The effects of astaxanthin supplementation on obesity, blood pressure, CRP, glycemic biomarkers, and lipid profile: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Previous studies lack consistent conclusions as to whether astaxanthin is actually linked to various health benefits as claimed. Here, we attempt to unravel the association of astaxanthin consumption with selected health benefits by performing a systematic review and meta-analysis. METHODS: Online literature search databases including Scopus, Web of Science, PubMed/Medline, Embase and Google Scholar were searched to discover relevant articles available up to 17 March 2020. We used mean changes and SD of the outcomes to assess treatment response from baseline and mean difference, and 95 % CI were calculated to combined data and assessment effect sizes in astaxanthin and control groups. RESULTS: 14 eligible articles were included in the final quantitative analysis. Current study revealed that astaxanthin consumption was not associated with FBS, HbA1c, TC, LDL-C, TG, BMI, BW, DBP, and SBP. We did observe an overall increase in HDL-C (WMD: 1.473 mg/dl, 95 % CI: 0.319-2.627, p = 0.012). As for the levels of CRP, only when astaxanthin was administered (i) for relatively long periods (≥ 12 weeks) (WMD: -0.528 mg/l, 95 % CI: -0.990 to -0.066), and (ii) at high dose (> 12 mg/day) (WMD: -0.389 mg/dl, 95 % CI: -0.596 to -0.183), the levels of CRP would decrease. CONCLUSION: In summary, our systematic review and meta-analysis revealed that astaxanthin consumption was associated with increase in HDL-C and decrease in CRP. Significant associations were not observed for other outcomes.

Nutraceutical characteristics of the brown seaweed carotenoid fucoxanthin.

Fucoxanthin (Fx), a major carotenoid found in brown seaweed, is known to show a unique and wide variety of biological activities. Upon absorption, Fx is metabolized to fucoxanthinol and amarouciaxanthin, and these metabolites mainly accumulate in visceral white adipose tissue (WAT). As seen in other carotenoids, Fx can quench singlet oxygen and scavenge a wide range of free radicals. The antioxidant activity is related to the neuroprotective, photoprotective, and hepatoprotective effects of Fx. Fx is also reported to show anti-cancer activity through the regulation of several biomolecules and signaling pathways that are involved in either cell cycle arrest, apoptosis, or metastasis suppression. Among the biological activities of Fx, anti-obesity is the most well-studied and most promising effect. This effect is primarily based on the upregulation of thermogenesis by uncoupling protein 1 expression and the increase in the metabolic rate induced by mitochondrial activation. In addition, Fx shows anti-diabetic effects by improving insulin resistance and promoting glucose utilization in skeletal muscle.

The Protective Role of Astaxanthin for UV-Induced Skin Deterioration in Healthy People-A Randomized, Double-Blind, Placebo-Controlled Trial.

Skin is a major safeguard tissue in humans. Because biological barrier function is deteriorated by several kinds of stresses including exposure to ultra-violet (UV) rays, the protection and treatment of skin conditions by dietary supplements are important. We therefore evaluated the effects of dietary supplementation with an algal food-derived antioxidant, astaxanthin, on UV-induced skin deterioration. Twenty-three healthy Japanese participants were recruited to a 10-week double-blind placebo-controlled study. They were assigned to the astaxanthin group supplemented with a capsule containing 4 mg of astaxanthin or the placebo group. To assess the protective role of astaxanthin for UV-induced skin deterioration, we determined the minimal erythema dose (MED) and analyzed UV-induced changes of moisture and transepidermal water loss (TEWL) at baseline and after 9 weeks of supplementation. Subjective skin conditions were assessed by the visual analog scale. The astaxanthin group showed increased MED compared with placebo. In addition, the astaxanthin group had a reduced loss of skin moisture in the irradiated area compared with placebo. Subjective skin conditions for “improvement of rough skin” and “texture” in non-irradiated areas were significantly improved by astaxanthin. Astaxanthin seems protective against UV-induced skin deterioration and helps maintain healthy skin in healthy people.

Astaxanthin in Skin Health, Repair, and Disease: A Comprehensive Review.

