The utilization of ozone for
external medical applications
by Gérard V.
Sunnen, M.D.
May 1998
INTRODUCTION
Ozone, an allotropic form of oxygen, possesses unique
properties which are being defined and applied to biological systems as well
as to clinical practice. As a molecule containing a large excess of energy,
ozone, through incompletely understood mechanisms, manifests bactericidal,
virucidal, and fungicidal actions which may make
it a treatment of choice in certain conditions and an adjunct to treatment in
others.
The oxygen atom exists in nature in several forms: (1)
As a free atomic particle (0), it is highly reactive and unstable. (2)
Oxygen (02), its most common and stable form, is colorless as a gas and pale
blue as a liquid. (3) Ozone (03), has a molecular weight of 48, a density one
and a half times that of oxygen, and contains a large excess of energy in its
molecule (03 -> 3/2 02 + 143KJ/mole). It has a bond anngle of 127 ± 3,
resonates among several forms, is distinctly blue as a gas, and dark blue as a
solid. (4) 04 is a very unstable, rare, nonmagnetic pale blue gas, which
readily breaks down into two molecules of oxygen.
Ozone is a powerful oxidant, surpassed in this regard only by fluorine.
Exposing ozone to organic molecules containing double or triple bonds yields
many complex and as yet incompletely configurated
transitional compounds (i.e. zwitterions, molozonides,
cyclic ozonides), which may be
hydrolysed, oxidized, reduced, or thermally
decomposed to a variety of substances, chiefly aldehydes,
ketones, acids or alcohols. Ozone also reacts with
saturated hydrocarbons, amines, sulfhydryl groups,
and aromatic compounds.
Importantly relevant to biological systems is ozone's interaction with
tissue--including blood--constituents. The most studied is lipid
peroxidation, although interactions have yet to be
more fully investigated with complex carbohydrates, proteins,
glycoproteins, and
sphingolipids.
WHY OZONE IS A DRUG
Ozone is a pan-virucidal, and a
pan-bactericidal agent. In addition, it is well documented that many species
of fungi are inactivated by its actions, as well as several types of protozoa.
Ozone is a gas which, properly interfaced with biological systems or
pathologically afflicted tissues, exerts significant therapeutic activity. As
is the case with many medications, however, ozone has a range of therapeutic
action which, in the terminology of pharmacokinetics, is termed a therapeutic
window. Indeed, ozone applied in concentrations that are too low, has little
therapeutic effect. More importantly, when it is applied in too high
concentrations, it is known to have some toxic sequelae.
Due to ozone's demarcated therapeutic range, ozone concentrations
administered to the patient need to be carefully calibrated and controlled.
The therapeutic ozone/oxygen mixture requires state of the art quantitative
(dosage, concentration), as well as qualitative (purity) controls, which can
only be provided by an appropriate contemporary technology.
At room temperature, approximately 50% of ozone reverts to pure oxygen.
This adds an important dimension to the calculation of the amount of ozone
administered. As regards the generation and delivery system, of foremost
importance is the oxygen source which must be of medical grade purity, and
thus devoid of nitrogen or impurities. The presence of nitrogen favors the
production of nitrogen oxides which are tissue-toxic. Due to these
considerations, ozone needs to be conceptualized as a medication with complex
therapeutic dynamics, which need to be carefully considered and evaluated in
relation to the particular medical conditions being treated.
METHODS OF OZONE GENERATION AND ADMINISTRATION
Ozone generation and delivery systems are intrinsically connected to the
fact that ozone, utilized for human or veterinary therapeutic purposes,
requires that it be created at the moment it is to be administered. Ozone, in
this sense is not a drug that has a shelf life, and that can be kept for long
periods of time at a certain determined dosage. As a gas with a half life of
approximately one hour at room temperatures, the gauging of ozone's dosage is
intrinsically connected to the sophistication of its manufacture technology
and its pharmacodynamics.
Ideally, the treating clinician should be able to be informed of the exact
concentration of the ozone drug being generated and delivered (i.e., a digital
readout of ozone output in micrograms per milliliter, or grams per cubic
meter). In addition, the clinician needs to factor the natural and constant
conversion of ozone into oxygen, so as to arrive at precise measurements of
dosage in relation to duration of administration.
