Ethyl eicosapentaenoic acid

Ethyl eicosapentaenoic acid
IUPAC name

Ethyl (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoate
Other names

Eicosapentaenoic acid ethyl ester; Ethyl eicosapentaenoate; Epadel; Icosapent; Ethyl icosapentate; EPA ethyl ester
Identifiers
CAS number 86227-47-6 Y
PubChem 9831415
Jmol-3D images Image 1
Properties
Molecular formula C22H34O2
Molar mass 330.5 g mol−1
 Y (verify) (what is: Y/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Ethyl eicosapentaenoic acid (E-EPA) is a highly purified, vacuum distilled derivate of the omega-3 fatty acid eicosapentaenoic acid (EPA). In Japan E-EPA is often called EPA-E.

Only EPA is considered to exihibit antipsychotic and antidepressive effects.[1] E-EPA is a psychotropic omega-3 fatty acid[2] and it is therefore of special interest in psychiatry.

Contents

Cardiovascular diseases, diabetes

The Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS) tested the effects of long-term use of E-EPA (1800 mg/day) in addition to a statin in Japanese patients with hypercholesterolemia. The results suggest that the addition of E-EPA to statin therapy prevents major coronary events, angina pectoris and clinical myocardial infarctions, apparently through mechanisms independent from regulation of the lipid metabolism. It has been suggested that the cardioprotective action of E-EPA is probably mediated by its anti-inflammatory properties.[3][4][5][6][7][8][9] In addition, E-EPA may improve the clinical outcome in type 2 diabetes [10][11][12][13] and its cardiovascular complications, such as coronary artery disease [14] and thickening of carotid arteries.[15] E-EPA may on the one hand reduce the platelet-derived microparticles (PDMP) and on the other enhance the cardioprotective hormone adiponectin in hyperlipidemic, diabetic patients.[16] According to Japanese mice studies, E-EPA may prevent and correct non-alcoholic fatty liver.[17][18]

Mental health

Acute psychosis

As adjuct therapy, E-EPA has been tested in first-episode psychosis.[19][20][21] The daily dosage of E-EPA given in these trials, i.e., 2 gram per day, corresponds to 10 to 15 helpings of Atlantic salmon.

In schizophrenia, the trials are based on the so-called membrane theory of the disease.[22][23][24][25][26][27][28][29] According to the Omega-3 Subcommittee of the American Psychiatric Association (APA), the evidence of the effects is still too weak to recommend the use of E-EPA,[30] but more studies are currently in progress.[31]

Clinical depression

Omega-3 fatty acids have been investigated as adjunct therapy for depression as they are anti-inflammatory agents and chronic low-grade inflammation has been linked to the disease.[32][33][34][35] Moreover, omega-3 content in the cell membranes of depressive persons is often decreased, and supplementation with omega-3 may correct this deficiency and improve the clinical outcome.[36][37][38][39][40][41] This hypothesis has been tested in a number of clinical trials using E-EPA, mostly 1 gram daily.[42]

Most (but not all) trials have yielded positive results.[43] In one study E-EPA boosted the effect of an antidepressive drug, fluoxetine.[44] According to a new report from Massachusetts General Hospital in Boston, E-EPA seems to be more effective than placebo as monotherapy in major depressive disorder.[45]

Bipolar depression

The first placebo-controlled study with ethyl esterized fish oil was carried out at Harvard University by professor Andrew L. Stoll, published in 1999.[46] His team later demonstrated that rigid cell mebranes in test subjects were smoothed by omega-3 fatty acids.[47] Subsequent studies at London's King's College Institute of Psychiatry have demonstrated the efficacy of E-EPA in bipolar patients.[48] One of the biochemical mechanisms seem to be enhancement of an amino acid called N-acetyl aspartate (NAA) in the brain.[49] E-EPA seems to exert similar effect on the NAA concentration as lithium which has been used for bipolar depression for decades.

