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Description  |
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BACKGROUND OF THE INVENTION 1. Field of the Invention
This invention relates in general to certain new and useful improvements in
methods for reducing dysfunction in angioplasty procedures, and more
particularly, to a method of the type stated which relies upon the
introduction of a selected amount of a prostaglandin compound into the
artery in which an angioplasty procedure is performed and compositions
containing specified amounts of the prostaglandin compound to produce a
high degree of efficacy. 2. Brief Description of the Prior Art
Angioplasty procedures were first used in the 1960's and since that time
have gained widespread acceptance as a means of obtaining dilation of
arteries. Particularly, angiomyocardial angioplasty procedures have become
widely adopted to obtain dilation of myocardial arteries.
In the conventional angioplasty procedure, a small balloon tipped catheter
is introduced into an artery, often using a guide wire or a catheter tube
in which a balloon may be positioned at an artery stenosis. These balloons
and catheter assemblies are often referred to as coronary balloon dilation
catheters. In many cases, the catheters are designed to permit continued
distal dye injections through the balloon to permit visual verification of
proper approach to a lesion or other area in which the procedure is to be
employed.
It is well known that cardiac angioplasty procedures involve a risk of both
local and systemic thromboembolic effects, which are even greater than
cardiac catheterization. Usually, the patient is injected with heparin and
various known blockers during the procedure. Moreover, for a substantial
period of time after the procedure, which may be six months to a year, or
longer, the patient must necessarily be treated with platlet inhibiting
drugs. Other complications which often occur during transluminal
angioplasty procedures include disection of an artery such as a coronary
artery, intramural hematoma, and occlusion of the artery resulting in
myocardial infarction.
Some of the problems which appear to arise after angioplasty procedures
include early restenosis and possibly abrupt occlusion. It is therefore
necessary to provide some means which exhibits a cytoprotective effect
during ischemia and which may salavage the myocardium during transluminal
angioplasty, particularly when high inflation pressures are needed for a
long duration, as for example, up to six minutes, or otherwise, in the
case of an unstable angina.
In order to overcome some of the dysfunction resulting from percutaneous
transluminal coronary angioplasty, heparin and intracoronary
nitroglycerine, as well as systemic calcium blockers have been used. In
addition, various preparations have been employed prior to the angioplasty
procedures and include, for example, aspirin, Persantine, intravenous
dextran, etc. Nevertheless, the various complications still persist.
Moreover, these complications account for virtually all of the problems in
percutaneous transluminal coronary angioplasty. In the NHLBI registry, as
reported by Cowley et al in the American Journal of Cardiology, 1984, the
results of the cases of 3,079 patients were examined and 418 patients
suffered some form of post angioplasty procedure complications.
There have been numerous publications dealing with the various types of
prostaglandin compounds and their effectiveness for providing antiplatelet
effects and antithrombotic effects and antispasmic effects. For example,
U.S. Pat. No. 4,239,778 to Venton et al, discloses a novel azaprostanoic
acid analog and its effectiveness as an inhibitor of platelet aggregation.
U.S. Pat. No. 4,095,036 to Yankee discloses an 8-beta 12-alpha PG-2
prostaglandin type analog and its effectiveness in controlling spasm,
particuarly in asthmatic conditions, as well as a decrease in blood
platelet adhesiveness. This patent also discloses the use of various
prostaglandin analogs as being effective to prevent the formation of
thrombi to thereby prevent post operative thrombosis and their
effectiveness in and prevention of myocardial infarcts.
In like manner, U.S. Pat. No. 4,205,178 to Axon discloses various
prostaglandin E derivatives and analog compounds which are also effective
in prevention of myocardial infarcts and effective in inhibiting platelet
aggregation. This patent also discloses the use of these compounds as
hypotensive agents when administered at a rate of about 0.01 to about 50
micrograms per kilogram of body weight per minute.
There have been several articles dealing with the effects of prostaglandin
reduction as a result of arterial insult. For example, the article
entitled "Vessel Wall Arachidonate Metabolism After Angioplasty" by Andrew
Cragg, M.D. et al discusses the mechanism of post angioplasty vasospasm
and the postulation that a reduction in prostaglandin I-2 or prostaglandin
E-2 might contribute to spasm of a dilated artery, as reported in the May
1, 1983 edition of the American Journal of Cardiology, Volume 51, pages
1441 et seq. In like manner, a discussion of paralysis and hyperemia of an
arterial wall and altered vasomotor tone has been demonstrated following
percutaneous transluminal angioplasty and the effect of reduction of
prostaglandin compounds generated by the body, in "Prostaglandins and
Angioplasty" as reported in Interventional Radiology, Dec. 1983, page 681
et seq.
