Algunas de las afirmaciones y estudios contenidos en los diferentes documentos de BIOFIL, BIOASTAX y BIOMEGA3, pueden ser revisados en las siguientes referencias:

Bibliografía:

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Determination of astaxanthin stereoisomers and colour attributes in flesh of rainbow trout (Oncorhynchus mykiss) as a tool to distinguish the dietary pigmentation source

Authors: V. M. Moretti a; T. Mentasti a; F. Bellagamba a; U. Luzzana b; F. Caprino a; G. M. Turchini c; I. Giani a; F. Valfr a

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scavenging by a disodium disuccinate astaxanthin derivative: Relative efficacy of individual stereoisomers versus the statistical mixture of stereoisomers by electron paramagnetic resonance imaging. Biochem Biophys Res Commun 2003; 307(3):704- 712. 1 Lawlor, S. M. and O'Brien, N. M. (1995) Astaxanthin: antioxidant effects in chicken embryo fibroblasts. Nutr. Res., 15:1695-1704. 1 Miki, W. (1991) Biological functions and activities of animal carotenoids. Pure Appl. Chem., 63(1):141-146. 1 Palozza, P. and Krinsky, N. I. (1992) Astaxanthin and canthaxanthin are potent antioxidants in a membrane model. Arch. Biochem. Biophys., 297:291-295. 1 Terao, J. (1989) Antioxidant activity of beta-carotene-related carotenoids in solution. Lipids, 24: 659-661. 1 Wang X, Willen R, Wadstrom T. Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Antimicrob Agents Chemother 2000; 44(9):2452-2457. 1 Naguib YM. Antioxidant activities of astaxanthin and related carotenoids. J Agric Food Chem 2000; 48(4):1150-1154. 1 Lyons NM, O'Brien NM. Modulatory effects of an algal extract containing astaxanthin on UVA-irradiated cells in culture. J Dermatol Sci 2002; 30(1):73-84. 1 O'Connor I, O'Brien N. Modulation of UVA light-induced oxidative stress by betacarotene, lutein and astaxanthin in cultured fibroblasts. J Dermatol Sci 1998; 16(3):226-230. 1 Kang JO, Kim SJ, Kim H. Effect of astaxanthin on the hepatotoxicity, lipid peroxidation and antioxidative enzymes in the liver of CCl4-treated rats. Methods Find Exp Clin Pharmacol 2001; 23(2):79-84. 1 Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H, Maoka T et al. Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. Antioxid Redox Signal 2003; 5(1):139-144. 1 Bennedsen M, Wang X, Willen R, Wadstrom T, Andersen LP. Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol Lett 1999; 70(3):185- 189. 1 Wang X, Willen R, Wadstrom T. Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Antimicrob Agents Chemother 2000; 44(9):2452-2457. 1 Kim JH, Kim YS, Song GG, Park JJ, Chang HI. Protective effect of astaxanthin on naproxen-induced gastric antral ulceration in rats. Eur J Pharmacol 2005; 514(1):53-59. 1 Gross GJ, Lockwood SF. Cardioprotection and myocardial salvage by a disodium disuccinate astaxanthin derivative (Cardax). Life Sci 2004; 75(2):215-224. 1 Lauver DA, Lockwood SF, Lucchesi BR. Disodium Disuccinate Astaxanthin (CardaxTM) Attenuates Complement Activation and Reduces Myocardial Injury Following Ischemia/Reperfusion. J Pharmacol Exp Ther 2005. 1 Li W, Hellsten A, Jacobsson LS, Blomqvist HM, Olsson AG, Yuan XM. Alphatocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits. J Mol Cell Cardiol 2004; 37(5):969-978. 1 Iwamoto T, Hosoda K, Hirano R, Kurata H, Matsumoto A, Miki W et al. Inhibition of low-density lipoprotein oxidation by astaxanthin. J Atheroscler Thromb 2000; 7(4):216-222. 1 Pengelly A. 2004 The Constituents of Medicinal Plants. 2nd ed. Sydney: Allen and Unwin. 1 Torrissen, O.J., R.W. Hardy, and K.D. Shearer. (1989) Pigmentation of salmonids-- carotenoid deposition and metabolism. CRC Crit. Rev. Aquat. Sci., 1: 209-225. 1 Torrissen, O. J. and Christiansen, R. (1995) Requirements for carotenoids in fish diets. J. Appl. Ichthyol., 11:225-230. 1 Britton, G., S. Liaaen-Jensen, and H. Pfander. (1995) Carotenoids today and challenges for the future. In: Britton, G., S. Liaaen-Jensen, and H. Pfander [eds], Carotenoids vol. 1A: Isolation and Analysis. Basel: Birkhäuser. 1 McCoy, M. (1999) Astaxanthin market a hard one to crack. Chem.& Eng. News, 77: 15-17.

