Krill Oil Original Research
`
`Evaluation of the Effects of
`Neptune Krill Oil on the Clinical Course
`of Hyperlipidemia
`
`Ruxandra Bunea, MD; Khassan El Farrah, MD, MSc;
`Luisa Deutsch, MD
`
`Abstract
`OBJECTIVE: To assess the effects of krill oil
`on blood lipids, specifically total cholesterol,
`triglycerides, low-density lipoprotein (LDL), and
`high-density lipoprotein (HDL). METHODS: A
`multi-center, three-month, prospective,
`randomized study followed by a three-month,
`controlled follow-up of patients treated with 1
`g and 1.5 g krill oil daily. Patients with
`hyperlipidemia able to maintain a healthy diet
`and with blood cholesterol levels between 194
`and 348 mg/dL were eligible for enrollment in
`the trial. A sample size of 120 patients (30
`patients/group) was randomly assigned to one
`of four groups. Group A received krill oil at a
`body mass index (BMI)-dependent daily
`dosage of 2-3 g daily. Patients in Group B were
`given 1-1.5 g krill oil daily, and Group C was
`given
`fish oil containing 180 mg
`eicosapentaenoic acid (EPA) and 120 mg
`docosahexaenoic acid (DHA) per gram of oil
`at a dose of 3 g daily. Group D was given a
`placebo containing microcrystalline cellulose.
`The krill oil used in this study was Neptune Krill
`Oil (NKO‚), provided by Neptune Technologies
`& Bioresources, Laval, Quebec, Canada.
`OUTCOME MEASURES: Primary parameters
`tested (baseline and 90-day visit) were total
`blood cholesterol, triglycerides, LDL, HDL, and
`glucose. RESULTS: Krill oil 1-3 g/day (BMI-
`dependent) was found to be effective for the
`reduction of glucose, total cholesterol,
`triglycerides, LDL, and HDL, compared to both
`fish oil and placebo. CONCLUSIONS: The
`
`results of the present study demonstrate within
`high levels of confidence that krill oil is effective
`for the management of hyperlipidemia by
`significantly reducing total cholesterol, LDL,
`and triglycerides, and increasing HDL levels.
`At lower and equal doses, krill oil was
`significantly more effective than fish oil for the
`reduction of glucose, triglycerides, and LDL
`levels.
`(Altern Med Rev 2004;9(4):420-428)
`
`Introduction
`The balance of polyunsaturated essential
`fatty acids (PUFAs) in the body is critical for the
`maintenance of healthy cell membranes and hor-
`mone regulation. During the last few decades the
`fatty acid content of the U.S. diet has shifted so it
`now contains much higher levels of omega-6 and
`less omega-3 fatty acids. When long-chain omega-
`6 fatty acids predominate in the phospholipids of
`cell membranes, the production of pro-inflamma-
`tory type-2 prostaglandins (PGs) and type-4
`leukotrienes (LTs) are encouraged; whereas, the
`presence of omega-3 fatty acids promotes the pro-
`duction of anti-inflammatory PGs and LTs.1,2
`
`Ruxandra Bunea, MD – Assistant Professor, Department of
`Internal Medicine, McGill University; Riverview Medical
`Center, Montreal, Quebec, Canada.
`Correspondence address: 1586 Ave des Pins O. #302,
`Montreal, Quebec, Canada H3G 1B4.
`
`Khassan El Farrah, MD, MSc – JSS Medical Research,
`Montreal, Quebec, Canada.
`
`Luisa Deutsch, MD – JSS Medical Research, Montreal,
`Quebec, Canada.
`
`RIMFROST EXHIBIT 1020 page 0001
`Page 420 Alternative Medicine Review ◆ Volume 9, Number 4 ◆
` 2004
`Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`

