
<td colspan="2"><p>18 patients with angina pectoris and accepted for
coronary artery bypass surgery were recruited. Both groups were on
antiangina medication and the patients were asked to discontinue
antiplatelet medication prior to operation. The subjects were
administered with n-3 FAs or placebo prior to operation.</p>
<p>n-3 group: n=9</p>
<p>placebo: n=9</p>
<p>Blood samples were collected from coronary sinus and aorta at 5, 10
and 30 minutes after the release of aortic cross-clamp.</p></td>
<td colspan="2"><p>Monocyte count: At 5 and 10 minutes monocyte count
was lower in both groups in the coronary sinus than in the aortic blood,
but the difference was NS.</p>
<p><u>Monocyte thromboplastin activity:</u> The activity <em>in
vivo</em> was slightly lower (NS) in blood samples from coronary sinus
compared to aortic samples, and the difference between the groups was
NS. In the <em>in vitro</em> LPS-stimulated monocytes the activity was
consistently lower in the coronary sinus samples compared to the aorta
at 5, 10 and 0 minutes (p&lt;0.05). NS difference between the groups. No
correlation was observed between the arteriovenous monocyte
thromboplastin gradient and the duration of cardioplegic ischemia.</p>
<p>Serum EPA ↑ (3 fold) with n-3 FAs compared to placebo.</p></td>
</tr>
<tr class="odd">
<td><p>Blok et al. 1997</p>
<h2 id="eur-j-clin-invest-1997271003-1008">Eur J Clin Invest
1997;27:1003-1008</h2>
<p>[Netherlands]</p></td>
<td colspan="2">To determine the effects of fish oil on cytokine
levels.</td>
<td colspan="2"><p>Randomized, single-blind, placebo controlled
trial.</p>
<p>Multicenter</p></td>
<td colspan="2"><p>52 weeks (1 year) on fish oil</p>
<p>2-week baseline period</p>
<p>6 month follow-up period</p></td>
<td colspan="2"><p>2.92 g/d EPA + DHA (2.43 g/d EPA, 0.49 g/d DHA from 9
g of fish oil as methyl esters) (9 g fish oil group)</p>
<p>1.95 g/d EPA + DHA from 6 g of fish oil (6 g fish oil group)</p>
<p>0.97 g/d EPA + DHA from 3 g of fish oil (3 g fish oil group)</p>
<p>Placebo</p>
<p>Compliance:</p>
<p>Capsule count, fatty acid analysis</p></td>
<td colspan="2"><p>58 healthy monks (10 vegetarians) (ages 21-87 years)
were recruited form one Trappist and three Benedictine monasteries. The
subjects were not on medications that would influence lipid metabolism
or non-steroidal anti-inflammatory drugs.</p>
<p>9 g fish oil group: n=14</p>
<p>6 g fish oil group: n=15</p>
<p>3 g fish oil group: n=15</p>
<p>Placebo: n=14</p></td>
<td colspan="2"><p><u>Circulating cytokines:</u> The levels of cytokines
were determined only in the placebo and 9 g fish oil group. The
concentrations of all cytokines were low.</p>
<p>IL-1β: The concentration was above the detection limit. No
significant difference between the two treatment groups at any time
point, either in absolute concentrations or changes relative to
baseline.</p>
<p><u>IL-6:</u> The concentration was below the detection limit.</p>
<p>TNF-α: The concentration was above the detection limit. No
significant difference between the two treatment groups at any time
point, either in absolute concentrations or changes relative to
baseline.</p>
<p>IL-1Ra: The concentration was above the detection limit. No
significant difference between the two treatment groups at any time
point, either in absolute concentrations or changes relative to
baseline.</p>
<p><u><em>Ex vivo</em> production of cytokines after whole blood
stimulation:</u></p>
<p><u>IL-1β:</u> Endotoxin-stimulated secretion was significantly ↑
during fish oil supplementation compared to the follow-up period. No
significant differences in the <em>ex vivo</em> production of IL-1β
between the four groups at any time point.</p>
<p><u>TNF-α:</u> Endotoxin-stimulated secretion was significantly ↑ with
fish oil supplementation. Although differences over time were not
statistically significant. No significant differences in the <em>ex
vivo</em> production of TNF-α between the four groups at any time
point.</p>
<p><u>IL-1Ra:</u> Endotoxin-stimulated secretion was significantly
higher during fish oil supplementation compared to the follow-up period.
