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Claims  |
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What is claimed is:
1. A process for the use of any ferromagnetic, paramagnetic, or diamagnetic
particles, electric or magnetic dipoles already in an atherosclerotic
lesion by the application of external electromagnetic energy capable of
generating heat to alter the biophysical and/or structural properties
intracellularly and extracellularly of said atherosclerotic lesions to
induce the resolution of said lesion comprising:
subjecting a host having an atherosclerotic lesion to an alternating
electromagnetic field to inductively heat and alter the biophysical and/or
structural properties of said particles, electric or magnetic dipoles
already in said atherosclerotic lesions, and thereby alter the
atherosclerotic lesions,
continuing the inductive heating of said particles, electric or magnetic
dipoles already in said atherosclerotic lesions to resolve said
atherosclerotic lesions.
2. A process wherein minute ferromagnetic, paramagnetic or diamagnetic
particles, electric or magnetic dipoles are intravenously or
intraarterially injected into a host having atherosclerotic lesions, said
particles being capable of being inductively heated and of a size less
than or not more than about 1 micron, so that said particles, electric or
magnetic dipoles are selectively absorbed intracellularly and
extracellularly into an atherosclerotic lesion, in said host having said
lesions, subjecting said host to an alternating electromagnetic field to
inductively heat said particles, electric or magnetic dipoles in said
atherosclerotic lesions and alter the biophysical and/or structural
properties of said atherosclerotic lesion,
continuing said inductive heating of said particles in said atherosclerotic
lesions and said electric and magnetic dipoles to resolve said
atherosclerotic lesions; said particles and dipoles being selected from
the group comprising cobalt, zinc, chromium, nickel, platinum, rare earth
metals such as dysprosium, erbium, europium, gadolinium, holmium,
samarium, terbium, thulium, ytterbium, yttrium and compounds thereof such
as dysprosium sulfate, erbium sulfate, europium oxide, europium sulfate,
gadolinium oxide, gadolinium sulfate, holmium oxide, samarium sulfate,
terbium sulfate, thulium oxide, ytterbium sulfide, yttrium oxide, yttrium
sulfate, yttrium ferrioxide (Y.sub.3 Fe.sub.5 OH.sub.12), yttrium aluminum
oxide (Y.sub.3 Al.sub.5 O.sub.12), dysprosium-nickel, dysprosium cobalt,
gadolinium-iron, ytterbium-iron, cobalt-samarium, gadolinium-yttrbium,
dysprosium-gallium, and actinide series elements and compounds thereof,
dextran metal complexes, iron transporting and chelating compounds and
porphyrins; and
mixtures thereof.
3. The process of claim 1 including an atherosclerotic seeking agent
exclusive of said particles, electric and magnetic dipoles, in a
concentration sufficient to combine with and selectively direct said
particles, electric and magnetic dipoles, to said atherosclerotic lesions.
4. The process of claim 2 where said particles and dipoles are organic
compounds selected from the group comprising:
(a) dextran metal complexes wherein said metal is selected from the group
consisting of cobalt, zinc, chromium, iron, gallium, manganese, nickel,
platinum, dysprosium, erbium, europium, gadolinium, holmium, samarium,
terbium, thulium, ytterbium, yttrium, dysprosium-nickel,
dysprosium-cobalt, gadolinium-iron, ytterbium-iron, cobalt-samarium,
gadolinium-yttrium, and dysprosium-gallium, and iron such as Fe.sub.2
O.sub.3 particles, Fe.sub.3 O.sub.4 particles and FeOOH particles and
Fe.sub.2 O.sub.3 -dextran complexes, Fe.sub.3 O.sub.4 -dextran complexes,
and FEOOH-dextran complexes;
(b) iron transporting and chelating compounds comprising ferric ammonium
citrate, enterochelin, transferrin, metallothionein, hydroxamates,
phenolates, ferrichromes, desferriferrichromes, ferrithin, ferric
mycobactins and iron sulfur proteins such as ferredoxin and rubredoxin;
(c) porphyrins comprising etioporphyrins, mesoporphyrins, uroporphyrins,
coproporphyrins, protoporphyrins, dicarboxylic acid containing porphyrins,
substituted porphyrins such as tetraphenylporphyrin sulfonate and
protoporphyrin containing molecules such as hematoporphyrins,
chlorophylls, and cytochromes; and
combinations thereof.
5. The process according to claim 4 wherein said porphyrin contains a
natural occurring metal moiety optionally being substituted with a metal
selected from the group comprising cobalt, zinc, chromium, gallium, iron,
manganese, nickel, platinum, dysprosium, erbium, europium, gadolinium,
holmium, samarium, terbium, thulium, ytterbium, yttrium,
dysprosium-nickel, dysprosium-cobalt, gadolinium-iron, ytterbium-iron,
cobalt-samarium, gadolinium-yttrium, and dysprosium-gallium; and
combinations thereof.
