CX-0262
`CX Page
`
`Original Research
`
`Evaluation of the Effects of Neptune Krill Oil
`
`on the Management of Premenstrual Syndrome
`
`Fotini Sampalis M.D Ph.D Roxandra Bunea M.D.2
`
`Marie France Pelland M.D.3 Odile Kowalski M.D.4
`Natalie Duguet M.D.4 SØbastien Dupuis BSc
`
`Neptune Technologies
`
`Bioressources Inc
`
`Assistant Professor Department of Internal Medicine McGill Universitv Riverview Medical
`Center Montreal Quebec Canada
`
`Obstetrics CLSC Bordeau Cartierville Department
`Marie Family Medicine
`SacrØ-Coeur
`Gynecology Montreal Quebec Canada Family Medicine
`Obstetrics
`
`of
`
`Hospital
`
`Family Medicine
`
`Obstetrics
`
`Clinique
`
`lEnvolØe Montreal Quebec Canada
`
`Altern Med Rev 2003 71-179
`
`NEP877ITC-00040204
`
`NEPN Ex. 2058
`Aker v. Neptune
`IPR2014-00003
`
`Page 1
`
`

`
`OiiginaI Research
`
`Kilil ON
`
`PMS
`
`CX Page
`
`Evaluation of the Effects of
`Neptune Knit OilTM on the
`Management of Premenstrual Syndrome
`and Dysmenorrhea
`
`Fotini Sampalis MD PhD Roxandra Bunea MD
`Marie France Pelland MD Odile Kowaiski MD
`Natalie Duguet MD Sbastien Dupuis BSc
`
`Abstract
`PRIMARY OBJECTIVE To evaluate
`the
`of Neptune Krill OilTM NKOTM for
`the management of premenstrual
`syndrome
`and dysmenorrhea SECONDARY OBJECTIVE
`of NKO for the
`To compare the effectiveness
`and
`management of premenstrual
`syndrome
`dysmenorrhea with that
`of omega-3 fish oil
`METHODS/
`DESIGN Double-blind
`random
`ized clinical trial SETTING Outpatient
`PARTICIPANTS
`
`effectiveness
`
`clinic
`
`of
`
`Seventy
`patients
`reproductive age diagnosed with premenstrual
`and
`to the Diagnostic
`syndrome
`according
`Statistical Manual of Mental Disorders
`Third
`Edition Revised DSM-lll-R INTERVENTIONS
`Treatment period of three months with either
`fish oil OUTCOME
`NKO or omega-3
`MEASURES Self-Assessment
`Questionnaire
`the American College
`based
`of
`on
`Gynecologists ACOG
`Obstetricians
`syndrome
`diagnostic criteria for premenstrual
`and dysmenorrhea and number of analgesics
`used for dysmenorrhea RESULTS In 70
`patients with complete data
`statistically
`improvement was demonstrated
`interim and final evaluations
`among baseline
`in the self assessment questionnaire p0.OOl
`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
`reduction of the number
`
`significant
`
`significant
`of analgesics used for dysmenorrhea within the
`
`significantly
`
`NKO group comparing baseline vs 45- vs 90-
`day visit The between-groups
`analysis
`illustrated that women taking NKO consumed
`fewer analgesics
`during the 10-
`period than women receiving
`day treatment
`0.03 CONCLUSION
`omega-3 fish oil
`Neptune Krill Oil can significantly reduce
`dysmenorrhea and the emotional symptoms
`of
`and is shown to be
`
`premenstrual
`
`syndrome
`for the complete
`significantly more effective
`management
`of premenstrual symptoms
`compared to omega-3 fish oil
`
`Altern Med Rev 2003 71-179
`
`Fotini
`
`Associate
`
`Professor
`
`of
`
`Technologies
`
`Sampalis MD PhD
`of
`Department of Experimental
`Surgery
`University
`Montreal Montreal Quebec Canada Vice President
`Research
`Development
`at Neptune
`Inc
`Bioressources
`1348 Elisabeth Blvd Laval
`address
`Correspondence
`H7W 3J8 Canada
`Quebec
`mpiypccc
`Bunea MD
`Medicine McGill University
`Internal
`Center Montreal Quebec Canada
`
`E-mail
`
`Roxandra
`
`Assistant
`
`Professor
`
`Riverview
`
`Department of
`Medical
`
`Marie France Pelland MD
`Family Medicine
`Obstetrics
`CLSC Bordeau Cartierville Department of Gynecology
`Family Medicine
`Montreal Quebec Canada
`Obstetrics
`SacrØ-Coeur Hospital
`
`Odile Kowalski MD
`Family Medicine
`Obstetrics
`lEnvolØe Montreal Quebec Canada