No significant differences in the <em>ex vivo</em> production of IL-1Ra
between the four groups at any time point.</p>
<p>Baseline circulating cytokine levels were not different between
vegetarians and non-vegetarians. Cytokine production capacity was not
different between the vegetarians and non-vegetarians at the end of the
follow-up period.</p>
<p>EPA levels in erythrocyte lipids ↑ with fish oil
supplementation.</p></td>
</tr>
<tr class="even">
<td><p>Engstrom et al. 1996</p>
<p>Prostaglandins, Leukotrienes and Essential Fatty Acids</p>
<p>1996;54(6);419-425</p>
<p>[Sweden]</p></td>
<td colspan="2">“To investigate the effects of supplementation of a
stabilized fish oil with extra vitamin E on the whole blood production
of some eicosanoids in man”</td>
<td colspan="2">Randomized, double-blind, controlled crossover
study</td>
<td colspan="2"><p>4 week treatment</p>
<p>with either fish oil or fish oil supplemented with vitamin E, at
which point patients crossed over following a six week washout
period</p></td>
<td colspan="2"><p>8.85 g/day EPA+DHA (Eskimo-3, 30 ml/day total
oil)</p>
<p>5.34 g/day EPA<br />
3.51 g/day DHA</p>
<p>Fish oil group: 30 ml/day fish oil w/ 1.5 IU/g vit.E</p>
<p>Supplemented group: 30 ml/day fish oil w/ 4.5 IU/g vit. E</p>
<p>Compliance:</p>
<p>Subject reports and fish oil count, as well as plasma fatty acid
analysis</p></td>
<td colspan="2">12 men with normal to slightly raised triglyceride
levels. 3 subjects are receiving medication for uncomplicated
hypertension, 1 had suffered MI, 1 had type 2 diabetes, 2 were being
treated for high cholesterol</td>
<td colspan="2"><p><u>6-keto-PGF<sub>1</sub>/TXB<sub>2</sub> ratio:</u>
↓ (27%) compared to baseline. Significant ↓ with fish oil + vit E from
baseline.</p>
<p><u>LTB<sub>4</sub>:</u> production ↓ 17% (p&lt;0.05) compared to
baseline.</p>
<p><u>6-keto PGF<sub>1α</sub>:</u> NS ↓ with fish oil (5%) and fish oil
+ vit E.</p></td>
</tr>
<tr class="odd">
<td><p>Eritsland et. al. 1995d</p>
<p><em>Thrombosis Res.</em> 1995;77(4):337-46</p>
<p>[Norway]</p></td>
<td colspan="2">To examine the influence of a moderate dietary
supplementation with EPA and DHA on LPS stimulated monocyte procoagulant
activity (PCA)</td>
<td colspan="2">Randomized controlled, trial.</td>
<td colspan="2"><p>24 weeks</p>
<p>(6 months)</p>
<p>All subjects studied before and 6 months after coronary artery bypass
grafting (CABG)</p></td>
<td colspan="2"><p>3.4 g/d EPA + DHA ethyl esters. The ratio of EPA:DHA
being about 2:1.</p>
<p>The EPA/DHA was given in</p>
<p>4 g n-3 PUFA concentrate (Omacor™,),</p>
<p>Series One:</p>
<p>(All received ASA)</p>
<p>12 receiving n-3 PUFA</p>
<p>12 controls</p>
<p>Series Two:</p>
<p>(5 pts from each group received ASA and the other 22 received
warfarin).</p>
<p>16 receiving n-3 PUFAs</p>
<p>16 controls</p>
<p>Compliance:</p>
<p>Fatty acids in serum phospholipids were measured</p></td>
<td colspan="2"><p>24 pts. Series One:</p>
<p>12 receiving n-3 PUFAs and</p>
<p>12 controls</p>
<p>32 pts. Series Two:</p>
<p>16 receiving n-3 PUFAs and</p>
<p>16 controls</p>
<p>All subjects had stenosing coronary artery disease and underwent
CABG.</p></td>
<td colspan="2"><p><u>Series 1, standard culture monocytes tested in
patient heparin plasma:</u></p>
<p>No differences between groups in the formation of FPA (p=0.69).</p>
<p>The amount of EPA 3X in the n-3 PUFA group and slightly in the
control group. A similar pattern was noted for DHA. The group
differences were statistically significant (DHA, p=0.015 and EPA p
&lt;0.001). No group differences in AA.</p>
