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INTRODUCTION
This invention relates generally to a process and composition for the
treatment of atherosclerosis in living blood vessels. More particularly,
the present invention relates to method and composition for the treatment
of atherosclerosis by the destruction of the atherosclerotic lesion
without injuring the normal blood vessel.
BACKGROUND OF THE INVENTION
There are presently a number of methods and techniques for the treatment of
atherosclerosis among which may be included chemotherapy and surgery.
Chemotherapeutic attempts have centered around decreasing serum lipid
(cholesterol and triglyceride) levels or altering the metabolism in order
to affect the scattered atherosclerotic lesions throughout the body.
Surgery is only effective in isolated symptomatic lesions and cannot
affect the multitude of atherosclerotic lesions throughout the body.
Theories relating to the etiology of atherosclerosis are many and vary from
genetic and ecologic factors to levels of lipids in the bloodstream to
injury of the arterial wall.
A safe and effective treatment for atherosclerosis has been the goal of
investigators for a substantial period of time. Such a technique, to be
successful in the destruction of the arterial lesions must be selective in
effect upon the atherosclerotic lesions and produce no irreversible damage
to the normal blood vessel. In sum, the treatment of atherosclerosis must
selectively differentiate the atherosclerotic portions of the vessel wall
from the normal portions of the vessel wall and must selectively destroy
the atherosclerotic lesions without affecting the normal vessel.
It has been known that there are certain physical differences that exist
between atherosclerotic lesions and a normal blood vessel. One primary
physical difference that exists is that atherosclerotic plaques and
certain extravascular related lesions (xanthomas, corneal arcus) arise
because altered endothelial permeability allows certain macromolecular
plasma proteins (which are normally confined to the circulation i.e.
lipids) to permeate endothelium and interact with charged components of
the connective tissue gel of the vessel wall. The early lesions of
atherosclerosis, the fatty streaks and fibrous plaques show evidence of
altered permeability in allowing the uptake of protein-bound dyes (trypan
blue), colloidal carbon or labeled cholesterol. These substances are taken
up by the atherosclerotic lesion but not by the normal blood vessel wall.
The normal intima presents a barrier, metabolic or structural, to the
influx of serum cholesterol. During atherogenesis this barrier breaks down
permitting the entry of blood consituents. This increased permeability has
been theorized to be secondary to the release of histamine, kinins, an
immunologic reaction or to previous injury or stress. With this increase
in permeability there is an uptake of particles normally excluded from the
vessel wall.
In addition it has been shown that to a large extent atherosclerotic
lesions are monoclonal in nature and result from the overgrowth and
excessive proliferation of a single cell line much like a tumor.
Profliferation of endothelial and medial smooth muscle cells occurs
secondary to trauma or to hyper-chloesterolemia. These proliferating cells
take in foreign particles to a high degree.
It is known therefore that the atherosclerotic lesion will take in large
amounts of particles secondary to increased permeability. Furthermore the
proliferating cells of the atherosclerotic lesion (endothelial and medial
smooth muscle cells), phagocytize these particles. The particles are
therefore intracellular in these cells of the atherosclerotic lesion as
well as being located between the endothelial cell and the internal
elastic membrane of the vessel.
OBJECT OF THE INVENTION
It is therefore the purpose and principal object of the present invention
to eliminate the atherosclerotic lesions selectively by intracellularly
and extracellularly generating a temperature and by changing biophysical
characteristics that will resolve the atherosclerotic lesion without
affecting the normal vessel.
DESCRIPTION OF THE INVENTION
The present invention achieves a precise increment of heat rise within the
atherosclerotic lesion and within the cytoplasm of the cells. The thermal
barrier that characteristically exists as the outer membrane or cell wall
of the cell is now utilized as a means of retaining the heat produced
within the cell, rather than, as in the past preventing any heat build-up
within the cell. By raising the temperature of the intracellular particles
as well as the particles between the endothelial cells and the internal
elastic membrane in the atherosclerotic lesion the atherosclerotic lesion
is resolved without affecting the normal vessel.
In accordance with the present invention, there are found to be a number of
approaches that can successfully achieve the end result of an
intracellular and extracellular heat rise with resolution of the
atherosclerotic lesion.
In its simplest and broadest aspect, the present invention contemplates the
introduction into the atherosclerotic lesion of a minute particle, such as
a ferromagnetic, diamagnetic or a paramagnetic material, and then
subjecting the entire body including the normal vessels to a high
frequency alternating electromagnetic field.
This principle on which the present invention is based is also grounded
upon the known fact that the atherosclerotic lesion has a far greater
affinity for particles and for foreign substances such as these minute
particles that are to be introduced, than does the normal blood vessel.