`Clinique
`
`MD
`Family Medicine
`Natalie Duguet
`Obstetrics
`lEnvolØe Montreal Quebec Canada
`
`Clinique
`
`SØbastien Dupuis
`Neptune
`Project Manager
`Inc Laval Quebec
`Bioressources
`
`BSc
`
`Technologies
`Canada
`
`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Page 171
`
`Copyright2003 Thorne Research
`
`Inc All Rights Reserved No Reprint Without Written Permission
`
`EP877ITC-00040205
`
`Page 2
`
`

`
`KriH Oil
`
`PMS
`
`Original Research
`
`CX Page
`
`Table
`
`Diagnostic Criteria for PMS
`
`Introduction
`Premenstrual syndrome PMS and dys
`
`menorrhea
`
`are characterized
`
`by
`
`combination of
`
`cyclic symptoms that occur during the luteal phase
`of the menstrual cycle Symptoms are practically
`in the follicular phase of the menstrual
`
`absent
`
`cycle begin at varying points after ovulation peak
`
`in the late luteal phase and subside with the onset
`or shortly thereafter The diagnostic cri
`of menses
`and Statistical
`teria based on the Diagnostic
`Manual of Mental Disorders DSM TIT-R Third
`in Table
`Edition Revised are outlined
`
`Page 172
`
`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Copyright2003 Thornc Research
`
`Inc All Rights Rcserved No Rcprint Without Writtcn Permission
`
`EP877ITC-00040206
`
`Page 3
`
`

`
`Original Research
`
`KrilI CMI
`
`PMS
`
`CX Page
`
`Multiple
`
`causes
`
`have
`
`been attributed to
`
`Omega-6 fatty acids mainly arachidonic
`
`the complex interplay of neuroendocrine
`and psychosocial
`
`chronobiological
`
`interactions
`
`acid are released following the reduction of
`
`progesterone prior to menstruation2122
`
`initiating
`
`an inflammatory
`
`process
`
`flux of
`
`by triggering
`and leukotrienes
`
`in
`
`inflanunatory
`
`the uterus.2122 At
`
`prostaglandins
`the same time cyclooxygenase
`metabolites of arachidonic
`
`acid prostaglandins
`E2
`and F2 cause vasoconstriction
`and myometrial
`that
`lead to ischemia and eventually
`contractions
`the pain of menstrual cramps.2122
`Research has uncovered
`abnormal
`acid metabolism in women with PMS Brush and
`examined
`plasma fatty acid levels in
`colleagues
`42 women with premenstrual
`syndrome They
`found
`that although levels of linoleic acid the
`bodys main dietary source of omega-6 fatty ac
`above normal
`in all
`the
`ids were significantly
`women levels of its anti-inflammatory metabo
`acid were all
`gamma-linolenic
`the theory that one of the
`deficient23
`reinforcing
`main causes of PMS is inflammation
`The role of long-chain
`fatty acids for the
`management of PMS has been
`eral studies.29-27 Omega-3 fatty acids mainly
`acid EPA and docosahexanoic
`acid DHA compete with the omega-6
`species
`synthetase The
`for the enzyme prostaglandin
`fatty acids trigger secretion of less po
`and anti-inflammatory prostag
`leukotrienes
`landins of the
`thromboxane
`series PE3 P13and
`A3 222832 The result is
`of myometrial
`decrease
`and uterine vasoconstriction
`ing ischemia and reducing pain This effect may
`be due to an increase in sensitivity of the uterus to
`effects of beta-adrenergic
`
`of PMS.2-8
`
`that comprise the symptomatology
`review reveals more than 200 symptoms that have
`been reported to occur premenstrually.27 Depend
`factors include
`ing on the symptom the causative
`hormonal
`
`imbalance psychological
`
`abnormalities
`
`nutritional deficiency
`
`or excess
`
`increased
`
`inflam
`
`matory prostaglandin
`
`synthesis
`
`and neurotrans
`
`mitter imbalance.28
`
`find
`
`Nevertheless laboratory
`ings vary from being completely normal
`in some
`of certain hor
`women to an excess or deficiency
`or nutrients in others
`
`symp
`interac
`
`mones neurotransmitters
