Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-12-27
2003-04-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S489000
Reexamination Certificate
active
06544543
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention provides methods and systems for the treatment of patients afflicted with coronary or peripheral artery disease. More particularly, the invention provides methods and systems for the treatment of ischemic tissue through a periodic, local administration of a vasoconstrictive drug to an open artery adjacent to regions of ischemic tissue.
2. Description of the Background
Ischemia is a condition which results from insufficient blood flow to an area of the body, usually due to an occlusion in a blood vessel. Ischemic heart disease results from insufficient coronary blood flow, which in turn is frequently caused by atherosclerosis. In certain persons who have a genetic predisposition to this condition, or in persons who eat excessive quantities of cholesterol and other fats, large quantities of cholesterol gradually become deposited beneath the intima (the innermost of three layers making up the blood vessel wall). Later, these areas of cholesterol deposit become invaded by fibrous tissue, and they also frequently become calcified. As a result, atherosclerotic plaque develops that protrudes into the vessels and either blocks or partially blocks blood flow. A very common site of development of atherosclerotic plaque is the first few centimeters of the coronary arteries, in which case the patient may suffer from myocardial ischemia.
FIG. 1
is an illustration of a mammalian heart
10
. Major arteries for heart
10
include the right coronary artery (“RCA”)
12
, the left anterior descending artery (“LAD”)
14
, and the left circumflex (“LCX”)
16
. If an occlusion
18
were to develop at the top of LAD
14
, then an ischemic region
20
(delineated by a hatch pattern) would develop within heart
10
, because this region of the heart would not be receiving an adequate supply of oxygenated blood. In this case, LAD
14
may be termed an “occluded” vessel.
A compensatory mechanism is observed in some ischemic patients, wherein collateral vessels
22
a
,
22
b
,
22
c
, and
22
d
adjacent to ischemic region
20
enlarge so as to carry more blood from RCA
12
toward ischemic region
20
. Of course, collateral vessels originating at LCX
16
could also (or alternatively) enlarge to carry more blood to ischemic region
20
. This process is termed “arteriogenesis.”
Occlusions and arteriogenesis are also seen in other areas of the body. For example, occlusions of the superficial femoral artery (“SFA”), which feeds blood to a person's leg, are common. In some patients, an enlargement of collateral vessels is observed, similar to the above-mentioned example of myocardial ischemia.
The precise mechanisms responsible for such arteriogenesis have not been definitively determined. A current theory is that arteriogenesis involves the concerted action of various growth factors, including vascular endothelial growth factor (VEGF), acidic and basic fibroblastic growth factors (aFGF and bFGF, respectively), platelet-derived endothelial cell growth factor (PD-ECGF), monocyte chemotractant factor (MCP
1
), and transforming growth factor &bgr;
1
(TGF-&bgr;
1
). See, e.g., Simons et al., “Clinical Trials in Coronary Angiogenesis: Issues, Problems, Consensus”
Circulation
, 102:e73-e86, 2000; Chilian et al., “Microvascular Occlusions Promote Coronary Collateral Growth”
Am. J Physiol
., 248 (4pt 2): H1103-11, 1995; Kersten et al., “DC Modulation of Coronary Collateral Angiogenesis: a Canine Model of Neo-vascularization Induced by Chronic Ischemia,”
J Card Surg
, 10:354-7, 1995; Sorman et al., “Enhanced External Counterpulsation in the Management of patients with Cardiovascular Disease,”
Clin. Cardiol
., 22:173-8, 1999.
Since the precise mechanisms for arteriogenesis have not been definitively determined, currently no single method for stimulating arteriogenesis exists which offers proven, predictable, repeatable results. Methods being used in or considered for use in clinical trials include protein therapy and gene therapy.
Protein therapy involves the repeated administration of growth factor proteins to the patient. Protein therapy allows administration of precise amounts of growth factors with a well-defined half-life, pharmacokinetics, and safety record. Unfortunately, since the process of arteriogenesis is not fully understood, it is not known what growth factor protein, or combination of growth factor proteins, should be administered to the patient. Several methods may be used to administer the growth factor proteins, but each method has its drawbacks. Such methods include intravenous infusions, and for the specific case of myocardial ischemia, intracoronary infusions and intramyocardial delivery.
Intravenous infusions, while practical and low-cost, may result in undesirable side effects, such as nitric oxide-mediated hypotension, due to the high concentration of growth factor protein(s) required for systemic administration.
Intracoronary infusions are easily performed in a cardiac catheterization laboratory and are also applicable in most patients with coronary artery disease. However, the need for left heart catheterization limits this approach to a single session or, at most, infrequent repetitions. Moreover, intracoronary infusions may result in systemic exposure to the growth factor protein and may precipitate systemic hypotension. Finally, both intravenous and intracoronary infusions are associated with relatively low uptake in the target ischemic tissue. It has been observed that very small amounts of the growth factor (e.g., often less than 1%) remain in the ischemic myocardium one hour after intravenous or intracoronary administration.
Intramyocardial delivery is another method of delivering growth factor proteins, offering the advantages of targeting the desired areas of the heart, likely higher efficiency of delivery, and prolonged tissue retention. However, intramyocardial delivery is very invasive, requires highly specialized equipment, and requires a high skill level of the operator.
Theoretically, arteriogenesis could also be stimulated by the introduction of genes encoding growth factor proteins, rather than administration of the growth factor proteins themselves. An argument in favor of gene therapy is that it may facilitate sustained local production of growth factors by the patient. However, the use of gene therapy also has drawbacks. While conventional drugs work outside cell walls, the DNA encoding the growth factor(s) must penetrate not only the cell wall, but also the nucleus within the cell. The fraction of cells that actually take up and express the new DNA is quite low, typically a few percent, and at best 10-20%. Secondly, the DNA that actually enters the cell nuclei may be attacked by the patient's immune system. When the immune system is activated in this manner, the immune system may also harm healthy genes in the target cells and other nearby cells. Thus, gene therapy in its present form is associated with much more variability in the levels of the proteins produced and duration of expression than is protein therapy.
Thus, there is a need for a mechanism for stimulating arteriogenesis that does not suffer from the disadvantages described above.
SUMMARY
The present invention treats ischemia by causing brief periods of occlusion of blood flow in an otherwise open target vessel adjacent to the ischemic region. The periods of occlusion are caused by means of periodic administration of a therapeutically effective amount of a vasoconstrictor to the target vessel. It is anticipated that the periods of occlusion will re-route blood flow to collateral vessels, increase shear stress on these collateral vessels and cause them to release growth factor proteins. This, in turn, induces the enlargement of the collateral vessels, with the result of increased blood flow to the ischemic region. Thus, the invention contemplates stimulating the natural production of all growth factor proteins associated with arteriogenesis in a specific region of the body, rather than by the systemic or local administration of select
Buchko Christopher J.
Mandrusov Evgenia
Roorda Wouter E.
Advanced Cardiovascular Systems Inc.
Bennett Rachel M.
Cameron Kerrigan Squire Sanders & Dempsey L.L.P.
Page Thurman K.
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