`

`Original Research Krill Oil
`
`Omega-6 fatty acids, mainly arachidonic
`acid, have been shown to initiate an inflamma-
`tory process by triggering a flux of inflammatory
`PGs and LTs.3,4 Omega-3 fatty acids, mainly
`eicosapentaenoic acid (EPA) and docosahexaenoic
`acid (DHA), compete with the omega-6 species
`for the enzyme prostaglandin synthetase. Omega-
`3 fatty acids trigger secretion of less potent 5-se-
`ries LTs and anti-inflammatory PGs of the 3 se-
`ries (PE3, PI3 and thromboxanes-A3).4-9 Conse-
`quently, supplementation with EPA and DHA pro-
`motes the production of less potent PGs and LTs,
`resulting in a decrease in the formation of inflam-
`matory mediators.10-13
`The exact mechanism of action by which
`omega-3 fatty acids favorably modify cardiovas-
`cular disease and associated disorders is not yet
`fully confirmed. Evidence suggests an increased
`intake of EPA and DHA results in an increase of
`EPA and DHA in tissue, cellular lipids, and circu-
`latory lipids.14 In parallel, they result in a simulta-
`neous reduction of omega-6 fatty acids in the
`body.14 This fatty acid shift is predominantly
`marked in cell membrane-bound phospholipids
`and results in alteration of the physicochemical
`properties of cell membranes. This favorably
`modifies cellular functions, including cell signal-
`ing, gene expression, biosynthetic processes, and
`eicosanoid formation.15
`Human studies have revealed the ability
`of EPA and DHA to significantly reduce circulat-
`ing levels of blood triglyceride and very low-den-
`sity lipoprotein (VLDL), which have been asso-
`ciated with increased risk of cardiovascular dis-
`ease.16,17
`Krill oil is extracted from Antarctic krill,
`Euphausia superba, a zooplankton crustacean rich
`in phospholipids carrying long-chain omega-3
`PUFAs, mainly EPA and DHA. Krill oil also con-
`tains various potent antioxidants, including vita-
`mins A and E, astaxanthin, and a novel flavonoid
`similar to 6,8-di-c-glucosylluteolin, but with two
`or more glucose molecules and one aglycone.
`Krill oil has a unique biomolecular pro-
`file of phospholipids naturally rich in omega-3
`fatty acids and diverse antioxidants significantly
`different from the usual profile of fish oils. The
`association between phospholipids and long-chain
`
`omega-3 fatty acids highly facilitates the passage
`of fatty acid molecules through the intestinal wall,
`increasing bioavailability and ultimately improv-
`ing the omega-3:omega-6 fatty acid ratio.18,19
`
`Materials and Methods
`A 12-week, double-blind, randomized
`trial was conducted comparing krill oil to high EPA
`and DHA (3:2 ratio) fish oil and placebo. Eligible
`patients were 18-85 years and had at least a six-
`month diagnosis of mildly high to very high blood
`cholesterol (193.9-347.9 mg/dL) and triglyceride
`levels (203.8-354.4 mg/dL). Patients with famil-
`ial hypercholesterolemia, severely high cholesterol
`(>349 mg/dL), pregnancy, known or suspected
`allergy to fish or seafood, known alcohol or drug
`abuse within the previous year, known
`coagulopathy or receiving anticoagulant therapy,
`or co-morbidity that would interfere with study
`results were excluded from the study.
`
`Enrolled patients were randomly assigned
`to one of four groups:
`▲ Group A: Krill oil (2-3 g once daily)
` Body Mass Index (BMI) < 30 – 2 g/day
` BMI > 30 – 3 g/day
`
`▲ Group B: Krill oil (1-1.5 g once daily)
` BMI < 30 – 1 g/day
` BMI > 30 – 1.5 g/day
` Follow-up 500 mg/day for 90 days
`
`▲ Group C: Fish oil (3:2) containing 180 mg
` EPA and 120 mg DHA per gram (3 g
` once daily)
`
`▲ Group D: placebo (3 g once daily)
`
`Patients were allowed to continue lipid-
`lowering medications at the usual daily dose and
`asked to report any change in dosage. Natural
`health products were discontinued for a two-week
`washout period prior to study initiation and there-
`after for the study duration. Patients were asked
`to record concomitant medications taken daily.
`
`RIMFROST EXHIBIT 1020 page 0002
`Alternative Medicine Review ◆ Volume 9, Number 4 ◆
` 2004 Page 421
`Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`