1 Mera Pharmaceuticals website. 2005 URL: http://www.astafactor.com/manufacture.htm Accessed: 07/09/2005 1 AstaReal website. 2005 URL: http://www.astareal.com/ Accessed: 07/09/2005 1 Gross GJ, Lockwood SF. Cardioprotection and myocardial salvage by a disodium disuccinate astaxanthin derivative (Cardax). Life Sci 2004; 75(2):215-224. 1 Bernhard, K. Synthetic astaxanthin. The route of a carotenoid from research to commercialization. In: "Carotenoids: Chemistry and Biology," N. I. Krinsky et al. (editors), Plenum Press, New York, 1990, pp. 337-363. 1 Choubert G. and O. Heinrich. 1993. Carotenoid pigments of the green alga Haematococcus pluvialis : assay on rainbow trout Onchorhynchus mykiss, pigmentation in comparison with synthetic astaxanthin and cantaxanthin. Aquaculture 112, 217-226. 1 Wilkinson, J Substantial Equivalence Application for the Approval of an Astaxanthin Rich. Carotenoid Oleoresin, Zanthin® derived from Haematococcus pluvialis for use in ditary supplements tablets and capsules 2004 URL: www.food.gov.uk/multimedia/pdfs/astaxanthinnonconf2.pdf Accessed 08/07/2006 1 Cardounel AJ, Dumitrescu C, Zweier JL, Lockwood SF. Direct superoxide anion scavenging by a disodium disuccinate astaxanthin derivative: Relative efficacy of individual stereoisomers versus the statistical mixture of stereoisomers by electron paramagnetic resonance imaging. Biochem Biophys Res Commun 2003; 307(3):704- 712. 1 Lawlor, S. M. and O'Brien, N. M. (1995) Astaxanthin: antioxidant effects in chicken embryo fibroblasts. Nutr. Res., 15:1695-1704. 1 Miki, W. (1991) Biological functions and activities of animal carotenoids. Pure Appl. Chem., 63(1):141-146. 1 Palozza, P. and Krinsky, N. I. (1992) Astaxanthin and canthaxanthin are potent antioxidants in a membrane model. Arch. Biochem. Biophys., 297:291-295. 1 Terao, J. (1989) Antioxidant activity of beta-carotene-related carotenoids in solution. Lipids, 24: 659-661. 1 Wang X, Willen R, Wadstrom T. Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Antimicrob Agents Chemother 2000; 44(9):2452-2457. 1 Naguib YM. Antioxidant activities of astaxanthin and related carotenoids. J Agric Food Chem 2000; 48(4):1150-1154. 1 Lyons NM, O'Brien NM. Modulatory effects of an algal extract containing astaxanthin on UVA-irradiated cells in culture. J Dermatol Sci 2002; 30(1):73-84. 1 O'Connor I, O'Brien N. Modulation of UVA light-induced oxidative stress by betacarotene, lutein and astaxanthin in cultured fibroblasts. J Dermatol Sci 1998; 16(3):226-230. 1 Kang JO, Kim SJ, Kim H. Effect of astaxanthin on the hepatotoxicity, lipid peroxidation and antioxidative enzymes in the liver of CCl4-treated rats. Methods Find Exp Clin Pharmacol 2001; 23(2):79-84. 1 Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H, Maoka T et al. Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. Antioxid Redox Signal 2003; 5(1):139-144. 1 Bennedsen M, Wang X, Willen R, Wadstrom T, Andersen LP. Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol Lett 1999; 70(3):185- 189. 1 Wang X, Willen R, Wadstrom T. Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Antimicrob Agents Chemother 2000; 44(9):2452-2457. 1 Kim JH, Kim YS, Song GG, Park JJ, Chang HI. Protective effect of astaxanthin on naproxen-induced gastric antral ulceration in rats. Eur J Pharmacol 2005; 514(1):53-59. 1 Gross GJ, Lockwood SF. Cardioprotection and myocardial salvage by a disodium disuccinate astaxanthin derivative (Cardax). Life Sci 2004; 75(2):215-224. 1 Lauver DA, Lockwood SF, Lucchesi BR. Disodium Disuccinate Astaxanthin (CardaxTM) Attenuates Complement Activation and Reduces Myocardial Injury