OBJECTS OF THE INVENTION
It is, therefore, a primary object of the present invention to reduce
dysfuction in an angioplasty procedure, by administering to a patient, a
pharmacological amount of a composition which will provide antiplatelet
effects, antispasmatic effects and probable antithrombotic effects.
It is another object of the present invention to reduce the problems which
frequently arise during percutaneous transluminal coronary angioplasty by
adminstering to the patient a pharmacological amount of a prostaglandin
composition.
It is a further object of the present invention to reduce the dysfunction
which can arise in or from an angioplasty procedure by administering to a
patient a prostaglandin E-1 composition, both during the angioplasty
procedure and intravenously for a selected time period thereafter.
It is another salient object of the present invention to provide a method
of reducing dysfunction which may arise in an angioplasty procedure by
adminstering to an intracoronary artery of the patient, an amount of a
prostaglandin compound substantially in excess of the amount which would
have been generated by a normal myocardial artery when insulted, such that
the amount of prostaglandin compound administered is substantially greater
than an amount which would be administered in a replacement therapy.
It is also an object of the present invention to provide a composition for
reducing the dysfunction which can normally arise in an angioplasty
procedure and which comprises a selected carrier containing a specified
amount of a prostaglandin compound to produce the desired efficacy.
It is still another object to provide a pre-packaged combination of
components which is effective for reducing dysfunction in an angioplasty
procedure.
With the above and other objects in view, our invention resides in the
novel method employed in using a prostaglandin composition to reduce the
effects of dysfunction in angioplasty procedures and the prostaglandin
compositions which are effective for this purpose.
BRIEF SUMMARY OF THE DISCLOSURE
The present invention relies on a discovery that it is possible to
substantially reduce dysfunction in angioplasty procedures in human
beings, by introduction in relation to an artery in which an angioplasty
procedure is to occur, a selected amount of intra-arterial prostaglandin
compound. This prostaglandin compound is administered in a proper amount
which will provide cyto-protection and provide antithrombotic effects,
antiplatelet effects and antispasmic effects.
The prostaglandin compound may adopt the form of several well known
prostaglandin analogs and isomers, as hereinafter described, and include,
for example, the prostaglandin E compounds, the prostaglandin I compounds,
the prostaglandin D compounds, the prostaglandin F compounds, Ciprostene,
etc. Some of the more preferred prostaglandin compounds used in accordance
with the present invention include, prostaglandin E-1, prostaglandin I-2
and Ciprostene.
The prostaglandin compound may be administered before the angioplasty
procedure and generally during the angioplasty procedure and in many
cases, it is administered for a selected time period thereafter. In the
case of a coronary angioplasty procedure, an intracoronary bolus injection
is administered, followed by a continuous intravenous injection for a
selected time period, as for example, 6 to 12 hours or more. More
preferably, an intracoronary prostaglandin bolus injection is administered
immediately prior to the procedure and another intracoronary prostaglandin
bolus injection is administered immediately after the procedure, and which
is followed by the intravenous administration. Intracoronary prostaglandin
administration during the procedure may also take place, as required.
The prostaglandin compound may be dissolved in a liquid carrier, as for
example, a dehydrated alcohol. However, other liquid carriers, hereafter
specified may be used. The liquid carrier must be pharmaceutically
acceptable and pharmacologically inactive.
It is well known that the normal body artery will generate one or more of
the selected prostaglandin compounds, as for example, prostaglandin I-2
when the artery is insulted, that is stressed or otherwise subjected to an
injury. See for example, "Vessel Wall Archiondonate Metabolism After
Angioplasty" by Andrew Cragg, M.D. et al, supra. See also, "The Treatment
of Vasospastic Disease With Prostaglandin E-1", British Medical Journal,
Volume 201. In a typical myocardial insult, the myocardial artery will
generate prostaglandin usually in an amount of about one picogram up to a
maximum of about three picograms. See for example, "Vascular Prostaglandin
and Thromboxane Production in a Canine Model of Myocardial Ischemia" by
James M. Schmitz et al, Circulation Research, Volume 57, No. 2, Aug. 1985;
"Prostaglandins in Cardiovascular Medicine: Part 1", by John G. Harold,
M.D., William E. Shell, M.D. et al; "Cardiovascular Reviews and Reports",
Volume 5, No. 9, Sept. 1984.
