Ozone,Oxygen, Prolozone IRB - by Dean Silver MD

2012 © Dean R. Silver, M.D.

Ozone/Oxygen/ProlozoneOzone/Oxygen/ProlozoneIRBIRB

Medical Motivational Speaker

WWW.DEANSILVERMD.COMINTEGRATED MEDICINE AND CARDIOLOGY

CredentialsCredentials

Medical Degree from Temple University School of Medicine, Philadelphia, PA

Internal Medicine Residency at Albert Einstein Medical Center

Cardiology Fellowship at the Deborah Heart and Lung Center

Board Certified by the American Board of Internal Medicine

Board Certified by the American Academy of Anti-Aging Medicine

Board CERTIFIER for the American Board of Anti-Aging Medicine

Member of the American Academy for the Advancement in Medicine

Staff Physician at Scottsdale Healthcare Hospital System

Board Certified in Insulin Potentiation Therapy2013 © Dean R. Silver, M.D.

FDG PET SCAN- WHOLE BODYFDG PET SCAN- WHOLE BODY

FDG PET SCAN- WHOLE BODY FDG PET SCAN- WHOLE BODY CONTINUEDCONTINUED

PET SCAN-SKULL BASE-THIGHPET SCAN-SKULL BASE-THIGH

OUR MISSIONOUR MISSIONTO EDUCATE

TO EMPOWER

TO IMPROVE HEALTH

ONE PATIENT AT A TIME . . .

Integrative MedicineIntegrative Medicine

3 criteria in selecting what particular alternative, “unproven” therapies I intend to use with my patients:– 1. They must be safer than the

approved therapies that are recommended

– 2. They must have some evidence, anecdotal or otherwise, or efficacy

– 3. They must be cost effective

What is Medical Ozone?What is Medical Ozone?

Oxygen/Ozone mixture– 98% Oxygen, 2% Ozone

Convert into active Ozonides which bind especially to Lipids and Amino Acids

The peroxides (Ozonides) (-C-O2) are short chained and can easily penetrate cellular membranes

And oxidize NADH to NAD

O3+ -C=C- -C-O3-C- -CO-CO2 -C=O+ -C-O2

Ozone Forms PeroxidesOzone Forms Peroxides

Reacts ionically with double bonds to produce peroxides called Ozonides

Most Ozonides are formed from the short chained lipids in cell membranes

Ozonides are stable for days to weeks, easily penetrate cell membranes, and are selectively reactive

Once in the cells these ozonides oxidize NADH to NAD

History of Medical OzoneHistory of Medical Ozone 1856: Used in operating rooms

to sterilize surgical instruments 1885: Florida Medical

Association Ozone 1892: Lancet, Ozone for TB 1914-1918: WWI, Used for

infected wounds 1916: Lancet, femur

osteomyelitis

History of Medical Ozone (cont.)History of Medical Ozone (cont.) 1940: Lancet, “Ozone Treatments of

Wounds” 1972: European cooperation of Medical

Ozone Guidelines 1977: Australian Medical Journal, “Ozone

in Healing” 1990-Present: Italy, Russia, Germany,

Cuba, Israel, Spain, Japan, Canada, Switzerland, Turkey, Bulgaria, United States and others practice Medical Ozone

2011: American Academy of Ozone Therapy

Madrid, 2010Madrid, 2010

Mitochondrial FactsMitochondrial Facts

Metabolically active cells contain thousands of mitochondria, which make up ~40% of the cytoplasm. There are said to be 10 million billion mitochondria in an adult human (i.e. ~10% of our body weight)

Mitochondria are not static. Triggered by a variety of physiological stimuli and differentiation states they are in constant movement within cells, and are constantly changing in size, number and mass

Mitochondrial Facts (cont.)Mitochondrial Facts (cont.) Mitochondria divide during mitosis, providing

daughter cells with a normal complement of mitochondria. Mitochondria also proliferate during myogenesis and following exercise