In the case of external application, the ozone generator supplies a dosage
of ozone/oxygen determined by the clinician to be therapeutically indicated.
This, in practice, may involve an infected foot, a post-surgical incision, an
area afflicted by a burn, a decubitus ulcer, or a
poorly healing post-traumatic wound.
In the practice of external ozone application, a specially designed
polyester envelope is used to enclose the area under treatment. A precise
fitting of the bag is needed in order to ensure (I) A proper constant
concentration of delivered ozone, (2) A suitable
containment of ozone/oxygen to the affected area. This guarantees that ozone
will be prevented from escaping into the ambient environment which, in higher
concentrations, may lead to respiratory epithelial irritation in the patient
or in the treating personnel, and (3) An
opportunity for the precise timing of the duration of ozone exposure under
controlled conditions.
In order to respect proper environmental controls, and to prevent ozone
from diffusing into the treatment space, an exit catheter connected to the
polyethelene envelope is directed to the ozone
generator for catalytic reconversion to oxygen.
Externally applied ozone concentrations need to be carefully adjusted. The
clinician must be able to gauge the proper ozone concentration geared to the
specific medical condition under treatment. In wet burns, for example, initial
ozone concentrations will need to be low, in order to prevent inordinate
systemic absorption. As the burn heals, and progressively dries, greater ozone
concentrations may then be administered in order to keep pace with the rate of
healing.
THE EFFECTS OF OZONE ON PATHOGENS
The antipathogenic effects of ozone have been
substantiated for several decades. Its killing action upon bacteria, viruses,
fungi, and in many species of protozoa, serve as the basis for its increasing
use in disinfecting municipal water supplies in cities worldwide.
Indicator bacteria in effluents, namely coliforms
and pathogens such as Salmonella, show marked sensitivity to ozone
inactivation. Other bacterial organisms susceptible to ozone's disinfecting
properties include Streptococci, Shigella,
Legionella pneumophila,
Pseudomonas aeruginosa,
Yersinia enterocolitica, Campylobacter
jejuni, Mycobacteria,
Klebsiella pneumonia, and Escherichia coli. Ozone
destroys both aerobic, and importantly, anaerobic bacteria which are mostly
responsible for the devastating sequelae of
complicated infections, as exemplified by decubitus
ulcers and gangrene.
The mechanisms of ozone bacterial destruction need to be further
elucidated. It is known that the cell envelopes of bacteria are made of
polysaccharides and proteins, and that in Gram negative organisms, fatty acid
alkyl chains and helical lipoproteins are present. In acid-fast bacteria, such
as Mycobacterium tuberculosis, one third to one half of the capsule is formed
of complex lipids (esterified
mycolic acid, in addition to normal fatty acids), and
glycolipids (sulfolipids,
lipopolysaccharides,
mycosides, trehalose
mycolates). The high lipid content of the cell walls of these
ubiquitous bacteria may explain their sensitivity, and eventual demise,
subsequent to ozone exposure. Ozone may also penetrate the cellular envelope,
directly affecting cytoplasmic integrity,
disrupting any one of numerous levels of its metabolic complexities.
Numerous families of viruses including poliovirus I and 2, human
rotaviruses, Norwalk virus, Parvoviruses, and
Hepatitis A, B, and non-A non-B (C), among many others, are susceptible to the
virucidal actions of ozone.
Most research efforts on ozone's virucidal
effects have centered upon ozone's propensity to break apart lipid molecules
at sites of multiple bond configuration. Indeed, once the lipid envelope of
the virus is fragmented, its DNA or RNA core cannot survive.
Non-enveloped viruses (Adenoviridae,
Picornaviridae, namely poliovirus,
Coxsachie, Echovirus, Rhinovirus, Hepatitis A and
E, and Reoviridae (Rotavirus), have also begun to
be studied. Viruses that do not have an envelope are called "naked viruses."
They are constituted of a nucleic acid core (made of DNA or RNA) and a nucleic
acid coat, or capsid, made of protein. Ozone,
however, aside from its well recognized action upon unsaturated lipids, can
also interact with certain proteins and their constituents, namely amino
acids. Indeed, when ozone comes in contact with capsid
proteins, protein hydroxides and protein hydroperoxides
are formed.
