How to Use Nutrition to
Heal Your Patients and Improve
Prolotherapy Outcomes
Presented by
Gray L. Graham, BA, NTP
1
Strategy
• Break the inflammation cycle
• Rebuild the joints
2
Inflammation
Time Magazine, Feb. 23, 1004, Vol. 163 No. 8
3
The Big Ideas of Inflammation
• Inflammation is the body’s normal physiologic response to
injury and is a complex, highly orchestrated process.
• Acute inflammation is an adaptive process that primarily
consists of defend and repair functions.
• Chronic inflammation is a destructive maladaptive process
responsible for a wide variety of diseases.
4
Inflammation
INJURY TO TISSUES
MAST CELL
VASOACTIVE SUBSTANCES
CHEMOTAXIS
VASCULAR RESPONSE
CELLULAR RESPONSE
NEUTRALIZATION OF OFFENDING
AGENT CLINICAL MANIFESTATIONS
REMOVAL OF NECROTIC DEBRIS
HEALING
5
Bio-Inflammation: Acute vs. Chronic
• Acute (more good than bad)
•
•
•
Rejection or sequestration of stressor
Usually localized (except anaphylaxis)
Usually adaptive (except allergy)
• Chronic: persistent “acute phase” reaction
•
•
•
•
•
Maladaptive : more detrimental than beneficial
Self-perpetuating/recursive
Disrupts homeostasis
Alters cellular physiology
Destruction of tissue
6
“C-reactive protein is the classic acute phase
reactant, the plasma levels of which can
increase as much as 10,000-fold in response to
tissue injury and infection.”
Danesh, John. JAMA, 12/8/99, Vol. 282: pp. 2165-2171.
7
Chronic Inflammation
Why?
• Genetic susceptibility to triggers
• Overabundance of inflammatory precursors (high
arachidonic acid or glycating diet)
• Insufficient dampening or excessive upregulation by
endogenous mediators
• Malfunctioning “off switch”
•
Insufficient TGF-Beta
•
Imbalanced Th1/Th2 lymphocytes
8
Copyright © 2002 American
Heart Association
“Is it possible that the adaptive pattern of an
earlier time has resulted in a maladaptive
response in our modern environment dominated
by increasingly sedentary habits, an abundance of
high-carbohydrate foods, and a reduced risk of
mortality due to common infections?”
9
NF-kappaB: the gateway to inflammation
10
NF-kappaB Amplifies Expression of
Pro-Inflammatory Genes
“Activation of the NF-kappaB…
...plays a central role in inflammation through
its ability to induce transcription of pro-inflammatory
genes.”
J Clin Invest. 2001 Jan: 107(1): 7-11.
11
NF-kappaB
A Pro-Inflammatory Transcription Factor
• Binds to DNA, stimulating production of TNF-α, IL-6,
and other inflammatory cytokines (IL-15)
• Activated by infection (LPS), oxidative stress, AGEs,
trans-fat, and inflammatory ctyokines (INF-α, TNF-α)
• Increased in cancer and chronic inflammatory disease
12
“Negative” Environmental Triggers
Activate NF-kappaB
Environment and Triggers
(highly variable and modifiable)
Environmental stimuli:
•
“Stress”
•
Radiation
•
Oxidative stress
•
Injury
•
Bacterial LPS from infection or “leaky gut”
•
Food and environmental allergens
•
Viral infections
•
Consumption of macronutrients: sugars > lipids >
protein
•
Arachidonic acid metabolites such as PG-E2
•
Nutrient-poor processed food diet with insufficient
phytonutrition, antioxidants, ALA, EPA, DHA, GLA, and
oleic acid
•
Vitamin D deficiency
Translation
Activation of
NF-kappaB
13
NF-kappaB Activates Genes Which
Promote Inflammation
Translation
Activation of
NF-kappaB
Genetic expression
(variable among individuals)
Increased expression
of pro-inflammatory and
anti-apoptotic genes
coding for production of
cytokines, adhesion
molecules and proinflammatory enzymes:
iNOS, COX, Lipox
14
Cytokines
Soluble Intercellular Messengers
•
Interferons
• INF-α & INF-γ antiviral/anti-inflammatory
•
Interleukins
• At least 17 identified
• IL-1 is endogenous pyrogen; acts synergistically with TNF-α (the two
main inducers of the acute phase response)
• IL-6 augments effects of IL-1 and TNF-α; plasma levels are a strong
marker of increased mortality in unstable CAD. Also associated with
insulin resistance and Metabolic Syndrome
•
Tissue necrosis factors
• TNF-α: endogenous pyrogen; stimulates CRF ACTH GC (activating
negative feedback loop); increased in obesity, induces insulin
resistance
15
NF-kappaB Activated Genes
Cause Inflammation
Genetic expression
(variable among individuals)
Mediators
(modifiable with vitamins, minerals, foods,
fatty acids, botanicals, and drugs)
IL-6
Increased expression
of pro-inflammatory and
anti-apoptotic genes
coding for production
of cytokines, adhesion
molecules and proinflammatory enzymes:
iNOS, COX, Lipox
Cyclooxygenase-2
CRP
Prostaglandins (PG-E2)
Thromboxanes
IL-1
Collagenase / MMP
Lipoxygenase
Leukotrienes
Inducible Nitric
Oxide Synthase
Nitric Oxide
TNF-a
Adhesion Molecules
16
Pro-Inflammatory Genes Activate Enzymes and
Cytokines to Create Inflammation and Disease
Mediators (modifiable with vitamins, minerals, foods,
fatty acids, botanicals, and drugs)
IL-6
Events
CRP
Prostaglandins (PG-E2)
Cyclooxygenase-2
Thromboxanes
•
•
•
IL-1
Lipoxygenase
Collagenase / MMP
Leukotrienes
•
•
Inducible Nitric
Oxide Synthase
Nitric Oxide
•
TNF-a
•
Health problems:
Pain
Inflammation
Cardiovascular disease,
thrombosis
Insulin resistance
Autoimmune and
rheumatic disease
Cancer
Neurodegeneration
Adhesion Molecules
17
The “Pro-Inflammatory Circuit”
Specific botanicals and nutrients can help end the cycle of
inflammation so your patients get better faster.
