Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-10-20
2004-11-09
Brumback, Brenda (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S579000, C514S638000, C530S331000, C564S300000
Reexamination Certificate
active
06815425
ABSTRACT:
The present invention is directed to a neuroprotectant composition wherein the active ingredient is pGLU-GLU-PRO-NH
2
or a combination of pGLU-GLU-PRO-NH
2
(EEP) and N-tert-Butyl-&agr;-(2-sulfophenyl)nitrone (SPBN). The present invention is also directed to a method of treating and preventing diseases and injuries of the brain, spinal cord and retina by administering the endogenous tripeptide EEP to a subject as a neuroprotectant or by administering EEP in combination with SPBN or other nitrone.
BACKGROUND OF THE INVENTION
Twenty percent of all combat wounds involve the head. Penetrating head wound have a greater than 50% risk of developing posttraumatic epilepsy. Closed head injuries are more prevalent in the military than in the civilian community, and certain groups (e.g. paratroopers) are at special risk for both head and spinal injury. Among Naval personnel, certain occupational specialties are at increased risk for air gas embolism or decompression sickness (DCS), and the major neurological complication of either is spinal cord damage. There is also risk of oxygen toxicity-induced seizures. Severe head injury, or cerebral ischemia, is associated with a high mortality rate and poor functional outcome. Despite extensive clinical and experimental research, there are no well-defined therapies for these conditions. There are very few available treatments for brain injury today and the gradual progressive biochemical changes which occur after head trauma can lead to the evolution of permanent neuronal damage.
Further, personnel in all branches of the U.S. military are at risk for laser injury to the retina. Laser energy could be deliberately directed at the cockpit of U.S. military aircraft (airplanes and/or helicopters) with the intent of impairing the vision of pilots and/or crews (door gunners or medics). The adverse effects on the retina may range from transient impairment which can impact operational performance, to lasting disability or blindness. Reconnaissance troops and TOW missile operators are also at risk. Other potential sources of laser-induced retinal injury include exposure to laser targeting and ranging devices. A common source of laser-induced retinal injury in soldiers is the hand held neodymium (Nd:YAG) laser target designator (range finder), which operates at a wavelength of 1064 nanometers. Ruby lasers operating at a wavelength of 694.3 nm have also been used in military range finders and represent an additional potential source of retinal damage. The normal function of the lens, focussing light onto the retina, also serves to concentrate incident laser energy, when exposure occurs. While the magnifying effect of the human lens on intraocular laser energy is large as much as 10,000 fold—the amplification in the case of a soldier using binoculars could reach as much as 10
6
. The amount of laser energy reaching the retina is also directly related to pupil diameter. Thus, soldiers are at greater risk under dark-adapted conditions. Finally, the location of the laser-induced lesion is clinically very important, with foveal location being the most severe. Laser injuries near the fovea present a risk of penumbral spread over time to include the fovea.
Naval personnel are also at risk for decompression sickness (DCS) in at least two operational scenarios: (1) SEALS on extended underwater operations; (2) Submariners, during emergency evacuation, of crew from a submarine disabled on the continental shelf. Navy SEAL operations often require prolonged (e.g. up to 10 hours) dives at shallow depth (e.g. 40-60 feet), breathing high concentration oxygen, sometimes followed by brief excursions at greater depth. These personnel are at risk for air embolism, which can cause spinal injury, similar to that seen in decompression sickness (DCS), and oxygen toxicity-induced seizures.
Submarines could become disabled (DISSUB) on the ocean floor, requiring emergency evacuation of the crew. In this scenario, arrival of a rescue ship could take days, during which time crews in a disabled submarine could be exposed to hyperbaric conditions. To accomplish a DISSUB rescue expeditiously, a submersible rescue vessel would transport the crew to the surface in groups, potentially without decompression. Once on the surface, crew members may be required to wait for access to treatment in a limited-capacity recompression chamber on the surface. Because of the delay in treatment, some personnel might be at significant risk for neurological complications of DCS. Spinal cord injury is a relatively common sequela of DCS; recompression treatment is not always successful and if delayed, prognosis for recovery is poor. The prolonged delay before submarine crews might be brought to the surface, provides a significant window of opportunity for administration of a safe, well-tolerated prophylactic treatment to mitigate risk and severity of possible neurological complications of DCS.
Leading causes of blindness include: age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and cataracts. The prevalence of diabetes in North America is estimated to reach almost 17 million by the year 2000. In cases of insulin-dependent diabetes mellitus (IDDM) with onset before age 30, the average prevalence of proliferative retinopathy (DPR) is estimated at 23%. In IDDM of more than 30 years duration, however, the incidence of DPR rises to 70%. DPR is the leading cause of new cases of blindness in the U.S., accounting for 12% of new cases annually. The prevalence of AMD increases from over 2% in the age group of 60-64 years to over 25% in the 75-80 year group. It is estimated that the prevalence of glaucoma in the United States will be 2.9 million by the year 2000, and that over 130,000 will have been blinded by this disease.
A major pathological mechanism in both AMD and DPR is retinal neovascularization. The mechanisms of DPR include excessive retinal vascular permeability, edema, ischemia and the principal causes of loss of vision are hemorrhage into the vitreous and/or retinal detachment. The only effective treatment known for either AMD or DPR is coagulation via exposure to focussed laser irradiation (Vinding, 1995). Laser photocoagulation in a grid pattern is an effective treatment for the macular edema seen in diabetic retinopathy, as well as the neovascularization.
Unfortunately, exposure of the retina to laser energy, whether therapeutic or accidental results in formation of scotoma and visual impairment. Even after therapeutic exposures, there may be immediate and progressive visual impairment, due to destruction of normal retinal cellular elements with subsequent spread of injury to adjacent retinal tissue. In one study, progressive enlargement of laser scars was found in 11 of 203 patients with diabetic retinopathy treated via laser photocoagulation in a grid pattern.
Since the retina contains neurons and axons and is part of the central nervous system, recent advances in understanding of mechanisms of neurotoxicity apply, as do the related advances in research on neuroprotective agents. Ganglion cells are the output neurons of the retina and axons projecting from these cells form the optic nerve and project to the lateral geniculate nucleus of the brain. In one study, 12 hours after laser exposure, ganglion cells in monkey retina were liquefied. Ganglion cells are also destroyed in glaucoma, and continue to perish even after institution of standard glaucoma therapy.
Currently, post-injury treatment of spinal injury is most likely to include administration of the steroid methylprednisolone for 24 or 48 hours to reduce swelling and inflammation. In patients with accident-related acute spinal cord injury, clinical outcome at six months was improved in those receiving treatment with methyl prednisolone within eight hours of injury, compared to placebo-treated (Bracken et al., 1990 & 1997). Unfortunately, there is some evidence that glucocorticoids (GCs) can exacerbate the excitotoxic phase of neural injury. Postulated mechanisms of GC-mediated synergy with excitotoxic effects of glutami
Koenig Michael L.
Long Joseph B.
Meyerhoff James L.
Arwine Elizabeth
Brumback Brenda
Gupta Anish
The United States of America as represented by the Secretary of
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