`The most probable cause of the physical
`toms of PMS seems
`to be the combined
`tion of hormones
`and essential nutrients leading
`response On the
`to an increased
`inflammatory
`other hand the emotional symptoms of PMS seem
`to be propagated
`response of
`by an exaggerated
`to psychosocial stresses These
`neurotransmitters
`imbalances have been shown to differ extensively
`from person to person as well as from cycle to
`cycle within the same person
`Evidence
`that alpha-tocopherol
`suggests
`reduce symptoms of PMS.29-6
`reduces
`release of arachidonic
`acid
`
`can significantly
`
`Tocopherol
`in for
`from phospholipids
`resulting in decrease
`mation ofprostaglandin E2 PGE2 inflammatory
`Alpha-tocopherol which
`prostaglandins.6
`the blood-brain barrier also has modulat
`
`crosses
`
`fatty
`
`evaluated
`
`in sev
`
`lites including
`
`eicosapentanoic
`
`omega-3
`
`tent
`
`ing effects on neurotransmitters.6
`
`Several
`
`studies
`
`contractions
`
`reliev
`
`the relaxing
`
`catechola
`
`effect of vitamin
`beneficial
`suggest
`treatment of PMS particularly
`headaches.78
`
`for the
`
`for premenstrual
`
`for the maintenance
`
`fatty acids in the body is critical
`of healthy cell membranes
`and hormone regulation
`During the last several decades the average Western
`diet has shifted to much higher
`of omega-6
`and
`fatty acid intake Long-chain
`less omega-3
`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 POE while omega-3 fatty
`acids promote the production of anti-inflammatory
`
`levels
`
`The balance of polyunsaturated
`
`essential
`
`mines.223337
`
`While prostaglandin
`
`PGE inhibits glu
`
`cose-induced
`
`insulin secretion
`
`ring either
`
`as
`
`result of an inadequate
`
`deficiency
`intake of es
`
`occur
`
`sential
`
`fatty acids in the form of cis-linoleic
`
`acid or
`
`result
`
`problems with conversion
`to gamma-linolenic acid
`GLA could
`in symptoms of hypoglyce
`and increase in appetite
`mia cravings
`for sweets
`by many PMS patients.2637
`reported
`omega-3 fatty acids in fish oil have
`be effective
`
`Long-chain
`been shown to
`
`for the control of cravings occurring prior
`
`prostaglandins
`
`19-20
`
`to menstruation.222-3234-36
`
`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Page 173
`
`Copyright2003 Thorne Research
`
`Inc All Rights Reserved No Reprint Without Written Permission
`
`EP877ITC-00040207
`
`Page 4
`
`

`
`KriH Oil
`
`PMS
`
`Original Research
`
`CX Page
`
`Neptune Krill OilTM NKOTM is
`from Antarctic
`ral health product extracted
`also known
`
`as Euphausia
`
`superba
`
`Euphausia
`
`natu
`
`krill
`
`visit
`
`and she was asked to complete it on her own
`no interviewer
`to seeing
`the physician
`
`allowed in the waiting
`
`room prior
`
`superba
`
`zooplankton crustacean is rich in phos
`and triglycerides
`long-chain
`pholipids
`carrying
`omega-3 polyunsaturated fatty acids mainly EPA
`and DHA and in various
`in
`and
`cluding vitamins
`
`potent antioxidants
`
`astaxanthin
`
`and
`
`novel
`
`flavonoid
`
`68-Di-C-
`similar
`hut with two or more glucose
`glucosylluteolin
`molecules and one aglycone
`
`to
`
`the
`
`Patients Materials and Methods
`Women of reproductive
`age who fulfilled
`for PMS were
`the DSM-III-R diagnostic
`eligible for the study Women who were pregnant
`feeding on concomitant anticoagulant
`or breast
`
`criteria
`
`alcohol
`
`experiencing
`psychotherapy
`therapy receiving
`or drug dependence on sex hormones
`known sea
`except for oral contraceptives with
`food allergy or diagnosed with dementia pituitary
`serious medical con
`disease coagulopathy
`dition were not eligible for enrollment Patients
`
`or
`
`or vitamins were
`
`at
`
`taking other dietary supplements