6. The process according to claim 4 or 5 wherein said iron transporting,
iron chelating and porphyrin compounds are chemically complexed with
dextran.
7. The composition according to claim 6 wherein said particles are
chemically complexed with an antibody.
8. The process according to claim 4 wherein said compounds are selected
from the group comprising Fe(III) Tetraphenylporphyrin sulfonate
(TPPS.sub.4) Acetate, Fe(III) TPPS.sub.4 Acetate 4Na Salt (H.sub.2 O),
Fe(III) Mesoporphyrin IX Chloride, Fe(III) TPPS.sub.4 Chloride, Co
TPPS.sub.4, Co(III) MesoTPPS.sub.4 Tetra Na Salt (Acetate), Fe
Phthalocyanine Tetrasulfonate Tetra sodium salt, Tetra Sodium-meso-Tetra
(4-sulfonate-phenyl) Porphine (12 hydrate), Fe(III) Tetra (N-Methyl
4-Puridyl) Prophyrin Pentachloride, Fe Phthalocyanine, Hemin,
Fe-Hematoporphyrin D. (HPD), Fe-Acetoxyethyl vinyl Deuteroporphyrin,
Fe-Protoporphyrin IX, Fe-Deuteroporphyrin 2,4 bis acetal, Mn-TPPS.sub.4,
Co-.sup.+ MTPYP, Mn-N.sup.+ MTPyp, Co-Mesoporphyrin X, Protohemin,
Deuterochemin, Meso-tetra (4-N methyl pyridyl) hemin tetraiodide,
Meso-tetra (4-carboxy phenyl) hemin, Ni-TPPS, Ni-HPD, Mn-Mesoporphyrin IX,
Co-Protoporphyrin IX, Mn-Protoporphyrin IX, Sn-Protoporphyrin IX, Co-HPD,
Mn-HPD, Gd-TPPS, Gd-HPD, Hematoporphyrin Mono-acetate-Fe, Ferretin-Fe,
Ferredoxin-Fe(4), Transferrin-Fe, Hematoporphyrin Diacetate-Gd, GdFe.sub.2
-TPPS.sub.4 GdFe-HPD, FeTPPS.sub.4 (OH.sub.2).sub.2 ClO.sub.4 --,
FeTPP(OH.sub.2).sub.2 ClO.sub.4 --, Fe-nitrolacetate, Fetetrasulfinated
phalocyanine, Bisimidozole (FeTPPS)ClO.sub.4 --,
Rubrium-ferricytochrome/c, and
combinations thereof.
9. The process according to claim 8 wherein said compounds are chemically
complexed with dextran.
10. The process according to claim 9 wherein said compounds are chemically
complexed with an antibody.
11. The process of claim 3 wherein said atherosclerotic seeking agent is an
atherosclerotic specific antibody.
12. The process of claim 1 or 2 wherein a biopsy of the atherosclerotic
plaque is obtained and exposed to said alternating electro magnetic field
at various frequencies to determine the ideal frequency with which to
treat the atherosclerotic lesion and exposing said host to said field at
said ideal frequency.
13. The process of claim 1 or 2 wherein as part of said process, a
stationary magnetic field is used before, during or after treatment to
help induce electric and magnetic dipoles in the atheorosclerotic plaque
to be treated.
14. The process of claim 1 or 2 wherein, as part of said process an
oscillating or pulsed electromagnetic field is used before, during or
after treatment to help induce electric and magnetic dipoles in the
atherosclerotic plaque to be treated.
15. The process of claim 1 or 2 wherein a local probe is utilized in the
blood vessel or around the blood vessel to create an alternating
electromagnetic field to treat the atherosclerotic lesion.
16. The process of claim 1 or 2 wherein a local probe is utilized in the
blood vessel or around the blood vessel to create a stationary magnetic
field to help induce electric and magnetic dipoles in the atherosclerotic
plaque to be treated. |
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Claims |
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Description |
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FIELD OF THE INVENTION
This invention relates generally to a process and composition for the
treatment of atherosclerosis by the application of external
electromagnetic energy capable of the generation of heat and biophysical
alterations in any electric or magnetic dipole present or capable of being
induced within the atherosclerotic plaque and the cells contained therein.
This process allows for the selective treatment of the atherosclerotic
plaque without damaging the normal blood vessel by the compartmentalized
alteration of biophysical and/or structural properties within the
atherosclerotic lesion.
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), colloidial 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 consistuents. 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 form 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.
Proliferation of endothelial and medial smooth muscle cells occurs
secondary to trauma or to hyper-cholesterolemia. 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.
The atherosclerotic lesion, itself, contains a large number of particles
which can act as an electric or magnetic dipole. The plaque besides
containing a large amount of hemoglobin and hemosiderin also contains a
large amount of iron.