The amount of prostaglandin compound which is administered in accordance
with the present invention will range, depending on the condition of the
patient, including his or her health, age, previous coronary history,
ability to accept the prostaglandin without adverse side effects and like
factors. Generally, in a coronary angioplasty procedure the amount of
intracoronary prostaglandin administered to a patient ranges from about 25
nanograms to about 400 nanograms in bolus administrations and preferably
ranges from about 80 nanograms to about 260 nanograms, based on
prostaglandin E-1. The amounts of intracoronary prostaglandin which are
administered represent generally the total amount immediately prior to,
during and immediately after the angioplasty procedure. Thus, the first
bolus injection may comprise about 12 to about 200 nanograms, and
preferably about 40 to about 130 nanograms. The second or post-procedure
bolus injection may also comprise about 12 to about 200 nanograms and
preferably about 40 to about 130 nanograms.
More preferably, about 65 nanograms of prostaglandin is administered
immediately prior to the angioplasty procedure and an additional amount of
about 65 nanograms of prostaglandin is administered immediately after the
angioplasty procedure in bolus injections, based on prostaglandin E-1. If
the prostaglandin compound is administered during the angioplasty
procedure, the amounts administered immediately prior to and/or
immediately after the procedure can be altered so that the total amount
administered falls within the above specified ranges.
The above ranges and specific amounts identified are those specifically for
prostaglandin E-1. The ranges for the other prostaglandin analogs and
isomers encompassed by the present invention and the specific amounts
therefore are based on the efficacy of such isomers or analogs compared to
prostaglandin E-1. Thus, for example, if a particular prostaglandin
compound encompassed by the present invention has an efficacy of about 50
per-cent of that of prostaglandin E-1, the ranges and the specific amounts
administered of that compound would be doubled.
Inasmuch as the prostaglandin compounds are adminstered in accordance with
the present invention in nanogram amounts (1-billionth of a gram) and at
minimum, 25 nanograms, and the amount of prostaglandin which may be
generated by any body artery on insult is no greater than picogram amounts
(1 trillionth of a gram) and usually less than 3 picograms, it can be seen
that the prostaglandin compounds administered in accordance with the
present invention are administered in amounts almost one thousand times,
and usually much greater than one thousand times the amount of
prostaglandin which could be generated by any normal body artery when
insulted. Thus, the administration of prostaglandin compounds in the
nanogram range as specified herein constitutes a pharmacological amount
and does not merely operate as a replacement, as for example, in
replacement therapy, that is, adminstration of an amount to replace that
which may have been lost. As an example, cortisone may be adminstered when
body cortisone generation is depleted, although in amounts massively
greater than the amounts depleted and is thus considered to be a
pharmacological administration.
In view of the above explanation of administered prostaglandin amounts, the
term "pharmacological amount" is used herein to mean the administration of
the prostaglandin compound in an amount substantially greater than the
amount of prostaglandin which would be generated by a myocardial artery
when insulted, and usually in an amount of about at least one thousand
times greater than the amount which would be generated by a normal
myocardial artery when insulted.
The administration of the prostaglandin compound in the pharmacological
amount produces unexpected results in that the coronary artery or other
artery in which the prostaglandin was administered remains dilated for a
period of two to three times longer than if nitroglycerine or verapamil or
both were adminstered. Moreover, the amount of arterial dilation is
substantially greater and in many cases, the duct of the artery will
remain dilated to twice its original size. As an example, in an
angioplasty procedure, the artery may remain dilated for a period of about
45 seconds after removal of the catheter tip. With administration of
nitroglycerine, the artery may remain dilated for a period of about two
minutes. With the administration of prostaglandin E-1, the same artery
will remain dilated for a period of seven minutes or longer. This dilation
period enables the body to overcome the results of abrupt occulsion or
other dysfunction which often results after an angioplasty procedure. In
addition, there is a substantially greater length of the myocardial artery
which is dilated after the adminstration of the prostaglandin compound in
the pharmacological amount. For example, a length of artery which is
dilated may easily exceed two to three times the length of artery section
which is dilated under the administration of nitroglycerine.
This inventive process has many other advantages and has other purposes
which may be made more clearly apparent from a consideration of the forms
in which it may be embodied. These forms are set forth in the following
detailed description. However, its to be understood that the detailed
description is only for purposes of illustrating the general principles of
the invention and that it is to be understood that such detailed
description is not to be taken in a limiting sense.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In accordance with the present invention, a prostaglandin compound, as
hereinafter described in more detail, is administered to the artery of a
human being in which an angioplasty procedure is to occur. As indicated
previously, this prostaglandin compound is administered in an amount
required to provide cyto-protection, antithrombotic effects, antiplatelet
effects and antispasmic effects.