`asked to stop supplementation for two weeks
`which time they were randomized
`in the trial
`The study was described
`to potentially eli
`gible patients by the treating physician Once the
`an eligibility form was
`
`patient agreed to participate
`
`to the patients
`completed by the physician according
`as she was eli
`Informed Consent
`
`answers
`
`If the patient
`
`referred
`
`gible she signed
`Form and was enrolled for randomization Patients
`
`written Patient
`
`either
`
`were randomly allocated according
`doni numbers Once the patient was randomized
`the NKO or an omega-3 fish oil group
`underwent
`physical examination
`for screening pur
`no rea
`poses If the physical examination revealed
`to be excluded from the study she
`son for the patient
`
`to
`
`list of ran
`
`to
`
`she
`
`was askedto
`
`an initial
`
`answered three
`
`self-assessment ques
`complete
`tioimaire as well as to record her usual daily con
`sumption of analgesics
`including type and fre
`quency for menstrual pain
`Each patient periodically
`self-assessment
`
`identical
`
`at
`
`Each patient was asked to take two 1-gram
`soft gels of either NKO or omega-3 1812 fish oil
`18% EPA and 12% DHA once
`fish oil containing
`daily with meals during the first month of the trial
`two months patients con
`on
`dose of two 1-gram soft gels
`tinued
`cyclic
`eight days prior to and two days during menstrua
`tion Study medication was given for three months
`time patients were asked to record all
`at which
`consumed
`for menstrual pain All pa
`tients were asked to follow
`normal healthy diet
`less than 10-percent
`consisting of 20-percent
`animal fat 40-percent protein and 40-percent
`45 and
`
`During the following
`
`analgesics
`
`fat
`
`and the
`
`Inter
`
`carbohydrates Patients were re-evaluated
`90 days after recruitment
`The treating physician the patient
`the analysis were
`epidemiologist performing
`The
`blinded until the completion of data analysis
`study was performed according to current
`on Harmonization guidelines
`on Good Clinical Practice Reasons
`for withdrawal
`events were reported immediately No
`was allowed
`The primary objective of the study was to
`
`national Conference
`
`and adverse
`
`crossover
`
`evaluate
`
`the effectiveness
`
`dysmenorrhea
`
`ofNeptune Krill Oil for
`and
`the management of premenstrual syndrome
`The secondary
`objective was to
`of NKO for the man
`compare the effectiveness
`agement of premenstrual syndrome with that of
`omega-3 fish oil The study hypotheses were that
`Neptune Krill Oil can significantly
`reduce
`and emotional symptoms of premenstrual
`and be significantly more effective
`syndrome
`the management of PMS symptoms than fish oil
`Primary outcome measures were based on
`the scores of
`PMS based on the American College of Obstetri
`criteria for pre
`Gynecologists diagnostic
`menstrual syndrome
`ranging from
`no symp
`and the difference
`in
`
`the
`
`for
`
`self-assessment
`
`questionnaire
`
`for
`
`physical
`
`cians
`
`toms to 10 unbearable37
`for menstrual
`quantity of analgesic
`consumption
`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
`
`questionnaires
`baseline and one at each of the two follow-up vis
`at each
`was given to
`
`its
`
`questionnaire
`
`patient
`
`Page 174
`
`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Copyright2003 Thorne Research
`
`Inc All Rights Reserved No Reprint Without Written Permission
`
`EP877ITC-00040208
`
`Page 5
`
`

`
`Original Research
`
`KrilI CMI
`
`PMS
`
`CX Page
`
`change in the efficacy
`measure were assessed
`
`with analysis of variance
`ANOVA The study was
`designed as prospective
`
`randomized controlled
`trial with
`
`double-blind