Astaxanthin, a xanthophyll carotenoid, is a secondary metabolite naturally synthesized by a number of bacteria, microalgae, and yeasts. The commercial production of this pigment has traditionally been performed by chemical synthesis, but the microalga Haematococcus pluvialis appears to be the most promising source for its industrial biological production. Due to its collective diverse functions in skin biology, there is mounting evidence that astaxanthin possesses various health benefits and important nutraceutical applications in the field of dermatology. Although still debated, a range of potential mechanisms through which astaxanthin might exert its benefits on skin homeostasis have been proposed, including photoprotective, antioxidant, and anti-inflammatory effects. This review summarizes the available data on the functional role of astaxanthin in skin physiology, outlines potential mechanisms involved in the response to astaxanthin, and highlights the potential clinical implications associated with its consumption.

Effects of Dietary Supplementation of Astaxanthin and Sesamin on Daily Fatigue: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study.

Severe fatigue can negatively affect quality of life, and oxidative stress may play a role in its mechanism. The aim of this study was to evaluate the effect of dietary supplementation of astaxanthin and sesamin (AS), strong food-derived antioxidants, on fatigue. Twenty-four healthy volunteers were supplemented with AS and placebo, each for four weeks. After each supplementation period, participants underwent tasks inducing mental and physical fatigue (visual display terminal task and ergometer task, respectively). Subjective fatigue was evaluated using a visual analogue scale during and after the mental and physical tasks, and daily subjective fatigue was evaluated by the Chalder fatigue questionnaire. Secondary outcomes included other subjective feelings, work efficiency, autonomic nerve activity, levels of an oxidative stress marker (plasma phosphatidylcholine hydroperoxide (PCOOH)) and safety. AS supplementation was associated with significantly improved recovery from mental fatigue compared with placebo. Increased PCOOH levels during mental and physical tasks were attenuated by AS supplementation. No differences between AS and placebo were detected in secondary outcomes, and no adverse effects of AS supplementation were observed. In conclusion, AS supplementation may be a candidate to promote recovery from mental fatigue which is experienced by many healthy people.

Protective Effect of Astaxanthin on Vocal Fold Injury and Inflammation Due to Vocal Loading: A Clinical Trial.

OBJECTIVES: Professional voice users, such as singers and teachers, are at greater risk of developing vocal fold injury from excessive use of voice; thus, protection of the vocal fold is essential. One of the most important factors that aggravates injury is the production of reactive oxygen species at the wound site. The purpose of the current study was to assess the effect of astaxanthin, a strong antioxidant, on the protection of the vocal fold from injury and inflammation due to vocal loading. STUDY DESIGN: This study is an institutional review board-approved human clinical trial. METHODS: Ten male subjects underwent a 60-minute vocal loading session and received vocal assessments prior to, immediately after, and 30 minutes postvocal loading (AST(-) status). All subjects were then prescribed 24 mg/day of astaxanthin for 28 days, after which they received the same vocal task and assessments (AST(+) status). Phonatory parameters were compared between both groups. RESULTS: Aerodynamic assessment, acoustic analysis, and GRBAS scale (grade, roughness, breathiness, asthenia, and strain) were significantly worse in the AST(-) status immediately after vocal loading, but improved by 30 minutes after loading. In contrast, none of the phonatory parameters in the AST(+) status were statistically worse, even when measured immediately after vocal loading. No allergic responses or adverse effects were observed after administration of astaxanthin. CONCLUSIONS: The current results suggest that astaxanthin can protect the vocal fold from injury and inflammation caused by vocal loading possibly through the regulation of oxidative stress.

Genetic Variants of LDLR and PCSK9 Associated with Variations in Response to Antihypercholesterolemic Effects of Armolipid Plus with Berberine.