Viruses have no protection against oxidative stress. Normal mammalian
cells, on the other hand possess complex systems of enzymes (i.e.,
superoxide dismutase,
catalase, peroxidase)
which tend to ward off the nefarious effects of free radical species and
oxidative challenge. It may thus be possible to treat infected tissues with
ozone, respecting the homeostasis derived from their natural defenses, while
neutralizing offending and attacking pathogen devoid of similar defenses.
The enveloped viruses are usually more sensitive to
physico-chemical challenges than are naked virions.
Although ozone's effects upon unsaturated lipids is
one of its best documented biochemical action, ozone is known to interact with
proteins, carbohydrates, and nucleic acids. This becomes especially relevant
when ozone inactivation of non-enveloped virions
is considered.
Fungi families inhibited and destroyed by exposure to ozone include
Candida, Aspergilus,
Histoplasma, Actinomycoses, and
Cryptococcus. The cell walls of fungi are multilayered and are composed of
approximately 80% carbohydrates and 10% of proteins and
glycoproteins. The presence of many disulfide bonds has been noted,
making this a possible site for oxidative inactivation by ozone.
In all likelihood, however, ozone has the capacity to diffuse through the
fungal wall into the organismic cytoplasm, thus
disrupting cellular organelles.
Protozoan organisms disrupted by ozone include Giardia,
Cryptosporidium, and free-living amoebas, namely
Acanthamoeba, Hartmonella, and
Negleria. The exact mechanism through which ozone
exerts anti-protozoal action has yet to be
elucidated.
CUTANEOUS PHYSIOLOGICAL EFFECTS OF OZONE
The positive effects of oxygenation of many
dermatological conditions has long been established, and forms the
basis for the use of hyperbaric oxygen treatment. Oxygen has the capacity to
diffuse into the tissues, inhibit the growth of anaerobic bacteria, and raise
the local oxygen content of treated tissues, thus alleviating their oxygen
deprivation.
Ozone, however, as an added ingredient, has properties which clearly
transcend oxygen administration alone. The two properties invoked are (I) A
much broader range of pathogen killing action, and (2) A
vasodilatation of arterioles, stimulating greater blood flow to tissues, with
all its attendant benefits, including the greater availabilities of nutrients
and of the component of vital immunological adaptations and defenses.
EXTERNAL MEDICAL CONDITIONS BENEFITED BY OZONE THERAPY
In view of the above-mentioned principles of external ozone/oxygen
applications, we may list the following common conditions to be beneficially
influenced by this unique drug therapy, utilized either in conjunction with
other modalities, or used alone:
INFECTED WOUNDS
This category of wound has, by definition, not yet reached the status of
chronicity due to a combination of circulatory
compromise and infective onslaughts. In fact, this category of wound may
simply be post-surgical, and only potentially prone to infection.
The use of topical ozone therapy in these cases may be solely preventive,
and aimed at improving circulation on one hand, and inhibiting the
proliferation of potentially infective organisms on the other.
POORLY HEALING WOUNDS
Wounds which heal in an indolent manner are frustratingly difficult to
master. Some of these wounds, are apt to regress,
thus encouraging therapeutic strategies to become more aggressive, even
experimental, but not necessarily effective.
Generally speaking, poorly healing wounds owe their definition by the
chronicity of their healing, which is most
commonly caused by the types and mixed variety of offending organisms they
harbor.
Living organisms are constantly in contact with pathogens which, under the
proper conditions, are able to parasitically proliferate to create
pathological conditions. Many different types of pathogens may be involved,
spanning a large spectrum of infective diversity:
Anaerobic bacteria--bacteria that do not need oxygen
for their proliferation (i.e. Bacteroides,
Clostridium, Streptococci), maybe noxiously active at deeper levels of the
dermis, insulated to the healing influence of oxygen. Anaerobic
bacteria are responsible for many devastating infections, which are
generically subsumed under the appellation of gangrene. Aerobic bacteria, on
the other hand, are closely identified with superficial epidermal layers; yet,
when the latter are broken down, they may become influential in infective
processes (i.e., Staphylococcus epidermis, Corynebacteria,
Propionobacteria).
