Table 2.

Beneficial effects of γT or mixed tocopherols in human intervention studies

Type of study	Subject characteristics	Supplementation details	Effect and major outcomes	Ref.
Patients with kidney diseases
Randomized, double-blinded, crossover	Patients on chronic hemodialysis therapy; n=15 patients and 15 healthy participants	300 mg αT or 300 mg γT-rich mixed toocpherols (60% γT, 28% δT and 10% αT) for 14 d	Supplementation of γT-rich mixed tocopherols decreased CRP in the plasma, whereas αT had on effect on CRC but increased IL-6.	[128]
Randomized, double-blinded, placebo-controlled	Hemodialysis maintenance patients;	308 mg γT plus 800 mg DHA (docosahexaenoic acid) for 4 and 8 wk; supplement (n=31) vs. placebo (n=30)	Compared to placeboes, supplementation of γT plus DHA decreased white blood cells, IL-6, neutrophils and erythropoietin index, but did not affect plasma CRP, F2-isoprostane or carbonyls.	[130]
Prospective, double-blind, randomized and placebo-controlled trial	Patients with chronic kidney disease undergoing coronary procedures	350 mg αT, or 300 mg γT, or placebo (n=101-102 per group) for 5 days prior to coronary procedure and 2 days afterwards	Prophylaxis administration with αT or γT decreased the risk of contrast-induced acute kidney injury in chronic kidney disease patients.	[132]
Prospective, placebo-controlled, double-blind, randomized	Patients undergoing maintenance hemodialysis therapy	A combination of mixed tocopherols (666 IU/d) plus α-lipoic acid (600mg/d) for 6 months (n=353)	The treatment, while generally safe and well-tolerated, had no significant effect on plasma CRP, IL-6, and F2 isoprostane and did not improve the erythropoietic response.	[133]
Patients with multiple sclerosis
randomized, blind, placebo-controlled	Patients with relapsing-remitting multiple sclerosis / Total n = 80	Group A: n-3 (EPA+DHA)/n-6 fatty acids at 1:1 with αT (22mg); group B: A plus γT (760mg); group C: γT (760mg); placebo, for 30 months. n=20 per group	The combination of n-3/n-6 (1:1) fatty acids and γT (group B) reduced relapse rate of multiple sclerosis by 64%, delayed disability progression by 72% and decreased the risk of the sustained progression disability by 85%.	[131]
Patients with metabolic syndromes
Double-blind, placebo-controlled trial	Type 2 diabetic patients	500 mg of RRR-αT, or γT-rich mixed tocopherols (75mg αT, 315mg γT and 110mg δT), and placebo (n=18-19 per group), for 6 wk.	αT or γT-rich mixed tocopherols decreased plasma F2-isoprostane, while increased blood pressure, without affecting inflammation markers. γT + αT reduced LTB₄ from stimulated neutrophils in vitro.	[138, 139]
Randomized, placebo-controlled double-blind trial	Participants with metabolic syndromes /	800 mg αT, or 800 mg γT, or their combination, or placebo (n=20 per group) for 6 wk	The combination of αT and γT decreased CRP, nitrotyrosine and oxidation markers, while αT and γT alone showed partial benefits regarding these markers.	[137]
The effect on asthma-related endpoints in healthy and mild asthma
Open-label, Phase I dosing study of two doses	Adults (18-50 y) with/without asthma (moderate to severe); n=16; allergic asthma n=8	γT-enriched (623 mg γT, 61.1 mg αT, 11.1 mg βT, 231mg δT)×1 or 2/d; 8d→8d-washout-→8d;	γT-rich tocopherols decreased serum concentrations of 5-nitro-γT, suggesting attenuation of oxidative stress and inhibited PBMC response to ex vivo LPS challenge.	[140]
Open-label, single-arm	Adults (22-43 y), n=5 healthy participants and n=5 mild asthma	γT-enriched tocopherols (612 mg γT, 7 mg αT, 28 mg βT, 8 mg δT)×2; every 12hr for 3 doses;	γT supplementation decreased ex vivo LPS-induced IL-6 and IL-1β production from PBMCs	[7]
Open-label, single-arm	Adults with dust mite allergy, n=20	γT-enriched supplement (612 mg γT, 7 mg αT, 28 mg βT, 8 mg δT)x2 daily for 7 days	γT treatment reduced IgE-mediated basophil activation with dust mite allergen.	[70]
Phase IIa randomized, double-blinded, placebo-controlled crossover	Healthy adults (19-33 y), challenged by intranasal endotoxin (LPS); (n=13)	γT-rich tocopherols (540mg γT, 50mg αT, and 240mg βT+δT)×2/d; 1wk prior to endotoxin inhalation challenge→ washout→1wk	γT-enriched supplement reduced intranasal LPS-induced infiltration of airway (sputum) neutrophils, reduced % eosinophils in sputum and neutralized LPS-induced increase of IL-β.	[88]
Randomized, double-blinded, placebo-controlled, phase IIa crossover	Adults (20-47 y) with mild asthma; total n=23; atopic n=17	γT-enriched supplement (612 mg γT, 7 mg αT, 28 mg βT, 8 mg δT) or placebo for 2wk, then treated with LPS inhalation →3-wk washout→2wk	γT reduced (pre-LPS) sputum eosinophils and mucins including mucin 5AC, and inhibited inhaled LPS challenge-induced airway neutrophil recruitment. γT also prevented post-LPS challenge caused slow-down of mucociliary clearance.	[8]
Randomized, double blind, placebo-controlled crossover study	Adults with mild intermittent allergic asthma, n=15	γT-enriched geltabs (600 mg, 89.5% γT)x2 and placebo (safflower oil 700 mg) every 12 hours for 4 doses; participants are then exposed to 0.25ppm O3 for 3 hours	γT pre-treatment did not affect ozone-induced airway inflammation.	[141]
The effect of γT on cardiovascular disease-relevant endpoints
Placebo controlled study	platelet aggregation after tocopherol supplementation in healthy volunteers	Mixed tocopherols (100mg γT, 40mg δT and 20mg αT) (n=18) or all-rac-αT acetate at 100mg (n=18), or placebo (n=10) for 8 wk	Mixed tocopherols suppressed ADP-induced platelet aggregation and induced endothelial nitric oxide synthase and nitric oxide release more strongly than αT. Both induced SOD and inhibited PKC activation.	[60]
Randomized placebo controlled	Healthy sedentary subjects in strenuous exercise	300 mg γT, or 400IU αT, every day or every other day for 6 wk (n=36)	γT but not αT ameliorated exercise-induced decrease of APTT (activated partial thromboplastin time) and exercise-increased platelet aggregation induced by collagen.	[134]
Randomized, crossover, single-blind design	Healthy men with oral glucose tolerance test following overnight fasting	Mixed tocopherols (500mg γT, 60mg αT, 170mg δT and 9mg βT) daily for 5 days (n = 15)	γT-rich tocopherols attenuated glucose-induced decrease of brachial artery flow-mediated dilation, lipid peroxidation and disruption in NO homeostasis as well as dicarbonyl methylglyoxal.	[135, 136]

All the major findings (outcomes) are statistically significant.