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Ehlers-‐Danlos Na.onal Founda.on August 2013 Conference

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Dr. Abbas Qutab

Botanical Medicine and Dietary Interventions to

Alleviate Pain and Inflammation

USA Today May 9, 2005



Inflammation Nation

Number of Americans who suffer from inflammatory disorders n  Arthritis (all types) – 70 million n  Allergies – 39 million n  Asthma – 17 million n  Cardiovascular Disorders – 60 million

These numbers do not include other inflammatory conditions like G.I. disorders, Neurological disorders, diabetes, cancer, etc.

Challem, Jack. The Inflammation Syndrome.

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.



Activation of NF-kappaB

NF-kappaB IkB:

Inhibitor of NF-kappaB

NF-kappaB is in the cytosol where it is made “inactive by Inhibitor kappaB .


Exposure to “stressful stimuli,” such as LPS or oxidative stress, activates “inhibitory kappaB kinase” which phosphorylates IkB for destruction.

NF-kappaB IkB:

Inhibitor of NF-kappaB

P

P P

P P

P IKK:IkB kinase (alpha, beta, & gamma)




Once IkB is destroyed, NF-kappaB is free to bind with DNA.

NF-kappaB enters the nucleus and binds with DNA to activate genes.




Genetic Expression

Genes encode for the

increased production of inflammatory

mediators.

NF-kappaB Activates Genes Which

Increased expression of pro-inflammatory and anti-apoptotic genes coding for production of cytokines, adhesion molecules and pro-inflammatory enzymes: iNOS, COX, Lipox


Translation Genetic expression

(variable among individuals)



Diseases Associated with Activation of NF-kappaB

MS, RA, IBS, AS, Lupus,

Cancer

Allergy

Neurologic Conditions, etc.

“Negative” Environmental Triggers Activate NF-kappaB

Environmental stimuli: n  “Stress” n  Radiation n  Oxidative stress n  Injury n  Bacterial LPS from infection or “leaky gut” n  Food and environmental allergens n  Viral infections n  Consumption of macronutrients: sugars > lipids > protein n  Arachidonic acid metabolites such as PG-E2 n  Nutrient-poor processed food diet with insufficient

phytonutrition, antioxidants, ALA, EPA, DHA, GLA, and oleic acid

n  Vitamin D deficiency

Specific botanicals and nutrients can help end the cycle of inflammation so your patients get better faster.

Environment and Triggers (highly variable and modifiable)


Translation



PHYSICAL n  Injury n  Inflammation n  Eccentric Exercise

NUTRITIONAL n  Preservatives n  Additives n  Alcohol n  Trans-fatty Acids

INFECTION Endotoxins & Exotoxins ð Bacterial ð Fungal ð Parasitic

CHEMICAL ð Xenobiotics ð Organics

Total Toxic Exposure

Exotoxins n  Pesticides

n  Insecticides n  Herbicides

n  Industrial Compounds & Chemical Byproducts n  Volatile Organics

n  Solvents & Detergents

n  Toxic Metals n  Plasticizers n  Insulators (asbestos)

n  Combustion/ Incineration Pollutants n  Synthetic Medications

n  Food Additives & Preparation Byproducts n  Cosmetic Additives



Xenobiotic Exposure

n  Since WW II, between 75,000 to 80,000 new synthetic chemicals have been released into the environment; less than half have been tested for potential toxicity to adult humans.

n  Over 4 billion pounds of pesticides are used annually in the U.S. This amounts to 8 pounds for every man, woman, and child (EPA’s Office of Prevention, Pesticides, and Toxic Substances, 1999).

n  Current law allows 350 different pesticides to be used on the food we eat.

n  The average home contains 3-10 gallons of hazardous materials.

n  400 synthetic chemicals can be found in the average human body.

Xenobiotic Compounds in the Adipose Tissue Of Americans

US EPA National Adipose Tissue Survey, 1982

Compound Frequency n  Styrene 100%

n  1,4-Dichlorobenzene 100%

n  Xylene 100%

n  Ethylphenol 100%

n  TCDD (Dioxin) 100%

n  9 Other Compounds 90-98%

ð  (Benzene, Toluene, DDE)

n  PCB’s 83%



“Of the roughly 900 pesticide active ingredients registered in the U.S., more than 160 have been classified as

known or suspected carcinogens by the U.S. EPA.”

Cancer and the Environment: What Health Care Providers Should Know

Physicians for Social Responsibility www.psr.org/enviro.htm

Pesticide Content of Common Foods (from highest to lowest)

Source: Sustainable Cuisine White Papers (Earth Pledge Foundation)

n  Strawberries n  Bell Peppers/ Spinach n  Cherries n  Peaches n  Cantaloupe n  Celery n  Apples n  Apricots n  Green Beans n  Grapes n  Cucumbers



Endotoxins (Internal Pollution)

n  CO2 from cellular respiration

n  Nitrogen from amino acid catabolism via the Urea Cycle.

n  Uric Acid from purine catabolism

n  Bilirubin from hemoglobin catabolism

n  All steroid hormones

n  Free radicals due to mitochondria dysfunction and pathological detoxification

n  Oxidized glucose

“In a study spearheaded by the Environmental Working Group researchers at two major laboratories found an average of 287 toxic

chemicals in newborn babies”

“180 of these chemicals are known to cause cancer, 217 are toxic to the brain and nervous system, and 208 cause developmental problems”

“The dangers of these chemicals in combination has never been studied.”



