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| United States Patent |
5,133,975
|
|
Harley
, et al.
|
July 28, 1992
|
Method for in vivo inactivation of blood borne HIV virus using a mixture
of ozone and oxygen
Abstract
The invention discloses a method for inactivating infectious agents in a
patient's blood in vivo. The method involves adminstering to the patient a
non-toxic, infectious agent inactivating amount of a mixture of oxygen and
ozone. The mixture is preferably administered via rectal insufflation or
via authohemotherapy.
| Inventors:
|
Harley; Richard J. (West Orange, NJ);
Bimbi; Peter (Tucson, AZ);
Greene; Don (Tucson, AZ);
Wainwright; Basil (Tucson, AZ)
|
| Assignee:
|
RJH and Company, Inc. (West Orange, NJ)
|
| Appl. No.:
|
394356 |
| Filed:
|
August 15, 1989 |
| Intern'l Class: |
A61K 033/40 |
| Field of Search: |
424/613
514/885
|
References Cited
U.S. Patent Documents
| 4375812 | Mar., 1983 | Vaseen et al. | 604/290.
|
| 4632980 | Dec., 1986 | Zee et al. | 530/380.
|
| Foreign Patent Documents |
| 3806230 | Sep., 1988 | DE.
| |
Other References
Bolton, D. G. et al. Environmental Res: 27:476-484 (1982).
Washuettl, J. et al. Chem. Abst. 106:60917w (1987) From: Erfahrungsheikunde
35(11): 749-59 (1986).
Rotter, M. et al. Chem. Abst. 83:539w (1975) From: Wein. Klin. Wochenschr.
86(24) 776-14 8 (1974).
|
Primary Examiner: Hollrah; Glennon H.
Assistant Examiner: Hollinden; Gary E.
Attorney, Agent or Firm: Felfe & Lynch
Claims
We claim:
1. Method for inactivating a human immunodeficiency virus (HIV) in blood or
a blood component comprising administering in a therapeutically effective
manner a non-toxic amount of a mixture of oxygen and ozone to a living
human subject with a human immunodeficiency virus infection sufficient to
inactivate said human immunodeficiency virus, wherein said mixture of
oxygen and ozone is administered to the blood of said living subject.
2. Method of claim 1, wherein said human is an adult.
3. Method of claim 1, wherein said human is a child.
4. Method of claim 1, wherein said mixture is administered via rectal
insufflation.
5. Method of claim 1, wherein said mixture is administered via
autohemotherapy.
6. Method of claim 1, comprising administering said mixture at least once a
day.
7. Method of claim 1, wherein said ozone is present in an amount ranging
from about 30 ug to about 45 ug per ml of oxygen.
8. Method of claim 7, wherein said oxygen is present at a volume ranging
from about 250 ml to about 1000 ml.
9. Method of claim 7, wherein said ozone is present in an amount equal to
about 33 ug/ml of oxygen and said oxygen is present in an amount equal to
about 500 ml.
Description
FIELD OF THE INVENTION
This invention relates to methods for in vivo treatment of individuals
suffering from blood borne infections. More particularly, it relates to a
method for inactivating an infectious agent in blood or a blood component
via administration to a subject of a non-toxic, infectious agent
inactivating amount of a mixture of ozone and oxygen.
BACKGROUND AND PRIOR ART
Many diseases well known to the physician or clinician are "blood borne"
diseases, i.e., they are characterized by the presence of the disease
causing agent in blood. The agent is carried by the blood to various
organs and cells, thereby spreading the infection. Among the diseases and
pathological conditions which are characterized by this factor include the
parasite diseases such as malaria, bacterial diseases such as
tuberculosis, and viral diseases including herpes and AIDs. Additionally,
when cancers metastasize, the "seed" cancers are frequently carried by
blood to other organs.
Logically, treatment of these blood borne diseases would involve
administration of an agent which inactivates them. In the case of treating
the infection or disease via treatment of blood, however, this must be
done in a manner which preserves the integrity of the blood itself. This
is extremely difficult to do in practice because infectious agents such as
bacteria, parasites, viruses and so forth usually possess adaptive
structures which make them somewhat resistant to antibody attack or other
immune system responses. These adaptations render the infectious agents
more resilient to therapeutic agents than the blood cells and blood
components themselves. As a result treatment protocols must then contend
with the problem of harming the blood itself. While this is appropriate in
some cases, in most cases it is not. In many diseases, including AIDs, the
patient or subject has become so debilitated by the infection that
additional trauma is to be avoided at all costs.
Ozone ("O.sub.3 ") is well known as an inhibitor of pathogenic organisms.