BACKGROUND: Armolipid Plus (AP) is a nutraceutical that contains policosanol, fermented rice with red yeast, berberine, coenzyme Q10, folic acid, and astaxanthin. It has been shown to be effective in reducing plasma LDL cholesterol (LDLc) levels. In the multicenter randomized trial NCT01562080, there was large interindividual variability in the plasma LDLc response to AP supplementation. We hypothesized that the variability in LDLc response to AP supplementation may be linked to LDLR and PCSK9 polymorphisms. MATERIAL AND METHODS: We sequenced the LDLR 3' and 5' untranslated regions (UTR) and the PCSK9 5' UTR of 102 participants with moderate hypercholesterolemia in trial NCT01562080. In this trial, 50 individuals were treated with AP supplementation and the rest with placebo. RESULTS: Multiple linear regression analysis, using the response of LDLc levels to AP as the dependent variable, revealed that polymorphisms rs2149041 (c.-3383C>G) in the PCSK9 5' UTR and rs14158 (c.*52G>A) in the LDLR 3' UTR explained 14.1% and 6.4%, respectively, of the variability after adjusting for gender, age, and BMI of individuals. Combining polymorphisms rs2149041 and rs14158 explained 20.5% of this variability (p < 0.004). CONCLUSIONS: Three polymorphisms in the 3' UTR region of LDLR, c.*52G>A, c.*504G>A, and c.*773A>G, and two at the 5' UTR region of PCSK9, c.-3383C>G and c.-2063A>G, were associated with response to AP. These results could explain the variability observed in the response to berberine among people with moderate hypercholesterolemia, and they may be useful in identifying patients who could potentially benefit from supplementation with AP.

Astaxanthin from shrimp by-products ameliorates nephropathy in diabetic rats.

AIM: This study investigated the hypoglycemic and antioxidant effects of shrimp astaxanthin on the kidney of alloxan-induced diabetic rats. METHODS: Animals were distributed into four groups of six rats each: a control group (C), a diabetic group (D), a diabetic group supplemented with Astaxanthin (D+As) dissolved in olive oil and a diabetic group supplemented with olive oil (D+OO). In vitro antidiabetic effect was tested in plasma and kidney tissue. RESULTS: The group D of rats showed significant (P < 0.05) increase of glycemia, creatinine, urea and uric acid levels compared to those of the control group (C). Moreover, plasma and kidney malondialdehyde (MDA) and protein carbonyl (PCO) levels for the rats of the group D were significantly increased compared to the control group. Contrariwise, antioxidant enzyme activities, such as catalase (EC 1.11.1.6), superoxide dismutase (EC 1.15.1.1) and non-enzymatic levels of reduced glutathione, were significantly (P < 0.05) decreased in the plasma and kidney of diabetic rats compared to the control ones. The astaxanthin supplementation in rats diet improved the antioxidant enzyme activities and significantly decreased the MDA and PCO levels compared to diabetic rats. Indeed, no significant (P ≥ 0.05) improvement was observed for the fourth group (D+OO) compared to the control group (C). Histological analysis of kidney showed glomerular hypertrophy and tubular dilatation for the diabetic rats. For D+As rats, these histopathological changes were less prominent. CONCLUSIONS: Our results suggest that shrimp astaxanthin may play an important role in reduction of oxidative damage and could prevent pathological changes in diabetic rats suggesting promising application of shrimp astaxanthin in diabet treatment.

Porcentagem de proteína em suplementos para ovinos mantidos em pasto de capim-aruana na época seca / Protein percentage in supplements for sheep grazing Aruana grass on dry season

Objetivou-se avaliar o consumo de forragem e o desempenho de ovinos mantidos em pastagem de capim-aruana, submetidos a porcentagens crescentes de proteína bruta (PB) no suplemento, na época seca. Vinte borregos da raça Santa Inês foram utilizados em delineamento inteiramente ao acaso, com cinco tratamentos e quatro repetições. Os suplementos foram fornecidos em 1,0% do peso corporal, nas porcentagens de 0, 15, 20, 25 e 30%. O aumento de proteína bruta influenciou o consumo total de matéria seca (kg/dia) e a porcentagem do peso vivo, com valores máximos estimados de 1.296g (3,2% de MS) com 21,48 e 21,89% de PB no suplemento, respectivamente. O consumo de forragem máximo, estimado de 893g/dia, ocorreu com a PB de 21,5%. O aumento de PB nos suplementos resultou em efeito quadrático sobre o ganho médio diário, com valor máximo de 104g/dia com a PB de 23% no suplemento. Recomenda-se o uso de suplementos múltiplos com 21 a 23% de PB fornecidos na proporção de 1% do peso corporal (PC) para ovinos mantidos em pastos de capim-aruana na época seca...

