Original Research Krill Oil & PMS
`
`Evaluation of the Effects of
`Neptune Krill Oil™ on the
`Management of Premenstrual Syndrome
`and Dysmenorrhea
`
`Fotini Sampalis, MD, PhD; Roxandra Bunea, MD;
`Marie France Pelland, MD; Odile Kowalski, MD;
`Natalie Duguet, MD; Sébastien Dupuis, BSc
`
`Abstract
`PRIMARY OBJECTIVE: To evaluate the
`effectiveness of Neptune Krill Oil™ (NKO™) for
`the management of premenstrual syndrome
`and dysmenorrhea. SECONDARY OBJECTIVE:
`To compare the effectiveness of NKO for the
`management of premenstrual syndrome and
`dysmenorrhea with that of omega-3 fish oil.
`METHODS/ DESIGN: Double-blind, random-
`ized clinical trial. SETTING: Outpatient clinic.
`PARTICIPANTS: Seventy patients of
`reproductive age diagnosed with premenstrual
`syndrome according to the Diagnostic and
`Statistical Manual of Mental Disorders, Third
`Edition, Revised (DSM-III-R). INTERVENTIONS:
`Treatment period of three months with either
`NKO or omega-3 fish oil. OUTCOME
`MEASURES: Self-Assessment Questionnaire
`based on
`the American College of
`Obstetricians & Gynecologists (ACOG)
`diagnostic criteria for premenstrual syndrome
`and dysmenorrhea and number of analgesics
`used for dysmenorrhea. RESULTS: In 70
`patients with complete data, a statistically
`significant improvement was demonstrated
`among baseline, interim, and final evaluations
`in the self assessment questionnaire (p<0.001)
`within the NKO group as well as between-
`group comparison to fish oil, after three cycles
`or 45 and 90 days of treatment. Data analysis
`showed a significant reduction of the number
`of analgesics used for dysmenorrhea within the
`
`NKO group (comparing baseline vs. 45- vs. 90-
`day visit). The between-groups analysis
`illustrated that women taking NKO consumed
`significantly fewer analgesics during the 10-
`day treatment period than women receiving
`omega-3 fish oil (p <0.03). CONCLUSION:
`Neptune Krill Oil can significantly reduce
`dysmenorrhea and the emotional symptoms of
`premenstrual syndrome and is shown to be
`significantly more effective for the complete
`management of premenstrual symptoms
`compared to omega-3 fish oil.
`(Altern Med Rev 2003;8(2)-171-179)
`
`Fotini Sampalis, MD, PhD – Associate Professor,
`Department of Experimental Surgery University of
`Montreal, Montreal, Quebec, Canada; Vice President of
`Research & Development at Neptune Technologies &
`Bioressources, Inc.
`Correspondence address: 1348 Elisabeth Blvd., Laval,
`Quebec H7W 3J8 Canada
`E-mail: tina.sampalis@sympatico.ca
`
`Roxandra Bunea, MD – Assistant Professor, Department of
`Internal Medicine, McGill University; Riverview Medical
`Center, Montreal, Quebec, Canada.
`
`Marie France Pelland, MD – Family Medicine & Obstetrics,
`CLSC Bordeau Cartierville, Department of Gynecology,
`Montreal, Quebec, Canada; Family Medicine & Obstetrics,
`Sacré-Coeur Hospital.
`
`Odile Kowalski, MD – Family Medicine & Obstetrics,
`Clinique l’Envolée, Montreal, Quebec, Canada.
`
`Natalie Duguet, MD – Family Medicine & Obstetrics,
`Clinique l’Envolée, Montreal, Quebec, Canada.
`
`Sébastien Dupuis, BSc - Project Manager, Neptune
`Technologies & Bioressources Inc., Laval, Quebec,
`Canada.
`
`RIMFROST EXHIBIT 1012 page 0001
`Alternative Medicine Review ◆ Volume 8, Number 2 ◆
` 2003 Page 171
`Copyright©2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`