Generally, the prostaglandin compound is administered in the region in
which the balloon catheter is to be inserted in order to reduce the
otherwise adverse side affects and dysfunctions which may result when
attempting to dilate an artery. While the prostaglandin compound is
generally administered just prior to the angioplasty procedure, in many
cases it is desirable to administer the prostaglandin compound to the
patient during the procedure and/or for some time period thereafter and
which is hereinafter described in more detail.
The method of the present invention was developed and has been proven to be
highly effective in myocardial angioplasty procedures. However, the method
of the present invention utilizing the administration of the prostaglandin
compound is also highly effective for conducting angioplasty procedures in
other portions of the human body. Thus, and while the preferred embodiment
of the invention deals with myocardial angioplasty procedures, it is to be
understood that the invention is applicable to other angioplasty
procedures as well.
Prostaglandin compounds which are used in accordance with the present
invention are unsaturated fatty acids containing 20 carbon atoms and which
usually include a pair of spaced apart side chains and each of which form
somewhat of a saw-tooth configuration, much in the same form as a hair
pin. The two side chains are joined at one end only, by means of a
cyclopentane ring. At the other end, one of the side chains terminates in
a carboxylic acid group. In addition, the two side chains may be provided
with one or more hydroxyl groups and/or ketone groups along the length
thereof. These prostaglandins generally have a chemical structure which
may be diagramatically illustrated in the following generalized structural
formula:
##STR1##
These prostaglandins, which are collectively often referred to as
"eicosanoids", are known to exhibit biological activitities. These
activities include effects on the muscles or vessels, and/or inflamatory
response, thermo-regulation, platelet aggregation and the like. However,
heretofore, it has not been recognized that the prostaglandin compound
could be effective in reducing and even overcoming most of the dysfunction
resulting from and in angioplasty procedures.
Prostaglandin E-1 is one of the preferred prostaglandin compounds which may
be used in accordance with the method of the present invention. The
prostaglandin E-1 compound is metabolically derived from the
polyunsaturated fatty acid, dihomo-y-linolenic acid. This protaglandin
E-1, has the empirical formula C.sub.20 H.sub.34 O.sub.5 and this
prostaglandin E-1 compound has the chemical formula
(11a,13E,15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid. Prostaglandin
compounds of this type are more fully described in U.S. Pat. No. 3,069,322
to Bergstromet al.
Prostaglandin E-1 can be structurally diagramed as follows:
##STR2##
The dotted lines between carbon No. 7 and carbon No. 8 indicate
orientation of the atom and any group attached thereto below the plane of
the ring in the alpha stereochemistry. In other words, that orientation is
below the plane of this paper. The same holds true with the hydroxyl
groups at the No. 11 and No. 15 carbon atoms.
The prostaglandin used in accordance with the present invention is not
limited to the prostaglandin E-1 compound but encompasses other
derivatives of prostanoic acid and includes all other prostaglandins which
provide the desired pharmacological effects such as cyto protection. Those
prostaglandins include, for example, prostaglandin E-2 and prostaglandin
E-3. The prostaglandin compounds are also deemed to include their lower
alkyl esters and salts and amides which exhibit the desired
pharmacological activity. The prostaglandin E-2 compounds are disclosed in
U.S. Pat. No. 3,598,858 and esters thereof are disclosed in U.S. Pat. No.
3,691,216 and U.S. Pat. No. 3,795,697.
The numerals following the designations "prostaglandin" or "prostaglandin
E" e.g. "1", "2", "3", represent the total number of double bonds in the
two side chains. Thus, prostaglandin E-2 has an additional double bond
between carbon No. 5 and carbon No. 6 and has a structural formula as
follows:
##STR3##
Prostaglandin E-3 has still an additional double bond between carbon No.