Borderline personality disorder

So far one small clinical trial conducted on women has been published yielding promising results.[50]

Psychological stress

Animal tests demonstrate that E-EPA balances the metabolism of glucocorticoids (cortisol and cortisone) and may thus alleviate stress symptoms[51][52] and attenuate interleukine 1-beta (IL-1b) induced changes in dopamine and it's metabolites in the shell of the Nucleus accumbens.[52][53] The fatty acid EPA may confer neuroprotection in the amyloid-ß challenged aged hippocampus.[54][55]

Other conditions

E-EPA has been tested and found beneficial in anorexia nervosa,[56][57] hepatitis C,[58] in children with ulcerative colitis,[59] nonalcoholic fatty liver (steatohepatisis)[60] in psychological stress in postmenopausal middle-aged women,[61] and in women suffering from menopausal hot flushes.[62]

Safety aspects

E-EPA 2 g/day is generally well tolerated. Clinicians should be aware of possible increases in bleeding time, as well as changes in weight and lipid metabolism.[63]

References

  1. ^ Horrobin D. The Madness of Adam and Eve. How schizophrenia shaped humanity. Bantam Press 2001
  2. ^ Horrobin DF (2002). "A new category of psychotropic drugs: neuroactive lipids as exemplified by ethyl eicosapentaenoate (E-E)". Prog Drug Res 59: 171–99. PMID 12458967. 
  3. ^ Yokoyama M, Origasa H, Matsuzaki M, et al. (March 2007). "Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis". Lancet 369 (9567): 1090–8. doi:10.1016/S0140-6736(07)60527-3. PMID 17398308. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60527-3. 
  4. ^ Saito Y, Yokoyama M, Origasa H, et al. (September 2008). "Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS)". Atherosclerosis 200 (1): 135–40. doi:10.1016/j.atherosclerosis.2008.06.003. PMID 18667204. 
  5. ^ Tanaka K, Ishikawa Y, Yokoyama M, et al. (July 2008). "Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial". Stroke 39 (7): 2052–8. doi:10.1161/STROKEAHA.107.509455. PMID 18451347. http://stroke.ahajournals.org/cgi/pmidlookup?view=long&pmid=18451347. 
  6. ^ King A. Does treatment with eicosapentaenoic acid prevent major coronary events in patients with hypercholesterolemia? Editorial. Commentary by William S. Harris Nat Clin Pract Cardiovasc Med. 2007 Aug 14; Free Full Text
  7. ^ Harris W (August 2008). "Omega-3 fatty acids: the "Japanese" factor?". J. Am. Coll. Cardiol. 52 (6): 425–7. doi:10.1016/j.jacc.2008.04.018. PMID 18672161. http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(08)01501-5. 
  8. ^ Jacobson TA (August 2007). "Beyond lipids: the role of omega-3 fatty acids from fish oil in the prevention of coronary heart disease". Curr Atheroscler Rep 9 (2): 145–53. doi:10.1007/s11883-007-0011-x. PMID 17877924. 
  9. ^ Itakura H, Yokoyama M, Matsuzaki M, et al. (2011). "Relationships between plasma fatty acid composition and coronary artery disease". J. Atheroscler. Thromb. 18 (2): 99–107. PMID 21099130. http://joi.jlc.jst.go.jp/JST.JSTAGE/jat/5876?from=PubMed.  as PDF
  10. ^ Westerveld HT, de Graaf JC, van Breugel HH, et al. (May 1993). "Effects of low-dose EPA-E on glycemic control, lipid profile, lipoprotein(a), platelet aggregation, viscosity, and platelet and vessel wall interaction in NIDDM". Diabetes Care 16 (5): 683–8. PMID 8495604. http://care.diabetesjournals.org/cgi/content/abstract/16/5/683. 
