U.S. patent number 4,824,436 [Application Number 07/042,569] was granted by the patent office on 1989-04-25 for method for the prevention of restenosis.
Invention is credited to Harvey Wolinsky.
United States Patent |
4,824,436 |
Wolinsky |
April 25, 1989 |
Method for the prevention of restenosis
Abstract
Process for local administration of heparin or other agents to
inhibit arterial smooth muscle cell proliferation utilizing a
catheter.
Inventors: |
Wolinsky; Harvey (New York,
NY) |
Family
ID: |
26719400 |
Appl.
No.: |
07/042,569 |
Filed: |
April 21, 1987 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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721386 |
Apr 9, 1985 |
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Current U.S.
Class: |
604/509;
604/101.03; 604/913; 604/919 |
Current CPC
Class: |
A61B
17/22 (20130101); A61M 25/1011 (20130101); A61M
25/104 (20130101); A61M 2025/1052 (20130101) |
Current International
Class: |
A61B
17/22 (20060101); A61M 25/10 (20060101); A61M
29/02 (20060101); A61M 005/00 () |
Field of
Search: |
;604/52-53,101,102
;128/344,348.1 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Truluck; Dalton L.
Attorney, Agent or Firm: Wyatt, Gerber, Shoup and Badie
Parent Case Text
RELATED APPLICATION
This application is a continuation in part application of copending
application Ser. No. 721,386 filed Apr. 9, 1985, now abandoned.
Claims
What is claimed is:
1. A method for inhibiting the proliferation of arterial smooth
muscle cells following angioplasty which comprises the steps
of:
1. Conducting an angioplasty using a catheter with an expansible
balloon to expand at least a portion of a plaque body and removing
the catheter,
2. Inserting into the artery a catheter comprising a main catheter
body having means including two spaced balloon elements adapted to
be positioned ajacent respective proximate and distal ends of the
original site of the plaque body and to hold said main catheter
body in place and expansible against the arterial walls for
providing a chamber about said site, and means carried by said main
catheter body for delivering heparin into said chamber,
3. Inflating said two spaced balloon elements, to form a chamber at
the site of the angioplasty,
4. Delivering heparin into said chamber through said heparin
delivering means under a pressure of 200 to 1000 mmHg at the site
of the angioplasty whereby the heparin sticks to and penetrates the
adjacent arterial tissue defined by the chamber,
5. Deflating said two spaced balloon elements, and
6. Removing the catheter from the artery.
2. A method as in claim 1 wherein the angioplasty is percutaneous
transluminal coronary angioplasty.
3. A method for relieving an arterial constriction caused by a body
of plaque and therafter inhibiting the proliferation of smooth
muscle cells at the site of the plaque which comprises the steps
of:
1. Inserting into the artery a chateter comprising a main catheter
body having means including two spaced balloon elements adapted to
be positioned adjacent respective proximate and distal ends of the
plaque body and expansible against the arterial walls for providing
a chamber about said plaque body and to hold said main catheter
body in place, means carried by said main catheter body for
delivering heparin into said chamber, and means including a third
expansible balloon element disposed intermediate said two spaced
balloon elements,
2. Inflating said third balloon element against said plaque body to
perform an angioplasty and to expand at least a portin of the
plaque body,
3. Deflating said third balloon element,
4. Inflating said two spaced balloon elements to form a chamber at
the site of the angioplasty,
5. Delivering heparin into said chamber through said heparin
delivering means under a pressure of 200 to 1000 mmHg at the site
of the angioplasty whereby the heparin sticks to and penetrates the
adjacent arterial tissue defined by the chamber,
6. Deflating said two spaced balloon elements, and
7. Revmoving the catheter from the artery.
4. A method as in claim 2 wherein the angioplasty is percutaneous
transluminal coronary angioplasty.
5. A method for inhibiting the proliferation of arterial smooth
muscle cells following angioplasty which comprises the steps
of:
1. Conducting an angioplasty and,
2. Depositing heparin under a pressure of 200 to 1000 mmHg at the
site of the angioplasty utilizing heparin depositing means, whereby
the heparin sticks to and penetrates the arterial tissue in and
adjacent to the angioplasty site.
6. A method for inhibiting the proliferation of arterial smooth
muscle cells following angioplasty which comprises the steps
of:
1. Conducting an angioplasty using a catheter with an expansible
balloon to expand at least a portion of the plaque body thereby
creating a lesion site, and
2. Depositing heparin under a pressure of 200 to 1000 mmHg at the
lesion site of the angioplasty utilizing heparin depositing means,
whereby the heparin sticks to and penetrates the arterial tissue of
the lesion site and adjacent thereto.
Description
BACKGROUND OF THE INVENTION
Recently an alternative approach to coronary bypass surgery has
been developed. In this non-operative procedure for the improvement
of blood flow in patients with coronary artery disease, a catheter
with an inflatable balloon at the distal end is inserted into the
femoral artery or by brachial cutdown, and is positioned by
fluoroscopic control at the appropriate coronary ostium. The
process is known as percutaneous transluminal coronary angioplasty
(PTCA).