IL-6
Activation of
NF-kappaB
Increased expression of
pro-inflammatory and
anti-apoptotic genes
coding for production
of cytokines, adhesion
molecules and proinflammatory enzymes:
iNOS, COX, Lipox
CRP
Cyclooxygenase-2
Prostaglandins (PG-E2)
Thromboxanes
IL-1
Collagenase / MMP
Health problems:
•
Pain
•
Inflammation
•
Lipoxygenase
Leukotrienes
•
Inducible Nitric
Oxide Synthase
Nitric Oxide
TNF-a
Adhesion Molecules
•
Cardiovascular
disease, thrombosis
Insulin resistance
Autoimmune and
rheumatic disease
•
Cancer
•
Neurodegeneration
IL-1, PG-E2
Reactive oxygen species and oxidative stress
Tumor necrosis factor and CRP
18
Medical Management of
Pain and Inflammation
NSAIDs are too often considered the “standard of
care” for musculoskeletal conditions despite their inherent
risks and the fact that they commonly exacerbate joint
destruction and compromise gastrointestinal integrity.
Over-reliance on NSAIDs deters doctors/patients
from utilizing treatments that are more effective and which
address the underlying systemic problem(s) commonly
associated with musculoskeletal pain and chronic
musculoskeletal dysfunction.
19
NSAIDs: The most widely used class of drugs
• Annually, more than 70 million prescriptions are
written, and more than 30 billion NSAIDs are sold OTC
in the U.S.
• 13 million people in the U.S. use NSAIDs regularly
• The estimated number of annual hospitalizations in the
U.S. for serious G.I. complications is at least 103,000
with direct costs exceeding $2 billion
• There are more deaths annually related to NSAID use
than AIDS-related deaths
Fnes, JF. NSAID gastropathy, the second most deadly rheumatic disease? Epidemiology and risk appraisal. J Rheumatol 1991:
(Suppl 28) 18: 6-10.
Bland J. Nutritional Management of the Underlying Causes of Chronic Disease. Seminar Series. Washington Institute of
Functional Medicine. 2000.
20
Medical Management of
Pain and Inflammation
“Conservative calculations estimate that approximately
107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)-related
gastrointestinal (GI) complications and at least 16,500
NSAID-related deaths occur each year among arthritis
patients alone. The figures for all NSAID users would be
overwhelming, yet the scope of this problem is generally
under-appreciated.”
Am J Med. 1998 Jul 27; 105(1B): 31S-38S.
21
Cont’d…
• Many NSAIDs exacerbate joint destruction and
cause numerous adverse effects
•
Many safer treatments and comprehensive approaches
are available
• Effective symptom suppression robs doctors and
patients of the impetus to create health-promoting
change
•
Just because the pain is reduced, this does not mean that
the underlying problem is diminished
22
Cont’d…
“…the administration of NSAIDs may lead to loss of
intestinal integrity, thus facilitating antigenic absorption
and perhaps contributing to persistence of the disease.”
Bjamason I, et al. Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal
anti-inflammatory drugs. Lancet. 1984, 2(8413): 1171-1174.
23
Cont’d…
In vivo studies with NSAIDs at physiologic concentrations
have shown that several NSAIDs reduce glycosaminoglycan
synthesis:
Acetylsalicylic Acid
Fenoprofen
Isoxicam
Tolmetin
Ibuprofen
“… femoral head collapse and acceleration of osteoarthritis
have been well documented in association with the
NSAIDs…”
Lancet. 1985, Jul 6; 2(8445): 11-4.
24
Cartilage Formation
Fructose,
Glucose,
Glutamine
Galactose
Glucose
X
X
NSAIDS
NSAIDS
Chondroitin sulfate
Glucosamine
X
Proteoglycans
Mucopolysaccharides
NSAIDS
“Cartilage”
Articular cartilage pharmacology: I. In vitro studies on glucosamine and non steroidal antiinflammatory drugs. Pharmacol Res Commun. 1978, Jun; 10(6): 557-69
25
Vicious Cycle of NSAID Use:
Chondrolysis and Intestinal Injury
Use of NSAIDS
Inhibition of
proteoglycan synthesis,
subchondrial osteonecrosis
Joint
degeneration
Pain and “arthritis”
Increased intestinal
permeability:
“leaky gut”
Excess antigen and
endotoxin absorption
Immune activation
and dysregulation
(e.g., superantigens
and NF-kappaB)
Intra-articular immune
complex deposition
26
Medical Management of
Pain and Inflammation
Adverse effects of NSAIDs:
•
Gastrointestinal bleeding and gastric ulceration
•
Increased intestinal permeability
•
Promotion of bone necrosis and cartilage
destruction
•
Promotion of hepatic and renal injury and failure
•
Unacceptable cost-benefit and risk-benefit ratios
•
Death
27
Common Side Effects of Corticosteroids
•
•
•
•
•
•
Muscle weakness; myopathy
Impaired wound healing
Increased gut permeability
Peptic ulcer; gut perforation
Osteoporosis
Calcium malabsorption
Physicians’ Desk Reference. 53rd ed., 1999.
