Table 4.
Human clinical study for astaxanthin: Update on efficacy from human clinical studies.
| (A) Oxidative Stress. | ||||||
|---|---|---|---|---|---|---|
| Author/Year/ Reference |
Study Design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Oxidative stress markers in “metabolic disorder” | ||||||
| Rad NR. et al. 2022 [691] |
Randomized, double-blind, placebo-controlled prospective study |
50 Type 2 Diabetes Mellitus (T2DM) patients receiving metformin | 0, 10 mg/day | 12 weeks |
|
Investigation of additive synergistic effects on metformin (1000–2000 mg/day). Significantly increased blood total antioxidant capacity (TAC) levels at the end of the intervention only in the AX-treated group, while MDA remained unchanged. Similarly, increased SOD and catalase activity in blood and increased Nrf2 protein in PBMCs were observed at the end of the intervention only in the AX-treated group. No safety concerns were identified in this study. |
| Ishiwata S. et al. 2021 [692] |
Open-labeled, prospective study |
17 patients with systolic heart failure |
12 mg/day * | 3 months |
|
After 3 months of AX supplementation, significantly decreased serum d-ROM (Diacron-Reactive Oxygen Metabolites), p = 0.018, but no change in plasma biological antioxidant potential (BAP) or urinary ratio of 8-OHdG/Cr No safety concerns were identified in this study. |
| Shokri-Mashhadi, N. et al. 2021 [693] |
Randomized, double-blind, placebo-controlled prospective study |
44 patients with type 2 diabetes | 0, 8 mg/day | 8 weeks |
|
Decrease plasma levels of MDA (p < 0.05) No safety concerns were identified in this study. |
| Kato T. et al. 2020 [694] |
Open-labeled, prospective study | 16 patients with systolic heart failure |
12 mg/day * | 3 months |
|
Increased left ventricular ejection fraction (LVEF) from 34.1 ± 8.6% to 38.0 ± 10.0% (p = 0.031), and the 6-min walk distance increased from 393.4 ± 95.9 m to 432.8 ± 93.3 m (p = 0.023). Significant relationships were observed between percent changes in serum dROM level and those in LVEF. No safety concerns were identified in this study. |
| Coombes J.S et al. 2016 [695] Fassett, R.G. et al. 2008, [696] |
Randomized, double-blind, placebo-controlled prospective study |
58 renal transplant recipients | 0, 12 mg/day | 12 months |
|
There was no effect on oxidative stress in renal transplant recipients. (The XANTHIN trial) No safety concerns were identified in this study. |
| Takemoto M. et al. 2015 [697] |
Case report | 1 Werner syndrome patient | 12 mg/day * | 6 months |
|
There was no significant changes after AX intervention in MDA-modified LDL. No safety concerns were identified in this study. |
| Choi H.D. et al. 2011 [698] |
Randomized, two-arm, prospective study |
23 obese and overweight subjects | 5 and 20 mg/day | 3 weeks |
|
5 mg/day: MDA decreased by 34.6%, isoprostane (ISP) decreased by 64.9%, SOD increased by 193%, and TAC increased by 121% after 3 weeks compared to baseline (p < 0.01). 20 mg/day: MDA decreased by 35.2%, ISP decreased by 64.7%, SOD increased by 194%, and TAC increased by 125% after 3 weeks compared to baseline (p < 0.01). No safety concerns were identified in this study. |
| Choi, H.D. et al. 2011 [699] |
Randomized, double-blind, placebo-controlled, prospective study |
27 overweight subjects | 0, 20 mg/day | 12 weeks |
|
MDA reduced by 17.3% and 29% after 8 and 12 weeks compared to placebo (p < 0.01), ISP reduced by 40.2% and 52.9% after 8 and 12 weeks compared to placebo (p < 0.01), SOD increased by 124.8% after 12 weeks compared to placebo (p < 0.01), and TAC increased by 130.1% after 12 weeks compared to placebo (p < 0.05). No safety concerns were identified in this study. |
| Iwabayashi M. et al. 2009 [700] |
Open-labeled, prospective study | 35 healthy female subjects (with high oxidative stress, postmenopausal) |
12 mg/day | 8 weeks |
|
Increased blood biological antioxidant potential (Biological Antioxidant Potential (BAP); +4.6%, p < 0.05). No safety concerns were identified in this study. |
| Kim Y.K. et al. 2004 [701] |
Open-labeled, prospective study |
15 healthy postmenopausal females | 0, 2, 8 mg/day | 8 weeks |
|
Decreased plasma TBARS levels: 2 mg group from 1.42 ± 0.18 to 1.13 ± 0.18 nM/mg (p < 0.05). 8 mg AX group from 1.62 ± 0.14 nM/mg to 1.13 ± 0.12 nM/mg after 8 weeks (p < 0.05). Increased TAS from 0.85 ± 0.42 mM/L to 1.90 ± 0.58 mM/L in the 8 mg group. Urinary 8-isoprostane excretion did not decrease significantly. No safety concerns were identified in this study. |
| Oxidative stress markers in “skin” | ||||||
| Chalyk, N. et al. 2017 [702] |
Open-label, prospective study |
31 subjects; 18 obese, 8 overweight, 5 healthy, over the age of 40 |
4 mg/day | 92 days |
|
Plasma MDA decreased with AX by 11.2% on day 15 and by 21.7% on day 29 (N.S.). No safety concerns were identified in this study. |
| Yoon HS. et al. 2014 [703] |
Randomized, double-blind, placebo-controlled prospective study |
44 healthy females with wrinkles grade ≥ 2 (≥40 yrs.) |
0, 2 mg/day * |
12 weeks |
|
AX (2 mg/day) combined with collagen hydrolysate (3 g/day). Skin biopsy after UV irradiation: no difference in oxidative markers (Thymine dimers, 8-OHdG) between the two groups in histological evaluation. Regarding mRNA expression, significantly upregulated expression of procollagen type I tended to upregulate fibrillin-1, while significantly downregulated MMP1 and MMP12 in the AX group compared to the placebo. No safety concerns were identified in this study. |
| Satoh A. et al. 2009 [704] |
Randomized, single-blind, placebo-controlled prospective study |
27 patients with atopic dermatitis | 0, 12 mg/day | 4 weeks. |
|
The Th1/Th2 balance shifted significantly toward Th1, and urinary 8-OHdG concentrations decreased slightly but significantly. No safety concerns were identified in this study [Article in Japanese] |
| Oxidative stress markers in “ophthalmology; after cataract surgery “ | ||||||
| Hashimoto H. et al. 2021 [705] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
The antioxidant effect of AX was analyzed in relation to age. None of the parameters were correlated with age before AX intake; however, only total hydroperoxide values were significantly correlated after AX intake (r = 0.4, p < 0.05). Total hydroperoxide levels were similar in younger and older age groups (<70 vs. ≥70 years) before AX intake but significantly decreased in younger age groups after intake (−0.21 ± 0.18 vs. −0.05 0.31, p < 0.05), resulting in a significant difference (p < 0.05). Thus, the previously observed decrease in mean total hydroperoxide levels after AX intake was likely due to a greater response in the younger age group analysis associated with this study [706]. No safety concerns were identified in this study. |
| Hashimoto H. et al. 2019 [707] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
In this analysis, the effect of AX intake on the relationship between VEGF levels and ROS-related parameters before and after bilateral cataract surgery was analyzed by gender. VEGF, hydrogen peroxide, and total hydroperoxide levels in the aqueous humor, as well as O2•− scavenging activity, were measured. For women only, VEGF levels and O2•− scavenging activity before AX intake were negatively correlated (r = −0.6, p < 0.01) and positively correlated with total hydrogen peroxide levels before and after AX intake (r = 0.7, p < 0.01, respectively). Analysis associated with this study [706] No safety concerns were identified in this study. |
| Hashimoto H. et al. 2016 [708] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
Superoxide anion scavenging activity (U/mL): 18.2 ± 4.1 at 0 weeks reduced to 19.9 ± 3.6 after 2 weeks of supplementation compared to baseline, p < 0.05. Total hydroperoxides (d-ROM) from 1.16 ± 0.18 at 0 weeks reduced to 1.04 ± 0.31 after 2 weeks were of supplementation compared to baseline, p < 0.05. Analysis associated with this study [706]. No safety concerns were identified in this study. |
| Hashimoto, H. et al. 2013 [709] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
Reduced total hydroperoxides (hydrogen peroxides, lipid peroxides, and peroxides of protein in aqueous humor; p < 0.05) increased superoxide scavenging activity (p< 0.05) Analysis associated with this study [706] No safety concerns were identified in this study. |
| Hashimoto H. et al. 2011 [706] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
Reduced total hydroperoxides (hydrogen peroxides, lipid peroxides, and peroxides of protein in aqueous humor; p < 0.05). No safety concerns were identified in this study. [Article in Japanese] |
| Oxidative stress markers in “sports/musculoskeletal function “ | ||||||
| Kawamura A. et al. 2021 [710] |
Randomized open-labeled, prospective study |
26 healthy male subject (22.3 ± 0.3 yrs.) |
N/A (1mg AX/100g salmon) * |
10 weeks |
|
Serum carbonylated protein level as an oxidative stress marker tended to be lower immediately after exercise than before exercise in the intervention group only (p = 0.056). No safety concerns were identified in this study. |
| McAllister M.J. et al. 2021 [711] |
Randomized, double-blind, placebo-controlled, crossover study |
14 healthy young subjects, (23 ± 2 yrs.) |
0, 6 mg/day | 4 weeks |
|
Glutathione was ∼7% higher following AX compared with placebo (p < 0.05). There was no effect on plasma hydrogen peroxide or MDA (p > 0.05). Advanced oxidation protein products (AOPP) were reduced by ∼28% (N.S.; p = 0.45). No safety concerns were identified in this study. |
| Baralic, I. et al. 2015 [712] |
Randomized, double-blind, placebo-controlled, prospective study |
40 healthy subjects (young soccer players) |
0, 4 mg/day | 90 days |
|
Improved prooxidant-antioxidant balance (PAB; p < 0.05) No safety concerns were identified in this study. |
| Baralic I. et al. 2013 [713] |
Randomized, double-blind, placebo-controlled prospective study |
40 healthy subjects (soccer players) | 0, 4 mg/day | 90 days |
|
Protected thiol groups against oxidative modification (increase in SH groups, p < 0.05; improved PON1 activity towards paraoxon and diazoxon, p < 0.05 and p < 0.01, respectively) No safety concerns were identified in this study. |
| Djordjevic B. et al. 2013 [714] |
Randomized, double-blind, placebo-controlled prospective study |
32 healthy subjects (soccer players) | 0, 4 mg/day | 90 days |
|
Regular training significantly increased O2•¯ levels (main training effect, p < 0.01). TBARS and AOPP levels did not change throughout this study. Decreased post-exercise TAS levels only in the placebo group (p < 0.01). Increased total SH levels in both the AX and placebo groups (by 21% and 9%, respectively), and the effect of supplementation was marginally significant (p = 0.08). Decreased basal SOD activity in both the placebo and AX groups at the end of this study (main training effect, p < 0.01). No safety concerns were identified in this study. |
| Klinkenberg L.J. et al. 2013 [715] |
Randomized, double-blind, placebo-controlled, prospective study |
32 well-trained male cyclists (25 ± 5 years, V˙O2peak = 60 ± 5 mL·kg−1·min−1, Wmax = 5.4 ± 0.5 W·kg−1) |
0, 20 mg/day * | 4 weeks |
|
Not significant (N.S.); changes in markers of antioxidant capacity (trolox equivalent antioxidant capacity; TEAC, uric acid, and MDA). No safety concerns were identified in this study. |
| Res T. et al. 2013 [716] |
Randomized, double-blind, placebo-controlled, prospective study |
32 trained male cyclists or triathletes (25 ± 1 years, V˙O2peak = 60 ± 1 mL·kg−1·min−1, Wmax = 395 ± 7 W) |
0, 20 mg/day | 4 weeks |
|
N.S.; Plasma TAC (p = 0.90) or attenuated malondialdehyde levels (p = 0.63). Whole-body fat oxidation rates during submaximal exercise (from 0.71 +/− 0.04 to 0.68 ± 0.03 g.min and from 0.66 ± 0.04 to 0.61 ± 0.05 g.min in the Placebo and AX groups, respectively; p = 0.73), time trial performance (from 236 ± 9 to 239 ± 7 and from 238 ± 6 to 244 ± 6 W in the Placebo and AX groups, respectively; p = 0.63). No safety concerns were identified in this study. |
| Djordjevic B. et al. 2011 [714] |
Randomized, double-blind, placebo-controlled, prospective study |
32 male elite soccer players | 0, 4 mg/day | 90 days |
|
Changes in elevated O2•¯ concentrations after football exercise were statistically significant only in the placebo group (exercise × supplement effect, p < 0.05); TAS values decreased significantly after exercise only in the placebo group (p < 0.01). After the intervention, total SH content increased in the SH group (21% and 9%, respectively), and the effect of AX was marginally significant (p = 0.08). Basal SOD activity was significantly reduced in both the Placobo and AX groups at the end of this study (main effect of training, p < 0.01). .No safety concerns were identified in this study. |
| Bloomer, R.J. et al. 2005 [717] |
Randomized, placebo-controlled, prospective study |
20 resistance trained male subjects (25.1 ± 1.6 years) |
0, 4 mg/day * | 3 months |
|
N.S.; Muscle soreness, creatine kinase (CK), and muscle performance were measured before and through 96 h of eccentric exercise No safety concerns were identified in this study. |
| Oxidative stress markers in “geriatrics “ | ||||||
| Nakanishi R. et al. 2021 [718] |
Randomized, double-blind, placebo-controlled prospective study |
29 nursing home residents healthy elderly subjects (80.9 ± 1.5 yrs.) |
0, 12 mg/twice a day * (0, 24 mg/day) |
16 weeks |
|
Decrease in d-ROM values with the AX group (p < 0.01) but not with the placebo group; No safety concerns were identified in this study. |
| Petyaev I.M., et al. 2018 [719] |
Randomized, blinded, four-arm, prospective study |
32 subjects with oxidative stress, 8 subjects taking AX only, (60–70 yrs) | 0, 7 mg/day * with DC |
4 weeks |
|
Reduced serum oxidized LDL by 55.4% after 4 weeks (p < 0.05). Reduced MDA by 52.7% after 4 weeks (p < 0.05). Increase in serum nitric oxide (NO) levels (p = 0.054). No safety concerns were identified in this study. |
| Kiko T. et al. 2012 [720] |
Randomized, double-blind, placebo-controlled prospective study |
30 healthy subjects (56.3 ± 1.0 yrs.) |
0, 6, 12 mg/day | 12 weeks |
|
Amyloid β (Aβ) 40 and Aβ42 concentrations were much higher in erythrocytes (RBC) than in plasma. RBC Aβ levels increased with aging. After AX supplementation, RBC Aβ concentrations decreased. The RBC Aβ levels were positively correlated with RBC PLOOH and inversely correlated with AX concentration in RBC. A study related to the ref. [721] No safety concerns were identified in this study. |
| Oxidative stress markers in “fatigues” | ||||||
| Imai A. et al. 2018 [722] |
Randomized, double-blind, placebo-controlled crossover study |
42 healthy subjects | 0, 6 mg/day * | 4 weeks |
|
Elevated PCOOH levels during mental and physical tasks were attenuated by AX supplementation. No safety concerns were identified in this study. |
| Hongo N. et al. 2017 [723] |
Randomized, double-blind, placebo-controlled, prospective study |
39 healthy subjects | 0, 12 mg/day * | 12 weeks |
|
The rate of change in BAP values at week 12 was not significantly different between the AX group and the control group. No safety concerns were identified in this study. [Article in Japanese] |
| Oxidative stress markers in “other disorders and unhealthy condition” | ||||||
| Ledda A. et al. 2017 [724] |
Open-labeled, two-arm prospective study |
59 patients with genitourinary cancers (prostate or bladder malignancies) who had undergone and completed cancer treatments (radiotherapy, chemotherapy or intravesical immunotherapy with increased oxidative stress and residual symptoms) | 0, 8 mg/day * | 6 weeks |
|
Oncotris: containing 264 mg/day curcumin, 500 mg/day extract of cordyceps, and 8 mg/day AX (from EP217785227). Oncotris supplementation reduced plasma d-ROM levels. No safety concerns were identified in this study. |
| Yagi H. et al. 2013 [725] |
Case reports | 34 OAB patients with anticholinergic agent-resistant (75.5 ± 8.0 years) |
0, 12 mg/day * |
8 weeks |
|
Significantly improved international prostate symptom score (IPSS), QOL scores, benign prostatic hyperplasia impact index (BII) scores, and urinary 8-OHdG in patients AX could improve both urinary symptoms and QOL for anticholinergic agent-resistant OAB. No safety concerns were identified in this study. [Article in Japanese] |
| Kim, J.H. et al. 2011 [726] |
Randomized, repeated measured, prospective study |
39 heavy smokers, 39 non-smokers | 0, 5, 20, or 40 mg/day | 3 weeks |
|