16 and carbon No. 17 and has a structural formula as follows:
##STR4##
The compositions used in the method of the present invention also include
the various isomers, as aforesaid, and include for example prostaglandin A
isomers and the prostaglandin B isomers. The prostaglandin A compounds do
not include the hydroxyl group at carbon No. 11, but have a double bond
within the ring between carbon No. 10 and carbon No. 11. Thus,
prostaglandin A-1 has a structural formula as follows:
##STR5##
The prostaglandin B compounds are isomers of the prostaglandin A compounds
having a double bond between carbon No. 8 and carbon No. 12. Thus,
prostaglandin B-1 has a structural formula as follows:
##STR6##
The compound prostaglandin F is also, for example, encompassed by the
present invention. The prostaglandin F compounds have a hydroxyl group at
the No. 9 carbon atom in place of a ketone group. Thus, prostaglandin F-2a
has a structural formula as follows:
##STR7##
Those prostaglandin compounds having the chemical name "Ciprostene",
namely, 9-methylcarbacyclin-calcuim salt and having the empirical formula
C.sub.20 H.sub.34 O.sub.5 are also prostaglandin compounds which are
encompassed by and achieve the efficacious results in accordance with the
present invention. The Ciprostene form of prostaglandin is usually
characterized as a calcuim salt and is a chemically stable analog of
prostacyclin. Ciprostene has a structural formula as follows:
##STR8##
It can be observed that the above are a non-limiting list of the
prostaglandins which can be used and show that essentially any
prostaglandin which provides the desired pharmacological effect can be
employed. Moreover, in a broad sense and considering the generalized
structural formula set forth above, it should be understood that the
orientation, as shown in dotted lines, may be in or out of the plane of
the cyclopentane, that is in or out of the plane of this paper.
Thus, the prostaglandin compound encompassed by the present invention, as
represented by the generalized formula set forth above, is comprised of a
cyclopentane ring having a pair of side chains therein and one of which
terminates with a COO-- moiety. The "dotted" bond in the generalized
structural formula may be in or out of the plane of the cyclopentane ring
and any of the bonds in the side chains may be single bonded or double
bonded and which may also be in or out of the plane of the side chains and
which side chains may include hydroxyl and ketone moieties thereon which
may be in or out of the plane of the cyclopentane ring.
The COO-- group, which may be represented by COOR, is preferably a
carboxylic acid group, e.g. COOH. However, the R may be hydrogen, as
aforesaid, C.sub.1 -C.sub.12 alkyl or C.sub.1 -C.sub.10 cycloalkyl,
C.sub.6 -C.sub.16 aralkyl, phenyl optionally substituted with one, two or
three chloro or C.sub.1 -C.sub.3 alkyl. In general any parmacologically
acceptable cation may be used.
The biosynthesis of prostaglandin compounds and their pharmacological
actions are technically complex and the details of the synthesis are not
necessary for the practice of the present invention. However, in general
terms, the immediate fatty acid precursers of prostaglandin biosynthesis
are dihomo-y-linoleic acid (chemically known as 5, 8, 11-eicosatrienoicc
acid) and arachidonic acid (chemically known as 5, 8, 11,
14-eicosatetraenoic acid). Substantial quanities of these acids, which are
primarily of dietary origin, may be synthesized in mammals from linoleic
acid. The fatty acids are then stored as phospholipids. These
phospholipids are then acted upon and released by the action of a
phospholipase which is then the first step, and also rate limiting step,
in the prostaglandin synthesis. The dihomo-y-linoleic acid is acted on by
cyclooxygenase and this gives rise to prostaglandin E-1 through the
endoperoxides PGG-1 and PGH-1.
Any carrier which is pharmaceutically acceptable and is pharmacologically
inactive may be used to deliver the prostaglandin compound. Generally,
dehydrated alcohols such as ethyl alcohol, normal propyl alcohol,
isopropyl alcohol, etc. may be employed. Other carriers which may be
employed are for example saline solutions. The amount of carrier used to
deliver a given amount of prostaglandin is determined by the duration of
the prostaglandin administration. Thus, if it is desired to administer the
prostaglandin over a nine hour period, a determination of the amount of
prostaglandin is made taking into consideration the patients weight, as
hereinafter described. The amount of carrier selected will be sufficient
to administer that determined amount of prostaglandin over the selected
time period.
In use, the prostaglandin compound can be stored in unopened amplules and
may be stable for up to two years in a refrigerated condition. When the
prostaglandin compound is dissolved in a saline solution or glucose to
form an infusion solution, this infusion solution can be stable for up to
about 24 hours.
The prostaglandin is administered to the region in which an angioplasty
procedure is to take place in an amount of about 25 nanograms to about 400
nanograms and preferably about 80 nanograms to about 260 nanograms and
even more preferably in an amount of about 130 nanograms, based on
prostaglandin E-1, for bolus injections. In some cases, it is desirable to
intravenously administer the prostaglandin compound after the angioplasty
procedure, as for example, generally continuously during a 12 hour period
after the procedure, and which may vary somewhere between about 9 to about
15 hours. In this case, the prostaglandin compound is administered in an
amount of about 10 to about 100 nanograms per kilogram of body weight per
minute after the procedure, based on prostaglandin E-1, and during the 9
to 15 hour period.