Electron micrographs have been taken of tissue following the introduction
of such particles and clearly illustrate the selective concentration of
the particles in the atherosclerotic lesion. This is expected due to the
higher permeability of the atherosclerotic lesion and of the proliferating
cells of the atherosclerotic lesion.
The particles which are useful in accordance with the present invention,
are those such as the ferromagnetic particles compatible with living
tissue may be useful. Similarly, the diamagnetic and paramagnetic
materials that may be useful include the following; radioactive isotope
labeled albumin, fibrinogen and cholesterol and any other diamagnetic and
paramagnetic materials compatible with living tissues (in addition any
electric or magnetic dipole present or capable of being induced within the
cell can be utilized). The particle size of the particles should be not
greater than about 1 micron. Preferably particle size would be less than
the 1 micron size.
The minute particles described are to be injected intravenously into the
patient through the use of any suitable compatible liquid vehicles.
Aqueous solutions of any such body-acceptable materials as dextran,
dextrose, saline or blood, as well as water alone, can be used. The liquid
vehicle should sustain the particles in suspension for the subsequent
injection. Concentrations of such body-acceptable materials that may be
useful are those that are up to about 50% by weight in water. Usually a
solution of about 1% to 10% is adequate. The concentration of the
particles in the solution is not critical and is usually in a range
between 50 to 75 mg/cc of the solution.
The intravenous injection into the patient generally is in an amount such
that between 1 to 10 mg. of the particles per kg of body weight of the
patient are injected at one time; however, up to approximately 20-45 mg.
total dosage per kg. of body weight is possible. The greater weight of the
patient, the higher the permissible dosage. The total amount of the dosage
is not critical though 2 to 3 injections, may be injected within a
.gtoreq.to 72 hour period. The time span for the injections may vary
greatly for various patients and for various objectives.
The minute particles contained in the aqueous medium are transported
through the bloodstream and have been found to be phagocytized by the
cells of the atherosclerotic lesions and the atherosclerotic lesions
themselves to a far greater degree than, and in fact in some cases to the
possible exclusion of their admittance into normal cells.
Electromicrographs of the atherosclerotic lesions have proven the selective
pickup of the magnetic particles.
The next stage of the present invention is to bring about by inductive
heating with high frequency alternating electromagnetic field a precise
rise in the temperature of the cell and of the atherosclerotic lesion. The
principle of inductive heating through the use of hysteresis is a known
principle. Similarly, the monitoring of the temperatures of the living
cells is a presently available technique well-known to the medical
science.
The inductive heating of the minute particles is achieved by using a
electronic oscillator operating in the high-frequency range which heats
the particles by subjecting them to an intense high-frequency field within
a large but otherwise conventional helical coil, field energy being
converted to heat through hysteresis losses and the resistive dissipation
of eddy currents. The helical inductive coil is of sufficient internal
diameter to permit the patient to pass within and of such length to
encompass the length of the patient. Generally, the internal diameter
should be at least 2 feet, but preferably would be greater than 3-6 feet
in diameter. No maximum diameter is known to exist except that required
from practical and economical considerations. Diameters of inductive coils
of greater than 6 feet have a preferential effect in the overall process
by providing a more uniform flux gradient to the patient.
The frequency of the electromagnetic alternating high frequency field will
range from 50 kilohertz to 10 megahertz and the power input of the
oscillator-generator will range from 0.5 kilowatts to 1.0 kilowatts per
kg. of patient body weight 0.75 kilowatts of power per 1.0 kilograms of
body weight has been found to be particularly useful. In this power and
frequency range, the coil is selected to produce from 400 to 800 oersteds,
preferably 550-650 oersteds.
The time necessary to inductively heat the minute particles held within the
cells and the atherosclerotic lesions to be treated depends substantially
upon the frequency and the power producing the alternating electromagnetic
field and ultimately the strength of the field produced. In general, it
has been found that subjecting the patient to 5 to 12 minutes or
preferably 8 to 10 minutes of the alternating elecromagnetic field would
be adequate to resolve the atherosclerotic lesion. It should be clearly
understood that the variables with respect to the type and concentration
of the particles in the vehicle and the electromagnetic treatment are not
critical provided that the necessary temperature is achieved.
EXAMPLE I
As a specific example of the simplest form of the present invention, ferric
hydroxide particles of 0.7 micron size are suspended in a 5% dextrose
aqueous solution in an amount of about 50 mg. of the particles per cc.
