Coated stents - Patents

Coated stents

Agent: Fulbright & Jaworski L.L.P. Fulbright Tower - Houston, TX, US
Inventor: Jordan U. Gutterman
Class: 424422000 (USPTO)
#20060099236
05/11/06
The invention provides novel compositions and methods related to stents, such as coronary stents, comprising avicins, which are triterpene saponin compositions. In particular aspects of the invention, the avicins have growth-inhibiting properties and/or anti-inflammatory properties. In specific embodiments of the invention, the stent comprising the avicin reduces at least in part restenosis, such as that associated with stent procedures.
[0001] The present invention claims priority to U.S. Provisional Patent Application Ser. No. 60/611,871, filed Sep. 20, 2004, which is incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to at least the field of medicine. More specifically, it relates to compositions and methods regarding triterpene-coated stents.
SUMMARY OF THE INVENTION
[0009] The present invention regards stents comprising a saponin composition including a triterpene or other aromatic terpenoid composition. Such a stent may be defined as "coated" with one or more active compound(s) as described herein. Those of skill in the art will understand that "coated" specifically encompasses any manner in which a given compound or collection of compounds can be associated with a stent, including permanent or non-permanent attachment to the surface of a stent, impregnation of a stent with the compound, encapsulation of a compound within the stent, local delivery of the compound with the stent, or any combinations thereof or other methods in which the compound is delivered in connection with the stent to obtain the associated benefits.
[0010] The saponins provided for producing coated stents may also comprise a glycosidic group. In a particular embodiment of the invention, there is provided a stent including triterpene saponins (called avicins), originally identified from the Acacia victoriae plant. In one embodiment, the present invention provides saponin compounds and mixtures thereof that may be isolated from the species Acacia victoriae and delivered in association with a stent. The use of any stent may benefit from comprising an avicin, including, for example, stents for arteriovenous fistula (a procedure that creates access to the blood for hemodialysis); reattaching the intestines after a temporary colostomy; and keeping the ureters open after surgery to repair a blocked ureter. In particular embodiments of the invention the stent is one to facilitate and maintain opening of a vessel, such as a coronary vessel, and this example is illustrated herein as an exemplary embodiment.
[0011] Avicins have a variety of properties indicating their efficacy in coating stents in accordance with the invention, including in particular general anti-inflammatory and anti-stress activities. Among specific characteristics are selective cytotoxic activity, the ability to release cytochrome c from mitochondria, induction of caspase activation and/or cleavage of PARP, inhibition of PI3-kinase and/or phosphorylation of Akt, induction of Rb gene hypophosphorylation, inhibition of carcinogenesis, inhibition of NF-.kappa.B activation, and/or inhibition of activators of cellular stress responses such as inducible nitric oxide synthase (NOS) and cyclooxygenase (COX-2).
[0012] In specific embodiments, avicins may be used in connection with stents for the prevention and/or therapy of restenosis. In specific embodiments of the present invention, avicins may be used in connection with stents to block platelet aggregation and/or thrombosis formation, for example, since both processes are a part of the primitive innate immune response. In further specific embodiments, the lipophilic properties of avicin provide an advantage, given the lipid solubility of the drug on the stents, making it particularly well-suited for sustained delivery from stents and prolonged deposition in blood vessels.
[0013] Avicins comprise potent anti-inflammatory effects, such as by their ability to inhibit activation of nuclear factor-.kappa.B (NF-.kappa.B) (a central regulator of an organism's response to stress signals) as well as its downstream targets of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) (Haridas et al., 2001a). Inflammation and oxidative stress have been linked (Frenkel et al., 1995; Marnett, 2000), and the production of reactive oxygen species (ROS) provides a frequent source of endogenous genotoxins (Lengauer et al., 1998). Thus, in specific embodiments of the present invention, avicins reduce cell damage by minimization of physiological stress, such as that associated with stent implantation.
[0014] NF-.kappa.B regulates the transcription of a number of genes related to immune and inflammatory pathways, including proinflammatory cytokines, adhesion molecules, and apoptosis. Avicins may therefore find use in minimizing acute inflammation, as well as reducing both oxidative and nitrosative cellular stress to suppress undesirable cell proliferation. In specific embodiments of the present invention, avicins inhibit formation of neointima, which involves the recruitment of inflammatory cells to the stent "injury" site, the migration of VSMC from the media to the intima, and their cellular proliferation. In particular embodiments, avicins target one or more of these steps toward formation of neointima.
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