<p>Series Two: patient monocytes tested in standard heparin plasma:</p>
<p>The change from baseline to 6 months for FPA formation was not
significantly different in the PUFA and control group nor were there any
differences between the groups.</p>
<p>There were no group differences in the LPS stimulated release of IL-6
after 6 months (p=0.79). There was a significant correlation between the
logged values of FPA and IL-6 at baseline (r=0.70, p=0.00001) and
between the logged changes (6 months – baseline) in FPA and IL-6 values
(r=0.64, p=0.0001).</p>
<p>Significantly amounts of EPA (p &lt;0.001) and total n-3 fatty acids
in the n-3 PUFA compared to the control group after 6 months (p
&lt;0.001).</p></td>
</tr>
<tr class="even">
<td><p>Kelley, et. al.</p>
<p>1999</p>
<h2 id="lipids">Lipids</h2>
<p>1999;34(4):317-24</p>
<p>[U.S.]</p></td>
<td colspan="2">To investigate the effects of feeding DHA on FA
composition, eicosanoid production and select activities of human
peripheral blood mononuclear cells (PBMSC), including natural killer
cell activity and production of inflammatory mediators in healthy young
men.</td>
<td colspan="2">Randomized controlled trial</td>
<td colspan="2"><p>13 weeks (90 days)</p>
<p>30 days of basal diet followed by 90 days of diet with DHA added.
Control group received basal diet for the entire 120 day
period.</p></td>
<td colspan="2"><p>6 g/day DHA (given as 15 g/day of DHASCO™ oil from
Martek Corporation, Columbia, MD) The DHASCO™ oil was added and replaced
an isocaloric amount of safflower oil. Thus, 6 g/day of linoleic acid
was replaced by an equivalent amount of DHA; N=7.</p>
<p>Control group received basal diet throughout the 120 day study
period; n=4.</p></td>
<td colspan="2"><p>11 healthy men, ages 20 – 40 years.</p>
<p>All non-smoking and nondrug users. All subjects were immunized on day
85 with a trivalent 1995-96 influenza vaccine. The subjects lived at the
Metabolic Research Unit of the Western Human Nutrition Research Center
for the duration of the study, except for daily walks or other scheduled
outings. They consumed only those foods prepared by the staff and were
under constant supervision.</p></td>
<td colspan="2"><p><u>NK cell activity:</u> DHA feeding for 83 days
(study day 113) caused a 20% in NK cell activity compared to the
activity before DHA treatment (p = 0.004). This effect was not seen
within the first 55 days (study day 85; p = 0.82). NK activity for the
control group did not change throughout the study.</p>
<p><u>Secretion of proinflammatory cytokines:</u> DHA feeding caused a
NS in the secretion of both IL-1 and TNF within 55 days (study day 85)(p
= 0.093 and 0.31, respectively). With continued feeding of DHA, the
secretion of these cytokines continued to , and by the end of the study
their concentrations were by 40-45% as compared to the concentrations
before DHA was fed (p = 0.0004 and 0.0002), respectively. In the control
group, the secretions of these 2 cytokines did not change during the
study.</p>
<p><u>Serum influenza Ab titers:</u> The preimmunization (day 30) and
post immunization (day 113) Ab titers against A/Texas, A/Johannesburg
and B/Harbin strains of influenza virus were not significantly different
between the 2 groups. The differential between the 2 dietary groups
after A/Texas immunization was almost statistically significant (p =
0.059).</p>
<p><u>Eicosanoid secretion:</u> when compared to day 30, DHA feeding
caused a 60-75% in concentrations of PGE2 and LTB4 secreted into the
tissue culture media by PBMNC stimulated with LPS (p&lt;0.01).