BRIEF DESCRIPTION OF THE INVENTION
This instant invention relates to eliminating the atherosclerotic lesions
selectively by intracellularly and extracellularly generating a
temperature and by changing biophysical characteristics and/or structural
properties resolving the atherosclerotic lesion without affecting the
normal vessel.
DETAILED DESCRIPTION OF THE INVENTION
The instant 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 instant 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 instant invention contemplates the
use of the ferromagnetic, paramagnetic or diamagnetic particles already
located in the atherosclerotic plaque with the entire body being subjected
to an alternating electromagnetic field.
The inductive heating of the minute particles is achieved by using an
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 subject to pass within and of such length to
encompass the length of the subject. 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
form 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 subject.
The frequency of the electromagnetic alternating high frequency field will
range from 1 hertz to 100 megahertz and the power input f the
oscillator-generator will range from 0.5 kilowatts per kg. of subjects's
body weight 0.75 kilowatts of power per 1.0 kilograms of body weight has
been found to particularly useful. In this power and frequency range, the
coil is selected to produce from 200-1000 oersteds, preferably 550-650
oersteds, but may function from 100-70,000 oersteds, as well as other
variations.
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 subject to 5 to 12 minutes or
preferably 8 to 10 minutes of the alternating electromagnetic field would
be adequate to bring about the necessary temperature rise of approximately
9.0.degree. Centigrade and 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 to resolve the atherosclerotic lesion. In further embodiment,
since the instant invention provides the possibilities for specific
particle distribution and a sensing of the responsiveness to the various
treatment fields, high temperature treatment modalities are also possible.
The 9.0.degree. Centigrade temperature rise as discussed supra is, of
course, predicated on the situation in which particle distribution,
magnetic state, and orientation were equal in all cells and in the
atherosclerotic lesions, under the treatment conditions. However,
employing the methods of this instant invention thereby affecting specific
particle distribution, orientation, differential magnetic susceptibility,
timing and other parameters described herein, within cells and
atherosclerotic lesions in the target area, increases in the
intracelllular temperature up to 100.degree. Centigrade are possible
without substantially damaging surrounding tissues and cells and without
injuring the normal blood vessel.
Biological alterations are induces by the energy input to the particle and
thereupon to the interior of the cells and the atherosclerotic lesions.
Thus, the same energy input may be accomplished by application over a long
period of time with a consistent small temperature rise for 10-20 minutes
or when the same total amount of energy is applied over a short period of
time a higher temperature results (100.degree. C. for a few seconds).
Obviously, timing and energy parameters may be adjusted to provide a
spectrum of intracellular temperature which may be utilized in this
instant invention depending upon the treatment appropriate in specific
cases.
Where necessary, a biopsy of the atherosclerotic lesion can be used to
determine the ideal frequency to be used in the treatment method through
in-vitro studies. However, in general this would not be necessary.
In addition, a local probe may be utilized by threading a catheter in the
blood vessel either percutaneously, at the time of surgery or around the
blood vessel. This probe may also be magnetically guided to the area of
interest. The probe then creates an alternating electromagnetic field to
treat the atherosclerotic lesion locally. The probe may also create a
steady magnetic field to help induce electric and magnetic dipoles in the
atherosclerotic plaque to be treated.
As further embodiment of this instant invention, a stationary magnetic
field in the range of 100 oersteds to 70,000 oersteds can be used before,
during or after treatment to help induce electric and magnetic dipoles and
thereby enhance the treatment modality. This provides a means of further
enhancement of the use of electric and magnetic dipoles present or capable
of being induced within the atherosclerotic lesion and the cells located
therein. described in U.S. Pat. No. 4,359,453.
In addition, an atherosclerotic seeking agent exclusive of said particles,
electric and magnetic dipoles, may be used in a concentration sufficient
to combine with and selectively direct the particles, electric and
magnetic dipoles, to the atherosclerotic lesions.