More preferably, the prostaglandin compound is intravenously administered
in an amount of about 15 to about 40 nanograms per kilogram of body weight
per minute after the procedure, based on prostaglandin E-1, and during the
9 to 15 hour post angioplasty period. Here again, the amounts which are
administered will vary from patient to patient, depending on those patient
factors mentioned above, e.g. health, age, coronory health history,
reaction to administration, etc.
The present invention also provides compositions which are effective for
reducing dysfunction in angioplasty procedures and which involve the use
of the prostaglandin compounds. The compositions generally comprise a
carrier which contains a selected amount of the prostaglandin. The carrier
must be one which does not alter the prostaglandin compound and does not
inhibit its effectiveness. The carrier must also release the prostaglandin
compound at a rate sufficient to dilate the blood vessels. Naturally, the
carrier should be in a form which is capable of being intravenously
introduced.
Each of the other prostaglandin compounds which are encompassed by the
present invention have an efficacy directly related to that of
prostaglandin E-1. Thus, the amounts of the other prostaglandin compounds
which may be employed in the present invention are based upon the efficacy
of such prostaglandin compounds compared to the efficacy of prostaglandin
E-1. For this purpose, the amount of any prostaglandin compound which is
used in a carrier is present in an amount necessary to produce an efficacy
approximately equivalent to the efficacy produced by at least a minimum of
25 nanograms of prostaglandin E-1 to the efficacy produced by a maximum
amount of about 400 nanograms of prostaglandin E-1.
The efficacy which is produced by any other prostaglandin compound
encompassed by the present invention can be easily related to the efficacy
produced by prostaglandin E-1 based on trial techniques. In other words,
it is relatively simple to determine the efficacy produced by using, for
example, prostaglandin I-2 and to determine the efficacy produced by using
prostaglandin E-1 such that the skilled artisan can easily determine the
amounts of any other prostaglandin to be used based on the use of
prostaglandin E-1. It should be understood that the efficacy which can be
achieved by the prostaglandin compounds will naturally vary from patient
to patient, although the beneficial results which have been achieved by
use of the method and the compositions of the present invention are easily
noticeable. Thus, the efficacy of a given prostaglandin compound cannot be
precisely determined with respect to prostaglandin E-1, but is capable of
being approximately equivalently determined taking into consideration the
various divergences which will occur from patient to patient.
In the case of the prostaglandin I-2 compound, this prostaglandin compound
would be present in the composition administered to the patient
immediately before and immediately after the angioplasty procedure in a
total amount of about 3.7 nanograms to about 75 nanograms. The
prostaglandin I-2 more preferably would be administered in a range of
about 12 nanograms to about 49 nanogram. The ciprostene prostaglandin
compound would be present in the composition and administered to the
patient immediately before and after the angioplasty procedure in a total
amount of about 187 nanograms to about 6000 nanograms. The ciprostene
prostaglandin preferably would be administered in a range of about 600
nanograms to about 3900 nanograms, and even more preferably about 1430
nanograms.
The above described quantities of prostaglandins are all based on the use
of bolus injections. The amounts specified are also based on one
intracoronary bolus injection prior to the angioplasty procedure and one
bolus injection after the angioplasty procedure. Thus, each injection
would be based on one-half the amounts specified. If intracoronary
injections are made during the procedure, the amounts administered before
and after would be altered. Further, the amounts administered may vary
from patient to patient for the reasons mentioned above.
There are three general groups of carriers which have been found to be
highly effective for use in the compositions of the invention. These
carriers include isotonic solutions as well as two forms of hypertonic
solutions. One type of hypertonic solution includes the angiographic
contrast materials and the second form of hypertonic solution includes the
biodegradable prostaglandin carrying spheres.
The isotonic solutions are generally all liquid in form and are typically
various salt solutions. One of the preferred isotonic solutions is a
saline solution present in an amount of about 5 cc. This amount of saline
is effective to hold about 25 to about 400 nanograms of the prostaglandin
E-1 compound. This amount of saline solution is also effective for
generally all of the other prostaglandins encompassed by the present
invention.
Other types of isotonic solutions which can be employed are 0.9 percent
sodium chloride or some dextrose solutions, as for example a five percent
(5%) dextrose solution. It is also possible to use a five percent (5%)
dextrose solution with 0.2 percent sodium chloride therein. Lactated
Ringers are also effective as one of the liquid carriers The isotonic
liquid carrier should have an osmolar strength about equivalent to that of
seawater.
Angiographic contrast material can also be used as an effective carrier for
the prostaglandin compounds. Many of the angiographic materials which may
be used are usually X-ray absorbent as for example, hypaque-sodium.
Potassium iodine and certain other recognized potassium salts may also be
used as the carrier solution. It is also possible to use multiple ionic
materials such as potassium iodide and iron combinations as the carrier
since they all function as angiographic contrast materials.
