Surgery – Means for introducing or removing material from body for... – Material introduced into and removed from body through...
Reexamination Certificate
2000-07-31
2004-01-20
Jacyna, J. Casimer (Department: 3751)
Surgery
Means for introducing or removing material from body for...
Material introduced into and removed from body through...
Reexamination Certificate
active
06679859
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of protecting living tissue from damage caused by hypoxic or ischemic conditions such as those resulting from acute vascular occlusions. More particularly, the present invention relates to the use of synthetic oxygen carriers, including perfluorocarbon-based emulsions, to carry gases to hypoxic or ischemic living tissue, and thereby ameliorate damage.
BACKGROUND OF THE INVENTION
Normal animal physiology requires efficient delivery of oxygen to living cells and tissues and efficient removal of carbon dioxide and other waste products of metabolism. In mammals, this is generally accomplished by gas exchange mediated by hemoglobin-containing red blood cells, and is primarily accomplished by red blood cells flowing through capillaries. When capillaries or larger arteries become occluded, such as by vessel constriction or solid emboli that block or partially block the blood vessels, the oxygen supply becomes compromised for tissues that depend on those vessels for oxygen. Tissue hypoxia results from failure to transport sufficient oxygen, often due to inadequate blood flow i.e. ischemia. Hypoxia can result from internal hemorrhage (e.g., intracerebral hemorrhage producing cerebral hypoxia), anemia or trauma. Ischemia is a deficiency of blood supply to the tissue due to functional constriction or actual obstruction of a blood vessel. For example, myocardial ischemia is a deficiency of blood supply to heart muscle due to obstruction or constriction of the coronary arteries. If ischemia continues for more than a few seconds, tissue damage can result from a complex series of biochemical events associated with the ischemia-induced tissue hypoxia.
Hypoxic or ischemic conditions produced by emboli can result in tissue damage that is particularly debilitating if the damaged tissue is heart tissue or neural tissue of the central nervous system (CNS). The two most serious consequences of emboli are heart attack (acute myocardial infarct or AMI), resulting from cardiac muscle ischemia, and stroke, resulting from brain tissue ischemia. Ischemia which does not lead to AMI or stroke can, nonetheless, produce serious symptoms in the individual such as chest pains (angina pectoris), partial paralysis, confusion, disorientation and/or memory loss.
Individuals with vascular disease, particularly atherosclerosis, are particularly at risk for developing emboli that can result in AMI or stroke. Ischemic heart disease affects millions of people worldwide, often leading to sudden death by AMI. Ischemia can result when solid emboli produced from portions of plaque that dislodge and move through the circulatory system lodge in a capillary or attach to another plaque deposit in a blood vessel, thus fully or partially occluding the vessel or capillary. Atheromatous plaque particles can also be generated during vascular and cardiac surgery procedures (e.g. cannulation, clamping) that manipulate or disturb any atherosclerotic blood vessels (e.g., carotids, coronaries, aorta, femoral or popliteal vessels).
Present day treatment of occlusions generally involves bypassing the blocked vessel, or removing and/or dissolving emboli using mechanical means and/or thrombolytic enzymes. For example, treatment of intracoronary thrombotic events such as myocardial infarcts usually involves one or a combination of treatments. These include coronary bypass surgery, percutaneous coronary angioplasty (PTCA) and systemic administration of thrombolytic agents, such as tissue plasminogen activator (tPA) or streptokinase. Although such treatments often successfully relieve the hypoxic or ischemic condition, significant damage to the tissue in the hypoxic zone can occur before treatment is completed.
