Effect of Mixed-Tocotrienols in Hypercholesterolemic Subjects

Kah Hay Yuen, Jia Woei Wong, Ai Beoy Lim, Bee Hong Ng, Wai Peng Choy

Functional Foods in Health and Disease: 3:106-117

Published

Objectives: Aims to investigate the cholesterol lowering activity of tocotrienols.

Study design: Randomized, double blind study

Subjects: Hypercholesterolemic patients

Intervention: Mixed tocotrienol 300 mg versus placebo (soya bean oil 300 mg)

Primary outcome: Tocotrienol and tocopherol concentrations and serum cholesterol levels

Methodology: Thirty-two hypercholesterolemic subjects were randomly assigned to orally receive either 300 mg of mixed tocotrienols capsules daily or placebo capsules containing 300 mg of soya bean oil for a period of 6 months. The subjects were monitored before supplementation and monthly thereafter for their serum cholesterol as well as tocotrienol and tocopherol concentrations.

Results: The serum total cholesterol and low density lipoprotein (LDL) cholesterol of the subjects in the tocotrienol supplementation group were decreased significantly by 8.9 ± 0.9% and 12.8 ± 2.6% respectively after 4 months of supplementation and the reduction persisted till the end of the 6-month study, with a reduction of 10.8 ± 1.0% and 17.3 ± 1.8%, respectively from baseline. Moreover, there was a 22fold increase in the total tocotrienol concentrations from baseline during supplementation compared to the placebo group, while the concentration of α-tocopherol recorded only a modest increase. On the other hand, the serum cholesterol, total tocotrienol and α-tocopherol concentrations of subjects in the placebo group remained essentially unchanged.

Conclusion: Supplementation with mixed tocotrienols at dose of 300 mg per day resulted in the lowering of the serum total and LDL cholesterol levels after 5 months of supplementation.

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A Phase I Dose-Escalation Study Evaluating the Pharmacokinetics, Safety and Tolerability of Oral Gamma-Delta-Tocotrienol (GDT) in Patients with Castration-Resistant Prostate Cancer (CRPC)

Prof Azad Hassan A. Razack, University of Malaya Medical Centre, Malaysia

Ongoing

Objective:  In this study, we intend to determine Gamma-Delta Tocotrienol’s (GDT) safety and tolerability in patients with castrate-resistant prostate cancer (CRPC). In addition, GDT’s pharmacokinetic profile in this cohort of patients will be investigated.

Study Type: Interventional

Study Design: Dose-escalation, pharmacokinetics study

Subjects: Castrate-resistant prostate cancer patients

Intervention: Gamma-Delta Tocotrienol (GDT; Davos Life Science Pte Ltd)

Primary Outcome:

  • Safety and tolerability
  • GDT isomer plasma concentration [ time frame: 0, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours ]

Secondary Outcome: Circulating tumor cell (CTC) levels and inflammatory biomarkers (IL-8, MCP-1, MIP-1 alpha, IFN-gamma, IL-1B, IL-4, IL-6, IL-10, IL-12 (p70), IL-17A, Il-23, IL-27, TNF-alpha, MIP-3 alpha, CRP) [time frame: baseline and day 22]

Methodology: During pharmacokinetic evaluation wherein GDT will be taken as a single dose, participants will receive oral GDT for 21 days at 400, 800, 1600, 2400 and 3200 mg/day for 21 days. Pharmakokinetic and safety profiles will be evaluated on the 8th, 15th and 22nd day.

Clinical evaluation of photoprotective effect by a topical antioxidants combination (tocopherols and tocotrienols)

Pedrelli VF, Lauriola MM, Pigatto PD.

J Eur Acad Dermatol Venereol. 2012 Nov;26(11):1449-53

Published

Objectives: In view of experimental evidence for the photoprotective properties of these antioxidants, we evaluated in 30 patients with photosensitivity, the prophylactic efficacy of a new topical agent, containing tocopherols 10% and tocotrienols 0.3%, compared with retinol, simple vehicle and untreated areas.

Subjects: Patients with photosensitivity

Intervention: Tocotrienol and tocopherol containing formulation

Primary outcome: Photosensitivity (erythema/oedema/itch/vesciculation) scores

Methodology: After determination of the minimal UVB erythema dose (MED), two areas of 2 × 2 cm were selected on the buttocks of each subject, one of which was treated with the antioxidant formulation whereas the other field did not undergo any treatment. Therefore, both areas were irradiated with a twofold MED. As further controls, other two similar areas, selected on the forearm of 15 patients, were photo-irradiated similarly, 30 min after application of the simple vehicle to a field and of vitamin A in the same vehicle to the other. Reactions (erythema/oedema/itch/vesciculation) assessment was carried out assigning scores indicative of their intensity; then, mean values +DS of scores were calculated. Results  The pre-treatment with the vitamin E formulation highly protects against photosensitivity, and all reactions to irradiation were significantly lower in the areas treated with the topical vitamin E formulation compared to those treated with the simple vehicle or vitamin A.