  11. ^ Satoh N, Shimatsu A, Kotani K, et al. (January 2007). "Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and C-reactive protein in metabolic syndrome". Diabetes Care 30 (1): 144–6. doi:10.2337/dc06-1179. PMID 17192349. http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=17192349. 
  12. ^ Shimizu H, Ohtani K, Tanaka Y, Sato N, Mori M, Shimomura Y (April 1995). "Long-term effect of eicosapentaenoic acid ethyl (EPA-E) on albuminuria of non-insulin dependent diabetic patients". Diabetes Res. Clin. Pract. 28 (1): 35–40. doi:10.1016/0168-8227(95)01056-J. PMID 7587910. 
  13. ^ Zhang M, Hagiwara S, Matsumoto M, et al. (December 2006). "Effects of eicosapentaenoic acid on the early stage of type 2 diabetic nephropathy in KKA(y)/Ta mice: involvement of anti-inflammation and antioxidative stress". Metab. Clin. Exp. 55 (12): 1590–8. doi:10.1016/j.metabol.2006.07.019. PMID 17142129. 
  14. ^ Oikawa S, Yokoyama M, Origasa H, et al. (October 2009). "Suppressive effect of EPA on the incidence of coronary events in hypercholesterolemia with impaired glucose metabolism: Sub-analysis of the Japan EPA Lipid Intervention Study (JELIS)". Atherosclerosis 206 (2): 535–9. doi:10.1016/j.atherosclerosis.2009.03.029. PMID 19447387. http://linkinghub.elsevier.com/retrieve/pii/S0021-9150(09)00240-8. 
  15. ^ Mita T, Watada H, Ogihara T, et al. (March 2007). "Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes". Atherosclerosis 191 (1): 162–7. doi:10.1016/j.atherosclerosis.2006.03.005. PMID 16616147. 
  16. ^ Nomura S, Inami N, Shouzu A, et al. (February 2009). "The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients". Platelets 20 (1): 16–22. doi:10.1080/09537100802409921. PMID 19172517. 
  17. ^ Nemoto N, Suzuki S, Kikuchi H, Okabe H, Sassa S, Sakamoto S (2009). "Ethyl-eicosapentaenoic acid reduces liver lipids and lowers plasma levels of lipids in mice fed a high-fat diet". In Vivo 23 (5): 685–9. PMID 19779101. http://iv.iiarjournals.org/content/23/5/685.abstract. 
  18. ^ Kajikawa S, Harada T, Kawashima A, Imada K, Mizuguchi K (April 2009). "Suppression of hepatic fat accumulation by highly purified eicosapentaenoic acid prevents the progression of d-galactosamine-induced hepatitis in mice fed with a high-fat/high-sucrose diet". Biochim. Biophys. Acta 1791 (4): 281–8. doi:10.1016/j.bbalip.2009.01.014. PMID 19416647. http://linkinghub.elsevier.com/retrieve/pii/S1388-1981(09)00021-3. 
  19. ^ Wood SJ, Cocchi L, Proffitt TM, et al. (May 2010). "Neuroprotective effects of ethyl-eicosapentaenoic acid in first episode psychosis: a longitudinal T2 relaxometry pilot study". Psychiatry Res 182 (2): 180–2. doi:10.1016/j.pscychresns.2009.12.003. PMID 20413278. http://linkinghub.elsevier.com/retrieve/pii/S0925-4927(09)00300-X.  as PDF
  20. ^ Berger GE, Proffitt TM, McConchie M, et al. (December 2007). "Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial". J Clin Psychiatry 68 (12): 1867–75. PMID 18162017. http://article.psychiatrist.com/?ContentType=START&ID=10003381.  as PDF
  21. ^ Berger GE, Wood SJ, Wellard RM, et al. (September 2008). "Ethyl-eicosapentaenoic acid in first-episode psychosis. A 1H-MRS study". Neuropsychopharmacology 33 (10): 2467–73. doi:10.1038/sj.npp.1301628. PMID 18199999. 
  22. ^ Horrobin DF, Glen AI, Vaddadi K (October 1994). "The membrane hypothesis of schizophrenia". Schizophr. Res. 13 (3): 195–207. doi:10.1016/0920-9964(94)90043-4. PMID 7841132. 
  23. ^ Peet M. Essential fatty acids: theoretical aspects and treatment implications for schizophrenia and depression. Advances in Psychiatric Treatment (2002) 8: 223-229 Free Full Text