`

`Krill Oil & PMS Original Research
`
`Table 1. Diagnostic Criteria for PMS
`
`A.
`
`B.
`
`In most menstrual cycles during the past year, symptoms occurred during the last
`week of the luteal phase and remitted within a few days after the onset of the
`follicular phase. In menstruating females, these phases correspond to the week
`before, and a few days after, the onset of menses. (In non-menstruating females
`who have had a hysterectomy, the timing of luteal and follicular phase may require
`measurement of circulating reproductive hormones.)
`
`At least five of the following symptoms have been present for most of the time
`during each symptomatic late luteal phase, at least one of the symptoms being
`either (1), (2), (3), or (4):
` 1. marked affective lability, e.g., feeling suddenly sad, tearful, irritable, or angry;
` 2. persistent and marked anger or irritability;
` 3. marked anxiety, tension, feelings of being "keyed up" or "on edge;"
` 4. decreased interest in usual activities, e.g., work, friends, hobbies;
` 5. easy fatigability or marked lack of energy;
` 6. subjective sense of difficulty in concentrating;
` 7. marked change in appetite, overeating, or specific food cravings;
` 8. hypersomnia or insomnia;
` 9. other physical symptoms, such as breast tenderness or swelling, headaches,
`
` joint or muscle pain, a sensation of "bloating," weight gain.
`
`C.
`
`The disturbance seriously interferes with work or with usual social activities or
`relationships with others.
`
`D.
`
`The disturbance is not merely an exacerbation of the symptoms of another
`disorder, such as major depression, panic disorder, dysthymia, or a personality
`disorder.
`Criteria A, B, C, and D are confirmed by prospective daily self-rating during at least
`two symptomatic cycles.
`
`From: Spitzer RL et al. Late luteal phase dysphoric disorder and DSM-III-R. Am J Psychiatry 1989; 146: 892-897.
`
`Introduction
`Premenstrual syndrome (PMS) and dys-
`menorrhea are characterized by a combination of
`cyclic symptoms that occur during the luteal phase
`of the menstrual cycle. Symptoms are practically
`absent in the follicular phase of the menstrual
`cycle, begin at varying points after ovulation, peak
`
`in the late luteal phase, and subside with the onset
`of menses or shortly thereafter. The diagnostic cri-
`teria based on the Diagnostic and Statistical
`Manual of Mental Disorders (DSM III-R), Third
`Edition, Revised are outlined in Table 1.1
`
`RIMFROST EXHIBIT 1012 page 0002
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` 2003
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`
`