In vitro experiments have shown that pure ozone inactivates coliform, S.
aureus, and Aeromonas hydrophilia, (Lohr, et al., J. Aquaric Aquat Sci 4:
1-8 (1984); enteroviruses (Ivanova, et al., Vopr. Virusol 6:693-698
(1983); poliovirus 2 and coxsachie (Roy, et al., Appl. Envir Microbiol
41:718-723 (1981); as well as other microorganisms. While a full
understanding of why or how pure O.sub.3 inactivates these microorganisms
is lacking, one theory hypothesizes that peroxidation of membrane
components, such as phospholipids and lipoproteins is involved. See, e.g.,
Mudd, et al. Atmos. Environ 3: 669-682 (1969); Ishizaki, et al., Water Res
21(7): 823-828 (1987). Of course, normal cells also possess lipoproteins
and phospholipids in their cell membranes, and disruption of these would
also be expected. In experiments on mammals, pure O.sub.3 has been shown
to exhibit a variety of effects, both positive and negative. Mice are
extremely sensitive, showing an LD.sub.50 of 22 ppm over a course of 3
hours of inhalation therapy. See Mittler, et al, AMA Arch. Ind. Health 15:
191-197 (1957). Overdoses are marked by pulmonary edema and hemorrhaging,
evidencing weakness of cellular structures. Exposure to ambient ozone
concentration (0.24 ppm) for two hours caused human subjects to show drops
in respiratory capacity, inhibition of certain cell functions, and wide
fluctuations in enzyme activities. Note in this regard Folinsbee, et al.,
Rev. Environ. Health 3:211-240 (1987); Hackney, et al., J. Appl. Physiol.
Respirat. Environ. Exercise Physiol 43: 82-85 (1977); Melton, Aviation,
Space and Environmental Med. 53: 105-111 (1982); Menzel, Toxicol &
Environ. Health 13: 183-204 (1984).
In summary, while O.sub.3 is unquestionably known as a potential
antimicrobial, antiviral, etc., use in its pure form is indicated only in
vitro. Its effects upon subjects including mice and humans indicates the
potential for great harm. One notes, for example, U.S. Pat. No. 4,632,980
to Zee, et al., which discourages the bubbling of O.sub.3 through blood,
due to the potential for hemolysis. This patent teaches the
decontamination of blood using O.sub.3 either alone, with air, or with
inert gases, via contact from 0.5 to 4 hours. The patent teaches purifying
blood for later use in transfusion, e.g., but does not show that the
treated blood has any therapeutic effect on the subject in which it is
injected. No therapeutic efficacy for pure O.sub.3 is described.
There has been some research where mixtures of oxygen and ozone have been
administered to subjects via intravascular injection. See, in this regard
Rokitanshy, Hospitalis 52:643, 711 (1982); Viebahn, OzoNachrichten 4:
18-30 (1985); Washuttl, et al., Erfahr 28: 766 (1979). At the outset, one
notes that intravascular injection of any gas or gas mixture must be done
with extreme care. The risk of a gas bubble reaching the heart is well
known to cause serious injuries and death. The above studies showed that
the injections, not surprisingly, resulted in enhanced activation of
enzymes involved in peroxide and oxygen radical scavenging, with expected
biochemical processes shifting their equilibria to account for the
increased concentrations. No studies were done to determine what effect
the injections had on infectious agents in the blood. Given the effect
pure ozone has on living organisms, as described, and the lack of any
information on the efficacy of mixtures of ozone and oxygen on infections,
it was not to be expected that such a mixture would be useful as an in
vivo agent for the treatment of blood borne infection.
It has now been found, surprisingly, that a mixture of oxygen and ozone may
be administered in vivo to patients or subjects having a blood borne
infection, resulting in selective inactivation of the infectious agent
with no resulting harm to the subject's blood. The therapeutic treatment
is efficacious against the difficult agents, including viruses such as
herpes and HIV. Further, via appropriate choice of parameters it is
possible to in fact bubble the gas mixture through blood, without the
hemolysis expected.
Hence it is an object of the invention to provide a method for inactivating
infectious agents in blood via administering a non-toxic, infectious agent
inactivating amount of a mixture of oxygen and ozone to a patient.
It is a further object of the invention to provide a treatment efficacious
against viral infections using the above mentioned O.sub.3 /O.sub.2
mixture.
It is yet a further object of the invention to provide autohemotherapy and
rectal insufflation based therapies using O.sub.3 /O.sub.2 mixtures as
above.
It is still a further object of the invention to provide a method for
inactivating blood born viruses such as herpes and HIV via use of the
aforementioned mixture.
