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MyTopic
(INTRODUCTION),
(WHY OZONE IS A
DRUG), (METHODS OF
OZONE GENERATION AND ADMINISTRATION), (THE EFFECTS OF
OZONE ON PATHOGENS), (CUTANEOUS
PHYSIOLOGICAL EFFECTS OF OZONE), (EXTERNAL
MEDICAL CONDITIONS BENEFITED BY OZONE THERAPY), (INFECTED
WOUNDS), (POORLY HEALING
WOUNDS), (DECUBITUS
ULCERS), (CIRCULATORY
DISORDERS), (LYMPHATIC
DISEASES), (FUNGAL SKIN
INFECTIONS), (BURNS),
(GENERAL VIRAL
CONDITIONS WITH REFERENCE TO CUTANEOUS AFFLICTIONS), (NAIL
AFFLICTIONS), (RADIODERMATITIS), (FROSTBITE),
(ADVANTAGES OF
TOPICAL OZONE THERAPY), (The salient
advantages of topical ozone therapy include:)
Proof of ozone>
From http://www.ozonehospital.com
The utilization of ozone for external medical applications
by Gerard V. Sunnen, M.D.
May 1998
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 angle 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.
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:
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.
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).
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.
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.
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.
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.
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.
Afflictions implicating nails which
are therapeutically assisted by topical ozone treatment include the following:
1.
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.
2.
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.
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.
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:
1.
The
ease of administration of this therapy, taking into consideration the strict
parameters of the technology-to-drug symbiosis.
2.
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.
3.
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.
4.
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.
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.
Possible Mechanisms
of Viral Inactivation by Ozone
by Gerard V. Sunnen, M.D.
This is an addendum to a
February/March 1994
article on Ozone in Medicine.
The inactivation of viral particles
by ozone may take place by a variety of mechanisms which range from direct physico-chemical effects to more indirect immunological
pathways. Virions coated by a lipid glycoprotein
envelope such as rectoviruses, hepatitis B and C,
Herpes 1 and 2, and Epstein-Barr among others, are vulnerable to the influence
of ozone by its intense oxidizing properties,
In retroviruses for example, which
possess a glycolipid encapsulation, ozone confronts
the double bond sites in its matrix thus destroying its architecture. Without
its envelope, the virus perishes.(60) In virions which lack a lipid envelope but whose nucleic acids
are surrounded by a protein capsid such as those of
the minovirus family, ozone may diffuse through the
protein coating and deform or cleave the genome core. Viruses, unlike cells,
lack enzymes designed to repair injured DNA or RNA, and are incapacitated by
this process.
In major autohemotherapy,
relatively large amounts of blood are treated with ozone, then reinfused into the patient. The dosage and
concentration of ozone administered is carefully calibrated so that maximal
antiviral action is mobilized while at the same time sparing the integrity and
viability of the cellular elements. Viruses are small, denuded of complex
defenses,(63) and vulnerable to the oxidative
challenge of ozone. Cells, in contrast, are large and incorporate a
multiplicity of homeostatic mechanisms. There are developing technologies which
are designed to treat whole blood in a manner similar to the dialysis process.
In the case of retroviral infection,
it is extracellular viral particles which are presumably most affected by ozone
oxidation. Intracellular virions or provirions on the other hand, were thought to be relatively
spared of destruction by ozone by the barrier of cellular membranes, the buffer
of cytoplasmic constituents, and by the refuge
provided by their incorporation into the genome of the host cell. However, it
has been demonstrated that ozone possesses the capacity to inactivate
intracellular virions as well.(64)
Major autohemotherapy, repeatedly administered, could thus
exert a culling action on circulating virions,
especially during phases of the viral life cycle associated with viral seeding
in the general circulation, the so-called viremic
episodes. Studies attempting to measure the efficacy of this treatment modality
should take into account the patient's clinical status as it relates to the
cycle phase of viral activity at the time of the therapeutic intervention.
Immunological mechanisms may be
invoked through several pathways. In minor autohemotherapy,
a small amount of blood is ozone-treated in such a manner as to fragment most virions without regard to preserving cellular elements.
This treated blood, injected intramuscularly, carries fragments of viral
envelope and nucleic acids which find their way into the general circulation
and to the immune network. The latter, if still relatively operational, begins
to manufacture appropriate antibodies which in turn, serve to counter the
evolution of the infection.
The interesting feature of this
technique is that antibodies thus manufactured are individualized to the
particular patient receiving the treatment, since they are derived from their
own viral stock, In view of the high mutability of retroviruses,
each patient carries a unique viral strain. Minor autohemotherapy
can thus be conceptualized as a method of autovaccination
providing a high degree of antibody specificity.
A non-invasive and increasingly
popular method of oxygen/ozone administration, the so-called "Sauna
bag" method, does not involve heat, but consists of enclosing the patient
up to the shoulders with a comfortable ozone-resistant plastic cover. An
oxygen/ozone mixture is introduced in the bag, and' the patient allows it to
interface with the entire skin surface for a few minutes. Surprisingly, the
mixture is able to penetrate far enough into the capillary networks to raise
blood oxygen pressure. Presumably then, ozone is able to exert its biochemical
influence. The added advantage in this technique is that superficial skin
conditions amenable to antiseptic influence are addressed. As with all ozone
therapies, gas mixture concentration and duration of exposure need to be
clinically adjusted and monitored.
In recent years, it has been
discovered that nitric oxide, a gas under atmospheric conditions traditionally
associated with toxicity, actually exerts essential biological functions. It
has a free radical structure, is short-lived, and is an eager electron
contributor. Aside from its activity as a neurotransmitter and as an
antihypertensive agent, nitric oxide appears to be an essential component of
the mechanisms by which macrophages become activated to destroy tumor cells,
bacteria and viruses. Macrophages, scavenger components of the immune network,
become activated by creating minuscule amounts of nitric oxide using arginine as a substrate and the enzyme nitric oxide synthase. Without nitrid oxide,
macrophages remain idle. It has also been shown that nitric oxide is directly
toxic to tumor cells.(62)
It may be theorized that ozone with
the mobilization of its own free radical structure could facilitate the
elaboration of nitric oxide in macrophages, thus promoting their scavenging
mission.
In January 1994, the first Phase 1
(human) clinical trial of ozone therapy will be conducted at 5 major University
centers in Italy. It will involve 300 volunteers, will be conducted according
to FDA-approved protocols, and will test the effectiveness of major auto-hemotherapy in AIDS and Hepatitis B. The scientific
community is eagerly awaiting the data generated by this breakthrough study.
Ozone's interactions with biological
systems and its activities in pathogen inactivation are varied, complex, and to
a large extent still largely unknown. The recent discoveries that nitne oxide and carBon monoxide(61)(62) assume crucial functions in regulating
metabolic and physiological health, may give new reasearch
impetus to the investigation of the therapeutic properties of ozone.
Gerard V. Sunnen, M.D, 200 East 33rd St.
#26J New York, NY 10016 212-679-0679
Editor's Comment: The original
article "Ozone in Medicine" (Feb/Mar 1994 TLfD)
was previously published in the Journal o Advancement in Medicine (1988).
References
60. Wells K, Latino J, Gavalchin
J, Poiesz B: Inactivation of Human lmmunodeficiency Virus Type 1 by Ozone in vitro. Blood. Oct. 1, 1991;78(7):1882-1890.
61.
Verma A, Hirsch D, Glatt C,
Ronnett G, Snyder S: Carbon Monoxide: A Putative
Neural Messenger. Science. 15 Jan
1993:259(5093):381-384.
62.
Snyder S. Bredt D: Biological Role of Nitric Oxide. Scientific American. May 1992;266(5):68-77.
63.
Evans E. ed: Viral
Infections of Humans. 1991. 3rd Edition. Plenum Medical
book Company. New York and London.
64.Baggs A: Are Worry-free Transfusions Just a Whiff of Ozone
Away? Can Med Assoc J. 1993:148(7):1156-1160
65.Carpendale M, Griffiss J: Is
There a Role for Medical Ozone in the Treatment of HIV and Associated
Infections? Proceedings, Eleventh Ozone World Congress,
San Francisco, 1993.