`

`Original Research Krill Oil & PMS
`
`Multiple causes have been attributed to
`the complex interplay of neuroendocrine,
`chronobiological, and psychosocial interactions
`that comprise the symptomatology of PMS.2-8 A
`review reveals more than 200 symptoms that have
`been reported to occur premenstrually.2,7 Depend-
`ing on the symptom, the causative factors include
`hormonal imbalance, psychological abnormalities,
`nutritional deficiency or excess, increased inflam-
`matory prostaglandin synthesis, and neurotrans-
`mitter imbalance.2,8 Nevertheless, laboratory find-
`ings vary from being completely normal in some
`women to an excess or deficiency of certain hor-
`mones, neurotransmitters, or nutrients in others.
`The most probable cause of the physical symp-
`toms of PMS seems to be the combined interac-
`tion of hormones and essential nutrients leading
`to an increased inflammatory response. On the
`other hand, the emotional symptoms of PMS seem
`to be propagated by an exaggerated response of
`neurotransmitters to psychosocial stresses. These
`imbalances have been shown to differ extensively
`from person to person, as well as from cycle to
`cycle within the same person.
`Evidence suggests that alpha-tocopherol
`can significantly reduce symptoms of PMS.2,9-16
`Tocopherol reduces release of arachidonic acid
`from phospholipids, resulting in a decrease in for-
`mation of prostaglandin E2 (PGE2) (inflammatory
`prostaglandins).16 Alpha-tocopherol, which
`crosses the blood-brain barrier, also has modulat-
`ing effects on neurotransmitters.16 Several studies
`suggest a beneficial effect of vitamin A for the
`treatment of PMS, particularly for premenstrual
`headaches.17,18
`The balance of polyunsaturated (essential)
`fatty acids in the body is critical for the maintenance
`of healthy cell membranes and hormone regulation.
`During the last several decades, the average Western
`diet has shifted to much higher levels of omega-6
`and less omega-3 fatty acid intake. Long-chain
`omega-6 fatty acids, such as arachidonic acid, pre-
`dominating in the phospholipids of cell membranes
`can encourage the production of pro-inflammatory
`type-2 prostaglandins (PGE2), while omega-3 fatty
`acids promote the production of anti-inflammatory
`prostaglandins.19-20
`
`Omega-6 fatty acids, mainly arachidonic
`acid, are released following the reduction of
`progesterone prior to menstruation,21,22 initiating
`an inflammatory process by triggering a flux of
`inflammatory prostaglandins and leukotrienes in
`the uterus.21,22 At the same time, cyclooxygenase
`metabolites of arachidonic acid, prostaglandins E2
`and F2, cause vasoconstriction and myometrial
`contractions that lead to ischemia and eventually
`the pain of menstrual cramps.21,22
`Research has uncovered abnormal fatty
`acid metabolism in women with PMS. Brush and
`colleagues examined plasma fatty acid levels in
`42 women with premenstrual syndrome. They
`found that although levels of linoleic acid, the
`body’s main dietary source of omega-6 fatty ac-
`ids, were significantly above normal in all the
`women, levels of its anti-inflammatory metabo-
`lites, including gamma-linolenic acid, were all
`deficient,23 reinforcing the theory that one of the
`main causes of PMS is inflammation.
`The role of long-chain fatty acids for the
`management of PMS has been evaluated in sev-
`eral studies.2,19-27 Omega-3 fatty acids, mainly
`eicosapentanoic acid (EPA) and docosahexanoic
`acid (DHA), compete with the omega-6 species
`for the enzyme prostaglandin synthetase. The
`omega-3 fatty acids trigger secretion of less po-
`tent leukotrienes and anti-inflammatory prostag-
`landins of the 3 series (PE3, PI3,and thromboxane
`A3). 22,28-32 The result is a decrease of myometrial
`contractions and uterine vasoconstriction, reliev-
`ing ischemia and reducing pain. This effect may
`be due to an increase in sensitivity of the uterus to
`the relaxing effects of beta-adrenergic catechola-
`mines.22,33-37
`While prostaglandin E1 (PGE1) inhibits glu-
`cose-induced insulin secretion, a deficiency – occur-
`ring either as a result of an inadequate intake of es-
`sential fatty acids in the form of cis-linoleic acid or
`problems with conversion to gamma-linolenic acid
`(GLA) – could result in symptoms of hypoglyce-
`mia, cravings for sweets, and increase in appetite
`reported by many PMS patients.26,37 Long-chain
`omega-3 fatty acids in fish oil have been shown to
`be effective for the control of cravings occurring prior
`to menstruation.2,22-32,34-36
`
`RIMFROST EXHIBIT 1012 page 0003
`Alternative Medicine Review ◆ Volume 8, Number 2 ◆
` 2003 Page 173
`Copyright©2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`