28
FDA failed public on Vioxx, scientist says
Congress probes agency on arthritis drug safety warnings
WASHINGTON — The American public is “virtually
defenseless” if another medication such as Vioxx proves to
be unsafe after it is approved for sale, a government drug
safety reviewer told a congressional committee Thursday.
The U.S. Food and Drug Administration failed the public in
its oversight of Merck & Co Inc.’s withdrawn painkiller
Vioxx and is “incapable of protecting America” from
another dangerous drug, agency researcher David Graham
told Congress.
“I would argue that the FDA as currently configured is
incapable of protecting America against another Vioxx,”
said Graham, who had warned that the arthritis drug had
been linked to an increased risk of heart attack and
stroke.
Kevin Lamarque / Reuters
He called the FDA’s actions “a profound regulatory failure.”
Concerns about a possible link between Vioxx and heart problems were building during the drug’s more than four years on the
market. The FDA required a warning about heart risks but felt the drug’s benefits made it worth keeping on the market.
Merck Chief Executive Raymond Gilmartin said the company had believed wholeheartedly in Vioxx and had followed a rigorous
scientific procedure every step of the way.
“In fact, my wife was taking Vioxx, using Vioxx, up until the day we withdrew it from the market,” Gilmartin told the Senate Finance
Committee.
msnbc.com new services
29ET
Updated 11/19/2004 10:08:16 AM
Vioxx = Killer
“David J. Gragam, MD, MPH, (Associate Director for
Science, Office of Drug Safety, US FDA) estimated that
139,000 Americans who took Vioxx suffered serious
side effects.
He estimated that the drug killed between
26,000 and 55,000 people.”
http://www.commondreams.org/views05/0223-35.htm
http://www.fda.gov/cder/drug/infopage/vioxx/vioxxgraham.pdf
30
Cont’d…
Considering the tens of millions of
patients who were taking Rofecoxib, we
are dealing with an enormous public
health issue. Even a fraction of a
percent of excess in the rate of serious
cardiovascular events would translate
into thousands of affected people.
Given the finding in the colon-polyp
trial in low-risk patients without known
cardiovascular disease – an excess of 16
myocardial infarctions or strokes per
1,000 patients – there may be tens of
thousands of patients who have had
major adverse events attributable to
Rofecoxib (see Figure).
Topol EJ. Failing the public health - rofecoxib, Merck and the FDA,
N Engl J Med. 2004 Oct 21; 351(17): 1707-9.
31
32
Cont’d…
When compared with placebo in cardiac-surgery
patients, Bextra/valdecoxib is associated with a 3-fold to
4-fold increased risk of heart attack, stroke and death;
and currently 7 million arthritis patients, many of whom
are already at high risk for cardiovascular disease, are
being treated with this drug.
Lenzer J Pfizer criticized over delay in admitting drug’s problems. BMJ. 2004; 329(7472): 934.
33
USA Today April 8, 2005.
34
35
36
Patients with
Pain and Inflammation…
WHAT DO YOU DO?
37
• Primum Non Nocere
• First, do no harm.
• Vis Medicatrix Naturae
• Utilize the healing power of nature.
38
Goals as a Practitioner
• Restore balance and homeostasis
• Treat the underlying causes of pain and
inflammation
39
Treatments for Pain and Inflammation
• Remove ongoing triggers (both identified and
potential)
• Decrease the total toxic load
• Optimize GI health
• Remove pathogens
• Control dysbiosis and repair the inflamed gut wall
• Identify potential antecedents
• Genetic markers and family history
• Modify mediators
• Correct nutritional deficiencies and oxidative stress
40
Cont’d…
• Introduce anti-inflammatory diet (oligoantigenic diet)
• Optimize fatty acids and eicosanoids synthesis
• Vitamin D – pro-inflammatory epidemic
• Phytonutritional modulation of NF-kappaB
• Restore structural integrity and remove subluxation
• Chondro-support
• Botanical analgesies: White Willow bark, Boswellia and
Devil’s Claw
• Proteolytic enzymes for acute/chronic pain and inflammation
41
Inflammation Related to the GI-Liver Connection
RESULTS IN ORGAN SYSTEM DYSFUNCTION
POSSIBLE CAUSES
Nutritional History
Leaky Gut
Toxic Burden
toxins
Stress
Medications
Infection
Food allergies
Some disease states
Dsybiosis and endotoxins
Environmental toxins
Endogenous metabolites (i.e. hormones)
Substance abuse
Alcohol
Tobacco
Eliminated in
Drugs
bile and feces
Liver Burden and Altered
Hepatic Detoxification
toxins
Oxidant
stress
Initiation of Systemic
Inflammation
Musculoskeletal
Immune
Endocrine
Nerves
Cardiovascular
Genitourinary
Mitochondrial
damage
42
Treatment for Pain and Inflammation
Remove the Sensitive Seven
Dairy
Wheat
Sugar
Corn
Soy
Eggs
Peanuts
43
Bad-fat/high-sugar Diets
Cause Inflammation
A single meal of egg and sausage muffin sandwiches with
2 hash browns caused an increase of 150% for NF-kappaB
(from ~190 to ~510 AUC) which lasted for approximately
two hours and was associated with increases in oxidative
stress and the inflammatory marker CRP.
Increase in intranuclear nuclear factor kappaB and
decrease in inhibitor kappaB in mononuclear cells after a
mixed meal: evidence for a pro-inflammatory effect.