How these and other objects of the invention are achieved will be seen from
the disclosure which follows.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention involves the administration of an infectious agent
inactivating amount of a mixture of oxygen and ozone ("O.sub.3 /O.sub.2 "
hereafter) to a patient's blood so as to inactivate the infectious agent
or agents present therein. Among the infectious agents which can be so
inactivated include bacteria, such as mycobacteria including causative
agents of tuberculosis; parasites, such as pneumocystis carinii, viruses,
such as herpes simplex and human immunodeficiency virus ("HSV" and "HIV"
respectively, hereafter), as well as other infectious agents. The
foregoing species are only provided as examples of infectious agents which
can be inactivated via the invention described herein, and the broad scope
of the invention is not to be interpreted as being limited in any way via
the foregoing examples.
The O.sub.3 /O.sub.2 mixture is non-toxic, meaning that the treated subject
does not suffer any side effects from the treatment protocol.
Preferred modes of administration in accordance with the invention
described herein are autohemotherapy and rectal insufflation.
"Autohemotherapy" as used herein refers to the treatment of a disease or
condition via removal of the patient's or subject's blood, treatment, and
reinjection of the blood into the patient. In autohemotherapy only a small
portion of the patient's blood is removed, as will be seen in the
following examples.
"Insufflation" is a general term, and refers to the filling of an organ
with air or a gas, generally via means of an apparatus provided therefor.
The term as used herein is equivalent to the term "insufflate" as it is
used in, e.g., Stedman's Medical Dictionary, 24th edition, the definition
being incorporated by reference herein.
In practice, the O.sub.3 /O.sub.2 mixture is provided via an apparatus
which includes an ozone generator and a supply of compressed oxygen. These
two elements, i.e., the ozone generator and the oxygen supply are
connected by means which include a means for regulating the volume of gas
delivered in a given period of time. For example, one may select criteria
which deliver 0.5 liters of O.sub.2 per minute.
The mixture of O.sub.3 /O.sub.2 is then delivered in a manner appropriate
for the particular treatment protocol being utilized. For example, in
autohemotherapy, the supply of gas is delivered via a means, such as a
tube hose, to a container or receptacle means which has been charged with
a volume of blood, for example, 200-300 ml. The O.sub.3 /O.sub.2 mixture
is allowed to interface with the blood sample, such as by bubbling through
it, for a predetermined time. As has been indicated supra, the apparatus
used to prepare the O.sub.3 /O.sub.2 mixture is equipped with means for
controlling the amount and length of time of the administration of the gas
mixture. When the previously chosen length of time has expired, the
O.sub.3 /O.sub.2 mixture is no longer administered, and is in fact
withdrawn from the blood sample. The treated blood is then reintroduced to
the patient.
In the case of rectal insufflation, again the parameters are chosen so as
to obtain the desired mixture of ozone and oxygen, and the length of time
for which the mixture will be delivered to the patient. A delivery means
is chosen which is selected so as to cause as little trauma as possible,
and is inserted into the patient's rectum. It is assumed that, due to the
extended vasculature in the rectum which lies so close to the tissue
surface, the O.sub.3 /O.sub.2 mixture contacts the blood in a fashion not
unlike that obtained in autohemotherapy as discussed supra.
The especially preferred parameters for use in this invention depend upon
the mode of administration and the size of the patient. For example, when
autohemotherapy is used with adults, a blood sample of about 300 ml is
used. The O.sub.3 /O.sub.2 mixture is one where 500 ml of O.sub.2 are
mixed with 33 mg of O.sub.3 per ml of O.sub.2. The delivery is over a
period of about 90-100 seconds, such as 99-100 seconds. When children are
treated, the amount of blood used will vary depending upon the child's
size. While the concentration of O.sub.3 will remain the same, the amount
of time is cut in half i.e., for about 45-50 seconds of administration. As
a result, a smaller volume of the mixture is used.
When rectal insufflation is the chosen mode of administration, again, the
apparatus is calibrated so that 500 ml of O.sub.2 mixes with 33 ug/ml of
O.sub.3, but for a period of about 60 seconds for adults. When children
are treated, the amount of time is reduced to about 30 seconds, so the
actual volume administered will, of course, be reduced accordingly.
Patients may be treated using various combinations of the foregoing therapy
including either autohemotherapy or rectal insufflation alone, or a
combination of both. The choice of therapy depends upon factors which vary
from patient to patient. Similarly, the frequency of treatment may vary,
but it has been found that treatment at least once per day is especially
effective. The length of time of the protocol will vary as well. This
depends upon the attending physician's view as to the status of a given
infection, longer or shorter periods of treatment may be appropriate. In
the examples which follow, it will be seen that after a given period,
certain "markers" characteristic of infections had disappeared. This may
be the choice of the physician, or it may be the case that reduction,
rather than elimination of the infection, is sufficient.