Comentaries on Prion Diseases and Ozone
by Gerard V. Sunnen, M.D.
A number of diseases afflicting
humans, animals and plants are, in contemporary times, stimulating great
interest. This is due to the fact that these conditions do not follow
traditional trajectories of infectivity, and that the responsible infective
agents have poorly understood structural configurations and/or mechanisms of
action.
Transmissible Spongiform Encephalopathies (TSEs) occur in humans and animals, and
are characterized by progressive pathological effects upon the nervous system,
invariably resulting in death. As their names suggest, they produce, usually
over long periods of time, neuronal loss and gliosis,
leading to microlacunae in brain tissue, which are
apt to fill, by unknown mechanisms, with amyloid-like
deposits.
Human TSEs include Creuzfeldt-Jacob disease (CJD), Familial fatal insomnia
(FFI), Kuru, and Gerstmann-Straussler-Scheinker
disease (GSS).
Animal TSEs include Scrapie in sheep, Feline spongiform encephalopathy (FSE),
Chronic wasting disease in deer and ungulates, and of
most concern in current times, Bovine spongiform encephalopathy (BSE). This
concern is derived from evidence of transmission of TSEs from animals to
humans.
These diseases were suspected of
having viral origins, until the 1960's when T Alper
suggested that the scrapie agent might have the
capacity of replicating without the presence of nucleic acid. In 1982, S Prusiner coined the word prion,
to stand for a new class of infective agents with highly novel characteristics.
Prions are not conventional viruses. Nucleic acid is apparently
not necessary for their infectivity. In addition, they appear to interact with
host genes, cell proteins, and cellular strucures in
very complex and yet unchartered fashion.
Properties which further
differentiate prions from viruses include their
resistance to radiation, to heat inactivation, to DNAse
and RNAse treatment, and to such protein-denaturing
chemicals as phenols. These characteristics point to a protein structure in prions. Some prions have been
shown to consist of glycoproteins with amino acid
sequences approximating 250 units. There is no evidence at this time that prions contain lipid components.
It appears, interestingly, that,
aside from the precise sequencing of amino acids within their structure, the
spatial configuration of prions may play an important
role in their pathogenecity, especially as it relates
to the disruption of neuronal membranes. There is evidence that this is true in
the case of scrapie prions
which contain two highly hydrophobic regions capable of spanning such
membranes. Presumably, an alteration in the molecular architecture of the prion could impair this capacity for membrane attachement, and thus compromise its destructive potential.
Prions, by all current evidence, are very precisely structured
molecules, whose specific stereotaxis needs to be
quintessentially intact for the expression of their infectivity.
Ozone has not yet been studied for
the inactivation of prions or viroids
(such as HDV). While the agents cited above such as heat, radiation, enzymes,
and cleaving chemicals, have proven to be unsuccessful in inactivating prions, ozone has properties which are sufficiently
distinct from these agents to embody a unique potential in offering novel
mechanisms of prion destruction. Specifically, ozone
has the proven ability to offer intense oxidizing action, which may provide a
means of altering the prion's precisely tuned
chemical and spatial design through:
1.
A
demonstrated capacity to react with C-C bonds of organic origin, resulting in:
2.
The
selective breakage of multiple bond linkages, thus permanently altering the
crucially needed proper sequencing of amino acid units, thus inducing a
probable alteration in their proper attachment and alignment to each other, and
to associated components such as carbohydrate-and possibly lipids-and,
3.
The
metamorphosis of the spatial configuration of the prion
in its globality, which, experimental data shows,
could have major implications in the mechanisms of its reproductive strategy,
It is theoretically plausible that in compact molecular structures such as prions, whose amino acid sequences have been so precisely
elaborated over long periods of time, that even miniscule alterations in their
composition and/or configuration could insure their deactivation.
4.
Ozone's
ability, when applied to fluids, to react with components of these fluids in
the entirety of their volume and space, almost instantaneously. Ozone, as a
gas, follows the laws of gas to liquid dynamics, as is thus distinctly and
intrinsically different from all other inactivating agents.
From: Cann A J 1997 Principles of
Molecular Virology. Academic Press, San Diego
The illustration shows two different
spatial configurations of the same prion structure.
The one on the right is infectious and pathogenic, while the other is not. The
factors which promote prions to metamorphose their
spatial architecture are unknown.
In conclusion, ozone offers unique
capabilities to potentially destroy prions. Ozone,
while altering these small infective protein molecules, is theoretically
capable of exerting its contrapathogenic role, while
leaving much larger and versatile protein and lipid molecules found in
mammalian serum functionally intact.
BIBLIOGRAPHY
Cann A J 1997 Principles of Molecular
Virology. Academic
Press, San Diego
Diener T 0 1987. The Viroids.
Plenum Press, New York
Eigen M 1996. Prionics or the kinetic basis of prion diseases. Biophysiological Chemistry Dec 10;63(1):1-18
Fleminger S et al Prion
diseases 1997. British
Journal of Psychiatry 170:103-105
Harrison P M 1997. The prion
folding problem. Current Opinion in Structural
Biology. Feb 7(1):53-59
Horwick A L et al 1997. Deadly
conformations-protein misfolding in prion diseases. Cell. May
16;89(4):449-510
McCardle L 1997. Human prion
diseases. British Journal of Biomedical Science 54(1):2-4
Prusiner S B 1995. The prion
diseases. Scientific American 272:48-57
Razumovskii S D, Zaikov G E 1984. Ozone and its reactions with organic compounds. Elsevier,
Amsterdam
Taylor D 1996. Inactivation of the causal
agents of Creutzfeldt-Jacob disease and other prion diseases. Brain pathology 6(2):197-198
Will R G et al 1996. A new variant of
Creutzfeldt-Jakob disease in the UK. Lancet 347:921-925
Diabetic Leg Ulcers: A Missing Ingredient
in Their Treatment and Management
by Gerard V. Sunnen, M.D.
March 2007
Introduction
Diabetes is a disorder of metabolism
and of the circulation. Chronic metabolic irregularities linked to poor
circulatory perfusion and nerve damage can affect a number of organ systems,
including skin tissues. In this article, the focus is on factors in diabetes
that can contribute to dermal breakdown, ulceration, and infection. Most
importantly, it proposes a treatment modality, which, backed by solid
experimental, and clinical data cumulated worldwide, shows great promise in the
management of diabetes-related skin lesions.
The conditions surveyed include
infected wounds, skin ulcers and gangrene. These wounds, in the context of
diabetes, are notoriously difficult to resolve. Healing resistance is thus a
well-recognized element of frustration in their clinical care.
In most of the above conditions,
multiple factors play into healing resistance. Among them are circulatory
impairments, neurological deficits, tissue injury, and immunological
compromise. A central factor is the proliferation of infectious microorganisms
that, by the variety of their families, their toxin-producing capacities, and
their resistance to antibiotics, offer daunting obstacles to standard treatment
regimens.
Approximately 15% of the estimated
20 million Americans afflicted with diabetes mellitus develop lower leg skin
ulcers. Of those patients, 20% will eventually require amputations. Diabetes
mellitus is the leading cause of nontraumatic lower
extremity amputation in the United States (LeRoith
2003).
Factors
contributing to skin lesions in diabetes:
Arteries and arterioles in chronic
diabetes are prone to plaque buildup (Tesfaye 2005).
The precise reason for this phenomenon is still elusive, yet it is well
documented that Type II non-insulin dependent diabetes is linked to abnormal
blood lipid profiles known as diabetic dyslipidemia
(Goldberg 2004). Low-density lipoproteins particles are smaller in size and
thus more apt to adhere to vessel walls, resulting in progressive vascular
occlusion (Beckman 2002; Renard 2004). Lowered oxygen
and nutrient supplies stress tissue resilience and impair recovery from injury
(Chapnick 1996).
Poorly controlled diabetes is
correlated with peripheral nerve dysfunction. The mechanisms of diabetic injury
to neurons are poorly understood. Higher blood glucose level
seem to promote oxidative stress in neurons, but much more complex
mechanisms are implicated (Tomlinson 2002).