Am J Clin Nutr. 2004; 79(4): 682-90
44
Optimize Fatty Acids
(metabolism)
Fatty Acid Families: Omega-3,
Omega-6, Omega-9
Omega-3 fatty acids: from flax oil and fish oil; generally
these have health-promoting benefits; these fats are
generally deficient in American diets.
Omega-6 fatty acids: from vegetable, corn and nut oils,
beef, liver, pork, lamb, turkey, and chicken; increases
cancer and inflammation; American intake is high.
Omega-9: Oleic acid is found in olive oil; reduces
inflammation, CAD and cancer risk; American intake is low.
45
Cont’d…
Paleolithic
n-3 intake
6.7 grams/d
American
n-3 intake
1 gram/d
Typical American diets are very poor in omega-3 fatty acids, providing only 1 gram
per day compared to the 6.7 grams that can be obtained in a “Paleo Diet.”
Loren Cordain, PhD
46
Cont’d…
Among omega-3 fatty acids, these
are the major players.
Alpha-linolenic acid
ALA
flax seed oil
ALA comes from flax oil, while EPA
and DHA come from fish oil.
Eicosapentaenoic
acid
EPA 20:5n3
fish oil
Other intermediate fats can either
be created from these major fats or
have little clinical relevance.
Docosahexaenoic
acid
DHA 22:6n3
fish oil, microalgae
47
Cont’d…
Alpha-linolenic acid is the essential omega-3 fatty acid and is the
precursor to all other n-3 fatty acids.
Conversion of ALA to the more potent EPA and DHA is slow,
unreliable and clinically insignificant. In fact, several studies show
that ALA supplementation only slightly increases EPA and can
actually lead to a reduction of DHA in humans.
ALA has anti-inflammatory benefits independent from its
conversion to EPA and DHA.
EPA and DHA are much more potent than ALA and show clinical
benefit in a wide range of common diseases.
48
Cont’d…
Alpha-linolenic acid reduces
prostaglandin formation… but this effect
is not mediated via conversion to EPA or
DHA nor by displacing arachidonic acid
or linoleic acid from the cell membrane.
J Lipid Res. 1986 Apr; 27(4): 421-6.
ALA most likely provides its antiinflammatory benefit by inhibiting the
genetic transcription of proinflammatory mediators.
(Probably via inhibition of genetic
transcription NF-kappaB)
Alpha-linolenic acid
ALA
flax seed oil
Eicosapentaenoic
acid
EPA 20:5n3
fish oil
Docosahexaenoic
acid
DHA 22:6n3
fish oil, microalgae
49
EPA: (n-3) Eicosapentaenoic Acid
• Available only from fish oil
• EPA has powerful, clinically significant antiinflammatory benefits
• Clinical studies have shown benefit in the treatment
of many different conditions
•
•
•
•
Rheumatoid arthritis, ulcerative colitis, Crohn’s disease
and lupus
Cancer
Eczema and psoriasis
Mental depression, anxiety and schizophrenia
50
EPA: Clinically Significant
Anti-Inflammatory Benefits
Fish oil supplementation allows patients with
inflammatory diseases such as rheumatoid arthritis to
reduce their need for anti-inflammatory drugs.
BR J Rheumatol. 1993 Nov; 32(11): 982-9.
This is important because NSAIDs, like aspirin,
hospitalize 107,000 people and kill more than 16,500
people each year.
Am J Med. 1998 Jul 27; 105(1B): 31S-38S.
51
EPA + DHA Benefit RA
“Conclusion: fish-oil ingestion results in subjective
alleviation of active rheumatoid arthritis and reduction in
neutrophil leukotriene B4 production.”
AM Intern Med. 1987 Apr; 106(4): 497-503.
52
EPA + DHA and Dietary
Modification Benefit RA
“Conclusion: A diet low in arachidonic acid ameliorates
clinical signs of inflammation in patients with RA and
augments the beneficial effect of fish oil
supplementation.”
Rheumatol Int. 2003 Jan; 23(1): 27-36.
53
GLA: Gamma-Linolenic Acid
(the “good” omega-6 fatty acid)
• Appears to be the only n-6 fatty acid with powerful
and uniformly beneficial effects
• Intermediate between linoleic acid (toxic) and
arachidonic acid (toxic)
• Clinical benefit seen in
• Psoriasis and eczema
• Asthma
• Rheumatoid arthritis and other inflammatory conditions
• Sources include borage oil, blackcurrant seed oil,
hemp oil, and evening primrose oil
54
GLA Benefits Rheumatoid Arthritis
“In this study, dietary supplements of black currant
seed oil (BCO) rich in the n-6 polyunsaturated fatty
acid (PUFA) gamma-linolenic acid were fed to both RA
patients and healthy volunteers, with sunflower seed
oil being fed to control subjects. A significant
improvement in morning stiffness was noted in the
RA patients receiving BCO.”
Br J Rheumatol. 1993 Dec; 32(12): 1055-8.
55
GLA Benefits Rheumatoid Arthritis
“GLA treatment is associated with clinical improvement
in patients with RA, as evaluated by duration of morning
stiffness, joint pain and swelling, and ability to reduce
other medications.”
Semin Arthritis Rheum. 1995 Oct; 25(2): 87-96.
56
Superiority of Balanced, Combination
Fatty Acid Supplementation:
ALA + GLA + EPA + DHA
Fish oil causes an adverse reduction in DGLA: need to
supplement GLA when using DHA+EPA.
“However, the intake of fish oil caused a significant
depression in the content of DGLA … Since DGLA is the
precursor of PG-E1, which has been shown to be antiinflammatory, our findings suggest that the antiinflammatory effects of fish oil consumption could be
mitigated by an associated reduction in DGLA.”