`

`Krill Oil Original Research
`
`Table 1. Results of Krill Oil (1.0 g/day) on Lipids
`
`1.0 g Krill Oil
`
`Time (d)/mg/dL
`
`0.00
`
`90.00
`
`% Change
`
`p-value
`
`Total Cholesterol
`
`235.83
`
`204.12
`
`-13.44%
`
`LDL
`
`HDL
`
`167.78
`
`114.05
`
`-32.03%
`
`57.22
`
`82.35
`
`43.92%
`
`Triglycerides
`
`120.50
`
`107.21
`
`-11.03%
`
`0.000
`
`0.000
`
`0.000
`
`0.114
`
`Table 2. Results of Krill Oil (1.5 g/day) on Lipids
`
`1.5 g Krill Oil
`
`Time (d)/mg/dL
`
`0.00
`
`90.00
`
`% Change
`
`p-value
`
`Total Cholesterol
`
`231.19
`
`199.49
`
`-13.71%
`
`LDL
`
`HDL
`
`164.74
`
`105.93
`
`-35.70%
`
`58.76
`
`83.89
`
`42.76%
`
`Triglycerides
`
`126.70
`
`111.64
`
`-11.89%
`
`0.000
`
`0.000
`
`0.000
`
`0.113
`
`Statistical
`Rationale
`and Analysis
`A sample
`size of 120 pa-
`tients (30 pa-
`tients/group) pro-
`vided 90-percent
`power to detect a
`1 5 - p e r c e n t
`change in total
`cholesterol from
`baseline to three
`months.
`
`Wi t h i n -
`group differences
`r e f l e c t i n g
`changes over time
`for the same pa-
`tient were as-
`sessed for statisti-
`cal significance
`with the Paired
`Student’s t-test.
`Between-group
`differences were
`assessed with
`planned compari-
`sons of one-way
`analysis of vari-
`ance.
`
` The primary parameters tested were
`blood glucose, cholesterol, triglycerides, low-den-
`sity lipoprotein (LDL), and high-density lipopro-
`tein (HDL). Fasting blood lipids and glucose were
`analyzed at baseline as well as 30 and 90 days
`after study initiation for all groups, and at 180 days
`for the 30 patients in Group B.
`
`Results
`One-hun-
`dred-twenty patients with a mean age of 51 years
`(standard deviation 9.46) and ranging between 25
`and 75 years were enrolled in the trial. BMI, a
`tool indicating weight status in adults, was calcu-
`lated according to the metric formula ([weight in
`kilograms/(height in centimeters) x (height in cen-
`timeters)] x 10,000).20,21 Of the 120 patients en-
`rolled, 30 (25%) had moderate-to-severe obesity,
`with a BMI higher than 30. Sixty-four (53%) sub-
`jects were overweight, and 26 (22%) were nor-
`mal weight, with a BMI between 25 and 30 and
`lower than 25, respectively. Women had a higher
`
`RIMFROST EXHIBIT 1020 page 0003
`Page 422 Alternative Medicine Review ◆ Volume 9, Number 4 ◆
` 2004
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`
`