The amount of the angiographic contrast material which is employed depends
upon the amounts which are normally used to achieve the necessary contrast
in an angiography procedure. Usually, about 3 cc to about 10 cc of the
angiographic contrast material is used as the carrier per bolus injection.
The third group of carrier materials are the prostaglandin carrying
microspheres. Generally, three major types of microspheres may be employed
and these include: (1) protein laden microspheres, (2) carbohydrate laden
microspheres and (3) free fatty acid laden microspheres.
The protein laden microspheres may include, for example, albumen laden
microspheres. The carbohydrate laden microspheres may include, for
example, various known and accepted starch laden microspheres as well as
various known polysaccharides. Liposome is an effective example of a fat
laden microsphere.
The term "microsphere" is used to represent particles ranging in size from
about 7 .mu., the diameter of a red blood cell, to about 100 .mu. in
diameter. A particular group of "uniformly" sized microspheres may vary in
diameter up to around 25%. Thus, a group of 10 .mu. diameter microspheres
might range in size from around 8.5 .mu. to around 11.5 .mu. in diameter.
Usually, about 225,000 to about 500,000 microspheres are present as the
carrier for a bolus injection.
The microspheres of the present invention may be composed of any long chain
compound susceptible to cross linking to a solid in which amide or
carboxyl groups are exposed or are capable of being exposed by suitable
treatment. This includes, but is not limited to, latex materials such as
polystyrene and styrene divinylbenzene, agarose, polyalkylcyanocrylate,
albumin, cross-linked albumin, sucrose, starch, cellulose and dextran.
Usually, about 225,000 to about 500,000 microspheres are present as the
carrier for a bolus injection.
As indicated previously, the prostaglandin compound may be administered for
a selected time period, as for example, nine to 15 hours after the
angioplasty procedure. This intravenous administration, when coupled with
the previously described intracoronary administration has been found to
produce highly effective results. The amount of prostaglandin in the
solution, which is administered drop-wise, should be in the range of about
10 nanograms to about 100 nanograms per kilogram of body weight per minute
for prostaglandin E-1. Preferably, the prostaglandin E-1 is administered
in a range of about 15 to about 40 nanograms per kilogram of body weight,
per minute and even more preferably about 20 nanograms per kilogram of
body weight per minute.
The amount of the other prostaglandin compounds which would be administered
intravenously is also based on the efficacy of such other prostaglandins
related directly to the efficacy of prostaglandin E-1. Thus, the
prostaglandin in the carrier to be administered to a patient is present in
an amount to deliver to the patient a desired weight of prostaglandin in
nanograms per kilogram of body weight of the patient per minute to produce
an efficacy equivalent to the efficacy of prostaglandin E-1 when
administered in the selected range.
In a more preferred embodiment, the amount of prostaglandin E-1 is
administered in a range of about 15 nanograms to about 40 nanograms per
kilogram of body weight per minute, as aforesaid. With respect to the
prostaglandin I-2 compound, this prostaglandin would be administered in an
amount of about 1.5 nanograms to about 19 nanograms and preferably in a
range of also 2 to about 7.5 nanograms per kilogram of body weight per
minute. Ciprostene would be administered in an amount of about 75
nanograms to about 1500 nanograms and preferably about 112 to about 600
nanograms per kilogram of body weight per minute.
It has also been found in accordance with the present invention, that the
intraveneous administration of the prostaglandin compound followed by the
intracoronary administration substantially reduces the restenosis which
was normally encountered in angioplasty procedures. It may be observed
from the following Example III that there was a marked decrease in
restenosis when the intraveneous administration of prostaglandin followed
the intracoronary administration. In addition, when the amount of
prostaglandin is reduced progressively to 0 during the last hour or two
hours of the intravenous administration, there is a reduced tendency for
the patient to suffer adverse effects.
The present invention is effective in providing compositions containing the
above identified amounts of prostaglandin for ready administration of the
same. Thus, and for example, a composition may contain a carrier and the
amount of prostaglandin carried by that carrier which is necessary to
produce an efficacy approximately equivalent to the efficacy produced by
adminstration of prostaglandin E-1 in a range of about 25 nanograms to
about 400 nanograms. More preferably, this composition would contain the
prostaglandin compound necessary to produce an efficacy in a range
approximately equivalent to the efficacy produced by the administration of
80 nanograms to about 260 nanograms of prostaglandin E-1.