Prostaglandins Leukot Essent Fatty Acids. 1990 May; 40(1): 9-12.
57
Superiority of Balanced, Combination
Fatty Acid Supplementation:
ALA + GLA + EPA + DHA + Oleic acid
ALA causes an adverse reduction in oleic acid: need to
supplement oleic acid when using ALA
“Accumulation of alpha-linolenic acid was compensated
by a decrease of oleic acid.”
J Lipid Res. 1986 Apr; 27(4): 421-6.
58
To Optimize Clinical Benefits,
Fatty Acids Must be Administered
in Combination
Doctors need to stop thinking in terms of “either/or.”
Doctors need to use health-promoting fatty acids in
combination to optimize biochemical status and thereby
maximize clinical effectiveness.
59
Vitamin D Deficiency is Pandemic
60
Cont’d…
Vitamin D deficiency is a common problem with
serious consequences.
Diagnosis is easy and treatment with oral
supplementation is easy, safe, affordable, and
beneficial.
Vasquez A, Manso G, Cannell J. The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with
Implications for All Healthcare Providers. Alternative Therapies in Health and Medicine 2004; 10: 28-37.
http://www.bioticsresearch.com/vitD.htm
61
Vitamin D Deficiency Causes
Chronic Musculoskeletal Pain
62
Vitamin D Deficiency is a
Treatable Cause of Pain
RESULTS: Findings showed that 83% of the study
patients (n=299) had an abnormally low level of vitamin
D before treatment with vitamin D supplements. After
treatment, clinical improvement in symptoms was seen
in all the groups that had a low level of vitamin D and in
95% of all the patients (n=341).
Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine.
2003 Jan 15; 28(2): 177-9.
63
Vitamin D “downregulates”
NF-kappaB
Downregulation of NF-kB protein levels in activated
human lymphocytes by 1,25-dihydroxyvitamin D3.
Immunology, Proc. Natl. Acad. Sci. USA, November 1995 Vol. 92, pp. 10990-10994.
64
Implementation of Vitamin D:
Supplementation in Your Clinical Practice
• Consider serum testing
• Begin supplementing patients on a routine basis
• Infants <1,000 IU per day
• Children 2,000 IU per day: “Children who regularly took the
recommended dose of vitamin D (2,000 per day) had a RR of
0.22 (0.05-0.89) compared with those who regularly received
less than the recommended amount.” Lancet. 2001 Nov 3;
358(9292): 1500-3)
• Adults 4,000 IU per day
• Monitor effectiveness with 25(OH)D
• Monitor for toxicity with serum calcium
65
Cont’d…
• Vitamin D supplementation is a safe, inexpensive, and
NATURAL intervention for restoring health
• Clinical response seen with pain, inflammation, MS,
RA, PCOS, hypertension, depression, epilepsy,
diabetes, and metabolic syndrome
• 4,000 IU per day in adults enhances well-being
Randomized comparison of the effects of the vitamin D3
adequate intake versus 100 mcg (4,000 IU) per day on
biochemical responses and the well-being of patients.
Nutr J. 2004 Jul 19; 3(1):8 http://www.nutritionj.com/content/3/1/8
66
Phytonutritional Modulation
Effective, safe, and natural inhibitors of NF-kappaB
•
•
•
•
•
•
•
•
Curcuminoids (with black pepper for piperine)
Boswellia
Green tea extract
Ginger
Rosemary
Resveratrol
Lipoic acid
Propolis
67
NF-kappaB Amplifies Expression of
Pro-Inflammatory Genes
“Activation of the NF-kB… plays a central role in
inflammation through its ability to induce transcription
of pro-inflammatory genes.”
J Clin Invest. 2001 Jan; 107(1): 7-11.
68
Diseases Associated with Activation
of NF-kappaB
MS, RA, IBS, AS, Lupus,
Neurologic Conditions, etc.
Cancer
Allergy
69
Curcuminoids
(An extract from the rhizomes of Curcuma longa.)
Chemistry: Contains Curcumin,
Bisdemethoxycurcumin (BDMC) and
Demethoxycurcumin (DMC)
Dose:
300 - 500 mg 3 times daily
70
Molecular Structures and
Biological Activity
• Parahydroxyl groups – antioxidant activity
• Keto groups – anti-inflammatory, anti-cancer, antimutagen
• Double bonds – anti-inflammatory, anti-cancer, antimutagen
71
Anti-thrombotic Effect
Curcumin inhibits the cyclooxygenese activity of platelets and
Platelet TX-B2, but did not affect the vascular PG-I2 synthesis.
Thrombosis res. (1985), 40, pp. 413-417.
72
Curcumin showed significant subjective
improvement for RA patients in a randomized,
double-blind, cross-over study. Dosage was 400 mg
TID. Improvements in morning stiffness, walking
time and joint swelling were noted.
Curcuminoids, Medical Economics, PDR of Nutritional Medicine, 1st Edition, 2001, pp 117-121.
73
Green Tea Blocks
NF-kappaB Activation
“We conclude that the anti-inflammatory mechanism of
green tea polyphenols is mediated at least in part
through down regulation of TNF-α gene expression by
blocking NF-kB activation. These findings suggest that
green tea polyphenols may be effective therapy for a
variety of inflammatory processes.”
J. Nutr. 1998, 128: 2334-2340.
74
Ginger (Zingiber officinalis)
(anti-inflammatory)
• Ginger (Zingiber officinalis) has shown remarkable
benefits for arthritic patients. Noted areas of
improvement have been pain, inflammation/swelling and
morning stiffness.
