Clinical Application of Palm-Tocotrienols: Challenges and Opportunities Dr. Fu Ju Yen Ms. Puvaneswari Meganathan Ms. Doryn Tan Meam Yee Dr. Zaida Zainal fujuyen@mpob.gov.my / fujuyen@gmail.com
WHY FUNCTIONAL INGREDIENTS? (Department of Statistics, Malaysia)
ROLE OF FUNCTIONAL INGREDIENTS
TYPES OF FUNCTIONAL INGREDIENTS
TOCOTRIENOLS Vitamin E R 1 R 2 α CH 3 CH 3 Tocopherol β CH 3 H γ H CH 3 δ H H Tocotrienol
VITAMIN E CONTENT (Aggarwal et al., Biochem Pharmacol. , 2010)
TOCOTRIENOL COMPOSITION Tocopherols α + β Tocotrienols γ + δ Tocotrienols
GRAS STATUS FROM FDA FOR TOCOTRIENOLS (APRIL 2010) Tocotrienol is now intended for use in the following foods: ▪ Margarines and spreads ▪ Designer fats and oils ▪ Salad dressing and Mayonnaise ▪ Potato chips and salty snacks ▪ Bakery products ▪ Cookies & crackers ▪ Ready To Eat (RTE) cereals, cereal bars, granola bars, protein bars and power bars ▪ Meal replacement and other functional beverage products and mixes ▪ Meatless meat products (soy-based)
TOCOTRIENOLS AND INFLAMMATION
TOCOTRIENOLS AND INFLAMMATION
NEUROPROTECTION WHITE MATTER LESION 2 years supplementation of T3 suppressed mean volume change in white matter lesion. Gopalan et al., Stroke. 2014 ALZHEIMER’S DISEASE PERIPHERAL NEUROPATHY Higher tocotrienol levels in blood had lower risk of 1 year supplementation developing Alzheimer’s disease. of T3 reduced Higher gamma-tocotrienol levels in their blood had lancinating pain in lower risk of developing cognitive impairment. diabetic patients with peripheral neuropathy. Mangialasche et al. 2010, 2012, 2013 The Vitamin E in Neuroprotection Study (VENUS) Investigators, JAMA Neurology. 2018
STROKE NEURAL CELL DAMAGE Nanomolar of tocotrienol prevented glutamate induced damage neural cells. Khanna et al., J. Neurochem. 2010 INFARC SIZE ARTERIOGENESIS T3 supplementation reduced occlusion-induced brain injury. T3 improved cerebrovascular circulation and fiber Park et al., Stroke, 2011 connectivity after ischemic stroke Rink et al., J Cereb Blood Flow Metab. 2011
MECHANISM
METABOLIC DISEASES • Rat study showed lower weight gain OBESITY and weight of adipose tissue with T3 supplementation • Normalised fasting glucose and insulin with T3 supplementation HF: high fat; LF: low fat; T3: tocotrienol; Epi: epididymal; Peri: perirenal; Mes: mesenteric (Mes) fat. (Zhao et al., Int. J. Obesity. 2014) INSULIN SENSITIVITY
MECHANISM • Reduced gene expression for macrophage recruitment in adipose tissue. HF: high fat; LF: low fat; T3: tocotrienol. (Zhao et al., Int. J. Obesity. 2014)
MECHANISM
CANCER PREVENTION
CANCER PREVENTION • • • • Breast EMT Cell cycle VEGF • • • Lung arrest MMP-9 IL24 • • Liver Apoptosis • Ovarian • Colon
MECHANISM (Kanchi et al., Drug Discovery Today, 2017)
SMOKE-INDUCED COPD PULMONARY DISEASES ASTHMA Zainal et al., IJMS, 2019 Peh et al., Free Rad Biology and Medicine, 2017
CHALLENGE 1. Bioavailability 2. Epidemiology study 3. Clinical trials 4. Adjuvant / Combination
CHALLENGE 1: BIOAVAILABILITY Gamma-tocotrienol from TRF 800 mg Gamma-tocotrienol from TRF 300 mg (Yap et al., 2001. Journal of Pharm and Pharmacol.) (Meganathan et al., 2015. Sci. Reports.) • Dose α -Tocotrienol: 27.7 ± 9.2% Oral Affected • Formulation γ -Tocotrienol: 9.1 ± 2.4% by bioavailability in • Population δ -Tocotrienol: 8.5 ± 3.5% rat (Yap et al., 2003) (Fu et al., 2014)
