clinical application of palm-tocotrienols: challenges and … · 2010 kungsholmen project 232...
TRANSCRIPT
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Clinical Application of Palm-Tocotrienols:
Challenges and Opportunities
Dr. Fu Ju Yen
Ms. Puvaneswari Meganathan
Ms. Doryn Tan Meam Yee
Dr. Zaida Zainal
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WHY FUNCTIONAL INGREDIENTS?
(Department of Statistics, Malaysia)
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ROLE OF FUNCTIONAL INGREDIENTS
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TYPES OF FUNCTIONAL INGREDIENTS
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TOCOTRIENOLS
Tocotrienol
Tocopherol
R1 R2
α CH3 CH3
β CH3 H
γ H CH3
δ H H
Vitamin E
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VITAMIN E CONTENT
(Aggarwal et al., Biochem Pharmacol. , 2010)
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TOCOTRIENOL COMPOSITION
Tocopherols
α + β Tocotrienols
γ + δ Tocotrienols
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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)
GRAS STATUS FROM FDA FOR TOCOTRIENOLS (APRIL 2010)
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TOCOTRIENOLS AND INFLAMMATION
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TOCOTRIENOLS AND INFLAMMATION
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Mangialasche et al. 2010, 2012, 2013
Higher tocotrienol levels in blood had lower risk of
developing Alzheimer’s disease.
Higher gamma-tocotrienol levels in their blood had
lower risk of developing cognitive impairment.
2 years supplementation
of T3 suppressed mean
volume change in white
matter lesion.
Gopalan et al., Stroke. 2014
ALZHEIMER’S DISEASE
WHITE MATTER LESION
PERIPHERAL NEUROPATHY1 year supplementation
of T3 reduced
lancinating pain in
diabetic patients with
peripheral neuropathy.
The Vitamin E in Neuroprotection
Study (VENUS) Investigators, JAMA
Neurology. 2018
NEUROPROTECTION
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Khanna et al., J. Neurochem.
2010
T3 supplementation reduced occlusion-induced
brain injury.Park et al., Stroke, 2011
NEURAL CELL DAMAGE
INFARC SIZEARTERIOGENESIS
T3 improved cerebrovascular circulation and fiber
connectivity after ischemic stroke Rink et al., J Cereb Blood Flow Metab. 2011
Nanomolar of tocotrienol
prevented glutamate
induced damage neural
cells.
STROKE
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MECHANISM
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METABOLIC DISEASES
(Zhao et al., Int. J. Obesity. 2014)
OBESITY
INSULIN SENSITIVITY
• Rat study showed lower weight gain
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.
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MECHANISM
HF: high fat; LF: low fat; T3:
tocotrienol.
(Zhao et al., Int. J. Obesity. 2014)
• Reduced gene expression for
macrophage recruitment in
adipose tissue.
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MECHANISM
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CANCER PREVENTION
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CANCER PREVENTION
• Breast
• Lung
• Liver
• Ovarian
• Colon
• Cell cycle
arrest
• Apoptosis
• VEGF
• IL24
• EMT
• MMP-9
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MECHANISM
(Kanchi et al., Drug Discovery Today, 2017)
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PULMONARY DISEASES SMOKE-INDUCED COPD
Peh et al., Free Rad Biology and Medicine, 2017
ASTHMA
Zainal et al., IJMS, 2019
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CHALLENGE
1. Bioavailability
2. Epidemiology study
3. Clinical trials
4. Adjuvant / Combination
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(Meganathan et al., 2015. Sci. Reports.)
Gamma-tocotrienol from TRF 300 mg
(Yap et al., 2001. Journal of Pharm and Pharmacol.)
Oral
bioavailability in
rat
α-Tocotrienol: 27.7 ± 9.2%
γ-Tocotrienol: 9.1 ± 2.4%
δ-Tocotrienol: 8.5 ± 3.5%
Affected
by
• Dose
• Formulation
• Population
(Yap et al., 2003) (Fu et al., 2014)
Gamma-tocotrienol from TRF 800 mg
CHALLENGE 1: BIOAVAILABILITY
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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
• 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.
CHALLENGE: BIOAVAILABILITY
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FORMULATION OF TOCOTRIENOLS
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FORMULATION OF TOCOTRIENOLS
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Lipid bilayer
Hydrophilic
polymer
Tocotrienols
VESICLE-BASED NANOCARRIERS
• Vesicular system with lipid bilayer
• Encapsulate tocotrienols at 40% efficiency
• Non-ionic vesicles using GRAS non-ionic surfactants
• Available in powder or suspension form
• Higher stability compared to nanoemulsion
• Storage stability tested for 2 months
207
nm PDI
< 0.3
(Maniam et al., Front. Pharmacol. 2018; Tan et al., Nanomedicine. 2017)
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(Fu et al., J Controlled Release. 2009)
• Tumour suppression up to 10
days
• Prolonged survival of 19 days
Tumour-targeted nano T3
Non-targeted nano T3
Free T3
Untreated
A431 xenograft models
Free T3
Non-targeted nano-T3
Targeted nano-T3
Untreated
MDA-MB-231 breast cancer models
Day 11 Day 20• Lower tumour volume in groups
treated with nano-T3
• Significant improvement at day
20
(Tan et al., Nanomedicine. 2017)
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CHALLENGE 2: EPIDEMIOLOGY STUDYFrancesca Mangialasche and team, Karolinska Institutet, Stockholm, Sweden
Year Subject / Cohort Findings
2010 Kungsholmen Project
232 advance-aged subjects
High plasma total vitamin E content reduced the risk of
developing Alzheimer’s disease
2012 AddNeuroMed-Project
168 Alzheimer disease
166 mild cognitive impairement
187 cognitively normal people
AD and MCI had lower levels of total tocopherols, total
tocotrienols, and total vitamin E.
Low plasma tocopherols and tocotrienols levels are
associated with increased odds of MCI and AD.
2013 AddNeuroMed-Project
81 Alzheimer disease
86 mild cognitive impairement
86 cognitively normal people
Plasma tocopherol and tocotrienol levels + MRI are
sensitive indicators of Alzheimer’s disease.
2013 Cardiovascular Risk Factors, Aging, and
Dementia (CAIDE) study
140 elderly subjects
High levels of serum tocopherol and tocotrienol are
associated with reduced risk of cognitive impairment.
2019 Finnish Geriatric Intervention Study to Prevent
Cognitive Impairment and Disability (FINGER)
Database of 2654 elderly subjects
On-going
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CHALLENGE 3: CLINICAL TRIALS
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Study Site:
• MPOB Nutrition Unit
• UPM Medical Faculty
• UM Medical Faculty
Anti-inflammatory effect of Tocotrienol supplementation in subjects with moderately
elevated inflammation (INTOC)
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CHALLENGE 4: ADJUVANT / COMBINATION THERAPY
Tocotrienols Conventional
Medicine
• Natural• Multi-targeted
• Powerful• Established
mechanism
• Hard to achieve therapeutic level in tissues
• High dose toxicity
• Resistance
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FUTURE PROSPECTS
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FUTURE PROSPECTS
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(Meganathan and Fu, IJMS, 2016)
TAKE HOME MESSAGE
PALM-TOCOTRIENOLS
Poster
Puvaneswari Meganathan
Health Properties of Tocotrienols: Evidence in
Human Studies
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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