August 2007, WHO released a report indicating that over 30% of all childhood diseases can be linked to

exposure to environmental toxins



To Make Matters Even Worse n  There are over 10,000 chemical additives

in our food supply n  The average American eats about 14lbs of

additives a year n  As well as 120lbs sugar and 8lbs of

iodized salt a year

n  Who knows how many Antibiotics, Steroids and Hormones found in foods



Promote Inflammation

Increased expression of pro-inflammatory and anti-apoptotic genes coding for production of cytokines, adhesion molecules and pro-inflammatory enzymes: iNOS, COX, Lipox

Pro-inflammatory Genes Activate Enzymes and Cytokines to Create Inflammation and Disease

Health problems: n  Pain n  Inflammation n  Cardiovascular

disease, thrombosis n  Insulin resistance n  Autoimmune and

rheumatic disease n  Cancer n  Neurodegeneration

IL-6 CRP

Cyclooxygenase-2 Prostaglandins (PG-E2)

Thromboxanes

IL-1 Collagenase / MMP

Lipoxygenase Leukotrienes

Inducible Nitric Oxide Synthase Nitric Oxide

TNF-a

Adhesion Molecules

Mediators (modifiable with vitamins, minerals, foods,

fatty acids, botanicals, and drugs) Events



The “Pro-inflammatory Circuit”

Increased expression of Pro-inflammatory and anti-apoptotic genes coding for production of cytokines, adhesion molecules and pro- inflammatory enzymes: iNOS, COX, Lipox

IL-6 CRP

Cyclooxygenase-2 Prostaglandins (PG-E2)

Thromboxanes

IL-1 Collagenase / MMP

Lipoxygenase Leukotrienes

Inducible Nitric Oxide Synthase

Nitric Oxide

TNF-a

Adhesion Molecules


Health problems: n  Pain n  Inflammation n  Cardiovascular

disease, thrombosis n  Insulin resistance n  Autoimmune and

rheumatic disease n  Cancer n  Neurodegeneration

IL-1, PG-E2

Reactive oxygen species and oxidative stress Tumor necrosis factor and CRP

Bio-Inflammation An Integrative Model

Environment

Genes Diet/Lifestyle

Bio-Inflammation



Obesity and Bio-Inflammation

“Adipose tissue secretes large amounts of TNF-α and IL-6 in a neutrally, hormonally and metabolically regulated fashion. 19 The plasma levels of these cytokines are proportional to the body mass index (BMI) and are further elevated in patients with visceral obesity. 20, 21”

“Thus, obesity, especially the visceral type, can be considered as a chronic inflammatory state, with many of the behavioral, immune, metabolic and cardiovascular sequelae of such a state.”

Chrousos, George P. The Stress Response and Immune Function: Clinical Implications: The 1999 Novera H. Spector Lecture Annals of the New York Academy of Sciences 917: 38-67 (2000).

High-fat/High-sugar Diets Cause Inflammation

n  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

n  Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect

Am J Clin Nutr. 2004; 79(4): 682-90.



Medical Management of Pain and Inflammation

“Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for non-steroidal 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.

Cartilage Formation

Articular cartilage pharmacology: I. In vitro studies on glucosamine and non steroidal anti-inflammatory drugs. Pharmacol Res Commun. 1978, Jun; 10(6): 557-69

Fructose, Glucose,

Glutamine Galactose Glucose

Glucosamine

Chondroitin sulfate

Proteoglycans Mucopolysaccharides

“Cartilage”

X NSAIDS

X NSAIDS

X NSAIDS



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

1) Any time cyclooxygenase is blocked, arachidonic acid will be forced into the leukotriene pathway, which is a major contributor to “silent inflammation” and cardiovascular death.

2) It is the COX-2 enzyme targeted by “coxib” drugs that creates the

cardioprotective substance known as prostacyclin – this is the “good prostaglandin” that reduces blood pressure and platelet adhesion. Obviously, when a drug is used that specifically targets the body’s production of a cardioprotective substance, then the clinical consequence will be, in this case, an increase in hypertension and blood coagulation which we would expect to result in an increase in stroke, thrombosis, and myocardial infarction. It has been estimated that Vioxx injured 139,000 Americans and killed more than 25,000 – 55,000 patients.

--Dr. Alex Vasquez, DC, ND

Cont’d . . .