`

`Original Research Krill Oil
`
`Table 3. Results of Krill Oil (2.0 g/day) on Lipids
`
`2 g Krill Oil
`
`Total Cholesterol
`
`LDL
`
`HDL
`
`Triglycerides
`
`Time (d)/mg/dL
`
`0.00
`
`90.00
`
`% Change
`
`p-value
`
`247.42
`
`202.58
`
`-18.13%
`
`182.86
`
`114.43
`
`-37.42%
`
`51.03
`
`79.25
`
`55.30%
`
`160.37
`
`116.07
`
`-27.62%
`
`0.000
`
`0.000
`
`0.000
`
`0.025
`
`BMI
`mean
`(28.2±5.1) com-
`pared
`to men
`(25.4±3.9) (p<0.001).
`A m o n g
`the 60 patients in
`the two groups re-
`ceiving krill oil,
`42 (70%) had a
`BMI of 30 or less.
`In Group A, 19
`patients received
`2 g krill oil daily
`and the remaining
`11 received 3 g
`daily. In Group B,
`23 patients were
`treated with a
`daily dose of 1 g
`krill oil and 7 with
`1.5 g. All patients
`in Group B con-
`tinued for an addi-
`tional 90 days
`with a mainte-
`nance dose of 500
`mg krill oil daily.
`Baseline
`analysis of demo-
`graphic criteria,
`laboratory data in-
`cluding total cho-
`lesterol and trig-
`lyceride levels,
`comorbidity, and
`c o n c o m i t a n t
`medication at baseline showed no significant dif-
`ferences among the four groups (p=0.102-0.850).
`After 12 weeks of treatment, patients re-
`ceiving 1 or 1.5 g krill oil daily had a 13.4-per-
`cent and 13.7-percent decrease in mean total cho-
`lesterol, from 236 mg/dL and 231 mg/dL to 204
`mg/dL (p=0.000) and 199 mg/dL (p=0.000), re-
`spectively (Tables 1 and 2). The group of patients
`treated with 2 or 3 g krill oil showed a significant
`respective reduction in mean total cholesterol of
`18.1 and 18 percent. Levels were reduced from a
`
`Table 4. Results of Krill Oil (3.0 g/day) on Lipids
`
`3 g Krill Oil
`
`Total Cholesterol
`
`LDL
`
`HDL
`
`Triglycerides
`
`Time (d)/mg/dL
`
`0.00
`
`90.00
`
`% Change
`
`p-value
`
`250.52
`
`205.67
`
`-17.90%
`
`172.81
`
`105.16
`
`-39.15%
`
`64.18
`
`102.45
`
`59.64%
`
`152.77
`
`112.27
`
`-26.51%
`
`0.000
`
`0.000
`
`0.000
`
`0.028
`
`baseline of 247 mg/dL and 251 mg/dL to 203 mg/
`dL (p=0.000) and 206 mg/dL (p=0.000), corre-
`spondingly (Tables 3 and 4). In comparison, people
`receiving 3 g fish oil had a mean reduction in to-
`tal cholesterol of 5.9 percent, from a baseline 231
`mg/dL to 218 mg/dL (p=0.000) (Table 5). Those
`enrolled in the placebo group showed a 9.1-per-
`cent increase in mean total cholesterol, from 222
`mg/dL to 242 mg/dL (p=0.000) (Table 6).
`
`RIMFROST EXHIBIT 1020 page 0004
`Alternative Medicine Review ◆ Volume 9, Number 4 ◆
` 2004 Page 423
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`
`