The number of mitochondria is controlled by T3, which specifically induces mitochondrial division

Genetic forms of obesity including diabetes have defective mitochondrial activity leading to a higher ratio of weight gain to food intake. Experimental evidence indicate the increasing mitochondrial activity in these patients will cure them

Oxygen UtilizationOxygen Utilization As oxygen utilization losses efficiency, the

rate of free radical damage escalates, and ultimately leads to mitochondrial decay

Accumulating mitochondrial decay is the central lesion in the aging process and in degenerative disease. This is why you can’t live forever

Your risk for premature aging and degenerative disease is determined by your starting point (mitochondrial genetics) and your rate of mitochondrial decay

Your starting point is predetermined and fixed. What is not inevitable is the rate of decay

Aging and Oxygen UtilizationAging and Oxygen Utilization

Oxygen Utilization (Aerobic Capacity)Oxygen Utilization (Aerobic Capacity) Aging and the diseases of aging

are caused primarily by decreased oxygen utilization

Decreased oxygen utilization causes degenerative disease through increased free radical formation and decreased antioxidant buffering capacity

Leads to mitochondrial decay, “functional hypoxia”

HypoxiaHypoxia

Generates excessive free radicals Deprives cells of vital functions

including repair mechanisms, membrane polarization, and enzyme synthesis. This includes the synthesis of anti-oxidant enzymes

Destroys mitochondria

““Functional Hypoxia”Functional Hypoxia”

Decreased Oxygen Utilization is the

Metabolic Equivalent of

Hypoxia

Oxygen Utilization (Aerobic Capacity)Oxygen Utilization (Aerobic Capacity)

The process whereby oxygen metabolizes either fat or glucose into water, heat, NAD (nicotinamide adenine dinucleotide), free radicals, carbon dioxide, and ATP

Oxygen works through NAD and ATP (and to a lesser degree, NADP and FAD). These “oxygen intermediates” are the bottom line for all cellular function

Aerobic CapacityAerobic Capacity

Maximal aerobic capacity is a measurement of oxygen utilization

Even highly trained marathon runners show a decrease in oxygen utilization with age. Unlike all of the other parameters of aging, it cannot be trained away

“Maximal aerobic capacity is an independent risk factor for cardiovascular disease, cognitive dysfunction, and all cause mortality.”

“Meta-analysis of the age associated decline in maximal aerobic capacity in men: relation to training status.”

Wilson & Tanaka, Am. J. Physiol. Heart Circ. Physiol.Vol. 278: 829-834, 2000

Oxidative Damage and Mitochondrial DecayOxidative Damage and Mitochondrial Decay

“Oxidants generated by mitochondria appear to be the major source of oxidative lesions that accumulate with age.”

“These lesions cause the age related deficits in mitochondrial function which are associated with the generalized physiological decline known as aging.”

These oxidative lesions are caused by reduced oxygen utilization

“Oxidative Damage and Mitochondrial Decay in Aging.”

Shigenaga MK, Hagen TM, Ames BN

Proc. Natl. Acad. Sci. USA

Vol. 91, 10771-78, Nov. 1994

Free Radical Damage is Caused By Free Radical Damage is Caused By “Excessive” Radical Activity Secondary to “Excessive” Radical Activity Secondary to

Decreased Oxygen UtilizationDecreased Oxygen Utilization

Decreased oxygen utilization creates “functional hypoxia” which accelerates free radical formation, while exhausting anti-oxidant buffering capacity

“Decreased oxygen utilization is toxic to the cell by exacerbating free radical generation in membranes housing electron transfer assemblies.”

Antioxidant AdaptationLevine & Kidd

Mitochondrial Rate of DecayMitochondrial Rate of Decay

This is determined by Oxygen Utilization, which is the same thing as your NAD/NADH ratio

Your starting point is predetermined and fixed

What is not inevitable is the rate of decay.

The better your Oxygen Utilization, the longer and better your life will be

If you are sick, your NAD/NADH ratio is decreased. This can be reversed with Ozone.