Eicosanoids secreted by the control group did no change during the
study.</p>
<p>PBMNC FA composition on day 30 was not different between the 2
dietary groups. Dietary DHA the concentration of DHA in PBMNC from 2.3
wt% on day 30 to 7.4 wt% on day 113. The AA content of PBMNC from 19.8
to 10.7 wt% with DHA feeding. The EPA concentration did not change, nor
did the concentration of major FAs in the PBMNC from control group (data
not given).</p></td>
</tr>
<tr class="odd">
<td colspan="2"><p>Meydani et al. 1993</p>
<p>The Journal of Clinical Investigation</p>
<p>1993;2:105-113</p>
<p>[U.S.]</p></td>
<td colspan="2">To investigate the effect of reductions in dietary fat,
saturated fat and cholesterol, as well as increased fish intake on human
cytokine production and immune response.</td>
<td colspan="2">Controlled trial</td>
<td colspan="2">24 week treatment period following a 6 week run-in
period. Subjects could take up to a 4 week break between run in and
treatment</td>
<td colspan="2"><p>1.23 g/day EPA+DHA (high fish intake diet)</p>
<p>control group: low fish intake diet which provided 0.27 g/day
EPA+DHA</p>
<p>Compliance:</p>
<p>Fatty acid profile</p></td>
<td colspan="2"><p>21 normolipidemic and normotensive volunteers (11
female, 11 male). Subjects had no evidence of any chronic illness
including endocrine, hepatic, renal, thyroid, or cardiac dysfunction.
Subjects were not on medications which might effect lipid levels, and
none smoked.</p>
<p>Treatment group: 10 individuals (including 3 who had participated in
the control group previously)</p>
<p>Control group: 11 individuals.</p></td>
<td><p><u>PGE<sub>2</sub></u>: ↓ in production, both spontaneous and PHA
(10 and 100ug/ml) stimulated cultures showed reductions (79, 63 and 68%
respectively) however, only the l00 μg/ml stimulated culture change was
statistically significant (p=0.02) compared to baseline.</p>
<p><u>IL-1β:</u> ↓ production (40%, p=0.07 using LPS stimulation and
25%, p=0.3 using <em>Staphylococcus epidermis</em> (S. epi) stimulation)
compared to baseline.</p>
<p><u>TNF:</u> ↓ production using S. epi stimulation (35%, p=0.08)
compared to baseline.</p>
<p><u>IL-6:</u> ↓ production (34%, p=0.03) compared to baseline.</p>
<p><u>Il-2:</u> no significant change from baseline.</p>
<p><u>White blood cells</u>: An analysis of 5 subjects indicated a
significant ↓ in CD4+ cells and an ↑ in CD8+ cells (p&lt;0.005 and
p&lt;0.006, respectively) compared to baseline.</p>
<p><u>Delayed skin hypersensitivity</u>: induration period significantly
↓ (45%, p=0.009) compared to baseline and compared to control (50%,
p=0.01).</p>
<p><u>T cell mitogens Con A</u>: response was ↓ (24%, p=0.03) compared
to baseline and compared to control (56%, p=0.057).</p>
<p><u>T cell mitogens PHA</u>: response was ↓ (30%, p=0.1) compared to
baseline and compared to control (53%, p=0.002).</p>
<p>Significant ↑ in EPA and DHA (313% and 73%, respectively, p=0.0001)
in plasma.</p></td>
</tr>
<tr class="even">
<td colspan="2"><p>Mori et al. 1992</p>
<p><em>Metabolism</em> 1992;41(10):1059-1067</p>
<p>[U.S.]</p></td>
<td colspan="2">To examine and compare the effects of supplementing the
existing diet with fish oil or olive oil on lipids and cell function in
patients with peripheral vascular disease.</td>
<td colspan="2"><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td colspan="2">4 weeks</td>
<td colspan="2"><p>4.6 g/d EPA+DHA</p>
<p>2.8 g/d EPA</p>
<p>1.8 g/d DHA</p>
<p>(MasEPA capsules)</p>
<p>Control: olive oil</p>
<p>Compliance:</p>
<p>capsule count, serum FAs analysis</p></td>
<td colspan="2"><p>29 males w/ angiographically demonstrated peripheral