Diabetic neuropathy can involve
motor, sensory, and autonomic system neurons. Sensory neuron malfunction is
translated as loss of feeling, reflex loss, problems with limb position sense,
tingling (paresthesias) and pain. Motor impairment shows
as muscle weakness. Autonomic neuropathy alters local circulation (Boulton 2004, Bensal 2006).
Chronic and repeating pressure on
the skin compresses dermal arterioles, inhibiting tissue perfusion. Tissue
weakness leads to ulceration. Ulcers are fertile ground for pathogenic
microorganisms, and surrounding tissues become prone to cellulitis.
At times, the ulcer crater reaches the underlying bone, initiating osteomyelitis (Boulton 2000).
The oxygen atom exists in nature in
several forms: (1) As a free atomic particle, singlet
oxygen (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 (03 g 3/2 02 + 143 KJ/mole).
It has a bond angle of 127� � 3�, resonates among several hybrid forms, is
distinctly blue as a gas, and dark blue as a solid. (4) 04, a very unstable, rare,
nonmagnetic pale blue gas readily breaks down into two molecules of oxygen.
Ozone, as a triatomic
configuration of oxygen, possesses supreme oxidizing power derived from its
marked tropism for extracting electrons from other molecules, simultaneously
releasing one of its own oxygen atoms in the process.
Ozone's capacity for inactivating
microorganisms has been increasingly appreciated since the turn of the last
century (Viebahn 1999). In the past few decades,
ozone's action against bacteria, viruses and fungi has sparked keen interest
for its use, not only for purifying water supplies, but also for medical
objectives.
Ozone/oxygen mixtures exert
significant antimicrobial activity. As with many medications, however, ozone
has a range of action that, in the terminology of pharmacokinetics, is referred
to as a therapeutic window (Bocci 2005). Indeed,
ozone applied in concentrations that are too low, has little therapeutic
effect. Applied externally in high concentrations, ozone may become irritating
and tissue-toxic.
Due to ozone's demarcated
therapeutic range, ozone concentrations administered to the patient need to be
carefully calibrated and controlled. Optimally therapeutic ozone/oxygen
mixtures require state of the art quantitative (dosage, concentration), as well
as qualitative (purity) controls currently available in contemporary ozone
generation technologies, all predicated upon the evaluation of the lesions
under treatment.
Ozone
generation and administration
Ozone is a gas with a half-life of
approximately one hour at room temperature. Medical ozone generation and
delivery systems therefore require that ozone be created at the moment it is to
be administered. Ozone, in this sense is not a drug that has a shelf life
enabling it to be kept for long periods of time.
Ozone is created by applying energy
to oxygen. The oxygen source should be pure and devoid of nitrogen or other
impurities. The presence of too much nitrogen favors the production of
tissue-toxic nitrogen oxides.
Importantly, the humidity level of
the ozone/oxygen mixture enters into the treatment protocol. Indeed, in certain
wounds, humidity added to the ozone/oxygen mixture, markedly enhances
therapeutic results.
Ozone's
actions on wound pathogens
Bacteria fare poorly when exposed to
ozone, a fact appreciated since the 19th century (Viebahn
1999). Ozone is a strong germicide needing only micrograms per liter for
measurable action. At a concentration of 1 mg per liter of water at 1�C, ozone
rapidly inactivates coliform bacteria, staphylococcus
aureus, and Aeromonas hydrophilia (Lohr 1984). The
inactivation rate for E. coli, takes place in relatively small concentrations
of ozone, and is influenced by pH and temperature (Ivanova
1983).
At dosage concentrations used in
external therapy, ozone essentially inactivates all bacterial species. This
holds true for oxygen-dependent aerobic organisms, for oxygen-independent
anaerobic bacteria associated with gangrene, and for facultative species that
can function with or without oxygen. Spores and cysts are neutralized as well (Ishizaki 1986, Langlais 1986).
Spores of Bacillus cereus and Bacillus megaterium are
susceptible to ozone exposure (Broadwater 1973). Ozone's universal
antibacterial action makes it an agent of choice in the management of wound
infections colonized by bacterial species belonging to diverse groups.
An incomplete list of bacterial
families susceptible to ozone inactivation includes the Enterobacteriaceae,
a large group whose natural habitat is the intestinal tract of mammals. These
Gram-negative organisms include Escherichia coli, Salmonella, Enterobacter, Shigella, Klebsiella, Serratia, and
Proteus. Other ozone-sensitive bacterial species include Streptococci,
Staphylococci, Legionella, Pseudomonas, Yersinia, Campylobacteri, and Mycobacteria (Dyas 1983,
Broadwater 1973).
The cell envelopes of bacteria are
composed of intricate multilayers. Covering the
bacterial cytoplasm to form the innermost layer of the envelope is the cytoplasmic membrane, made of phospholipids and proteins.
Next, a polymeric layer built with giant peptidoglycan
molecules provides bacteria with a stable architecture. In Gram-positive
organisms, the pepticoglycan shell is thick and
rigid. By contrast, Gram-negative bacteria possess a thin pepticoglycan
lamella on which is superimposed an outer membrane made of lipoproteins and lipopolysaccharides. In acid-fast bacteria, such as
Mycobacterium, up to one half of the capsule is formed of complex lipids
(Parish 2005, Hogg 2005).
The most cited explanation for
ozone's bactericidal effects centers on disruption of cell membrane integrity
through oxidation of its phospholipids and lipoproteins. There is evidence for
interaction with proteins as well (Mudd 1969). In one
study exploring the effect of ozone on E. coli, evidence was found for ozone's
penetration through the cell membrane, breaking the closed circular plasmid
DNA, which would presumably diminish the efficiency of bacterial procreation (Ishizaki 1987).
Fungi are frequent inhabitants of
chronically infected wounds. One study (Moussa 1999)
found colonization by Candida and Aspergillus. Fungal
organisms neutralized by ozone exposure include Candida, Aspergillus,
Histoplasma, Actinomycoses,
and Cryptococcus. The multilayered cell walls of fungi, composed of
carbohydrates, proteins and glycoproteins, contain
many disulfide bonds sensitive to ozone oxidation.
Protozoan organisms are often found
in chronically infected wounds. Species disrupted by ozone include Giardia, Cryptosporidium, and free-living amoebas,
including Acanthamoeba, Hartmonella,
and Negleria. Several authors have demonstrated
ozone�s capacity to penetrate through the walls of Giardia
cysts causing fatal structural damage (Widmer 2002, Wickramanayake 1984).
Ozone's cutaneous physiological effects
Oxygen has long been established as
beneficial in many pathological conditions, forming the basis for the use of
hyperbaric oxygen treatment for carbon monoxide poisoning, decompression
sickness, gas gangrene and stroke, among others. Oxygen under pressure, applied
to infected tissues, inhibits the proliferation of anaerobic bacteria and
stimulates local circulation (Wunderlich 2000).
Ozone, when added to oxygen,
however, has properties that clearly transcend oxygen administration alone. The
two properties invoked are:
1.
Ozone's
extremely broad range of antipathogenic action and,
2.
The
vasodilation of arterioles promoting tissue
oxygenation and the delivery of nutrients and immunological factors to
compromised tissues; and the vasodilation of veins,
increasing venous outflow and the removal of toxins.
Diabetic skin
conditions benefited by ozone therapy:
Wounds with a
potential for infection
This category addresses wounds that
are not yet infected but have a high probability for eventual infection.
Post-surgical wounds, injuries such as abrasions, contusions and lacerations
are salient examples.
The use of topical ozone therapy in
these cases may be solely preventive, aimed at inhibiting the proliferation of
potentially infective organisms. Preventative topical ozone therapy may thus
stave off the development of potentially disastrous infectious complications.
Poorly healing
wounds
Wounds healing in an indolent manner
are apt to regress if treatment continuity is interrupted.
In these wounds, anaerobic bacteria
- bacteria that do not need oxygen for their growth (e.g., Bacteroides,
Clostridium) - may be active at deeper levels of the dermis, insulated from the
influence of oxygen. While anaerobic bacteria are responsible for many
devastating infections including gas gangrene, aerobic bacteria normally found
on skin surfaces such as Staphylococcus epidermis, Corynebacteria,
and Propionobacteria, given propitious circumstances,
are capable of remarkable aggressive infectivity.
