Use of Evidence Based Phytopharmaceuticals in the Physician’s Clinic
Transcript of Use of Evidence Based Phytopharmaceuticals in the Physician’s Clinic
Use of
Evidence Based
Phytopharmaceuticals
in the Physician’s Clinic
Romulo S. de Villa, MD, PhD, Cert. Biochemistry Molecular & Nutritional Oncologist
Prof. of Biochemistry & Nutrition
Molecular Biology & Biotechnology Consultant
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0 1946 ‘50 ‘60 ‘70 ‘80 ‘90
Philippine Health Statistics, 1996 (Department of Health)
Communicable Disease
Rate per 100,000 Population, Philippines, 1946-1996
MORTALITY TREND
Communicable Disease
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1946 ‘50 ‘60 ‘70 ‘80 ‘90
Diseases of the Heart
Diseases of the Heart
Malignant Neoplasms
Philippine Health Statistics, 1996 (Department of Health)
Malignant Neoplasms
Rate per 100,000 Population, Philippines, 1946-1996
MORTALITY TREND
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1946 ‘50 ‘60 ‘70 ‘80 ‘90
Philippine Health Statistics, 1996 (Department of Health)
Communicable Disease
Diseases of the Heart and
Malignant Neoplasms
Rate per 100,000 Population, Philippines, 1946-1996
MORTALITY TREND
Communicable Disease
Diseases of the Heart
Malignant Neoplasms
LEADING CAUSES OF DEATH Number and Rate/100,000 Population
PHILIPPINES, 1997
CAUSES NUMBER RATE*
1. Diseases of the Heart 49,962 69.8
2. Diseases of the Vascular System 38,693 54.1
3. Pneumonia 30,811 43.1
4. Accidents 28,563 39.9
5. Malignant Neoplasm (cancer) 26,842 37.5
6. Tuberculosis, All Forms 23,056 32.2
7. Chronic Obstructive Pulmonary
Diseases and Allied Condition 11,807 16.5
8. Other Dses of Respiratory System 6,961 9.7
9. Diabetes Mellitus 6,749 9.4
10. Nephritis, Nephrotic Syn &
Nephrosis 6,704 9.4
Source: Philippine Health Statistics 1997
Scientific Evidence is Mounting • The common culprit in non-communicable
diseases is oxidative stress (excess free radicals over antioxidant capacity) – Free radicals and antioxidants in normal physiological functions
and human disease
Cardiovascular Disease
– Oxidative stress has been suggested to be involved in the pathogenesis of hypertension
– Reactive oxygen species remodels vascular system in hypertension
Diabetes and its Vascular Complications
– Oxidative stress is the leading cause of acute myocardial infarction in diabetics
– Controlling oxidative stress is a novel molecular approach to protecting the vascular wall in diabetes
– Hypertension Induces Oxidative Stress but Not Macrophage Infiltration in the Kidney in the Early Stage of Experimental Diabetes Mellitus
Phytochemicals
Substances
found exclusively in plants
Phytochemicals
have biomolecular targets! • Non-communicable, degenerative, lifestyle
diseases can be prevented and addressed by substances found exclusively in plants called phytochemicals – Polyphenols from grape seeds protect against high glucose-
induced oxidative stress
– Ganoderma lucidum inhibits oxidative stress-induced invasiveness of cancer cells through the suppression of interleukin-8 secretion
– Lycopene consumption decreases oxidative stress and bone resorption markers in postmenopausal women
– Corosolic acid prevents oxidative stress, inflammation and hypertension in SHR/NDmcr-cp rats, a model of metabolic syndrome
– Lutein and EPA interact to modulate iNOS mRNA expression
Phytochemicals in plant foods,
shown to have
biologic functions in the body,
are now called
Phytonutrients
Foods that contain Phytonutrients
are called
Functional Foods
The nutritional or dietary
supplement industry
is growing by leaps and bounds.
However,
it is essentially unregulated.
As Responsible Physicians
• Practice based on current up-to-date scientific evidence
• Recommend and prescribe based on credible criteria
– Safety from contamination
– Contains what is in the label
– Standardized to maintain consistency of effects
– Substantiated claims
“If we don’t guide our patients, they will be at the mercy of layman testimonial claims or just anecdotal evidence when there are already stronger scientific evidence.”