5 mg/day: MDA and ISP were significantly lower after 2 and 3 weeks compared to baseline in smokers (p < 0.05). SOD and TAC significantly increased after 1, 2, and 3 weeks compared to baseline in smokers (p < 0.05) 20 mg/day: MDA and ISP significantly were lower after 1, 2, and 3 weeks compared to baseline in smokers (p < 0.05). SOD and TAC significantly increased after 1, 2, and 3 weeks compared to baseline in smokers (p < 0.05). 40 mg/day: MDA and ISP were significantly lower after 1, 2, and 3 weeks compared to baseline in smokers (p < 0.05). SOD and TAC significantly increased after 2 and 3 weeks compared to baseline in smokers (p < 0.05). No safety concerns were identified in this study. |
| Yamada T. et al. 2010 [727] |
Open-labeled, prospective study | 6 healthy subjects and 6 Sjoegren’s syndrome (SS) subjects |
12 mg/day | 2 weeks |
|
Reduced protein oxidation (−10%, p < 0.05) No safety concerns were identified in this study. |
| Oxidative stress markers in “healthy subjects” | ||||||
| Chen JT, Kotani K. 2017 [728] |
Randomized, double-blind, placebo-controlled, prospective study |
29 healthy females | 0, 12 mg/day | 3 months |
|
N.S.: Serum d-ROM levels, urinary 8-OHdG, and BAP following AX treatment. A Significant increase in blood leukocytes was also found in the AX-treated group. No safety concerns were identified in this study. |
| Balcerczyk A. et al. 2014 [729] |
Randomized, double-blind, placebo-controlled prospective study |
66 healthy females, (35–55 yrs.) |
0, 15 mg/day * |
12 weeks |
|
Test supplement (NucleVital Q10): omega-3 acids (1350 mg/day), ubiquinone (300 mg/day), lycopene (45 mg/day), lutein palmitate (30 mg/day), zeaxanthin palmitate (6 mg/day), L-selenomethionine (330 mg/day), cholecalciferol (30 µg/day), α-tocopherol (45 mg/day), and AX (15 mg/day). Oxidative stress: significantly increased TAC of plasma and activity of erythrocyte SOD, with slight effects on oxidative stress biomarkers in erythrocytes: MDA and 4-hydroxyalkene levels. Antiaging effect: significant changes in mRNA expression of SIRT1 and 2 in PBMCs. No safety concerns were identified in this study. |
| Miyazawa T. et al. 2011 [730] |
Randomized, double-blind, placebo-controlled, prospective study |
30 middle- aged & senior subjects (mean: 50.6 yrs.) |
0, 1, 3 mg/day |
12 weeks |
|
Erythrocyte AX concentrations There was no significant changes in erythrocyte phospholipid hydroperoxide concentration after astaxanthin intake in either the 1 mg/day or 3 mg/day groups. No safety concerns were identified in this study. |
| Nakagawa K. et al. 2011 [721] |
Randomized, double-blind, placebo-controlled prospective study |
30 healthy subjects | 0, 6, 12 mg/day | 12 weeks |
|
6 mg/day: Reduction in total phospholipid hydroperoxides (PLOOH) at 12 weeks compared to baseline (p < 0.01) and compared to placebo (p < 0.05). Reduced phosphatidyl ethanolamine hydroperoxide (PEOOH) at 12 weeks compared to baseline (p < 0.05) and compared to placebo (p < 0.05). Increased plasma AX concentration at 12 weeks (86 nM) compared to baseline (p < 0.01, 6 to 9 nM) and compared to placebo (p < 0.01, 8 nM). 12 mg/day: 48% reduction in total PLOOH at 12 weeks compared to baseline (p < 0.01) and 35% less total PLOOH at 12 weeks compared to control (p < 0.05). The 12 mg/day group had 46% less phosphatidylcholine hydroperoxide (PCOOH) at 12 weeks compared to baseline (p < 0.01). No safety concerns were identified in this study. |
| Peng L. et al.,
2011 [731] |
Randomized, placebo-controlled study |
115 healthy subjects | 0, 40 mg/day |
90 days |
|
Comparing with the control group, MDA contents in the test group decreased significantly (p < 0.01), and SOD and GSH-Px activities increased significantly (p < 0.01). No safety concerns were identified in this study. |
| Park J.S. et al. 2010 [732] |
Randomized, double-blind, placebo- controlled, prospective study |
42 healthy subjects | 0, 2, 8 mg/day | 8 weeks |
|
2 mg/day: Concentrations of plasma 8-hydroxy-2′-deoxyguanosine reduced after 4 weeks and 8 weeks compared to placebo (p < 0.05). 8 mg/day: Concentrations of plasma 8-hydroxy-2′-deoxyguanosine reduced after 4 weeks and 8 weeks compared to placebo (p < 0.05). No safety concerns were identified in this study. |
| Karppi, J. et al. 2007 [733] |
Randomized, double-blind, placebo-controlled, prospective study |
39 healthy subjects | 0, 8 mg/day | 3 months |
|
Decreased oxidation of fatty acids in healthy men (p < 0.05) No safety concerns were identified in this study. |
| Oxidative stress markers in “infertility” | ||||||
| Jabarpour M. et al. 2023 [652] |
Randomized, placebo-controlled prospective study |
53 Patients with polycystic ovary syndrome (PCOS) |
0, 6 mg/twice a day (0,12 mg/day) |
60 days |
|
Antioxidant markers: Increased levels of total antixoidant capacity (TAC) in follicular fluid. ART outcomes: higher rates of high-quality oocytes, high-quality embryo, and oocyte maturity in the AX group (the oocyte number, fertilization rate, and fertility rate; N.S.). No safety concerns were identified in this study. |
| Rostami S. et al. 2023 [653] |
Randomized, triple-blind, placebo-controlled prospective study |
50 Patients of endometriosis (stage III/ IV) |
0, 6 mg/day | 12 weeks |
|
Antioxidant markers: Increased serum levels of TAC (p = 0.004) and superoxide dismutase (SOD, 13.458 ± 7.276 vs. 9.040 ± 5.155; p = 0.010) were observed in the AX intervention group after therapy. In addition, serum Malondialdehyde (MDA, p = 0.031) decreased significantly after AX treatment. No safety concerns were identified in this study. |
| Ghantabpour T. et al. 2022 [734] |
N/A | The first phase; 10 semen samples from healthy men, the second phase; 25 semen samples from healthy men |
0, 0.5, 1, 2 μM | N/A |
|
Supplementation of sperm freezing medium with 1 µM AX was found to improve all parameters of sperm motility and viability (p ≤ 0.05). In addition, reduced levels of ROS parameters (intracellular hydrogen peroxide and superoxide) compared to the control group (p ≤ 0.05). AX also significantly reduced phosphatidylserine exogenous levels (p ≤ 0.05) and lipid peroxidation (p ≤ 0.05) after the freeze-thaw process. (in vitro study) |
| Gharaei R. et al. 2022 [651] |
Randomized, double-blind, placebo-controlled prospective study |
40 Patients with polycystic ovary syndrome (PCOS) |
0, 8 mg/day | 40 days |
|
AX supplementation resulted in significantly higher serum catalase and TAC levels in the AX group compared with the placebo group. However, there were no significant differences in serum MDA and SOD levels between groups. The expression of antioxidant genes such as Nrf2, HO-1, and NQ-1 was significantly increased in the granulosa cells (GC) of the AX group. No safety concerns were identified in this study. |
| Comhaire F.H. et al. 2005 [735] |
Randomized, double-blind, placebo-controlled, prospective study |
30 males with infertility of ≥ 12 months |
0, 16 mg/day |
3 months |
|
Significantly decreased ROS (chemiluminescence) in spermatozoa in the Astaxanthin group (n = 11), but not in the placebo group (n = 19). No safety concerns were identified in this study. |
| (B) Skin Health | ||||||
|
Author/year/
reference |
Study Design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Evaluation of the effects on the skin under normal condition. | ||||||
| Sudo A et al. 2020 [736] |
Placebo-controlled prospective study |
11 healthy subject (College floorball athletes for women in physical education |
0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil) studied the efficacy of V7 on subjective fatigue, sports performance, and skin conditions in floorball athletes. Significant improvements in ‘firmness’ and ‘whiteness’, which are subjective measures of skin condition, were observed in the V7 supplementation group compared to pre-supplementation, while no significant changes were observed in the placebo group. No safety concerns were identified in this study. [Article in Japanese] |
| Sudo A et al. 2019 [737] |
Placebo-controlled prospective study |
19 healthy subject (College softball player for women in physical education |
0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil) studied the efficacy of V7 on subjective fatigue, sports performance, and skin conditions in college softball players. Subjective symptoms were evaluated with the VAS. The change of VAS in PRE and POST in the V7 group showed statistically significant improved skin blemishes; a comparison of V7 and placebo POST showed statistically significant improved skin elasticity and whitening. The percent change between PRE and POST in V7 was statistically significantly higher in dull skin and total score. No safety concerns were identified in this study. [Article in Japanese] |
| Chalyk, N. et al. 2017 [702] |
Open-label, prospective study |
31 subjects; 18 obese, 8 overweight, 5 healthy, over the age of 40 |
4 mg/day | 92 days |
|
Morphological analysis of the residual skin surface components (RSSC; age-related changes in corneocyte desquamation, microbial presence, and lipid droplet size): decreased levels of corneocyte desquamation (p = 0.0075) and microbial presence (p = 0.0367); increase in lipid droplet size among obese (body mass index >30 kg/m2) subjects (p = 0.0214). No safety concerns were identified in this study. |
| Tominaga K. et al. 2017 [738] |
Randomized, double-blind, placebo-controlled prospective study |
65 healthy female (age, 35–60 years) with a wrinkle grade of 2.5 to 5.0 |
0, 6, 12 mg/day |
16 weeks |
|
Water content (cheeks): no significant difference from the placebo group regarding improvement. However, it was significantly worse in the placebo group over the period, but unchanged in the low and high AX-treated groups. TEWL (cheek): no significant change during the study. Wrinkle depth (eye rims): no significant difference. However, it worsened during the study period in the placebo group but did not change in the low and high AX-treated groups. Elasticity (cheeks): significantly improved in the two AX groups IL-1α: increased during the study but not in the high AX dose group (p < 0.05). No safety concerns were identified in this study. |
| Tsukahara H. et al, 2016 [739] |
Randomized, double-blind, placebo-controlled prospective study |
40 healthy subjects, those concerned about skin dullness or age-related skin deterioration. | 0, 3 mg/day | 8 weeks |
|
TEWL (left cheek): significantly improved. Moisture content (left cheek): significant improvement. Melanin and color difference (left cheek): Melanin improved significantly. Elasticity (left cheek): Significant improvement in partial (R6). Facial image analysis (left part): “texture” significantly improved. No safety concerns were identified in this study. [Article in Japanese] |
| Phetcharat L. et al. 2015 [740] |
Randomized, double-blind, placebo-controlled, prospective study |
34 healthy subjects with wrinkles on the face (crow’s-feet) (35–65 yrs.) |
4 mg/day | 8 weeks |
|
The comparative control was rose hip powder. Therefore, the results of the evaluation before and after the intervention in the AX group are shown. Moisture content (forehead): improved from the pre-treatment level at week 8 (p < 0.001) in the AX group. Elasticity (cheeks): improved from the pre-treatment level in the AX group at week 8 (p < 0.05). Crow’s-feet wrinkle depth (buttocks of the eyes): improved from pre-treatment levels at Weeks 4 and 8 in the AX group (p < 0.05). No safety concerns were identified in this study. |
| Yoon HS. et al. 2014 [703] |
Randomized, double-blind, placebo-controlled prospective study |
44 healthy females with wrinkles grade ≥ 2 (≥40 yrs.) |
0, 2 mg/day * |
12 weeks |
|
AX (2 mg/day)is combined with collagen hydrolysate (3 g/day). Skin condition of non-UV- irradiated skin: significantly improved TEWL (cheek) at week 12 (p = 0.045), tended to improve water content (cheek), tended to improve elasticity (cheek) at week 4, and significantly improved at week 12. No safety concerns were identified in this study. |
| Suganuma K. et al. 2012 [741] |
Randomized, double-blind, placebo-controlled, prospective study |
44 female subjects (Mean 37.26 yrs.) |
0, 6 mg/day * |
20 weeks |
|
Water content (cheeks): increasing trend over the study period. The AX+VC+VE group showed an increase compared to the VC+VE (p < 0.10). Elasticity (upper cheekbones): no significant change. Fine wrinkles: significant improvement in the AX+VC+VE group (also improved compared to VC+VE group) No safety concerns were identified in this study. |
| Tominaga K. et al. 2012 [742] (Study 2) |
Randomized, double-blind, placebo-controlled, prospective study |
36 male subjects (20 to 60 yrs.) |
0, 3 mg/twice a day * (0,6 mg/day) |
6 weeks |
|
TEWL: significantly decreased in AX (p < 0.01). Water content: increasing trend in the left cheek in the AX group (p = 0.08). Elasticity: significantly improved in the AX group (p < 0.05). Fine wrinkles: the total area ratio and volume of wrinkles in the AX group decreased (p < 0.05). Sebum production: decreased in the AX group (p = 0.085). No safety concerns were identified in this study. |
| Evaluation of protective effect against UV irradiation | ||||||
| Ito N. et al. 2018 [743] |
Randomized, double-blind, placebo-controlled, prospective study |
22 healthy subjects with skin phototype was type II or III (30–56 yrs.) |
0, 6 mg/day | 10 weeks |
|
Subjective skin condition was assessed on a visual analog scale; the AX group showed an increase in minimum erythema dose (MED) compared to placebo. The AX group had a reduced loss of skin moisture in the irradiated area compared with the placebo. Subjective skin conditions for “improvement of rough skin” and “texture” in non-irradiated areas were significantly improved by AX. No safety concerns were identified in this study. |
| Carrascosa JM et al. 2017 [744] |
Randomized, double-blind, placebo-controlled, prospective study |
31 healthy subjects with skin phototypes II and III |
4 mg/day * | 56 days |
|
Intervention: Genosun oral a combination of AX (4 mg), β-carotene(4.8 mg), vitamin E (6 mg), vitamin C(40 mg), lutein (2.4 mg), and lycopene (2.4 mg). MED at Days 1, 29, and 57 was evaluated.The Intervention group showed a significant increase over placebo in the tolerance to an erythemal dose of UVR. Increased UVR tolerance was reflected in an increase in MED of 12.4% and 20.51% over baseline after 29 and 57 days, respectively, with a significant difference between treatment and control groups at the end of the study. No safety concerns were identified in this study. |
| Yoon HS. et al. 2014 [703] |
Randomized, double-blind, placebo-controlled prospective study |
44 healthy females with wrinkles grade ≥ 2 (≥40 yrs.) |
0, 2 mg/day * |
12 weeks |
|
AX (2 mg/day) combined with collagen hydrolysate (3 g/day). Skin biopsy after UV irradiation: no difference in oxidative markers (Thymine dimers, 8-OHdG) between the two groups in histological evaluation. Regarding mRNA expression, significantly upregulated expression of procollagen type I tended to upregulate fibrillin-1, while significantly downregulated MMP1 and MMP12 in the AX group compared to placebo. No safety concerns were identified in this study. |
| Satoh A. et al. 2011 [745] |
Randomized, single-blind, placebo-controlled prospective study |
26 healthy subjects | 0, 3 mg/day | 4 + 4 weeks |
|
After 4 weeks of administration, UV light was irradiated (2 MED), and the given test substance was administered for another 4 weeks. Skin color was evaluated with a colorimeter, a mexameter, and a skin color scale before administration, before UV irradiation, and 1, 7, 14, 21, and 28 days after UV irradiation. The results showed that the L value of the colorimeter and skin color scale scores were significantly higher in the Ax group than in the placebo group, and the amount of melanin after UV irradiation was significantly lower in the Ax group than in the placebo group. No safety concerns were identified in this study. [Article in Japanese] |
| Yamashita E. 2006 [746] |
Randomized, single-blind, placebo-controlled, prospective study |
49 female subjects (Mean 47 yrs.) |
0, 2 mg/twice a day (0, 4 mg/day) * |
6 weeks |
|
Water content (left cheek): significant improvement in the 6-week treatment group (compared to the start of treatment). Elasticity (left eye rim): significant improvement in the placebo group at weeks 3 and 6 (p < 0.05). Inspection/Palpation by a dermatologist: improvement in fine lines, wrinkles, and elasticity (week 6). Skin surface observation: improvement in fine lines, wrinkles, and elasticity (week 6). No safety concerns were identified in this study. |
| Yamashita E. 2002 [747] |
Randomized, double-blind, placebo-controlled, prospective study |