vascular disease, recruited by referral from major teaching hospitals
and general practitioners.</p>
<p>Test: 15</p>
<p>Control: 14</p>
<p>No dropouts after study initiation.</p></td>
<td><p><u>TXB2:</u> NS fish oil</p>
<p><u>LTB4:</u></p>
<p><u>LTB5:</u></p>
<p><u>Neutrophil PAF:</u> NS</p>
<p><u>Plasma lyso-PAF:</u> NS</p></td>
</tr>
<tr class="odd">
<td><p>Nilsen et al. 1993</p>
<p>Thrombosis and Haemostasis</p>
<p>1993;70(6):900-902</p>
<p>[Norway]</p></td>
<td colspan="2">This study “was designed to evaluate whether
preoperative loading with n-3 fatty acids might modify the postoperative
acute phase changes in monocyte-reactivity, tissue factor pathway
inhibitor and tissue plasminogen activator inhibitor.”</td>
<td colspan="2">Randomized, double-blind, controlled trial.</td>
<td colspan="2">10 weeks (67 30 days) for treatment group and 12 weeks
(85 23 days) for control group prior to surgery</td>
<td colspan="2"><p>5.1 g/day EPA+DHA (Pronova fish oil capsules, 6 g/day
total oil)</p>
<p>control group: 6 g/day corn oil</p>
<p>Compliance:</p>
<p>Serum phospholipid FA analysis.</p></td>
<td colspan="2"><p>20 patients with CHD and elevated serum lipids prior
to coronary bypass surgery. Patients on oral anticoagulants were
excluded from the trial</p>
<p>Fish oil group: 10 patients</p>
<p>Control group: 10 patients</p>
<p>The treatment was discontinued prior to surgery.</p></td>
<td colspan="2"><p><u>Thromboplastin synthesis</u>: LPS stimulated
thromboplastin synthesis significantly in the fish oil group (99%,
p=0.01) and the control group 44% (p=0.02) compared to baseline. The
synthesis further by 83% in the fish oil group and 169% in the control
group one week after the surgery. In the control group thromboplastin
activity in the unstimulated cells one week after the surgery.</p>
<p><u>TxB<sub>2</sub></u>: release from platelets after LPS stimulation
was not significantly changed in either group during the preoperative
period compared to baseline.</p>
<p><u>Fibrinogen</u>: no significant change with fish oil compared to
baseline or control group during preoperative period. Significant in
both groups postoperatively, but no differences between the groups.</p>
<p><u>TFP1</u>: no significant change with fish oil compared to baseline
or control group during preoperative period. NS ↓ in both groups during
the postoperative period.</p>
<p><u>TAT</u>: no significant change with fish oil compared to baseline
or control group during preoperative period. Significant in both groups
postoperatively, but no differences between the groups.</p>
<p><u>PAI</u>: no significant change with fish oil compared to baseline
or control group during preoperative period. Significant in both groups
postoperatively, but no differences between the groups.</p>
<p>Serum phospholipid EPA tripled with fish oil
supplementation.</p></td>
</tr>
<tr class="even">
<td><p>Osterud et al. 1995</p>
<p><em>Lipids</em> 1995. 30:1111-1118</p>
<p>[Norway]</p></td>
<td colspan="2">To assess the effects of supplemental intake of various
marine oils known to be part of the Eskimo diet in changing biological
parameters that might be important in explaining their low incidence of
coronary heart disease</td>
<td colspan="2">Randomized, parallel, controlled</td>
<td colspan="2">10 weeks</td>
<td colspan="2"><p>Not quantified.</p>
<p>15 ml/day Harp seal blubber oil, cod liver oil, oil from blubber of
Minke whales, seal blubber oil/ cod liver oil</p>
<p>(Minke whale oil: 12.2 % w/w EPA + DHA</p>
<p>Harp seal oil:</p>
<p>17.9 % w/w EPA + DHA</p>
<p>Cod liver oil:</p>
<p>22.6 % w/w EPA + DHA)</p>
<p>Control: no oil</p>
