Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Arterial prosthesis – Stent structure
Reexamination Certificate
1999-03-01
2003-12-02
Prebllic, Paul B. (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Arterial prosthesis
Stent structure
C623S001430, C623S023710, C623S926000, C604S266000
Reexamination Certificate
active
06656217
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to novel drug delivery systems containing a nitric oxide-releasing metal compound entrapped therein and methods for using them, more particularly for the inhibition of restenosis after percutaneous transluminal coronary angioplasty and for the inhibition of acute or subacute thrombotic occlusion related to the use or deployment of a synthetic device within the vascular tree or extracorporeally.
2. Description of the Prior Art
Sodium nitroprusside (SNP) and similar nitrosyl-containing organometallic compounds, whether ionic salts or chelates, which can release nitric oxide (NO), have been known since the mid-1950's to exhibit short-term hypotensive effects. The mechanism by-which this drug elicited its pharmacological activity was not known until the discovery that endothelial cells secreted a factor, which regulated vascular tone, termed Endothelial-Derived Relaxation Factor (EDRF) (Furchgott and Zawadzki,
Nature
, 288: 373-376, 1980). In 1987, Palmer and coworkers (
Nature
, 327: 524-526, 1987) determined that the free radical nitric oxide mimicked many of the physiologic properties reported for EDRF. Besides regulating vascular tone, nitric oxide has been found to control a wide variety of physiologic functions, including (a) inhibition of neutrophil adhesion (Kubes, et al.,
Proc. Natl. Acad. Sci. USA
, 88:4651-4655, 1991), (b) enhancement of macrophage-mediated microbial killing (De Groote and Fang,
Clin. Infect. Dis
. 12 (Suppl 2): S162-S165, 1995) (c) amelioration of impotence (Burnett, et al.,
Science
, 257: 401-403, 1992) and (d) regulation of various CNS functions (Dawson, et al.,
Ann. Neurol
. 32: 297-311, 1992). Of relevance to this invention are those studies demonstrating that nitric oxide inhibits platelet aggregation (Furlong, et al.,
Brit. J Pharmacol
. 90: 687-692, 1987; Radomski, et al.,
Lancet, ii
, 1057-1058, 1987) and prevents restenosis (McNamara, et al.,
Biochem. Biophys. Res. Commun
. 193: 291-296, 1993).
Since nitric oxide regulates many physiologic functions, this free radical is an essential ingredient for maintaining normal life processes. However, pharmacological applications of nitric oxide are limited, since systemic use can result in severe toxicity. For instance, administration of gaseous nitric oxide systemically to treat localized abnormalities or diseases is impractical except in a hospital intensive care setting, because control of its dosage in the therapeutic range cannot easily be achieved. Even if it were possible to carefully titrate the gaseous dose of nitric oxide to minimize systemic toxicity, it would be very difficult to locally administer this drug to sites of interest. Therefore, the development of therapeutic agents, which would mimic the pharmacological action of nitric oxide, has received considerable attention. Several classes of nitric oxide-releasing compounds have been developed, including syndnoeimine (Noack and Feelisch,
J. Cardiovasc. Pharmacol
. 14S: 51-55, 1989), nitroglycerin (Noack and Feelisch,
J. Cardiovasc. Pharmacol
. 14S: 51-55, 1989), S-nitroso derivatives (Ignarro, Lippton, Edwards, Baribos, Hyman, Kadowitz and Gretter,
J. Pharmacol. Exp. Ther
. 218: 729-739, 1981; Kowaluk and Fung,
J Pharmacol. Exp. Ther
. 255: 1254-1256, 1990; Stamler, Loscalzo, Slivka, Simon, Brown and Drazen, U.S. Pat. No. 5,380,758, 1995) and N-nitroso compounds (Maragos, Morley, Wink, Dunams, Saavedra, Hoffman, Bove, Issac, Hrabie and Keefer,
J. Med Chem
. 34: 3242-3247, 1991; Keefer, Dunans and Saavedra, U.S. Pat. No. 5,366,997, 1994, Keefer and Hrabie, U.S. Pat. No. 5,405,919, 1995; Keefer, Hrabie and Saavedra, U.S. Pat. No. 5,525,357, 1996). These compounds require either hydrolysis or metabolic activation, through either oxidation or reduction, to generate nitric oxide. Alternatively, several studies have reported on the development of photolyzed “caged-nitric oxide” compounds. For example, the organometallic compound sodium nitroprusside has been found to release nitric oxide upon light activation (Bates, Baker, Guerra and Harrison,
Biochem. Pharmacol
. 42S: S157-S165, 1991). Contrary to this, nitric oxide generation from light activation of ruthenium nitrosyl trichioride failed to inhibit platelet aggregation, thereby questioning the utility of this approach (Makings and Tsien,
J. Biol. Chem
. 269: 6282-6285, 1994).