• Ginger’s mechanism of action appears to be its ability to
quench 5-lipoxygenase, thromboxane, platelet
aggregation, and its dose dependent inhibition of
prostaglandin (PG-E2).
Werbach M, Murray M. Botanical Influences on Illness 2nd Ed. 2000.
75
Cont’d…
• Zingiber officinalis not only inhibits platelet aggregation
but alters arachidonic acid metabolism as well. It potently
inhibits thromboxane synthetase, yet raises prostacyclin
levels without concomitant rise in PG-E2 or PG-F2-α.
Med Hyp, 1986, 20: 271-8.
76
Restore Structural Integrity
“…when chiropractic or hospital therapists treat
patients with low-back pain as they would in a day to
day practice, those treated by chiropractic derive more
benefit and long term satisfaction than those treated
by hospitals.”
Randomized comparison of chiropractic and
hospital outpatient management for low-back pain:
results from extended follow up.
BMJ. 1995; 311(7001): 349-5.
77
Chondro-support
Cartilage Formation
Fructose,
Glucose,
Glutamine
Galactose
Glucose
X
X
NSAIDS
NSAIDS
Chondroitin sulfate
Glucosamine
X
Proteoglycans
Mucopolysaccharides
NSAIDS
“Cartilage”
Articular cartilage pharmacology: I. In vitro studies on glucosamine and non steroidal antiinflammatory drugs. Pharmacol Res Commun. 1978, Jun; 10(6): 557-69
78
Glucosamine Sulfate
• 1,500 - 2,000 mg per day is customary dose according
to the research
• Clearly safe and effective for preventing, slowing and
reversing osteoarthritis
• Adverse effects are either minimal or nonexistent;
allergy is rare
• No adverse effects in diabetics
Long-term effects of glucosamine sulfate on osteoarthritis
progression: a randomized, placebo-controlled clinical
trial.
Lancet. 2001, 357(9252): 251-6.
79
Clinical Trials:
Glucosamine Sulfate vs. Placebo
80 patients; 30 day, double-blind trial; 1,500 mg/day
Placebo
Parameter
Overall symptom reduction
Symptoms reduced by half
Completely symptom free
No more movement restriction
No more pain/tenderness
Glucosamine
Group
Group
73%
20 days
20%
23%
25%
41%
36 days
0%
0%
0%
Drovanti A, et al. Clin Ther. 1980;3:260-72.
Corroborating Studies: Pujaite MJ, et al. Curr Med Res Opin. 1980;7:110-14. Crolle G. Curr Med Res Opin. 1980;7: 104-9.
Vajaradul Y. Clin Ther. 1981;3:336-43. Vaz AL. Curr Med Res Opin. 1982;8:145-49. Tapadinhas MJ, et al. Pharmatherapeutica.
1982;3:157-68. Muller-FaBbender H, et al. Osteoarthritis Cartilage. 1994;2:61-9.
80
Glucosamine Sulfate vs. Ibuprofen
Double-blind; 40 patients; 1,500 mg/day
Glucosamine sulfate; 1,200 mg/day Ibuprofen
• Pain decreased in both groups for 2 weeks,
better in Ibuprofen groups, but effects faded
• At end of 8 weeks:
• On a pain scale of 0 - 3: Glucosamine 0.8;
Ibuprofen 2.2
• Swelling of knee – reduced 20% of Glucosaminetreated patients; 0% in Ibuprofen-treated
patients
• 29% more patients in Glucosamine group had
good outcome
Vaz Al. Curr Med Res Opin. 1982; 8: 145-9.
Corroborating Studies: Muller-FaBbender H, et al. Osteoarthritis Cartilage. 1994; 2; 61-9.
81
Botanical Analgesies
(Reducing pain naturally with a botanical combination)
• White Willow Bark (Salix): inhibits inflammation by
means including and other than COX-2 inhibition
• Boswellia (Boswellia serrata): inhibits lipoxygenase to
reduce production of leukotrienes
• Devil’s Claw (Harpagophytum): anti-inflammatory and
analgesic properties have been demonstrated in
humans
82
Salix alba (White Willow Bark)
•
Recognized in the United States Pharmacopoeia (USP)
between 1820-1926
• Predominated until replaced by cheaper synthesized ASA
(acetyl-salicylic acid)
• Better tolerated than ASA
• Significant differences between WWB and ASA
• Salicin converted in the liver to ASA, thus bypassing
gastrointestinal toxicity problems
•
•
Salicin in WWB appears to suppress the production of
prostaglandins. It also appears to inhibit cyclooxygenase-2
(COX-2) and to a lesser degree cyclooxygenase-1 (COX-1)
enzymes
Individuals allergic to ASA should avoid WWB extracts
PDR Herbal Medications, 2nd Edition.
83
White Willow Bark
An extract of willow tree bark is as effective as a
common prescriptive drug for the treatment of low back
pain. The study compared the efficacy of white willow
bark extract to Rofecoxib (Vioxx) in 228 randomly
assigned individuals with low back pain treated for a
period of 4 weeks. In all measures of pain relief WWB
was found to be as effective as Rofecoxib.
Rheumatology 2001; 40: 1388-93.
84
Boswellia
(A gum extract from Boswellia serrata )
Chemistry:
a mixture of Boswellic acids,
primarily beta Boswellic acid
Standardized extract:
minimum 60% Boswellic acids
Indications:
RA, osteoarthritis, low-back pain
85
Cont’d…
Mechanism of Anti-Inflammatory Action of Boswellia serrata
Boswellia
blocks here
Phospholipids
Arachidonic acid
5-lipoxygenase
pathway
Leukotrienes
(LTB-4, LTC-4, LTD-4,
LTE-4, 5-HPETE, 5-HETE)
Cyclooxygenase
pathway
Prostaglandins,
Thromboxanes
86
Boswellia
Boswellia displayed marked anti-inflammatory activity
in carrageenan-induced edema in rats and mice. It was
equally effective in adrenalectomized rats. Boswellia
inhibited elevations of serum transaminase enzymes
and leukocyte counts.
