Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2002-02-05
2004-09-28
Hayes, Michael J. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S082000, C604S084000, C604S087000, C604S200000, C604S218000, C604S236000, C222S386000, C222S387000
Reexamination Certificate
active
06796966
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
REFERENCE TO A MICROFICHE APPENDIX
Not applicable.
BACKGROUND OF THE INVENTION
The field of the invention is alleviation of vasoconstriction and vasospasm. Vasoconstriction and vasospasm are important causes of ischemic damage in a wide variety of human maladies, including, for example, ischemic heart diseases such as myocardial infarction, angina pectoralis, and atherosclerotic injury, stroke, cerebral vasoconstriction, and cramps and ischemic muscle injury associated with muscle spasm.
Chronic delayed cerebral vasoconstriction (CDCV) following aneurysmal subarachnoid hemorrhage (SAH) is a serious and often fatal condition in humans. Considerable clinical and laboratory evidence has accumulated to indicate that endothelin-1 (ET-1) is involved in development of CDCV following SAH (Suzuki et al., 1990, Annals of Medicine 22:233-236; Suzuki et al., 1992, J. Neurosurgery 77:96-100; Fuwa et al., 1993, Neurologia Medico-Chirurgica 33:739-743; Kasuya et al., 1993, J. Neurosurgery 79:892-98; Ohlstein et al., 1992, J. Neurosurgery 77:274-278). A similar body of evidence exists for role of ET-1 in the failure of intrinsic vasodilatory mechanisms in the cerebral blood vessel wall as a result of SAH (Hongo et al., 1988, J. Neurosurgery 69:247-253; Snyder et al., 1992, Scientific American 266:68-77; Toda et al., 1993, Stroke 24:1584-1588).
The action of nitric oxide (NO) is implicated in intrinsic local vasodilation mechanisms. NO is the smallest biologically active molecule known and is the mediator of an extraordinary range of physiological processes (Nathan, 1994, Cell 78:915-918; Thomas, 1997, Neurosurg. Focus 3:Article 3). NO is also a known physiologic antagonist of endothelin-1, which is the most potent known mammalian vasoconstrictor, having at least ten times the vasoconstrictor potency of angiotensin II, which has been implicated in CDCV by many investigations (Yanagisawa et al., 1988, Nature 332:411-415; Kasuya et al., 1993, J. Neurosurg. 79:892-898; Kobayashi et al., 1991, Neurosurgery 28:5:673-679). The biological half life of NO is extremely short (Morris et al., 1994, Am. J. Physiol. 266:E829-E839; Nathan, 1994, Cell 78: 915-918, 1994). NO accounts entirely for the biological effects of endothelium-derived relaxing factor (EDRF) and is an extremely potent vasodilator that works through the action of cGMP-dependent protein kinases to effect vasodilation (Henry et al., 1993, FASEB J. 7:1124-1134; Nathan, 1992, FASEB J. 6:3051-3064; Palmer et al., 1987, Nature 327:524-526; Snyder et al., 1992, Scientific American 266:68-77).
As a free radical gas, NO is difficult to measure directly, but two pieces of evidence support its insufficiency or dysfunction during SAH-induced cerebral vasospasm. First, cGMP is depleted in the vessel wall following SAH and second, oxyhemoglobin, released by erythrocyte lysis in the SAH clot, binds NO avidly (Gibson et al., 1957, Am. J. Physiol. 136:507-526; Kim et al., 1992, Circulation Research 70:248-56; Martin et al., 1985, J. Pharmacol. Exp. Ther. 232:708-716).
It is likely that the phenomenon of CDCV simultaneously involves the increased activity of ET-1 and the decreased activity of NO. Validation of such a hypothesis requires that attenuation or reversal of CDCV by either interfering with the action of ET-1 or by somehow making NO more available to the blood vessel wall is demonstrated. This has been attempted by several groups of investigators using different methods with varying degrees of success. The former strategy has enjoyed more popularity in the recent literature and the use of endothelin receptor antagonists to attenuate CDCV has provided promising initial results (Foley et al., 1994, Neurosurgery 34:108-113; Itoh et al., 1994, J. Neurosurgery 81:759-764).
