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TECHNICAL FIELD
The present invention relates to a method and composition for treating
pathological hydrophobic interactions in which there is acute impairment
of the circulation, especially the microcirculation. More particularly,
the present invention relates to compositions and methods for treating
circulatory diseases comprising using certain ethylene oxide-propylene
oxide condensation copolymers either alone or in combination with other
compounds, including but not limited to, fibrinolytic enzymes,
anticoagulants, free radial scavengers, antiinflammatory agents,
antibiotics, membrane stabilizer and/or perfusion media.
BACKGROUND OF THE INVENTION
The term "pathological hydrophobic interactions" means detrimental adhesion
of components, including but not limited to, cells and molecules in blood
or other biological fluids thereby slowing or stopping the flow of blood
or other biological fluid. The term "fibrinolytic enzyme" means any enzyme
that is capable of cleaving fibrin or capable of causing fibrin to be
cleaved. Enzymes that are capable of cleaving fibrin or causing fibrin to
be cleaved include, but are not limited to, streptokinase, urokinase,
tissue plasminogen activator (t-PA) produced from cell cultures, tissue
plasminogen activator produced by recombinant DNA technology and
plasminogen activator produced from prourokinase. The terms "isotonic" or
"isoosmotic" solution are defined as solutions having the same osmotic
pressure as blood. The term "SOD" means superoxide dismutase and refers to
any enzyme capable of neutralizing oxygen radicals. The terms clot, fibrin
clot and thrombus are used interchangeably. The term "microcirculation"
means blood circulation through blood vessels that are about 50 microns in
diameter or less. The term "soluble fibrin" means soluble high molecular
weight polymers of fibrinogen and fibrin. The term "biological fluids"
means blood, lymph, or other fluids found in animals or humans. The term
"platelet suspension" means a suspension of platelets that has a higher
concentration of platelets than that found in blood. The term "plasma
extender" means any substance that can be added to animal or human blood
to maintain or increase coloid osmotic pressure. The term "cytoprotective"
as used herein, means an increased ability of myocardinal, endothelial and
other cells to withstand ischemia or recover from ischemia or other
noxious insults including but not limited to burns. The term "ischemic
tissue" is any tissue that is damaged from reduced blood flow. The term
"anticoagulant" is any compound or agent that inhibits the blood
coagulation process. The term "reperfusion injury" means injury to tissue
or cells which occurs during reperfusion of damaged tissue with blood. The
term "damaged tissue" means tissue damaged by ischemia, burns, toxins or
other noxious insult.
It is to be understood that the citation of art contained herein is in no
way to be construed as an admission that said art is suitable reference
against the present patent application nor should this citation act as a
waiver of any rights to overcome said art which may be available to the
applicant.
A number of reports have described high amounts of fibrinogen and/or
soluble fibrin in the blood of patients with thrombosis, impending
thrombosis and many other diseases. These conditions include acute or
chronic infection severe trauma, burns, sickle cell crisis, malaria,
leukemia, myocardial infarction, sepsis, shock, and almost any serious
illness which produces tissue damage or surgical maneuvers. Evidence
indicates that the high concentrations of fibrinogen and/or soluble fibrin
may play an inportant role in the pathology of the conditions.
Furthermore, much of the pathology that is encountered in disease may be
due to pathological hydrophobic interactions which may be at least
partially mediated by high concentration of fibrinogen and/or soluble
fibrin.
What is needed is a means of decreasing the adverse effects of soluble
fibrin. This would involve blocking the adhesion of soluble fibrin to
cells in the circulation thereby blocking the aggregation of such cells
and their adhesion or friction to vessel walls in the microvasculature.
This would also decrease the risk of thrombosis.
Each year about 550,000 Americans die from heart attacks. Even more--close
to 700,000--have heart attacks and live. While a heart attack victim may
survive, part of his or her heart will almost certainly die. The death of
heart muscle, called myocardial infarction, is due to coronary artery
thrombosis in 70-90% of the cases. When a thrombosis, or blood clot,
occludes one of the arteries of the heart, it stops the flow of blood to
the surrounding muscle which deprives it of oxygen and other nutrients. In
the past, nothing could be done to reverse this process. The high
technology devices in intensive care units mostly support patients so they
can live while a portion of their heart dies.