Diabetic ulceration is accelerated
by poor circulation and neuropathy. One study (Anandi
2004) reported bacterial culture results for 107 patients with diabetic foot
lesions. They included E. coli, Klebsiella,
Pseudomonas, Proteus, Enterobacter, Clostridium perfringens, Bacteroides, Prevotella, and Peptostreptococcus.
The treatment of diabetic ulcers
requires a multidisciplinary approach, including surgical, topical, and
systemic interventions when indicated (Cavanagh 2005,
Kruse 2006). Topical antibiotics often fail to penetrate far enough into the
wound and frequently cause secondary dermatitis and allergy in their own right
(De Groot 1994). For this reason, they are not
generally recommended. Systemic antibiotics, prescribed for infections
transgressing ulcer borders, can only address a portion of the spectrum of
microorganisms cultured from such wounds. Bacterial resistance is common (e.g.,
�-lactam antibiotic resistance, as in methicillin-resistant staphylococcus).
Ozone applications in diabetic ulcers
provide essential dual functions of topical broad-spectrum coverage and
circulatory stimulation. In addition, ozone, via multiple serial applications
and higher dose ranges, is able to further its penetration into deeper tissue
layers where anaerobic bacteria are apt to reside.
Gas gangrene, also known as
necrotizing fascitis, myositis,
and myonecrosis is feared because of its rapid
evolution leading to the galloping breakdown of affected tissues (Chapnick 1996, Falanga 2002)).
Several bacterial species are
implicated in this process, the most common being Clostridium and
toxin-producing Group A Streptococcus families. Other
bacterial species implicated in gas gangrene include E. coli, Proteus,
Staphylococcus, Vibrio, Bacteriodes,
and Fusiforms (Caballero 1998). Gas gangrene may
become a fatal complication of diabetic and decubitus
ulcers.
Anaerobic and facultative bacteria
feed on sugars and glycogen, produce lactic acid, and gases such as methane,
carbon dioxide, and hydrogen. Their life threatening toxins cause severe tissue
breakdown, hemolysis, renal failure, and shock.
These impressively destructive
wounds demand emergency ozone application as an important adjunct to their
multidisciplinary interventions.
The practice
of external ozone therapy in diabetic skin lesions
In every case, an individual
assessment has to be made relative to the skin lesion under treatment. Noted in
this evaluation are the size (diameter and depth) of the lesion, and in deeper
lesions, the involvement of dermal tissues, ligaments, muscle and bone. Also, the presence of purulence and necrosis, the relative health
of surrounding tissues, and adjacent circulatory competence.
Ozone therapy is always
individualized to incorporate these clinical observations. Accordingly, ozone
concentrations are adjusted, as are lengths and frequencies of treatment, all
recalibrated as treatment progresses.
In the practice of external ozone
application, a specially designed ozone-resistant envelope is used to enclose
the area being treated. A precise fitting of the envelope is needed in order to
ensure a constant ozone/oxygen concentration within the envelope milieu and a
proper containment of the gas. Ozone will thus be prevented from escaping into
the ambient environment, reducing respiratory exposure to treating personnel.
The ozone concentrations prescribed
during the course of treatment, the duration and frequency of individual
sessions, and the lengths of the overall course of therapy are all predicated
upon the evolution of the specific medical condition under treatment. In
extensive wet ulcers and burns, for example, initial topical ozone
concentrations need to be low in order to prevent excessive systemic ozone
absorption. With gradual epitheliazation of the ulcer
wound, applied ozone concentrations will require corresponding adjustments.
Advantages of
topical ozone therapy in diabetes
1.
The
ease of administration of this therapy. Once the principles of ozone dynamics
and the art of adapting ozone dosages and treatment protocols are mastered by
the clinician, topical oxygen/ozone therapy can safely be applied to a broad
range of diabetes-related afflictions.
2.
Ozone
is an effective antagonist to an enormous range of pathogenic organisms. In
this regard, ozone cannot be equaled. It inactivates aerobic, facultative, and
anaerobic bacterial organisms, a wide spectrum of
viruses, and a comprehensive range of fungal and protozoan pathogens. To
replicate this therapeutic action, ulcerative conditions would have to be
treated with an assortment of various systemic antibiotic agents. In the
context of accepted contemporary medical practice, this is not feasible.
3.
External
ozone therapy, applied in a timely fashion, may obviate the need for systemic antipathogen therapy, thus saving the patient from all the
side effects and organ stresses this option entails. External ozone is both a
preventive, acute care, and chronic care therapeutic agent.
4.
External
ozone application to superficial tissues whose blood supply is reduced enhances
tissue blood and oxygen perfusion.
5.
There
is evidence that ozone, via its oxidizing properties, inactivates bacterial
toxins. Toxins, whose function is to destroy tissues, provide bacteria with
colonizing advantage.
6.
Ozone
exerts its anti pan-pathogenic actions through entirely different mechanisms
than conventional antibiotic agents. The latter must be constantly upgraded to
surmount pathogen resistance and mutational change. Ozone, on the other hand,
presents a direct and powerful oxidative challenge that any and all pathogens
are incapable of circumventing.
7.
Externally
applied ozone/oxygen mixtures are entirely compatible with systemically
administered antibiotics, as they are with debridement and other local wound
care procedures.
Disadvantages
of topical ozone therapy in diabetes
1.
Ozone/oxygen
mixtures are not transportable and need to be created at the site and time of
administration.
2.
Ozone/oxygen
mixtures need to be administered serially in diabetic wounds. This may
translate, in many circumstances, to daily applications until the lesion
resolves.
3.
Ozone/oxygen
mixtures, applied externally, have limited penetrability. While they possess panpathogenic power on ulcer surfaces, their therapeutic
action has limited range at greater depths of ulcer boundaries.
Topical ozone/oxygen therapy has
shown effectiveness and safety in healing diabetic skin afflictions. In this
article, the following are cited: Wounds with potential for infection, infected
wounds, poorly healing wounds, diabetic leg ulcers, decubitus
ulcers and gangrene.
Ozone possesses unique physico-chemical attributes enabling it to exert potent antipathogenic activity. Applied to the adjunctive
treatment and management of diabetic leg lesions, ozone can tip the balance
from chronic failure to resolution. There is one crucial element missing from
contemporary therapeutic regimens for diabetic skin lesions: Ozone
Suggested
Reading and References
by Gerard V. Sunnen, M.D.
February
2001
Hepatitis C (HCV) is a global disease with an expanding
incidence and prevalence base. Of massive public health importance, hepatitis C
presents supremely challenging problems in view of its adaptability and its
pathogenic capacity. The unique strategies that HCV utilizes to parasitize its
host make it a formidable enemy and therapeutic interventions need considerable
honing to counter its progress. Ozone, because of its special biological
properties, has theoretical and practical attributes to make it a potent HCV inactivator.
History of the virus A form of hepatitis became recognized
in the 1970's that resembled hepatitis B, serum hepatitis, and to a lesser
extent hepatitis A, infectious hepatitis. It had, however, novel features,
amongst them, a distinctive serological profile. In 1989, the genome of
hepatitis C (HCV) was deciphered.
It is possible, by means of extrapolation from the genetic evolution of a
virus, to approximate its age. Sequence genetic analysis points to the
diversification of different HCV genotypes 200 to 400 years ago. Ancestors to
these genotypes probably date back 100,000 or so years when viruses co-evolved
with modern humans. Further analysis of genetic viral trees and Old and New
World primates take the primordial forms of these viruses to primate speciation
periods some 35 million years ago.
Today, in the context of human population growth, migration, and global travel,
the hepatitis C virus has expanded its territories, geographically, and
demographically. There is every indication that the evolution of this virus, in
all its forms, is currently manifesting an accelerated phase.