Following Ischemia/Reperfusion. J Pharmacol Exp Ther 2005. 1 Li W, Hellsten A, Jacobsson LS, Blomqvist HM, Olsson AG, Yuan XM. Alphatocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits. J Mol Cell Cardiol 2004; 37(5):969-978. 1 Iwamoto T, Hosoda K, Hirano R, Kurata H, Matsumoto A, Miki W et al. Inhibition of low-density lipoprotein oxidation by astaxanthin. J Atheroscler Thromb 2000; 7(4):216-222. 1 Jacobsson LS, Yuan XM, Zieden B, Olsson AG. Effects of alpha-tocopherol and astaxanthin on LDL oxidation and atherosclerosis in WHHL rabbits. Atherosclerosis 2004; 173(2):231-237. 1 Hussein G, Nakamura M, Zhao Q, Iguchi T, Goto H, Sankawa U et al. Antihypertensive and neuroprotective effects of astaxanthin in experimental animals. Biol Pharm Bull 2005; 28(1):47-52. 1 Hussein G, Goto H, Oda S, Iguchi T, Sankawa U, Matsumoto K et al. Antihypertensive potential and mechanism of action of astaxanthin: II. Vascular reactivity and hemorheology in spontaneously hypertensive rats. Biol Pharm Bull 2005; 28(6):967-971. 1 Chew BP, Park JS. Carotenoid action on the immune response. J Nutr 2004; 134(1):257S-261S. 1 Jyonouchi H, Zhang L, Tomita Y. Studies of immunomodulating actions of carotenoids. II. Astaxanthin enhances in vitro antibody production to T-dependent antigens without facilitating polyclonal B-cell activation. Nutr Cancer 1993; 19(3):269- 280. 1 Jyonouchi H, Sun S, Gross M. Effect of carotenoids on in vitro immunoglobulin production by human peripheral blood mononuclear cells: astaxanthin, a carotenoid without vitamin A activity, enhances in vitro immunoglobulin production in response to a T-dependent stimulant and antigen. Nutr Cancer 1995; 23(2):171-183. 1 Ohgami K, Shiratori K, Kotake S, Nishida T, Mizuki N, Yazawa K et al. Effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Invest Ophthalmol Vis Sci 2003; 44(6):2694-2701. 1 Lee SJ, Bai SK, Lee KS, Namkoong S, Na HJ, Ha KS et al. Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation. Mol Cells 2003; 16(1):97-105. 1 Mahmoud FF, Haines DD, Abul HT, Abal AT, Onadeko BO, Wise JA. In vitro effects of astaxanthin combined with ginkgolide B on T lymphocyte activation in peripheral blood mononuclear cells from asthmatic subjects. J Pharmacol Sci 2004; 94(2):129- 136. 1 Chan A, Wong WM, Lam SK, Wong BC Prevention of gastric cancer Chinese Journal of Digestive Diseases 2003; 4; 100-104 1 Nishino H, Murakosh M, Ii T, Takemura M, Kuchide M, Kanazawa M et al. Carotenoids in cancer chemoprevention. Cancer Metastasis Rev 2002; 21(3-4):257- 264. 1 Li Z, Wang Y, Mo B. [The effects of carotenoids on the proliferation of human breast cancer cell and gene expression of bcl-2]. Zhonghua Yu Fang Yi Xue Za Zhi 2002; 36(4):254-257. 1 Tanaka T, Morishita Y, Suzui M, Kojima T, Okumura A, Mori H. Chemoprevention of mouse urinary bladder carcinogenesis by the naturally occurring carotenoid astaxanthin. Carcinogenesis 1994; 15(1):15-19. 1 Tanaka T, Makita H, Ohnishi M, Mori H, Satoh K, Hara A. Chemoprevention of rat oral carcinogenesis by naturally occurring xanthophylls, astaxanthin and canthaxanthin. Cancer Res 1995; 55(18):4059-4064. 1 Chew BP, Park JS, Wong MW, Wong TS. A comparison of the anticancer activities of dietary beta-carotene, canthaxanthin and astaxanthin in mice in vivo. Anticancer Res 1999; 19(3A):1849-1853. 1 Jyonouchi H, Sun S, Iijima K, Gross MD. Antitumor activity of astaxanthin and its mode of action. Nutr Cancer 2000; 36(1):59-65. 1 Kurihara H, Koda H, Asami S, Kiso Y, Tanaka T. Contribution of the antioxidative property of astaxanthin to its protective effect on the promotion of cancer metastasis in mice treated with restraint stress. Life Sci 2002; 70(21):2509-2520.