Dosages in the amount of 30 mg. per kg. of body weight each of the
particles should be made twice, by intravenous injections, each being 24
hours apart. The patient is then ready for the electromagnetic treatment
by insertion entirely within an inductive coil 3 feet in diameter. The
coil is connected to an alternating current generator, producing a
frequency of 3 megahertz and a field of 600 oersteds. The patient is to be
subjected to the electromagnetic treatments about 6 hours after the last
injection. The inductive heating of the particles within the
atherosclerotic lesion is between 8 and 10 minutes during which time the
temperature within the cells will have increased 8.5.degree. centigrade.
At this temperature the proliferating cells within and the atherosclerotic
lesion itself will be resolved while the normal vessel is unaffected.
While the simplest aspect of the invention has been described in detail,
the selectivity of the magnetic particles for the atherosclerotic lesions
may be increased through the use of several techniques.
The addition of an atherosclerotic seeking agent such as radioisotope
labelled substances or a specific anitbody is useful in directing the
minute particles more selectively to the atherosclerotic lesions. It is
known that radio-isotope labelled albumin, fibrinogen and chloesterol as
well as antibodies have an affinity for and are taken up by
atherosclerotic lesions. It is also possible that the radio-isotopes may
be used to substitute for the magnetic particles and be injected
intravenously so as to be selectively taken up by the atherosclerotic
lesions. Many of these radio-isotopes are inherently paramagnetic or
diamagnetic and whether chemically or physically combined with other
particles or used alone the effect of the alternating electromagnetic
field upon the magnetic particles and/or the radio-isotopes would be to
raise the temperature of the atherosclerotic lesions. Typical examples of
useful radio-isotopes are: I-131 albumin, I-131 fibrinogen, H.sup.3
cholesterol, technetium-99 m. A great many other radioisotopes are useful
and the above are only examples. The size and concentration of the
radioisotopes alone or attached to the minute particles and the manner of
injection is precisely the same as previously described.
These radioisotopes or antibodies may be bound to the particles as
iodine-131 (the radioisotope) has been bound to albumin for lung scanning
in the past. Antibodies, for instance, may be attached to the
ferromagnetic, paramagnetic, or diamagnetic particles by use of an
intermediate reducing glucose unit or its derivation such as
metasaccharinic acid, in a conventional manner and as described in Example
III, much as high molecular weight dextran is bound to ferric hydroxide.
It is known that antibodies can be formed by injection of lipoproteins
removed from one patient with atherosclerosis and injected into another
patient. These antibodies can then be selectively isolated and have
usefulness in the present invention as a selective atherosclerotic lesion
cell seeking agent.
These antibodies may be bound chemically or physically to the minute
particles and then re-injected into the patient to be treated. Due to the
antibodies' specificity for the original atherosclerotic lesion, the
antibodies bound to the particles will even more selectively induce the
particles to be phagocytized by the atherosclerotic lesion.
Antibodies with radioactive isotopes may be produced by feeding the animals
producing the antibodies, labeled amino acids. This labeled amino acid is
then incorporated into the antibody.
Large chemical entities can be attached to antibody molecules. Large
proteins may be attached via diagotized atoxyl (p-amino-benzene arsenic
acid). Antibodies may be bound while they are attached to a hapten or to
an antigen. This protects the immunologically specific site of the
antibody during the binding procedure.
There does not appear to be any danger in an increased concentration of the
particles in the normal vessel in view of the phagocytic charcteristics of
the atheroclerotic lesion but to efficiently use all of the magnetic
particles and to permit the smallest dosage possible, it is desirable to
utilize where beneficial a selective atherosclerotic seeking agent such as
the radioisotopes or the antibodies. In this manner, an even greater
concentration of the magnetic particles should be found in the
atherosclerotic lesion and a very minor amount if not an exclusion of such
particles in the normal vessel.
A specific example of the use of a radioisotope in accordance with the
present invention is as follows.
EXAMPLE II
I-131 Albumin is incorporated into a sterilized isotomic 5% saline solution
the concentration being 75u C./cc and the dosage being 15u C./kg body
weight. Upon injection a 6 hour period is allotted for the I-131 albumin
to isolate itself and selectively concentrate within the atherosclerotic
lesion. Thereafter the same alternating electromagnetic field is applied
in exactly the same manner as previously described in Example I. This
produces resolution of the atherosclerotic lesion.
When the I-131 albumin is to be utilized as an atherosclerotic seeking
agent it may be bound to the particle. This combined particle may be
injected into the patient in precisely the same manner and it would be
found that the I-131 albumin selectively delivers the particle to the
atherosclerotic lesions. Thereafter when the atherosclerotic lesions are
subjected to the alternating electromagnetic field, the atherosclerotic
lesions are selectively destroyed.