Singh GB, Atal CK. Pharmacology of an extract of Salai guggal ex-Boswellia serrata, a new
non-steroidal anti-inflammatory agent. Agents Actions, 18(3-4): 407-12, 1986.
87
Effects of Boswellic Acids
Administration in RA
Double-blind study on 30 subjects
Mean Arthritis Score (MAS) before
treatment and after 4 weeks
238.4
Double-blind study on 30 subjects
Erythrocyte Sedimentation Rate (ESR)
before treatment and after 4 weeks
300
100
Initial
49.2
200
94.67
4 Weeks on BA
181.06
Before Cross-over 4 Weeks on
Placebo after
Cross-over
ES
20
0
200
150
100
50
0
60
40
MAS
Before
Double-blind study on 30 subjects
Mean Arthritis Score (MAS) before treatment
and 4 weeks after placebo cross-over
125.6
80
65.93
After
0
Double-blind study on 30 subjects
Erythrocyte Sedimentation Rate (ESR) before
treatment and 4 weeks after placebo cross-over
45.13
38.06
MAS
Before Cross-over 4 Weeks on Placebo
after Cross-over
50
45
40
35
30
ES
88
Boswellia serrata extract in treatment of
osteoarthritis of knee – a randomized double-blind
placebo controlled trial.
“All patients receiving drug treatment reported
decrease in knee pain, increased knee flexion and
increased walking distance. The frequency of swelling
in the knee joint was decreased.”
Phytomedicine. 2003 Jan; 10(1): 3-7.
89
Devil’s Claw
Harpagophytum is therapeutically equivalent to, and
therefore clinically superior to, Vioxx.
A randomized double-blind pilot study comparing
Doloteffin and Vioxx in the treatment of low-back pain.
Conclusion: Though no significant intergroup
differences were demonstrated, large numbers will be
needed to show equivalence.
Rheumatology 2003; 42: 141-148. Doi: 10. 1093/rheumatology/keg053, available online at
www.rheumatology.oupjournals.org
90
Devil’s Claw
European Journal of Anesthesiology, 1999; 16, 118-129.
91
Proteolytic Enzymes for
Acute/Chronic Pain
Proteolytic Enzymes: Effects
•
•
•
•
•
•
•
Anti-tumor
Anti-metastatic
Anti-infectious
Immune-stimulatory
Anti-inflammatory
Analgesic
Anti-edematous
Note: well-absorbed from oral administration
92
Proteolytic Enzymes: Mechanisms
• Dose-dependent stimulation of reactive oxygen
species production and anti-cancer cytotoxicity in
human neutrophils
• Pro-differentia effect
• Reduction in PG-E2 production
• Reduction in substance P production
• Modulation of adhesion molecules and cytokine
levels
• Fibrinolytic effects and an anti-thrombotic effect
mediated at least in part by a reduction in 2-series
thromboxanes
93
Polyenzyme Therapy
94
Cont’d…
•
•
•
•
•
•
Pancreatin
Bromelain
Papain
Amylase
Lipase
Trypsin and alpha-chymotrypsin
Note: The combination of enzymes works better than a single
enzyme.
Loes M and Steinman MA. The Aspirin Alternative, Freedom Press, 1999.
Loes M and Steinman MA. The Non-drug European Secret to Healing Sports Injuries
Naturally, Freedom Press, 1999.
Lopez DA, et al. Enzymes: The Foundation of Life, The Neville Press, 1994.
95
The 10 Green-Gene Food Guidelines
Here are the ten elements of the Green-Gene Guidelines, the essential principles for
activating the food-gene-health link we've discussed throughout this book.
1. Eat fresh whole food in its natural state as often as possible.
2. Eat a wide variety of foods.
3. Select organic, grass-fed, free-range, local and sustainable foods whenever
possible.
4. Consume high-quality food with the proportion of protein, carbohydrates, and
fats our genes adapted to over the millennia.
5. Choose ONLY minimally processed oils and fats that have retained their naturally
occurring proportion of nutrients.
6. Choose plant and animal foods that have been grown or raised on sustainable
and nutrient-rich soil.
7. Choose wild-caught fish from the least-polluted waters.
8. Select store, and prepare food in ways that preserve its nutrients.
9. Drink clean water.
10. Give regard to every aspect of the meal.
Graham, Gray L. Pottenger’s Prophecy.
96
Green-Gene Food Tips
Cook smart. Overcooking vegetables reduces their nutrient content, while high temperatures change
the chemical structure of proteins, fats, and even carbohydrates. Some suggestions: consider poaching
eggs or serving them sunny-side up instead of scrambling them in hot oil, and steam or sauté
vegetables over a low flame. The most healthful step you can take toward cooking smart is this: don't
heat cooking oil so much that it smokes.
Get fresh. If you find that you don't eat all the vegetables and fruits you purchase within three or four
days; that you forget about them; or they age and spoil in the refrigerator bin, consider shopping for
fresh fruits and vegetables twice weekly, and purchase smaller amounts.
Figure in ferments. What do sourdough bread, sauerkraut, yogurt, and cheese have in common?