Similar situations occur in many other tissues when the blood supply to the
tissue is affected by a thrombus or embolus. Stroke, deep vein thrombosis
and pulmonary embolus are examples. Typically, the clot forms and is not
treated for a relatively long period of time. Blood flow distal to the
clot is greatly diminished or is stopped completely. The tissue that is
normally fed by that vessel will be severely damaged unless blood flow is
reestablished in a short period of time.
It has been found that certain enzymes are able to degrade, initiate or
activate other enzymes that can degrade fibrin deposits to open clogged
arteries. The enzymes which have been used successfully include
streptokinase, urokinase, prourokinase, tissue plasminogen activator
produced from cell cultures and tissue plasminogen activator produced by
recombinant DNA technology. These enzymes are most successful if
administered shortly after the occulusion of the blood bessels before the
heart tissue has sustained irreversible damage. In one study of 11,806
patients treated with intravenous or intracoronary artery streptokinase,
an 18% improvement of survival was demonstrated. If the treatment was
begun within one hour after the initial pain onset of the heart attack,
the in-hospital mortality was reduced by 47%. (See The Lancet, Vol. 8478,
p. 397-401, Feb. 22, 1986). It was demonstrated that early lysis of the
thrombus resulted in salvage of a portion of heart tissue which would have
otherwise have died. In studies using angiography to assess the patency of
blood vessels, it was found that tissue plasminogen activator could
completely open the vessels of 61% of the 129 patients versus 29% of
controls who were not treated with the enzyme. (See Verstraete, et al.,
The Lancet, Vol. 8462, p. 965-969, Nov. 2, 1985). Tissue plasminogen
activator requires the addition of approximately 100 .mu.l of Tween 80 per
liter of solution to promote dispersion of the enzyme. (See Kominger, et
al., Thrombos, Haemostas, (Stuttgart) Vol. 46(2), p. 561-565 (1981)).
The natural enzymes that lyse thrombi in vessels do so by activating
fibrinolysis. Fibrin is the protein produced by polymerization of
fibrinogen. It forms a gel which holds the thrombus together. The fibrin
molecules which form clots gradually become cross-linked to make a more
stable clot. All three enzymes, urokinase, streptokinase and tissue
plasminogen activator, are effective because of their ability to activate
an enzyme, plasmin, which degrades fibrin. Thus, they have similar effects
on fibrin but they have different toxicities. If the fibrinolytic
mechanisms (i.e., plasmin) are activated in the vicinity of a clot, the
clot is lysed. If, however, they are activated systemically throughout the
circulation, the body's capacity to stop bleeding or hemorrhage is
markedly reduced. Streptokinase and urokinase tend to activate systemic
fibrinolysis. Consequently, they have been most effective when injected
directly into the affected blood vessel.
Tissue plasminogen activator or t-PA, in contrast, becomes effective only
when it is actually attached to fibrin. This means its activity is largely
localized to the immediate area of a clot and does not produce systemic
fibrinolysis. For this reason, tissue plasminogen activator is thought to
produce less risk of hemorrhage than the other enzymes. If high doses are
used in an effort to increase the rate of clot lysis or to lyse refractory
clots, then the amount of systemic fibrinolysis and risk of hemorrhage can
become significant. t-PA can be injected intravenously into the general
circulation. It circulates harmlessly until it contacts the fibrin in a
glood clot where it becomes activated and causes the lyses of the clot.
Tissue plasminogen activator is able to cause the lysis of a clot which is
extensively cross-linked. This means it is possible to lyse clots which
have been present for many hours.
Remarkable as the new enzyme therapies are, they are subject to serious
complications and are not effective in all patients. Clots in the anterior
descending branch of the left coronary artery are much more readily lysed
than those in other arteries. If the enzyme is not delivered by the blood
stream directly to the thrombus, it has no effect. For various reasons,
more blood passes by or trickles around thrombi in the left anterior
descending coronary artery than in the other major arteries. In addition,
the presence of collateral circulation which forms in response to
compromised blood flow in the major arteries adversely affects the rate of
reopening or recanalization of the thrombosed major arteries. It is
thought the presence of many collateral vessels which allow blood to
bypass the clot reduces the pressure gradient across the clot. This in
turn reduces the blood flow through the tiny openings which may persist in
the clot, impedes the delivery of enzymes to the clot, and prevents the
clot from being lysed.
Even after the clot has been lysed, the factors which led to the formation
of the thrombus persist. This produces a high incidence of re-thrombosis
and further infarction in the hours and days following lysis of the clot.