It is also possible that the known utility of specific anti-atherosclerotic
agents such as the chemotherapeutic agents, the radioisotopes or specific
antibodies may be utilized in accordance with the present invention. For
example, chemotherapeutic agents include antihistamines, C-AMP
phosphodiesterase inhibitors or enzyme blocking agents (to block elastose,
collagenase, hyaluronidase, trypsin, and B-glucuronidase which increase
the permeability of the atherosclerotic lesion). It is an aspect of the
present invention that such known chemotherapeutic agents in a size less
than 1 micron may be coated with ferromagnetic material to produce a total
particle of a size less than the approximate 1 micron particle size. The
particles in effect encapsulate the chemotherapeutic agent and form a
micro-sphere around the chemotherapeutic agent. The coating thickness of
the magnetic particle should be approximately 0.1 micron. Thus, the size
of the chemotherapeutic agent particle should be about 0.1 micron or less
in order to bring about the total particle size of not greater than 1
micron and preferably less.
EXAMPLE III
The following is an example of coating C-AMP with a ferromagnetic material:
C-AMP known to make the endothelial membrane less permeable to lipids is
taken in a solid state and pulverized into particles 0.5 micron in size.
These particles, in turn, are then coated with ferric hydroxide
approximately 0.1 micron in thickness, in accordance with any of the
conventional methods of coating submicron particles as described in U.S.
Pat. No. 3,294,686.
These particles are then colloidally suspended in a 6% by weight aqueous
dextran solution. This solution is introduced intravenously to the patient
with the result that due to the phagocytic characteristics of the
atherosclerotic lesion most of these particles will be deposited in the
cytoplasm inside the atherosclerotic lesions' cells. This would take place
about 4 to 8 hours after the intravenous injection. After the particles'
deposition into the cytoplasm, the ferric hydroxide is acted upon by the
cytoplasm and is converted to an organic iron complex (ferritin) which is
then absorbed.
After approximately 24 hours, the ferric hydroxide coating is thus
solubilized and the chemotherapeutic agent C-AMP is released within the
atherosclerotic lesion where it can effectively resolve the
atherosclerotic lesion. Time is not critical, and may vary from 1 to 48
hours or more. The other atherosclerotic specific agents may be similarly
utilized.
EXAMPLE IV
The chemotherapeutic agent as encapsulated in a ferromagnetic material, as
described in Example III, may be injected in precisely the same manner and
alternatively subjected to the high frequency alternating electromagnetic
field of Example I which then is capable of breaking up the micro-sphere
of the magnetic material by a vibrational frequency produced by the
electromagnetic field at which the outer surface resonates and its
integrity is destroyed. Upon breakup of the micro-spheres the
chemotherapeutic agent is released intracellularly and selectively within
the atherosclerotic lesions. The same example may be applied in the same
manner to the atherosclerotic specific agents.
EXAMPLE V
The encapsulating material may also contain a low melting solid such as
wax. This wax is in combination with the ferromagnetic material and
applied as in Example III. In this alternative embodiment the application
of the alternating electromagnetic field, as in Example I, would melt the
low melting solid due to the induction heating of the ferromagnetic
material and release the chemotherapeutic agent within the atherosclerotic
lesion. Similarly, the other atherosclerotic agents may be similarly
utilized.
As previously stated, an atherosclerotic seeking agent such as the
radioisotope or antibodies may be utilized to more selectively direct the
micro-sphere containing the chemotherapeutic agent to the atherosclerotic
lesions. As is known, chemotherapeutic agents sometimes have adverse side
effects upon normal cells, but the present procedure would selectively
release the chemotherapeutic agent intracellularly and selectively.
Compared to the presence of the chemotherapeutic agent in the
atherosclerotic lesion, the concentration of the chemotherapeutic agent in
the normal cell would be minimal. The undesirable side effects upon the
normal cells should therefore be greatly minimized if not totally avoided.
A further embodiment of the present invention which typifies the broad
nature of the invention is the incorporation of any atherosclerotic
specific antibody or radioisotope within the encapsulating ferromagnetic
micro-sphere in the manner previously described in Example III. Thereafter
the antibody or radioactive isotope so coated may be introduced within the
atherosclerotic lesion and the alternating electromagnetic field applied
as in Example IV to cause the micro-spheres of the ferromagnetic material
to release the antibody or the radioisotope intracellularly. It is also
possible that the release of the encapsulated material may be by
solubilizing the spheres within the cell, as previously described in
Example III. A localized field may also be utilized to localize the
particles or micro-spheres in particular atherosclerotic lesions.
One of the important features of the present invention is that there is
destruction of the atherosclerotic lesions wherever they are located in
the patient.
There are many variations of the invention as described and this invention
should be limited solely by the scope of the following claims.
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