The aim of this study was to evaluate the forage intake and grazing sheep performance keep on Aruana grass subjected to increasing crude protein (CP) levels in the supplement on dry season. Twenty Santa Ines male lambs were used, with initial body weight of 31.80kg by a completely randomized design with five treatments and four replications. The supplements were provided daily at 1% of body weight, with protein levels of 0, 15, 20, 25 and 30%. The increase of the crude protein levels promoted a squarely effect on dry matter intake (kg/day and % of BW), with maximum estimated values of 1296g and 3.2% of DM in CP levels of 21.48 and 21.89, respectively. The maximum forage intake estimated of 893g/day occurred in CP level de 21.51%. The increased of crude protein level in supplements increased squarely the average daily gain, with a maximum of 104g/day, for the 23% crude protein in the supplement. Thus, the use of the multiple supplements supplied in 1% of body weight with CP levels ranged 21 a 23% is indicated for sheep grazing Aruana grass on dry season...

Astaxanthin: sources, extraction, stability, biological activities and its commercial applications--a review.

There is currently much interest in biological active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Astaxanthin (3,3'-dihydroxy-ß, ß'-carotene-4,4'-dione) is a xanthophyll carotenoid, contained in Haematococcus pluvialis, Chlorella zofingiensis, Chlorococcum, and Phaffia rhodozyma. It accumulates up to 3.8% on the dry weight basis in H. pluvialis. Our recent published data on astaxanthin extraction, analysis, stability studies, and its biological activities results were added to this review paper. Based on our results and current literature, astaxanthin showed potential biological activity in in vitro and in vivo models. These studies emphasize the influence of astaxanthin and its beneficial effects on the metabolism in animals and humans. Bioavailability of astaxanthin in animals was enhanced after feeding Haematococcus biomass as a source of astaxanthin. Astaxanthin, used as a nutritional supplement, antioxidant and anticancer agent, prevents diabetes, cardiovascular diseases, and neurodegenerative disorders, and also stimulates immunization. Astaxanthin products are used for commercial applications in the dosage forms as tablets, capsules, syrups, oils, soft gels, creams, biomass and granulated powders. Astaxanthin patent applications are available in food, feed and nutraceutical applications. The current review provides up-to-date information on astaxanthin sources, extraction, analysis, stability, biological activities, health benefits and special attention paid to its commercial applications.

Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3.

IMPORTANCE: The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. OBJECTIVE: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS: The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONS: In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURE: S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCE: The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00345176.

Studies on meso-zeaxanthin for potential toxicity and mutagenicity.

The purpose of these studies was to examine the potential toxicity and genotoxicity of meso-zeaxanthin (MZ). Toxicity was assessed by administering MZ daily to rats for 13 weeks followed by a 4-week recovery period. Potential genotoxicity was assessed in separate experiments using the Ames test method. Rats were randomly assigned to four groups to receive corn oil (control) or MZ at dose levels of 2, 20 and 200 mg/kg/day by oral gavage (10/sex/group). Additional rats (five of each sex) in the control and the 200 mg/kg/day groups were retained for the recovery period. No compound-related clinical, biochemical or pathological signs or symptoms were noted and the no-observed-adverse-effect-level (NOAEL) of MZ was >200 mg/kg/day. To investigate genotoxicity, MZ was tested for its ability to induce reverse mutations (±microsomal enzymes) at 2 genomic loci; the histidine locus of 4 strains of Salmonella typhimurium and the tryptophan locus of Escherichia coli strain WP2uvrA. Six doses of MZ ranging from 10 to 5000 µg/plate were tested twice with vehicle and positive controls using 3 plates/dose. MZ did not cause any increase in the mean number of revertants/plate with any bacterial strain, with or without microsomal enzymes, and was therefore unlikely to be mutagenic.

Inhibitory effects of astaxanthin, ß-cryptoxanthin, canthaxanthin, lutein, and zeaxanthin on cytochrome P450 enzyme activities.