The particles are selected from the group comprising ferromagnetic,
paramagnetic and diamagnetic elements, inorganic compounds, organic
compounds, and combinations thereof such as particles or dipoles based on
compounds selected from the group comprising cobalt, zinc, iron, chromium,
nickel, platinum, rare earth metals such as dysprosium, erbium, europium,
gadolinium, holmium, samarium, terbium, thulium, ytterbium, yttrium and
compounds thereof such as dysprosium sulfate, erbium sulfate, europium
oxide, europium sulfate, gadolinium oxide, gadolinium sulfate, holmium
oxide, samarium sulfate, terbium sulfate, thulium oxide, ytterbium
sulfide, yttrium oxide, yttrium sulfate, yttrium ferrioxide (Y.sub.3
Fe.sub.5 O.sub.12), yttrium aluminium oxide (Y.sub.3 Al.sub.5 O.sub.12),
dysprosium-nickel, dysprosium cobalt, gadolinium-iron, ytterbium-iron,
cobalt-samarium, gadolinium-ytterbium, dysprosium-gallium, and actinide
series elements and compounds thereof and combinations thereof as well as
organic compounds selected from the group comprising:
(a) dextran metal complexes wherein said metal is selected from the group
consisting of cobalt, zinc, chromium, iron, gallium, manganese, nickel,
platinum, dysprosium, erbium, europium, gadolinium, holmium, samarium,
terbium, thulium, ytterbium, yttrium, dysprosium-nickel,
dysprosium-cobalt, gadolinium-iron, ytterbium-iron, cobalt-samarium,
gadolinium-yttrium, and dysprosium-gallium, and iron such as Fe.sub.2
O.sub.3 particles, Fe.sub.3 O.sub.4 particles and FeOOH particles and
Fe.sub.2 O.sub.3 -dextran complexes, Fe.sub.3 O.sub.4 -dextran complexes,
and FeOOH-dextran complexes;
(b) iron transporting and chelating compounds comprising ferric ammonium
citrate, enterochelin, transferrin, metallothionein, hydroxamates,
phenolates, ferrichromes, desferriferrichromes, ferritin, ferric
mycobactins and iron sulfur proteins such as ferredoxin and rubredoxin;
(c) porphyrins comprising etioporphyrins, mesoporphyrins, uroporphyrins,
coproporphyrins, protoporphyrins, dicarboxylic acid containing porphyrins,
substituted porphyrins such as tetraphenylporphyrin sulfonate and
protoporphyrin containing molecules such as hematoporphyrins,
chlorophylls, and cytochromes; and combinations thereof.
Additionally, the natural occurring metal moiety of said porphyrin may be
optionally substituted with a metal selected from the group comprising
cobalt, zinc, chromium, gallium, iron, manganese, nickel, platinum,
dysprosium, erbium, europium, gadolinium, holmium, samarium, terbium,
thulium, ytterbium, yttrium, dysprosium-nickel, dysprosium-cobalt,
gadolinium-iron, ytterbium-iron, cobalt-samarium, gadolinium-yttrium, and
dysprosium-gallium; and combinations thereof. The above iron transporting,
iron chelating and porphyrin compounds may be chemically complexed with
dextran which in turn may be chemically complexed with an antibody.
The particles or dipoles are also made from metal-organic compound
complexes are selected from the group comprising Fe(III)
Tetraphenylporphyrin sulfonate (TPPS.sub.4) Acetate, Fe(III) TPPS.sub.4
Acetate 4Na Salt (H.sub.2 O), Fe(III) Mesoporphyrin IX Chloride, Fe(III)
TPPS.sub.4 Chloride, Co TPPS.sub.4, Co(III) MesoTPPS.sub.4 Tetra Na Salt
(Acetate), Fe Phthalocyanine Tetrasulfonate Tetra sodium salt, Tetra
Sodium-meso-Tetra (4-sulfonate-phenyl) Porphine (12 hydrate), Fe(III)
Tetra (N-Methyl 4-Puridyl) Porphyrin Pentachloride, Fe Phthalocyanine,
Hemin, Fe-Hematoporphyrin D. (HPD), Fe-Acetoxyethyl vinyl
Deuteroporphyrin, Fe-Protoporphyrin IX, Fe-Deuteroporphyrin 2,4 bis
acetal, Mn-TPPS.sub.4, Co-N.sup.+ MTPyP, Mn-N.sup.+ MTPyp,
Co-Mesoporphyrin X, Protohemin, Deuterohemin, Meso-tetra (4-N methyl
pyridyl) hemin tetraiodide, Meso-tetra (4-carboxy phenyl) hemin, Ni-TPPS,
NI-HPD, Mn-Mesoporphyrin IX, Co-Protoporphyrin IX, Mn-Protoporphyrin IX,
Sn-Protoporphyrin IX, Co-HPD, Mn-HPD, Gd-TPPS, Gd-HPD, Hematoporphyrin
Mono-acetate-Fe, Ferretin-Fe, Ferredoxin-Fe(4), Transferrin-Fe,
Hematoporphyrin Diacetate-Gd, GdFe.sub.2 -TPPS.sub.4, GdFe.sub.2 -HPD,
FeTPPS.sub.4 (OH.sub.2).sub.2 ClO.sub.4 --, FeTPP(OH.sub.2).sub.2
ClO.sub.4 --, Fe-nitrolacetate, Fetertrasulfinated phalocyanine,
Bisimidozole (FeTPPS)ClO.sub.4 -- Rubrium-ferricytochrome/c; and
combinations thereof optionally chemically complexed with dextran which in
turn may be chemically complexed with an antibody.
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Description |
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