`

`Krill Oil Original Research
`
`Table 5. Results of Fish Oil (3.0 g/day) on Lipids
`
`(4.6%), with
`blood levels de-
`creased from 122
`mg/dL at baseline
`to 118 mg/dL
`(p=0.141) after 12
`weeks. Patients
`receiving placebo
`showed a nega-
`tive effect, with a
`13-percent
`in-
`crease in LDL
`levels, from 137
`mg/dL to 154 mg/
`dL (p=0.000).
`HDL was
`significantly in-
`creased in all pa-
`tients receiving
`krill oil (p=0.000)
`or
`fish
`oil
`(p=0.002). HDL
`levels increased
`from 57.2 mg/dL
`to 82.4 mg/dL
`(44% change) at
`krill oil 1 g/day;
`58.8 mg/dL to
`83.9 mg/dL (43%
`increase) for krill
`oil 1.5 g/day; 51
`mg/dL to 79.3
`mg/dL (55% in-
`crease) at krill oil
`2 g/day; and from
`64.2 mg/dL to
`102.5 mg/dL (59% increase) at a daily krill oil
`dose of 3 g. Fish oil taken at 3 g/day increased
`HDL from 56.6 mg/dL to 59.03 mg/dL (4.2% in-
`crease). No significant decrease of HDL (p=0.850)
`was observed within the placebo group, with lev-
`els of HDL remaining almost stable, 56.8 mg/dL
`to 56.7 mg/dL.
`Krill oil taken 1 g/day reduced blood
`triglycerides by a non-significant 11 percent, from
`120.5 mg/dL to 107.2 mg/dL (p=0.114). A daily
`dose of 1.5 g krill oil resulted in a non-significant
`
`% Change
`
`p-value
`
`0 0
`
`.141
`
`0.002
`
`0.239
`
`-5.88%
`
`-4.56%
`
`4.22%
`
`-3.15%
`
`% Change
`
`p-value
`
`9.06%
`
`13.03%
`
`4.00%
`
`-9.88%
`
`0.000
`
`0.000
`
`0.850
`
`0.215
`
`3 g Fish Oil
`
`Time (d)/mg/dL
`
`0.00
`
`90.00
`
`Total Cholesterol
`
`231.15
`
`217.55
`
`LDL
`
`HDL
`
`121.67
`
`117.83
`
`56.64
`
`59.03
`
`Triglycerides
`
`140.87
`
`136.44
`
`Table 6. Results of Placebo on Lipids
`
`Placebo
`
`Time (d)/mg/dL
`
`0.00
`
`90.00
`
`Total Cholesterol
`
`221.91
`
`242.01
`
`LDL
`
`HDL
`
`136.47
`
`154.25
`
`56.83
`
`56.70
`
`Triglycerides
`
`143.53
`
`129.36
`
`An analogous effect on LDL levels was
`observed in all groups. Krill oil at a daily dose of
`1 g, 1.5 g, 2 g, or 3 g achieved significant reduc-
`tions of LDL of 32, 36, 37, and 39 percent, re-
`spectively (p=0.000). Baseline levels were de-
`creased in the krill oil 1-g/day group from 168
`mg/dL to 114 mg/dL, in the 1.5-g/day group from
`165 mg/dL to 106 mg/dL, and in the 2- and 3-g/
`day groups from 183 mg/dL and 173 mg/dL to
`114 mg/dL and 105 mg/dL, respectively. The labo-
`ratory results of patients treated daily with 3 g fish
`oil did not achieve a significant reduction in LDL
`
`RIMFROST EXHIBIT 1020 page 0005
`Page 424 Alternative Medicine Review ◆ Volume 9, Number 4 ◆
` 2004
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`
`