`
`20-percent
`
`difference
`
`in
`
`the change
`
`in physical
`
`and
`
`emotional
`
`scores accepted
`
`90-percent
`
`power
`
`percent
`
`as clinically significant
`and 5-
`Sev
`significance
`were en
`enty patients
`rolled in the study ran
`domly assigned
`the active NKO or
`fish oil group
`
`to either
`
`the
`
`control
`
`Results
`
`enrolled
`
`Of the 70 patients
`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 335
`and
`that of
`the control
`
`group was 327
`As illustrated in
`
`Tables
`
`and
`
`the scores
`
`of
`
`the self-assessment
`demon
`
`questionnaire
`
`strated
`
`statistically
`
`sig
`
`the
`
`nificant
`difference
`pO.OOl within
`NKO group after
`intervals
`ofhoth 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
`sta
`significant difference was attained after
`tistically
`45 days only with symptoms of weight gain and
`abdominal pain pO.O4 Other related physical
`
`Changes
`
`over time within the same group
`in the efficacy measures
`intragroup differences
`using the paired Students t-test
`were assessed
`between the two groups NKO versus
`intergroup variance with respect
`to the
`
`Differences
`
`fish oil
`
`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Page 175
`
`Copyright2003 Thorne Research
`
`Inc All Rights Reserved No Reprint Without Written Permission
`
`EP877ITC-00040209
`
`Page 6
`
`

`
`KriH Oil
`
`PMS
`
`Original Research
`
`CX Page
`
`tenderness
`
`symptoms breast
`joint pain swelling and bloat
`as emotional
`ing as well
`feeling over
`symptoms
`whelmed stress
`and depression
`significant difference between
`baseline and 45-day follow-up
`visits At the 90-day interval or
`third stndy visit of the fish oil
`
`irritability
`
`revealed no
`
`differences
`group significant
`were observed only with
`weight gain pO.Ol abdomi
`nal pain pc0.001 and swell
`other physi
`ing p0.001.All
`cal and emotional symptoms
`revealed
`no significant differ
`
`ence between baseline and 90-
`
`day follow-up visit ofpatients
`
`in the control group
`The analysis of data
`showed the types of analgesics
`consumed most
`by
`frequently
`women in both groups were
`ibuprofen 68% acetami
`nophen 28% and acetylsali
`cylie acid 4% Analysis of
`
`Table
`
`Statistical Sign fficance of Within and Between
`
`Group VariationI-flI
`oan
`aoooo
`
`Irritable
`
`Depression
`
`variance
`
`showed
`
`difference
`
`no significant
`between the two groups for daily anal
`during PMS as well
`as during
`gesic consumption
`menstruation prior to initiation of study medica
`tions The reported mean consumption
`prior to
`initiation of the trial was the same for both study
`ibuprofen or 2.5
`1.2
`acetaminophen
`groups
`The number of pain relievers used for menstrual
`pain by women taking NKO was significantly
`re
`duced
`of 0.9
`mean daily consumption
`ibuprofen and 1.5
`acetaminophen
`and 40 percent respectively
`33 percent
`
`to
`
`decrease of
`
`during the
`
`first treatment
`
`cycle recorded at the 45-day visit
`The mean reported analgesic
`consumption
`during
`treatment cycles in the NKO group
`the following
`ibuprofen total de
`at the 90-day visit was 0.6
`total de
`crease of 50% or 1.0
`acetaminophen
`crease of 50% per day Students t-test analysis
`showed
`intra-group reduction
`significant
`
`pO.Ol
`for daily analgesic
`usage comparing
`baseline vs 45 pO.O2 vs 90-day visit p0.OOS
`Women
`similar
`in the fish oil group reported
`
`decrease
`
`of 0.9
`
`nophen
`
`decrease
`
`tively during the first treatment
`
`acetami
`
`acetaminophen
`
`decrease
`
`Studenfs t-test
`
`for the
`
`ibuprofen and 1.65
`of 33 and 34 percent
`respec
`cycle The anal
`gesic use remained essentially constant
`during the