Rethrombosis has been reported in between 3% and 30% of cases in which the
initial treatment successfully lysed the clot. Anticoagulants are
currently used to prevent the formation of new thrombi, but they tend to
induce hemorrhage. There is a delicate balance between the amount of
anticoagulation necessary to prevent re-thrombosis of the vessels and that
which will produce serious hemorrhage.
A reported advantage of t-PA is its short half-life of less than 10
minutes, which may allow rapid reversal of bleeding problems should they
occur. However, the clinical value of this consideration has not yet been
demonstrated. Moreover, the short half-life may lead to an increased
reocclusion rate following discontinuation of thrombolytic therapy, (See
Williams, D. O., et al., "Intravenous recombinant tissue-type plasminogen
activator in patients with acute myocardial infarction: a report from the
NHLBI Thrombolysis in Myocardial Infarction Trial.", Circulation
1986;73:338-46). To counter this problem, t-PA infusions have been
continued for up to 6 hours in phase II of the TIMI (Thrombolysis in
Myocardial Infarction Trial). Whether this will effectively reduce the
incidence of reocclusion without increased bleeding remains to be proven.
Although active thrombosis ceases shortly after discontinuing
administration of t-PA, it takes several hours to replace fibrinogen, so
that the risk of continued bleeding does not terminate when t-PA is
stopped. (See Rich, M. W., "tPA: Is it worth the price?", American Heart
Journal, 1987, Vol. 114:1259-1261.
Finally, dissolving the clot after irreversible damage has taken place has
little effect. the irreversible damage could be either to the heart muscle
or vacular bed of the tissue supplied by the blood vessel. Once a cell is
dead, the change is irreversible. However, the term irreversible damage is
frequently applied to tissue in which a chain of events leading to cell
death has been initiated, even though most cells are not yet dead. If this
chain of events were broken, for example by restoring the microvasculature
blood supply or stabilizing fragile membranes, then many cells could be
saved. A major problem in widespread implementation of this new enzyme
therapy is to find ways of identifying and treating the patients earlier
in their disease and to find ways to make the treatment effective for a
longer period of time after the initiation of thrombosis.
Animal studies have provided a better understanding of the events which
control blood flow and tissue death following coronary artery thrombosis.
Much of the heart muscle receives blood from more than one vessel. For
this and other reasons, the tissue changes following a coronary thrombosis
are divided into distinct zones. The central zone of tissue, i.e., usually
that zone of tissue closest to the thrombus, becomes almost completely
necrotic. This is surrounded by an area of severe ischemia. Outside this
is an area of lesser ischemia called the marginal zone. Finally, there is
a jeopardized zone which surrounds the entire area.
In studies with baboons, the central necrotic area was not affected by
recanalization of the vessel after several hours. However, muscle in the
other zones which had undergone less severe damage during the ischemic
period could be salvaged. A surprising finding was that lysing of the
thrombus to produce a perfect arteriograph was insufficient to restore
normal flow in the majority of animals. (See Flameng, et al, J. Clin.
Invest., Vol. 75, p. 84-90, 1985). Some further impediment to flow had
developed in the area supplied by the vessel during the time that it was
occluded. In further studies, it was demonstrated that immediately after
removing the obstruction to the vessel, the flow through the damaged
tissue began at a high rate. However, within a short time the blood flow
through the ischemic zone decreased and the tissue died.
Consequently, the regional blood flow immediately after reperfusion is a
poor predictor of the salvage of myocardial tissue. If the blood flow
through the damaged tissue remained near the normal levels, the success of
tissue salvage was much greater. Hemorrhage occurred almost exclusively in
the severely ischemic zone reflecting damage to the small blood vessels.
The hemorrhage, however, remained limited to the severely ischemic tissue
and did not cause extension of the infarction or other serious
complication. Therapies which could preserve the blood flow through the
small blood vessels distal to the major area of thrombus after reperfusion
could be expected to markedly increase the salvage of myocardial tissue.
The damage to heart muscle cells which occurs after lysing the thrombus is
due to other factors as well as ischemia. Contact of fresh blood with
damaged or dead cells induces the influx of neutrophils, or pus cells,
which can damage or kill heart cells which would otherwise have recovered.
Much of the damage caused by neutrophils has been attributed to superoxide
ions. (For a general review, please see "Oxygen Radicals and Tissue
Injury" Proceedings of a Brook Lodge Symposium, Augusta Michigan, Barry
Halliwell, Ed.) The superoxide anion can damage tissue in several ways.