Results: The pre-treatment with the vitamin E formulation highly protects against photosensitivity, and all reactions to irradiation were significantly lower in the areas treated with the topical vitamin E formulation compared to those treated with the simple vehicle or vitamin A.

Conclusions: The use of a new topical formulation containing significant concentrations of tocotrienols and tocopherols represents a promising strategy to reduce the photo-induced skin damage.

Human Blood Outcomes Following Tocotrienol Supplementation – NUTRITION Phase I and Phase IIA

Chandan K Sen, Ph.D. Andrew Slivka, MD Cameron Rink, PhD

Ongoing

Objective: Plan to conduct two trials (I & IIA) to determine the effects of orally supplemented TCT on platelet function and cholesterol.

Study type: Interventional

Study Design: Randomized, Double-blind

Subjects: Phase I – healthy volunteers; Phase IIa- hyperlipidemic subjects

Intervention: Tocotrienol, low dose aspirin

Primary Outcome: 1) Platelet function panel. Blood draw followed by platelet aggregometry.

2) Lipid profile. Blood lipid panel including HDL, LDL, total cholesterol

Secondary Outcome: Tape Stripping Test. HPLC vitamin E analysis of tape strips for compliance

Methodology: We plan to conduct two trials (I & IIA) to determine the effects of orally supplemented TCT on platelet function and cholesterol. Phase I subjects will be healthy volunteers, recruited by an advertisement. Phase IIA subjects will be hyperlipidemic (having high cholesterol), and will be referred to us by their Wound Care Center Physicians. Patients will be randomized to receive placebo pills, (400 or 800 mg) TCT pills, low-dose 81 mg aspirin (commonly used for secondary prevent stroke), or TCT and aspirin together. potential subjects for Phase-I who meet study criteria and agree to participate will be in the study for 6 months and have following study related procedures,blood draw total 3 times, tape stripping(non-invasive procedure) and blood pressure measurement in each visit (every month). For participants in Phase-IIA will have total 5 times blood draw, tape stripping and blood pressure measurement and participants will be in the study for 12 months.

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A Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Vitamin E δ-Tocotrienol Administered to Subjects With Resectable Pancreatic Exocrine Neoplasia

Gregory Springett, M.D., Ph.D.H., Moffitt Cancer Center (USA)

Ongoing

Objective: The purpose of this study is to determine the safest dose of the study drug Vitamin E delta-tocotrienol, how often it should be taken, and how well people with pancreatic tumors tolerate Vitamin E delta-tocotrienol.

Study Type: Interventional

Study Design: Open Label, Safety Efficacy Study

Subjects: Patients with resectable pancreatic neoplasia

Intervention: Vitamin E delta-tocotrienol

Primary Outcome: To determine the recommended Phase II dose of Vitamin E δ-Tocotrienol which will be defined as the biologic effective dose (BED) which induces significant apoptosis in the pancreatic neoplastic cells of resected tumor specimens following oral administration of Vitamin E δ-Tocotrienol twice daily for 14 (± 2)days prior to surgery, and one dose the day of surgery.

Secondary Outcome: To characterize the safety and tolerability of Vitamin E δ-Tocotrienol when orally administered at up to 5.6 times the predicted biological effective dose (1600mg twice daily) for 14 (± 2) consecutive days and one dose the day of surgery in patients with pancreatic neoplasia.

Methodology: This study consists of the following: (1) A Pre-Treatment Period in which participants are consented and qualified for the study; (2) A Study Treatment Period in which participant will receive Vitamin E δ-Tocotrienol administered orally twice daily for 14 (±2) consecutive days and once on the day of surgery, with associated pharmacokinetic and pharmacodynamic sampling; (3) A Post Treatment Period in which laboratory and physical examinations are performed. Adverse events will be recorded throughout the study.