`

`Krill Oil & PMS Original Research
`
`Neptune Krill Oil™ (NKO™) is a natu-
`ral health product extracted from Antarctic krill
`also known as Euphausia superba. Euphausia
`superba, a zooplankton crustacean, is rich in phos-
`pholipids and triglycerides carrying long-chain
`omega-3 polyunsaturated fatty acids, mainly EPA
`and DHA, and in various potent antioxidants in-
`cluding vitamins A and E, astaxanthin, and a novel
`flavonoid
`(similar
`to
`the 6,8-Di-C-
`glucosylluteolin, but with two or more glucose
`molecules and one aglycone).
`
`visit and she was asked to complete it on her own
`(no interviewer allowed) in the waiting room, prior
`to seeing the physician.
`Each patient was asked to take two 1-gram
`soft gels of either NKO or omega-3 18:12 fish oil
`(fish oil containing 18% EPA and 12% DHA) once
`daily with meals during the first month of the trial.
`During the following two months, patients con-
`tinued on a cyclic dose of two 1-gram soft gels
`eight days prior to and two days during menstrua-
`tion. Study medication was given for three months,
`at which time patients were asked to record all
`analgesics consumed for menstrual pain. All pa-
`tients were asked to follow a normal healthy diet
`consisting of 20-percent fat (less than 10-percent
`animal fat), 40-percent protein, and 40-percent
`carbohydrates. Patients were re-evaluated 45 and
`90 days after recruitment.
`The treating physician, the patient, and the
`epidemiologist performing the analysis were
`blinded until the completion of data analysis. The
`study was performed according to current Inter-
`national Conference on Harmonization guidelines
`on Good Clinical Practice. Reasons for withdrawal
`and adverse events were reported immediately. No
`crossover was allowed.
`The primary objective of the study was to
`evaluate the effectiveness of Neptune Krill Oil for
`the management of premenstrual syndrome and
`dysmenorrhea. The secondary objective was to
`compare the effectiveness of NKO for the man-
`agement of premenstrual syndrome with that of
`omega-3 fish oil. The study hypotheses were that
`Neptune Krill Oil can significantly reduce the
`physical and emotional symptoms of premenstrual
`syndrome and be significantly more effective for
`the management of PMS symptoms than fish oil.
`Primary outcome measures were based on
`the scores of a self-assessment questionnaire for
`PMS based on the American College of Obstetri-
`cians & Gynecologists diagnostic criteria for pre-
`menstrual syndrome ranging from 0 (no symp-
`toms) to 10 (unbearable),37 and the difference in
`quantity of analgesic consumption for menstrual
`pain at baseline, 45-day, and 90-day visits. Sec-
`ondary outcome measures were based on the over-
`all treatment assessment, adverse event monitor-
`ing, and compliance checks.
`RIMFROST EXHIBIT 1012 page 0004
`Page 174 Alternative Medicine Review ◆ Volume 8, Number 2 ◆
` 2003
`Copyright©2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`Patients, Materials, and Methods
`Women of reproductive age who fulfilled
`the DSM-III-R diagnostic criteria for PMS were
`eligible for the study. Women who were pregnant
`or breast feeding, on concomitant anticoagulant
`therapy, receiving psychotherapy, experiencing
`alcohol or drug dependence, on sex hormones
`except for oral contraceptives, with a known sea-
`food allergy, or diagnosed with dementia, pituitary
`disease, coagulopathy, or a serious medical con-
`dition were not eligible for enrollment. Patients
`taking other dietary supplements or vitamins were
`asked to stop supplementation for two weeks at
`which time they were randomized in the trial.
`The study was described to potentially eli-
`gible patients by the treating physician. Once the
`patient agreed to participate, an “eligibility form” was
`completed by the physician according to the patient’s
`answers. If the patient (referred as “she”) was eli-
`gible, she signed a written Patient Informed Consent
`Form and was enrolled for randomization. Patients
`were randomly allocated according to a list of ran-
`dom numbers. Once the patient was randomized to
`either the NKO or an omega-3 fish oil group, she
`underwent a physical examination for screening pur-
`poses. If the physical examination revealed no rea-
`son for the patient to be excluded from the study, she
`was asked to complete an initial self-assessment ques-
`tionnaire, as well as to record her usual daily con-
`sumption of analgesics (including type and fre-
`quency) for menstrual pain.
`Each patient periodically answered three
`identical self-assessment questionnaires, at
`baseline and one at each of the two follow-up vis-
`its. A questionnaire was given to a patient at each
`
`