The interaction of the superoxide anion with hydrogen peroxide leads to
the production of hydroxyl radicals which are highly toxic and react
rapidly with most organic molecules. Mannitol is a selective scavenger of
hydroxyl radicals. The enzyme, superoxide dismutase, catalyzes the
decomposition of the superoxide anion. Enzymes such as superoxide
dismutase, free radical scavengers or agents which prevent the influx on
neutrophils are able to increase the salvage of heart muscle cells.
Continuing therapy is needed even after restoration of blood flow and
salvage of damaged tissue. The arteriosclerosis that caused the original
heart attack remains. American and European researchers have found that
arteriosclerosis still narrows the arteries in 70-80% of patients whose
clots were lysed by thrombolytic therapy. Many physicans believe this
obstruction must be opened for long term benefits.
Balloon angioplasty is a procedure whereby a catheter with a small balloon
is inserted into the narrowed artery. The balloon is inflated, compresses
the atherosclerotic plaque against the vessel wall and dilates the artery.
The effectiveness of this procedure is limited by the effects of ischemia
produced by the balloon, by embolization of atheromatous material which
lodges in distal vessels and by an increased tendency for immediate or
delayed thrombosis in the area damaged by the balloon. The balloon tears
the tissue exposing underlying collagen and lipid substances which induce
formation of thrombi. The thrombus may occlude the vessel immediately or
set up a sequence of events which leads to occlusion many days or weeks
later. In addition, there is an interruption of blood flow to the heart
tissue when the balloon is inflated. When the blood flow is interrupted,
tissue downstream from the balloon is deprived of blood and can be
damaged. Balloon angioplasty is representative of numerous clinical and
experimental procedures for repairing the lumen of diseased arteries and
vessels.
What is needed is a means of rendering the surface of the dilated vessel
less thrombogenic, improving the blood flow through the distal tissue and
breaking the embolized material into smaller pieces which are less likely
to produce embolic damage. A means of restoring blood flow through the
microcapillaries downstream from the site of balloon inflation is also
required.
Another area where fibrinogen/fibrin plays a role is tumors. There is now
strong evidence that fibrinogen-related proteins are localized in solid
tumors. The anatomical distribution of fibrin in tumors varies depending
on the tumor type. In carcinomas, fibrin is deposited in the tumor stroma
and around tumor nests and may be particularly abundant toward the tumor
periphery and at the tumor host interface. By contrast, fibrin is often
less prominent in older, more central tumor stroma characterized by
sclerotic collagen deposits. Fibrin may also be found between individual
carcinoma cells. In some, but not all such cases, interepithelial fibrin
deposits are related to zones of tumor necrosis; however, zones of turmor
necrosis are not necessarily sites of fibrin deposition. Fibrin deposition
in sarcomas has been less carefully studied than that in carcinomas. In
lymphomas, fibrin deposits may be observed between individual malignant
tumor cellas as well as between adjacent, apparently reactive benign
lymphoid elements. Fibrin has been reported to appear in zones of tumor
sclerosis, as in Hodgkin's disease. Research has indicated that the
pattern and extent of fibrin deposition are characteristic for a given
tumor. (See Hemostasis and Thrombosis, Basic Principles and Clinical
Practice, "Abnormalities of Hemostasis in Malignancy", pp. 1145-1157, ed.
by R. W. Colman, et al., J. B. Lippincott Company, 1987).
The lack of a uniform vascular supply to tumors can impede diagnostic and
therapeutic procedures. For example, hyposic tumors are less susceptible
to many drugs and to radiation. Conventional drugs and new drugs, such as
monoclonal antibody conjugates, are not effective unless they are
delivered to tumor cells. Fibrin deposits that surround some types of
tumors inhibit delivery of the drugs to the tumor. The blood supply of
tumors is further comprised by other factors as well. Blood vessels in
tumors are frequently small and tortuous. The hydrodynamic resistance of
such channels further impedes the flow of blood to tumors.
Finally, lipid material on the atherosclerotic wall contributes to the bulk
of the plaque which narrows the lumen of the artery and produces a highly
thrombogenic surface. What is needed is a method of extracting or covering
lipids from atherosclerotic plaques which leaves their surfaces less
thrombogenic and reduces their bulk.
