Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2000-04-05
2002-11-12
Casler, Brian L. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C607S127000, C607S120000
Reexamination Certificate
active
06478776
ABSTRACT:
FIELD OF THE INVENTIONS
The inventions described below relate to site-specific delivery of therapeutic agents, devices, structures and catheter systems, means for implanting and using these systems to enable delivery of therapeutic agents to the body, and methods for manufacturing these devices.
BACKGROUND OF THE INVENTIONS
Cardiovascular disease is the leading cause of death in the United States and many other developed countries. A major contributing factor to cardiovascular disease is atherosclerosis, or the hardening of the arteries due to plaque formation. As atherosclerosis progresses, the blood vessels narrow and may close entirely. As a result, ischemia, or inadequate blood flow to tissues, can result and damage the affected tissue. In patients with coronary artery disease, ischemia in the heart can lead to severe chest pain, impaired cardiac function or, if very severe, heart attacks. Approximately 50% of deaths attributable to cardiovascular disease are due to coronary artery disease.
Treatment alternatives for coronary artery disease range from risk factor modification and exercise programs for patients with limited disease to major surgical procedures in severely diseased patients. Drug therapy is a mainstay of treatment for coronary artery disease. Surgical intervention such as angioplasty and/or stent placement are often used to open occluded vessels for patients with severe disease. Angioplasty procedures typically use an inflatable balloon catheter to physically open a narrowed blood vessel. Studies have shown that 30% to 40% of the time the artery narrows again, or undergoes restenosis within seven months following angioplasty. The procedure is difficult or impossible to perform on certain patients with multiple vessel disease, diffuse disease, calcified vessels or vessels that are too small to access. Stent placement has become a good alternative to angioplasty, but the challenges of re-occlusion of the stent have not been completely solved, and stents are not generally used to treat multiple occlusions. For patients with severe coronary artery blockages, the preferred treatment is still the coronary artery bypass graft surgery, in which the occluded coronary arteries are replaced with the patient's saphenous vein. The conventional CABG procedure requires cutting through the sternum of the chest and placing the patient on cardiopulmonary bypass, both of which involve significant risk of morbidity and mortality. In addition, it is difficult or impossible to perform CABG on certain patients with diffuse atherosclerotic disease or severe small vessel disease or patients, who have previously undergone a CABG procedure.
Pacemakers provide another treatment for heart disease. Pacemakers with helical tipped active fixation leads have been in clinical use for greater than 25 years. Often when implantable leads become infected or fail due to fatigue, physicians will extract the entire body of the lead and leave behind the active fixation element which is buried in the myocardium. Furman S.; Hayes, D.; Holmes, D.:
A Practice of Cardiac Pacing
, Futura, Mount Kisco, N.Y., 3
rd
ed., 1993 shows an image of a patient with four separate abandoned intramyocardial electrodes in addition to two more additional electrodes for dual chamber pacing left behind in the heart with no apparent effect. It is well recognized that a helical intramyocardial implant remnant resulting from the extraction of a lead system poses no known risk to the patient.
Restoring blood flow to areas of ischemia through angiogenesis offers one of the most promising therapeutic options for treatment of coronary artery disease. Angiogenesis, or the formation of new blood vessels, is the body's natural response to ischemia. It also occurs as a normal physiological process during periods of tissue growth, such as an increase in muscle or fat, during the menstrual cycle and pregnancy, and during healing of wounds. Under ischemic conditions, expression of certain genes leads to the production of growth factors and other proteins involved in angiogenesis. The endothelial cells, which line blood vessels, contain receptors that bind to growth factors. Binding of the growth factors to these receptors triggers a complex series of events, including the replication and migration of endothelial cells to ischemic sites, as well as their formation into new blood vessels. However, in ischemic conditions, the growth factor genes often may not produce sufficient amounts of the corresponding proteins to generate an adequate number of new blood vessels. A logical therapeutic approach to this problem is to enhance the body's own response by temporarily providing higher concentrations of growth factors at the disease site. For cardiac disease, this will require a cardiovascular delivery system. Current delivery systems however are undesirable for a number of reasons.
One delivery system that has been proposed is the delivery of angiogenic agents through the coronary arteries. However, the extent of collateralization (growth of blood vessels elsewhere in the body, like the brain and lenses of the eye) observed is undesirable, so the dose provided must be less than desired. Delivery of recombinant growth factors bFGF and VEGF to the coronary arteries has entered Phase II human clinical trials, but the route of administration does not appear to be optimal. This is best shown by the recently completed VIVA phase II clinical trial in which rhVEGF 165 was delivered to both the coronary arteries and intravenously over periods of time, and yet did not show a statistically significant improvement in the patients who received the drug versus the placebo.
Additionally, arterial delivery treats the tissue subtended by the vessel with agents delivered to the most highly perfused tissue and rapidly washing away from the tissue. If agents are delivered to the coronary artery, the coronary artery bed, which includes richly and poorly perfused regions, will receive the drug therapy. Due to the nature of the restenosis or flow restriction, poorly perfused (ischemic) areas will receive less angiogenic agents, and healthy tissue will receive more. As the underlying problem of ischemic tissue is poor perfusion, excess growth factor must be delivered in order to obtain the desired effects in the poorly perfused tissue. Because of the high flow in the arteries, growth factor that is not bound by receptors in the vessels is quickly distributed to the rest of the body.
The pharmacokinetics of these clinical studies has not been discussed scientifically, yet it has been shown that sustained delivery is important to promote optimal angiogenesis. Gene therapy preparations are being used in the clinic to provide for sustained delivery of different forms of angiogenic agents VEGF and FGF to increase the magnitude of the therapeutic effect. Gene therapy currently suffers the difficulty that agents must be (1) delivered to the site, (2) gain access to the targeted cell cytosol, (3) become incorporated in the host cell's DNA, (4) be transcribed to produce mRNA, (5) the mRNA must be translated to produce the protein, and then (6) the protein must find a means of egress from the cytosol to the extracellular space in order to have its intended endogenous effects of promoting angiogenesis. At each of these six steps there are substantial efficiency issues that are difficult to control. There are currently three clinical trials entering Phase II studies in which the effective dose (step 6 of the cascade) of therapeutic protein that is being delivered to the tissue is not well understood.
Implantation of local drug delivery depots is an alternative to poorly controllable injection of gene therapy preparations. However, currently proposed depots pose difficulties. The processing steps needed to make them can render the therapeutic agent to be delivered biologically inactive. Nugent, M. A., Chen O. S., and Edelman, E. R., Controlled release of fibroblast growth factor: activity in cell culture. 252 Mat. Res. Soc. Symp. Proc.: 273 (1992) illustra
Altman Peter A.
Lovich Mark A.
Miller Aaron J.
Rosenman Daniel C.
Schwartz Micheal A.
BioCardia, Inc.
Casler Brian L.
Crockett & Crockett
Crockett, Esq. K. David
Thissell Jeremy
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