`

`Original Research Krill Oil & PMS
`
`change in the efficacy
`measure were assessed
`with analysis of variance
`(ANOVA). The study was
`designed as a prospective,
`randomized, controlled,
`double-blind trial, with a
`20-percent difference in
`the change in physical and
`emotional scores accepted
`as clinically significant,
`90-percent power, and 5-
`percent significance. Sev-
`enty patients were en-
`rolled in the study, ran-
`domly assigned to either
`the active (NKO) or the
`control (fish oil) group.
`
`0.1
`0.2
`0.2
`0.2
`0.2
`0.1
`0.1
`0.1
`0.1
`0.2
`diff.**
`Mean
`
`=0.08
`<0.001
`<0.001
`<0.01
`=0.18
`=0.27
`=0.13
`=0.07
`=0.40
`=0.38
`
`P-value
`
`6.4(2)
`5.2(2)
`5.6(3)
`6.8(1)
`4.0(2)
`6.3(2)
`5.2(2)
`6.1(2)
`6.7(2)
`5.0(2)
`(SD)
`Score
`
`=0.08
`=0.07
`=0.04
`=0.04
`=0.18
`=0.27
`=0.13
`=0.07
`=0.06
`=0.38
`
`P-value
`
`6.0(3)
`4.7(3)
`4.9(4)
`4.7(3)
`3.7(3)
`5.4(3)
`4.9(2)
`5.4(2)
`5.9(1)
`4.9(2)
`(SD)
`Score
`
`7.1
`6.9
`7.0
`8.0
`5.2
`7.2
`5.8
`6.9
`7.0
`5.9
`line*
`Base-
`
`0.1
`0.2
`0.2
`0.2
`0.5
`0.2
`0.3
`0.2
`0.3
`0.3
`diff.**
`Mean
`
`90 days
`
`45 days
`
`90 days
`
`45 days
`
`Control
`
`Krill Oil
`
`at each Visit
`Table 2. Summary of Scores on the Premenstrual Syndrome Self-assessment Questionnaire
`
`**Mean difference refers to the mean difference observed between baseline and 90 days of treatment.
`* Higher scores indicate more severe symptoms.
`Range:0-10
`
`Results
`Of the 70 patients
`enrolled, all patients com-
`pleted the three-month
`study period. Of those, 36
`were randomized to the
`active group and 34 to the
`control group. The mean
`(SD) age of the active
`group patients was 33(±5)
`and that of the control
`group was 32(±7).
`As illustrated in
`Tables 2 and 3, the scores
`of the self-assessment
`questionnaire demon-
`strated a statistically sig-
`nificant
`difference
`(p<0.001) within the
`NKO group after intervals
`of both 45 days (first men-
`strual cycle) and 90 days
`(second and third cycle) in
`both emotional and physical symptoms related to
`PMS. By contrast, within the fish oil group a sta-
`tistically significant difference was attained after
`45 days only with symptoms of weight gain and
`abdominal pain (p<0.04). Other related physical
`
`P-value
`
`P-value
`
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`
`6(2)
`4.8(2)
`4.9(2)
`5.3(3)
`2.1(2)
`4.2(2)
`3.2(2)
`4.5(3)
`3.9 (2)
`4.0(2)
`(SD)
`Score
`
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`
`6.1(2)
`5.6(2)
`5.6(2)
`5.8(2)
`4.7(2)
`5.4(2)
`5.1(2)
`5.7(2)
`5.2(2)
`5.7(2)
`(SD)
`Score
`
`7.6
`7.6
`7.4
`7.5
`5.8
`6.9
`6.0
`7.2
`6.7
`6.9
`line*
`Base-
`
`Bloating
`Swelling
`Abdominal Pain
`Weight Gain
`Joint Pain
`Depression
`Irritable
`Stress
`Overwhelmed
`Breast Tenderness
`
`Symptom
`
`Changes over time within the same group
`(intragroup differences) in the efficacy measures
`were assessed using the paired Student’s t-test.
`Differences between the two groups, NKO versus
`fish oil (intergroup variance), with respect to the
`
`RIMFROST EXHIBIT 1012 page 0005
`Alternative Medicine Review ◆ Volume 8, Number 2 ◆
` 2003 Page 175
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`
`

`

`Krill Oil & PMS Original Research
`
`Table 3. Statistical Significance of Within and Between