Use of copolymers prepared by the condensation of ethylene oxide and
propylene oxide to treat an embolus or a thrombus has been described (See
U.S. Pat. No. 3,641,240). However, the effect is limited to recently
formed, small (preferably microscopic) thrombi and emboli which are
composed primarily of platelets. To be effective, the compound must be
used within 20 minutes after the initiation of thrombosis.
The use of the ethylene oxide and propylene oxide copolymer has little or
no effect on a clot in a patient who has suffered a severe coronary
infarction because such patients almost never receive treatment within 20
minutes following initiation of thrombosis. It is likely that many persons
do not develop symptoms until the thrombus reaches considerable size. The
clots that are occluding the blood vessel in these patients are large and
stable clots. Stable clots are clots in which the fibrin has undergone
cross linking. Fibrin which has undergone crosslinking is not effected by
presence of the ethylene oxidepropylene oxide copolymers. The copolymers
only affect new clots composed primarily of platelets in which the newly
formed fibrin has not crosslinked.
Another problem that commonly occurs in damaged tissue where blood blow is
interrupted is a phenomenon called "no reflow" phenomenon. This is a
conditions wherein blood flow is interrupted to a tissue. When blood flow
is restarted, such as after a clot is removed, flow in the smaller
microcapillaries is often impared because blood cells tend to clump in the
microcapillaries thereby inhiviting flow of blood to the tissue. This can
result in damage to the tissue.
In addition, such a composition would be helpful in removing clots from
solid tumors, increasing flow through tortuous channels and thereby allow
delivery of therapeutic drugs to the tumor.
A further need is a composition that can be used to prevent or treat "no
reflow" phenomenon. Such a composition should be capable of causing blood
to flow in tissue after blood flow has stopped thereby preventing tissue
damage.
Increased demand for platelet concentrates to treat bleeding associated
with thrombocytopenia has prompted the need to determine optimal methods
of storing platelets prior to transfusing them into patient.
Viability, as measured by survival of .sup.51 Cr-labeled platelets, seems
best preserved when stored at 22.degree. C., whereas platelet function, as
measured by the ability of platelets to aggregate in response to
epinephrine, collagen, and adenosine diphosphate is better preserved at
4.degree. C. Platelets stored at room temperature for 48 to 72 hours as
well as those kept refrigerated for 24 to 48 hours have been found by
different investigators to produce satisfactory increases in platelet
levels when transfused to thombocytopenic patients.
Thus, blood banks wishing to store platelets prior to their transfusion
into a patient are faced with the dilemma of whether they should be kept
at room temperature, thus preserving their lifespan but possibly
compromising their functional capacity, or whether they should be stored
in the approximately 4.degree. C. with the resultant preservation of
function but shortening of posttransfusion survival time.
What is needed is a composition and method which can be added to a
suspension of platelets which will preserve both lifespan and function of
the platelets so that the platelet suspension can be stored for longer
periods of time. Such a composition should also be capable of inhibiting
the aggregation or clumping of platelets in the suspension.
Finally, the present inventor has identified a phenomenon called
pathological hydrophobic interactions between blood components and those
cells which line the blood vessels. This phenomenon is typically
encountered when tissue is damaged in some manner. These pathological
hydrophobic interactions cause blood flow to be reduced or stopped thereby
causing damage to surrounding tissue. What is needed is a composition and
method for reducing the pathological hydrophobic interactions and thereby
allowing blood to flow into the damaged tissue.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method is provided for treating
pathologic hydrophobic interactions in blood and other biological fluids.
In particular, the method of the present invention limits or prevents
damage due to (1) high concentrations of hydrophobic soluble fibrin, (2)
cell damage due to the exposing of hydrophobic domains in the cell
membrane that are usually hidden or buried. The method of the present
invention also has a cytoprotective effect.
The method of the present invention increases flow of biological fluids in
diseased tissue. The flow in such tissue is commonly impeded because of
the pathological hydrophobic interactions between cells and/or certain
molecules. The present invention includes the use of a surface active
copolymer for treatment of diseases and conditions in which resistance to
blood flow is caused by injury due to the presence of adhesive proteins or
damaged membranes. Such proteins and damaged membranes increase resistance
in the microvasculature by increasing friction and reducing the effective
radius of the blood vessel. The most important of these proteins are
fibrinogen and soluble fibrin.