Virion architecture and molecular biology The HCV
particle is composed of a nucleocapsid containing its
genome, an RNA single strand composed of approximately 9600 nucleotides, and
its protein coating. The nucleocapsid is surrounded
by an envelope which allows attachment and penetration into host cells. The
genome encodes structural proteins designated as core (C), envelope 1 (E1),
envelope 2 (E2), and P7 (unknown function), providing for virion
architecture, and nonstructural proteins, mainly enzymes essential to the virion's life cycle, designated as NS2, NS3, NS4A, NS4B,
NS5A, and NS5B. Proteases release structural and nonstructural proteins. Helicases unwind viral nucleic acid. Polymerases replicate
RNA. Within this genome is located a hypervariable
region implying an area of intensive genetic fluidity and mutational potential.
HCV displays great genotypic flexibility which makes for sophisticated
evasiveness to host defenses.
The nucleocapsid is surrounded by an envelope, a
lipid bilayer associated with a union of
carbohydrates and proteins, glycoproteins. Up to 60%
of the lipid component of the envelope is phospholipid
and the remainder is mostly cholesterol. It possesses projections called peplomers which facilitate attachment to host cells. One
protein on peplomers of the HCV particle which is
thought to be instrumental in the attachment process is designated CD-81.
The sequence of nucleotides within the HCV genome shows significant variations.
Strains obtained from different parts of the world, for example, may differ
substantially in their structural and nonstructural protein compositions. This
has lead to a system of classification of the HCV family into 6 genotypes (1 to
6), and approximately 100 subtypes (designated a, b, c, ect.). Genotypes vary from each other by a factor of
30% over the entire genome. Subtypes vary by about 20%. Genotypes 1 to 3 have
global distribution, while genotype 4 and 5 are found mainly in Africa, and 6
is distributed in Asia. Importantly, genotype and subtype differences have
shown varying susceptibility to antiviral therapy.
Within any one afflicted individual, HCV particles do not show a homogeneous
population. Instead, they function as a pool of genetically variant strains
known as quasispecies. This is due to the high
replication error inherent in the function of the polymerase enzymes. Herein lies one of the important armaments of HCV. Continuously
generated genetic diversity gives it great advantage in negotiating and
conquering immune defense and therapeutic strategies. Furthermore, the
antigenic differences between genotypes may have implications regarding the
proper evaluation and the therapeutic regimen of patients.
Viral life cycle A freely circulating virion enters a host cell by binding to a cell surface
receptor. In the case of HCV the host cell is a hepatocyte.
However, bone marrow, kidney cells, macrophages, lymphocytes, and granulocytes
may also be trespassed.
Once cell entry is achieved, the virion sheds its
envelope to commence its replication. It binds to cellular ribosomes
and released viral polymerase begins the RNA replication cycle. Newly formed nucleocapsids continue their assembly with the acquisition
of new envelopes by means of budding through membranes of the cell's endoplamic reticulum. Newly formed virions
may number in the range of 10 billion daily. The average life span of virions is in the order of a few hours.
Virions are then released into the general blood and
lymphatic circulation, ready to infect new cells, re-infect already diseased
cells, or a new host, mainly through bodily fluid transmission pathways. HCV
RNA, as measured by polymerase chain reaction (PCR) may show 10 million or more
virions per ml. As little as 0.0001 ml of blood may
be sufficient to impart infection. The evolution of hepatitis C is
characterized by phases of accentuated viremia
punctuated by periods of relative quiescence. The presence and timely detection
of these viremic waves may offer novel therapeutic
considerations.
Clinical and laboratory manifestations Hepatitis, from anyone of the several
viruses capable of inducing liver inflammation, produce a spectrum of clinical
and laboratory manifestations. Hepatitis C distinguishes itself by the low
incidence of acute phases and by the high incidence of progression to chronicity. Acute hepatitis C progresses from exposure, to
incubation, to pre-icteric, icteric,
and convalescent phases. With an incubation period of about 6 weeks, the first
and sometimes only symptoms include weakness, fatigue, indolence, headache,
nausea, poor appetite, and vague abdominal pain. The pre-icteric
period extends from the onset of symptoms to the appearance of jaundice,
ranging usually from 2 to 12 days. The icteric phase
corresponds to the declaration of jaundice and darkened urine. The convalescent
phase is marked by the gradual disappearance of symptoms.
Chronic hepatitis C is characterized by the presence of HCV RNA and the
elevation of liver enzymes for 6 months or longer. Patients may be asymptomatic,
or at times suffer an acute exacerbation with a return of symptoms.
Approximately 75% of acutely ill patients continue into a chronic phase
evidenced by parameters of viral presence.
Hepatitis C can only be distinguished from other viral hepatic conditions by
serological and virological determinations. Liver
enzymes characteristically affected by HCV infection include serum alanine transfesferase (ALT), aspartate aminotransferase (AST),
gamma- glutamyl transpeptidase
(GGTP), and alkaline phosphatase; in addition, there
may be abnormalities in bilirubin, serum albumin, prothrombin time, and platelet density.
Cirrhosis, a diffuse disruption of liver tissue architecture with regenerative
nodules surrounded by fibrosis, is an important sequel to hepatitis C. Within
20 years post HCV infection 20 to 25% of patients will develop cirrhosis.
Hepatic decompensation ensues with ascites as the salient marker.
Hepatocellular carcinoma, another notable outcome of
HCV infection is present in approximately 5% of patients post infection. The
presence of cirrhosis is central to its genesis. Although the mechanisms by
which cirrhosis ushers carcinoma are unknown, it is likely that chronic
inflammation and the sustained pressure of cellular regeneration play important
roles.
Up to 10% of patients appear to have fully conquered the disease. HCV
antibodies are undetectable, as is HCV RNA. Liver enzymes are fully normalized,
but liver biopsy may show lingering areas of stagnant inflammation and spotty
necrosis. It is thus possible for host immunocompetence
to vanquish HCV infection and therapeutic strategies aim to assist the host
immune system to achieve this goal.
Immunological response to the virus HCV particles are detected early in the
infection, usually 1 to 2 weeks following exposure. Antibodies to HCV core,
nonstructural, and envelope elements appear about 6 weeks after exposure. A
broad range of cytokines are mobilized. Cellular immunity is activated with
broad recruitment of neutrophils, natural killer
(NK), macrophages, and CD4 and CD8 T helper cells.
Current and experimental treatment strategies As of
this date the main treatment strategies for hepatitis C include interferon and ribavirin. Interferons are
natural cellular products which activate macrophages, neutrophils
and natural killer cells. There is controversy as to interferon's biological
effects, be they mostly immunoregulatory or directly
antiviral. Ribavirin is a guanosine
analog that represses messenger RNA formation thus inhibiting the replication
of many DNA and RNA viruses. It is, however, mutagenic to mammalian cells. Ribavirin and interferon have significant medical and
psychiatric side effects.
Treatment response is defined as undetectable viral load 6 months following
therapy. Contemporary detection methods of quantitative HCV RNA determinations
are capable of detecting approximately 1000 viral copies per serum ml.
Resistance to antiviral therapies is a particularly vexing problem in anti HCV
treatment. Novel and experimental antiviral compounds include inhibitors of
protease, polymerase and helicase.
Vaccine development needs to take into account HCV's antigenic rainbow and its
high mutability. High mutation rates in this condition
implies a dauntingly diverse and variable array of viral antigenic
components. It is estimated, for example, that HCV mutates significantly in its
own host approximately a thousand times a year. This implies that within any
one afflicted individual there exists an awesomely large array of viral quasispecies, which in turn creates commensurate
difficulties in the creation of effective vaccines.
Ozone: Physical and physiological properties Ozone (O3) is a naturally
occurring configuration of three oxygen atoms. With a molecular weight of 48,
the ozone molecule contains a large excess of energy. It has a bond angle of
127� and resonates among several forms. At room temperature, ozone has a half
life of about one hour, reverting to oxygen. A powerful oxidant, ozone has
unique biological properties which are being investigated for applications in
various medical fields. Basic research on ozone's biological dynamics have
centered upon its effects on blood cellular elements (erythrocytes, leucocytes,
and platelets), and to its serum components (proteins, lipoproteins, lipids,
carbohydrates, electrolytes). Administrating increaing
dosages of ozone to whole blood shows that beyond a certain threshold there is
a rise in the rate of hemolysis. This threshold,
depending upon various parameters, begins to be reached at 40 to 60 micrograms
per milliliter, and becomes significant when higher levels are attained.