The balloon at the distal end of the catheter has a predetermined
maximum diameter. It is filled with a radio opaque dye to permit
visualization. Alternatively, the balloon itself may be radio
opaque. When the balloon is positioned in the stenosis it is
inflated at pressures of from 2 to 11 atmospheres for from 15 to 60
seconds and then deflated. The inflation cycle may be repeated
several times to achieve satisfactory results. Normally the luminal
diameter of the stenotic vessel increases at least 20% as a result
of the treatment.
Angioplasty is not limited to the cardiac vasculature. It has been
employed for treatment of single, large atherosclerotic lesions of
the renal, iliac and even vertebral arteries. The effect of the
expanded balloon is to literally blow open the stenotic zone.
Disruption of the wall is marked, including fracture of the calcium
in the lesion, tearing of the plaque itself and extravasation of
plaque lipid and gruel into the adjacent vessel wall.
The clinical results of angioplasty include endothelial denudation,
vascular wall damage, and rupture of the tunica intima vasorum.
These injuries have been found to result in many cases in
unregulated proliferation of the arterial smooth muscle cells (SMC)
with a resulting restenosis. A recent study by Levine et al (The
American Journal of Cardiology, Volume 55, pages 673 to 676, March
1985) has shown that restenosis may be expected to occur in as many
as 40% of patients that have undergone angioplasty. Often the only
practical treatment for restenosis is to repeat the treatment. This
may cause further damage to the cell wall and the need for
subsequent repetition of the angioplasty procedure.
Heparin is a mucopolysaccharide composed of amino sugar and uronic
acid residues which is obtained from beef, porcine, sheep, whale
and other mammalian tissue by extraction with a solution of
potassium acetate, alkaline ammonium sulfate and the like.
Commercial heparin preparations are now widely available from a
number of pharmaceutical companies. Heparin preparations are
clinically utilized principally as anticoagulants.
Recently it has become known that in addition to its anticoagulant
activities, heparin is a powerful inhibitor of arterial smooth
muscle proliferation. See, for example, Guyton et al. Circulation
Research Volume 46, Number 5 pages 625 to 633, 1980 and Hoover et
al. Circulation Research Volume 47, Number 4, pages 578 to 583,
1980.
My co-pending U.S. patent application Ser. No. 364,408, filed Apr.
2, 1982 describes and claims catheters which can be used to insert
a solubilizing agent into an artery to dissolve plaque thereby
relieving arterial constrictions. The disclosure of this
application is incorporated herein by reference.
This invention will be better understood by reference to the
figures. In the drawing:
FIG. 1 is a schematic longitudinal sectional view of a catheter
element which may be employed in this invention at the distal end
of a main catheter body.
FIG. 2 is a cross section taken along the line 2--2 of FIG. 1.
FIG. 3 is a view of the catheter element of FIG. 1 operatively
positioned within a stenotic artery.
FIGS. 1 and 2 illustrate the solubilizing fluid delivery, balloon
carrying element of a catheter useful in the practice of this
invention. In the embodiment illustrated it comprises a main
catheter body generally designated as 1 with a distal end 2 and a
proximate end 3 formed with a main catheter body wall 4. The main
catheter body 1 is formed with three conduits; a ring balloon
expansion conduit 5, a central balloon expansion conduit 6 and a
fluid delivery conduit 7. The catheter body 1 carries two ring
balloons 8 and 9 at either end, and an optional central balloon 10
disposed intermediate the spaced balloons. It also carries a third
conduit 7 which exits through the catheter body. Conduits 5, 6 and
7 are fitted with appropriate valves 11, 12 and 13.
THE INVENTION
It has been found that catheters of the class described are useful
for delivering heparin or other SMC growth regulators to the site
of the angioplasty and depositing it in and about the site of the
vascular wall damage to retard SMC growth.
The term `heparin` as used herein refers to any of a variety of
heparin products which inhibit SMC proliferation. Heparin from
various sources is known to be heterogeneous. There are both
anticoagulant and non-anticoagulant fractions. Each has varying
degress of N- and O-sulfation and acetylation. Fractions with
anticoagulant activity may contain as many as 20 saccharide
moieties. It has been found that both anticoagulant and
non-anticoagulant fractions manifest inhibition of SMC
proliferation, and that heparin fractions or derivatives containing
at least six saccharide monomers have this activity. Fractions and
derivatives with varying degrees of sulfation manifest varying
abilities to inhibit SMC proliferation. The active materials are
described in detail in the Circulation Research publications cited
above. All such fractions and derivatives are useful in the
practice of this invention and are included within the term
heparin.
The operation of the catheter to form a chamber within the artery
is schematically illustrated in FIG. 3.