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A Double Blind Placebo Controlled Study On The Neuroprotective And Anti-Atherogenic Effects Of Palm Tocotrienol Rich Fraction (Palm Vitamin E)

Yuen Kah Hay, Phd

Ongoing

Objective: The purpose of the study is to assess the neuroprotective, anti atherogenic and hepatoprotective properties of tocotrienols (palm vitamin E) supplementation as determined by white matter lesion load on serial magnetic resonance imaging (MRI), carotid artery magnetic resonance angiography (MRA) and liver ultrasound (US) as well as lipid profile analysis.

Study Type: Interventional

Study Design:  Phase 2, Randomized, Double –Blind

Subjects: Patients with cerebrovascular disorders

Intervention: Tocotrienol, placebo

Primary Outcome: Regression of white matter lesion load in terms of numbers and size in the brain [ Time Frame: 1 to 2 years ]

Secondary Outcome: 1) Regression of the carotid artery stenoses in terms of percentage [ Time Frame: 1 to 2 years ]

2) The improvement in the lipid profile other markers associated with increased cardiovascular risk [ Time Frame: 1 to 2 years ]

3) Improvement in liver echogenicity. [ Time Frame: 1 to 2 years ] [ Designated as safety issue: No ]

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Suppression of Nitric Oxide Production and Cardiovascular Risk Factors in Healthy Seniors and Hypercholesterolemic Subjects by a Combination of Polyphenols and Vitamins

Qureshi AA, Khan DA, Mahjabeen W, Papasian CJ, Qureshi N.

J Clin Exp Cardiolog. 2012 Jun 7;S5:8.

Published

Objectives: To determine whether serum nitric oxide (NO) levels increase with age in humans, and whether the combined cholesterol-lowering and inflammation-reducing properties of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid would reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

Subjects: Healthy Seniors and Hypercholesterolemic Subjects

Intervention: δ-tocotrienol, resveratrol, pterostilbene, Morin hydrate, quercetin, riboflavin, and nicotinic acid

Primary outcome: Serum NO, C-reactive protein (CRP), γ-glutamyltransferase (γ-GT) activity, uric acid, total antioxidant status (TAS), total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides levels

Methodology: Elderly human subjects were stratified into two groups based on total serum cholesterol levels. Initial total serum cholesterol levels were normal and elevated in Group 1 and 2 subjects, respectively. Baseline serum NO, C-reactive protein (CRP), γ-glutamyltransferase (γ-GT) activity, uric acid, total antioxidant status (TAS), total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides levels were established over a four week period. Group 1 subjects subsequently received nutritional supplementation with one of two different combinations (NS-7 = 25 mg of each, resveratrol, pterostilbene, quercetin, δ-tocotrienol, nicotinic acid, morin hydrate or NS-6 = morin hydrate replaced with quercetin, 50 mg/capsule). Group 2subjects also received these nutritional supplements (two capsules/d), but an AHA Step-1 diet was also implemented. After these interventions were administered for four weeks, the above parameters were re-measured and changes from baseline levels determined. Nitric acid (NO) levels in children, young adults, and seniors were also compared.

Results: The key results of the current study were: 1) that serum NO levels were significantly increased in seniors compared to both children (~80%) and young adults (~65%); 2) that the intake of two capsules/d of NS-7 or NS-6 for four weeks significantly (P < 0.05) decreased serum NO (39%, 24%), CRP (19%, 21%), uric acid (6%, 12%) levels, and γ-GT activity (8%, 6%), respectively in free-living healthy seniors; 3) that serum NO (36%, 29%), CRP (29%, 20%), uric acid (6%, 9%) γ-GT activity (9%, 18%), total cholesterol (8%, 11%), LDL-cholesterol (10%, 13%), and triglycerides (16%, 23%) levels were significantly (P < 0.02) decreased in hypercholesterolemic subjects restricted to AHA Step-1 diet plus intake of SN-7 or SN-6 (two capsules/d), respectively; 4) that TAS was increased (3%, 9%; P < 0.05) in free-living healthy seniors receiving NS-7 or NS-6 alone, and in hypercholesterolemic subjects plus AHA Step-1 diet (20%, 12%; P < 0.02) with either of the combinations tested.

Conclusions: Serum NO levels are elevated in elderly humans compared to children or young adults. Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients

Patel V, Rink C, Gordillo GM, Khanna S, Gnyawali U, Roy S, Shneker B, Ganesh K, Phillips G, More JL, Sarkar A, Kirkpatrick R, Elkhammas EA, Klatte E, Miller M, Firstenberg MS, Chiocca EA, Nesaretnam K, Sen CK.

J Nutr. 2012 Mar;142(3):513-9. Epub 2012 Feb 1.

Abstract

The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP) and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg α-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1-96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. α-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans.