Phytonutrient containing
nutritional supplements with claims that are
scientifically substantiated
are now called
Nutraceuticals
6S Process
of a Nutraceutical
• Selection
• Sourcing
• Structure
• Safety
• Standardization
• Substantiation
Substantiation
with studies
• Supplementation as adjuvant to disease
management and prevention
– Suboptimal intake of some vitamins, above levels
causing classic vitamin deficiency, is a risk factor for
chronic diseases
– Multivitamin and multimineral supplementation
reduces incidence of infection among type 2 diabetics
• Antioxidants as adjuvant to disease prevention
– Antioxidant (vitamins C & E) use associated with
reduced risk of Alzheimer’s disease
– Increase in beta-carotene, vitamin C and selenium is
associated with a 10-20% reduction in asthma
prevalence
• Low carotenoid levels correlate with disease
– Higher lycopene (a carotenoid) associated with lower
risk of CVD in women
– Lower levels of beta-carotene and higher levels of uric
acid and MDA among those with hypertension
compared to normotensive participants.
– Lower alpha- and beta-carotene in patients with acute
ischemic stroke than in healthy controls and associated
with higher hs-CRP levels and neurologic deficits.
– Early-stage breast cancer survivors with the highest
plasma total carotenoid concentrations had reduced risk
for a new breast cancer event
• Carotenoids as marker of antioxidant status
– Plasma carotenoids correlate with intakes of
antioxidants in coffee, wine, and vegetables
• Raman Spectroscopic Measurement of Macular Pigments
– Macular pigment Raman detector for clinical applications
– Noninvasive detection of macular pigments in the human eye
– Resonance Raman measurement of macular carotenoids in normal
subjects and in ARMD
– Resonance Raman measurement of macular carotenoids in retinal,
choroidal, and macular dystrophies
– Resonance Raman measurement of macular carotenoids in the
living human eye
– Simple Raman instrument for in vivo detection of macular
pigments
• Non-invasive measurement of carotenoids in:
– Resonance Raman spectroscopic measurement of carotenoids in
the skin and retina
– NIR-FT-Raman spectroscopy of carotenoids in intact tissue
• Raman Spectroscopic Measurement of Skin
– Noninvasive selective detection of lycopene and beta-
carotene in human skin using Raman spectroscopy
• Diagnostic Application of
Raman Spectroscopy
– Results indicate that Raman spectroscopic technique
will play an important role in clinical diagnosing
– Non-invasive raman spectroscopic detection of
carotenoids in human skin
Substantiation of
Skin Carotenoid Measurement
• Skin carotenoid levels correlate with
– blood level standard
• Resonance Raman quantification correlates with HPLC-determined blood carotenoid levels
– Fruit and vegetable intake
• Plasma carotenoids are biomarkers of fruit and vegetable intake
– Body mass index
– Air pollution exposure • People with high oxidative stress, like smokers, and subjects with
high sunlight exposure have reduced skin carotenoid levels, independent of their dietary carotenoid consumption
– Free radical level
– Antioxidant supplementation
Scanner Readings Correlate with
Fruits & Vegetable Intake
10,000
15,000
20,000
25,000
30,000
35,000
Reported Daily Fruit & Vegetable Servings
Ra
ma
n In
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sit
y, C
ou
nts
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21,981
1 or Less
n = 9,336
24,773
2 to 3
n = 13,600
28,560
4 to 5
n = 6,916
p < 0.01 p < 0.01 p < 0.01
2004 Data of 32,648 Non-Supplement Users
6 or More
n = 2,796
31,100
BACK
Scanner Readings Correlate with
Body Mass Index
29,236
25,612
20,835
16,603
10,000
15,000
20,000
25,000
30,000
35,000
< 25 25-29 30-39 > 40
Body Mass Index (BMI, kg/m 2 )
Ram
an
In
tes
ity,
Co
un
ts .
n = 11,588 n = 8,475 n = 422
p < 0.01 p < 0.01 p < 0.01
n = 4,550
2004 Data of 25,035 Subjects Overweight people need extra
antioxidant protection through
diet and supplementation.