<p>Compliance: Serum phospholipid FA analysis</p></td>
<td colspan="2"><p>134 healthy subjects</p>
<p>age range: 18-60 years (mean age: 29 years)</p>
<p>72 male/62 female</p>
<p>Seal oil: n=27</p>
<p>Cod liver oil: n=26</p>
<p>Seal/Cod liver oil: n=27</p>
<p>Whale oil: n=26</p>
<p>Control: n=28</p></td>
<td colspan="2"><p><u>LPS-induced TNF- activity in monocytes of whole
blood</u>: significantly in whale oil group; NS in seal/cod liver oil
group</p>
<p><u>LPS-induced TF activity in monocytes of whole blood</u>:
significantly in seal/cod liver oil and whale oil groups; NS in all
other groups</p>
<p><u>Thromboxane B<sub>2</sub></u>: significantly (-43.7%) in whale oil
group (p&lt;0.01); NS in all other fish oil groups</p>
<p>Serum levels of EPA and DHA were significantly increased in all fish
oil groups.</p></td>
</tr>
<tr class="odd">
<td><p>Schmidt et al. 1996</p>
<p>Scand J Clin Lab Invest</p>
<p>1996;56:87-92</p>
<p>[Denmark]</p></td>
<td colspan="2">To examine the effect of a very low dose of n-3 FAs on
monocyte function in healthy humans.</td>
<td colspan="2">Double-blind, randomized and placebo-controlled</td>
<td colspan="2">12 weeks</td>
<td colspan="2"><p>0.5 g/d EPA + DHA (given as one capsule of
re-esterified triglyceride fish oil concentrate containing 0.65 g on n-3
PUFA; EPAX 5500).</p>
<p>Placebo was a mixture of fat approximating the FA content of the
average Danish diet. Capsules (1/d) were given with the evening
meal.</p>
<p>Compliance:</p>
<p>FA composition measured in monocytes.</p></td>
<td colspan="2"><p>32 healthy men (n = 15, age 27-49) and women (n = 17,
age 24-52). Subjects were free of medication, aspirin and other
non-steroidal anti-inflammatory drugs were not allowed for 2 weeks
before inclusion and during the whole study period.</p>
<p>Two groups:</p>
<ol type="1">
<li><p>placebo control</p></li>
<li><p>n-3 PUFA</p></li>
</ol>
<p>Participants were paired (one from control group and one from n-3
group) and each pair was examined on the same day to avoid day-to-day
variability.</p></td>
<td colspan="2"><p>No effects of n-3 PUFAs was observed on monocyte
chemotaxis and chemiluminesence, or on the production of leukotriene
B<sub>4</sub>, IL-6, TNF or IL-6 from stimulated monocytes.</p>
<p>EPA levels significantly (p&lt;0.001) in monocytes in subjects
randomized to n-3 PUFA group. DHA and DPA levels in monocyte membranes
after n-3 PUFA, but the changes in these two long-chain n-3 PUFAs were
not significantly different from baseline or from controls.</p></td>
</tr>
<tr class="even">
<td><p>Schmidt et al., 1992b</p>
<p>Scand J. Clin. Lab. Invest.</p>
<p>1992;52:229-236</p>
<p>[Denmark]</p></td>
<td colspan="2">To examine the effect of supplementation with n-3 PUFA
for 9 months on neutrophil and monocyte chemotaxis.</td>
<td colspan="2">Clinical trial</td>
<td colspan="2">36 weeks (9 months)</td>
<td colspan="2"><p>3.2 g/d EPA+DHA (4 g/d n-3 FAs, Pikasol fish oil
capsules)</p>
<p>2.04 g/day EPA</p>
<p>1.14 g/day DHA</p>
<p>Compliance:</p>
<p>EPA and DHA platelet fatty acid composition.</p></td>
<td colspan="2"><p>24 healthy volunteers (14 female, 10 males)</p>
<p>All subjects were free of medication, including aspirin, and
non-steroidal anti-inflammatory drugs for at least two weeks prior to
the study.</p>
<p>Participants maintained normal dietary and life-style
patterns.</p></td>
<td colspan="2"><p><u>Neutrophil chemotaxis</u>: spontaneous migration
significantly ↓ after 39 weeks (p &lt;0.01). Directed migration was
significantly inhibited towards two types of chemoattractants
(autologous serum and n-formyl-methionyl-leucylphenylalanine (FMLP)