1 Hix LM, Lockwood SF, Bertram JS. Bioactive carotenoids: potent antioxidants and regulators of gene expression. Redox Rep 2004; 9(4):181-191. 1 Uchiyama K, Naito Y, Hasegawa G, Nakamura N, Takahashi J, Yoshikawa T. Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice. Redox Rep 2002; 7(5):290-293. 1 Naito Y, Uchiyama K, Aoi W, Hasegawa G, Nakamura N, Yoshida N et al. Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice. Biofactors 2004; 20(1):49-59. 1 Soon Park. J, Chyun. JH. Line LL, Maloney. MC, Chew. BP Immune Stimulating Action of Dietary Astaxanthin in Humans URL: http://www.beta-glucan-info.com/pdf/Chew.pdf Accessed: 09/07/2005 1 Nutrex Hawaii company website. URL: http://www.nutrex-hawaii.com/news.html Accessed: 09/07/2005 1 Fry, Andrew C.; Schilling, Brian K.; Chiu, Loren Z.F.; Hori, Naruhiro; Weiss, Lawrence W. FACSM Fiber Type-Specific Responses to Perceptions of Delayed Onset Muscle Soreness with Astaxanthin Supplementation [Annual Meeting Abstracts: D-32 – Free Communication/Poster: Supplements and Ergogenic Aids] 1 Lignell, A. 2001. Medicament for improvement of duration of muscle function or treatment of muscle disorders or diseases. US Patent 5,744,502 1 AstaReal website URL: http://www.astareal.com/ Accessed: 09/07/2005 1 Comhaire FH, Mahmoud A. The role of food supplements in the treatment of the infertile man. Reprod Biomed Online 2003; 7(4):385-391. 1 International Research and Development Corporation. 1989. Acute oral toxicity Study in Rats for Microbio Resources Inc. Appendix 23, in: FDA website Docket Number 95S-0316, Report #45, (cited in Astafactor Techreports URL: http://www.astafactor.com/techreports/tr3005-001.htm Accessed: 4.7.05) 1 MB research laboratories. 1999. 28 day repeated dose oral toxicity study in rates. Confidential report to Mera Pharmaceuticals Inc. 1 Koyo Mercantile Company ltd. 1988. Acute Toxicity Test for Riken Vitamin K.K. Appendix 24, in FDA website, Docket Number 95S-0316, Report #45, (URL: http://www.fda.gov/ohrms/dockets /dailys/062199/rpt00045.htm). Access date: November 27, 1999. (cited in Astafactor Techreports URL: http://www.astafactor.com/techreports/tr3005- 001.htm Accessed: 4.7.05) 1 Amar EC, Kiron V, Satoh S, Watanabe T. Enhancement of innate immunity in rainbow trout (Oncorhynchus mykiss Walbaum) associated with dietary intake of carotenoids from natural products. Fish Shellfish Immunol 2004; 16(4):527-537. 1 Verlhac V., Gabaudan J., Schierle J. 1995. Influence of astaxanthin on non-specific immune response of rainbow trout. Presented at the Nordic Symposium on Fish Immunology. May 1995, Reykiavik, Iceland. Clem, L.W. Warr G.W. (Eds.). The VIth ISDC congress. Abstracts. Presented at the Nordic Symposium on Fish Immunology. May 1995, Reykiavik, Iceland. 1 Waagbo R, Hamre K, Bjerkas E, Berge R, Wathne E, Lie O et al. Cataract formation in Atlantic salmon, Salmo salar L., smolt relative to dietary pro- and antioxidants and lipid level. J Fish Dis 2003; 26(4):213-229. 1 Darachai J., S. Piyatiratitivorakul, P. Kittakoop, C. Nitithamyong, P. Menasveta. 1998. Effects of astaxanthin on larval growth and survival of the giant tiger prawn, Penaeus monodon. the Vth Asian Fisheries Forum in Chiang Mai, Thailand (November 11-13, 1998). 1 Astafactor Techreports URL: http://www.astafactor.com/techreports/tr3005-001.htm Accessed: 4.7.05) 1 Cyanotech Corp. 1999. Haematococcus algae safety summary. FDA website Docket Number 95S-0316, Report #45, (URL: http://www.fda.gov/ohrms/dockets /dailys/062199/rpt00045.pdf)062199.htm). Access date: November 27, 1999. (cited in Astafactor Techreports URL: http://www.astafactor.com/techreports/tr3005-001.htm Accessed: 4.7.05) 1 Mera Pharmaceuticals Inc. 1999. A human safety trial of natural astaxanthin from Haematococcus pluvialis algae, produced with Mera Pharmaceuticals’ proprietary technology. Confidential Report: RD.0100.001.

