Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-10
2001-08-28
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06281225
ABSTRACT:
TECHNICAL FIELD
This invention relates to methods, compounds and devices for inhibiting smooth muscle proliferation at a site of injury.
BACKGROUND
Arteriosclerosis is a class of diseases characterized by the thickening and hardening of the arterial walls of blood vessels. Although all blood vessels are susceptible to this serious degenerative condition, the aorta and the coronary arteries serving the heart are most often affected. Arteriosclerosis is of profound clinical importance since it can increase the risk of heart attacks, myocardial infarctions, strokes, and aneurysms.
The traditional treatment for arteriosclerotic vessels has been coronary bypass surgery. More recently, however, vascular recanalization procedures for treating arteriosclerotic vessels have been developed. These procedures involve using intravascular devices threaded through blood vessels to the obstructed site, including for example, percutaneous transluminal angioplasty (PTA), also known as balloon angioplasty. Balloon angioplasty uses a catheter with a balloon tightly packed onto its tip. When the catheter reaches the obstruction, the balloon is inflated, and the atherosclerotic plaques are compressed against the vessel wall. A shortcoming of this and other intravascular procedures, however, is that in a number of individuals some of the treated vessels restenose (ie. the vessels narrow) by six months post-angioplastic treatment. The restenosis is thought to be due in part to mechanical injury to the walls of the blood vessels caused by the intravascular device.
The walls of most blood vessels are composed of three distinct layers, or tunics, surrounding a central tubular opening, the vessel lumen. The innermost layer that lines the vessel lumen is called the tunica intima. The middle layer, the tunica media, consists mostly of circularly arranged smooth muscle cells and connective tissue fibers. In a non-injured vessel the smooth muscle cells are normally not actively dividing. The outmost layer of the blood vessel wall, the tunica adventitia, is composed largely of collagen fibers that protect the blood vessel. Mechanical injury, resulting in damage to the tunica intima, initiates a number of events, including the release of chemicals such as platelet-derived growth factors (PDGF), which prompts the migration and proliferation of smooth muscle cells at the site of injury over many weeks.
Several methods for inhibiting smooth muscle cell proliferation following the use of an intravascular device have been reported. These include the administration of agents, including, for example, anti-proliferative agents such as cell cycle inhibitors and anti-coagulant agents, by local or systemic delivery systems. Delivery of agents systemically, however, has required dosages that are both prohibitively toxic and prohibitively costly. Local delivery of agents, for example heparin, as described in U.S. Pat. No. 4,824,436, has proven ineffective in inhibiting restenosis due in part to problems related to inadequate residence time at the site of injury before the agent diffuses to ineffective concentrations. Cell cycle inhibitors such as taxol, which do not react covalently and require prolonged residence time for effectiveness, are likely to have similar problems. In addition, prolonged residence times are likely to have a greater risk of toxicity.
Other methods reported for inhibiting smooth muscle cell proliferation involve locally delivering agents that are contained in sustained release formulations. In one example, agents contained within a physiologically compatible, biodegradable polymeric microparticle are delivered locally to the site of injury such that the agents are released from the arterial wall for 72 hours or more. U.S. Pat. No. 5,171,217. Still other methods reported for inhibiting smooth muscle cell proliferation involve administering photochemically activated agents by local delivery systems. In one example, photochemically activated agents, for example, 8-methoxypsoralen, are locally delivered to the site of injury and then activated by a visible light source. U.S. Pat. No. 5,354,774. Another approach is the use of radiation-emitting catheters or guide wires, which can cause damage to nucleic acid and inhibit smooth muscle cell proliferation. Each of these methods, however, requires an added level of complexity, namely incorporation of the agent on or within a sustained release formulation, photoactivation using a complex intravascular light source, or delivery of a radiation dose which requires the presence of a radiologist and presents exposure hazards to the attending personnel.
A need therefore exists for safer and less complex methods for inhibiting smooth muscle cell proliferation at a site of injury following vascular recanalization procedures.
SUMMARY OF THE INVENTION
The present invention includes methods for inhibiting smooth muscle cell proliferation in a blood vessel subjected to recanalization. The methods include administration of an alkylating compound, not in a sustained or controlled release process, to an individual undergoing vascular recanalization, by local delivery to the vascular recanalization site.
Advantages of the present invention include the following. First, because the compounds for use in the methods of the invention are rapidly taken up by cells, and they react rapidly and permanently with cellular nucleic acid, these compounds need not remain long at the site of administration to be effective. Unlike sustained exposure processes, the compounds and methods of the present invention have a sustained effect with a very short exposure time. Thus, the problem of insufficient residence time associated with local delivery of previously reported agents for inhibiting smooth muscle cell proliferation is overcome. In addition, because the compounds for use in the methods of the invention are rapidly taken up by cells, and they react rapidly with cellular nucleic acids, their toxicity can be significantly reduced by shorter exposure times and lower concentrations.
Second, administration of the alkylating compounds by local delivery to the site of the recanalization allows for the use of lower dosages as compared, for example, to the administration of these compounds by systemic delivery. Using lower dosages decreases the toxicity of these compounds
A third advantage of the present invention is that the methods do not necessarily require the use of alkylating compounds in a sustained release formulation. Methods that do not require the incorporation of the compound on or within a sustained release formulation are easier to prepare and require less complex technology. While it is not required that the compounds of the present invention be used in a sustained release formulation, they would provide an advantage in such a formulation over current compounds for the reasons discussed above, i.e. they react rapidly and permanently such that lower concentrations and exposures are effective, which reduces the risk of toxicity and eliminates problems of formulating sufficiently high levels, in a sustained release formulation, for effectiveness.
A fourth advantage of the present invention is that the methods do not require use of an intravascular light source to activate the compounds for use in the methods of the invention, nor do they require irradiation. The lack of requirement for a source of light or radiation again allows for easier and less complex technology.
The methods of the invention use alkylating compounds which are rapidly taken up by cells and react rapidly with the intracellular nucleic acid to inhibit proliferation. In a preferred embodiment, an alkylating compound rapidly forms covalent bonds with the nucleic acid of a smooth muscle cell. Diffusion of the compound into a smooth muscle cell and reaction with smooth muscle cell nucleic acid sufficient to inhibit restenosis is essentially complete within 2 minutes, more preferably within one minute, and most preferably within 30 seconds after delivery of the compound to a site of vascular injury.
The alkylating comp
Alfonso Ryan D.
Greenman William M.
Hearst John E.
Wollowitz Susan
Cerus Corporation
Morrison & Foerester LLP
Spivack Phyllis G.
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