Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-09-24
2004-01-27
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C424S522000, C424S523000, C424S725000, C424S757000
Reexamination Certificate
active
06683066
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is related to medical formulations used to treat and protect the central nervous system and methods of using those formulations. In particular, the invention relates to neuroprotective compositions and methods using those compositions to protect the brain or minimize lasting damage.
2. Background Information
Most Central Nervous System (CNS) injuries, including stroke, trauma, hypoxia-ischemia, multiple sclerosis, seizure, infection, and poisoning directly or indirectly involve a disruption of blood supply to the CNS, and share the same common pathologic process, that is: rapid cerebral edema leading to irreversible brain damage, and eventually to brain cell death.
One common injury to the CNS is stroke, the destruction of brain tissue as a result of intracerebral hemorrhage or infarction. Stroke is a leading cause of death in the developed world. It may be caused by reduced blood flow or ischemia that results in deficient blood supply and death of tissues in one area of the brain (infarction). Causes of ischemic strokes include blood clots that form in the blood vessels in the brain (thrombus) and blood clots or pieces of atherosclerotic plaque or other material that travel to the brain from another location (emboli). Bleeding (hemorrhage) within the brain may also cause symptoms that mimic stroke.
CNS tissue is highly dependent on blood supply and is very vulnerable to interruption of blood supply. Without neuroprotection, even a brief interruption to the blood flow to the central nervous system can cause neurologic deficit. The brain is believed to tolerate complete interruption of blood flow for a maximum of about 5 to 10 minutes.
It has been observed that after blood flow is restored to areas of the brain that have suffered an ischemic injury, secondary hemodynamic disturbances have long lasting effects that interfere with the ability of the blood to supply oxygen to central nervous system tissues. This has been called the “no-reflow” phenomenon.
Similarly, interruption of the blood flow to the spinal cord, for even short periods of time, can result in the “no-reflow” phenomenon leading to paralysis.
Recognition of the “ischemic penumbra,” a region of reduced cerebral blood flow in which cell death might be prevented, has focused attention on treatments that might minimize or reverse brain damage when administered soon after stroke onset. Enlargement of infarct volume is determined by changes in metabolism caused by initiation of the ischemic cascade. This cascade involves energy supply failure, membrane depolarization, release of neurotransmitters (including glutamate in large amounts), accumulation of intracellular calcium, increased production of nitric oxide and free radicals, development of cellular edema, and finally, cell death. Each step along the ischemic cascade offers a potential target for therapeutic intervention. To date, several classes of neuroprotective compounds have been investigated in phase 3 trials for acute stroke. They have included calcium channel antagonists, N-methyl-D-aspartate (NMDA) receptor antagonists, free radical scavengers, anti-intercellular adhesion molecule 1 antibody, GM-1 ganglioside, [gamma]-aminobutyric acid agonists, and sodium channel antagonists, among others. All of the trials have yielded disappointing efficacy results and some showed safety problems, including increased mortality or psychotic effects, which resulted in their early termination.
A neuroprotectant is a substance that can increase the tolerance of CNS tissues to injury or disruption of blood supply. A broad spectrum of compounds with disparate mechanisms of action have been considered, from oxygen free radical scavengers, calcium channel blockers and glutamate receptor antagonists to monoclonal antibodies that attempt to curtail inflammatory cascades occurring in cerebral injuries. Although several of these agents seems have been effective in vitro, very few have shown real advantages in in vivo testing or clinical studies. These agents are directed to molecular mechanisms of nerve cell injuries, but they do not address the one injury path common to all CNS injuries, cerebral edema.
Current treatments for stroke include recombinant tissue plasminogen activator (rt-PA), a thrombolytic agent, that has been shown to be effective dissolving clots to restore blood flow to injured areas of the brain if used within 3 hours after the onset of the stroke.
U.S. Pat. No. 5,755,237 to Rodriguez discloses acetazolamide for the treatment of brain edema. Acetazolamide can inhibit cerebrospinal fluid production, but administering of acetazolamide alone does not have a neuroprotective effect.
A series of patents, U.S. Pat. Nos. 4,981,691, 4,758,431, 4,445,887, 4,445,500, and 4,393,863 to Osterholm disclose a fluorocarbon solution for treatment of hypoxic-ischemic neurologic tissue.
SUMMARY OF THE INVENTION
Many proposed neuroprotective agents such as oxygen free radical scavengers, NMDA receptor antagonists, and apoptosis inhibitors seem to have measurable effect in vitro. However, during in vivo study and clinical trials, these agents do not show a neuroprotective effect.
I have now found that draining the cerebrospinal fluid (CSF) from the central nervous system, and replacing the CSF with an oil combined with an amphipathic lipid to adsorb edematous liquid in the CNS prevents cerebral edema. Elimination of this cerebral edema prevents the onset of the no-reflow phenomenon, enabling blood to reperfuse CNS tissue after significant periods of ischemia. Preventing the continuing hemodynamic disturbance, the no-reflow phenomenon, protects the CNS tissue making it resistant to injuries, and lengthening the therapeutic window for all other therapies.
This invention provides compositions and methods for protecting brain and spinal cord from injuries resulting from interruption of blood flow. Compositions according to this invention may be used to treat neurological disorders, such as stroke, hypoxia-ischemia, hemorrhage, trauma, multiple sclerosis, seizure, infection, or poisoning. The compositions are also useful during open-heart surgery, neurosurgery, shock, or other procedures where blood flow to the CNS is interrupted.
There are many advantages to the compositions and method I have discovered.
One advantage is improving the efficacy of existing treatments for stroke, head trauma, and other invasive procedures. Administering an effective neuroprotectant agent according to this invention will increase the therapeutic window, the period of time in which any other treatment, including thrombolytic agents can be used. For example, tPA, the only FDA approved medication for stroke, is a thrombolytic agent targeted on dissolving the blood clots that led to the stroke. tPA is not targeted on, and has no observed effect on cerebral edema. tPA is now only approved for use within 3 hours after onset of ischemia. When used in combination with the instant composition and method, the therapeutic window for all known treatments now used for supporting CNS tissue will be much longer.
This invention, if combined with other known techniques such as controlled hypothermia, may significantly increase the length of time a patient can tolerate cerebral ischemia. A patient treated according to this invention may survive invasive procedures performed on any part of the CNS without injury, including areas of the brain that have not been surgically accessible prior to this invention. Additionally, procedures that require interruption of the blood flow, such as heart surgery, repair of aortic aneurysm, or any other surgery where systemic blood circulation is interrupted can be performed with increased safety.
The compositions and methods I have invented extend the therapeutic window for successfully recovering from a stroke or cardiac arrest from mere minutes to hours. In addition, this compositions and method are useful for screening neuroprotective agents developed based on other mechanisms.
The formulations I have found that
Cesari and McKenna LLP
Witz Jean C.
LandOfFree
Composition and treatment method for brain and spinal cord... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Composition and treatment method for brain and spinal cord..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Composition and treatment method for brain and spinal cord... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3220099