The composition also preferably includes those carriers which were
mentioned above and include those selected from the class consisting of
(a) an isotonic solution, (b) an angiographic contrast material and (c)
biodegradable prostaglandin carrying microspheres.
In another embodiment, the composition of the present invention may be
described as that composition which comprises the carrier for the
prostaglandin compound and also the prostaglandin compound which is
carried by that carrier. The prostaglandin is present so that it can
administered over a selected time period at a relatively constant rate and
in an amount to produce an efficacy approximately equivalent to that
produced by the administration of prostaglandin E-1 in a range of about 10
nanograms to about 100 nanograms per kilogram of body weight per minute.
In this way, the composition thereby provides the cyto-protection and the
antithrombotic effects and the antiplatelet effects and the antispasmic
effects.
The present invention also provides a kit or package containing the
necessary components containing the prostaglandin compound in amounts to
be administered in the proper dosage. Thus, a kit may be initially
provided with a first syringe containing the amount of prostaglandin
compound necessary to produce an efficacy produced by administration of 12
to about 200 nanograms of prostaglandin E-1 and preferably the efficacy
produced by the administration of about 40 to about 130 nanograms of
prostaglandin E-1. The kit would also contain a second syringe for a bolus
injection and which would also contain a prostaglandin compound present in
an amount to produce an efficacy approximately equivalent to the efficacy
of about 12 nanograms to about 200 nanograms of prostaglandin E-1 and
preferably an efficacy approximately equivalent to that produced by the
administration of about 40 nanograms to about 130 nanograms of
prostaglandin E-1. Finally, this kit or package would also include a
container such as a sealed package containing the amount of prostaglandin
compound necessary to provide intraveneous administration or the selected
time period of 9 to about 15 hours.
As a specific example of a package, the first syringe or container would
contain about 65 nanograms of prostaglandin E-1 in a 1 cc saline solution
and which may be diluted to about a 5 cc saline solution for use. The kit
would also include a second syringe or container which contains about 65
nanograms of prostaglandin E-1 in 1 cc of a saline solution and which
again may be dilluted to about a 5 cc saline solution in use. Finally, the
package or kit of the present invention would include, in this example, a
container of the saline solution which administers about 15 to about 40
nanograms of prostaglandin E-1 per kilogram of body weight per minute for
a 12 hour period.
EXAMPLES
The invention is further described by but not limited to the following
examples.
EXAMPLE I
In order to assess the effects of intracoronary prostaglandin E-1 on
myocardial blood flow in relation to a successful coronary angioplasty,
twelve patients were given sixty five nanograms of the prostaglandin E-1
which was hand injected by bolus under blinded conditions. The angioplasty
procedure involved a residual luminal diameter of less than 40 percent.
The sixty five nanograms prostaglandin E-1 was dissolved in about four
mililiters of dehydrated alcohol. Twelve additional patients were given
four mililiters of dehydrated alcohol as a placebo and control agent.
Digital radiographic assessments of contrast medium appearance time distal
to the stenosed coronary artery under hypermic conditions were made 45
seconds after the start of the angioplasty procedure. The same
radiographic assessment was made as a control under non-hypermic
conditions on an intracoronary placebo 45 seconds after the start of the
angioplasty procedure. This information was used to measure myocardial
blood flow immediately before and after the administration of the
prostaglandin E-1. The known accepted method of the reciprocal of the
coronary flow ratio (CFR) was used to measure myocardial blood flow.
Neither the prostaglandin E-1, nor the placebo elicited any angina,
dysrythemia or any significant pressure changes.
This study revealed the following data in which PGE-1 is the prostaglandin
E-1 compound and PTCA represents the percutaneous transluminal coronary
angioplasty procedure. N represents the number of patients, MBF represents
the myocardial blood flow and CFR represents the coronary flow ratio, LAD
represents the left anterior descending coronary artery and RCA represents
the right coronary artery.
______________________________________
LAD or
RCA
Parameter N Stenosis CFR
______________________________________
IC Placebo
Pre-PTCA 6 80.4 .+-. 11
1.02 .+-. 0.13]p = NS
IC PGE-1
Pre-PTCA 6 80.4 .+-. 11
1.14 .+-. 0.17
IC Placebo
Post-PTCA 6 24.6 .+-. 10
1.48 .+-. 0.14]p = .001
IC PGE-1
Post-PTCA 6 24.6 .+-. 10
2.16 .+-. 0.34
______________________________________
EXAMPLE II
In order to evaluate post angioplasty effects in which prostaglandin was
administered, 40 patients were selected between the ages of 18 and 75. The
patients were males or otherwise post-menopausal or sterilized females.
The patients undergoing the post transluminal coro | | |