`second cycle with reported daily quantities of 0.8
`ibuprofen and 1.48
`of33 and 41 percent
`respectively
`analysis showed an intra-group
`reduction
`fish oil group pO.O2 for daily analgesic
`usage
`to 45-day pO.02 and 90-
`baseline
`comparing
`day pO.O2 visits At the end of the entire study
`between groups illus
`the comparative analysis
`trated that women taking NKO consumed signifi
`fewer pain relievers during the 10 days of
`than women receiving
`
`cantly
`
`treatment
`
`fish oil pO 03
`
`Page 176
`
`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Copyright2003 Thorne Research
`
`Inc All Rights Reserved No Reprint Without Written Permission
`
`NEP877ITC-0004021
`
`Page 7
`
`

`
`Original Research
`
`KrilI CMI
`
`PMS
`
`CX Page
`
`showed that NKO
`Analysis of variance
`was statistically more effective pO.Ol than fish
`for the management of emotional symptoms
`and de
`feeling overwhelmed
`pression p0 01 breast
`pO .01
`and joint pain pO.O4 There was no significant
`observed between NKO and fish oil for
`
`oil
`
`difference
`
`stress irritability
`
`tenderness
`
`the management of weight gain abdominal pain
`and swelling pO.5
`No serious adverse
`
`gel
`
`caps
`
`events were reported
`during the duration of the trial Three of the 36
`women in the NKO group reported
`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
`per day for 10 days per month NKO
`exhibited minor oiliness of the fa
`group patients
`cial skin Patients taking NKO did not experience
`such as regurgita
`any gastrointestinal difficulties
`tion while 64 percent of the women in the fish oil
`of unpleasant reflux On the
`group complained
`contrary the NKO subjects reported
`an increase
`of alertness
`energy and well-being
`
`Discussion
`
`Premenstrual
`
`syndrome is
`
`complex
`
`psychoneuroendocrine
`
`disorder
`
`characterized
`
`by
`
`combination ofphysiological
`
`psychological
`that 85-97 per
`
`and
`
`social symptoms It is estimated
`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
`of women symp
`to significantly
`
`percent
`
`toms are severe
`
`enough
`
`disrupt
`
`their everyday
`Given
`
`life
`
`the complexity
`
`in the cause and
`
`vast
`
`meta
`
`ofpremenstrual syndrome
`symptomatology
`have been suggested
`array of treatments
`analysis performed by Wyatt et a139 on the annual
`rates of diagnoses and prescribing
`in pre
`patterns
`years 1993-1998
`menstrual syndrome during the
`showed
`in the number of pre
`to PMS diagnoses Simulta
`in
`neously the meta-analysis
`
`decrease
`
`yearly
`
`linked
`
`scriptions
`
`revealed
`
`recent
`
`crease
`
`edies.39
`
`rem
`or natural
`in popularity
`survey of medical herbalists in 1998
`showed PMS to be the second-most
`common con
`
`of alternative
`
`dition treated with natural health products.4
`
`Numerous studies have shown
`
`benefi
`
`fatty acids on menstrual
`cial effect of omega-3
`that men
`pain.41-43 This is consistent with the fact
`strual pain and cramps are caused by inflamma
`tion mediated
`by ornega-6 fatty acid-derived
`
`eicosanoids
`
`Following ovulation there is shift of fatty
`acid balance in the phospholipids of the cell mem
`amounts
`branes.43 Prior to menstruation excessive
`
`of arachidonic
`
`acid are released and an increase
`and leukotrienes LT5 is trig
`in prostaglandins
`gered in the uterus The inflammatory
`response
`by the PGs and LTs
`results in vasocon
`
`initiated
`
`striction myometrial
`
`contractions
`
`and ischemia
`
`symptoms such
`that cause pain gastrointestinal
`as nausea vomiting and bloating and head
`aches.43 Supplementation with omega-3 fatty ac
`ids mediates the production of less potent PGs and
`of
`LTs resulting in
