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Intravenous Hydrogen
Peroxide
HYDROGEN PEROXIDE THERAPIES:
RECENT INSIGHTS INTO OXYSTATIC AND ANTIMICROBIAL ACTIONS
Majid Ali, M.D.
My colleagues at the Institute and I routinely prescribe hydrogen peroxide foot
soaks for patients with acute and chronic lower leg edema caused by peripheral
arterial insufficiency, varicose veins, unresolved trauma, low-grade chronic
infectious and atopic processes. Based on clinical results obtained in several
hundred patients, I now consider this therapy (described later in this article)
to be the safest and most effective therapy for those conditions.
We have also prescribed intravenous hydrogen peroxide infusions for over 3,000
patients with varying degrees of respiratory-to-fermentative (RTF) shift in ATP
generation associated with chronic fatigue states.1,2 Based on that experience,
we now consider that therapy as one of the safest and most effective therapies
for such patients. The long-term clinical outcomes of integrative protocols with
focus on hydrogen peroxide infusions have been published.3 In this article, I
briefly review some basic aspects of hydrogen peroxide chemistry and
therapeutics, and then present newer information about hydrogen peroxide
signaling that sheds light on the molecular mechanisms that explain our clinical
observations.
Discovery and Natural Occurrence
Hydrogen peroxide was discovered in 1818 by the French chemist Louis-Jacques
Thenard. He coined the term eau oxygenee, to express his belief that it was an
oxygenated form of oxygen. It is not clear if he fully understood the enormous
medical significance of his discovery. Hydrogen peroxide is colorless, heavier
than water, and has a larger liquid range than water, the melting point ranging
from -11C (70%) to -39C (70%). It is produced within the plant biomass and plays
diverse and pivotal roles in the cellular communication and energetic systems in
the plant kingdom. It is present in trace amounts both in rainwater and snow.
Interestingly, it is found in higher concentrations in natural spring waters of
many healing shrines, most notably in Lourdes in France, Fatima in Portugal, and
St. Anne's in Quebec. In light of my observations of the clinical benefits of
H2O2 therapies in a host of clinical entities, I am tempted to speculate that
many of the putative benefits of the shrine waters accrue from the oxystatic
roles of H2O2. It is also likely that the mineral compositions of such waters
enhance their oxystatic benefits.
Hydrogen Peroxide: A Misunderstood Molecule
Hydrogen peroxide is a misunderstood molecule. It is a potent in vitro oxidant.
And yet, it serves as an effective in vivo antioxidant in clinical states
associated with chronic accelerated oxidative molecular stress.4,5 It is
procoagulant under certain conditions and anticoagulant under others.6 It is
proinflammatory in some roles and anti-inflammatory in others.7 It induces some
genes and suppresses others.8,9 It is a critically important second messenger in
many pathways. 10-14 It is procancer in some aspects and anti-cancer in others.
Hydrogen peroxide plays multiple Dr. Jekyll/Mr. Hyde roles in enzymatic dynamics
of the body, inducing some and impairing the functions of others,15-19
including: (1) inactivation of xanthine oxidase by reactions that involve
formation of hydroxyl radicals; (2) oxidation of the oxidation- sensitive thiol
groups at the active site of glucose-3-phosphate dehydrogenase and so inhibits
the enzyme, thus reducing ATP-dependent synthesis of many proteins; (3)
inhibition of glyceraldehyde phosphate dehydrogenase (GAPDH), providing a
mechanism by which hydrogen peroxide exerts a regulatory effect on endothelial
pathophysiology; (4) regulation of activities of crucial energy enzymes, such as
sodium-potassium ATPase18; activation of potent enzymatic antioxidant defenses,
including glutathione peroxidase.19 Other important metabolic aspects of
hydrogen peroxide include: (1) hexose monophosphate shunt20; (2) mitochondrial
enzymatic pathways21; (3) enzymes of membrane transport systems22; (4)
thyroglobulin iodinases23; (5) prostaglandin synthesis24; (6) bioamine metabolic
pathways, including those of norepinephrine, dopamine, and serotonin25; and (7)
progesterone and estrogenic synthetic pathways.26 By those and other roles,
hydrogen peroxide activates a host of oxyenzymes—enzymes that are directly
involved in oxygen homeostasis—and alters the expression of oxygenes in many
ways.