The cause of the problem is obvious for two reasons when looked at from a biochemical perspective:



Treatments for Pain and Inflammation

n  Remove ongoing triggers (both identified and potential) n  Decrease the total toxic load

n  Optimize GI health n  Remove pathogens n  Control dysbiosis and repair the inflamed gut wall

n  Identify potential antecedents n  Genetic markers and family history

n  Modify mediators n  Correct nutritional deficiencies and oxidative stress

Cont’d . . .

n  Introduce anti-inflammatory diet (oligoantigenic diet) n  Optimize fatty acids and eicosanoids synthesis n  Vitamin D – pro-inflammatory epidemic n  Phytonutritional modulation of NF-kappaB n  Restore structural integrity and remove subluxation n  Chondro-support n  Botanical analgesies: White Willow bark, Boswellia and

Devil’s Claw n  Proteolytic enzymes for acute/chronic pain and

inflammation



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.

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.



Curcuminoids

(An extract from the rhizomes of Curcuma longa.) Chemistry: Contains Curcumin,

Bisdemethoxycurcumin (BDMC) and Demethoxycurcumin (DMC)

Dose: 300 - 500 mg 3 times daily

Molecular Structures and Biological Activity

n  Parahydroxyl groups – antioxidant activity n  Keto groups – anti-inflammatory, anti-cancer,

anti-mutagen n  Double bonds – anti-inflammatory, anti-cancer,

anti-mutagen



Anti-inflammatory Activity

0

1

2

3

4

5

1 2 3 4 5 6

Placebo

Curcumin

Phenylbutazone

Day of Assessment

Tot

al I

nten

sity

of

Infl

amm

atio

n Comparative effect of curcumin and phenylbutazone

on post-operative inflammation reduction.

Int. J. Clin. Pharmacol. Toxicology, (1986), 24, 651-654.

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.



Glucosamine Sulfate vs. Ibuprofen

Double-blind; 40 patients; 1,500 mg/day Glucosamine sulfate; 1,200 mg/day Ibuprofen

n  Pain decreased in both groups for 2 weeks, better in Ibuprofen groups, but effects faded

n  At end of 8 weeks: n  On a pain scale of 0 - 3: Glucosamine 0.8; Ibuprofen

2.2 n  Swelling of knee – reduced 20% of Glucosamine-

treated patients; 0% in Ibuprofen-treated patients n  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.

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.



Cont’d . . .

Mechanism of Anti-Inflammatory Action of Boswellia serrata

Phospholipids

Arachidonic acid

Leukotrienes (LTB-4, LTC-4, LTD-4,

LTE-4, 5-HPETE, 5-HETE)

Prostaglandins, Thromboxanes

Cyclooxygenase pathway

5-lipoxygenase pathway

Boswellia blocks here

Effects of Boswellic Acids Administration in RA

94.67

238.4

0

100

200

300

Initial 4 Weeks on BA

MAS

49.265.93

0

20

40

60

80

Before After

ES

181.06125.6

050100150200

Before Cross-over 4 Weeks onPlacebo after

Cross-over

MAS

45.13

38.06

3035

4045

50

Before Cross-over 4 Weeks on Placeboafter Cross-over

ES

Double-blind study on 30 subjects Mean Arthritis Score (MAS) before

treatment and after 4 weeks

Double-blind study on 30 subjects Erythrocyte Sedimentation Rate (ESR)

before treatment and after 4 weeks

Double-blind study on 30 subjects Mean Arthritis Score (MAS) before treatment

and 4 weeks after placebo cross-over

Double-blind study on 30 subjects Erythrocyte Sedimentation Rate (ESR) before treatment and 4 weeks after placebo cross-over



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

Inflammation Related to the GI-Liver Connection

Nutritional History

Toxic Burden

Stress Medications Infection Food allergies Some disease states Dysbiosis and Endotoxin Environmental toxins Endogenous metabolites (i.e. hormones)

Substance abuse Alcohol Tobacco Drugs

Mitochondrial damage

Initiation of Systemic Inflammation

Liver Burden and Altered Hepatic Detoxification

Leaky Gut

Oxidant stress

POSSIBLE CAUSES RESULTS IN ORGAN SYSTEM DYSFUNCTION

Eliminated in bile and feces

toxins

toxins

Musculoskeletal Immune Endocrine Nerves Cardiovascular Genitourinary



Easy 3-Step Bio-Detox Program

Step 1

Reduce Inflammation 10 days or more Remove common food allergens

Anti-Inflammatory Supplementation

Introduce Hypo-Allergenic/Anti-Inflammatory Diet


Step 2

Metabolic Cleansing 10 – 20 days Addresses: Toxic Overload

Harmful Bacteria and Fungus Heavy Metal Toxicity Leaky Gut




Step 3

Regeneration and Repair Stage Addresses: Cell Malnourishment

Joint Damage

For More Information:

n Dr. Abbas Qutab www.evmedcenter.com 508-753-0006

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