Synthetic oxygen carriers, often referred to as “blood substitutes” have been shown to augment delivery of oxygen through the circulatory system when red blood cells (i.e., hemoglobin) are partially depleted, such as during surgery, or resulting from injury with bleeding or hemorrhagic disorders. Similarly, synthetic oxygen carriers can be used to treat conditions where the red blood cells are partially non-functional, as may occur in patients with certain genetic disorders, or patients undergoing hypothermic procedures such as cardiopulmonary bypass or circulatory arrest. Such oxygen carriers or blood substitutes are disclosed in U.S. Pat. No. 5,344,393 and U.S. Pat. No. 5,451,205. Other blood substitutes are known as disclosed in U.S. Pat. No. 5,114,932, U.S. Pat. No. 4,423,077, U.S. Pat. No. 4,397,870, U.S. Pat. No. 4,186,253, U.S. Pat. No. 4,173,654, U.S. Pat. No. 4,423,077, U.S. Pat. No. 3,962,439 and U.S. Pat. No. 3,937,821. Perfluorocarbon emulsions, such as FLUOSOL™ (Green Cross Corporation, Japan) and OXYGENT™ (perflubron-based emulsion) (Alliance Pharmaceutical Corp., San Diego, USA), are known to be efficient synthetic oxygen carriers that are generally well tolerated in vivo by humans. Synthetic oxygen carriers comprising hemoglobin, which can be derived from human, animal, or recombinant sources, is also known in the art
Given the excellent oxygen dissolving characteristics and biocompatibility of perfluorochemicals, previous efforts have led to their use in neurologic ischemia. For example, one system includes perfluorocarbon in a nutrient emulsion or “synthetic cerebrospinal fluid” to treat CNS hypoxic-ischemic conditions (U.S. Pat. No. 4,445,514). In this case the oxygenated emulsion is administered directly into the cerebrospinal fluid and artificially circulated through extracorporeal means.
Perfluorocarbon emulsions have also been used in an experimental animal model of partial brain stem ischemia and shown to enhance recovery of brain stem function following reperfusion (Guo et al.,
Neurosurgery
36(2): 350-357, 1995).
Perfluorocarbons and blood substitutes have also been used for drug delivery. For example, infusions of a neuroprotectant and a perfluorochemical emulsion have been disclosed as a treatment for conditions involving cerebral hypoxia (PCT International Application No. WO 97/15306).
SUMMARY OF THE INVENTION
According to the invention, there is provided a method of preventing or treating tissue hypoxia or ischemia, including the step of administering systemically a synthetic oxygen carrier to an individual having or suspected of having blood vessel obstruction. Preferably, the invention may be used to provide neuroprotection or retard neurodegeneration in a patient in need thereof through a reduction in the adverse effects of cerebral ischemic hypoxia. Other preferred embodiments comprise the use of synthetic oxygen carriers in chronic or long-term therapeutic regimens for the reduction or treatment of ischemic or hypoxic associated effects. Another embodiment comprises the use of perfluorochemical-based formulations to reduce the inflammatory process triggered locally by the ischemic insult and related tissue hypoxia. In selected embodiments, the oxygen carrier is administered by intravenous injection or infusion. Preferably, the synthetic oxygen carrier is a perfluarocarbon emulsion, crystalloid blood substitute, a colloid blood substitute, or combinations thereof.
As such, in a broad sense the present invention comprises the use of a synthetic oxygen carrier in the manufacture of an oxygen carrying medicament for the treatment of tissue hypoxia due to ischemia or acute anemia, wherein said oxygen carrying medicament is administered systemically to an individual having or suspected of having blood vessel obstruction caused by solid emboli, or temporary clamping of vessels during surgery.
Particularly preferred embodiments of the invention comprise the use of synthetic oxygen carriers which are fluorocarbon-in-water emulsions comprising a discontinuous fluorocarbon phase and a continuous aqueous phase. In another embodiment, the fluorocarbon-in-water emulsion includes a perfluorocarbon phase and an aqueous phase. In another embodiment, the fluorocarbon emulsion also includes an emulsifying agent or dispersant, osmotic agent, buffer, electrolyte o
Faithfull N. Simon
Flaim Stephen F.
Keipert Peter E.
Rosenberg Gwen H.
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