The Beginning of H2O2 Therapeutics
In 1898, Cortelyou of Marietta, Georgia, reported successful results obtained in
patients with disorders of the nose and throat.27 In the same year, I.N. Love
reported his successful use of H2O2 for treating scarlet fever, diphtheria,
pneumonia, and uterine cancer in the Journal of the American Medical
Association.28 A clear record of what appears to be the first clinical use of
intravenously administered hydrogen peroxide appeared in an article published in
Lancet in 1920 by Oliver and Cantab.29 They were military physicians treating
Indian Gurkha soldiers. During an influenza epidemic, they encountered 80%
mortality among soldiers who developed pneumonia. In desperation—possibly
emboldened by a lack of fear of serious censure if the treatment were to be
fatal for some terminally ill Indian soldiers—they undertook intravenous
infusions of hydrogen peroxide to treat pneumonia. They were fortunate. In their
landmark paper, they reported more than 50% reduction in mortality — 13 of 25
treated soldiers survived! There were no cases with clinical or pathologic
evidence of air embolism. It puzzles me why that report was not followed by
widespread use of that treatment of pneumonia in Britain.
A pioneer of intravenous H2O2 therapy was Charles Farr. During the mid-1990s, he
honored me by having me serve as his co-director of courses on bio-oxidative
therapies. Farr made several important original clinical and experimental
observations about intravenous hydrogen peroxide infusions. He documented
short-term and long-term effects of that therapy on various aspects of the
immune system. One of his astute observations concerned the dramatic changes—up
to 100% increase from the pre-infusion levels—in oxygen consumption rate. He
clearly established the fact that biologic effects of that therapy cannot be
merely attributed to the miniscule amounts of oxygen liberated from the infused
hydrogen peroxide.30
Mechanisms by Which H2O2 Improves Arterial, Venous, and Lymphatic Circulations
A large number of short-term and long-term observations have convinced us that
H2O2 improves arterial, venous, and lymphatic circulation. Those effects are
mediated by a host of mechanisms. Personal morphologic observations with
phase-contrast microscopy have convinced me that the most important of those
mechanisms is control of oxidative coagulopathy by myriad molecular mechanisms
listed below. Microclots and microplaques in the circulating blood are readily
detected by examination of freshly prepared and unstained smears of the
peripheral circulating blood with high-resolution, phase-contrast
microscopy.31-33 The arrest of oxidative lymphopathy occurs concurrently with
control of oxidative coagulopathy, though a suitable lymph specimen for direct
documentation of that phenomenon is generally not forthcoming.
The primary mechanism by which H2O2 exerts those circulatory effects is
proteolytic dissolution of microclots and microplaques in the vascular channels.
Less important effects of H2O2 include the following: (1) peripheral
vasodilatation34; (2) coronary vasodilatation35; (3) cerebral arteriolar
dilatation36; and (4) pulmonary vasodilatation37; and (5) peripheral
vasodilatation.36
H2O2 and Phagocytosis
Antimicrobial properties of hydrogen peroxide were recognized soon after its
discovery. It was to be expected that the seminal work of the Russian biologist,
Elie Metchnikoff, concerning humoral immunity during the late nineteenth century
would also bring hydrogen peroxide into sharper focus. That, indeed, happened.