  24. ^ Berger GE, Smesny S, Amminger GP (April 2006). "Bioactive lipids in schizophrenia". Int Rev Psychiatry 18 (2): 85–98. doi:10.1080/09540260600583072. PMID 16777663. http://informahealthcare.com/doi/abs/10.1080/09540260600583072.  as PDF
  25. ^ Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, Roukas DK (August 2005). "Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review". Eur. Psychiatry 20 (5-6): 409–15. doi:10.1016/j.eurpsy.2004.12.007. PMID 16171655. 
  26. ^ Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ (September 2002). "Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia". Am J Psychiatry 159 (9): 1596–8. PMID 12202284. http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=12202284.  Full Free Text
  27. ^ Emsley R, Oosthuizen P, van Rensburg SJ (2003). "Clinical potential of omega-3 fatty acids in the treatment of schizophrenia". CNS Drugs 17 (15): 1081–91. doi:10.2165/00023210-200317150-00003. PMID 14661986. 
  28. ^ Peet M, Horrobin DF (2002). "A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms". J Psychiatr Res 36 (1): 7–18. doi:10.1016/S0022-3956(01)00048-6. PMID 11755456. 
  29. ^ Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M (December 2001). "A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia". Am J Psychiatry 158 (12): 2071–4. PMID 11729030. http://ajp.psychiatryonline.org/cgi/content/full/158/12/2071. 
  30. ^ Freeman MP, Hibbeln JR, Wisner KL et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. Journal of Clinical Psychiatry. 2006;67(12):1954-67 Free Full Text
  31. ^ Clinical Trials
  32. ^ Maes M, Smith RS (March 1998). "Fatty acids, cytokines, and major depression". Biol. Psychiatry 43 (5): 313–4. PMID 9513744. http://linkinghub.elsevier.com/retrieve/pii/S0006322397004010. 
  33. ^ Kiecolt-Glaser JK, Belury MA, Porter K, Beversdorf DQ, Lemeshow S, Glaser R (April 2007). "Depressive symptoms, omega-6:omega-3 fatty acids, and inflammation in older adults". Psychosom Med 69 (3): 217–24. doi:10.1097/PSY.0b013e3180313a45. PMC 2856352. PMID 17401057. http://www.psychosomaticmedicine.org/cgi/pmidlookup?view=long&pmid=17401057. 
  34. ^ Raison CL, Capuron L, Miller AH (January 2006). "Cytokines sing the blues: inflammation and the pathogenesis of depression". Trends Immunol. 27 (1): 24–31. doi:10.1016/j.it.2005.11.006. PMID 16316783. http://linkinghub.elsevier.com/retrieve/pii/S1471-4906(05)00288-7.  as PDF
  35. ^ Song C, Li X, Kang Z, Kadotomi Y. Omega-3 Fatty Acid Ethyl-Eicosapentaenoate Attenuates IL-1beta-Induced Changes in Dopamine and Metabolites in the Shell of the Nucleus Accumbens: Involved with PLA2 Activity and Corticosterone Secretion. Neuropsychopharmacology 2007;32(5):1207 Free Full Text
  36. ^ Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, Meltzer H (April 1996). "Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids". J Affect Disord 38 (1): 35–46. doi:10.1016/0165-0327(95)00092-5. PMID 8735157. 
  37. ^ McNamara RK (2006). "The emerging role of omega-3 fatty acids in psychiatry". Prostaglandins Leukot. Essent. Fatty Acids 75 (4-5): 223–5. doi:10.1016/j.plefa.2006.07.003. PMID 16930969. http://linkinghub.elsevier.com/retrieve/pii/S0952-3278(06)00117-7.  as PDF
  38. ^ McNamara RK, Carlson SE (2006). "Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology". Prostaglandins Leukot. Essent. Fatty Acids 75 (4-5): 329–49. doi:10.1016/j.plefa.2006.07.010. PMID 16949263. http://linkinghub.elsevier.com/retrieve/pii/S0952-3278(06)00125-6.  as PDF