16 healthy female subjects with dry skin |
0, 2 mg/day * | 4 weeks |
|
Moisture content: trend of improvement in the AX group compared to placebo at week 2 on the left eye corner and at week 4 on the cheeks, with significant improvement at week 4 on the eye corner (p < 0.05). Wrinkle depth (eye corner): no significant difference. Subjective symptoms (questionnaire): subjective improvement in spots/freckles (week 2), acne/wipes (week 4). Inspection/Palpation by a dermatologist: improvement in smoothness, moistness, and firmness. No safety concerns were identified in this study. [Article in Japanese] |
| Evaluation of efficacy in skin diseases. | ||||||
| Satoh A. et al. 2009 [704] |
Randomized, single-blind, placebo-controlled prospective study |
27 patients with atopic dermatitis | 0, 12 mg/day | 4 weeks. |
|
Severity (SCORAD), pruritus (VAS), quality of life (Skindex-16, STAI), immune function (Th1/Th2, blood catecholamines), and antioxidant status (urinary 8-OHdG, isoprostanes) were assessed. There were significant differences in the degree of itching between the Ax and placebo groups. However, there was significant improvement in Skindex-16 symptoms and STAI status anxiety in the Ax group. In addition, the Th1/Th2 balance shifted significantly toward Th1. No safety concerns were identified in this study [Article in Japanese] |
| (C) Eye health | ||||||
|
Author/year/
reference |
Study design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Evaluation of efficacy in “asthenopia (eyestrain)”. | ||||||
| Sekikawa T. et al. 2023 [748] |
Randomized, double-blind, placebo-controlled prospective study |
59 healthy subjects with VDT operation (Mean 39 yrs.) |
0, 9 mg/day |
6 weeks |
|
Visual acuity: In participants ≥40 yrs, AX had a higher protective effect of on corrected visual acuity of the dominant eye after visual display terminal (VDT) work at 6 weeks after intake in the AX group vs the control group (p < 0.05). In <40 yrs, no significant difference between the AX and control groups. Functional visual acuity and pupil constriction rate: No significant difference between the AX and control groups No safety concerns were identified in this study. |
| Kizawa Y. et al. 2021 [749] |
Randomized double-blind, placebo-controlled, prospective study |
40 healthy subjects with VDT operation | 0, 6 mg/day * | 6 weeks |
|
Intervention (active group): 72 mg anthocyanin from blueberry (bilberry) extract, 10 mg lutein and 6 mg AX. After 6 weeks, there was a significant improvement in the active group compared to the placebo group in the average percentage of pupillary response in both eyes and in the dominant eye before and after operating the visual display terminal. In addition, the scores for “A sensation of trouble in focusing the eyes” and “Difficulty in seeing objects in one’s hand and nearby, or fine print” were significantly improved in the active group compared to the placebo group before and after ingestion. No statistically significant improvements were observed in tear degradation time, visual acuity, Schirmer test value, macular pigment optical density level, or muscle hardness. No safety concerns were identified in this study. |
| Sudo A et al. 2019 [750] |
Open-labeled, prospective study |
19 healthy females (Mean 47.3 yrs.) |
0, 0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil) studied the efficacy of V7 on subjective fatigue and skin conditions in typical middle-aged females. Subjective symptoms were evaluated with the VAS. The change in VAS in PRE and POST in the V7 group showed no statistically significant improved in eye strain. No safety concerns were identified in this study. [Article in Japanese] |
| Sudo A et al. 2019 [737] |
Placebo-controlled prospective study |
19 healthy subject (College softball player for women in physical education |
0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil) studied the efficacy of V7 on subjective fatigue, sports performance, and skin conditions in college softball players. Subjective symptoms were evaluated with the VAS. A comparison of V7 and placebo POST showed statistically significant increases in eye strain. The percent change between PRE and POST in V7 was statistically significantly higher in eye strain. No safety concerns were identified in this study. [Article in Japanese] |
| Kono K. et al. 2014 [751] |
Randomized, double-blind, placebo-controlled prospective study |
48 healthy subjects who complained of eye strain |
0, 4 mg/day * |
4 weeks |
|
Test supplement (Enkin; lutein (10mg), 20 mg of bilberry extract, and 26.5 mg of black soybean hull extract (a total of 2.3 mg of cyanidin-3-glucoside in both extracts), DHA (50mg), and AX (4mg). The variation of the “near-point accommodation” of both eyes from baseline to 4 weeks after-intervention in the test supplement group (TS) was significantly higher than in the placebo (P) group (1.321 ± 0.394 diopter (D) in the TS group and 0.108 ± 0.336 D in the P group, p = 0.023, respectively). Regarding subjective symptoms, there was a significant improved on “stiff shoulders or neck” and “blurred vision” in the TS group compared to the P group (p < 0.05). No safety concerns were identified in this study. |
| Nagaki Y. et al. 2010 [46] |
Randomized, single-blind, placebo-controlled prospective study |
82 healthy subjects with VDT operation (6 h or more per day for more than 1 year) and frequently experienced eyestrain |
0, 9 mg/day | 4 weeks |
|
(1) The post-treatment accommodation ability of the AX group with respect to value and rate of change was significantly higher than that of the control group. (2) The distribution of rate of change also showed significant improvement in post-treatment accommodation ability of the AX group when compared to control group. (3) Subjective questionnaire regarding 4 conditions (“eyestrain,” “hazy vision,” “flickering images,” and “my shoulders/back feel stiff”) showed that the AX group significantly improved compared to the of control group. No safety concerns were identified in this study. [Article in Japanese] |
| Kajita M et al. 2009 [47] |
Open-labeled, prospective study | 82 healthy males with presbyopia (Mean 53.9 yrs.) |
6 mg/day | 4 weeks |
|
The pupillary constriction ratio before and after AX supplementation was measured by TriIRIS C9000. The change in subjective symptoms after supplementation was examined by a questionnaire. The results showed a significant increase in pupillary constriction ratio after supplementation with AX, therefore suggesting that astaxanthin may also improve the accommodation function of the eye and some subjective symptoms related to presbyopia in middle-aged and older people with complaints of eye strain. No safety concerns were identified in this study. [Article in Japanese] |
| Seya Y. et al. 2009 [752] |
Open-labeled, prospective study |
10 healthy subjects with VDT operation (Mean Age 24.6 yrs., VDT 6.9 h/day) |
6 mg/day |
4 weeks. |
|
The effects of visual fatigue on reaction times measured in a visual pursuit task. Regardless of the duration of the intake period for AX, the reaction times at the early trials/blocks of the reaction time task were shorter than those at the late trials/blocks during a long-lasting, 500-trial experimental session. In addition, the reaction times at the late stages (14th and 28th days) of the AX intake were shorter than those at the early stage (1st day). No safety concerns were identified in this study [Article in Japanese] |
| Tsukahara H. et al. 2008 [753] |
Open-labeled, prospective study | 13 healthy subjects with shoulder Stiffness | 6 mg/days * | 4 weeks |
|
6mg of AX and 50mg of flaxseed lignin. All patients completed the efficacy evaluation, which confirmed significant improvement in physical symptoms such as shoulder stiffness, physical fatigue, mental irritability, cold hands and feet, eye fatigue, and redness of the eyes. At the end of the treatment, laser Doppler graphics also confirmed a significant increase in blood flow in the shoulders. No safety concerns were identified in this study. [Article in Japanese] |
| Iwasaki T. et al. 2006 [44] |
Randomized, double-blind, placebo-controlled crossover study |
39 healthy females (Mea 20.5 yrs.) |
0, 6 mg/day |
2 weeks |
|
Accommodative function and subjective symptoms relating to eyestrain were measured before and after the task and after the 10-min rest following the task. The data were then compared between the AX and Placebo groups by the double-blind cross-over method. After the task, accommodation contraction and relaxation times were extended in both the AX and Placebo groups. Comparison between the two groups showed that after the task, accommodation relaxation time was significantly extended in the Placebo group, in contrast to AX. Accommodative contraction and relaxation times were significantly prolonged after the 10-min rest in the P group as compared to AX. The symptoms of eye fatigue, eye heaviness, blurred vision, and eye dryness in the Placebo group increased; however, the AX group only showed increases in eye fatigue and eye heaviness. No safety concerns were identified in this study. [Article in Japanese] |
| Nagaki Y. et al. 2006 [45] |
Randomized, double-blind, placebo-controlled, prospective study |
48 healthy subjects with VDT operation (6 h or more per day for more than 1 year) and frequently experienced eyestrain |
0, 6 mg/day | 4 weeks |
|
1. Significantly improved the magnitude of change in amplitude of accommodation before and after supplementation in the AX supplemented group compared with the control group. 2. Significantly better scores of the distribution of the percentage change in amplitude of accommodation after supplementation in the AX supplemented group compared with the control group. 3. In the subjective asthenopia evaluation, the AX supplemented significantly improved for the two items “dimness of sight” and “stiff shoulders and back” compared with the control group, and an improvement tendency was seen in “heavy head.” No safety concerns were identified in this study. [Article in Japanese] |
| Nitta T. et al. 2005 [41] |
Randomized, placebo-controlled, prospective study |
30 health subjects (Mean time consumed for close work (e.g., VDT work) was approx. 7 h./day) | 0, 6, 12 mg/day | 4 weeks |
|
l. Significantly increased the objective accommodation power of the AX 12 mg group compared to that of pre-dosing. 2. Significantly shortened was the positive accommodation time in the AX 6 mg and the 12 mg groups compared to those of pre-dosing, and the negative accommodation time was significantly shortened in the AX placebo and the 6 mg groups compared to those of pre-dosing. 3. VAS; many parameters of subjective symptoms were improved in the AX 6 mg group. No safety concerns were identified in this study. [Article in Japanese] |
| Shiratori K. et al. 2005 [42] |
Randomized, placebo- controlled, prospective study |
39 healthy subjects who complained of eyestrain | 0, 6 mg/day | 4 weeks |
|
1. Significantly higher sub-objective accommodation power (changing rate) in the AX group than that of the control group. 2. Significantly higher rate of positive and negative accommodation times (rate of change) in the AX group compared to those of the control group. 3. In the AX group, subjective degree of asthenopia (eye strain) measured by VAS showed significant improvement in two parameters, i.e., “My eyes get bleary” and “I get irritated easily”, compared to the control group. No safety concerns were identified in this study. [Article in Japanese] |
| Takahashi N. et al. 2005 [43] |
Open-labeled, prospective study |
10 healthy subjects | 6 mg/day |
2 weeks |
|
Effects of astaxanthin on accommodative recovery derived from a rest after VDT work were studied. Evaluated (9 dominant eyes) by values for objective diopter, HFC (High Frequency Component in Accommodative micro-fluctuation), and accommodative reaction. Increased HFC after rest was significantly restrained by AX supplementation compared to the increase shortly after working. No safety concerns were identified in this study. [Article in Japanese] |
| Nakamura A. et al. 2004 [40] |
Randomized, placebo- controlled, prospective study |
49 healthy subjects | 0, 2, 4, 12 mg/day | 4 weeks |
|
For far visual acuity (5 m), there was no significant difference in the results for uncorrected visual acuity between the 0 mg group and the 2 mg group before and after the start of peroral administration; however, uncorrected visual acuity improved significantly for the 4 mg group and 12 mg group (p < 0.05). For corrected visual acuity, no significant difference was found for any of the groups. No significant changes were found in refraction or flicker fusion frequency. For the accommodation test, positive accommodation time was shortened significantly for the 4mg group and the 12 mg group (p < 0.05). No significant change was found in the other items. For pupillary reflex, no significant difference was found in the miosis ratio (%), T1 (ms), T2 (ms), or VC (mm2/s). No safety concerns were identified in this study. [Article in Japanese] |
| Nagaki Y. et al. 2002 [39] |
Randomized, placebo- controlled, prospective study |
26 VDT subjects + 13 non-VDT subjects (control) |
0, 5 mg/day | 4 weeks |
|
Group A: 13 non-VDT workers/no supplementation. Group B: 13 VDT workers with AX, 5 mg/day, for 4 weeks, Group C: 13 VDT workers with placebo, 5 mg/day, for 4 weeks. Accommodation amplitudes in Groups B and C before supplementation were significantly (p < 0.05) lower than in Group A. After AX supplementation, the accommodation amplitude in Group B was significantly (p < 0.01) larger than before supplementation, while the accommodation amplitude in Group C after placebo supplementation was unchanged. The CFFs in Groups B and C before supplementation were significantly (p < 0.05) lower than in Group A. The CCFs in Groups B and C did not change after supplementation. Amplitudes and latencies of P100 in PVEP in Groups B and C before supplementation were similar to those in Group A and did not change after supplementation. No safety concerns were identified in this study. |
| Evaluation of benefits in cataract surgery | ||||||
| Hashimoto H. et al. 2021 [705] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
We analyzed the antioxidant effect of AX in relationship to age. None of the parameters were correlated with age before AX intake, but only total hydroperoxide values were significantly correlated after AX intake (r = 0.4, p < 0.05). Total hydroperoxide levels were similar in younger and older age groups ( < 70 vs. ≥70 years) before AX intake, but significantly decreased in younger age groups after intake (−0.21 ± 0.18 vs. −0.05 ± 0.31, p < 0.05), resulting in a significant difference (p < 0.05). Thus, the previously observed decrease in mean total hydroperoxide levels after AX intake was likely due to a greater response in the younger age group. Analysis associated with the study [706]. No safety concerns were identified in this study. |
| Hashimoto H. et al. 2019 [707] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
In this analysis, the effect of AX intake on the relationship between VEGF levels and ROS-related parameters before and after bilateral cataract surgery was analyzed by gender. VEGF, hydrogen peroxide, and total hydroperoxide levels in the aqueous humor, as well as O2 scavenging activity, were measured. For women only, VEGF levels and O2 scavenging activity before AX intake were negatively correlated (r = −0.6, p < 0.01) and positively correlated with total hydrogen peroxide levels before and after AX intake (r = 0.7, 0.8, p < 0.01, respectively). Analysis associated with this study [706] No safety concerns were identified in this study. |
| Hashimoto H. et al. 2016 [708] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
Superoxide anion scavenging activity (U/mL): 18.2 ± 4.1 at 0 weeks reduced to 19.9 ± 3.6 after 2 weeks of supplementation compared to baseline, p < 0.05. Total hydroperoxides (U CARR) from 1.16 ± 0.18 at 0 weeks were reduced to 1.04 ± 0.31 after 2 weeks of supplementation compared to baseline, p < 0.05. Analysis associated with this study [706]. No safety concerns were identified in this study. |
| Hashimoto, H. et al. 2013 [709] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
Reduced total hydroperoxides (hydrogen peroxides, lipid peroxides, and peroxides of protein in aqueous humor; p < 0.05) increased superoxide scavenging activity (p < 0.05). Analysis associated with this study [706] No safety concerns were identified in this study. |