They're all fermented. made by the ancient process of fermentation, which occurs when lactic acid
bacteria convert starch and sugar into lactic acid and alcohol and in the process make milk, grains, and
fiber more digestible. Supplementing your daily diet with fresh fermented foods, which contain living
microbes, provides a plethora of health benefits mostly through the probiotics they produce that
protect the gut from harmful pathogens, and increases absorption of nutrients.
Get personal. Residing within your genes are the dietary requirements and food tolerances that fit you
best, personally. In other words, the foods on which you're likely to thrive are based on the genetics
you inherited from your ancient ancestors and the epigenetics that were passed on from more recent
relatives.
97
Pottenger’s Prophecy
• 290-pages
• Reveals the foods that
launch your genes on a path
toward illness, as well as the
diet that can promote a
longer, healthier life.
• Excellent source for anyone
who wants to eat to resetgenes-NOW-for-health,
healing, and longevity.
98
The Anti-inflammatory Diet
Foods to Include
Unsweetened fresh, frozen, water-packed, or
canned; unsweetened fruit juices except orange
Fruits
Vegetables
Foods to Exclude
Oranges
All fresh raw, steamed, sautéed, juiced, or roasted
vegetables
Brown rice, oats, millet, quinoa, amaranth, teff,
tapioca, buckwheat, and products made from these
and rice, potato flour, or arrowroot
Corn, creamed vegetables
Legumes
All beans (except soy), peas, lentils
Soybeans, tofu, tempeh, soy milk, other soy foods
Nuts & Seeds
Almonds, walnuts, sesame (tahini), sunflower,
pumpkin seeds; and butters made from these
Peanuts, peanut butter, cashews, cashew butter
Meat, Fish & Eggs
All canned or fresh fish, chicken, turkey, wild game, Beef, pork, cold cuts, frankfurters, sausage, canned
lamb
meats, eggs, shellfish
Dairy Products & Milk Substitutes
Milk substitutes, such as rice milk, almond milk, oat Cream, yogurt, butter, ice cream, frozen yogurt, nonmilk, coconut milk, other nut milks
dairy creamers, margarine
Fats
Cold-expeller pressed olive, flaxseed, canola,
Shortening, processed (hydrogenated) oils,
safflower, sunflower, sesame, walnut, pumpkin,
mayonnaise, spreads
almond oils
Filtered water, herbal tea, seltzer, or mineral water Soft drinks, alcoholic beverages, coffee, tea, other
caffeinated beverages
Starch
(Non-gluten)/Bread/Cereal
Beverages
Wheat, corn, barley, spelt, kamut, rye (be sure to check
all packaged and processed food labels for these
grains)
Spices & Condiments
All spices (unless excluded): cinnamon, cumin, dill,
garlic, ginger, carob, oregano, parsley, rosemary,
tarragon, thyme, turmeric, vinegar
Chocolate, ketchup, mustard, pickle relish, chutney, soy
sauce, barbecue sauce (be sure to read condiment
labels carefully)
Sweeteners
Brown rice syrup, fruit sweetener, blackstrap
molasses, stevia
White or brown refined sugar, honey, maple syrup,
corn syrup, high fructose corn syrup; desserts made
with these sweeteners; candy
Cordain L. The Paleo Diet Mayo Cline Proc. 2004 Jan; 101-8.
99
Sugar Control Diet
PROTEINS: Each meal should include a minimum of 4-6 ounces of protein, but you can have
as much as you desire. Meat, poultry, fish, eggs are unlimited, if no sensitivity exists.
VEGETABLES: Eat as much as you desire. You cannot eat too much. Focus on dark, leafy
greens and a variety of colors. No potatoes, yams, or other starchy vegetables (ie: corn, peas,
winter squash, cooked beets or carrots).
FRUITS: Careful here – only to be eaten between meals as a snack with nuts or seeds or a
piece of cheese or a bite of plain, full fat yogurt. Leave the sweeter fruits such as bananas,
mangos, persimmons, papayas, dried fruits, etc. alone. One or two small sized pieces of fruit
per day is plenty (ie: apples, pears, peaches, plums, all berries).
GRAINS: No grain including breads, rolls, muffins, and pasta. No beans or legumes. No rice.
NUTS: Soaked or slow-roasted nuts make a great snack.
DAIRY: No dairy is allowed, unless approved by your practitioner.
FATS: No artificial or hydrogenated fats allowed, such as margarine or shortening.
SWEETENERS: No sweeteners of any kind. Stevia OK if no hyperinsulinemia (high insulin
levels) exists.
100
Nutrients to support Healthy Joints
•
•
•
•
•
Water and the electrolytes to hold it
Chondroitin sulfates
Glucosamine
Sulfur
Silicon
For Collagen
• Amino Acids
• Vitamin C
• Iron
• Copper
• Manganese
101
Treatment Synergism
Integrated Module
Gut and liver detox, oligoantigenic diet, fatty acids, chondro support,
structural integrity restoration, and Vitamin D
NF-kappa blockade
with botanicals
• Inhibits NF-kappaB: reduces the
production of pro-inflammatory
enzymes and mediators
White Willow Bark,
Boswellia, Devil’s Claw
• Impairs NF-kappaB, COX, and Lipox
• Analgesic benefit already
documented for White Willow Bark
and Devil’s Claw
Proteolytic enzymes
• Safe and effective for reductions in
swelling, edema, …
102
Integrative Orthopedics
www.OptimalHealthResearch.com
•
•
•
•
•
•
•
•
Third edition
610-pages
More than 2,650 citations
Integrative management
of outpatient orthopedic
disorders
Head-to-Toe Review
Concepts
Algorithms
Therapeutics
103
Questions?
Gray L. Graham
grayleegraham@gmail.com
www.pottengersprophecy.com
104