`reduction
`in the severity
`myometrial contractions
`in the formation of inflammatory
`tion
`reduced isehemia and
`mediators and subsequently
`blood flow.41-43
`
`decrease
`
`improved
`
`and uterine vasoconstrie
`
`The results of the present
`study indicate
`that Neptune Krill Oil has statistically
`and clinically marked benefits against
`
`the inflam
`
`significant
`
`ference
`
`as well
`
`to
`
`symptom complex
`matory dysmenorrhea
`that charac
`as on the emotional symptomatology
`intra-group dif
`terizes premenstrual syndrome
`p0.OOl CI 95% When
`compared
`the effect of NKO was compa
`omega-3
`fish oil
`rable with respect
`to weight gain abdominal pain
`variance
`and bloating inter-group
`swelling
`pO.5 CI 95% NKO was shown to be signifi
`for the man
`than fish oil
`cantly more effective
`symptoms of PMS
`agement of all emotional
`pO.Ol CI 95% breast
`tenderness pO.Ol CI
`95% and joint pain pO.O4 CI 95%
`Evidence has shown that phospho lipids of
`the brain have
`of the
`high content
`an especially
`omega-3 fatty acid DHA and that these
`are centrally involved in
`phospholipid
`species
`of NKO on
`The effectiveness
`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
`to NKO since
`ids and phospholipids are specific
`
`long-chain
`
`brain function.46
`
`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Page 177
`
`Copyright2003 Thorne Research
`
`Inc All Rights Reserved No Reprint Without Written Permission
`
`NEP877ITC-0004021
`
`Page 8
`
`

`
`KriH Oil
`
`PMS
`
`Original Research
`
`CX Page
`
`the solvent-based
`
`cold extraction
`
`process
`
`used to
`
`produce this oil maintains
`
`pholipids Processes
`
`the integrity ofthe phos
`can in
`
`for fish oil extraction
`
`volve conditions
`
`that
`
`irrevocably
`
`damage certain
`
`components
`
`like phospholipids
`
`Conclusion
`
`gest within
`
`The final
`results of the present study sug
`high level of confidence that Nep
`reduce the physi
`tune Krill Oil can significantly
`cal and emotional symptoms related to premen
`strual syndrome and is significantly more effec
`tive for the management of dysmenonhea and
`emotional premenstrual symptoms than
`fish oil
`NKO has
`unique biomolecular profile of phos
`pholipids omega-3 fatty acids and diverse anti
`
`oxidants
`
`that surpasses
`The association
`
`the usual
`
`fish oil profile
`
`between phospholipids and long-
`
`chain
`
`facilitates
`
`the
`
`fatty acids highly
`omega-3
`passage of fatty acid molecules through the intes
`and ul
`their hioavailahility
`
`tinal wall
`
`increasing
`
`10
`
`11
`
`12
`
`Clare AW Hormones
`menstrual cycle JPsychosom Res 1985
`
`behaviour
`
`and the
`
`233
`
`Halbreich
`
`Endicott
`
`Lesser
`
`The clinical
`
`diagnosis and classification
`
`of premenstrual
`
`Can JPsychiatiy 1985
`
`changes
`True BL Goodrier SM Burns EA Review of
`and treatment of premenstrual
`syndrome Drugintell Clin Pharm 1985
`the etiology
`
`722
`Abraham GE Premenstrual
`Obstet Gynecol 198031-39
`Abraham GE Role of nutrition
`in managing the
`premenstrual tension syndromes JRep rod Med
`
`tension Pro hi
`
`1987
`
`London RS Sundaram
`The effect of alpha-tocopherol on premenstrual
`
`Manimekalai
`
`et al
`
`symptomatology
`Endocrine
`
`correlates
`
`double-blind study 11
`JAm Coil Nutr
`
`in the
`
`Clinical
`
`and biochemical
`
`effects of
`
`timately improving the omega-3 omega-6 ratio
`Furthermore phospholipid molecules play 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
`to risk profile for PMS.47
`
`positive
`
`benefit
`
`References
`
`Spitzer RL Severino SK Williams JB Pany
`BL Late luteal phase dysphoric disorder
`and
`DSM-III-R Am JPsychiatry
`1989 146 892-