  39. ^ Nemets B, Osher Y, Belmaker RH (2004). "Omega-3 fatty acids and augmentation strategies in treating resistant depression". Essent Psychopharmacol 6 (1): 59–64. PMID 15612654. 
  40. ^ Osher Y, Belmaker RH, Nemets B (2006). "Clinical trials of PUFAs in depression: State of the art". World J. Biol. Psychiatry 7 (4): 223–30. doi:10.1080/15622970600960173. PMID 17071542. 
  41. ^ Parker G, Gibson NA, Brotchie H, Heruc G, Rees AM, Hadzi-Pavlovic D (June 2006). "Omega-3 fatty acids and mood disorders". Am J Psychiatry 163 (6): 969–78. doi:10.1176/appi.ajp.163.6.969. PMID 16741195. http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=16741195.  Free Full Text
  42. ^ Puri BK, Counsell SJ, Hamilton G, Richardson AJ, Horrobin DF (October 2001). "Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover". Int. J. Clin. Pract. 55 (8): 560–3. PMID 11695079. 
  43. ^ Keck PE, Mintz J, McElroy SL, et al. (November 2006). "Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder". Biol. Psychiatry 60 (9): 1020–2. doi:10.1016/j.biopsych.2006.03.056. PMID 16814257. 
  44. ^ Jazayeri S, Tehrani-Doost M, Keshavarz SA, et al. (March 2008). "Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder". Aust N Z J Psychiatry 42 (3): 192–8. doi:10.1080/00048670701827275. PMID 18247193. 
  45. ^ Mischoulon D, Papakostas GI, Dording CM, et al. (December 2009). "A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder". J Clin Psychiatry 70 (12): 1636–44. doi:10.4088/JCP.08m04603. PMC 2918427. PMID 19709502. http://article.psychiatrist.com/?ContentType=START&ID=10006170. 
  46. ^ Stoll AL, Severus WE, Freeman MP, et al. (May 1999). "Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial". Arch. Gen. Psychiatry 56 (5): 407–12. doi:10.1001/archpsyc.56.5.407. PMID 10232294. http://archpsyc.ama-assn.org/cgi/content/full/56/5/407. 
  47. ^ Hirashima F, Parow AM, Stoll AL, et al. (October 2004). "Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder". Am J Psychiatry 161 (10): 1922–4. doi:10.1176/appi.ajp.161.10.1922. PMID 15465995. 
  48. ^ Frangou S, Lewis M, McCrone P (January 2006). "Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study". Br J Psychiatry 188: 46–50. doi:10.1192/bjp.188.1.46. PMID 16388069. http://bjp.rcpsych.org/cgi/pmidlookup?view=long&pmid=16388069. 
  49. ^ Frangou S, Lewis M, Wollard J, Simmons A. Preliminary in vivo evidence of increased N-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. J Psychopharmacol. 2006 Aug 4 Free Full Text
  50. ^ Zanarini MC, Frankenburg FR (January 2003). "omega-3 Fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study". Am J Psychiatry 160 (1): 167–9. PMID 12505817. http://ajp.psychiatryonline.org/cgi/content/full/160/1/167. 
  51. ^ Taepavarapruk P, Song C (February 2010). "Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1beta administrations: effects of omega-3 fatty acid EPA treatment". J. Neurochem. 112 (4): 1054–64. doi:10.1111/j.1471-4159.2009.06524.x. PMID 19968753.  as PDF
  52. ^ a b Song C, Li X, Kang Z, Kadotomi Y (March 2007). "Omega-3 fatty acid ethyl-eicosapentaenoate attenuates IL-1beta-induced changes in dopamine and metabolites in the shell of the nucleus accumbens: involved with PLA2 activity and corticosterone secretion" (PDF). Neuropsychopharmacology 32 (3): 736–44. doi:10.1038/sj.npp.1301117. PMID 16794572. http://www.biovita.fi/suomi/pdf/Song_2006.pdf. 