CHALLENGE: BIOAVAILABILITY • The fraction of an ingested compound that is absorbed and available for physiological functions, reaches the systemic circulation in an active form. • Unfortunately, like most nutraceutical ingredients, tocotrienols suffer from low bioavailability. Solubility: Low • Insoluble in water/ aqueous environment • Soluble in ethanol but limited solubility in DMSO Permeability: High • A drug can be assumed to have high permeability across epithelium cell membranes if its log P value is greater than 1. • Tocotrienol Log P: 8.2
FORMULATION OF TOCOTRIENOLS
FORMULATION OF TOCOTRIENOLS
VESICLE-BASED NANOCARRIERS Lipid bilayer • Vesicular system with lipid bilayer • Encapsulate tocotrienols at 40% Tocotrienols efficiency Hydrophilic • Non-ionic vesicles using GRAS non- ionic surfactants polymer • Available in powder or suspension form • Higher stability compared to nanoemulsion • Storage stability tested for 2 months 207 PDI nm < 0.3 (Maniam et al., Front. Pharmacol. 2018; Tan et al., Nanomedicine. 2017)
A431 xenograft models Tumour-targeted nano T3 • Tumour suppression up to 10 Non-targeted nano T3 Free T3 days Untreated • Prolonged survival of 19 days (Fu et al., J Controlled Release. 2009) MDA-MB-231 breast cancer models • Lower tumour volume in groups Day 11 Day 20 treated with nano-T3 Free T3 • Significant improvement at day Non-targeted nano-T3 Targeted nano-T3 20 Untreated (Tan et al., Nanomedicine. 2017)
CHALLENGE 2: EPIDEMIOLOGY STUDY Francesca Mangialasche and team, Karolinska Institutet, Stockholm, Sweden Year Subject / Cohort Findings 2010 Kungsholmen Project High plasma total vitamin E content reduced the risk of developing Alzheimer’s disease 232 advance-aged subjects 2012 AddNeuroMed-Project AD and MCI had lower levels of total tocopherols, total 168 Alzheimer disease tocotrienols, and total vitamin E. 166 mild cognitive impairement Low plasma tocopherols and tocotrienols levels are 187 cognitively normal people associated with increased odds of MCI and AD. 2013 AddNeuroMed-Project Plasma tocopherol and tocotrienol levels + MRI are sensitive indicators of Alzheimer’s disease. 81 Alzheimer disease 86 mild cognitive impairement 86 cognitively normal people 2013 Cardiovascular Risk Factors, Aging, and High levels of serum tocopherol and tocotrienol are Dementia (CAIDE) study associated with reduced risk of cognitive impairment. 140 elderly subjects 2019 Finnish Geriatric Intervention Study to Prevent On-going Cognitive Impairment and Disability (FINGER) Database of 2654 elderly subjects
CHALLENGE 3: CLINICAL TRIALS
Anti-inflammatory effect of Tocotrienol supplementation in subjects with moderately elevated inflammation (INTOC) Study Site: • MPOB Nutrition Unit • UPM Medical Faculty • UM Medical Faculty
CHALLENGE 4: ADJUVANT / COMBINATION THERAPY Tocotrienols Conventional Medicine • High dose • Natural toxicity • Multi-targeted • Resistance • • Powerful Hard to achieve • Established therapeutic level mechanism in tissues
FUTURE PROSPECTS
FUTURE PROSPECTS
TAKE HOME MESSAGE Poster Puvaneswari Meganathan Health Properties of Tocotrienols: Evidence in PALM-TOCOTRIENOLS Human Studies (Meganathan and Fu, IJMS, 2016)
ACKNOWLEDGMENT • Dr. Tee E Siong, Chair of Organizing Committee • Nutrition Society of Malaysia • MPOB • Dr. Ahmad Parveez, Deputy Director-General, MPOB • Ms. Rosidah Radzian, Director of PDAS, MPOB • Dr. Kanga Rani Selvaduray, Head of Nutrition, MPOB • Co-researchers • Industrial partners • Colleagues, research assistants and students
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