Ozone,Oxygen, Prolozone IRB - by Dean Silver MD

2012 © Dean R. Silver, M.D.
Ozone/Oxygen/ProlozoneOzone/Oxygen/Prolozone
IRBIRB
IRBIRB
Medical Motivational Speaker
WWW.DEANSILVERMD.COM
INTEGRATED 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 Therapy

FDG PET SCAN- WHOLE BODYFDG PET SCAN- WHOLE BODY

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

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

OUR MISSIONOUR MISSION
TO 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 ByFree 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 Adaptation
Levine & 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/NADHThe 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 40%

Pharmacological Stimulation of NADH OxidationPharmacological 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 OxidationPharmacological 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.
 “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

37
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

38
Percentage values of biochemical parameters fromPercentage values of biochemical parameters from
glutathione redox system after 5 and 15 endovenous ozoneglutathione 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

39
Cytokine Production After OzoneCytokine Production After Ozone
Studies on the Biological Effects of OzoneStudies on the Biological Effects of Ozone
5 Bocci V, Luzzi E, et al5 Bocci V, Luzzi E, et al
Biotherapy. 7;83-90, 1994Biotherapy. 7;83-90, 1994
Biotherapy. 7;83-90, 1994Biotherapy. 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 ozonatedNrf2 activation is involved in ozonated
human serum upregulation of HO-1 inhuman serum upregulation of HO-1 in
endothelial cellsendothelial cells
Pecorelli 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
2013 Feb 15; 267(1):30-402013 Feb 15; 267(1):30-40
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 ozonatedNrf2 activation is involved in ozonated
human serum upregulation of HO-1 inhuman serum upregulation of HO-1 in
endothelial cellsendothelial cells
Pecorelli 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
2013 Feb 15; 267(1):30-402013 Feb 15; 267(1):30-40
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 Bacteria
The 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

StudiesStudies

China

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

Spain

Italy

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.

81
Benefits of Musculoskeletal UltrasoundBenefits 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

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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