Precise ozone dosing capacity is therefore essential in clinical practice and
research.
Leucocytes show good resistance to ozone because they have enzymes which
protect them from oxidative stress. These enzymes include superoxide dismutase,
glutathione, and catalase. Research has shown that
platelets also maintain their integrity after ozone administration. In ozone
therapy, the doses applied to blood are gauged to avoid disruption of its
cellular elements. Serum components remain viable during ozone therapy. Lipid
and protein peroxides, produced in small amounts by ozonation,
have demonstrable antiviral properties. Interestingly, ozone tends to stimulate
leucocyte function and cytokine production. Ozone
increases the oxygen saturation (p02) in erythrocytes and enhances their
pliability so that capillary circulation is facilitated.
Ozone: Antiviral properties Recently, there has surged
renewed interest in the potential of ozone for viral inactivation. It has long
been established that ozone neutralizes bacteria, viruses, and fungi in aqueous
media. This has prompted the creation of water purification processing plants
in many major municipalities worldwide.
Ozone's antiviral properties may also be applied to the treatment of biological
fluids, albeit in technologically and physiologically appropriate ways. Indeed,
it is noted that ozone, administered in such dosages designed to respect the
integrity of blood's cellular and constituent elements, is capable of
inactivating a spectrum of viral families.
Some viruses are much more susceptible to ozone's action than others. It has
been found that lipid-enveloped viruses are the most sensitive. This group
includes, amongst others, HCV, Herpes 1 and 2, Cytomegalus,
HIV1 and 2.
The envelopes of viruses provide for intricate cell attachment, penetration,
and cell exit strategies. Peplomers, finely tuned to adjust to changing receptors on a variety
of host cells, constantly elaborate new glycoproteins
under the direction of E1 and E2 portions of the HCV genome. Envelopes are
fragile. They can be disrupted by ozone and its by-products.
In HCV, viral load appears to be a major factor in the invasiveness and
virulence of the disease process. Preliminary research has shown that reduction
of viral load in Hepatitis C by means of ozone therapy can significantly
normalize hepatic enzymes and improve measures of global patient health.
Volunteers administered ozone therapy according to the method outlined below
achieved a viral load reduction in the order of 5 log, or 99.9%, along with a
normalization of liver enzyme levels.
Ozone: Clinical methodology Ozone may be utilized for the therapy of a spectrum
of clinical conditions. Routes of administration are varied and include
external and internal (blood interfacing) methods. In the technique of ozone
major autohemotherapy for hepatitis C, an aliquot of
blood is withdrawn from a virally-afflicted patient, anticoagulated,
interfaced with an ozone/oxygen mixture, then
re-infused. This process is repeated serially until viral load reduction is
documented.
The aliquots of blood range from 50 ml. to 300 ml. Ozone dosages and treatment
frequency vary according to treatment protocols. The reason aliquots of blood
are treated and not, as one would propose, the entire blood volume,
is that in the latter case the total ozone dosage administered would exceed
toxic limits.
The average adult has 4 to 6 liters of blood, accounting for about 7% of body
weight. How can the viral load reduction observed via ozone therapy be
explained in the face of a technique that treats relatively small amount of
blood, albeit serially?
Ozone:
Possible mechanisms of anti-viral action
The viral culling effects of ozone in infected blood may
recruit the following mechanisms:
Denaturation of virions
through direct contact with ozone. Ozone, via this mechanism, disrupts viral
envelope proteins, lipoproteins, lipids, and glycoproteins.
The presence of numerous double bonds in these unsaturated molecules makes them
vulnerable to the oxidizing effects of ozone which readily donates its oxygen
atom and accepts electrons in these redox reactions.
Double bonds are thus reconfigured, molecular architecture is disrupted and
widespread breakage of the envelope ensues. Deprived of an envelope, virions cannot sustain nor replicate themselves.
Ozone proper, and the peroxide compounds it creates, may directly alter
structures on the viral envelope which are necessary for attachment to host
cells. Peplomers, the viral glycoproteins
protuberances which connect to host cell receptors are likely sites of ozone
action. Alteration in peplomer integrity impairs
attachment to host cellular membranes foiling viral attachment and penetration.
Introduction of ozone into the serum portion of whole blood induces the
formation of lipid and protein peroxides. While these peroxides are not toxic
to the host in quantities produced by ozone therapy, they nevertheless possess
oxidizing properties of their own which persist in the bloodstream for several
hours. Peroxides created by ozone administration show long-term antiviral
effects which serve to further reduce viral load. This factor may explain in
part the reason for the fact that ozonated blood in
the amount processed in usual treatment protocols is able to reduce viral load
values in the total blood volume.
Immunological effects of ozone have been documented. Cytokines are proteins
manufactured by several different types of cells which regulate the functions of
other cells. Mostly released by leucocytes, they are important in mobilizing
the immune response. It has been found that ozone induces the release of
cytokines which in turn activate a spectrum of immune cells. This is likely to
constitute a significant avenue for the reduction of circulating virions.
Ozone action on viral particles in infected blood yield several possible
outcomes. One outcome is the modification of virions
so that they remain structurally grossly intact yet sufficiently dysfunctional as
to be nonpathogenic. This attenuation of viral particle functionality through
slight modifications of the viral envelope, and possibly the viral genome
itself, modifies pathogenicity and allows the host to
increase the sophistication of its immune response. The creation of
dysfunctional viruses by ozone offers unique therapeutic possibilities. In view
of the fact that so many mutational variants exist in any one afflicted
individual, the creation of an antigenic spectrum of crippled virions could provide for a unique host-specific
stimulation of the immune system, thus designing what may be called a
host-specific autovaccine.
Viruses are far from being static entities. As
quintessential intracellular parasites they have developed, through millions of
years of cohabitation with their hosts, astoundingly sophisticated structures,
survival, and propagation mechanisms. They have adapted, modified their
biological strategies, and evolved impressive genetic diversity and mutational
capacity to cope with the changing ecology of planetary life.
HCV has an extremely high rate of mutation and within any one individual there
may exist millions of antigenic quasispecies. The
disease process is marked by periods of viral quiescence alternating with viremic waves whereby billions of virions
are poured into the blood and lymphatic reservoirs. Their astounding numbers
stress the immune system relentlessly and produce an inexorable compromise in
all parameters of its functioning.
Viral load reduction by means of ozone blood treatment alleviates immune system
fatigue. Ozone-mediated viral culling may be achieved by anyone of a number of
possible mechanisms. Direct virion denaturation, peplomer
alteration, lipid and protein peroxide formation, cytokine induction, host pan-humoral activation, and host-specific autovaccine
creation are suggested mechanisms. Due to the excess energy contained within
the ozone molecule, it is theoretically likely that ozone, unlike antiviral
options available today, will show effectiveness across the entire genotype and
subtype spectrum.
Ozone embodies unique physico-chemical and biological
properties which suggest an important role in the therapy of hepatitis C,
either as a monotherapy, or as an adjunct to standard
treatment regimens.
BIBLIOGRAPHY
Cardile V, et al. Effects of ozone on
some biological activities of cells in vitro. Cell Biology and Toxicology
1995 Feb; 11(1):11-21
A Virology Primer: With Special Reference to Ozone
Revised October 2001
by Gerard V. Sunnen, M.D.
First
published September 22, 1997
Viruses are intracellular parasites.
They require a living host cell in order to replicate and to infect new hosts.
Viruses have been enormously successful in parasitizing most known forms of
living organisms in both the animal and plant world.
1.
Nucleic
acid core. At the core of viruses is genetic material which encodes the
transcription of all viral components, mostly proteins (such as enzymes). This
genetic material is either RNA or DNA, never both. The nucleic acid may be
single or double stranded. Viral nucleic acid has been described as the
software program for making copies of the virus.
2.
The
nucleic acid coat or capsid. Surrounding the core is
a protective coating made of protein, called the capsid.