| Hashimoto H. et al. 2011 [706] |
Open-labeled, prospective study |
35 subjects who underwent bilateral cataract surgery (intraocular lens implantation) (Mean c.a 71 yrs.) |
6 mg/day | 2 weeks |
|
Reduced total hydroperoxides (hydrogen peroxides, lipid peroxides, and peroxides of protein in aqueous humor; p < 0.05) No safety concerns were identified in this study. [Article in Japanese] |
| Evaluation of efficacy in other ophthalmological categories. | ||||||
| Yoshida K. et al. 2023 [754] |
Randomized, double-blind, placebo-controlled prospective study |
57 healthy subjects | 0, 6 mg/day |
8 weeks |
|
Active group: 10 mg lutein, 2 mg zeaxanthin, and 6 mg of AX. Significantly improved eye–hand coordination after visual display terminal (VDT) operation at 8 weeks in the active group. No clear improvement in the effect of the supplementation on smooth-pursuit eye movements. The active group also showed a significant increase in macular pigment optical density (MPOD) levels. No safety concerns were identified in this study. |
| D’Aloisio R. et al., 2022 [755] |
Retrospective study | 15 AMD patients treated with daily oral nutritional supplement with AX. 13 AMD patients treated w/o. daily oral nutritional supplement (control) |
0, 12 mg/day * |
6 months |
|
Nutritional supplement: 100 mg lutein, 80 mg bromelain, 120 mg VC, 30 mg VE, 400 μg folic acid, Zn, Cu, 1000 IU D3 vitamin, and 12 mg AX (Astazin 10). There was a statistically significant difference in choriocapillary vessel density (CCVD) values between cases and controls at baseline (p < 0.001) and at follow-up (p < 0.001); choroidal thickness measurements were statistically significant between cases and controls (p = 0.002) and in cases at follow-up (p < 0.001). No safety concerns were identified in this study. |
| Tian L. et al. 2022 [756] |
Open-labeled, prospective study |
60 middle-aged and elderly patients with mild-to-moderate dry eye disease (DED) | 6 mg/twice a day (12mg/day) |
30 days |
|
Significantly improved (p < 0.05) to varying degrees after treatment compared to pre-treatment for the ocular surface disease index (OSDI) score, non-invasive tear break-up time (NIBUT), fluorescein break-up time (BUT), corneal fluorescein staining (CFS) score, eyelid margin signs, MG expressivity, mibum quality, and blink frequency, but no differences were found for tear meniscus height, Schirmer I test, conjunctival hyperemia, tear fluid lipid layer thickness, meibum quality, meibomian gland dropout (MGDR), incomplete blink rate, Visual acuity (VA), intraocular pressure (IOP). No safety concerns were identified in this study. |
| Huang J.Y. et al. 2016 [757] |
Randomized, double-blind, placebo-controlled prospective study |
43 patients with dry eye disease (DED) | 0, 2 mg/day * |
16 weeks |
|
Supplement: Commercially available antioxidant supplements contain anthocyanosides, vitamins A, C, and E, and crudely extracted additives from several Chinese herbal extracts and AX. Lower diastolic blood pressure in the treated group. There were no statistically significant differences in systolic blood pressure, dry eye symptoms, serum anti-SSA and anti-SSB, visual acuity, intraocular pressure, or fluorescein corneal staining between the two groups. Significantly improved tear film break time scores and Schirmer test without local anesthesia in the treatment group. Tear ROS levels differed between groups and decreased after treatment. The overall subjective impression was significantly improved by treatment compared to placebo. No safety concerns were identified in this study. |
| Piermarocchi S. et al. 2012 [758] |
Randomized, two-arm, prospective study |
145 patients with nonexudative (dry) age-related macular degeneration (AMD) (72.5 ± 7 yrs.) |
0, 4 mg/days * | 24 months |
|
Two-year results of the CARMIS study: Interventions were vitamin C (180 mg), vitamin E (30 mg), zinc (22.5 mg), copper (1 mg), lutein (10 mg), zeaxanthin (1 mg), and AX (4 mg). The treated group showed stabilization of visual acuity (VA), with significantly (p = 0.003) better VA scores compared to the non-treated group at 24-month follow-up. An improvement in contrast sensitivity (CS, p = 0.001) and final mean National Eye Institute visual function questionnaire (NEI VFQ-25) composite scores at 12 and 24 months were higher in the treated group compared to the non-treated group (p < 0.001). No safety concerns were identified in this study. |
| Saito M. et al. 2012 [685] |
Randomized, double-blind, placebo-controlled, prospective study |
20 healthy subjects | 0, 12 mg/day | 4 weeks |
|
Significant increase in the macular square blur rate (SBR) after 4 weeks after AX (p = 0.018). No statistical difference in the macular SBR was detected in the placebo group (p = 0.598). No safety concerns were identified in this study. |
| Parisi V.. et al. 2008 [759] |
Randomized, two-arm, prospective study |
27 patients with nonadvanced AMD and visual acuity ≥0.2 logarithm of the minimum angle of resolution (69.4 ± 4.3 yrs.) |
0, 4 mg/days * | 12 months |
|
one-year results of the CARMIS study; Interventions were vitamin C (180 mg), vitamin E (30 mg), zinc (22.5 mg), copper (1 mg), lutein (10 mg), zeaxanthin (1 mg), and AX (4 mg). In nonadvanced AMD eyes, selective dysfunction of the central retina (0°−5°) was ameliorated by carotenoid and antioxidant supplementation. There were no functional changes in the more peripheral (5°−20°) retina. No safety concerns were identified in this study. |
| Nagaki Y. et al. 2005 [684] |
Randomized, placebo-controlled, prospective study |
36 health subjects (c.a. 41 yrs.) |
0, 6 mg/day | 4 weeks |
|
After 4 weeks of supplementation, retinal capillary blood flow in the AX group was significantly (p < 0.01) higher than before supplementation in both eyes, while retinal capillary blood flow in the placebo group after placebo treatment was unchanged. Intraocular pressures in both groups remained unchanged during the supplementation period. No safety concerns were identified in this study. [Article in Japanese] |
| Sawaki et al. 2002 [760] |
Randomized, double-blind, placebo-controlled, prospective study |
18 healthy male Subjects (College handball player) |
0, 6 mg/day | 4 weeks |
|
No changes in static and dynamic visual acuity measurements were observed before and after administration of AX. Regarding the deep vision measurements after administration of AX, the AX group showed better values compared to the placebo group. Flicker values after AX administration showed that visual acuity was significantly more acute in the AX group than in the placebo group. No safety concerns were identified in this study. [Article in Japanese] |
| (D) Cardiovascular Health: Dyslipidemia, Glucose/Lipid Metabolisms, Chronic Inflammation and Type 2 Diabetes | ||||||
|
Author/year/
reference |
Study Design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Evaluation of efficacy in obesity, dyslipidemia, hypertension, glucose intolerance and T2DM. | ||||||
| Ciaraldi T.P. et al. 2023 [761] |
Randomized, double-blind, placebo-controlled prospective study |
34 Obese subjects with prediabetes and dyslipidaemia | 0, 12 mg/day |
24 weeks |
|
After 24 weeks, there was a significant decrease in low-density lipoprotein (−0.33 ± 0.11 mM) and total cholesterol (Chol, −0.30 ± 0.14 mM) (both p < 0.05) in the AX group. Reduced levels of the cardiovascular disease (CVD) risk markers fibrinogen (−473 ± 210 ng/mL), L-selectin (−0.08 ± 0.03 ng/mL), and fetuin-A (−10.3 ± 3.6 ng/mL) (all p < 0.05) in the AX group. The trend of improvement in insulin action was also observed in insulin-stimulated whole-body glucose treatment (+0.52 ± 0.37 mg/m2/min, p = 0.078), as well as in fasting [insulin] (−5.6 ± 8.4 pM, p = 0.097) and HOMA2-IR (−0.31 ± 0.16, p = 0.060). No consistent, significant differences from baseline were observed in any of these results in the placebo group. No safety concerns were identified in this study. |
| Saeidi A. et al. 2023 [762] |
Randomized placebo-controlled prospective study |
Obese subjects; 15 control group (CG), 15 supplement group (SG), 15 training group (TG), 15 training plus supplement group (TSG). BMI: 33.6 ± 1.4 |
0, 20 mg/day | 12 weeks |
|
Intervention: AX with/without high-intensity functional training. BW,% of Fat, BMI, Fat-Free Mass: After 12 weeks, there was significant improvement in SG, TG, and TSG, but not in CG (p < 0.05). VO2 peak: Increases after 12 weeks of exercise were significant in the TG (p = 0.0001) and TSG (p =0.0001) but not in the CG (p = 0.32) and SG (p = 0.21). Lipid profile (HDL, LDL, Total Cholesterol(Chol.), and Triglycerides(TG)): After 12 weeks, there was significant improvement in SG, TG, and TSG, but not in CG (p < 0.05). Metabolic Factors (Insulin, Glucose, HOMA-IR): Glucose and Insulin levels decreased significantly in the SG (p <0.001), TG (p < 0.001), and TSG (p <0.001), but not significantly in the CG (p > 0.05), and decreased HOMA-IR following 12 weeks of training in the SG (p = 0.0001), TG (p = 0.0001), and TSG (p = 0.0001), while the difference in HOMA-IR in the CG was not significant (p = 0.17). Adipokines and Growth Differentiation Factors: [Cq1/TNF-related protein 9 and 2 (CTRP9 and CTRP2) levels, and growth differentiation factors 8 and 15 (GDF8 and GDF15)] were measured. There were significant differences in all indicators between the groups (p < 0.05). No safety concerns were identified in this study. |
| Wika A.A. et al. 2023 [763] |
Randomized, double-blind, placebo-controlled prospective study |
19 obese subjects (Mean, age: 27.5 yrs; BF%: 37.9; BMI: 33.4 kg/m2; VO2peak: 25.9 ml·kg−1·min−1) |
0, 12 mg/day |
4 weeks |
|
Subjects performed a graded exercise test on a cycling ergometer and were measured for changes in glucose and lactate levels, fat and carbohydrate (CHO) oxidation rates, heart rate, and rating of perceived exertion (RPE). Although there were no changes in fat oxidation rate, blood lactate or glucose, or RPE (all p > 0.05), a significant decrease in CHO oxidation rate was observed in the AX group only, before and after supplementation. In addition, in the AX group, heart rate decreased by 7% during the graded exercise stress test. No safety concerns were identified in this study. |
| Rad NR. et al. 2022 [691] |
Randomized, double-blind, placebo-controlled prospective study |
50 Type 2 Diabetes Mellitus (T2DM) patients receiving metformin | 0, 10 mg/day | 12 weeks |
|
Investigation of additive synergistic effects on metformin (1000–2000 mg/day). T2DM: After the intervention, while FBS, HbA1c (probably maintained in the high-normal range by metformin even at baseline), and systolic blood pressure (in the normal range) tended to decrease in both groups, blood lipids (within normal range) remained unchanged. Significantly reduced FBS in the AX group rather than the placebo group. Oxidative stress: Significantly increased blood TAC levels at the end of the intervention only in the AX-treated group, while MDA remained unchanged. Similarly, increased SOD and catalase activity in blood and increased Nrf2 protein in PBMCs were observed at the end of the intervention only in the AX-treated group. No safety concerns were identified in this study. |
| Shokri-Mashhadi, N. et al. 2021 [693] |
Randomized, double-blind, placebo-controlled prospective study |
44 patients with T2DM | 0, 8 mg/day | 8 weeks |
|
Decrease plasma levels of MDA and IL-6 (p < 0.05) and decrease the expression level of miR-146a, associated with inflammatory markers (fold change: −1/388) (p < 0.05). No safety concerns were identified in this study. |
| Urakaze M et al. 2021 [764] |
Randomized, double-blind, placebo-controlled prospective study |
44 subjects including prediabetes (Av. 46–48 yrs.) |
0, 12 mg/day | 12 weeks |
|
Glucose levels at 120 min after the 75 g oral glucose tolerance test (OGTT) were significantly lower than before supplementation. HbA1c (p < 0.05), apo E (p < 0.05), and MDA-modified LDL (p < 0. 05) also decreased, while total cholesterol, triglycerides, and HDL-C levels were unchanged. Matuda index, a measure of insulin resistance, was improved in AX-treated subjects compared to pre-treatment. Plasma AX levels were undetectable at baseline and increased to 122.69 ng/mL (c.a. 205 nM) after 4 weeks in the intervention group, and this level was maintained until 12 weeks. No safety concerns were identified in this study. |
| Birudaraju D. et al. 2020 [765] |
Randomized, double-blind, placebo-controlled prospective study |
22 healthy subjects (48.8 ± 16.0 yrs.) |
0, 6 mg/twice a day * (0,12 mg/day) |
4 weeks |
|
Combination with Cavacurcumin, Eicosapentaenoic acid (Omega-3s), AX and γ-linoleic acid (Omega-6) (CEAG) The CEAG group had significantly lower mean systolic blood pressure at 4 weeks [4.7 ± 6.8 (p = 0.002)] compared to the placebo group. A significant decrease in high-sensitivity C-reactive protein (hsCRP) (−0.49 ± 1.9 vs. + 0.51 ± 2.5, p = 0.059) and a blunt increase in IL-6 (+0.2 vs. +0.4, placebo = 0.60) were observed compared to placebo. No safety concerns were identified in this study. |
| Chan K. et al. 2019 [766] |
Randomized, double-blind, placebo-controlled prospective study |
54 patients With type 2 diabetes |
0, 6, 12 mg/day | 8 weeks |
|
Increased plasma AX levels and decreased fasting plasma glucose and HbA1c levels. In the 12 mg AX group, there was a reduction in plasma triglyceride, total cholesterol, and LDL levels. Lowered changes in plasma IL-6 and TNF- levels and plasma vWF level and higher changes in AT-III level. In 12 mg AX group, there were decreased changes in plasma FVII and PAI-1levels. No safety concerns were identified in this study. |
| Landi F et al. 2019 [767] |
Randomized open-labeled, prospective study |
47 subjects with higher level of serum Chol. (not needing statins or statin intolerant) (58.7± 8.7 yrs.) |
0.5 mg/day * in Nutraceutical B |
6 weeks |
|
Nutraceutical B: policosanol (10 mg), red yeast rice (200 mg; 3 mg monacolin K), Berberine (500 mg), Astaxanthin (0.5 mg), folic acid (200 mcg), and Coenzyme Q10 (2 mg) Both nutraceutical combinations improved the lipid profile including total Chol., HDL-Chol., LDL-Chol., and TG. No safety concerns were identified in this study. |
| Mashhadi N.S. et al. 2018 [768] |
Randomized, double-blind, placebo-controlled, prospective study |
44 participants with type 2 diabetes | 0, 8 mg/day | 8 weeks |
|
Increased the serum adiponectin concentration, reduced visceral body fat mass (p < 0.01), serum triglyceride and very-low-density lipoprotein (VLDL) cholesterol concentrations, systolic blood pressure, fructosamine concentration (p < 0.05), and marginally reduced the plasma glucose concentration (p = 0.057). No safety concerns were identified in this study. |
| Sarkkinen ES., et al. 2018 [769] |
Randomized, double-blind, placebo-controlled, prospective study |
35 overweight subjects with mildly or moderately elevated blood pressure | N/A (0, 4 g of kirill oil powder /day) |
56 days |
|
Average values of hematological measurements were within the reference range for all subjects, and no significant changes were observed in blood pressure or lipid levels. No serious adverse events were reported. |
| Canas J. A. et al. 2017 [770] |
Randomized, double-blind, placebo-controlled, prospective study |
20 children with simple obesity (BMI > 90%) |
500 μg/day * (MCS) |
6 months |
|
Mixed-carotenoid supplementation (MCS) increased carotene, total adiponectin, and high-molecular-weight adiponectin in plasma compared to placebo; MCS decreased BMI z-score, waist-to-height ratio, and subcutaneous adipose tissue compared to placebo. AX was used as a part of MCS. No safety concerns were identified in this study. |
| Maki KC. et al. 2015 [771] |
Randomized, double-blind, placebo-controlled, prospective study |
102 subjects with TAG 150–499 mg/dL and LDL cholesterol (LDL-C) ≥70 mg/dL | 0, 12 mg/day * |
8 weeks |
|
Test food (PDL-0101): 1.8 g/day eicosapentaenoic acid, 100 mg/day tocopherol-freeγ/δ tocotrienols enriched with geranylgeraniol, extracted from annatto, and 12 mg/day AX. After 8 weeks of treatment, PDL-0101 significantly reduced median TAG compared to placebo (−9.5% vs. 10.6%, p < 0.001), but there was no significant change in mean LDL-C (−3.0% vs. −8.0% for PDL-0101 and placebo, respectively, p = 0.071), no significant change in mean high-density lipoprotein cholesterol (approximately 3% reduction in both groups, p = 0.732), or median oxidized LDL concentration (5% vs. −5% for PDL-0101 and placebo, respectively, p = 0.112). No safety concerns were identified in this study. |
