Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-03-26
2002-10-01
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S006900, C514S277000, C514S315000, C514S579000, C530S362000, C530S385000, C544S184000, C544S216000, C548S401000, C548S541000
Reexamination Certificate
active
06458758
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the therapeutic and diagnostic use of nitroxides, including the combined use of a membrane permeable nitroxide with a membrane impermeable nitroxide including nitroxide-labelled macromolecules, including polypeptides e.g., hemoglobin, albumin, immunoglobulins, and polysaccharides, e.g., dextran, hydroxylethyl starch, and artificial membranes, e.g., liquid bilayer, hemoglobin and albumin microbubbles. Nitroxide-containing formulations are disclosed which alleviate the toxic effects of oxygen-related species in a living organism and provide ability to diagnose and treat a wide variety of pathological physiological conditions. This invention also relates to nitroxides, synthetic nitroxide polymers and copolymers and nitroxide-labelled macromolecules used in combination with low molecular weight and membrane-permeable nitroxides to sustain the in vivo effect of nitroxides. This invention also discloses novel compounds and methods featuring nitroxides used in combination with physiologically compatible cell-free and encapsulated hemoglobin solutions for use as a red cell substitute. Furthermore, this invention describes the methods and novel compounds for the topical delivery of cell membrane impermeable nitroxides in its membrane permeable form leading to intracellular accumulation of therapeutic concentrations of the said nitroxide for treatment of skin photo aging and as an anti-skin wrinkle agent. Additionally, this invention describes the above nitroxides in combination with other physiologically active compounds, including other nitroxides, to protect from pathological damage and oxidative stress caused by free radicals and describes their use in diagnosis and in the treatment of disease.
BACKGROUND OF THE INVENTION
Although the physiological mechanisms of oxygen metabolism have been known for many years, the role played by oxidative stress in physiology and medicine is not completely understood. The impact of oxygen-derived free radicals on physiology and disease is a topic of increasing importance in medicine and biology. It is known that disease and injury can lead to levels of free radicals which far exceed the body's natural antioxidant capacity—the result is oxidative stress. Oxidative stress is the physiological manifestation of uncontrolled free radical toxicity, most notably that which results from toxic oxygen-related species. Toxic free radicals are implicated as a causative factor in many pathologic states, including ischemia-reperfusion injury resulting from heart attack or stroke, shock, alopecia, sepsis, apoptosis, certain drug toxicities, toxicities resulting from oxygen therapy in the treatment of pulmonary disease, clinical or accidental exposure to ionizing radiation, trauma, closed head injury, burns, psoriasis, in the aging process, and many others.
Therefore, a need exists for compositions and methods which detoxify free radicals and related toxic species and which are sufficiently active and persistent in the body to avoid being rapidly consumed when increases in free radical concentrations are encountered.
Furthermore, evidence has been developed which demonstrates that free radicals aggravate a number of other disease states including cancer, ulcers and other gastro-intestinal conditions, cataracts, closed head injury, renal failure, injury to the nervous system, and cardiovascular disease to name a few. As a result of their high reactivity, free radicals can oxidize nucleic acids, biological membranes, and other cell components, resulting in severe or lethal cellular damage, mutagenesis, or carcinogenesis. Anti-cancer radiotherapy, as well as a number of antitumor drugs, act by generating free radicals which are toxic to tumor cells, but are also toxic to normal cells which are exposed during cell division causing the undesirable side-effects of cancer therapy. Indeed, it is believed that many pathologic processes have as their common final pathway the generation of free radicals which are the direct, or a substantial contributing cause, of the observed pathology. Additionally, a dramatic increase in free radical concentrations can be observed as part of a cascade initiated by the interruption of the flow of oxygenated blood, such as in heart attack or stroke, often followed by the reperfusion of oxygenated blood to the affected area. As the importance of such oxidative stress in living systems becomes appreciated, a continuing need exists for compounds and methods that can function as anti-oxidants and which can be designed to interact with oxygen-derived free radicals to alleviate their toxicity in biological systems, particularly in humans. In other applications, the toxic free radicals may be coincident to a beneficial treatment such as radiation administered as part of cancer radiotherapy. For example, since the mechanism by which ionizing radiation causes physiologic damage to an organism involves, at least in part, a free radical interaction with cells, compounds which possess or interact with free radicals exhibit a localized effect on tissues exposed to radiation therapy thereby controlling the collateral damage caused by a therapeutic treatment. Additionally, apart from any clinically significant function, since the unpaired electrons in free radicals species are detectable by spectroscopy, free radical reactions may be monitored in vivo and compounds which interact with free radicals are observable by spectroscopic techniques.
Several therapeutic approaches have been proposed to reduce pathologic levels of free radicals. Ideally, safe and effective antioxidant agents would augment a patient's antioxidant capacity and assist in blocking many pathologic free-radical based toxicities at the stage of free radical generation. However, the development of methods and compounds to combat oxidative stress or the toxicity associated with oxygen-related species has enjoyed limited success. The usefulness of many anti-oxidants is limited by short duration of action in vivo, toxicity at effective dosage levels, the inability of many compounds to cross cell membranes, and an inability to counter the effects of high levels of free radicals. For example, the administration of the enzyme superoxide dismutase (SOD) or catalase can promote the conversion of toxic free radical related species to a non-toxic form. However, these enzymes do not function effectively in the intracellular space. Procysteine as a GSH precursor, as well as vitamins and other antioxidant chemicals, can enhance the body's natural antioxidant capacity, but are unable to deal with the higher levels of free radicals encountered in injury and disease and are rapidly consumed by the body.
Free radical species are notoriously reactive and short-lived. Such reactivity is a particularly serious hazard in biological systems because detrimental chemical reactions between a free radical and body tissue occurs in very close proximity to the site where the free radial is generated. Therefore, compounds which inherently function to reduce free radical concentrations have some beneficial effect, although the effect may not be clinically significant unless the therapeutic effect can be concentrated and localized in a particular region of the body such as the brain, the epidermis, the gut, the cardiovascular system or in discrete tissue such as the site of radiation administration.
The difficulties encountered in creating a blood substitute suitable for large volume intravenous administration are an acute example of the difficulty in preventing or alleviating systemic toxicity caused by oxygen-related species in the vascular space. Scientists and physicians have struggled for decades to produce a blood substitute that could be safely transfused into humans. Persistent blood shortages and the problems of incompatible blood types, cross-matching, and the communication of disease have led to a broad-based effort by private industry, universities, and governments to discover a formulation that would allow a large volume of a blood substitute
Gupta Anish
Low Christopher S. F.
Lyon & Lyon LLP
Synzyme Technologies, Inc.
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