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`Clare AW Premenstrual
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`London RS Sundaram GS Murphy
`Goldstein PJ Evaluation and treatment of breast
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`
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`
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`
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`
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`NYAcadSci 1982
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`Simopoulos AP Omega-3
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`Wilson ML Murphy PA Herbal
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`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Copyright2003 Thorne Research
`
`Inc All Rights Reserved No Reprint Without Written Permission
`
`NEP877ITC-0004021
`
`Page 9
`
`

`
`Original Research
`
`KrilI CMI
`
`PMS
`
`CX Page
`
`10
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
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`and
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`Alvin PE Litt IF Current status of etiology
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`of dysmenorrhea
`management
`Pedialrica 1982 16-525
`IT Fraser IS Smith SK Clinical
`Cameron
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`Brush MG Evening primrose oil
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`Horrobin DF ed Clinical
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`Quebec Canada Eden
`Fatly Acidc Montreal
`Press 1982155-162
`Horrobin DF The role of essential
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`and prostaglandins in the premenstrual syn
`
`drome JRep rod Med 1983
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`Puolakka
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`Makarainen
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`Viinikka
`
`Ylikorkala
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`Biochemical
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`of treating the premenstrual syndrome with
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`
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`
`Torella
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`Giugliano
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`Prostaglandin El
`insulin
`secretion
`inhibits glucose-induced
`man Prostaglandins Med 1978 1165-166
`
`in
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`Delion
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`Chalon
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`Guilloteau
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`Linolenic acid dietary deficiency alters age-
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`
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`
`1998
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`
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`
`Ghorbani
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`
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`
`polyunsaturated fatty acids
`
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`
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`16
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`Deutch
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`Bioresources
`Neptune
`Technologies
`Scientific Report NKOTh The Synergistic
`Choice Product Safety Assessment Jan
`2003 18-32
`
`Inc
`
`Alternative Medicine Review
`
`Volume
`
`Number
`
`2003
`
`Page 179
`
`Copyright2003 Thorne Research
`
`Inc All Rights Reserved No Reprint Without Written Permission
`
`NEP877ITC-0004021
`
`Page 10