Oxygen Utilization and OzoneOxygen Utilization and Ozone

Since decreased oxygen utilization is the primary cause of degenerative disease, the treatment of all diseases including aging, auto-immune disorders, cancer, ASCVD, etc. is maximally enhanced in the presence of optimal oxygen utilization. This is why ozone therapy should be used in virtually every patient you see.

NAD/NADH RatioNAD/NADH Ratio

Oxygen does not directly catalyze cellular reactions. It indirectly catalyzes them using NAD

When NAD catalyzes a reaction, it is converted to NADH

Oxygen then recycles the NADH back to NAD

The problem with decreased oxygen utilization is that it results in decreased levels of NAD combined with increased levels of NADH

NAD/NADH Ratio (cont.)NAD/NADH Ratio (cont.)

As the NAD/NADH ratio decreases, all cellular activity slows down

Less NADH is produced in the Krebs Cycle

The decrease in NADH further decreases the ratio because there is no NADH for oxygen to react with and form NAD

The decreasing NAD/NADH ratio spirals downward in a vicious cycle. We call this aging

NAD/NADH reactions are reversed in order to normalize the ratio

The Cost of Reversing NAD/NADH The Cost of Reversing NAD/NADH ReactionsReactions

Increased lactic acidosis- 19 times! Decreased apoptosis leading to

cancer Increased protein catabolism Increased intra-cellular free radical

stress Increased extracellular free radical

stress via PMOR (Plasma Membrane Oxidoreductase) system

The genesis of all chronic disease

Ozone TherapyOzone Therapy

Chronically ill patients have decreased NAD/NADH ratios.

Ozone activates all three levels of energy production– 1. Increases acetyl coenzyme A to

fuel the Kreb Cycle– 2. Increases the function of the Kreb

Cycle– 3. Increases the function of oxidative

phosphorylation Studies show it raises ATP as much as

Pharmacological Stimulation of NADH Oxidation Pharmacological Stimulation of NADH Oxidation Ameliorates Obesity and Related Phenotypes in MiceAmeliorates Obesity and Related Phenotypes in Mice

Hwang JH, Kim DK, Jo EJ, et al.Hwang JH, Kim DK, Jo EJ, et al.Diabetes Apr; 58(4):956-74. Epub 2009, Jan 9Diabetes Apr; 58(4):956-74. Epub 2009, Jan 9

The NAD/NADH ratio “plays a crucial role in cellular energy metabolism, and dysregulated NAD/NADH ratio is implicated in metabolic syndrome.”

Used beta-lapachone to oxidize NADH in diet-induced obesity mice

NADH oxidation “strongly provoked mitochondrial fatty acid oxidation in vitro and in vivo, and dramatically ameliorated their key symptoms such as increased adiposity, glucose intolerance, dyslipidemia, and fatty liver.”

Pharmacological Stimulation of NADH Oxidation Pharmacological Stimulation of NADH Oxidation Ameliorates Obesity and Related Phenotypes in MiceAmeliorates Obesity and Related Phenotypes in Mice

Hwang JH, Kim DK, Jo EJ, et al.Hwang JH, Kim DK, Jo EJ, et al.Diabetes Apr; 58(4):956-74. Epub 2009, Jan 9Diabetes Apr; 58(4):956-74. Epub 2009, Jan 9

“The treated mice also showed higher expresssions of the genes related to mitochondrial energy metabolism (PGC-1alpha, NRF-1) and caloric restriction (Sirt1), consistent with the increased mitochondrial biogensis and energy expenditure.”

“Conclusions: Pharmacological activation of NADH oxidation by NQO1 resolves obesity and related phenotypes in mice, opening the possibility that it may provide the basis for a new therapy for the treatment of metabolic syndrome.”

Optimal NAD/NADH Ratio is 700:1Optimal NAD/NADH Ratio is 700:1

Everyone of these reactions is 100% dependent on how much NAD is available.