| Takemoto M. et al. 2015 [697] | Case report | 1 Werner syndrome patient | 12 mg/day * | 6 months |
|
Improved blood transaminase concentrations before AX intervention and 3 and 6 months after initiation were AST 40 IU/L, 41 IU/L, and 20 IU/L; ALT 69 IU/L, 62 IU/L, and 34 IU/L; GGT 38 IU/L, 41 IU/L, and 35 IU/L; and cholinesterase 360 IU/L, 366 IU/L, and 331 IU/L, respectively. Liver-to-spleen Hounsfield units on CT were 0.41 before AX initiation, 0.71 at 3 months, and 0.94 at 6 months. No significant changes after AX intervention in hyaluronic acid, a marker of liver fibrosis; high-sensitivity C-reactive protein, a marker of inflammation; or MDA-modified LDL. No safety concerns were identified in this study. |
| Ni Y. et al. 2015 [772] |
Randomized, single-blind, placebo-controlled, prospective study |
12 NASH patients | 0, 12 mg/day | 24 weeks |
|
Improved steatosis (p < 0.05), marginally improved lobular inflammation (p = 0.15), and NAFLD activity score (p = 0.08) No safety concerns were identified in this study. |
| Choi H.D. et al. 2011 [698] |
Randomized, two-arm, prospective study |
23 obese and overweight subjects | 5 and 20 mg/day | 3 weeks |
|
5 mg/day: MDA decreased by 34.6%, isoprostane (ISP) decreased by 64.9%, SOD increased by 193%, and TAC increased by 121% after 3 weeks compared to baseline (p < 0.01). 20 mg/day: MDA decreased by 35.2%, ISP decreased by 64.7%, SOD increased by 194%, and TAC increased by 125% after 3 weeks compared to baseline (p < 0.01). Decreased LDL cholesterol and ApoB. No safety concerns were identified in this study. |
| Choi, H.D. et al. 2011 [699] |
Randomized, double-blind, placebo-controlled, prospective study |
27 overweight subjects | 0, 20 mg/day | 12 weeks |
|
MDA reduced by 17.3% and 29% after 8 and 12 weeks compared to placebo (p < 0.01), ISP reduced by 40.2% and 52.9% after 8 and 12 weeks compared to placebo (p < 0.01), SOD increased by 124.8% after 12 weeks compared to placebo (p < 0.01), and TAC increased by 130.1% after 12 weeks compared to placebo (p < 0.05). No safety concerns were identified in this study. |
| Yoshida H. et al. 2010 [773] |
Randomized, double-blind, placebo- controlled, prospective study |
61 non-obese subjects with fasting serum triglyceride of 120–200mg/dl and without diabetes and hypertension | 0, 6, 12, 18 mg/day | 12 weeks |
|
Multiple comparison: triglycerides were significantly decreased by 12 and 18 mg/day, and HDL-cholesterol was significantly increased by 6 and 12 mg. Serum adiponectin was increased by AX (12 and 18 mg/day), and changes in adiponectin were positively correlated with changes in HDL-cholesterol. No safety concerns were identified in this study. |
| Satoh A. et al. 2009 [774] |
Open-labeled, prospective study |
20 subjects at risk for developing metabolic syndrome (from 127 healthy subjects) |
4, (8, 20) mg/day | 4 weeks |
|
When subjects who met the diagnostic criteria for metabolic syndrome in Japan (SBP ≥ 130 mmHg, DBP ≥ 85 mmHg, TG ≥ 150 mg/dL, FG ≥ 100 mg/dL) at the start of the study were selected from the 4mg group, there was a significant decrease in SBP (p < 0.01). On the other hand, there was no significant decrease in DBP. Reduced TG after treatment (218 mg/dL) than the baseline value (292 mg/dL), marginally reduced fasting glucose after the intervention (p < 0.1). No safety concerns were identified in this study |
| Uchiyama A. et al. 2008 [775] |
Open-labeled, prospective study | 17 subjects at risk for developing metabolic syndrome | 8 mg twice day | 3 months |
|
Significant decreases in plasma HbAlc (p = 0.0433) and TNF-α levels (p = 0.0022) and an increase in adiponectin concentration (p = 0.0053). N.S: body weight, BMI, and waist circumference. The blood concentration reached the plateau after a month of treatment and was retained at that level until 3 months of treatment (0.2–0.25 μg/mL (0.34–0.42 μmol/L)). No safety concerns were identified in this study. |
| Evaluation of efficacy in cardiovascular diseases (CVDs) patients | ||||||
| Heidari M. et al. 2023 [776] |
Randomized, double-blind, placebo-controlled prospective study |
44 CAD patients (40–65 yrs.), angiographic evidence of 50% stenosis in at least one of the major coronary arteries, 25 < BMI <35 |
0, 12 mg/day |
8 weeks |
|
12 mg of AX or placebo (microcrystalline cellulose) groups along with a low-calorie diet for a period of 8 weeks. Significant reductions in total cholesterol (−14.95 ± 33.57 mg/dL, p < 0.05) and LDL-C (−14.64 ± 28.27 mg/dL, p < 0.05) in the AX group with coronary artery disease (CAD). However, TG and HDL-C levels could not be affected by AX did not change “serum” levels of Sirtuin1 and TNF-α, Body composition, or glycemic indices. (Comments: BMI 25–27, mild obesity, non-insulin resistance with normoglycemia, normal TC, slightly elevated TG, and very low HDL-Chol. The effect on body composition seems to be more influenced by the low calorie diet. The clinical significance of the serum-free form of Sirt-1 remains unclear. No safety concerns were identified in this study. |
| Ishiwata S. et al. 2021 [692] |
Open-labeled, prospective study |
17 patients with systolic heart failure |
12 mg/day * | 3 months |
|
After 3 months of AX supplementation, the ”Specific Activity Scale” score increased from a median of 4.5 (interquartile range, 2.0) to 6.5 (interquartile range, 1.1) metabolic equivalents (p = 0.001), and the physical and mental component summary scores increased from 46.1 ± 9.2 to 50.8 ± 6.8 (p = 0.015) and 48.9 ± 9.1 to 53.8 ± 4.8 (p = 0.022), respectively. There was a linear relationship between baseline heart rate or mental component summary score and rate of change in the “Specific Activity Scale” score (r = 0.523, p = 0.031, r = −0.505, p = 0.039, respectively). Furthermore, there was a direct relationship between ischemic etiology and the rate of change in the physical component summary score (r = 0.483, p = 0.049, respectively). There was also a linear relationship between the rate of change in the “Specific Activity Scale” score and the rate of change in the mental component summary score (r = 0.595, p = 0.012). No safety concerns were identified in this study. |
| Kato T. et al. 2020 [694] |
Open-labeled, prospective study | 16 patients with systolic heart failure |
12 mg/day * | 3 months |
|
Increased left ventricular ejection fraction (LVEF) from 34.1 ± 8.6% to 38.0 ± 10.0% (p = 0.031), and the 6-min walk distance increased from 393.4 ± 95.9 m to 432.8 ± 93.3 m (p = 0.023). Significant relationships were observed between percent changes in dROM level and those in LVEF. No safety concerns were identified in this study. |
| Marazzi G et al. 2017 [777] |
Randomized, single-blind, placebo-controlled, prospective study |
100 patients with CVD, percutaneous coronary intervention in the past 12 months, high-dose statin intolerance, and LDS treatment alone did not reduce LDL-C by more than 50%. | 0, 0.5 mg/day * (Armolipid Plus) |
12 months |
|
The aim was to compare the efficacy and tolerability of low-dose statin (LDS) therapy versus combined therapy of LDS plus a nutraceutical combination (Armolipid Plus: red yeast rice (200 mg), policosanol (10 mg), berberine (500 mg), folic acid (0.2 mg), AX (0.5 mg), and coenzyme Q10 (2 mg) After 3 months, LDL-C and total cholesterol were significantly lowered in the LDS + Almolypid Plus (n = 50) group (p < 0.0001), and 70% of this group achieved the treatment goal (LDL-C <70 mg/dL), while patients in the LDS group did not. No safety concerns were identified in this study. |
| Evaluation of efficacy in postmenopausal females | ||||||
| Iwabayashi M. et al. 2009 [700] |
Open-labeled, prospective study | 35 healthy female subjects (with high oxidative stress, postmenopausal) |
12 mg/day | 8 weeks |
|
Increased blood biological antioxidant potential (Biological Antioxidant Potential (BAP); +4.6%, p < 0.05). After eight-week treatment with astaxanthin, significant improvement was observed in 5 of the 34 physical symptoms listed in the common questionnaire, including “tired eyes”, “stiff shoulders”, “constipation”, “gray hair”, and “cold skin”, and in 3 of the 21 mental symptoms, including “daily life is not enjoyable”, “difficulty falling asleep”, and “a sense of tension”. In addition, systolic (p = 0.021) and diastolic blood pressure (p < 0.001) significantly decreased. No safety concerns were identified in this study. |
| Kim Y.K. et al. 2004 [701] |
Open-labeled, prospective study |
15 healthy postmenopausal females | 0, 2, 8 mg/day | 8 weeks |
|
Decreased plasma TBARS levels: 2 mg group from 1.42 ± 0.18 to 1.13 ± 0.18 nM/mg (p < 0.05). 8 mg AX group from 1.62 ± 0.14 nM/mg to 1.13 ± 0.12 nM/mg after 8 weeks (p < 0.05). Increased TAS from 0.85 ± 0.42 mM/L to 1.90 ± 0.58 mM/L in the 8 mg group. Urinary 8-isoprostane excretion did not decrease significantly. Increase HDL-cholesterol levels in 2 mg and 8mg group increased significantly after 8 weeks from 50.6 ± 5.8 to 60.4 ± 7.1 mg/dL, 44.4 ± 10.7 to 49.4 ± 2.7 mg/dL respectively (p < 0.05). In the 2mg group, triglyceride decreased significantly from 171.6 ± 67.4 mg/dL to 145.8 ± 5.1 mg/dL (p < 0.05). No safety concerns were identified in this study. |
| Evaluation of efficacy in healthy subjects | ||||||
| Takami M. et al. 2019 [778] |
Open-labeled, prospective study | 20 healthy young male subjects |
c.a, 4.5 mg/day * from salmon |
4 weeks |
|
Increased maximum work load by training in both groups (p = 0.009), while increased oxygen consumption during exercise in the antioxidant group only (p = 0.014). There were positive correlations between maximum work load and fat (r = 0.575, p = 0.042) and carbohydrate oxidations (r =0.520, p = 0.059) in the antioxidant group. Higher carbohydrate oxidation during rest in the post-training than that in the pre-training only in the antioxidant group. More decreased levels of serum insulin and HOMA-IR after training were observed in the antioxidant group than in the control group. No safety concerns were identified in this study. |
| Fukamauchi M. et al. 2007 [779] |
Randomized, double-blind, placebo- controlled, prospective study |
32 healthy subjects | 0, 6 mg/day | 6 weeks |
|
The synergistic effects of AX intake (12 mg/day, 6 weeks) and aerobic exercise (walking) were studied. AX contributed to the reduction of body fat and suppressed the increase in blood lactate levels after exercise. No safety concerns were identified in this study. [Article in Japanese] |
| Others | ||||||
| Miyawaki H. et al. 2008 [686] |
Single-blind, placebo-controlled prospective study |
20 healthy subjects | 0, 6 mg/days | 10 days |
|
The time for blood to pass through the microchannel array flow analyzer decreased from 52.8 ± 4.9 s to 47.6 ± 4.2 s in the AX group (p < 0.01), and a significant difference was found when comparing values in the AX group (47.6 ± 4.2 s) and placebo group (54.2 ± 6.7 s) (p < 0.05). No safety concerns were identified in this study. |
| (E) Exercise/Sports performance, skeletal | ||||||
|
Author/year/
reference |
Study Design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Evaluation of efficacy in exercise/sports performance in healthy subjects/athletes (muscular damages) | ||||||
| Barker G.A. et al. 2023 [780] |
Double-blind, placebo-controlled prospective study |
19 Resistance-trained males | 0, 12 mg/day |
4 weeks |
|
Significantly decreased in delayed onset muscle soreness (SORE score (p = 0.02)) for the AX group post-supplementation compared to pre-supplementation test. There is no effect on Placebo. Significantly decreased in VAS (visual analog scale; p = 0.01) for the AX group post-supplementation compared to the pre-supplementation test, whereas these had no effect in the Placebo group. No effect on performance. No safety concerns were identified in this study. |
| Nieman, D.C. et al. 2023 [781] |
Randomized, double-blind, placebo-controlled crossover study |
18 healthy subjects (Capable of running 2.25 h on laboratory treadmills at 70% maximal oxygen consumption rate (VO2max)) |
0, 8 mg/day |
4 weeks |
|
The running bout for 2.25 h induced significant muscle soreness, muscle damage, and inflammation; AX supplementation had no effect on exercise-induced muscle soreness, muscle damage, or increases in 6 plasma cytokines and 42 oxylipins. However, AX supplementation inhibited exercise-induced decreases in 82 plasma proteins (at 24 h post-recovery). Most of these proteins were involved in immune-related functions. Twenty plasma immunoglobulins were identified that differed significantly between the AX and placebo groups; plasma levels of IgM were significantly reduced after exercise but recovered in the AX trial but not in the placebo trial after a 24-h recovery period after exercise. No safety concerns were identified in this study. |
| Sudo A et al. 2019 [737] |
Placebo-controlled prospective study |
19 healthy subject (College softball player for women in physical education |
0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil). Studied the efficacy of V7 on subjective fatigue, sports performance, and skin conditions in college softball players. Subjective symptoms were evaluated with the VAS. The change of VAS in PRE and POST in the V7 group showed statistically significant improvement in 50 m running performance; a comparison of V7 and placebo POST showed statistically significant increases in leg fatigue, knee, and hip pain. The percent change between PRE and POST in V7 was statistically significantly higher in leg fatigue, hip and back pain, and total score. No safety concerns were identified in this study. [Article in Japanese] |
| Baralic, I. et al. 2015 [712] |
Randomized, double-blind, placebo-controlled, prospective study |
40 healthy subjects (young soccer players) |
0, 4 mg/day | 90 days |
|
The increase in neutrophil count and hs-CRP level was found only in the placebo group, indicating a significant blunting of the systemic inflammatory response in the subjects taking AX. Improved prooxidant-antioxidant balance (PAB; p < 0.05) AX supplementation improves the sIgA response and attenuates muscle damage. No safety concerns were identified in this study. |
| Baralic I. et al. 2013 [713] |
Randomized, double-blind, placebo-controlled prospective study |
40 healthy subjects (soccer players) | 0, 4 mg/day | 90 days |
|
Protected thiol groups against oxidative modification (increase in SH groups, p < 0.05; improved PON1 activity towards paraoxon and diazoxon, p < 0.05 and p < 0.01, respectively) No safety concerns were identified in this study. |
| Djordjevic B. et al. 2013 [714] |
Randomized, double-blind, placebo-controlled prospective study |
32 healthy subjects (soccer players) | 0, 4 mg/day | 90 days |
|
Regular training significantly increased O2•¯ levels (main training effect, p < 0.01). O2•¯ concentrations. Not change TBARS and AOPP levels throughout the study. Decreased TAS levels post- exercise only in the Placebo group (p < 0.01). The increased total SH group content both in the AX and in the placebo groups (by 21% and 9%, respectively) and supplementation effect were marginally significant (p = 0.08). Decreased basal SOD activity both in the Placebo and in the AX group by the end of the study (main training effect, p < 0.01). Significant decrease in basal CK and AST activities after 90 days (main training effect, p < 0.01 and p < 0.001, respectively). Post-exercise CK and AST levels were significantly lower in the AX group compared to the Placebo group (p < 0.05) No safety concerns were identified in this study. |
| Klinkenberg L.J. et al. 2013 [715] |
Randomized, double-blind, placebo-controlled, prospective study |
32 well-trained male cyclists (25 ± 5 years, V˙O2peak = 60 ± 5 mL·kg−1·min−1, Wmax = 5.4 ± 0.5 W·kg−1) |
0, 20 mg/day * | 4 weeks |
|
N.S; effect on exercise-induced cardiac troponin T release (p = 0.24), changes in antioxidant capacity markers (trolox equivalent antioxidant capacity, uric acid, and malondialdehyde). Markers of inflammation (high-sensitivity C-reactive protein) and exercise-induced skeletal muscle damage (creatine kinase). No safety concerns were identified in this study. |
| Djordjevic B. et al. 2011 [714] |
Randomized, double-blind, placebo-controlled, prospective study |
32 male elite soccer players | 0, 4 mg/day | 90 days |
|