`Group Variation
`
`symptoms (breast tenderness,
`joint pain, swelling, and bloat-
`ing) as well as emotional
`symptoms (feeling over-
`whelmed, stress, irritability,
`and depression) revealed no
`significant difference between
`baseline and 45-day follow-up
`visits. At the 90-day interval or
`third study visit of the fish oil
`group, significant differences
`were observed only with
`weight gain (p<0.01), abdomi-
`nal pain (p<0.001), and swell-
`ing (p<0.001). All other physi-
`cal and emotional symptoms
`revealed no significant differ-
`ence between baseline and 90-
`day follow-up visit of patients
`in the control group.
`The analysis of data
`showed the types of analgesics
`consumed most frequently by
`women in both groups were
`ibuprofen (68%), acetami-
`nophen (28%), and acetylsali-
`cylic acid (4%). Analysis of
`variance showed no significant
`difference between the two groups for daily anal-
`gesic consumption during PMS as well as during
`menstruation, prior to initiation of study medica-
`tions. The reported mean consumption prior to
`initiation of the trial was the same for both study
`groups – 1.2 g ibuprofen or 2.5 g acetaminophen.
`The number of pain relievers used for menstrual
`pain by women taking NKO was significantly re-
`duced to a mean daily consumption of 0.9 g
`ibuprofen and 1.5 g acetaminophen, a decrease of
`33 percent and 40 percent, respectively, during the
`first treatment cycle (recorded at the 45-day visit).
`The mean reported analgesic consumption during
`the following treatment cycle(s) in the NKO group
`at the 90-day visit was 0.6 g ibuprofen (total de-
`crease of 50%) or 1.0 g acetaminophen (total de-
`crease of 50%) per day. Student’s t-test analysis
`showed a significant intra-group reduction
`
`GROUP P-VALUE
`
`Symptom
`
`Breast Tenderness
`Overwhelmed
`Stress
`Irritable
`Depression
`Joint Pain
`Weight Gain
`Abdominal Pain
`Swelling
`Bloating
`
`NKO™
`45 days 90 days
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`
`OMEGA-3 FISH OIL
`45 days 90 days
`
`=0.38
`=0.06
`=0.07
`=0.13
`=0.27
`=0.18
`=0.04
`=0.04
`=0.07
`=0.08
`
`=0.38
`=0.40
`=0.07
`=0.13
`=0.27
`=0.18
`<0.01
`<0.001
`<0.001
`=0.08
`
`(p<0.01) for daily analgesic usage comparing
`baseline vs. 45 (p<0.02) vs. 90-day visit (p=0.005).
`Women in the fish oil group reported a similar
`decrease of 0.9 g ibuprofen and 1.65 g acetami-
`nophen, a decrease of 33 and 34 percent, respec-
`tively, during the first treatment cycle. The anal-
`gesic use remained essentially constant during the
`second cycle, with reported daily quantities of 0.8
`g ibuprofen and 1.48 g acetaminophen, a decrease
`of 33 and 41 percent, respectively. Student’s t-test
`analysis showed an intra-group reduction for the
`fish oil group (p<0.02) for daily analgesic usage
`comparing baseline to 45-day (p<0.02) and 90-
`day (p<0.02) visits. At the end of the entire study,
`the comparative analysis between groups illus-
`trated that women taking NKO consumed signifi-
`cantly fewer pain relievers during the 10 days of
`treatment than women receiving fish oil (p<0.03).
`
`RIMFROST EXHIBIT 1012 page 0006
`Page 176 Alternative Medicine Review ◆ Volume 8, Number 2 ◆
` 2003
`Copyright©2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`