The classical concept of phagocytic microbial killing may be summarized as
follows38-42: (1) The invading microbes are exposed to serum factors, opsonized,
and engulfed within the phagocytic cells; (2) The engulfed microbes are
encapsulated by a series of fusion processes culminating in the development of
the mature phagosome41; (3) Phagosomes merge with early endosomes to increase
the vesicle size; (4)Membrane-bound vacuolar ATPases and proteolytic enzymes
necessary for particle and microbial degradation are acquired42; (5)
Bactericidal molecular machinery of cytoplasmic granules is brought into action
with the release of their granules; and (6) Actual demise of microbes is
attributed to production of free radicals—superoxide, hydrogen peroxide, and
others—during respiratory burst.43
H2O2, Matrix Regulation, and Microbial Killing
Recent studies have revealed that actual molecular dynamics of microbial killing
are far more complex than simple destruction of mirobes by free radicals.44,45
Specifically, certain conditions of the granular matrix are essential for
completing the process of microbial disintegration. The matrix within the
granules is highly charged. Granular proteases are normally adsorbed to it in an
inactive form. When the ionic strength in the vacuoles rises, the enzymes are
activated and unleashed to serve their microbiocidal roles. Those enzymes
function optimally at elevated pH levels which exist in the vacuoles under those
conditions. The respiratory burst within the phagocytic vacuoles is accompanied
by a surge in the intravacuolar pH—from 6 to nearly 8. A large influx of
potassium ions through the vacuolar membrane occurs and offsets the anionic
charge. That happens in spite of the release of predominantly acidic granular
contents since protons are consumed in neutralizing the excess of basic
superoxide ions and other radicals.46,47
Concurrently, osmotically potent degradation products are released from
disintegrating microbes, rendering the vacuole markedly hypertonic and shrinking
the viable bacteria by as much as 50%. Such microbial shrinking is prevented if
protease inhibitors are introduced into the system. Undue expansion of the
vacuoles is prevented by a dense network of membrane cytoskeletal proteins.
Neutrophilic myeloperoxidase, itself capable of destroying microbes, appears to
protect proteases from oxidative damage, to which they are vulnerable,
especially cathepsin G.48
The Role of Potassium Ions
The passage of electrons across the vacuolar membrane is electrogenic.
Specifically, the superoxide-generating NADPH oxidase of human neutrophils is
electrogenic and is associated with an H+ channel.49 There are important changes
in H+ dynamics during phagocytosis. For example, protein C kinase activates an
H+-(equivalent) conductance in the plasma membrane of human neutrophils.
Activation of NADPH oxidase-related proton and electron currents occurs
simultaneously in human neutrophils. Potassium ions play a central role in the
microbial killing process. Oxidases generate a potential difference across the
membrane. Potassium ions move to compensate for that difference and in doing so
enable the pH to rise to a level necessary for optimal function of proteases.
Potassium ions activate granule enzymes. When phagocytes are inactive (not
engulfing and killing microbes), the granules contain a strongly anionic
sulfated proteoglycan matrix that binds tightly to cationic proteases. In the
bound form, proteases cannot digest microbes. There is evidence that hypertonic
K+ driven into vacuoles by NADPH oxidase is responsible for unleashing (by
solubilizing) those enzymes, since elevated pH on its own is unable to activate
proteases. 50
Would one expect the other ionic channels to sit out the action of phagocytosis?
Hardly, in view of Nature's preoccupation with complementarity and contrariety.