DECUBITUS ULCERS
This common condition arises when a patient stays in bed, or in a
wheelchair, in one position for a prolonged period of time. The pressure
exerted upon the skin contact points compresses the dermal arterioles
preventing proper perfusion of tissues. This leads to the oxygen starvation of
tissues, impaired skin resilience, then to eventual breakdown of the skin
itself. An ulcer develops, which may become quite large and usually infected
with a spectrum of pathogenic organisms. At times the breakdown is so severe
and the denudation of skin tissues so complete that the bottom of the ulcer
reaches the bone and osteomyelitis begins.
The treatment of decubitus ulcers requires a
multidisciplinary approach, including surgical, topical, and
mechanico-physiological interventions. Topical
antibiotics often fail to penetrate the wound and not infrequently cause
secondary dermatitis in their own right.
Aside from the benefits of topical ozone therapy enunciated in this text,
it should be mentioned that an added therapeutic feature of ozone, especially
as it relates to the treatment of deep ulcers, is its capability to penetrate
to deeper tissue level, thereby affecting pathogens which would normally be
protected by tissue overlay.
CIRCULATORY DISORDERS
This extremely common class of disorders have
one common denominator, namely impaired circulation to tissues via compromise
of vascular patency and integrity. A prototypic
disease showing this phenomenon is diabetes. Diabetes is a complex disease
which manifests both vascular disturbances to many organ systems (i.e. retina,
kidney, peripheral nerves), and, in addition, disturbances to carbohydrate
metabolism.
In cases where diabetes affects the peripheral circulation, tissues such as
the epidermis and dermis become vascularly
compromised, and thus are more prone to injuries and recalcitrant infections.
Diabetic ulcers frequently develop following simple abrasions, contusions,
and lacerations. These ulcers, not unlike decubitus
ulcers, are notoriously difficult to treat, and are apt to be chronically
treated with topical creams and ointments, which can only address the
viability of a minor proportion of putative infectious organisms. These
organisms may easily develop resistance to these therapeutic agents.
Concurrently, pathogens resistant to these therapies continue to proliferate
and to aggravate the condition.
Ozone topical therapy, applied serially, offers the opportunity to
inactivate most, if not all, offending pathogens, thus stopping the vicious
cycle of infection, thus leading to ulcer healing and
cicatrization. In addition, circulatory
stimulation, brings essential nutritional and immunological aids to
healing.
Arteriosclerosis is a condition marked by the thickening and hardening of
all arterial conduits in the body. The normal pliability and
patency of blood vessels is compromised, leading
to disturbed circulation to many organ systems. In the case of impaired
peripheral circulation (Arteriosclerosis obliterans),
skin disorders may develop which include trophic
changes (dry hair, shiny skin), apt to injury and eventual ulcer formation. As
in the case with diabetic ulcers, these circumstances often invite
multi-pathogenic infections.
LYMPHATIC DISEASES
The lymphatic system is essential for proper fluid equilibration within the
body, and most importantly for adequate defense against infections.
Lymphedema is a condition caused by blockage to
lymphatic drainage. It may be secondary to trauma, surgical procedures, and
infections (i.e. streptococcal cellulitis,
filiriasis, lymphogranuloma
venereum).
Increasingly common is lymphedema resulting
from surgical removal of lymph nodes following surgery for breast cancer. The
affected arm in these patients is likely to be chronically swollen, and
exercises are often prescribed to develop collateral circulation. Most
importantly, however, is the occurrence of infections following even minor
injuries to the arm. Injuries are then much more
apt to become infected due to the absence of lymphatic system defenses. In
these cases intensive topical wound care is resorted to and systemic
antibiotic treatment is often prescribed.
Topical ozone treatment applied as soon as injury is noted in the affected
hand or arm may prevent secondary infection, lymphedema,
and the use of topical and/or systemic antibiotics.
FUNGAL SKIN INFECTIONS
Fungi are present on human skin in a quasi symbiotic relationship. Candida,
Aspergillus, Histoplasma,
are often found on intact skin, without causing clinical problems.