Astaxanthin, ß-cryptoxanthin, canthaxanthin, lutein and zeaxanthin, the major xanthophylls, are widely used in food, medicine, and health care products. To date, no studies regarding the inhibitory effects of these xanthophylls on the nine CYPs isozymes have been reported. This study investigated the reversible and time-dependent inhibitory potentials of five xanthophylls on CYPs activities in vitro. The reversible inhibition results showed that the five compounds had only a weak inhibitory effect on the nine CYPs. Lutein did not inhibit the nine CYPs activities. Astaxanthin weakly inhibited CYP2C19, with an IC50 of 16.2 µM; and ß-cryptoxanthin weakly inhibited CYP2C8, with an IC50 of 13.8 µM. In addition, canthaxanthin weakly inhibited CYP2C19 and CYP3A4/5, with IC50 values of 10.9 and 13.9 µM, respectively. Zeaxanthin weakly inhibited CYP3A4/5, with an IC50 of 15.5 µM. However, these IC50 values were markedly greater than the Cmax values reported in humans. No significant IC50 shift was observed in the time-dependent inhibition screening. Based on these observations, it is unlikely that these five xanthophylls from the diet or nutritional supplements alter the pharmacokinetics of drugs metabolized by CYPs. These findings provide some useful information for the safe use of these five xanthophylls in clinical practice.

Effects of formulation on the bioavailability of lutein and zeaxanthin: a randomized, double-blind, cross-over, comparative, single-dose study in healthy subjects.

PURPOSE: Lutein and zeaxanthin are macular pigments with a protective function in the retina. These xanthophylls must be obtained from the diet or added to foods or supplements via easy-to-use, stable formulations. The technique employed to produce these formulations may affect the bioavailability of the xanthophylls. METHODS: Forty-eight healthy volunteers were randomized into this double-blind, cross-over study investigating the plasma kinetics of lutein provided as two different beadlet formulations. Subjects (n = 48) received a single dose of 20 mg of lutein as either a starch-matrix ("SMB", FloraGLO® Lutein 5 %) or as a cross-linked alginate-matrix beadlet ("AMB", Lyc-O-Lutein 20 %) formulation. Plasma concentrations of lutein and zeaxanthin were measured at 0, 1, 3, 6, 9, 12, 14, 24, 26, 28, 32, 36, 48, 72, 168, and 672 h. RESULTS: The mean plasma AUC(0-72h), AUC(0-672h), and C(max) for total lutein and zeaxanthin and their all-E-isomers were significantly increased (p < 0.001) from pre-dose concentrations in response to SMB and AMB. There was no difference in lutein T max between the two test articles. However, by 14 h post-dose, total plasma lutein increased by 7 % with AMB and by 126 % with SMB. Total lutein AUC(0-72h) and AUC(0-672h) were 1.8-fold and 1.3-fold higher, respectively, for SMB compared to AMB. Both formulations were well tolerated by subjects in this study. CONCLUSION: These findings confirm that the bioavailability of lutein and zeaxanthin critically depends on the formulation used and document a superiority of the starch-based over the alginate-based product in this study.

Lutein and zeaxanthin supplementation in preterm very low-birth-weight neonates in neonatal intensive care units: a multicenter randomized controlled trial.

BACKGROUND: Human milk feeding protects against oxidative stress-induced damage in preterm neonates, including severe multifactorial diseases such as retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD). The carotenoids, which are not found in formula milk, might play a key role in these actions. METHODS: A multicenter, double-blind, randomized controlled trial was conducted in three tertiary Italian neonatal intensive care units. All preterm infants < 32(+6) weeks' gestational age were eligible and were randomized to a single, oral, daily 0.5-mL dose of carotenoid supplementation (0.14 mg lutein + 0.0006 mg zeaxanthin) or placebo (5% glucose solution) from birth till 36 weeks' corrected gestational age. Primary outcomes were threshold ROP, NEC > second stage, and BPD. Surveillance for detection of these diseases and for intolerance/adverse effects was performed. RESULTS: No treatment-related adverse effect was documented in the 229 analyzed infants, whose clinical/demographical characteristics were similar in the two groups. Threshold ROP incidence did not significantly differ in treated (6.2%) versus not treated infants (10.3%; p = 0.18). The same occurred for NEC (1.7% versus 5.1%; p = 0.15) and BPD (4.5% versus 10.3%; p = 0.07). Noteworthy, the progression rate from early ROP stages to threshold ROP was decreased by 50% (0.30 versus 0.44; p = 0.23). CONCLUSION: Lutein/zeaxanthin supplementation in preterm infants is well tolerated. No significant effect was seen on threshold ROP, NEC, or BPD. The decreasing trends of these outcomes in the treatment group need to be assessed and confirmed on larger sample-sizes.