(p&lt;0.01)). Neutrophil chemotactic responsiveness was decreased
towards autologous serum (p&lt;0.01) after 6 weeks and 9 months, but
unchanged with respect to FMLP.</p>
<p><u>Cell density</u>:</p>
<p>NS change.</p>
<p><u>Monocyte chemotaxis</u>: Significantly ↓ (p&lt;0.01) using both
autologous serum and FMLP.</p></td>
</tr>
<tr class="odd">
<td><p>Seljeflot et al. 1998</p>
<p><em>Eur Clin Invest</em> 1998;28:629-635</p>
<p>[Norway]</p></td>
<td colspan="2">To determine the effects of n-3 FAs and/or antioxidants
on some biochemical markers of vascular endothelial function such as
sTM, vWF, tPAag, soluble forms of E-selectin, P-selectin and vascular
cell adhesion molecule 1 (VCAM-1) in hyperlipidemic men.</td>
<td colspan="2">Randomized, double-blind, placebo-controlled, two-by-two
factorial design.</td>
<td colspan="2">6 weeks</td>
<td colspan="2"><p>4.8 g/d EPA + DHA (n-3 FA)</p>
<p>n-3 placebo (n-placebo)</p>
<p>antioxidant (vitamin E, C and β carotene)</p>
<p>antioxidant placebo (a-placebo)</p>
<p>The subjects received either</p>
<p>n-3 + a-placebo, n-3 + antioxidant, n-placebo + antioxidant or</p>
<p>n-placebo + a-placebo</p>
<p>Compliance:</p>
<p>FA analysis in serum phospholipids</p></td>
<td colspan="2"><p>41 men were recruited from the population attending
the screening program for risk of CHD. The subjects were divided into
n-3 or placebo group and then within each group they were subdivided
into antioxidant or a-placebo group (4 groups).</p>
<p>n-3 group: n=22</p>
<p>antioxidant group: n=19</p>
<p>41 subjects of the 42 completed the study. One subject dropped out
because of the onset of non-fatal MI.</p></td>
<td colspan="2"><p><u>sTM:</u> Significant ↓ with n-3 FA compared to
n-placebo (p&lt;0.001). ↓ more with a-placebo vs. antioxidant
supplementation (p=0.04).</p>
<p><u>tPAag:</u> No difference in the changes between n-3 and n-placebo
groups. No difference with antioxidant supplementation vs.
a-placebo.</p>
<p><u>VCAM-1:</u> Significant ↑ with n-3 FA (p=0.010). No difference
with antioxidant supplementation vs. a-placebo.</p>
<p>E-selectin: Significant ↑ with n-3 FA (p=0.001).</p>
<p>P-selectin: No difference in the changes between n-3 and n-placebo
groups.</p></td>
</tr>
<tr class="even">
<td><p>Seljeflot et al. 1999</p>
<p><em>Thrombosis and Hemostasis</em> 1999. 81:566-570</p>
<p>[Norway]</p></td>
<td colspan="2"><p>To investigate the effect of n-3 fatty acid
supplementation on LPS induced production and release of markers of
thrombin generation (procoagulant activity) and markers of inflammation
(cytokines and TNF) in whole blood cultures from patient with
atherosclerosis.</p>
<p>To look for differences between groups at baseline and possible
alleviation of such differences after 4 weeks of
supplementation.</p></td>
<td colspan="2">Randomized, double-blind, controlled</td>
<td colspan="2"><p>4 weeks</p>
<p>6 month pre- study period</p>
<p>baseline measurements taken after 6 month pre- study period</p></td>
<td colspan="2"><p>5.1 g/day of highly concentrated ethyl esters of
fatty acids (ratio of EPA to DHA was 2:1)</p>
<p>Prior to this study, subjects in the fish oil group received fish oil
(same dose as above) and subjects in placebo group received placebo for
6 months.</p>
<p>In this study, subjects from both groups (11 from fish oil, 12 from
placebo group) received fish oil for 4 weeks.</p>
<p>Compliance: serum phospholipids</p></td>
<td colspan="2"><p>23 subjects with atherosclerosis but without clinical
symptoms</p>
<p>7 male/16 female</p>
<p>age range: 43-75 years</p>
<p>All subjects received fish oil.</p></td>
<td colspan="2"><p>Lipopolysaccharide-induced production of inflammatory