  53. ^ Song C, Zhao S (October 2007). "Omega-3 fatty acid eicosapentaenoic acid. A new treatment for psychiatric and neurodegenerative diseases: a review of clinical investigations". Expert Opin Investig Drugs 16 (10): 1627–38. doi:10.1517/13543784.16.10.1627. PMID 17922626. http://informahealthcare.com/doi/abs/10.1517/13543784.16.10.1627. 
  54. ^ Lynch AM, Loane DJ, Minogue AM, et al. (June 2007). "Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus". Neurobiol. Aging 28 (6): 845–55. doi:10.1016/j.neurobiolaging.2006.04.006. PMID 16714069. http://linkinghub.elsevier.com/retrieve/pii/S0197-4580(06)00121-7. 
  55. ^ Lynch AM, Lynch MA (June 2002). "The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation". Eur. J. Neurosci. 15 (11): 1779–88. doi:10.1046/j.1460-9568.2002.02012.x. PMID 12081657. http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0953-816X&date=2002&volume=15&issue=11&spage=1779. 
  56. ^ Ayton AK, Azaz A, Horrobin DF (August 2004). "Rapid improvement of severe anorexia nervosa during treatment with ethyl-eicosapentaenoate and micronutrients". Eur. Psychiatry 19 (5): 317–9. doi:10.1016/j.eurpsy.2004.06.002. PMID 15276668. http://linkinghub.elsevier.com/retrieve/pii/S0924933804001336.  as PDF
  57. ^ Ayton AK, Azaz A, Horrobin DF (October 2004). "A pilot open case series of ethyl-EPA supplementation in the treatment of anorexia nervosa". Prostaglandins Leukot. Essent. Fatty Acids 71 (4): 205–9. doi:10.1016/j.plefa.2004.03.007. PMID 15301789. http://linkinghub.elsevier.com/retrieve/pii/S0952327804000584.  as PDF
  58. ^ Kawashima A, Tsukamoto I, Koyabu T, et al. (April 2008). "Eicosapentaenoic acid supplementation for chronic hepatitis C patients during combination therapy of pegylated interferon alpha-2b and ribavirin". Lipids 43 (4): 325–33. doi:10.1007/s11745-008-3157-6. PMID 18320252. 
  59. ^ Shimizu T, Fujii T, Suzuki R, et al. (November 2003). "Effects of highly purified eicosapentaenoic acid on erythrocyte fatty acid composition and leukocyte and colonic mucosa leukotriene B4 production in children with ulcerative colitis". J. Pediatr. Gastroenterol. Nutr. 37 (5): 581–5. doi:10.1097/00005176-200311000-00015. PMID 14581801. 
  60. ^ Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T (April 2008). "Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis". J. Clin. Gastroenterol. 42 (4): 413–8. doi:10.1097/MCG.0b013e31815591aa. PMID 18277895. 
  61. ^ Lucas M, Asselin G, Mérette C, Poulin MJ, Dodin S (February 2009). "Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial". Am. J. Clin. Nutr. 89 (2): 641–51. doi:10.3945/ajcn.2008.26749. PMID 19116322. 
  62. ^ Lucas M, Asselin G, Mérette C, Poulin MJ, Dodin S (2009). "Effects of ethyl-eicosapentaenoic acid omega-3 fatty acid supplementation on hot flashes and quality of life among middle-aged women: a double-blind, placebo-controlled, randomized clinical trial". Menopause 16 (2): 357–66. doi:10.1097/gme.0b013e3181865386. PMID 19034052. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1072-3714&volume=16&issue=2&spage=357. 
  63. ^ Emsley R, Niehaus DJ, Oosthuizen PP, et al. (December 2008). "Safety of the omega-3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: results from a randomized, placebo-controlled trial". Psychiatry Res 161 (3): 284–91. doi:10.1016/j.psychres.2007.06.029. PMID 18962989. 

External links