Supplementation with all three macular carotenoids: response, stability, and safety.

PURPOSE: This study was designed to investigate serum and macular response to, and safety of supplementation with, meso-zeaxanthin (MZ), lutein (L), and zeaxanthin (Z), the carotenoids that constitute macular pigment (MP). METHODS: Forty-four healthy subjects were recruited into this randomized, placebo-controlled, clinical trial. Subjects consumed one tablet per day containing 10.6 mg MZ, 5.9 mg L, and 1.2 mg Z (intervention, I group) or placebo (P group). The spatial profile of MP optical density (MPOD) was measured with customized heterochromatic flicker photometry (cHFP), and serum concentrations of L and Z were quantified by using high performance liquid chromatography (HPLC). Subjects were assessed at baseline and at 3 and 6 months. Clinical pathology analysis was performed at baseline and 6 months. RESULTS: Serum concentrations of L and Z increased significantly in the I group (P = 0.001 and 0.003, respectively) and remained stable in the P group (P > 0.05). There was a significant increase in central MPOD in the I group (0.25°: P = 0.001; 0.5°: P = 0.001), with no significant change in the P group (P > 0.05). Clinical pathology analysis confirmed that all variables remained within the normal reference range, with the exception of total cholesterol and low-density lipoprotein (LDL), which exhibited baseline values outside the accepted normal reference range before supplementation. CONCLUSIONS: Subjects supplemented with MZ, L, and Z exhibited significant increases in serum concentrations of these carotenoids and a subsequent increase in central MPOD. Pathology analysis suggested no adverse clinical implications of consuming these carotenoids. (http://isrctn.org number, ISRCTN60816411).

Safety assessment of lutein and zeaxanthin (Lutemax 2020): subchronic toxicity and mutagenicity studies.

Lutein and zeaxanthin, naturally occurring carotenoids, have shown to reduce the risk of cataracts and age-related macular degeneration. Lutemax 2020 is a lutein and zeaxanthin (including meso-isomer) enriched product obtained from Marigold flowers (Tagetes erecta L). The objective of the present study was to investigate adverse effects, if any, of Lutemax 2020 in acute and subchronic toxicity, and mutagenicity studies. In acute toxicity study in rats no lethality was noted at 2000 mg Lutemax 2020/kg body weight (bw). In the subchronic study, Wistar rats (10/sex/group) were administered (gavage) lutein/zeaxanthin concentrate at dose levels of 0, 4, 40 and 400mg/kg bw/day for 90-days. Compared with the control group, administration of lutein/zeaxanthin concentrate did not result in any toxicologically significant treatment-related changes in clinical observations, ophthalmic examinations, body weights, body weight gains, feed consumption, and organ weights. No toxicologically relevant findings were noted in urinalysis, hematology or clinical biochemistry parameters at the end of the treatment or recovery period. Terminal necropsy did not reveal any treatment-related gross or histopathology findings. The results of mutagenicity testing in Salmonella typhimurium did not reveal any genotoxicity. The no observed-adverse-effect level (NOAEL) for lutein/zeaxanthin concentrate was determined as 400mg/kg bw/day, the highest dose tested.

Astaxanthin: a potential therapeutic agent in cardiovascular disease.

Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin.

The in vitro effects of Xancor, a synthetic astaxanthine derivative, on hemostatic biomarkers in aspirin-naïve and aspirin-treated subjects with multiple risk factors for vascular disease.