markers (measured as):</p>
<p><u>Interleukin-1</u>: NS difference at baseline or 4 weeks</p>
<p><u>Interleukin-6</u>: in group I at baseline compared to group II
(p=0.053); NS difference between groups at 4 weeks; changes from
baseline between groups significant (p=0.001)</p>
<p><u>Tumor necrosis factor</u> : in group I at baseline compared to
group II (p=0.047); NS difference between groups at 4 weeks; changes
from baseline between groups significant</p></td>
</tr>
<tr class="odd">
<td><p>Turini et al. 1994</p>
<p><em>Am. J. Clin. Nutr.</em> 1994. 60:717-724</p>
<p>[Canada]</p></td>
<td colspan="2">To compare the effect of dietary supplementation with a
liquid formula containing fish oil or vegetable oil on platelet
aggregation, ethanolamine-containing lysophospholipid generation in
stimulated platelets, and leukotriene production in stimulated
neutrophils</td>
<td colspan="2">Randomized, parallel, controlled</td>
<td colspan="2">6 weeks</td>
<td colspan="2"><p>4.5 g/day EPA + DHA from 8 oz bottled liquid formula
of fish oil (sardine oil)</p>
<p>Control: 13.8 g/day vegetable oil (mixture of high oleic acid (6.3 g)
safflower and soy oil)</p>
<p>Compliance: phospholipid FA analysis</p></td>
<td colspan="2"><p>20 healthy male subjects</p>
<p>average age: 26 years for controls; 27 years for fish oil
subjects</p>
<p>Fish oil: n=10</p>
<p>Control: n=10</p></td>
<td colspan="2"><p><u>Leukotriene B<sub>4</sub> production by stimulated
neutrophils</u>: significantly in fish oil group (-41%)</p>
<p><u>5-Hydroxyeicosatetraenoic acid (HETE) production by stimulated
neutrophils</u>: significantly in fish oil group (-30%)</p>
<p>Fish oil supplementation also resulted in increased concentrations of
leukotriene B<sub>5</sub> and 5-hydroxyeicosapentaenoic acid (HEPE);
concentrations of these products were not detected before treatment and
vegetable oil had no effect on their production.</p></td>
</tr>
<tr class="even">
<td><p>Wallace et al. 1995</p>
<p><em>Thromb Vasc Biol</em> 1995;15:185-189</p>
<p>[Northern Ireland]</p></td>
<td colspan="2">To determine the effect of low dose of fish oil
supplementation on cytokines and white cell function in women.</td>
<td colspan="2">Double-blind trial.</td>
<td colspan="2"><p>4 weeks of treatment</p>
<p>9 weeks post-treatment washout period</p></td>
<td colspan="2"><p>0.72 g/d EPA + DHA (2.4 g/d fish oil containing 18%
DHA and 12% EPA, 0.432 g/d DHA and 0.288 g/d EPA)</p>
<p>Fish oil group</p>
<p>Fish oil + vitamin E group</p>
<p>Compliance:</p>
<p>interview</p></td>
<td colspan="2"><p>33 healthy non-smoking females were recruited. They
were not on any prescribed medication or nutritional supplements.</p>
<p>Fish oil group: n=16</p>
<p>Fish oil + vitamin E group: n=17</p></td>
<td colspan="2"><u>Mean peroxidase index:</u> ↑ significantly with fish
oil (10.0 ± 2.0, p≤0.01) and fish oil + vitamin E (-1.2 ± 1.7, p≤0.001)
supplements after 4 weeks compared to initial values (fish oil: –3.9 ±
2.3, fish oil + vitamin E: –5.4 ± 1.8 ng/l). At the end of washout
period the levels had not returned to baseline but were not
significantly different from initial values. NS difference between the
groups.<u><br />
Myeloperoxidase:</u> ↓ significantly with fish oil (34.8 ± 3.4 μg/l,
p≤0.01) and fish oil + vitamin E (34.6 ± 7.4 μg/l, p≤0.05) supplements
after 4 weeks compared to initial values (fish oil 70.1 ± 9.8, fish oil
+ vitamin E 60.4 ± 11.7 μg/l). At the end of washout period the levels
↑, but did not return to baseline. NS difference between the
groups.</td>
</tr>
</tbody>
</table>

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