One important limitation of the use of NO donors in vivo has been their tendency to induce severe systemic hypotension (Heros et al., 1976, Surgical Neurology 5:354-362; Raynor et al., 1963, J. Neurosurgery 20:94-96). A reliably effective treatment for CDCV that follows aneurysmal SAH remains elusive. The mainstay of treatment for this complication, now the most important cause of mortality and neurological morbidity following aneurysmal SAH, is hypertensive/hypervolemic/hemodilution (HHH) therapy (Solomon et al., 1998, Neurosurgery 23:699-704). Because severe cases of CDCV are refractory to HHH therapy, and because some patients do not tolerate HHH therapy for medical reasons, an alternative treatment for CDCV is needed. Effective treatments for vasoconstriction and vasospasm in cerebral and other tissues are needed, as are prophylactic treatments for preventing vasoconstriction and vasospasm.
The present invention satisfies these needs.
BRIEF SUMMARY OF THE INVENTION
The invention relates to a method of alleviating vasoconstriction in a mammal. The method comprises adventitially administering a nitric oxide donor compound to a constricted blood vessel in the mammal. Constriction of the blood vessel is thereby alleviated. In one embodiment of this method, the animal is a human. The blood vessel can, for example, be one that supplies blood a tissue selected from the group consisting of an erectile tissue (e.g., penile or clitoral tissue), an ocular tissue, a non-cardiac muscle tissue (e.g., a spastic muscle tissue), a non-cerebral neuronal tissue (e.g., a peripheral afferent or efferent nerve, retina, or an optic nerve of a patient afflicted with diabetic retinopathy), and an epithelial or endothelial tissue such as a skin tissue or an oral tissue. The compound can be administered directly to the tissue (e.g., by topically applying it to a normally or surgically exposed tissue or by injecting it into the tissue) or it can be administered to a fluid that normally contacts the tissue. By way of example, a solution of a nitroprusside salt or adenosine can be administered to an ocular tissue by applying the solution directly to the eyeball, by providing the solution to lacrimal fluid surrounding the eyeball, or by injecting the solution into an ocular compartment containing the aqueous or vitreous humor of the eye.
In one embodiment of this method, the compound is administered in the form of a sustained-release formulation of the compound. The compound can, for example, be selected from the group consisting of nitroglycerine, arginine, and a nitroprusside salt. Preferably, the compound is sodium nitroprusside (SNP). The dosage of SNP for established vasospasm in an adult human in a one-day period is in the range from about 10 milligrams to 88 milligrams, more preferably from about 10 milligrams to 30 milligrams. Prophylactic treatment can comprise administration of a composition comprising an amount of a NO donor compound in the range from less than 1 milligram to about 10 milligrams, preferably in the range of from about 2 milligrams to 4 milligrams, the composition being administered 1 to about 5 times per day, and preferably 1 to 3 times per day. The amount of the compound administered daily for prophylactic purposes should not exceed about 24 milligrams. The NO donor compound can be administered in conjunction with or, in certain situations, replaced with a vasodilating compound that is not an NO donor compound. By way of example, adenosine is known to be a potent vasodilator. Inhibition, prevention, or reversal of vasoconstriction and vasospasm effected by one or both of an NO donor compound or a vasodilating compound can reduce or prevent ischemic tissue damage that would occur if the vasoconstriction or vasospasm were left untreated. Thus, in one embodiment, the NO donor compound, the non-NO-donor vasodilating compound, or both are chronically administered to a blood vessel that supplies the tissue (e.g., a blood vessel situated within the tissue) in order to inhibit or prevent ischemic damage in the tissue. By way of example, an NO donor compound, a vasodilating compound, or both can be chronically (e.g., repeatedly or continuously over a period of days, weeks, months, or years) administered to the
Benesch Friedlander Coplan & Aronoff LLP
Hayes Michael J.
Rodriguez Cris L.
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