`

`Original Research Krill Oil & PMS
`
` Analysis of variance showed that NKO
`was statistically more effective (p<0.01) than fish
`oil for the management of emotional symptoms
`(feeling overwhelmed, stress, irritability, and de-
`pression) (p<0.01); breast tenderness (p<0.01);
`and joint pain (p<0.04). There was no significant
`difference observed between NKO and fish oil for
`the management of weight gain, abdominal pain,
`and swelling (p<0.5).
`No serious adverse events were reported
`during the duration of the trial. Three of the 36
`women in the NKO group reported a reduction of
`the duration of the menstrual cycle by 3-7 days
`during the first month of treatment. This was no
`longer observed after the dose was reduced to 2
`gel caps per day for 10 days per month. NKO
`group patients exhibited minor oiliness of the fa-
`cial skin. Patients taking NKO did not experience
`any gastrointestinal difficulties such as regurgita-
`tion, while 64 percent of the women in the fish oil
`group complained of unpleasant reflux. On the
`contrary, the NKO subjects reported an increase
`of alertness, energy, and well-being.
`
`Discussion
`Premenstrual syndrome is a complex
`psychoneuroendocrine disorder characterized by
`a combination of physiological, psychological, and
`social symptoms. It is estimated that 85-97 per-
`cent of women of reproductive age experience
`some symptoms in the premenstrual phase of the
`cycle and 30-40 percent of these women will seek
`medical advice.38 For 3-5 percent of women, symp-
`toms are severe enough to significantly disrupt
`their everyday life.
`Given the complexity in the cause and
`symptomatology of premenstrual syndrome, a vast
`array of treatments have been suggested. A meta-
`analysis performed by Wyatt et al39 on the annual
`rates of diagnoses and prescribing patterns in pre-
`menstrual syndrome during the years 1993-1998
`showed a yearly decrease in the number of pre-
`scriptions linked to PMS diagnoses. Simulta-
`neously, the meta-analysis revealed a recent in-
`crease in popularity of alternative or natural rem-
`edies.39 A survey of medical herbalists in 1998
`showed PMS to be the second-most common con-
`dition treated with natural health products.40
`
`Numerous studies have shown a benefi-
`cial effect of omega-3 fatty acids on menstrual
`pain.41-43 This is consistent with the fact that men-
`strual pain and cramps are caused by inflamma-
`tion mediated by omega-6 fatty acid-derived
`eicosanoids.
`Following ovulation, there is shift of fatty
`acid balance in the phospholipids of the cell mem-
`branes.43 Prior to menstruation, excessive amounts
`of arachidonic acid are released, and an increase
`in prostaglandins and leukotrienes (LTs) is trig-
`gered in the uterus. The inflammatory response
`initiated by the PGs and LTs results in vasocon-
`striction, myometrial contractions, and ischemia
`that cause pain; gastrointestinal symptoms such
`as nausea, vomiting, and bloating; and head-
`aches.43 Supplementation with omega-3 fatty ac-
`ids mediates the production of less potent PGs and
`LTs, resulting in a reduction in the severity of
`myometrial contractions and uterine vasoconstric-
`tion, a decrease in the formation of inflammatory
`mediators, and subsequently reduced ischemia and
`improved blood flow.41-43
`The results of the present study indicate
`that Neptune Krill Oil has statistically significant
`and clinically marked benefits against the inflam-
`matory dysmenorrhea symptom complex as well
`as on the emotional symptomatology that charac-
`terizes premenstrual syndrome (intra-group dif-
`ference p<0.001, CI 95%). When compared to
`omega-3 fish oil, the effect of NKO was compa-
`rable with respect to weight gain, abdominal pain,
`swelling, and bloating (inter-group variance
`(p<0.5, CI 95%). NKO was shown to be signifi-
`cantly more effective than fish oil for the man-
`agement of all emotional symptoms of PMS
`(p<0.01, CI 95%), breast tenderness (p<0.01, CI
`95%), and joint pain (p<0.04, CI 95%).
`Evidence has shown that phospholipids of
`the brain have an especially high content of the
`long-chain omega-3 fatty acid DHA, and that these
`phospholipid species are centrally involved in
`brain function.44-46 The effectiveness of NKO on
`emotional menstrual symptoms may thus be based
`on potential modulating effects on neurotransmit-
`ters that affect emotional and psychological symp-
`toms. The synergistic effects of omega-3 fatty ac-
`ids and phospholipids are specific to NKO since
`
`RIMFROST EXHIBIT 1012 page 0007
`Alternative Medicine Review ◆ Volume 8, Number 2 ◆
` 2003 Page 177
`Copyright©2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`