Other Effects of OzonidesOther Effects of Ozonides Anti-bacterial: selective for anaerobes Anti-fungal Anti-viral No resistance Enhances chemotherapy and radiation Activates Nrf2, which activates ARE, which

increases gluthathione, catalase and SOD Increase 2,3DPG with Oxygen-Hemoglobin

dissociation to right to unload O2 in RBC Increase cytokine production

– IL-I, IL-2, IL-6, TNF-a, IFNb, IFNg, GM-CSF, TGFb I Increases RBC flexibility Enhances NO, to induce vasodilation

Anti-Oxidant EnzymesAnti-Oxidant Enzymes

Nrf2 activates anti-oxidant response elements (ARE) in the mitochondria

Superoxide dismutase (SOD)- Mn, Cu, Zn

Catalase- Fe Glutathione peroxidase-

Selenium, glutathione, NAC

Percentage values of biochemical parameters from Percentage values of biochemical parameters from glutathione redox system after 5 and 15 endovenous ozone glutathione redox system after 5 and 15 endovenous ozone

therapy sessiontherapy session

Parameter Session Mean SEM

GPx 5 141.8 25.9

15 178.9 50.0

LPO 5 112.8 21.1

15 84.5 19.4

GPx= glutathione peroxidase; LPO= lipid peroxidation level; SEM= standard error of mean

Cytokine Production After OzoneCytokine Production After OzoneStudies on the Biological Effects of OzoneStudies on the Biological Effects of Ozone

5 Bocci V, Luzzi E, et al5 Bocci V, Luzzi E, et alBiotherapy. 7;83-90, 1994 Biotherapy. 7;83-90, 1994

Increased production of: IL-1, IL-2, IL-6, IL-10, IL-8, IFN-g, IFN-b, GM-CSF, TNF-a, TGF-b

IL-1B IL-2 IL-6 TNF-a IFN-b IFN-g GM-CSF

Control 61 0.8 17 14 2 1 108

O3 157 1.8 36 52 27 3.3 265

Nrf2Nrf2

“Master Regulator of CytoProtection” Increases Detoxification Regulates production of Phase 2

Enzymes Enhances stability and turnover of

proteins Reduces inflammation Protects against neurodegeneration Anti-tumorigenic Promotes apoptosis Promotes longevity

Lewis et al (2010), Integr Comp Biol (May 6, 2010)

Nrf2- Nuclear Factor Like 2Nrf2- Nuclear Factor Like 2

Nrf2 is a transcription factor which when activated increases the expression of antioxidant enzyme systems

The Nrf2 antioxidant response pathway is “the primary cellular defense against the cytotoxic effects of oxidative stress.”

One drug that activates Nrf2, dimethyl fumarate, significantly reduces the progression of multiple sclerosis

Nrf2 activation is involved in ozonated Nrf2 activation is involved in ozonated human serum upregulation of HO-1 in human serum upregulation of HO-1 in

endothelial cellsendothelial cellsPecorelli A, Bocci V, et al Toxicol Appl Pharmacol.Pecorelli A, Bocci V, et al Toxicol Appl Pharmacol.

2013 Feb 15; 267(1):30-402013 Feb 15; 267(1):30-40

Endothelial cells treated with increasing doses of ozonated serum at 20, 40, and 80 gamma

Nrf2 is activated in a dose-dependent manner

Nrf2 activation is involved in ozonated Nrf2 activation is involved in ozonated human serum upregulation of HO-1 in human serum upregulation of HO-1 in

endothelial cellsendothelial cellsPecorelli A, Bocci V, et al Toxicol Appl Pharmacol.Pecorelli A, Bocci V, et al Toxicol Appl Pharmacol.