The capsid is rigid and determines the shape of the
virus. It is made of repeating protein units called capsomeres.
The architecture of capsomere assembly is quite fascinating. A very common
crystal-like configuration is the 20-sided isocahedral
construction, with each capsomere forming an
equilateral triangle.
Another main pattern is helical or
rod shape. The nucleic material and its capsid curls
unto itself like a snake, forming a spherical structure.
A few viruses have capsids that are neither icosahedral
nor helical; these configurations are termed complex, and may be spiral, brick
shaped, or may show other non-standard appearances.
The capsid
and its nucleic acid core together form the nucleocapsid.
3.
The
nucleocapsid is sometimes surrounded a membrane
called an envelope. Enveloped viruses are usually spherical because the
envelope, unlike the capsid, is loose-fitting.
Envelopes are lipid bilayers that contain proteins.
Some proteins incorporate carbohydrates and are thus called glycoproteins.
Glycoproteins usually protrude out of the envelope as
spikes called peplomers. The function of peplomers is to form points of attachments to host cell
receptors for entry into cells.
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FIGURE 1-1 SIZE OF MICROSCOPIC
ENTITIES AND MICROSCOPE RESOLUTION. Viruses are smaller than the smallest
bacteria and larger than macromolecules. They can be seen with the electron
microscope. (Illustration demonstrates relative sizes and is not drawn to
scale.) From: Leland DS 1996 Clinical
Virology, Saunders, New York |
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FIGURE 1-2 ICOSAHEDRAL CAPSID CONFIGURATION IN NAKED AND ENVELOPED VIRUSES. Naked icosahedral viruses appear cubic or crystalline (A, B,
and C). Enveloped icosahedral viruses appear nearly
spherical (D, E, F). (Fig. 1-2C from Ryan KJ (Ed), Sherris Medical Microbiology: An Introduction to
Infectious Diseases, 3rd ed. Norwalk, CT: Appleton & Lange, 1994. Fig.
1-2F From: Murray PR, Kobayashi GS, Pfaller MA, Rosenthal KS. Medical Microbiology, 2nd ed.
St. Louis: Mosby Year Book, 1994, p 573 |
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FIGURE 1-3 HELICAL CAPSID CONFIGURATION IN NAKED AND ENVELOPED VIRUSES. Naked
helical viruses are cylindrical or rod shaped (A, B, and C). Enveloped
helical viruses appear nearly spherical because the nucleocapsid
(capsid and nucleic acid) may curl inside the
envelope (D, E, and F). Fig. 1-3C from: Tortora et
al. Microbiology, 4th ed., Benjamin Cummings, Redwood City CA, 1992, p 336.
Fig. 1-31F From: Ryan KJ (Ed), Sherris Medical Microbiology: An Introduction to
Infectious Diseases, 3rd ed. , Appleton & Lange,
Norwalk CT, 1994. |
The envelope is sometimes connected
to the nucleocapsid by a matrix made of proteins
(matrix proteins).
4.
Viruses
that do not have an envelope are called "naked viruses".
5.
The
term virion describes the mature viral particle
capable of infecting other cells. In non-enveloped viruses, the virion consists of the nucleocapsid
alone. In enveloped viruses, the nucleocapsid and the
envelope make up the virion.
Enveloped viruses are usually
comfortable in bodily fluids and are transmitted by such routes as blood
transfusion, or mucosa to fluid contact, as in sexual contact.
Naked viruses, on the other hand,
are usually transmitted via the intestinal route.
Major
Enveloped Viruses Include the Following Families:
Hepadnaviridae (from
Hep: liver; dna:
DNA)
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Hepatitis B (HBV). |
Retroviridae (from
retro:reverse, to describe
the reverse transciption allowing these viruses to
make DNA from RNA)
|
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HIV-1, Immunodeficiency syndrome |
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HIV-2, Immunodeficiency syndrome |
Herpesviridae (herpes:
to creep, describing creeping vesicular lesions)
|
Herpes simplex, types I and 2 |
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Varicella-zoster: Chicken pox and shingles |
|
Cytomegalovirus (from cyto: cell; megalo: large) |
|
|
Epstein-Barr causes infectious
mononucleosis; implicated in chronic fatigue syndrome |
Filoviridae (filamentous
viruses with hook shapes)
|
Ebola virus (Ebola river, Zaire):
Hemorrhagic fever |
|
Marburg (Marburg, Germany):
Hemorrhagic fever |
Orthomyxoviridae (Ortho: normal; myxo: mucus)
|
Influenza A and B |
Paramyxoviridae (resembles
Orthomyxoviridae)
|
Measles |
|
Mumps |
|
Parainfluenza |
|
|
Respiratory syncytial
virus: Flu-like syndrome |
Coronaviridae (Capsid resembles a crown of
thorns). Syndrome resembles flu.
Togaviridae (Toga: coat)
|
|
Rubella - German measles |
|
|
Eastern and Western equine
encephalitis. Transmitted by mosquitoes. |
Rhabdoviridae (Rhabdos: rod)
|
Rabies |
Bunyaviridae (Bunyamera, Uganda): Encephalitis
Flaviviridae (Flavus:
yellow)
|
Hepatitis C |
Major
Non-Enveloped (Naked) Viruses:
Adenoviridae (from
adenoid tissues)
|
Adenovirus: Respiratory
infections, gastroanteritis, cystitis |
Papovaviridae (from
papilloma, polyoma, vacuolating
|
Polyomavirus, Papillomavirus
(warts) |
Picornaviridae (pico: small)
|
Poliovirus (polios: gray; myelitis: infection of the myelin in the spinal cord) |
|
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Echovirus (from E-enteric, C-cytopathogenic, H-human, 0-orphan): Aseptic meningitis |
|
|
Coxsachie virus: Pharyngitis,
aseptic meningitis, pericarditis, myocarditis |
|
|
Hepatitis A: Infectious hepatitis |
|
|
Rhinovirus (Rhino: nose):
respiratory infection |
Reoviridae (Respiratory,
enteric, orphan)
|
Rotavirus (Rota: Wheel) - Severe
diarrhea in infants and adults |
Caliciviridae (Chalice-like):
Gastroenteritis
Viruses have complex life cycles
which demonstrate their extraordinary symbiosis with their hosts. They lack the
tools for self sufficient growth and thus depend upon more advanced life
systems for their existence.
Viral replication, in broad strokes,
starts with viral attachment to host cells. Enveloped viruses use glycoprotein
molecules on surface peplomers for binding to the
cell membrane. Viral and cell membranes fuse and the viral nucleocapsid penetrates into the cell's cytoplasm. Naked viruses
may be engulfed by the cell membrane in a process called endocytosis.
Once inside the cell, the capsid is reconfigured to
prepare it for replication.
In the replication phase, viral
nucleic acid has the capacity to direct the host cell to manufacture all
components of the mature virion. These are then
assembled and mass produced. The virions are then
released into the circulation in a process that may or may not involve cell destruction , or lysis.
A wave of viral particle carried
through the blood stream to infect organs throughout the body is called a viremic episode. Many viruses travel free in the plasma.
Others may attach themselves to platelets, lymphocytes or red blood cells.
Recent research has shown that the
number of virions involved in infection is much more
important than previously realized. In both HIV and hepatitis C, several
billion new particles may be produced each day. The amount of viral
concentration present at any one time is called the viral load. The immune
system is placed under constant stress to deactivate these new infective
particles, and to regenerate its own decimated cellular components.
Any reduction in the viral load
offers an advantage to the immune system, and thus enhances the probability for
easing clinical symptoms.
Commentaries
on the Evolution of Viruses
Viruses are far from being static
entities. As quintessential intracellular parasites they have developed,
through millions of years of cohabitation with their hosts, astoundingly
sophisticated structures, survival, and propagation mechanisms. They have
adapted, modified their biological strategies, and incorporated genetic
diversity and mutational capacity to cope with the changing ecology.
In the twentieth century, this
ecology, namely the human reservoir, has changed dramatically. The eruptive
world population and the mobility of the planet's inhabitants are two major
factors responsible for the accelerated evolution of viruses into new frontiers
of pathogenicity.