The method comprises administering to an animal or human an effective
amount of a surface active copolymer with the following general formula:
HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4
O).sub.b H
wherein a is an integer such that the hydrophobe represented by (C.sub.3
H.sub.6 O) has a molecular weight of approximately 950 to 4000, preferably
about 1200 to 3500, and b is an integer such that the hydrophile portion
represented by (C.sub.2 H.sub.4 O) constitutes approximately 50% to 95% by
weight of the compound.
Also in accordance with the present invention, a fibrinolytic composition
and method is provided that is effective in dissolving blood clots and
reestablishing and maintaining blood flow through thrombosed coronary or
other blood vessels. The fibrinolytic composition of the present invention
comprises an enzyme, such as streptokinase, urokinase, prourokinase,
tissue plasminogen activator, or other proteolytic enzyme, and a surface
active copolymer. The surface active copolymer can be an ethylene
oxide-propylene oxide condensation product with the following general
formula:
HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4
O).sub.b H
wherein a is an integer such that the hydrophobe represented by (C.sub.3
H.sub.6 O) has a molecular weight of approximately 950 to 4000, preferably
about 1200 to 3500, and b is an integer such that the hydrophile portion
represented by (C.sub.2 H.sub.4 O) constitutes approximately 50% to 95% by
weight of the compound.
The fibrinolytic composition of the present invention is usually
administered by intravenous injection into a patient but can be
administered by intramuscular or other parenteral injection.
The present invention provides a composition that can be administered to
patients who have a blood clot occluding a blood vessel. The combination
of proteolytic enzyme and surface active copolymer according to the
present invention increases blood flow around a clot, rapidly lyses a
clot, and provides further protection to the patient by preventing a new
clot from forming and reducing reperfusion injury.
Because the fibrinolytic composition of the present invention stabilizes
the patient to a greater extent than treatments in the prior art, the
administration of more invasive procedures, such as balloon angioplasty,
can be delayed thereby permitting selection of conditions for the invasive
treatment that are most favorable to the patient. In addition, the
treatment of myocardinal infarction by use of a proteolytic enzyme such as
t-PA or steptokinase can be delayed because the addition of the surface
active copolymer will limit the damage to the heart tissue.
Another embodiment of the present invention is a composition comprising the
combination of the surface active copolymer and free radical scavengers
including but not limited to, superoxide dismutase and mannitol,
mercaptopropionyl glycine. The surface active copolymer can also be used
with agents that prevent the generation of free radical species including,
but not limited to, ibuprofen, BW 755C, nafazatrom, prostacyclin,
iloprost, allopurinol, phenytoin as well as other antiinflammatory or
cytoprotective drugs. It is to be understood that the term free radical
scavengers includes both the scavenger compounds and the compounds that
prevent the generation of free radical species. The present invention
includes a composition comprising the combination of surface active
copolymer, clot lysing enzyme and free radical scavenger and also the a
composition comprising combination of surface active copolymer and free
radical scavenger alone.
In accordance with the present invention, a composition and method is
provided that is effective in prolonging the function and lifespan of
platelets in suspension. The method comprises adding an effective amount
of a surface active copolymer to the platelet suspension. The surface
active copolymer can be an ethylene oxide-propylene oxide condensation
product with the following general formula:
HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4
O).sub.b H
wherein a is an integer such that the hydrophobe represented by (C.sub.3
H.sub.6 O) has a molecular weight of approximately 950 to 4000, preferably
about 1200 to 3500, and b is an integer such that the hydrophile portion
represented by (C.sub.2 H.sub.4 O) constitutes approximately 50% to 95% by
weight of the compound.
The present invention also embodies a method for efficiently delivering
drugs to and into diseased or damaged tissue. This includes tissue damaged
by infection, trauma, burns, or other noxious insult.
Accordingly, it is an object of the present invention to provide a method
for treating pathologic hydrophobic interactions of components in blood or
other biological fluids.
It is a further object of the present invention to provide a method for
protecting cells during and after an ischemic period.
It is a further object of the present invention to provide a method and
composition for protecting tissue after a burn.
It is yet another object of the present invention to provide a method for
protecting myocardinal cells, endothelial cells and other cells from
ischemia.
It is another object of the present invention to provide a method of
enhancing the ability of cells and tissue to recover from ischemia.
It is an object of the present invention to provide a combination of
fibrinolytic enzymes with a surface active copolymer to produce a
synergistic action in lysing blood clots. This combination can be
formulated either with standard doses of enzyme to increase the rate or
likelihood of lysing a clot or at lower doses of enzyme to reduce side
effects while maintaining efficacy for lysing clots.
