Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Arterial prosthesis – Drug delivery
Reexamination Certificate
2001-11-26
2003-11-04
Hartley, Michael G. (Department: 1616)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Arterial prosthesis
Drug delivery
C623S001110, C424S400000, C424S422000, C424S423000
Reexamination Certificate
active
06641611
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a therapeutic coating for an intravascular implant, and in particular to a coating that prevents or treats hyperproliferative vascular disease including intimal smooth muscle cell hyperplasia, restenosis, and vascular occlusion.
BACKGROUND OF THE INVENTION
As discussed in more detail below, the prior art discloses many examples of therapeutic coatings that have been applied to intravascular devices. The objective behind applying the therapeutic coating is to either mediate or suppress a tissue response at the site of implantation. For example in intravascular situations, one of the obvious outcomes of implanting a foreign body is for an intense reaction at the site of implantation. This intense reaction can result from either the implantation itself or the stresses generated after implantation. Due to the reaction, there is an obvious interaction by the vessel wall to compensate for this injury by producing a host of tissue related responses that is generally called “healing due to injury.” It is this healing process that the therapeutic coating attempts to mediate, suppress, or lessen. In some instances, this healing process is excessive in which it occludes the entire lumen providing for no blood flow in the vessel. This reoccluded vessel is also called a resteinotic vessel.
Therapeutic coatings can behave in different ways. For example, depending upon the kind of therapeutic agent used, the various cellular levels of mechanisms are tackled. Some of the therapeutic agents act on the growth factors that are generated at the site of implantation or intervention of the vessel. Some other therapeutic agents act on the tissues and suppress the proliferative response of the tissues. Others act on the collagen matrix that comprises the bulk of the smooth muscle cells. Some examples of prior art relating to therapeutic coatings follow.
U.S. Pat. No. 5,283,257 issued to Gregory et al. provides a method of preventing or treating hyperproliferative vascular disease in a mammal by administering an amount of mycophenolic acid effective to inhibit intimal thickening. This drug can be delivered either after angioplasty or via a vascular stent that is impregnated with mycophenolic acid.
U.S. Pat. No. 5,288,711 issued to Mitchell et al. provides a method of preventing or treating hyperproliferative vascular disease in a mammal by administering an antiproliferative effective amount of a combination of rapamycin and heparin. This combination can be delivered either after angioplasty or via a vascular stent that is impregnated with the combination.
U.S. Pat. Nos. 5,516,781 and 5,646,160 issued to Morris et al. disclose a method of preventing or treating hyperproliferative vascular disease in a mammal by administering an antiproliferative effective amount of rapamycin alone or in combination with mycophenolic acid. The rapamycin or rapamycin/mycophenolic acid combination can be delivered via a vascular stent.
U.S. Pat. No. 5,519,042 issued to Morris et al. teaches a method of preventing or treating hyperproliferative vascular disease in a mammal consists of administering to a mammal an effective amount of carboxyamide compounds. This can also be delivered intravascularly via a vascular stent.
U.S. Pat. No. 5,646,160 issued to Morris et al. provides a method of preventing or treating hyperproliferative vascular disease in a mammal by administering an antiproliferative effective amount of rapamycin alone or in combination with mycophenolic acid. This can be delivered intravascularly via a vascular stent.
Each of the above-identified patents utilizes an immunosuppressive agent. Since the mid 1980's, many new small molecular weight molecules of natural product, semi-synthetic or totally synthetic origin have been identified and developed for the control of graft rejection. These include mizoribine, deoxysperguzalin, cyclosporine, FK 506, mycophenolic acid (and its prodrug form as mycophenolate mofetil), rapamycin, and brequinar sodium. The mechanisms of some of these agents will now be briefly summarized.
Both cyclosporine and FK 506 suppress T-cell activation by impeding the transcription of selected cytokine genes in T cells. Neither has any known direct effects on B cells. The suppression of interleukin 2 (IL-2) synthesis is an especially important effect of these two agents, because this cytokine is required for T cells to progress from initial activation to DNA synthesis. Both cyclosporine A and FK 506 bind to cytoplasmic proteins. It has been recently proposed that cyclosporine A and FK 506 are bifunctional: one segment of the immunosuppressant molecule is responsible for binding to the rotamase and, once bound, a separate part of the molecule interacts with a cytoplastmic phosphatase (calcineurin) and causes the phosphatase to become inactive or have altered specificity. Unlike all previously developed immunosuppressants and even the most recent xenobiotic immunosuppressants, FK 506 is the only compound in the history of immunosuppressive drug development that is the product of a drug discovery program designed specifically to identify an improved molecule for the control of allograft rejection. Every other past and “new” immunosuppressive xenobiotic drug is the unanticipated result of drug discovery programs organized to identify lead compounds for anticancer, anti-inflammatory, or antibiotic therapy.
Neither cyclosporine, FK 506, rapamycin nor other immunosuppressants are the product of evolutionary pressures that led to our current use of them as immunosuppressants. The agents are fungal (cyclosporine A) or bacterial (FK 506, rapamycin) metabolites that suppress lymphocyte proliferation purely through coincidental molecular interactions. Therefore, as our ability to design drugs that perform specific intravascular functions increases, there should be a reciprocal decrease in the severity of their adverse effects.
There is a need for safer versions of cyclosporine, FK 506, rapamycin and mycophenolic acid as well as for analogues with higher immunosuppressive efficacy. Because of their toxicities, these agents cannot be used at maximally immunosuppressive doses. Our understanding of the molecular basis of toxic effects of these agents is far less clear than their proposed mechanisms of action on T cells. Until we can combine an understanding of the molecular mechanisms responsible for both the agent's immunosuppressive actions and its toxic effects, it will be difficult to use rational drug design to limit an agent's effects solely to suppression of T cell activation.
The other significant issue that complicates the delivery of relatively high dosage of the agents is the relatively narrow therapeutic window. This narrow window of therapeutic vs. toxicity restricts most of these agents to be used as monotherapy for intravascular delivery.
Rapamycin, for example, inhibits the IL-2 induced proliferation of specific IL-2 responsive cell lines, but neither cyclosporine nor other drugs can suppress this response. Because rapamycin acts late in the activation sequence of T cells, it also effectively inhibits T cells inactivated by a recently described calcium independent pathway. Thus, T cells stimulated through this alternative route are insensitive to suppression by cyclosporine A and FK 506, but rapamycin inhibits their proliferation only.
The toxicity profile of rapamycin resembles cyclosporine A and FK 506. Rapamycin is associated with weight loss in several species, and treatment with high does of rapamycin causes diabetes in rats, but not in nonhuman primates. Initial animal data suggests that rapamycin may be less nephrotoxic than cyclosporine A, but its effects on kidneys with impaired function have not been evaluated. Rapamycin at highly effective therapeutic doses is highly toxic and its usage is recommended along with a combination of other immunosuppressants. The combination with cyclosporine A results in a significant increase in the therapeutic level in blood when compared with monotherapy. A lower dosage of the
Bianco Paul D.
Fleit Martin
Fleit, Kain, Gibbons, Gutman and Bongini
George Konata M
Hartley Michael G.
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