`

`Original Research Krill Oil
`
`Table 7. Effect of a Lower Maintenance Dose of Krill Oil on Lipids
`
`Time (d)/mg/dL
`
`0.00
`
`180.00
`
`% Change
`
`p-value
`
`235.83
`
`192.53
`
`18.90%
`
`167.78
`
`107.47
`
`44.40%
`
`57.22
`
`120.50
`
`77.71
`
`89.89
`
`33.40%
`
`25.40%
`
`0.000
`
`0.000
`
`0.000
`
`0.025
`
`0.5 g krill oil daily (Table 7). These patients main-
`tained a mean total cholesterol level of 192.5 mg/
`dL, a reduction of 19 percent (p=0.000) from
`baseline. LDL was further reduced from baseline
`by 44 percent, a reduction from 233 mg/dL to
`107.5 mg/dL (p=0.000). A moderate decrease in
`HDL was seen, from 36 percent increase at 90 days
`to 33 percent after 180 days of treatment, which
`was still a significant increase from baseline
`(p=0.000). Triglycerides were slightly decreased
`further to a reduction of 25 percent from baseline
`(p=0.000), compared to the 12-percent reduction
`observed after 90 days of treatment. Blood glu-
`cose decreased by 6.6 percent from baseline
`(p=0.20), versus the 6.3-percent decrease at 90
`days.
`
`Discussion
`Arteriosclerosis is the generic term for a
`number of diseases in which arterial walls become
`thickened and lose elasticity, with atherosclerosis
`being considered the most important. With its ef-
`fects on the brain, heart, kidneys, and other vital
`organs and extremities, and despite medical ad-
`vancements, atherosclerotic heart disease and
`stroke combined remain the number one cause of
`morbidity and mortality in the United States,
`Canada, and most Western countries.22
`
`0.5 g Krill Oil
`
`Total Cholesterol
`
`LDL
`
`HDL
`
`Triglycerides
`
`1 1 . 9 - p e r c e n t
`reduction
`of
`t r i g l y c e r i d e s ,
`from 122.7 mg/dL
`to 112 mg/dL
`( p = 0 . 1 1 3 ) .
`Subjects achieved
`a
`significant
`reduction
`of
`triglycerides at
`daily doses of 2 g
`and 3 g daily krill
`oil – 28 percent
`(p=0.025) and 27
`percent (p=0.0228)
`– decreasing from
`baseline levels of
`160.4 mg/dL and
`152.8 mg/dL to 116.1 mg/dL and 112.3 mg/dL,
`respectively. Fish oil at 3 g/day did not achieve a
`significant reduction of triglycerides (3.2%),
`decreasing from 140.9 mg/dL to 136.4 mg/dL
`(p=0.239). Interestingly patients in the placebo
`group experienced a 9.8-percent decrease in
`triglycerides (p=0.215).
`Blood glucose levels were reduced by 6.3
`percent, from 105 mg/dL to 98 mg/dL (p=0.025),
`in patients receiving 1 g and 1.5 g krill oil daily,
`and 5.6 percent, from 92 mg/dL to 88 mg/dL
`(p=0.011), in those receiving 2 g and 3 g krill oil
`daily. A daily dose of 3 g fish oil reduced blood
`glucose by 3.3 percent, from 90 mg/dL to 87 mg/
`dL (p=0.275). Placebo treatment resulted in a non-
`significant blood glucose increase of 0.1 percent,
`from 92 mg/dL to 93 mg/dL (p=0.750).
`The between-group comparison showed
`1 g and 1.5 g krill oil daily was significantly more
`effective than 3 g fish oil in reducing glucose and
`LDL, whereas 2 g and 3 g krill oil demonstrated a
`significantly greater reduction of glucose, triglyc-
`erides, and LDL compared to 3 g fish oil. Both
`fish oil and krill oil performed significantly better
`than placebo for the regulation of glucose, trig-
`lycerides, total cholesterol, and HDL.
`As mentioned previously, patients receiv-
`ing 1 g and 1.5 g daily krill oil continued for an-
`other 12 weeks with a lower maintenance dose of
`
`RIMFROST EXHIBIT 1020 page 0006
`Alternative Medicine Review ◆ Volume 9, Number 4 ◆
` 2004 Page 425
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`
`