Changes in elevated O2-¯ concentrations after soccer exercise were statistically significant only in the Placebo group (exercise × supplementation effect, p < 0.05); TAS values decreased significantly only in the Placebo group after exercise (p < 0.01). After intervention, total SH group content increased (21% and 9%, respectively), and the effect of AX was marginally significant (p = 0.08). Basal SOD activity was significantly reduced in both the Placobo and AX groups at the end of this study (main training effect, p < 0.01).Post-exercise CK and AST levels were significantly lower in the AX group than in the Placebo group (p < 0.05) No safety concerns were identified in this study. |
| Bloomer, R.J. et al. 2005 [717] |
Randomized, placebo-controlled, prospective study |
20 resistance trained male subjects (25.1 ± 1.6 years) |
0, 4 mg/day * | 3 months |
|
N.S; Muscle soreness, creatine kinase (CK), and muscle performance were measured before and through 96 h of eccentric exercise No safety concerns were identified in this study. |
| Sawaki et al. 2002 [760] |
Randomized, double-blind, placebo-controlled, prospective study |
18 healthy male Subjects (College handball player) |
0, 6 mg/day | 4 weeks |
|
Although there was no difference between the two groups in post-exercise CK levels or heart rate, the AX group had significantly lower blood lactate levels 2 min after exercise. No safety concerns were identified in this study. [Article in Japanese] |
| Evaluation of efficacy in exercise/sports performance in healthy subjects/athletes (performance/energy metabolisms) | ||||||
| Waldman H.S. et al. 2023 [782] |
Randomized, double-blind, placebo-controlled crossover study |
Resistance-trained males (Mean 23.4 yrs.) |
0, 12 mg/day |
4 weeks |
|
AX supplementation had no statistical effect on markers of substrate metabolism, Wingate variables, or markers of muscle damage, inflammation, or delayed-onset muscle soreness during the graded exercise test (GXT) compared to placebo (p > 0.05). However, 4 weeks of AX supplementation significantly reduced oxygen consumption during the final phase of the GXT compared to placebo (12%, p = 0.02), reduced systolic blood pressure (approximately 7%, p = 0.04), and significantly reduced baseline insulin levels (c.a. 24%, p = 0.05). No safety concerns were identified in this study. |
| McAllister MJ. et al. 2022 [711] |
Randomized, double-blind, placebo-controlled crossover study |
14 healthy subjects (23 ± 2 yrs) |
0, 6 mg/day | 4 weeks |
|
A graded exercise test was performed after each treatment to measure substrate utilization during exercise at increased intensity. Glutathione was approximately 7% higher after AX treatment compared to placebo (p = 0.02, d = 0.48). Plasma hydrogen peroxide and malondialdehyde (MDA) did not differ between treatments (p > 0.05). Although not statistically significant (p = 0.45), highly oxidized protein products were reduced by approximately 28%. In the graded exercise stress test, mean fat oxidation rates did not differ between treatments (p > 0.05); however, fat oxidation was reduced from 50 to 120 W (p < 0.001) and from 85 to 120 W (p = 0.004) in both conditions. No safety concerns were identified in this study. |
| Brown, R.D. et al. 2021 [783] |
Randomized, double-blind, placebo-controlled crossover study |
12 recreationally trained male cyclists (27.5 ± 5.7 years, VO2peak: 56.5 ± 5.5 mL⋅kg−1⋅min−1, Wmax: 346.8 ± 38.4 W) |
0, 12 mg/day | 7 days |
|
Completion time of the 40-km cycling time trial improved by 1.2 ± 1.7% with AX supplementation, from 70.76 ± 3.93 min in the placebo condition to 69.90 ± 3.78 min in the AX condition (mean improvement time = 51 ± 71 s, p = 0.029, g = 0.21). Whole body fat oxidation rate was also greater in the AX group between 39 and 40 km (+0.09 ± 0.13 g ⋅ min−1, p = 0.044, g = 0.52) and respiratory exchange ratio was lower (−0.03 ± 0.04, p = 0.024, g = 0.60). No safety concerns were identified in this study. |
| Kawamura A. et al. 2021 [710] |
Randomized open-labeled, prospective study |
26 healthy male subject (22.3 ± 0.3 yrs.) |
N/A (1 mg AX/100g salmon) * |
10 weeks |
|
The skeletal muscle mass was higher after training than before training in both the control and intervention groups (p < 0.05). Increased maximal voluntary contraction after training in the intervention group (p < 0.05), but not significantly increased in the control group. Higher resting oxygen consumption after training in the intervention group only (p < 0.05). Serum carbonylated protein level as an oxidative stress marker tended to be lower immediately after exercise than before exercise in the intervention group only (p = 0.056). No safety concerns were identified in this study. |
| McAllister M.J. et al. 2021 [711] |
Randomized, double-blind, placebo-controlled, crossover study |
14 healthy young subjects, (23 ± 2 yrs.) |
0, 6 mg/day | 4 weeks |
|
Glutathione was ~7% higher following AX compared with placebo (p < 0.05). There was no effect on plasma hydrogen peroxide or MDA (p > 0.05). Advanced oxidation protein products (AOPP) were reduced by ~28% (N.S.; p = 0.45) not affect substrate utilization during exercise. No safety concerns were identified in this study. |
| Fleischmann C. et al. 2019 [784] |
Randomized, double-blind, placebo-controlled prospective study |
22 healthy subjects (23.1 ± 3.5 yrs.) |
0, 12 mg/day | 30 days |
|
Decreased raised blood lactate caused by the VO2 Max test in the AX group (9.4 ± 3.1 and 13.0 ± 3.1 mM in the AX and Placebo groups, respectively, p < 0.02). Change in oxygen uptake during recovery (−2.02 ± 0.64 and 0.83 ± 0.79% of VO2 Max in the AX and Placebo groups, respectively, p = 0.001). N.S; anaerobic threshold or VO2 Max. physiological or biochemical differences in the heat tolerance test (HTT) (2 h walk at 40 °C, 40% relative humidity. No safety concerns were identified in this study. |
| Sudo A et al. 2020 [736] |
Placebo-controlled prospective study |
11 healthy subjects (College floorball athletes for women in physical education |
0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil). Studied the efficacy of V7 on subjective fatigue, sports performance, and skin conditions in floorball athletes. Subjective symptoms were evaluated with the VAS. The change in VAS in PRE and POST in the V7 group showed that fatigue was significantly alleviated overall and in the torso. Significantly improved on a seated toe touch, increasing from 48.6 cm pre-intake to 51.8 cm post-intake. No safety concerns were identified in this study. [Article in Japanese] |
| Takami M. et al. 2019 [778] |
Open-labeled, prospective study | 20 healthy young male subjects |
c.a, 4.5 mg/day * from salmon |
4 weeks |
|
Increased maximum work load by training in both groups (p = 0.009), while increased oxygen consumption during exercise in the antioxidant group only (p = 0.014). There were positive correlations between maximum work load and fat (r = 0.575, p = 0.042) and carbohydrate oxidations (r =0.520, p = 0.059) in the antioxidant group. Higher carbohydrate oxidation during rest in the post-training than that in the pre-training only in the antioxidant group. No safety concerns were identified in this study. |
| Talbott I. et al. 2016 [785] |
Randomized, double-blind, placebo-controlled prospective study |
28 recreational runners (42 ± 8 yerars) |
0, 12 mg/day | 8 weeks |
|
Reduced average heart rate at submaximal endurance intensities (aerobic threshold, AeT, and anaerobic threshold, AT), but not at higher “peak” intensities. No safety concerns were identified in this study. |
| Res T. et al. 2013 [716] |
Randomized, double-blind, placebo-controlled, prospective study |
32 trained male cyclists or triathletes (25 ± 1 years, V˙O2peak = 60 ± 1 mL·kg−1·min−1, Wmax = 395 ± 7 W) |
0, 20 mg/day | 4 weeks |
|
N.S; total plasma antioxidant capacity (p = 0.90) or attenuated malondialdehyde levels (p = 0.63). Whole-body fat oxidation rates during submaximal exercise (from 0.71 +/− 0.04 to 0.68 ± 0.03 g.min and from 0.66 ± 0.04 to 0.61 ± 0.05 g.min in the Placebo and AX groups, respectively; p = 0.73), time trial performance (from 236 ± 9 to 239 ± 7 and from 238 ± 6 to 244 ± 6 W in the Placebo and AX groups, respectively; p = 0.63). No safety concerns were identified in this study. |
| Earnest C.P. et al. 2011 [786] |
Randomized, double-blind, placebo-controlled, prospective study |
14 amateur endurance-trained subjects (18–39 years, V˙O2peak = 52.84 ± 3.5 mL·kg−1·min−1, Wmax = 330 ± 26 W |
0, 4 mg/day | 28 days |
|
Improved performance in the 20-km cycling time trial in the AX group (n = 7, −121 s; 95% CI, −185, −53), but not in the Placebo group (n = 7, −19 s; 95% CI, −84, 45). The AX group significantly increased power output (20 W; 95% CI, 1, 38), while the Placebo group did not (1.6 W; 95% CI, −17, 20). N.S: carbohydrate, fat oxidation, and blood indices indicative of fuel mobilization. No safety concerns were identified in this study. |
| Malmstena C.L.L. et al. 2008 [787] |
Randomized, double-blind, placebo-controlled prospective study |
40 young healthy subjects (17–19 years) |
0, 4 mg/day | 3 months |
|
The increased average number of knee bending (squats) increased by 27.05 (from 49.32 to 76.37, AX group) vs. 9.0 (from 46.06 to 55.06, placebo subjects), p = 0.047. No safety concerns were identified in this study. |
| Tajima T. et al. 2004 [788] |
Randomized, double-blind, placebo-controlled, crossover study |
18 healthy subjects (35.7 ± 4 years) |
0, 5 mg/day | 2 weeks |
|
Increases in CVRR and HF/TF (Heart rate variability) were significant during exercise at 70% maximum heart rate (HRmax) intensity (p < 0.05). Moreover, after the AX supplementation there was, decreased minute ventilation (VE) during exercise at 70% HRmax (p < 0.05). Decreased LDL cholesterol (p < 0.05) and respiratory quotient after exercise. No safety concerns were identified in this study. [Article in Japanese] |
| Evaluation of efficacy in exercise performance in elderly subjects (sarcopenia) | ||||||
| Liu S.Z. et al. 2021 [789] |
Randomized, double-blind, placebo-controlled, prospective study |
42 elderly subjects (65–82 yrs.) |
0, 12 mg/day * | 12 weeks |
|
Intervention: 6 mg Zn, 10 mg tocotrienol and 12 mg AX. In endurance training (ET), specific muscular endurance was improved only in the AX group (Pre 353 ± 26 vs. Post 472 ± 41), and submaximal graded exercise test duration was improved in both groups (Placebo 40.8 ± 9.1% vs. AX 41.1 ± 6.3%). The increase in fat oxidation at low intensity after ET was greater in AX (Placebo 0.23 ± 0.15g vs AX 0.76 ± 0.18g) and was associated with reduced carbohydrate oxidation and improved exercise efficiency in men but not in women. Analysis associated with the study [790]. No safety concerns were identified in this study. |
| Nakanishi R. et al. 2021 [718] |
Randomized, double-blind, placebo-controlled prospective study |
29 nursing home resident’s healthy elderly subjects (80.9 ± 1.5 yrs.) |
0, 12 mg/twice a day * (0, 24 mg/day) |
16 weeks |
|
There was a decrease in d-ROM values with the AX group (p < 0.01) but not with the placebo group; the AX group had a therapeutic effect on 6-min walking distance compared with the placebo group (p < 0.05). The AX group had an increase in distance and number of steps in the 6-min walking test compared to the placebo group. Furthermore, the rate of increase in blood lactate levels after walking was lower in the AX group than in the placebo group (p < 0.01). No safety concerns were identified in this study. |
| Liu S.Z. et al. 2018 [790] |
Randomized, double-blind, placebo-controlled, prospective study |
42 elderly subjects (65–82 yrs.) |
0, 12 mg/day * | 12 weeks |
|
Administration of AX increased maximal voluntary force (MVC) by 14.4% (± 6.2%, p < 0.02), tibialis anterior muscle size (cross-sectional area, CSA) by 2.7% (±1.0%, p < 0.01), and specific impulse increased by 11.6% (MVC/CSA, ±6.0%, p = 0.05), respectively, whereas placebo treatment did not alter these characteristics (MVC, 2.9% ± 5.6%; CSA, 0.6% ± 1.2%; MVC/CSA, 2.4 ± 5.7%; all p > 0.6). No safety concerns were identified in this study. |
| Evaluation of efficacy in joint health (osteoarthritis (OA), carpal tunnel syndrome) | ||||||
| Stonehouse W et al. 2022 [791] |
Randomized, double-blind, placebo-controlled prospective study |
235 Healthy adults (40–65 yrs, BMI >18.5 to <35 ) w/.clinically diagnosed with mild to moderate knee OA |
0, 0.35 mg/day (in krill oil) |
6 months |
|
Knee pain scores (Western Ontario and McMaster Universities Osteoarthritis Index: WOMAC, numeric scale) improved in both groups, with greater improvement with krill oil than placebo. Knee stiffness and physical function also showed greater improvement with krill oil than placebo. NSAID usage, serum lipid profile, inflammatory markers, and safety markers did not differ between groups. No safety concerns were identified in this study. |
| Macdermid J.C. et al. 2012 [792] |
Randomized, triple-blind, placebo-controlled prospective study |
63 patients with carpal tunnel syndrome |
0, 4 mg/days with splinting |
9 weeks |
|
The Symptom Severity Scale (SSS) over the course of treatment in both AX treated and placebo groups (p = 0.002) showed no differences between the groups (p = 0.18). The Disability of Arm, Shoulder, and Hand Questionnaire and the Short Form 36-item Health Survey showed no effects over time or between treatment groups. No safety concerns were identified in this study. |
| (F) Brain Health | ||||||
|
Author/year/
reference |
Study design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Evaluation of efficacy in cognitive functions | ||||||
| Hayashi M. et al. 2018 [793] |
Randomized, double-blind, placebo-controlled prospective study |
54 healthy subjects (45–64 yrs.) |
0, 8 mg/day from Paracoccus |
8 weeks |
|
(After 8 weeks of AX administration, the serum AX concentration increased to 0.173 ± 0.058 μg/mL (0.29 μM).( Not detected in the placebo group.) Evaluation: word memory test, verbal fluency test, and Stroop test. AX group significantly larger increase in blood AX level. No significant intergroup differences in the results of the evaluations. Subgroup analysis (<55 yrs. old and ≥55 yrs. old): “words recalled after 5 min” in word memory test in <55 year old subjects showed significant improvement in the AX group than in the placebo group, which was not found in ≥55 year old subjects. No safety concerns were identified in this study. |
| Hongo N. et al. 2018 [794] |
Randomized, double-blind, placebo-controlled prospective study |
40 Healthy subjects aged 60–79 years reporting awareness of cognitive and/or physical decline (Mean 65.8 yrs.) |
0, 12 mg/day * |
12 weeks |
|
AX group (12 mg AX, 10 mg tocotrienols, 6 mg zinc, and 600 IU vitamin D) and control group (same formulation w/o. AX). Cognitive functions/Fatigues: AX intake shortened the reaction time in working-memory tasks (particularly improved the speed of processing newly-provided visual information by comparing it with previously-provided information while appropriately retaining the previous information in the memory for several seconds). In addition, AX promoted efficacy in the improvement of self-assessed memory ability. Furthermore, in the subjects with improved endurance, AX enhanced the recognition memory function of nonverbal information, particularly the accuracy of memorizing faces and distinguishing them from newly presented faces. Moods/Stress: Improved the scores of “Anger-Hostility,” “Confusion-Bewilderment,” “Fatigue-Inertia,” and TMD in the POMS survey and the decrease in the score of “irritated” in the VAS survey in the AX group No safety concerns were identified in this study. [Article in Japanese] |
| Ito N. et al. 2018 [795] |
Randomized, double-blind, placebo-controlled, prospective study |
14 patients diagnosed with MCI (57–78 yrs.; MMSE scores 24–27). |
0, 6 mg/day * | 12 weeks |
|
Evaluation of cognitive improvement in patients with mild cognitive impairment (MCI). The Central Nervous System Vital Signs (CNSVS, also known as ‘Cognitrax’) test significantly improved “psychomotor speed” and “processing speed” in the AX group compared to the placebo group. No safety concerns were identified in this study. |
| Zanotta D. et al. 2014 [796] |
Open-labeled, prospective study |
104 subjects diagnosed with mild cognitive impairment (Mean 71.2 yrs.) |
c.a. 4.2 mg/day * | 60 days |
|
