Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Hydrogen metal cyanide – cyanide – cyanate – or thio analog...
Reexamination Certificate
1998-10-02
2002-03-19
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Hydrogen metal cyanide, cyanide, cyanate, or thio analog...
C514S579000, C514S645000, C514S929000
Reexamination Certificate
active
06358536
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is alleviation of vasoconstriction and vasospasm.
BACKGROUND OF THE INVENTION
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.
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, and the blood vessel is selected from the group consisting of a cerebral blood vessel, the right anterior cerebral artery, the right middle cerebral artery, the right posterior communicating artery, the left anterior cerebral artery, the left middle cerebral artery, the left posterior communicating artery, a cardiac blood vessel, the right coronary artery, the left coronary artery, and a blood vessel situated within a spastic muscle tissue. Preferably, the blood vessel is a cerebral blood vessel and the compound is adventitially administered to the blood vessel by delivering the compound to the cerebrospinal fluid of the mammal. One way of achieving this is to deliver the compound to the cerebrospinal fluid of the mammal by withdrawing an aliquot of the cerebrospinal fluid from the subarachnoid space of the mammal, to combine the compound with the aliquot of cerebrospinal fluid, and then to return the cerebrospinal fluid to the subarachnoid space of the mammal. Another way to achieve this is to deliver the compound to the cerebrospinal fluid of the mammal by withdrawing an aliquot of the cerebrospinal fluid from the subarachnoid space of the mammal, to combine a pharmaceutical composition comprising the compound with the aliquot of cerebrospinal fluid, and then to return the cerebrospinal fluid to the subarachnoid space of the mammal.
In another embodiment of this method, the blood vessel is a cardiac blood vessel, and the compound is adventitially administered by providing the compound to the pericardial cavity of the mammal.
The mammal of this method may, for example, be selected from the group consisting of a mammal experiencing chronic delayed cerebral vasoconstriction, a mammal which has experienced a subarachnoid hemorrhage, a mammal which has experienced an aneurysmal subarachnoid hemorrhage, a mammal experiencing an early embolic stroke, a mammal which has experienced a stroke, a mammal experiencing cardiac ischemia, a mammal which has experienced a myocardial infarction, a mammal afflicted with angina pectoralis. Preferably, the mammal is a human.
In one embodiment of this method, the compound is administered in the form of a sustained-release formulation of the compound. The compound may, 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 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.
In another embodiment of this method, the compound is administered in the form of a pharmaceutical composition comprising the compound and a scavenger compound selected from the group consisting of a cyanide scavenger, a cyanate scavenger, hydroxycobalamin, and thiosulfate.
Preferably, the amount of the NO donor compound administered to the blood vessel is an amount that is sufficient to alleviate constriction of the blood vessel, but that is insufficient to induce systemic hypotension or cerebral hypertension in th
Akin Gump Strauss Hauer & Feld L.L.P.
Choi Frank
Dees Jose′ G.
Thomas Jefferson University
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