`

`Krill Oil Original Research
`
`In the United States, cardiovascular dis-
`ease has a mortality rate of 39.9 percent for males
`and 43.7 percent for females, a 15-21 percent dif-
`ference from malignant disease, which ranks sec-
`ond.22 It is estimated that 59.7 million Americans
`have one or more forms of cardiovascular dis-
`ease.22 Of the population with self-reported heart
`disease, 56-64 percent report restricted activity,
`23-37 percent require one or more disability days
`per week, and 28-34 percent are unemployed be-
`cause of disability or illness.22 The primary lesion
`of atherosclerosis is the fatty streak, which even-
`tually evolves into a fibrous plaque. Numerous
`randomized trials have proven that lowering se-
`rum cholesterol slows or reverses progression of
`coronary artery disease (CAD) and reduces coro-
`nary events.22-29
`A daily intake of 1-3 g EPA and DHA or
`3-9 g fish oil is currently recommended to reduce
`the risk of cardiovascular diseases.22,23 Neverthe-
`less, epidemiological studies evaluating the effects
`of fish oil on coronary heart disease are contra-
`dictory, ranging from reverse associations to vir-
`tually no effect to a beneficial effect.30-33 One is-
`sue in the efficacy of EPA/DHA may be the
`bioavailability of these fatty acids.
`A recent study demonstrated in vivo PUFA
`bioavailability depends on several factors, such
`as the type of lipids in which they are esterified,
`their physical state; i.e., lipid solution or colloidal
`particle systems, and the presence of co-ingested
`lipids.18 In vivo PUFA absorption was evaluated
`by fatty acid analysis of thoracic lymph of duct-
`cannulated rats after intragastric feeding of dietary
`fats.19 Evidence demonstrates oral essential fatty
`acid supplementation in the form of phospholip-
`ids is more effective than triglycerides in increas-
`ing concentrations of long-chain PUFAs in liver
`and brain.18,19 DHA is better absorbed when de-
`livered by liposomes than by fish oil (relative lym-
`phatic absorption equal to 91 percent and 65 per-
`cent after liposome and fish oil administration,
`respectively). The best bioavailability of DHA
`delivered by liposomes is revealed by an increase
`in DHA proportions in both lymphatic
`triacylglycerols and phospholipids, compared to
`a fish oil diet.18,19
`
`Krill oil is a complex combination of
`multiple active ingredients with synergistic bio-
`activity. The exact mechanism of action for krill
`oil’s lipid-lowering effects is not yet entirely clear.
`However, krill oil’s unique biomolecular profile
`of omega-3 (EPA/DHA) fatty acids already incor-
`porated into phospholipids has exhibited a lipid-
`lowering effect on the level of the small intestine,
`which distinguishes krill oil from other known
`lipid-lowering principals.18,19 Werner et al demon-
`strated essential fatty acids in the form of phos-
`pholipids were superior to essential fatty acids as
`triglycerides in significantly decreasing the satu-
`rated fatty acid ratios of liver triglycerides and
`phospholipids (each p < 0.05), while significantly
`increasing the phospholipid concentrations of the
`long-chain PUFAs (p < 0.05).19
`LDL oxidation is believed to increase ath-
`erosclerosis through high serum LDL levels in-
`ducing LDL particles to migrate into subendothe-
`lial space. The process by which LDL particles
`are oxidized begins with lipid peroxidation, fol-
`lowed by fragmentation to short-chain aldehydes.
`At the same time, lecithin is converted to lyso-
`lecithin, a selective chemotactic agent for mono-
`cytes, which become macrophages that ingest oxi-
`dized LDL. The new macrophage becomes en-
`gorged with oxidized LDL cholesteryl esters and
`becomes a foam cell. Groups of foam cells form a
`fatty streak, the earliest indication of atheroscle-
`rosis.34,35
`The unique molecular composition of krill
`oil, with its abundance of phospholipids and anti-
`oxidants, may explain the significant effect of krill
`oil for blood lipid regulation. In comparison to
`fish oil, krill oil significantly lowered blood lip-
`ids at lower doses.
`The effect of fish oil on cardiovascular
`disease is tempered by the presence of methyl-
`mercury in many fish.33 In fact, the U.S. Food and
`Drug Administration has advised pregnant women
`and women who may become pregnant not to eat
`swordfish, king mackerel, tilefish, shark, or fish
`from locally contaminated areas.36 Therefore, it
`may be prudent to obtain these essential fatty ac-
`ids via supplementation. Krill oil, and most fish
`oil concentrates, are molecularly distilled to re-
`move heavy metals.
`RIMFROST EXHIBIT 1020 page 0007
`Page 426 Alternative Medicine Review ◆ Volume 9, Number 4 ◆
` 2004
`Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`

`

`Original Research Krill Oil
`
`Conclusion
`Atherosclerotic cardiovascular disease is
`a major health problem in the Western world, with
`CAD being the leading cause of mortality in the
`United States. Extensive observational
`epidemiologic data strongly associate high CAD
`risk to elevated total and LDL cholesterol and low
`levels of HDL cholesterol. Extensive clinical trial
`evidence has established that favorably altering
`dyslipidemias produces clear improvements in
`CAD end points.15-17
`The results of this clinical trial demon-
`strate that daily doses of 1-3 g krill oil are signifi-
`cantly more effective than 3 g EPA/DHA fish oil
`in the management of hyperlipidemia. Further-
`more, a maintenance dose of 500 mg krill oil is
`significantly effective for long-term regulation of
`blood lipids. The unique molecular composition
`of krill oil, which is rich in phospholipids, omega-
`3 fatty acids, and diverse antioxidants, surpasses
`the profile of fish oils and offers a superior ap-
`proach toward the reduction of risk for cardiovas-
`cular disease.
`
`2.
`
`3.
`
`4.
`
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`Page 428 Alternative Medicine Review ◆ Volume 9, Number 4 ◆
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`Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`