Weight Control
• Balance of calorie intake and calorie
consumption through metabolism and
physical activity
BACK
Scanner Readings Correlate with the
Pollutant, Cigarette Smoking
19890
13030
17600 17591
13056 11593
0
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10000
15000
20000
25000
30000
Non-
Smokers
Smokers
(all)
Past
Smokers
< 1/day 1-5/day > 5/day
n = 1047
n = 58
p < 0.01
n = 39 n = 10
n = 16
n = 32
Air Pollution
• Cigarette Smoke
• Factory Emissions
• Vehicle Exhaust
• Burning of Leaves, Plastics, Rubber
• Cooking Oil Fumes
BACK
Correlation of Scanner Readings with Free Radical Levels
Measured by Urinary MDA
U r i n a r y M D A
BACK
Substantiation of
an Antioxidant Supplement* (evidence for a responsible recommendation)
• Improvement of antioxidant status
• Bioavailability
• Protection of LDL against oxidation
– Clinical applications of circulating oxidized LDL
biomarkers in cardiovascular disease
– Flavonoids Vit C Vit E Enhance LDL resistance to
oxidation
– Vitamin E supplementation increases LDL resistance to
oxidation
* LifePak® NEXT
32175
25991
28924
18828
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15000
20000
25000
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35000
40000
0 4 8 12
Time (Weeks)
Ram
an
In
ten
sit
y, C
ou
nts
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p < 0.001
p < 0.01
p = 0.23
Effects of Supplementation with an Antioxidant*
* LifePak® BACK
Clinical Study Showing Effects of
a Nutritionally Complete Dietary Supplement*
Smidt CR, Seidehamel RJ, Devaraj S, Jialal I. The Effects of a Nutritionally Complete Dietary Supplement on Antioxidant Status and LDL-Oxidation in Healthy Non-Smokers. Federation of American Societies for Experimental Biology (FASEB) 1999;13(4):A546.
(means +/- SD)
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3.429 3.305
Baseline
PL
NCDS
3.477
6.248
Endpoint
p < 0.001
(means +/- SD)
0
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800
1000
1200
331 335
Baseline
PL
NCDS
299
716
Endpoint
p < 0.001
b-Carotene
* LifePak®
Vitamin E
BACK
Clinical Study Showing Effects of
a Nutritionally Complete Dietary Supplement*
Smidt CR, Seidehamel RJ, Devaraj S, Jialal I. The Effects of a Nutritionally Complete Dietary Supplement on Antioxidant Status and LDL-Oxidation in Healthy Non-Smokers. Federation of American Societies for Experimental Biology (FASEB) 1999;13(4):A546.
(means +/- SD)
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60
65
42.1 43.4
Start
Placebo
NCDS
42
50.9
After 6 Weeks
p < 0.001
Protection of LDL against free radicals
* LifePak® BACK
Lipoic Acid
• Phytonutrient found in spinach
• Differential Effect – Transformed vs Non-transformed
• Reversible cell cycle arrest of non-transformed cells
• Apoptosis of – human tumor cell lines (FaDu, Jurkat)
– Transformed cells (Ki-v-Ras-transformed Balb/c-3T3 murine mesenchymal cell line)
– Leukemic vs Normal T Lymphocytes • Toxic via apoptosis of Jurkat cells
• Non-toxic to normal T Lymphocytes
– Low dose vs High dose • Low dose (1 umol/L) acts as growth factor
• High dose (100 umol/L) antiproliferative
• Enhances high dose ascorbate cytotoxicity to cancer cells
• Prolongs survival of leukemic mice when added to Doxorubicin therapy
• Reduces ROS and raises GPx which correlates with good ECOG performance status
• Increase glutathione synthesis
• Neuroprotective
• Restores mitochondrial function in old rats
• Restores T-cell function of cancer patients
• Improves clinical outcome of cancer patients
• Treats oxaliplatin induces polyneuropathy
• Enhance cytotoxicity of high dose ascorbate and doxorubicin
Omega-3 Fatty Acids (evidence for a responsible recommendation)
• Polyunsaturated fatty acids (PUFA) have anti-inflammatory effects
• Gamma Linolenic Acid (GLA) and EPA suppress growth of cancer cells
• Omega-3 Fatty Acids – hypotriglyceridemic effect
– inhibit vascular calcification
– in Retinal Health and Disease
– reduce risk factors associated with cardiovascular diseases, diabetes, and cancer