Free calcium ions initiate, augment, or perpetuate an enormous variety of
cellular processes. For example, calcium is involved with coupling of diverse
stimuli to their respective specific responses,51,52 including: (1) light; (2)
touch; (3) gravity; (4) cold shock; (5) hormones; (6) bacterial compounds; and
(7) mycotoxins. Stimulus specificity appears to be encoded through a multitude
of Ca2+ mobilization pathways. For example, vacuolar ligand-gated Ca2+
mobilization pathways may involve both Ca2+- and voltage- operated Ca2+ release
channels in the same membrane, acting singly or coordinately. Directly or
indirectly, such calcium-related responses are involved in nearly all crucial
steps in phagocytosis. Not unexpectedly, many of the specific calcium responses
depend on their spatio-temporal concentrations. To render the calcium-related
cellular happenings yet more fascinating, some nuclear processes appear to be
executed in response to an autonomously regulated nuclear calcium signal. It may
be added parenthetically that chloride ions also play a role in phagocytic
dynamics. Specifically, chloride efflux regulates adherence, spreading, and
respiratory burst of neutrophils stimulated by tumor necrosis factor- (TNF) on
biologic surfaces.53
In discussion of the structure and function of the matrix, little, if any,
attention is given to the matrix within the cell as well as within cellular
organelles. And yet, the matrix in those locations serves key redox metabolic
and defense roles. The complexities in the phagocytic destruction of microbes
should not be surprising because Nature, first and foremost, has to protect
cells and vacuoles from the self-destructive impulses of their own enzymatic
arsenals. An enormous number of phagocytic cells infiltrate the inflamed tissues
invaded by microbes. Such cells deliver a huge load of autolytic enzymes fully
capable of damaging autologous tissues. Thus, the 'packaging' of the enzymes
provides the needed defense against self-inflicted injury triggered by free
radical sparks. It may be added here that the matrix of phagocytic granules —
seldom a point of focus — also plays a central role in destruction of microbes
after phagocytosis.
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Table 1. Composition of
Hydrogen Peroxide - I |
|
Nutrient |
Concentration |
Volume |
|
Hydrogen peroxide |
3.75% |
0.35 ml |
|
Sodium Bicarbonate |
0.5 mEq/ml = 1.25 mEq |
2.5 ml |
|
Normal saline 0.9% |
|
150 ml |
|
Table 2. HYDROGEN PEROXIDE-II
(Hydrogen Peroxide-I Followed By Infusion Given Below In 30-45 Minutes
|
|
Nutrient |
Concentration |
Volume |
|
Magnesium sulfute. |
500 mg/ml =1.5 ml |
750 mg |
|
Zinc |
5 mg/ml = 2 ml |
12 mg |
|
Calcium gly/lac |
10 mg/ml = 7.5 ml |
75 mg |
|
Pantothenic acid |
250 mg/ml = 1.5 ml |
375 mg |
|
Pyridoxine |
100 mg/ml = 1 ml |
100 mg |
|
Vitamin C |
500 mg/ml = 1 ml |
0.5 gm |
|
Vit. B Complex |
* |
1 ml |
|
Molybdenum |
25 mcg/ml = 5 ml |
125 mcg |
|
Sodium Bicarbonate |
2.5 mEq/5 ml = 1.5 ml |
--------- |
|
Lidocaine |
20 mg/ml = 1.5 ml |
30 mg |
|
0/45% Saline |
|
50 ml |
I
might point out here that matrix proteases perform the microbial killing
rituals, but oxygen and the oxygen-driven oxidative phenomena provide the
initial sparks.
Protocol for Hydrogen Peroxide Foot
Soaks and Baths
Hydrogen peroxide soaks can be used with different concentrations of and H2O2
and salt. The following is the standard protocol prescribed at the Institute
protocol:
H2O2 Soaks Protocol
Water 20 parts
H2O2 3% 1 part
Salt One teaspoon
Time 20 minutes
The recommended choices of salt are as follow: (1) Epsom salt; (2) sea salt; and
(3) common table salt.
Stronger solutions of H2O2, such as one part of H2O2 and 10 parts of water or 1
part of H2O2 and 15 parts of water may also be tried to test for variations in
efficacy for individual persons.
For chronic conditions, I generally prescribe foot soaks on a four or five day a
week basis. For subacute conditions, daily soaks are recommended. Uncommonly, I
have prescribed such soaks on a twice daily basis.
There are several good brands of foot soak and foot massage units available on
the market. The one made by Brookstone Company creates effective whirlpool
conditions and includes a "nodule" for effective massaging of tender points on
the feet or ankles.
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