However, under certain conditions, the normal balance of the dermis is
disturbed, allowing superficial fungi to proliferate.
Tinea capitis is manifested by
pustular eruptions of the scalp, with scaling and
bald patches. Tinea cruris
is a fungal pruritic
dermatitis in the inguinal region.
Serial topical ozone applications have shown marked success in eradicating
the most chronic and stubborn fungal skin conditions.
BURNS
Thermal burns are divided into first, second, and third degrees, depending
upon the depth of tissue damage. First degree burns are superficial, and
include erythema, swelling, and pain. In second
degree burns, the epidermis and some portion of the underlying dermis are
damaged, leading to blister and ulcer formation. Healing occurs in one to
three weeks, usually leading to little or no scar formation.
In third degree burns, muscle tissue and bone may be involved, and
secondary infection is very common.
It is in cases marked by significant tissue injury, and especially in cases
involving infections, that topical ozone therapy finds the most usefulness. In
the case of burns, the range of pathogenic organisms may be extremely wide
(see the section on poorly healing wounds), and thus may be ideally suited for
ozone therapy.
GENERAL VIRAL CONDITIONS WITH REFERENCE TO CUTANEOUS AFFLICTIONS
Ozone is actively virucidal to a staggering
number of viral families. Most clearly documented are ozone's neutralizing
effects upon lipidenveloped
virions. These include diverse viral groups as the
Hepadnaviridae (Hepatitis B and C), the
Retroviridae (HIV-I and HIV-II), the Herpesviridae
(Herpes simplex I and II, Cytomegalovirus, Epstein-Barr),
Filoviridae (Ebola virus and Marburg virus),
Orthomyxoviridae (Influenza A and B ), the
Paramyxoviridae (Measles, Mumps,
Parainfluenza, Respiratory
syncytial virus), the Coranoviridae, the
Togaviridae (Rubella, Eastern and Western equine
encephalitis), and the Rhabdoviridae (Rabies).
Although lipid-enveloped viruses appear to be most susceptible to ozone
inactivation due to their dependency on their outer lipid sheath,
non-enveloped viruses are also negatively subject to ozone through its ability
to interact with proteins, amino acids, carbohydrates and
glycoproteins.
Herpes simplex viruses are extremely widespread in the human population.
Two distinct types of viruses are known, namely Herpes simplex type I and II.
Type I is transmitted via contact through mucosa or broken skin (often through
saliva), while type II is more specifically sexually propagated.
In herpetic lesions, fluid accumulates between the dermis and epidermis,
producing vesicles which rupture, thus releasing more
virions. They then become easily infected by secondary organisms.
Herpes lesions have been extensively studied with reference to topical
ozone administration. Ozone in these cases (I) Directly
inactivated herpes viruses which are lipid-enveloped (2) Act as a
pan-bactericidal agent in cases involving secondary infections, and (3)
Promotes healing of tissues through circulatory enhancement. It is also
postulated that ozone may have beneficial effects upon the peripheral neurons
which harbor these viruses.
NAIL AFFLICTIONS
Afflictions implicating nails which are therapeutically assisted by topical
ozone treatment include the following:
- Candida
albicans. Nails in this condition are painful,
with swelling of the nail fold, and often, thickening and transverse
grooving of the nail architecture. Loss of the nail itself is not
infrequent. Another frequent condition is Tinea
Unguium, marked by thickened,
hypertrophic, and dystrophic toenails. There are
currently no antifungal agents of proven efficacy for this condition.
- Tinea
Pedis (Athlete's Foot). This very common
disorder is caused by infection with species of
Trichophyton, and with Epidermophyton
floccosum. Chronic infection involving the
webbing of the toes may evolve to secondary bacterial involvement.
Lymphangitis and lymphadenitis may present
themselves, as well as infection of the nails themselves (Tinea
unguium, Onychomycosis).
Nails may become thickened, yellow, and brittle. The patient may then
develop allergic hypersensitivity to these organisms which may manifest in
other parts of their bodies.
Topical ozone therapy offers unique treatment opportunities
to these recalcitrant infections. Ozone penetrates the affected areas,
including the nails proper, and with repeated administration, is capable of
inactivating all species of fungi mentioned above.