– suppress HER-2/neu signaling pathways involved in the pathogenesis of breast cancer
• Nutrigenomics – Omega-3 influence gene expression
– FISH increase transcription of the antioxidant enzyme, peroxidase
– PUFA induced changes in gene expression of white adipose tissue
Lactobacillus fermentum VRI Strain
(evidence for a responsible recommendation)
• Resiliency to stomach acids
• Colonization of the large intestine
• Reduction of abdominal disturbances
Lactobacillus fermentum
(evidence for a responsible recommendation)
Lactobacillus fermentum
(evidence for a responsible recommendation)
Lactobacillus fermentum
(evidence for a responsible recommendation)
Lactobacillus fermentum
(evidence for a responsible recommendation)
Gac Fruit
(evidence for a responsible recommendation)
Gac Fruit (evidence for a responsible recommendation)
Gac Fruit (evidence for a responsible recommendation)
Carotene
• Associated with lower mortality from cancer
• Differential Effect:
– Smokers vs Non-smokers
• Directly associated with risk among smokers
• Inversely associated with risk among non-smokers
– Low vs High Levels
• Low levels associated with disease progression
• Lycopene at high conc reduces LNCaP cancer cell survival
• Plasma carotenoids – markers of fruits and vegetable
intake
– CELLULAR CAROTENOID MEAUREMENT
Cili Fruit
Chinese Lycium Fruit
Cordyceps sinensis
(evidence for a responsible recommendation)
Cordyceps sinensis
Cordyceps sinensis
Cordyceps sinensis
Krill Phospholipids
(evidence for a responsible recommendation)
Flavonoids
• Antitumor
• Antimetastatic
– to melanoma
– down regulate MMP from DU145 prostate cancer cells
• Induce apoptosis
– human leukemia cells
• Reverse Multidrug Resistance
– Modulate Organic Anion Transporting Polypeptide OATP1B1
– Reverse multidrug resistance
• Suppress angiogenesis
Resveratrol • Actions
– Improved • function of T, B lymphocytes
• killing activity of NK cells
• release of antibodies
• total complement activity in serum
– increased • IL-2
• TGF-beta1
– reduced • IL-8
• VEGF
Isoflavones • Found in soya
• Action – inhibit steroidogenesis
– block several protein tyrosine kinases, including epidermal growth factor receptor and src tyrosine kinases
– arrests the cell cycle
– induces apoptosis
– antiangiogenic
– antimetastatic
– antioxidant
Biological Effects of
Genistein • Growth inhibition of Melanoma cells in
vivo & in-vitro » Rocoral et al, Int J. Cancer 72(5)860,1997
• Inhibits lung tumor nodule formation in rats
& increases life span » Menon et al, Nutri Cancer 30(1)74, 1998
• Cytotoxic to breast cancer cells » Uckun et al, Clin Cancer Res 4(4)901, 1998
• Chemoprevention of NMU induced rat
mammary tumors » Gotoh et al, Jpn J Cancer Res 9(2)137, 1998
DR. DE VILLA
Biological Effects of Genistein
• Induce cell cycle arrest at S/G2-M and
apoptosis in HN4
• upregulates CDKI, p21waf-1
• induces BAX accompanied apoptosis
» Alhasan, 1999 (AACR abstract # 1710)
DR. DE VILLA
Curcumin
• Curcuminoids inhibit human multi-drug
resistance protein
Green Tea Polyphenols
(evidence for a responsible recommendation)
Large group of plant substances that
include catechins, flavonol,
isoflavones, and more
Polyphenols from Green Tea
Green Tea Polyphenols
(evidence for a responsible recommendation)
• Medicinal Uses of Green Tea Polyphenolic
Catechins
• Diabetes
– Prevention
• EGCG suppresses cytokine-induced pancreatic beta-cell
damage
– Blood Effects
• Effects of green tea catechin on phospholipase A2 activity and
antithrombus in streptozotocin diabetic rats
• Anti-diabetic Effect – Anti-diabetic activity of green tea polyphenols
– Anti-diabetic activity of green tea polyphenols n role in reducing ox stress in exp diabetes
– Epigallocatechin gallate supplementation alleviates diabetes in rodents
– Green tea supplementation ameliorates insulin resistance and increases glucose transporter IV
– Nutrigenomics - Administration of green tea that contains EGCG caused a reduction in the level of mRNAs for gluconeogenic enzymes.