Clinically, sodium nitroprusside is used therapeutically to treat hypertension acutely. Its use is limited to acute hospital-based treatment because this nitric oxide releasing compound has a short lifetime of several minutes in blood (Palmer and Lasseter,
New Engl. J. Med
. 292: 294-297, 1975; Packer, Meller, Medine, Gorlin and Herman,
New Engl. J. Med
. 301: 1193-1197, 1979). The degradation of sodium nitroprusside is thought to arise through reductive processes taking place in the bloodstream. Even though it has been suggested that sulfhydryl groups attached to endothelial cells lining the vascular walls might initiate this reaction, other reductants such as glutathione or ascorbic acid may likewise contribute to its unusually short physiologic lifetime (Höbel, Kreye and Raithelhuber,
Herz
. 1: 130-136, 1976; Ivankovitch, Miletich and Tinker,
Int. Anesthesiol. Clin
. 16: 1-29, 1978; Kreye and Reske,
Arch. Pharmacol
. 320: 260-265, 1982). Based on this pharmacological behavior, the current clinical use of this drug requires that it is given continuously as an intravenous solution or it rapidly looses its efficacy concomitant with an increase in blood pressure to a hypertensive level.
Apparatuses and methods have been developed for delivering nitric oxide-releasing compounds and other drugs selectively and locally to a specific internal body site, e.g., for preventing restenosis after percutaneous transluminal coronary angioplasty. For instance, Cooke, Dzau and Gibbons (U.S. Pat. No. 5,428,070, 1995) described the use of orally administered L-arginine as a dietary supplement to enhance nitric oxide production by providing the substrate to nitric oxide synthase, the enzyme which metabolizes L-arginine to L-citrulline and nitric oxide. This would not be applicable to restenosis, since in this pathology, the endothelial cell levels of L-arginine are not diminished, but rather the specific isoform of nitric oxide synthase localized in endothelial cells is dysfunctional. Furthermore, even if levels of L-arginine were low, replacement therapy through supplementation of dietary L-arginine is an inappropriate treatment as cellular sources of L-arginine arise primarily from the reverse metabolism of L-citrulline to L-arginine (Sessa, Hecker, Mitchell and Vane,
Proc. Natl. Acad Sci. USA
, 87: 8607-8611, 1990).
U.S. Pat. No. 5,282,785 employs a drug delivery apparatus comprising a flexible catheter for insertion into an internal target area of the body and a drug delivery means connected to the catheter. In this version, the latter delivers the drug in a radially restricted manner and comprises (a) a drug delivery chamber at the distal end of the drug delivery apparatus, which has a selectively permeable outer membrane portion and circumferential lips adjacent to both the proximal and distal ends of the drug delivery system to minimize movement of a drug beyond a segment of internal tissue and a fluid delivery passageway extending from the chamber to the proximal end of the catheter; and (b) a non-permeable balloon affixed to and surrounding a portion of the chamber, which, when inflated, secures the chamber at the target area and radially restricts local delivery of the drug by providing intimate contact between balloon and a portion of the internal body tissue. The use of such an indwelling catheter device is limited to short term applications (usually no longer than 10-20 minutes), because it obstructs arterial blood flow. The apparatus also includes means of assisting the transport of the drug across the selectively permeable outer membrane with or without application of pressure.
Similarly, U.S. Pat. No. 5,286,2
Herzog, Jr. William R.
Pou Sovitj
Rosen Gerald M.
Zhao Yi-Ju
Gollin Michael A.
Haddaway Keith G.
NovoVascular, Inc.
Prebllic Paul B.
Venable LLP
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