2013 Feb 15; 267(1):30-402013 Feb 15; 267(1):30-40

Moreover, the treatment with ozonated serum was associated with a dose-dependent activation of extracellular-signal-regulated kinases (ERK1/2) and p38 MAP kinases (p38), not directly involved in Nrf2 activation

“These data, provide a new insight on the mechanism responsible for the induction of HO-1 expression by ozonated serum in the endothelium

Nrf2 Activation (Parkinson's)Nrf2 Activation (Parkinson's)

Nrf2 Activation (Cancer)Nrf2 Activation (Cancer)

Anti-bodies make Ozone to Kill BacteriaAnti-bodies make Ozone to Kill BacteriaThe Scripps Research Institute

Primary Applications of OzonePrimary Applications of Ozone Coronary artery and cardiovascular disease Claudication Gangrene Macular degeneration Aging Oncology Chronic infections Disc Pain Herpes Chronic fatigue Cutaneous fungi Interstitial cystitis Dental ostitis Allergies Auto-immune disease Ulcerative colitis Others

StudiesStudies

Israel

US Physician M.D.US Physician M.D.

Went to Germany in 1983

Founder of Prolozone and Ozone in the USA

What Causes Chronic Pain?What Causes Chronic Pain? Oxygen tension in ligaments and

joints is only 1/10th of that of other tissues

With aging, O2 Utilization is compromised

Trauma produces edema and inflammation which decreases O2 Utilization leading to increased lactic acid, free radical damage, necrosis, sensory irritation with chronic pain

Chronic Pain Happens LocallyChronic Pain Happens Locally

Chronic localized pain is caused by localized areas of chronically decreased oxygen utilization

Vicious cycle starts with trauma or infection

Edema, inflammation, hyper-coagulation, and endothelial damage lead to a further localized decrease in oxygen utilization

Decreased oxygen utilization disables the healing mechanism, and condition becomes chronic resulting in permanent edema, inflammation, hyper-coagulation, endothelial damage, and pain

How Does Prolozone Work?How Does Prolozone Work?

Works by improving Oxygen Utilization in a localized area of damaged tissue allowing it to heal and restore full function

Neoangiogenesis Anti-inflammatory Stimulates growth factors

ProlozoneProlozone Each component of Prolozone has a

specific biological purpose Procaine acts to re-establish cellular

membrane potentials Anti-inflammatory agents decrease

edema and swelling Vitamins and minerals provides

necessary substrates for Oxygen Utilization that are deficient in damaged tissue

Oxygen Utilization is directly stimulated by ozone

Prolozone (cont.)Prolozone (cont.)

Increase NAD/NADH ratio increases protein synthesis, cellular division, growth factors, membrane potential

Net result is that tissues get what they need to heal/energy

Circulation to the area is reestablished

Pain is cured

StudiesStudies

Canada

Ukraine

What To ExpectWhat To Expect

European Journal of Pharmacology, 2009– Prevents allodynia–Decreases pro-inflammatory

caspases in the orbito-frontal cortex of neuropathic mice

The pain goes away.

Benefits of Musculoskeletal Ultrasound Benefits of Musculoskeletal Ultrasound Guided ProlozoneGuided Prolozone

Highly accurate needle placement of ozone delivery which is dramatically better than blind injections

No ionzining radiation (X-ray) No contraindications Cost only a fraction of other

studies

Before ProlozoneBefore Prolozone

After ProlozoneAfter Prolozone

Ozone StudiesOzone Studies

Adult Stem CellsAdult Stem Cells

Autologous harvested human stem cells

5 IRBs– Pain– Type 2 Diabetes– COPD– Erectile Dysfunction– Critical Limb Ischemia

What is Health?What is Health? Not the absence of symptoms

Not the absence of disease

Not the absence of abnormal tests

Not the absence of anything- health is the presence of something- Optimum Oxygen Utilization

SummarySummary

For further reading:– Principles and Applications of

Ozone Therapy, A Practical Guideline for Physicians by Frank Shallenberger, M.D.

WWW.DEANSILVERMD.COM

(480)860-2030

Ozone,Oxygen, Prolozone IRB - by Dean Silver MD

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