In FIG. 3, 14 is the arterial wall of an artery constricted due to
the presence of plaque body 15. The figures shows the main catheter
body 1 held in place by the inflation of spaced balloons 8 and 9.
The inflation of the balloons forms a chamber 16 in the artery and,
as shown, surrounding the plaque. The catheter 1 is shown with the
central balloon 10 in the deflated configuration. It also shows the
delivery end of the third conduit 7.
In the practice of this invention, the two balloon catheter
illustrated in the figures is employed following conventional
angioplasty which removes at least a portion of the plaque. The
angioplasty catheter is removed and the catheter 1 is inserted. The
catheter 1 is guided by standard procedures which may include the
use of a flexible probe, a guide wire and/or a fluoroscope to a
position overlaying the original site of the plaque body 15
preferably, but not necessarily, in the position shown in FIG. 3
with the distal end balloon 8 just beyond the distal end of the
original site and proximate end balloon 9 just ahead of the
proximate end of the site. When the balloons 8 and 9 are inflated
by forcing fluid such as isotonic saline through valve 11 and
conduit 5, the catheter is held in place by the pressure of the
balloons and a chamber 16 is formed surrounding the site. The
closing of valve 11 will maintain the pressure in the conduit 5 and
balloons 8 and 9 so that the catheter is held in place. The
position of the catheter can be checked fluoroscopically or by
passing a small amount of solubilizing liquid containing a dye into
the chamber. If the position is not satisfactory the pressure can
be released sufficiently to slightly deflate the ring balloons 8
and 9, the catheter moved in the appropriate direction, and the
balloons reinflated.
Once the catheter is in place, the heparin is forced under pressure
through the conduit 7 and the chamber 16 on and into the adjacent
surfaces. Pressures of 200 to 1000 mm Hg are generally sufficient
for this purpose although variations from this range are
acceptable. The preferred range is 300 to 1000 mm Hg. The pressure
at which the fluid is forced into the chamber may be generated by a
pump upstream of valve 12. After the heparin is injected, the
catheter is held in place for 5 to 60 seconds to hold the heparin
in the chamber and provide time for it to stick to and penetrate
the depths of the adjacent arterial tissue defined by the chamber
in high concentration and not be prematurely washed away or diluted
with the flowing blood. Balloons 8 and 9 are deflated, and the
catheter removed.
Because of the large number of functional groups present, heparin
is a highly charged molecule. When forced through the chamber 16 it
enters the damaged wall and readily interacts with the surfaces of
the various cells within the injured wall, as well as with the
connective tissue between the cells. In effect it "sticks to" the
injured site and inhibits, but does not completely stop the
multiplying of SMC. Because heparin is `sticky` it will stay in an
effective position until the injury is healed.
The general process by which the injured artery repairs itself
involves the bathing of the injured area with platelets and other
cell growth promoters in the blood. The cells within the injured
area of arterial wall continue to divide and multiply to generate
new cellular tissue and repair the wound. When the growth reaches
the appropriate level, the body's feedback mechanism signals the
growth to stop. Restenosis occurs when the feed back mechanism is
not functioning properly and the SMC continues to multiply in an
uncontrolled manner in the damaged angioplasty site. The presence
of the heparin appears in some manneer to control the
multiplication of the SMC cells so that they continue to multiply,
but in a controlled manner until the regular control mechanism of
the body takes over. The heparin affects only the deeper SMC cells
and does not affect the surface endothelial cells.
An alternative procedure to the use of the two balloon catheter as
described above is to use the three balloon catheter. In this
method the catheter is inserted and placed over the plaque using
the procedure described. The first step is to inflate the middle
balloon, 10 to rupture the plaque. The balloon is deflated; after
restoration of blood flow for a brief period, expansion of balloons
8 and 9 create a chamber around the angioplasty site. The heparin
is then administered as described above. The chamber is held in
place for 5 to 60 seconds so that the heparin can stick to and
enter the adjacent surfaces, the balloons are deflated and then the
catheter is removed.
The catheter body can be prepared from any of a number of readily
available, non-toxic, flexible polymers including, for example,
polyolefins, such as polyethylene or polypropylene, and polyvinyl
halides, such as polyvinyl chloride or polyvinylidene chloride. The
balloon can be fabricated from similar materials manufactured so as
to be expansible under pressure and with sufficient elasticity to
collapse when the pressure is released and negative pressure
applied. The dimensions of the balloons will be such that they will
reach the desired diameter at a pressure of from about 75 to 150 mm
Hg and hold the dimensions even if the pressure is increased to as
high as 5 or more atmospheres.
The absolute dimensions selected for the balloons will depend upon
the diameter of the arteries involved. For example, the ring
balloons may be from 2 to 5 mm in length and their expanded
diameters will be approximately the same. The central balloon will
be of the same diameter range as the end balloons, but the length
will be from about 10 to 50 mm.
* * * * *