Astaxanthine is a polar carotenoid metabolite derived from a proprietary prodrug, Xancor, which aligns parallel with the membrane phospholipids exhibiting potent antioxidant, anti-inflammatory, and cell protective properties, although the precise mechanism of action is unknown. This prodrug is currently under development for hepatic, neurologic, and vascular disease indications. Considering established links between heart disease and stroke with platelets, coagulation cascade, and fibrinolysis, the aim of the study was to assess the effect of asthaxantine on human biomarkers of hemostasis. The rationale was to test a hypothesis that the drug may diminish activation of hemostasis, making it a potentially attractive addition to treat patients with vascular disease. In vitro effects of whole blood preincubation with escalating concentrations of asthaxantine (0.3 microM, 1 microM, 3 microM, 10 microM, 30 microM, and 100 microM) were assessed from 12 aspirin-naïve and eight aspirin-treated volunteers with multiple risk factors for vascular disease. A total of 25 biomarkers were measured, of which 12 were related to platelet function, 10 to coagulation, and three to fibrinolysis. Platelet aggregation induced by ADP, collagen, and arachidonic acid and expression of CD31, CD41, GP IIb/IIIa, CD51/61, P-selectin, CD63, CD107a, CD151+CD14, and CD154 were not affected. Coagulation indices such as aPTT, prothrombin time, thrombin time, fibrinogen, antithrombin III (antigen and activity), Protein C, Protein S (free and activity), and von Willebrand factor remained unchanged after incubation with astaxanthine. Fibrinolytic activity biomarkers such as plasminogen, D-dimer, and FDP were also not affected after in vitro pretreatment of blood samples with astaxanthine. In the projected subclinical (less than 1 microM), therapeutic (3 microM to 30 microM), and supratherapeutic concentration (100 microM), astaxanthine in vitro does not affect platelet, coagulation, or fibrinolytic indices in either aspirin-naïve or aspirin-treated subjects. These results are important for the assessment of the safety profile, but remain to be confirmed preclinically, in vivo, and ultimately in the clinic.

Competitive inhibition of carotenoid transport and tissue concentrations by high dose supplements of lutein, zeaxanthin and beta-carotene.

BACKGROUND: Carotenoids may interact differently in their absorption and transport in animals and humans. The simultaneous administration of large amounts of lutein, zeaxanthin and beta carotene would affect not only plasma values but also their concentrations in the retina and other tissues. OBJECTIVE: In this study, we investigated the transport, distribution and interactions of lutein, zeaxanthin and beta-carotene in the plasma, retina and other tissues of chicks fed supplements rich in lutein, zeaxanthin or beta-carotene. METHODS: Newly hatched male Leghorn chicks were randomly assigned to ten groups. One group provided baseline data (1-day-old group). The other groups were fed one of the following six diets for 14 or 28 days: high lutein diet; high zeaxanthin diet; three high beta-carotene supplemented diets and the control diet. Plasma and tissues including retina were analyzed for lutein and zeaxanthin and beta-carotene at baseline and at 14 and 28 days. RESULTS: All tissues had increased concentrations of lutein after the high lutein diet and had increased concentrations of zeaxanthin after the high zeaxanthin diet. After 28 days, the retinal concentrations of lutein and zeaxanthin in the chicks supplemented with lutein (27.2 mg/kg diet) and zeaxanthin (15.3 mg/kg diet) increased 128 and 116%, respectively, compared to the retinas of chicks fed the control diet (lutein 5.2 mg/kg and zeaxanthin 1.7 mg/kg). Lutein was decreased in plasma and other non-retinal tissues when the diet was supplemented with zeaxanthin; likewise, zeaxanthin was decreased in plasma and non-retinal tissues after the lutein supplement. Zeaxanthin increased in the retina after the high lutein supplement, and retinal lutein was maintained after the high zeaxanthin supplement. The high beta-carotene supplement increased the beta-carotene content of plasma and liver very little, and beta-carotene was not found in any other tissue in the chick, including the retina. More importantly, beta-carotene decreased the concentrations of both lutein and zeaxanthin in the plasma and most tissues, including the retina. CONCLUSION: High dose dietary supplementation of a single carotenoid may alter the assimilation of other carotenoids. The retina appears to have the capacity to preserve accumulation of lutein and zeaxanthin, but this capacity is diminished when intake of beta-carotene is high.