Most of the families of viruses
mentioned above have produced new strains. Of great concern is the
diversification of retroviruses and of Hepatitis B and C. Since 1985, for
example, the following viruses are among the many that have been discovered:
Human herpesvirus 6, 7, and 8; Hepatitis C; Hepatitis
E; Morbillivirus, causing encephalitis; Hantaviruses
causing the hantavirus pulmonary syndrome.
Principles of
Viral Inactivation
The inactivation of viral particles
in the test tube is possible by a number of interventions. The enveloped viruses
are usually more sensitive to physico-chemical
challenges than are naked virions. Chemical agents
and other adverse conditions that affect the envelope invariably destroy the
entire virus. These include drying, high temperature, freezing and thawing, pH
below 6 or above 8, lipid solvents, hydrogen peroxide, chloroform, chemicals
containing chlorine, ultraviolet irradiation, phenols, and ozone.
The test tube environment presents
different parameters than, let us say, a biologically active substance e.g.., a
serum, or a vaccine. In this case the virions in
solution need to be destroyed while the components of the biological solution
need to be preserved.
Ozone is an exemplary agent capable
of deactivating a wide range of viruses while significantly sparing the
biological integrity of their medium. There is, as concerns ozone, a
therapeutic range of administration. Like many other drugs, ozone may be said
to have a therapeutic window which defines its optimal levels of
administration. Below the window, concentrations of administered ozone are
poorly effective; within the window they function optimally; and above the
window, deleterious effects take place.
Ozone offer distinct advantages over
other antiviral agents. It is above all, a gas. When a gas is administered to a
liquid, an immediate dispersion of the gas occurs, thus effecting reactions in
the entire fluid volume. This may be contrasted to any fluid additive, such as
hydrogen peroxide or detergents which mix with the fluid being treated much
more slowly due to the physics of fluid-fluid dynamics. Furthermore, at the
interface of the fluids, the concentrations of the chemicals are inordinately
high and potentially toxic. As concerns the viability of cellular elements such
as red and white blood cells, the oxidizing potential of ozone may be
accurately calibrated so that it is fatal to virions,
but innocuous to cells. Cells protect themselves from oxidative injury by means
of protective enzymes (glutathione, superoxide dismutase, catalase), in contrast to virions
which have no protection against oxidation.
The enveloped viruses are more
fragile than the naked viruses. Their envelope, made up of lipids and glycoproteins are especially vulnerable to ozone's capacity
for oxidation (oxidation is defined as the removal of electrons from
compounds). Envelope lipids which are unsaturated, when exposed to ozone,
become saturated, are cleaved at their double bond sites, and break apart. The
envelope thus becomes torn and the viral capsid, by
itself, cannot survive.
Although ozone's effects
upon unsaturated lipids is one of its best documented biochemical
actions, ozone is known to interact with proteins, carbohydrates, and nucleic
acids. This becomes especially interesting when ozone inactivation of
non-enveloped virions is considered.
The protective layer surrounding the
DNA or RNA of virions (the capsid),
is made up of proteins. Circulating freely in the bloodstream, the capsid's protein coat, in the case of naked viruses, is
thus its first and last line of defense. Challenged by ambient ozone or its
peroxides, the protein coating itself becomes denatured and incapable of
sustaining its protective role (The viral nucleic acid material, by itself
cannot survive). Indeed, when ozone comes in contact with capsid
proteins, protein hydroxides and protein hydroperoxides
are formed.
In the viral decontamination of a
serum sample, it is assumed that several viral species may be present. Each
virus has its own tolerance, and intolerance, for ozone challenge. There is an
optimal concentration range, however, within which ozone may be administered to
the serum sample, destroying its viral and bacterial occupants, and at the same
time preserving the great majority of its biological activity (i.e., in the
case of, vaccines, antigen purity; or in passive immunization, the sustenance
of antibody titers).
The task of viral inactivation in
vivo becomes more difficult. In this case we are dealing with a live patient
and the awesomely complex dynamics determining the evolution of a viral
infection. Some general guiding principles nevertheless stand out:
We have seen that viremic episodes represent invasions of virions
into bodily fluids. In the case of acute infections such as Ebola, or more
commonly in the flu syndrome, there may be one viremic
episode, which in the first instance may be fatal, and in the second, may be
hardly noticed by the patient. depending upon host
factors.
In the case of chronic infections
such as hepatitis or HIV, however, viremic episodes
may occur numerous times in periods spanning several years. Viral load may be
high, indicating a shift towards virus victory in relation to immune
surveillance, defense and reserve, or may be low, indicating a quiescence
within the viral life cycle.
Any intervention which will safely
decrease the numbers of virions from the circulation
will proffer an advantage to beleaguered immune function.
Ozone hemotherapy
consists in the regular treatment of aliquots of blood with precise doses of
ozone. The result is a culling action due to the direct action of ozone and the
biologically active compounds it produces on viral particles, which translates
into a progressive diminution in the viral load, and a corresponding
enhancement of immune potency.
Another mechanism of viral inactivation
with ozone is indirect. Subsequent to the treatment of blood with ozone, there
exists in the serum a plethora of fragmented virions
most of which are excreted through the kidneys. Some of these fragments,
however, are processed by the immune system for the elaboration of its own
defenses.
We know that each HIV-afflicted
patient, for example, is infected with a unique subspecies of HIV virion. Both intact virions - and
once destroyed, their fragments - have one of a kind antigenic structures (an
antigen is defined as a substance capable of stimulating the production of
antibodies). The immune system is thus able to manufacture organism-specific
antibodies. The still poorly appreciated uniqueness of ozone therapy in this
regard, is that - assuming the preservation of a minimum of immunocompetence
- it provides the patient with an opportunity to make his own individualized autovaccine to the distinctive type of virus particle
harbored.
Ozone: Clinical Methodology Ozone
may be utilized for the therapy of a spectrum of clinical conditions. Routes of
administration are varied and include external and internal (blood interfacing)
methods. In the technique of ozone major autohemotherapy
for viral diseases, an aliquot of blood is withdrawn from a virally-afflicted
patient, anticoagulated, interfaced with an
ozone/oxygen mixture, then re-infused. This process is
repeated serially until viral load reduction is documented.
Ozone: A Review of Possible
Mechanisms of Anti-viral Action
The viral culling effects of ozone
in infected blood may recruit the following mechanisms:
Conclusion and
Commentaries on Ozone Therapy and Research
In view of these considerations, it
is evident that ozone presents fascinating opportunities for experimental and
clinical research. Of all the antiviral agents known, none appear to offer the
unique features of ozone, including its potent oxidizing power, and its gaseous
nature. Indeed, as a gas, ozone is incomparably able to penetrate fluids with
great ease and rapidity, delivering its biochemical actions almost
instantaneously.
Research is needed to determine the
effective range of ozone administration for the inactivation of each viral
strain within all viral families. While this has been done for some members of
major viral families, e.g., HIV and Hepatitis C, this knowledge applied to
every main viral species will assist greatly in the precise methods for
decontamination of mammalian products (serum, vaccines, etc.), and in the
proper administration of therapeutic ozone in clinical situations. Research is
needed, as well, to elucidate more precisely the mechanisms by which ozone
decreases viral load.
Viral diseases are expanding
worldwide. This is not a science fiction scenario but a regrettable fact. Old
diseases are not only finding increased population reservoirs, but are also
developing novel mechanisms of infectivity. Of special concern are emergent
viruses, products of mutational creativity, never before encountered by humans,
which are potentially devastating to health and life.
Ozone has the unparalleled promise to find a major place in the armamentarium
against these new plagues.
Viral load reduction by means of
ozone blood treatment alleviates immune system fatigue. Due to the excess
energy contained within the ozone molecule, it is theoretically likely that
ozone, unlike antiviral options available today, will show effectiveness across
the entire genotype and subtype spectrum. Ozone embodies unique physico-chemical and biological properties which suggest an
important role in the therapy of a variety of viral conditions,
most likely those mediated by lipid enveloped viruses, either as a monotherapy, or as an adjunct to standard treatment
regimens.
Bibliography
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