Trial registration: ClinicalTrials.gov NCT00678834.

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Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study

Chin, S. F.,Ibahim, J.,Makpol, S.,Abdul Hamid, N. A.,Abdul Latiff, A.,Zakaria, Z.,Mazlan, M.,Mohd Yusof, Y. A.,Abdul Karim, A.,Wan Ngah, W. Z.

Nutr Metab (Lond) 2011;8(1):42

Abstract

Background: Vitamin E supplements containing tocotrienols are now being recommended for optimum health but its effects are scarcely known. The objective was to determine the effects of Tocotrienol Rich Fraction (TRF) supplementation on lipid profile and oxidative status in healthy older individuals at a dose of 160 mg/day for 6 months.

Methods: Sixty-two subjects were recruited from two age groups: 35-49 years (n = 31) and above 50 years (n = 31), and randomly assigned to receive either TRF or placebo capsules for six months. Blood samples were obtained at 0, 3rd and 6th months.

Results: HDL-cholesterol in the TRF-supplemented group was elevated after 6 months (p < 0.01). Protein carbonyl contents were markedly decreased (p < 0.001), whereas AGE levels were lowered in the > 50 year-old group (p < 0.05). Plasma levels of total vitamin E particularly tocopherols were significantly increased in the TRF-supplemented group after 3 months (p < 0.01). Plasma total tocotrienols were only increased in the > 50 year-old group after receiving 6 months of TRF supplementation. Changes in enzyme activities were only observed in the > 50 year-old group. SOD activity was decreased after 3 (p < 0.05) and 6 (p < 0.05) months of TRF supplementation whereas CAT activity was decreased after 3 (p < 0.01) and 6 (p < 0.05) months in the placebo group. GPx activity was increased at 6 months for both treatment and placebo groups (p < 0.05).

Conclusion: The observed improvement of plasma cholesterol, AGE and antioxidant vitamin levels as well as the reduced protein damage may indicate a restoration of redox balance after TRF supplementation, particularly in individuals over 50 years of age.

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Effectiveness of Tocotrienol-rich Fraction Combined With Tamoxifen in the Management of Women With Early Breast Cancer: A Pilot Clinical Trial

Kalanithi Nesaretnam, PhD

Breast Cancer Res. 2010;12(5):R81.

Completed

Objective: To determine if tocotrienol Rich Fraction (TRF) in combination with Tamoxifen will improve breast cancer specific survival and recurrence free survival, in women with early breast cancer and estrogen receptor positive tumors.

Study Type: Interventional

Study Design: Non-randomized, double-blind

Subjects: Early Breast Cancer Patients

Intervention: Tocotrienol Rich Fraction, placebo plus tamoxifen

Primary Outcome: The primary end point was breast cancer specific survival, defined as the time from minimization to death due to breast cancer.

Secondary Outcome: The secondary end points included disease free survival, biochemical parameters, liver function and plasma levels of vitamin E.

Methodology: The study is a  double-blinded, placebo controlled trial of TRF plus tamoxifen versus placebo plus tamoxifen in women with primary breast cancer for five years. Both the TRF and placebo drugs were prepared and supplied by Hovid Sdn Bhd, Malaysia. Hovid Sdn. Bhd. absolutely did not have any influence in the trial designing, patient recruitment, data collection, analysis and reporting. The placebo drug which contained soy oil without tocotrienols had similar appearance and taste as the TRF drug. A total of 240 women breast cancer patients were assigned to two groups by minimization method that balanced treatment groups. The intervention group was given TRF plus tamoxifen, (n = 120) while control group was given placebo plus tamoxifen, (n = 120).

Results: During the five years of study, 8 patients died due to breast cancer while 36 patients developed local or systemic recurrence. Five-yearbreast cancer specific survival was 98.3% (95% confidence interval (CI): 95.9% to 100%) in the intervention group and 95%, (95% CI: 91.1% to 98.9%) in the control group, while 5-years disease free survival was 86.7% (95% CI: 80.6% to 92.8%) and 83.3% (95% CI: 76.6% to 90.0%), respectively. Risk of mortality due to breast cancer was 60% (HR: 0.40; 95% CI: 0.08 to 2.05) lower in the intervention group versus the controls following adjustment for age, ethnicity, stage and lymph node status but this was not statistically significant. Adjuvant TRF therapy was not associated with breast cancer recurrence (HR: 0.84; 95% CI: 0.43-1.65).

Conclusion: From the current study, there seems to be no association between adjuvant tocotrienol therapy and breast cancer specific survival in women with early breast cancer.

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