Test supplement (Illumina); 20mg Bacosides from Bacopa monnieri, 30 mg Phosphatidylserine, 30 mg V.E and 2 mg AX. Significantly improved in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) total score from 13.7 ± 5.8 at baseline to 9.7 ± 4.9 at 60 days and in the clock drawing test from 8.5 ± 2.3 to 9.1 ± 1.9. The greatest improvement in each component of the ADAS-cog was in the memory task. The largest improvement in each component of the ADAS-cog was in the memory tasks. In multivariate analysis, larger improvements in ADAS-cog scores were associated with less deterioration in baseline Mini-Mental State Examination scores. Efficacy was rated “excellent” or “good” by 62% of subjects. The study compounds were well tolerated, with one non-serious adverse event (gastric disturbances in a subject who was taking concomitant oral corticosteroids) reported in the entire study population and tolerability rated as “excellent” or “good” by 99% of subjects. |
| Katagiri M. et al. 2012 [797] |
Randomized, double-blind, placebo-controlled, prospective study |
89 healthy middle-aged and elderly subjects who complained of age-related forgetfulness. | 0, 6, 12 mg/day | 12 weeks |
|
After 12 weeks, CogHealth battery scores improved in the high-dose group (12 mg AX/day). Improved Groton Maze Learning Test scores were seen earlier in the low-dose group (6 mg AX/day) and in the high-dose group than in the placebo group. However, the sample size was too small to show significant differences in cognitive function between the AX and placebo groups. No safety concerns were identified in this study. |
| Satoh A. et al. 2009 [774] |
Open-labeled, prospective study | 10 healthy male subjects (50–69 yrs.) |
12 mg/day | 12 weeks |
|
In the CogHealth tasks (simple response, choice response, working memory, delayed memory, and divided attention), significant reductions in reaction time were observed in the “divided attention” task after 6 weeks and in all tasks after 12 weeks. Accuracy on the “working memory” task was significantly improved after 12 weeks of treatment; however, no such effect was observed on the “delayed recall” task. No safety concerns were identified in this study |
| Evaluation of efficacy in fatigue | ||||||
| Yamazaki I. et al, 2022 [798] |
Randomized, double-blind, placebo-controlled prospective study |
257 subjects feeling fatigue with aging and on daily (Av. 44–45 yrs.) |
0, 6 mg/day * | 8 weeks |
|
Combination with sesamins (sesame lignans). Visual Analogue Scale (VAS) scores of the fatigue feeling at 4 weeks in the test food groups compared to the placebo food groups (p < 0.05), and these scores tended to be lower in the test food groups than the placebo food groups at 8 weeks (p < 0.1). Subgroup analysis: (A) There was a trend toward greater improvement in the group with a greater VAS value at screening than in the group with a smaller VAS value for fatigue at screening. (B)The frequency of exercise at screening was divided into two groups: “most/several times a month” and “at least once a week/every day.” The “at least once a week/every day” group, which exercised more frequently, showed more improvement in the VAS. No safety concerns were identified in this study. [Article in Japanese] |
| Sudo A et al. 2020 [736] |
Placebo-controlled prospective study |
11 healthy subjects (College floorball athletes for women in physical education |
0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil). Studied the efficacy of V7 on subjective fatigue, sports performance, and skin conditions in floorball athletes. Subjective symptoms were evaluated with the VAS. The change in VAS in PRE and POST in the V7 group showed that fatigue was significantly alleviated overall and in the torso significantly improved on a seated toe touch, increasing from 48.6 cm pre-intake to 51.8 cm post-intake. No safety concerns were identified in this study. [Article in Japanese] |
| Sudo A et al. 2019 [750] |
Open-labeled, prospective study |
19 healthy females (Mean 47.3 yrs.) |
0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil). Studied the efficacy of V7 on subjective fatigue and skin conditions in typical middle-aged females. Subjective symptoms were evaluated with the VAS. The change of VAS in PRE and POST in the V7 group showed statistically significantly improved general fatigue, leg fatigue, and the state of the lower back (p < 0.05, respectively); significantly improved dark spots, blotches, and the elasticity and appearance of the skin; no significant change in eye strain or memory loss. No safety concerns were identified in this study. [Article in Japanese] |
| Sudo A et al. 2019 [737] |
Placebo-controlled prospective study |
19 healthy subject (College softball player for women in physical education |
0.3 mg/day * in V7 |
30 days |
|
Test supplement (V7; astaxanthin, reduced coenzyme Q10, leucine, arginine, citrulline, DHA, Krill oil). Studied the efficacy of V7 on subjective fatigue, sports performance, and skin conditions in college softball players. Subjective symptoms were evaluated with the VAS. The change of VAS in PRE and POST in the V7 group showed statistically significant improvement in fatigue, shoulder pain, skin blemishes, and 50 m running performance; a comparison of V7 and placebo POST showed statistically significant increases in leg fatigue, knee and hip pain, skin elasticity and whitening, memory loss, and eye strain. The percent change between PRE and POST in V7 was statistically significantly higher in leg fatigue, hip and back pain, dull skin, eye strain, and total score. No safety concerns were identified in this study. [Article in Japanese] |
| Imai A. et al. 2018 [722] |
Randomized, double-blind, placebo-controlled crossover study |
42 healthy subjects | 0, 6 mg/day * | 4 weeks |
|
Elevated PCOOH levels during mental and physical tasks were attenuated by AX supplementation. Improved recovery from mental fatigue compared to placebo. No differences were found between AX and placebo in other secondary outcomes such as subjective feelings, work efficiency, and autonomic activity. The treatment group showed a significant reduction (p < 0.05) in fatigue during recovery after the mental task compared to the placebo group. (Evaluated by VAS) No safety concerns were identified in this study. |
| Hongo N. et al. 2017 [723] |
Randomized, double-blind, placebo-controlled, prospective study |
39 healthy subjects | 0, 12 mg/day * | 12 weeks |
|
Intent-to-treat (ITT) analysis; fatigue after physical and mental stress was significantly lower in the AX group than in the placebo at week 8; the change in POMS friendliness was significantly higher in the AX group than in the control group at week 8; the rate of change in BAP values at week 12 was not significantly different between the AX and control groups. The rate of change in BAP values at week 12 was not significantly different between the AX group and the control group. No safety concerns were identified in this study. [Article in Japanese] |
| Kono K. et al. 2014 [751] |
Randomized, double-blind, placebo-controlled prospective study |
48 healthy subjects who complained of eye strain |
0, 4 mg/day * |
4 weeks |
|
See Kono K. et al. (2014) in Table 4 (C). [Evaluation of efficacy in “asthenopia (eyestrain)”] |
| Tsukahara H. et al. 2008 [753] |
Open-labeled, prospective study | 13 healthy subjects with shoulder Stiffness | 6 mg/days * | 4 weeks |
|
See Tsukahara H.et al. (2008) in Table 4 (C). Evaluation of efficacy in “asthenopia (eyestrain)”. |
| Evaluation of efficacy in stress/mood/sleep quality | ||||||
| Hayashi M. et al. 2020 [799] |
Randomized, double-blind, placebo-controlled prospective study |
54 healthy subjects (Av. 45–46 yrs.) |
0, 12 mg/day from Paracoccus |
8 weeks |
|
After 8 weeks of AX administration, the serum AX concentration increased to 0.171 ± 0.082 μg/mL (0.29 μM) not detected in the placebo group. Evaluated with the Profile of Mood States 2nd Edition for stress (POMS2) and the Oguri-Shirakawa-Azumi Sleep Inventory. I did not observe any significant intergroup differences in stress or sleep. Subgroup analysis (>65 and ≤65 in the ”Depression-Dejection”in POMS): sleep of subjects who scored >65 (”Depression-Dejection”) showed significant improvement in the AX group compared with the placebo group; however, no significant improvement was observed in stress or the other subjects. No safety concerns were identified in this study. |
| Hongo N. et al. 2018 [794] |
Randomized, double-blind, placebo-controlled prospective study |
40 Healthy subjects aged 60–79 years reporting awareness of cognitive and/or physical decline (Mean 65.8 yrs.) |
0, 12 mg/day * |
12 weeks |
|
See Hongo N.et al. (2018) in Table 4 (G). [Evaluation of efficacy in cognitive functions] |
| Imai A. et al. 2018 [722] |
Randomized, double-blind, placebo-controlled crossover study |
42 healthy subjects | 0, 6 mg/day * | 4 weeks |
|
See Imai A. et al. (2018) in Table 4 (G). [Evaluation of efficacy in cognitive functions] |
| Hongo N. et al. 2017 [723] |
Randomized, double-blind, placebo-controlled, prospective study |
39 healthy subjects | 0, 12 mg/day * | 12 weeks |
|
See Hongo N.et al. 2017 in Table 4 (G). [Evaluation of efficacy in fatigue] |
| Saito H et al. 2017 [800] |
Randomized, double-blind, placebo-controlled prospective study |
120 healthy subjects | 0, 1.5, 3 mg/day * (1.5 mg from krill, 3.0 mg from Haematococcus algae) |
12 weeks |
|
Subjects were divided into four groups: (A) placebo, (B) zinc-rich food, (C) zinc- and AX-rich food (krill), and (D) placebo supplemented with zinc-enriched yeast and AX oil (from Haematococcus algae). Pittsburgh sleep quality index (PSQI): improved significantly within all groups at the endpoint. Total sleep time (TST): No significant difference was noted in any groups in comparison to group A. Sleep onset latency (SOL): significantly improved in group B and group D in comparison to the placebo group. Body positional changes: Although the number increased in the group A (3.74 ± 4.38), this increase was suppressed in group B ( 0.71 ± 5.01), group C (0.58 ± 5.75) and group D ( 0.95 ± 4.33) (N.S.). No safety concerns were identified in this study. |
| Iwabayashi M. et al. 2009 [700] |
Open-labeled, prospective study | 35 healthy female subjects (with high oxidative stress, postmenopausal) |
12 mg/day | 8 weeks |
|
Increased blood biological antioxidant potential (Biological Antioxidant Potential (BAP); +4.6%, p < 0.05). After eight-week treatment with astaxanthin, significant improvement was observed in five of the 34 physical symptoms listed in the common questionnaire, including “tired eyes”, “stiff shoulders”, “constipation”, “gray hair”, and “cold skin”, and in 3 of 21 mental symptoms, including “daily life is not enjoyable”, “difficulty in falling asleep”, and “a sense of tension”. In addition, systolic (p = 0.021) and diastolic blood pressure (p < 0.001) significantly decreased. No safety concerns were identified in this study. |
| (G) Infertility | ||||||
|
Author/year/
reference |
Study design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Evaluation of efficacy in gynecological disorders and assisted reproductive technology (ART) | ||||||
| Jabarpour M. et al. 2023 [652] |
Randomized, placebo-controlled prospective study |
53 Patients with polycystic ovary syndrome (PCOS) |
0, 6 mg/twice a day (0,12 mg/day) |
60 days |
|
ER stress (Granulosa cells): After the intervention, AX treatment reduced the mRNA expression levels of 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and X-box-binding protein 1 compared to the placebo group, but activated transcription factor 6 (ATF6) was not statistically significant. However, AX significantly increased the ATF4 expression level. GRP78 and CHOP protein levels represented a considerable decrease in the treatment group after the intervention. Antioxidant markers: Increased levels of TAC in follicular fluid. ART outcomes: higher rates of high-quality oocytes, high-quality embryos, and oocyte maturity in the AX group (the oocyte number, fertilization rate, and fertility rate; N.S.) No safety concerns were identified in this study. |
| Rostami S. et al. 2023 [653] |
Randomized, triple-blind, placebo-controlled prospective study |
50 Patients of endometriosis (stage III/ IV) |
0, 6 mg/day | 12 weeks |
|
Antioxidant markers: Increased serum levels of total antioxidant capacity (TAC, p = 0.004) and superoxide dismutase (SOD, 13.458 ± 7.276 vs. 9.040 ± 5.155; p = 0.010) were observed in the AX intervention group after therapy. In addition, serum Malondialdehyde (MDA, p = 0.031) decreased significantly after AX treatment. Inflammation markers: Serum IL-1β (p = 0.000), IL-6 (p = 0.024), and TNF-α (p = 0.038) showed significantly lower levels after AX treatment. ART outcomes: AX supplementation resulted in a significantly improved number of oocytes retrieved (p = 0.043), mature (MII) oocytes (p = 0.041), and improved quality embryos (p = 0.024). No safety concerns were identified in this study. |
| Gharaei R. et al. 2022 [651] |
Randomized, double-blind, placebo-controlled prospective study |
40 Patients with polycystic ovary syndrome (PCOS) |
0, 8 mg/day | 40 days |
|
AX supplementation resulted in significantly higher serum Catalase and TAC levels in the AX group compared to the placebo group. However, there were no significant differences in serum MDA and SOD levels between groups. The expression of antioxidant genes such as Nrf2, HO-1, and NQ-1 was significantly increased in the granulosa cells (GC) of the AX group.ART: MII oocyte and high quality embryo rates were significantly increased in the AX group compared to the placebo group. There were no significant differences in chemical and clinical pregnancy rates between groups. No safety concerns were identified in this study. |
| Nakayama T. et al. 2015 [801] |
Open-labeled, prospective study |
18 subjects with normal menstrual cycles who have severe menstrual cramps or hypermenorrhea |
12 mg/day | 12 weeks |
|
VAS values for menstrual cramps: After 12 weeks of AX supplementation it, decreased significantly with duration of supplementation (p < 0.05 vs. pre; 60.2 ± 16.3, 4 weeks; 45.3 ± 17.0, 12 weeks; 38.5 ± 19.0). After12 weeks washout, it increased to 55.0 ± 18.3 (p < 0.05 vs. 12 weeks). VAS values for menstrual flow: Significantly decreased at 12 weeks (p < 0.05, pre; 67.0 ± 15.7 vs. 12 weeks; 45.1 ± 20.3), but increased again after 12 weeks of washout (55.6 ± 16.6, p < 0.05 vs. 12 weeks). Day-dysmenorrhea: Significantly decreased at 12 weeks (p < 0.05, pre; 2.5 ± 1.8 vs. 12 weeks; 1.3 ± 0.8), but increased again after 12 of weeks washout (2.5 ± 2.0, p < 0.05 vs. 12 weeks). Others: No significant changes in the frequency of NSAID dosing or the blood levels of CA125 and Hb over the study period. No safety concerns were identified in this study. [Article in Japanese] |
| Evaluation of efficacy in improving sperm quality and assisted reproductive technology (ART) | ||||||
| Dede G et al. 2022 [802] |
N/A | 30 Semen samples from normozoospermic individuals |
0, 50, 100, 500 μM | N/A |
|
Purpose: the protective efficacy of AX against the damage that occurs during sperm cryopreservation. The loss of motility due to cryopreservation of sperm was highest in the control group, and the least loss of motility was seen in the 100 μM AX group. Chromatin condensation of spermatozoa showed that the number of condensed spermatozoa was higher in the 100 μM AX group than in the other groups. (in vitro study) |
| Ghantabpour T. et al. 2022 [734] |
N/A | The first phase; 10 semen samples from healthy men, the second phase; 25 semen samples from healthy men |
0, 0.5, 1, 2 μM | N/A |
|
Supplementation of sperm freezing medium with 1 µM AX was found to improve all parameters of sperm motility and viability (p ≤ 0.05). In addition, there were reduced levels of ROS parameters (intracellular hydrogen peroxide and superoxide) compared to the control group (p ≤ 0.05). AX also significantly reduced phosphatidylserine exogenous levels (p ≤ 0.05) and lipid peroxidation (p ≤ 0.05) after the freeze-thaw process. (in vitro study) |
| Kumalic SI. et al. 2020 [803] |
Randomized, double-blind, placebo-controlled prospective study |
72 patients with oligo-astheno-teratozoospermia (Av. 35–36 yrs) |
0, 16 mg/day | 3 months |
|
In theAX group, no improvements in the total number of spermatozoa, concentration of spermatozoa, total motility of spermatozoa, morphology of spermatozoa, DNA fragmentation, and mitochondrial membrane potential of spermatozoa, or serum follicle-stimulating hormone were determined in patients with oligo-astheno-teratozoospermia. No safety concerns were identified in this study. |
| Terai K. et al. 2019 [649] |
Randomized, two-arm, open-labeled, prospective study |
31 males with oligozoospermia and/or asthenozoospermia | 0 (HE), 16mg/day * | 12 weeks |
|