• Management of Diabetes Complications – Green tea polyphenols and diet fibre protect against kidney
damage in rats with diab nephropathy
– Black n Green Teas inhibit diabetic cataracts in rat model of diabetes
– green tea extract may be an adjuvant to management of diabetic neuropathic pain
Polyphenols from
Green Tea
Tegreen97
Polyphenols from
Green Tea
Green Tea and the Cardiovascular System
(evidence for a responsible recommendation)
– Therapeutic effect of green tea extract on
advanced glycation and cross-linking of
collagen in the aorta
– Therapeutic effect of green tea extract on
oxidative stress in aorta and heart of
streptozotocin diabetic rats
Tegreen97
Green Tea and Cancer
(evidence for a responsible recommendation)
• Prostate Cancer Prevention
– Clinical trials in cancer prevention
– Chemoprevention of human prostate cancer
– Lycopene, a potent antioxidant found in tomatoes, may exert a protective effect in the prostate
• Breast Cancer Management
– Green tea polyphenols and its constituent epigallocatechin gallate inhibits proliferation of human breast cancer cells
• Prostate Cancer Management
– Growth inhibition of prostate cancer cells by epigallocatechin gallate in the presence of Cu2
– phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma.
– Prostate carcinoma and green tea
– Protective effects of green tea against prostate cancer
– Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells
– Role of vitamins, minerals and supplements in the prevention and management of prostate cancer
Tegreen97
Catechins • Found in green tea, grapes, apples, pears
• Forms found in green tea – epicatechin (EC)
– epigallocatechin (EGC)
– epicatechin gallate (ECG)
– epigallocatechin gallate (EGCG)
• Actions – antioxidant activity
– anticarcinogenic
– anti-inflammatory
– anti-atherogenic
– thermogenic
– antimicrobial activities
EGCG • Induce apoptosis in some tumor cell lines
• Inhibit angiogenesis
• Inhibit tyrosine phosphorylation of the receptor tyrosine kinase PDGF-Rbeta (platelet-derived growth factor receptor-beta) and its downstream signaling pathway and, consequently, to inhibit transformation of human glioblastoma cells
• Upregulate the synthesis of some hepatic phase II enzymes that are involved in the detoxification of some xenobiotics, including chemical carcinogens
• Inhibit the proteolytic enzyme urokinase used by cancer cells to invade normal tissue and metastasize
• Downregulate the expression of the androgen receptor in human prostate cancer cells in culture, consequently inhibiting androgen action
• Inhibit 5-alpha reductase of human prostate cancer cells
Studies on EGCG
• Catechin reverses Tamoxifen induced liver injury
• Protects cells from free radical damage (w/ Ames test)
• 80x more than Vit C
• 10x more than Vit E
• 2x more than anti-ox in red wine
• Blocks phase I enzymes and prevents formation of nitrosoamines
• Increase • Glutathione Peroxidase
• Catalase
• Inhibit spontaneous & photoenhanced lipid peroxidation
DR. DE VILLA
Biological Effects of
Epigallocatechin-3-Gallate
• Go/G1 phase arrest » 1999 (AACR abstract # 3507)
• induce expression of p21 & p27 (cdki) » Lin et al, 1999
• induce apoptosis by down regulating ras-
p21 & enhance p53 expression in MCF7 » Jin et al, 1999 (AACR abstract # 3506)
• inhibit EGFR, MAPK activation, AKT
activation & p21 induction » Chen, 1999 (AACR abstract # 3518)
DR. DE VILLA
Biological Effects of
Epigallocatechin-3-Gallate
• Induce WAF1/p21 in LNCAP & DU145 » Gupta, 1999 (AACR abstract # 3509)
• macrophage activation in mice which is tumoricidal
» Naraparaju, 1999(AACR abstract # 3515)
• inhibit erb-B1 activation and impair AKT (PI3 kinase) activation
» Bhatia, 1999 (AACR abstract # 3517)
DR. DE VILLA
Reishi (Ganoderma lucidum)
(evidence for a responsible recommendation)
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