It is another object of the present invention to provide a composition that
will reduce the need for anticoagulation in therapy of thrombosis and
thereby lessen the danger of hemorrhage.
It is another object of the present invention to provide a composition that
accelerates the dissolution of clots by freeing aggregated platelets and
blocking further platelets from aggregating to the clot.
It is yet another object of the present invention to provide a composition
that acan reduce the dose of proteolytic enzyme required to lyse a clot
and thereby reduce the incidence of complications.
It is another object of the present invention to provide a composition that
contains a surface active copolymer and a free radical or oxygen
scavenger, such as superoxide dismutase mannitol, and/or mercaptopropionyl
glycine.
It is a further object of the present invention to provide a composition
that can promote blood flow through microvascular channels of tissue
damaged by ischemia and reduce the amount of tissue which undergoes
necrosis.
It is a further object of the present invention to provide a method for
delivering drugs to damaged or diseased tissue.
It is a further object of the present invention to provide a composition
that will significantly reduce the risk of rethrombosis after treatment
with fibrinolytic enzymes.
It is a further object of the present invention to provide a composition
that will promote removal of lipids from atherosclerotic vessel walls and
thereby lessen the incidence of rethrombosis.
It is another object of the present invention to provide an improved
fibrinolytic composition that is capable of lysing fibrin deposits
associated with tumors.
It is another object of the present invention to provide a composition
which will increase blood flow through tortuous channels such as occur in
tumors and during crisis of sickle cell disease.
It is another object of the present invention to provide an improved
composition and method for ex vivo preservation of organs.
It is another object of the present invention to provide a composition that
will reduce the risk of rethrombosis and thereby allow delay in
administering balloon angioplasty or other invasive procedures for
treatment of the compromised vessels.
It is another object of the present invention to provide a composition
which will reduce the risk of thrombosis immediately or at some time after
invasive procedures such as balloon angioplasty which damage endothelial
cells of the vasculature.
It is a further object of the present invention to provide a composition to
block the aggregation of platelets in blood vessels distal to the
thrombosis and thereby limit extension of tissue damage.
It is yet another object of the present invention to provide a composition
to improve blood flow through and around tissue with extensive necrosis of
myocardial or other cells thereby retarding necrosis of additional
myocardial tissue.
It is another object of the present invention to provide a composition
which will reduce the influx of neutrophils into damaged tissue and
thereby reduce the extent of injury caused by toxic products of
neutrophils.
It is yet another object of the present invention to provide a composition
that will decrease the amount of ischemia caused blockage of blood flow by
a thrombus.
It is yet another object of the present invention to provide a method for
increasing blood flow in ischemic or damaged tissue thereby reducing
damage to the tissue.
It is another object of the present invention to provide a method for
treating burns.
It is a further object of the present invention to provide a combination of
a thrombolytic enzyme, balloon angioplasty or other procedures and a
surface active copolymer to produce an improved method of removing a
thrombus or thrombogenic occlusion and reducing obstructive conditions
which promote rethrombosis.
It is another object of the present invention to provide a composition and
method for the treatment of crisis in sickle cell disease.
It is another object of the present invention to provide a composition that
is effective in restarting blood flow through microcapillaries after
ischemia.
It is an object of the present invention to provide composition and method
for prolonging the life-span and function of platelets.
It is another object of the present invention to provide a composition and
method that will allow platelet suspensions to be stored for longer
periods of time then is presently possible with prior art methods.
It is another object of the present invention to provide a composition and
method that can be added to conventional platelet containers so that
platelet suspensions can be stored for a longer period of time.
It is yet another object of the present invention to provide a composition
and method that can be used to prolong the lifespan of cell suspensions.
It is yet another object of the present invention to provide a method of
storing a concentrated suspensions of platelets whereby platelet function
is prolonged thereby allowing longer storage times.
It is another object of the present invention to provide a a method of
storing a concentrated suspension of platelets for transfusion into a
patient.
It is yet another object of the present invention to provide a composition
and method for treatment of shock using a surface active copolymer with a
plasma extender.
It is another object of the present invention to provide a method and
composition for treating microvascular diseases caused by endotoxin such
as endotoxin shock or laminitis in horses.
These and other objects, features and advantages of the present invention
will become apparent after a review of the following detailed description
of the disclosed embodiments and the appended claims.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a graph showing the effect of the surface active copolymer on
dissolving a clot with and wi | | |