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Chem 2000; 48(4):1150-1154. 19 Lyons NM, O'Brien NM. Modulatory effects of an algal extract containing astaxanthin on UVA-irradiated cells in culture. J Dermatol Sci 2002; 30(1):73-84. 20 O'Connor I, O'Brien N. Modulation of UVA light-induced oxidative stress by beta-carotene, lutein and astaxanthin in cultured fibroblasts. J Dermatol Sci 1998; 16(3):226-230. 21 Kang JO, Kim SJ, Kim H. Effect of astaxanthin on the hepatotoxicity, lipid peroxidation and antioxidative enzymes in the liver of CCl4-treated rats. Methods Find Exp Clin Pharmacol 2001; 23(2):79-84. 22 Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H, Maoka T et al. Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. Antioxid Redox Signal 2003; 5(1):139-144. 23 Bennedsen M, Wang X, Willen R, Wadstrom T, Andersen LP. Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol Lett 1999; 70(3):185-189. 24 Wang X, Willen R, Wadstrom T. Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Antimicrob Agents Chemother 2000; 44(9):2452-2457. 25 Kim JH, Kim YS, Song GG, Park JJ, Chang HI. Protective effect of astaxanthin on naproxeninduced gastric antral ulceration in rats. Eur J Pharmacol 2005; 514(1):53-59. 26 Gross GJ, Lockwood SF. Cardioprotection and myocardial salvage by a disodium disuccinate astaxanthin derivative (Cardax). Life Sci 2004; 75(2):215-224. 27 Lauver DA, Lockwood SF, Lucchesi BR. Disodium Disuccinate Astaxanthin (CardaxTM) Attenuates Complement Activation and Reduces Myocardial Injury Following Ischemia/Reperfusion. J Pharmacol Exp Ther 2005. 28 Li W, Hellsten A, Jacobsson LS, Blomqvist HM, Olsson AG, Yuan XM. Alpha-tocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits. J Mol Cell Cardiol 2004; 37(5):969-978. 29 Iwamoto T, Hosoda K, Hirano R, Kurata H, Matsumoto A, Miki W et al. Inhibition of lowdensity lipoprotein oxidation by astaxanthin. J Atheroscler Thromb 2000; 7(4):216-222. 30 Jacobsson LS, Yuan XM, Zieden B, Olsson AG. Effects of alpha-tocopherol and astaxanthin on LDL oxidation and atherosclerosis in WHHL rabbits. Atherosclerosis 2004; 173(2):231-237. 31 Hussein G, Nakamura M, Zhao Q, Iguchi T, Goto H, Sankawa U et al. Antihypertensive and neuroprotective effects of astaxanthin in experimental animals. Biol Pharm Bull 2005; 28(1):47-52. 32 Hussein G, Goto H, Oda S, Iguchi T, Sankawa U, Matsumoto K et al. Antihypertensive potential and mechanism of action of astaxanthin: II. Vascular reactivity and hemorheology in spontaneously hypertensive rats. Biol Pharm Bull 2005; 28(6):967-971. 33 Chew BP, Park JS. Carotenoid action on the immune response. J Nutr 2004; 134(1):257S- 261S. 34 Jyonouchi H, Zhang L, Tomita Y. Studies of immunomodulating actions of carotenoids. II. Astaxanthin enhances in vitro antibody production to T-dependent antigens without facilitating polyclonal B-cell activation. Nutr Cancer 1993; 19(3):269-280. 35 Jyonouchi H, Sun S, Gross M. Effect of carotenoids on in vitro immunoglobulin production by human peripheral blood mononuclear cells: astaxanthin, a carotenoid without vitamin A activity, enhances in vitro immunoglobulin production in response to a T-dependent stimulant and antigen. Nutr Cancer 1995; 23(2):171-183. 36 Ohgami K, Shiratori K, Kotake S, Nishida T, Mizuki N, Yazawa K et al. Effects of

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