Healing occurs slowly yet consistently, and skin integrity along with nail
anatomy, gradually regain their normal
configuration.
RADIODERMATITIS
This condition occurs during times when the body is exposed to ionizing
radiation. This may occur during an accident, or within the course of
radiation therapy. Radiation energy is imparted to individual cells, leading
to alteration in cellular DNA, thus favoring cellular injury and/or death.
Clinical findings are commensurate with the type, amount, and duration of
radiation exposure. Several clinical syndromes have been delineated, including
Radiation Erythema, Acute
Radiodermatitis, and Chronic Radiodermatitis.
While DNA damage cannot be easily repaired (except perhaps partially
through nutritional avenues such as vitamin E), secondary infections made more
likely by decreased tissue resistance, may be countered by topical ozone
therapy. This avoids the systemic absorption of topical creams and ointments,
and ensures pan-pathogen protection.
FROSTBITE
Factors contributing to skin injuries due to cold derive from
vasoconstriction and the formation of ice crystals within tissues. As
frostbite progresses, loss of sensation occurs, and tissues become
increasingly hard to the touch. Depending upon length of exposure and
processes related to rewarming, dry gangrene may
develop. Dry gangrene may evolve to wet gangrene if infection occurs.
Topical ozone therapy has proven to be effective in decelerating or halting
the pathogenesis of frostbite through (I) The immediate oxygenation of
tissues, (2) Increasing blood flow through a direct
vasodilatory effect upon the dermal arterioles, and (3) The prevention
of secondary infection.
ADVANTAGES OF TOPICAL OZONE THERAPY
Topical ozone therapy for the disorders mentioned above requires
sophisticated medical diagnosis of the underlying conditions, and an
appropriately tailored treatment plan, which may include any one of several
therapeutic modalities utilized concomitantly,
including ozone, or may call for the utilization of ozone as the sole
therapeutic intervention.
The salient advantages of topical ozone therapy
include:
- The ease of administration
of this therapy, taking into consideration the strict parameters of the
technology-to-drug symbiosis.
- Ozone is an effective
antagonist to the viability of an enormous range of pathogenic organisms. In
this regard, ozone cannot be equaled. It is effective in inactivating
anaerobic and aerobic bacterial organisms, a wide spectrum of viral
particles--lipid as well as non-lipid enveloped--and a substantial spectrum
of fungal and protozoal pathogens.
To replicate this therapeutic action, the medical conditions
in question would have to be treated with a conglomeration of antibiotic
agents, systemically and/or topically applied. This would present, in the
context of contemporary medical practice, massive clinical difficulties.
- Ozone therapy,
appropriately applied in a timely fashion, may obviate the need for systemic
anti-pathogen therapy, thus saving the patient from all the side effects and
organ stresses this option could entail.
- Ozone exerts its anti pan-pathonegic
actions through entirely different mechanisms than conventional antibiotic
agents. The latter must be constantly upgraded to surmount pathogen
resistance and mutational defenses. Ozone, on the other hand, presents
direct oxidative challenge which cannot, by all
available pathogen defenses cannot be circumvented.
CONCLUSIONS
Topical ozone therapy has shown effectiveness in an impressive array of
medical conditions. In this article, the following are cited: Infected wounds;
poorly healing wounds; decubitus ulcers;
circulatory disorders; lymphatic diseases; fungal skin infections; burns;
cutaneous viral afflictions; nail afflictions;
radiodermatitis; and frostbite.
Ozone presents many features that are common to many drugs, namely a
therapeutic window demarcated by sub-optimal dosage on one hand, and toxic
higher dose levels on the other. For this reason ozone dosage must be
carefully calibrated and delivered, a feasibility which has only currently
been achieved through advances in contemporary technology.
Ozone is a pan-bactericidal, pan-virucidal,
anti-fungal and antiprotozoan therapeutic agent
which, utilized under treatment protocols which
continue to need proper delineation through research, promises to become a
potent adjunct to current medical treatment. It is also likely to show promise
as a drug used as a sole therapeutic agent in our global growing need to
bolster our antipathogen armamentarium.
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