`

`Krill Oil & PMS Original Research
`
`the solvent-based cold extraction process used to
`produce this oil maintains the integrity of the phos-
`pholipids. Processes for fish oil extraction can in-
`volve conditions that irrevocably damage certain
`components like phospholipids.
`
`Conclusion
`The final results of the present study sug-
`gest within a high level of confidence that Nep-
`tune Krill Oil can significantly reduce the physi-
`cal and emotional symptoms related to premen-
`strual syndrome, and is significantly more effec-
`tive for the management of dysmenorrhea and
`emotional premenstrual symptoms than fish oil.
`NKO has a unique biomolecular profile of phos-
`pholipids, omega-3 fatty acids, and diverse anti-
`oxidants that surpasses the usual fish oil profile.
`The association between phospholipids and long-
`chain omega-3 fatty acids highly facilitates the
`passage of fatty acid molecules through the intes-
`tinal wall, increasing their bioavailability, and ul-
`timately improving the omega-3:omega-6 ratio.
`Furthermore, phospholipid molecules play a ma-
`jor role in membrane fluidity, which may in turn
`play an active role in the management of emo-
`tional symptoms. Findings from this trial raise the
`possibility that Neptune Krill Oil has a positive
`benefit to risk profile for PMS.47
`
`2.
`
`3.
`
`4.
`
`References
`1.
`Spitzer RL, Severino SK, Williams JB, Parry
`BL. Late luteal phase dysphoric disorder and
`DSM-III-R. Am J Psychiatry 1989;146: 892-
`897.
`Stevinson C, Ernst E. Complementary/alterna-
`tive therapies for premenstrual syndrome: a
`systematic review of randomized controlled
`trials. Am J Obstet Gynecol 2001;185:227-235.
`Clare AW. Premenstrual syndrome: single or
`multiple causes? Can J Psychiatry 1985;30:474-
`482.
`Rubinow DR, Hoban C, Roy-Byrne P, et al.
`Premenstrual syndromes: past and future
`research strategies. Can J Psychiatry
`1985;30:469-473.
`Abraham GE, Rumley RE. Role of nutrition in
`managing the premenstrual tension syndromes.
`J Reprod Med 1987;32:405-422.
`
`5.
`
`19.
`
`20.
`
`RIMFROST EXHIBIT 1012 page 0008
`Page 178 Alternative Medicine Review ◆ Volume 8, Number 2 ◆
` 2003
`Copyright©2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`Clare AW. Hormones, behaviour and the
`menstrual cycle. J Psychosom Res 1985;29:225-
`233.
`Halbreich U, Endicott J, Lesser J. The clinical
`diagnosis and classification of premenstrual
`changes. Can J Psychiatry 1985;30:489-497.
`True BL, Goodner SM, Burns EA. Review of
`the etiology and treatment of premenstrual
`syndrome. Drug Intell Clin Pharm 1985;19:714-
`722.
`Abraham GE. Premenstrual tension. Probl
`Obstet Gynecol 1980;3:1-39.
`Abraham GE. Role of nutrition in managing the
`premenstrual tension syndromes. J Reprod Med
`1987;32:405-422.
`London RS, Sundaram G, Manimekalai S, et al.
`The effect of alpha-tocopherol on premenstrual
`symptomatology: a double-blind study. II.
`Endocrine correlates. J Am Coll Nutr
`1984;3:351-356.
`London RS, Murphy L, Kitlowski KE, Reynolds
`MA. Efficacy of alpha-tocopherol in the
`treatment of the premenstrual syndrome. J
`Reprod Med 1987;32:400-404.
`Stewart A. Clinical and biochemical effects of
`nutritional supplementation on the premenstrual
`syndrome. J Reprod Med 1987;32:435-441.
`London RS, Sundaram GS, Murphy L,
`Goldstein PJ. Evaluation and treatment of breast
`symptoms in patients with the premenstrual
`syndrome. J Reprod Med 1983;28:503-508.
`London RS, Sundaram GS, Murphy L,
`Goldstein PJ. The effect of alpha-tocopherol on
`premenstrual symptomatology: a double-blind
`study. J Am Coll Nutr 1983;2:115-122.
`Panganamala RV, Cornwell DG. The effects of
`vitamin E on arachidonic acid metabolism. Ann
`N Y Acad Sci 1982;393:376-391.
`Block E. The use of vitamin A in the premen-
`strual tension. Acta Obstet Gynecol Scand
`1960;39:586-592.
`18. Wilson ML, Murphy PA. Herbal and dietary
`therapies for primary and secondary dysmenor-
`rhoea. Cochrane Database Syst Rev
`2001;3:CD002124.
`Horrobin DF. The role of essential fatty acids
`and prostaglandins in the premenstrual syn-
`drome. J Reprod Med 1983;28:465-468.
`Simopoulos AP. Omega-3 fatty acids in health
`and disease and in growth and development. Am
`J Clin Nutr 1991;54:438-463.
`
`

`

`Original Research Krill Oil & PMS
`
`34.
`
`35.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`33.
`
`Alvin PE, Litt IF. Current status of etiology and
`management of dysmenorrhea in adolescence.
`Pediatrics 1982;70:516-525.
`Cameron IT, Fraser IS, Smith SK. Clinical
`Disorders of the Endometrium and Menstrual
`Cycle. Oxford, United Kingdom: Oxford
`University Press; 1998;359.
`Brush MG. Evening primrose oil in the treat-
`ment of the premenstrual syndrome. In:
`Horrobin DF, ed. Clinical Uses of Essential
`Fatty Acids. Montreal, Quebec, Canada: Eden
`Press; 1982:155-162.
`Horrobin DF. The role of essential fatty acids
`and prostaglandins in the premenstrual syn-
`drome. J Reprod Med 1983;28:465-468.
`Puolakka J, Makarainen L, Viinikka L,
`Ylikorkala O. Biochemical and clinical effects
`of treating the premenstrual syndrome with
`prostaglandin synthesis precursors. J Reprod
`Med 1985;30:149-153.
`Giugliano D, Torella R. Prostaglandin E1
`inhibits glucose-induced insulin secretion in
`man. Prostaglandins Med 1978;1:165-166.
`Delion S, Chalon S, Guilloteau D, et al. alpha-
`Linolenic acid dietary deficiency alters age-
`related changes of dopaminergic and
`serotoninergic neurotransmission in the rat
`frontal cortex. J Neurochem 1996;66:1582-1591.
`Drevon CA. Marine oils and their effects. Nutr
`Rev 1992;50:38-45.
`Hansen HS. Dietary essential fatty acids and in
`vivo prostaglandin production in mammals.
`World Rev Nutr Diet 1983;42:102-134.
`Endres S, Ghorbani R, Kelley VE, et al. The
`effect of dietary supplementation with n-3
`polyunsaturated fatty acids on the synthe