EXAMPLE 1
Patient GW, an adult male has been diagnosed as having HIV, and suffered
from herpes simplex and Pneumocystis carinii infections. At the time
treatment began, GW was receiving prednisone, acyclovir and nizoral for
his herpes infection, and biweekly parenteral pentamidine for prophylactic
treatment of P. carinii.
GW received daily major autohemotherapy and rectal insufflation therapy as
described supra over a period of 13 days, for a total of 18 treatments (9
of each). His p24 blood levels were measured at the start, and at weekly
intervals during the course of the treatment. To the skilled artisan, the
level of p24 in the blood of a patient is a clear indication of the extent
of HIV infection. This protein is a characteristic "marker" for HIV
infection. It is only found in approximately 40% of those patients who are
HIV positive and who are diagnosed with either ARC or AIDS, but it is a
measure of the course of an HIV infection.
The patient's p24 levels were thus measured at three different times.
I (start of treatment): 53.01 pg/ml
II (seven days): 12.41 pg/ml
III (thirteen days): 11.49 pg/ml
The dramatic drop in p24 levels is astounding, and is indicative of an
inactivating effect on HIV in the patient's blood, as only active HIV
produces p24.
Over the course of this treatment, it was found that the patient's dosage
of prednisone could also be reduced. Further, there was a marked increase
in the patient's T4 cell count, which is another indication that the HIV
infection was being alleviated.
EXAMPLE 2
Patient WA is a woman who had been diagnosed as being HIV positive. Due to
complications from anemia and leukogenia, AZT therapy had been stopped.
She presented toxoplasmosic, mycobacteria and P. carinii infections.
The patient received O.sub.3 /O.sub.2 in the form of major autohemotherapy
and rectal insufflation therapy over a period of about one month, and
received 36 treatments (18 of each). Her p24 values, in pg/mole were taken
at 7 day intervals for a total of five values. These are as follows:
I: 33.32
II: 43.16
III: 58.54
IV: 26.56
V: 5.96
The initial rise in the values indicates that a serious infection was in
progress when the treatment began. By the end of the month, however, the
p24 values were showing nearly complete remission in her blood, and her T4
cell counts remained constant
EXAMPLE 3
Patient OH had been receiving AZT therapy at the time O.sub.3 /O.sub.2
therapy began. The former was suspended while the new treatment protocol
began. He was also receiving diazaprim and acyclovir for treatment of
herpes simplex, and suffered from persistent diarrhea.
Again, following the protocol described supra, patient OH received 34
treatments, divided equally between autohemotherapy and rectal
insufflation.
Patient OH did not show p24 titer in his blood at any given time, so
comparison values cannot be provided in this case. His T4 cells, however,
rose from 24 at the start of treatment to 56. While a T4 cell count of 56
is still dangerously low, it will be seen to be more than double the
initial value, and indicates that the infection of T4 cells has been
substantially reduced, if not stopped.
In addition, the patient had been exhibiting symptoms of a severe herpes
infection when treatment began, including ulcerous lesions on the face and
perioral regions. These had persisted during treatment with acyclovir, the
standard medicament for herpes infections. Yet, following treatment, the
lesions remitted. The remission persisted 3 weeks after the patient
concluded therapy with the O.sub.3 /O.sub.2 mixture, indicating remission
of herpes simplex infection. Similarly, over the course of treatment the
patient's diarrhea improved, indicating a reduction in the infection via
causative agents of the diarrhea.
The foregoing examples all show that when patients received therapy in the
form of about 500 ml of oxygen containing about 33 mg/ml of ozone, the
patients showed remission in the content and nature of blood borne
infectious agents. While these ranges are preferred, the ozone
concentration may range anywhere from about 30 mg to about 45 mg of ozone
per ml of oxygen. Similarly, the amount of oxygen may range anywhere from
about 250 to about 1000 ml, given the foregoing concentrations of ozone.
The protocol described supra discussed the length of time over which the
mixture is administered to the patient. This is not a critical parameter.
The aim in administering the mixture, especially via rectal insufflation,
is to administer it was rapidly as possible without causing patient
discomfort. As has been shown, supra, preferably one administers the
mixture so that 500 ml of oxygen containing 33 ug/ml of ozone are
administered via rectal insufflation over 60 seconds, or over 99-100
seconds for autohemotherapy, when children are the subjects, the full
volume is not administered, as the time of application is cut in half.
It will be understood that the specification and examples are illustrative
but not limitative of the present invention and that other embodiments
within the spirit and scope of the invention will suggest themselves to
those skilled in the art.
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