Intervention; Combination of antioxidant supplements (L-carnitine, Zn, CoQ10, vitamin C, vitamin B12, vitamin E, and AX) and a Chinese herbal medicine, hochu-ekki-to (HE). There were no significant improvements in endocrinological findings in the supplement group. Although no statistically significant improvement was observed in semen volume, sperm concentration, or sperm motility, total motile sperm counts were significantly improved. On the other hand, the HE group tended to increase semen concentration, semen motility, and total motile sperm count, but not significantly improve any endocrinological factors or semen findings. No safety concerns were identified in this study. |
| Andrisani A. et al., 2015 [804] |
N/A | 24 Semen samples from healthy male donors of proven fertility, 27 Semen samples from patients who had failed to conceive after at least one year of regular unprotected intercourse | 0, 2 μM | N/A |
|
Evaluation of sperm capacitation, which involves a series of modifications, including regulation of reactive oxygen species, depletion of cholesterol in the sperm outer membrane, and protein tyrosine phosphorylation (Tyr-P) processes in the head region, that acquire sperm for the essential functions for fertilization of oocytes. AX successfully triggered Lyn translocation in patient-derived sperm(PG), bypassing the impaired ROS-related mechanisms for raft and Lyn translocation. In this study, ROS generation, lipid raft, and Lyn relocation are interdependent, leading to a continuous cellular acrosome reaction (AR). AX could be potentially used to ameliorate male idiopathic infertility by improving PG sperm function. A study related to the ref. [805]. (in vitro study) |
| Dona G. et al. 2013 [805] |
N/A | 24 Semen samples from healthy male donors | 0 to 2 μM | N/A |
|
The AX improved Tyr-P and acrosome reaction cells (ARC) values in sperm heads without affecting the ROS generation curve, while diamide successfully increased Tyr-P levels in flagella but did not increase ARC values. This suggests that AX, when inserted into the membrane, causes membrane changes, such as capsulation, that allow for Tyr-P conversion of the head. In other words, an acrosome reaction can occur, and more cells can be involved. A study related to the ref. [804]. (in vitro study) |
| Comhaire F.H. et al. 2005 [735] |
Randomized, double-blind, placebo-controlled, prospective study |
30 males with infertility of ≥12 months |
0, 16 mg/day |
3 months |
|
Significantly decreased ROS and Inhibin B and sperm linear velocity increased in the Astaxanthin group (n = 11), but not in the placebo group (n = 19). The total and per cycle pregnancy rates among the Astaxanthin group (54.5% and 23.1%) were higher compared with 10.5% and 3.6%, respectively, in the placebo cases (p = 0.028; p = 0.036). No safety concerns were identified in this study. |
| (H) Absorption Distribution Metabolism and Excretion (ADME) | ||||||
|
Author/year/
reference |
Study design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Continuous dosing pharmacokinetic evaluation | ||||||
| Urakaze M et al. 2021 [764] |
Randomized, double-blind, placebo-controlled prospective study |
44 subjects Including Prediabetes (Av. 46–48 yrs.) |
0, 12 mg/day | 12 weeks |
|
Plasma AX levels were undetectable at baseline and increased to 122.69 ng/mL (c.a. 205 nM) after 4 weeks in the intervention group, and this level was maintained until 12 weeks. No safety concerns were identified in this study. |
| Hayashi M. et al. 2020 [799] |
Randomized, double-blind, placebo-controlled prospective study |
54 healthy subjects (Av. 45–46 yrs.) |
0, 12 mg/day from Paracoccus |
8 weeks |
|
After 8 weeks of AX administration, the serum AX concentration increased to 0.171 ± 0.082 μg/mL (0.29 μM). Not detected in the placebo group. No safety concerns were identified in this study. |
| Hayashi M. et al. 2018 [793] |
Randomized, double-blind, placebo-controlled prospective study |
54 healthy subjects (45–64 yrs.) |
0, 8 mg/day from Paracoccus |
8 weeks |
|
After 8 weeks of AX administration, the serum AX concentration increased to 0.173 ± 0.058 μg/mL (0.29 μM). Not detected in the placebo group. No safety concerns were identified in this study. |
| Petyaev I.M., et al. 2018 [719] |
Randomized, blinded, four-arm, prospective study |
32 subjects with oxidative stress, 8 subjects taking AX only, (60–70 yrs) | 0, 7 mg/day * with DC |
4 weeks |
|
Plasma AX concertation was seen in the volunteers supplemented with a lycosomal formulation of dark chocolate (DC) containing 7 mg of co-crystalized AX (L-DC-ASTX). Increase in plasma AX concertation. Plasma AX concentrations after 4 weeks were higher in the L-DC-ASTX formulation than other groups (5.22–7.31 nmol/L vs. 17.34 nmol/L ). No safety concerns were identified in this study. |
| Coombes J.S et al. 2016 [695] Fassett, R.G. et al. 2008, [696] |
Randomized, double-blind, placebo-controlled prospective study |
58 renal transplant recipients | 0, 12 mg/day | 12 months |
|
Plasma AX concentrations were 0.29 ± 0.18 μmol/L at 6 months and 0.28 ± 0.17 μmol/L at 12 months (Mean ± SD). (The XANTHIN trial) No safety concerns were identified in this study. |
| Miyazawa T. et al. 2011 [730] |
Randomized, double-blind, placebo-controlled, prospective study |
30 middle- aged & senior subjects (Mean: 50.6 yrs.) |
0, 1, 3 mg/day |
12 weeks |
|
Erythrocyte AX concentrations after 4 or 12 weeks of supplementation (3 mg/day administration, 2.5 nM AX in packed cells for 4 weeks, and 2.9 nM for 4 weeks respectively) were significantly higher than after placebo or 1 mg AX supplementation. No safety concerns were identified in this study. |
| Miyazawa T. et al. 2011 [568] |
Randomized, double-blind, placebo-controlled, prospective study |
20 middle- aged & senior subjects (Mean: 50.6 yrs.) |
1, 3 mg/day |
12 weeks |
|
Plasma AX concentrations were significantly higher in a dose-dependent manner after AX supplementation than before in both the 1 mg/day (0.4, 12.3, and 18.9 nM for 0, 4, and 12 weeks after administration, respectively) and 3 mg/day (0.7, 14.4, and 62.4 nM for 0, 4, and 12 weeks after administration, respectively) groups. No safety concerns were identified in this study. |
| Nakagawa K. et al. 2011 [721] |
Randomized, double-blind, placebo-controlled prospective study |
30 healthy subjects | 0, 6, 12 mg/day | 12 weeks |
|
6mg/day: Increased AX concentration in plasma after 12 weeks (86 nM) compared to baseline (p < 0.01, 6 to 9 nM) and compared to placebo (p < 0.01, 8 nM). 12mg/day: Increased AX concentration in plasma after 12 weeks (109 nM) compared to baseline (p < 0.01, 8 to 9 nM) and compared to placebo (p < 0.01, 8 nM) No safety concerns were identified in this study. |
| Park J.S. et al. 2010 [732] |
Randomized, double-blind, placebo- controlled, prospective study |
42 healthy subjects | 0, 2, 8 mg/day | 8 weeks |
|
Plasma AX concentration From 4 weeks after administration, c.a. 0.1 µM (2 mg AX/day), c.a. 0.12–0.14 µM (8 mg AX/day) No safety concerns were identified in this study. |
| Uchiyama A. et al. 2008 [775] |
Open-labeled, prospective study | 17 subjects at risk for developing metabolic syndrome | 8 mg twice day | 3 months |
|
The blood concentration reached the plateau after a month of treatment and was retained at that level unti1 3 months of treatment (0.2–0.25 μg/mL (0.34–0.42 μmol/L)). No safety concerns were identified in this study. |
| Karppi, J. et al. 2007 [733] |
Randomized, double-blind, placebo-controlled, prospective study |
39 healthy subjects | 0, 8 mg/day | 3 months |
|
AX supplementation elevated plasma AX levels to 0.032 nM (c.a. 0.02μg/mL, p < 0.001 for the change compared with the placebo group). No safety concerns were identified in this study. |
| Nagaki Y. et al. 2005 [684] |
Randomized, placebo-controlled, prospective study |
36 health subjects (c.a. 41 yrs.) |
0, 6 mg/day | 4 weeks |
|
The fasting plasma AX level in the AX group was significantly (p < 0.001, 35.6 ng/mL at 4 weeks) higher than before supplementation. The fasting plasma AX level in the placebo group after placebo treatment remained unchanged. No safety concerns were identified in this study. [Article in Japanese] |
| Single dosing pharmacokinetic evaluation | ||||||
| Madhavi D. et al. 2018 [806] |
Open-label, crossover study |
6 healthy subjects | 60 mg | Single dosing |
|
Test articles: AX-SR; 2.5% AX in a sustained-release matrix: AX (control); 10% AX (unformulated AX oil). Dissolution study: AX-SR formulation formed a stable dispersion in simulated gastric and intestinal fluids. Single-dose pharmacokinetic study (clinical study); AX-SR formulation (AUC0–24h: 4393 ± 869 ng/mL-h) showed 3.6 times higher bioavailability than AX oil (AUC0–24h: 1227 ± 1328 ng/mL-h) (p < 0.0005). AX oil showed very low absorption in 3 of 6 subjects, whereas the AX-SR formulation appeared in the blood of all subjects. No safety concerns were identified in this study. |
| Okada Y. et al. 2009 [807] |
Open-labeled, prospective study |
Healthy subjects; before the meal to nonsmokers (n = 7), after the meal to nonsmokers (n = 6), and after the meal to smokers (n = 7) |
48 mg | Single dosing |
|
Dosing timing significantly affected AX bioavailability, including area under the curve (AUC0–168h, 2968 ± 959 μg·h/L in the pre-meal group and 7219 ± 3118 μg·h/L in the after-meal group), suggesting a higher availability in the after-meal group. Smoking also affected pharmacokinetic parameters, significantly reducing the elimination half-life (t1⁄2) of AX. No safety concerns were identified in this study. |
| Coral-Hinostroza G.N. et al. 2004 [808] |
Open-labeled, prospective study |
3 male subjects (41–50 yrs, BMI 27.7–27.8) |
10, 100 mg |
Single dose |
|
Test meal: Dissolved the oily AX diesters in warm olive oil (30% of meal weight) and served as a dressing to a pasta salad. 100 mg (Cmax: 0.28 ± 0.1 mg/L, Tmax: 11.5 ± 1.2 hr, T1/2: 52.2 ± 39.5 hr. AUC(0–∞) 11.0 ± 2.8 mg h/L) Cmax at the low dose (10 mg): 0.08 mg/L (non-linear dose response). AX esters were not detected in plasma. No safety concerns were identified in this study |
| Mercke Odeberg J. et al. 2003 [809] |
Open-labeled, prospective study |
32 healthy male Subjects (nonsmoker/no medications) |
40 mg | Single dose |
|
Test meal: Haematococcus algal meal and dextrin in hard gelatin capsules (reference) and with long-chain triglyceride (palm oil) and polysorbate 80 (formulation A), glycerol mono- and dioleate and polysorbate 80, (formulation B), and glycerol mono- and dioleate, polysorbate 80 and sorbitan monooleate (formulation C). The highest bioavailability was observed with formulation B (3.7 times higher UC(0–∞) compared to the reference control). No safety concerns were identified in this study. |
| Østerlie M. et al. 2000 [810] |
Open-labeled, prospective study |
3 male subjects (37–43 years, BMI 27.5–31.7) |
100 mg | Single dose |
|
Test meal: prepared by dispersing the AX beadlets in warm water (40 °C) and mixing with olive oil (50% of meal weight) and cereals. Cmax: 1.3 ± 0.1 mg/L, Tmax: 6.7 ± 1.2 hr, T1/2: 21 ± 11 hr, AUC(0–∞) 42 ± 3 mg h/L. Accumulated 13Z-AX selectively, whereas the steroisomer distribution was similar to that of the experimental meal. AX was present mainly in VLDL containing chylomicrons (36–64% of total AX), whereas LDL and HDL contained 29% and 24% of total AX, respectively. The AX isomer distribution in plasma, VLDL/CM, LDL, and HDL were not affected by time. No safety concerns were identified in this study. |
| (I) Others | ||||||
|
Author/Year/
Reference |
Study Design | Subjects | Dose #,## | Duration | Major Outcome † | Description |
| Continuous dosing pharmacokinetic evaluation | ||||||
| Ledda A. et al. 2017 [724] |
Open-labeled, two-arm prospective study |
59 patients with genitourinary cancers (prostate or bladder malignancies) who had undergone and completed cancer treatments (radiotherapy, chemotherapy or intravesical immunotherapy with increased oxidative stress and residual symptoms) | 0, 8 mg/day * | 6 weeks |
|
Oncotris: containing 264 mg/day curcumin, 500 mg/day extract of cordyceps, and 8 mg/day AX (from EP217785227). Signs and symptoms (treatment-related) and the intensity of residual side effects were significantly reduced after 6 weeks in the supplemented group: minimal changes were seen in the control group. Oncotris supplementation was associated with significant improvements in blood cell counts and reductions in levels of plasma PSA and oxidative stress. No safety concerns were identified in this study. |
| Kaneko M et al. 2017 [811] |
Open-label, prospective study |
10 male subjects | 24 mg/day | 28 days |
|
Aerodynamic assessment, acoustic analysis, and the GRBAS scale (grade, roughness, breathiness, asthenia, and strain) were significantly worse in the no AX status (day 0) immediately after vocal loading but improved by 30 min after loading. On the other hand, in AST(+) (day 35), no statistical worsening of any of the phonatory parameters was observed when measured immediately after the vocal load. No safety concerns were identified in this study. |
| Yagi H. et al. 2013 [725] |
Case reports | 34 OAB patients with anticholinergic agent-resistant (75.5 ± 8.0 years) |
0, 12 mg/day * |
8 weeks |
|
Significantly improved international prostate symptom score (IPSS), QOL scores, benign prostatic hyperplasia impact index (BII) scores, and urinary 8-OHdG in patients AX could improve both urinary symptoms and QOL for anticholinergic agent-resistant OAB. No safety concerns were identified in this study. [Article in Japanese] |
| Park J.S. et al. 2010 [732] |
Randomized, double-blind, placebo- controlled, prospective study |
42 healthy subjects | 0, 2, 8 mg/day | 8 weeks |
|
Immunity Increased natural killer (NK) cell cytotoxic activity and increased total T and B cell subpopulations; however, did not influence populations of Th, Tcytotoxic or NK cells. No difference in TNF-α and IL-2 concentrations, but plasma IFN-γ and IL-6 increased after 8 weeks in subjects given 8 mg AX. No safety concerns were identified in this study. |
| Yamada T. et al. 2010 [727] |
Open-labeled, prospective study | 6 healthy subjects and 6 Sjoegren’s syndrome (SS) subjects |
12 mg/day | 2 weeks |
|
Although the increased amount of salivary secretion after the intake of AX for 2 weeks was faint in the SS group (1.02 g/2 min to 1.04 g/2 min, p = 0.69), a significant increase was also observed in the normal group (6.23 g/2 min to 7.02 g/2 min, p = 0.03). reduced protein oxidation (−10%, p < 0.05) No safety concerns were identified in this study. |
| Kupcinskas L. et al. 2008 [812] |
Randomized, single-blind, placebo-controlled prospective study |
131 patients with functional dyspepsia with or without Helicobacter pylori infection |
0, 8, 20 mg/twice a day (0,16, 40 mg/day) |
4 weeks |
|
No statistically significant differences were observed between the three treatment groups at the end of treatment (week 4) for mean scores on the Gastrointestinal Symptom Rating Scale (GSRS) for abdominal pain, indigestion, and reflux syndrome, and similar results were observed at the end of follow-up (week 8). The reflux syndrome tended to improve at the higher dose (40 mg) compared to the other treatment groups (16 mg and placebo), and this response was more pronounced (p = 0.04) in H.pylori-infected patients. No safety concerns were identified in this study. |
| Andersen LP. et al. 2007 [813] |
Randomized, double-blind, placebo-controlled, prospective study |
44 patients with functional dyspepsia with or without Helicobacter pylori infection |
0, 20 mg/twice a day (0, 40 mg/day) |
4 weeks |
|
There were no significant changes in either H. pylori density or interleukins during or after treatment; significant upregulation of CD4 (p < 0.05) and downregulation of CD8 (p < 0.001) were observed in H. pylori patients treated with AX. No safety concerns were identified in this study. |
This table was updated and prepared from Ref. [130] to May 2023. For statistical analysis of efficacy, most analyses were performed with “Per Protocol Set”, thus the number of subjects adopted for the final analysis is shown. This table sorts each clinical trial by category. As a result, some of the trial outcomes have been multiplied and listed. Tables without overlap are summarized in Supplementary Table S4. † With the exception of the study in which safety was the only primary outcome, the other outcomes were noted. * In addition to AX, other nutrients, such as antioxidants, were used in the study. # All the studies in the “Dose” column that did not indicate the origin were conducted using AX derived from Haematococcus algae. ## AX concentrations were shown in free form.