Table 2.

Clinical trials that assessed the efficacy of natural and synthetic molecules with antioxidant properties in DS subjects.

Type of Trial	Antioxidant	Subjects/Cell Type	Dosage and Treatment Duration	Results	References
R, DB, PC	α-tocopherol, ascorbic acid and α-lipoic acid	53 individuals with DS and dementia (average age ≈ 50 years)	Daily dose of 900 IU of α-tocopherol, 200 mg of ascorbic acid, and 600 mg of α-lipoic acid for 2 years	No improvement in cognitive functioning or stabilization of cognitive decline	[103]
R, DB, PC	Vitamin E (α-tocopherol)	337 adults with DS older than 50 years of age	1000 IU of vitamin E, twice daily for 3 years	No retardation in the progression of cognitive deterioration	[104]
DB, case-control study, PC crossover trial	Mixture of vitamins and minerals	A total of 115 children with DS (in the four studies) aged between 7.5 months and 17 years old	Between 4 and 8 months depending on the study	No significant effect on development or behavior. No effect on intelligence quotient tests. No effect on standard psychological tests. Induction of various side-effects	[120,121,122,123,124]
R, PC	Mixture of vitamins and minerals	156 children with DS, less than 7 months old	Daily supplementation with 10 μg of selenium, 5 mg of zinc, 0.9 mg of vitamin A, 100 mg of vitamin E, 50 mg of vitamin C, and 0.1 mg of folinic acid for 18 months	No benefits in psychomotor development, language acquisition or in the levels of markers of OS in red blood cells	[125]
R, DB	Leucovorin (folinic acid)	117 children with DS aged between 3 and 30 months old	Daily dose of 1 ± 0.3 mg/kg for 12 months	Improvement of psychomotor development. No effect on sociability, language or coordination	[126]
Pilot study	Mixture of nutrients zinc, vitamins (A, C, E, B1, B2, B3, B6, B9, B12) and minerals	40 children with DS aged between 5 and 16 years old	5000 IU of vitamin A, 25 IU of vitamin E, 100 mg of ascorbic acid, 10 mg of thiamine mononitrate, 10 mg of riboflavin, 3 mg of pyridoxine hydrochloride, 5 µg of cyanocobalamin, 50 mg of niacinamide, 1 mg of folic acid, 12.5 mg of calcium pantothenate, 2.5 mg of copper, 60 µg of selenium, 1.4 mg of manganese and 5 µg of chromium for 6 months	Reduction of serum acetyl- and Butyrylcholinesterase. Improvement in cognitive skills and behavioral patterns	[127]
DB	Acetyl-l-carnitine	40 adults with DS aged between 18 and 30 years old	Ascending doses: 10 mg/kg/day for the first month, 20 mg/kg/day for the second month and afterwards 30 mg/kg/day for the rest of the study. Duration: 6 months, followed by a 3-month “wash-out” period	No effect on cognitive abilities, behavioral problems or daily living skills	[128]
Pilot study	Epigallocatechin-3-gallate (EGCG)	31 young adults with DS aged between 14 and 29 years old	9 mg/kg/day for 6 months	Positive effects on memory recognition, working memory, and quality of life	[116]
R, DB, PC	EGCG	84 young adults with DS aged between 16 and 34 years old	9 mg/kg/day for 12 months	Improvement in visual recognition memory, inhibitory control, and adaptive behavior	[129]
CR	EGCG plus omega-3 fish oil	One DS child, 10 years and 3 months old	EGCG: 10 mg/kg/day and omega-3 fish oil: 8 mg/kg/day for 6 months	Improvement in the ability to perform tasks requiring concentration. Restoration of mitochondrial respiratory chain complex activities in lymphocytes from peripheral blood	[130]
	Vitamin E, vitamin C	Healthy and DS children between 3 and 14 years of age	Vitamin C (500 mg/day), vitamin E (400 mg/day) administered daily for 6 months	Attenuation of systemic oxidative damage in the blood of DS subjects. These effects persisted for at least 6 months after the cessation of the antioxidant therapy	[38,131]
	α-tocopherol or α-lipoic acid	93 DS children between 7 and 15 years of age	α-tocopherol (400 IU/day) or α-lipoic acid (100 mg/day) for 4 months	Attenuation of OS at the DNA level in serum after 20 months of treatment. No effect on RNA or DNA oxidation after 4 years of treatment	[132]
	Coenzyme Q10	Children (aged 5–12 years, n = 20) and teenagers (aged 13–17 years, n = 8) with DS	4 mg/kg/day for 20 months (children), and 4 years (teenagers)	Reduced the activity of GPx in erythrocytes	[65,133]
	Selenium	48 children with DS (aged between 6 months and 16 years)	10 µg/kg body weight/day for 6 months	Improvement of the rest-activity rhythms	[134]
	α-lipoic acid and L-cysteine	20 children with DS (aged between 1 and 16 years old) with redox imbalance	One capsule per day that contained 200 mg of α-lipoic acid, and 200 mg of L-cysteine, over several treatment cycles (one treatment cycle = 30 days plus a 30 day wash-out period)	Reduction of serum ROS	[135]

R = randomized; DB = double-blind; PC = placebo-controlled; CR = case report.