Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-03-12
2002-04-30
Kumar, Shailendra (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S396000, C514S399000, C514S400000, C514S378000, C514S538000, C514S561000, C514S554000, C514S557000, C514S563000, C548S540000, C548S335500, C562S443000, C562S553000, C562S563000, C562S575000
Reexamination Certificate
active
06380254
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method and composition for treating and preventing pathogenic effects in mammals caused by intracellular calcium overload. Calcium overload occurs in the tissue and organs of mammals suffering from a disease condition associated with or resulting from insufficient tissue oxygenation. By treating the pathogenic effects of intracellular calcium overload, the present invention also effectively prevents irreversible cell damage and cell lysis in cells transiently deprived of oxygen.
Healthy cells regulate free cytosolic calcium concentrations by limiting influx of the cation across the cell's plasma membrane, sequestering free calcium, and pumping calcium ions out of the cytosol. When a cell becomes ischemic, insufficient free energy exists to operate the ion pumps. As calcium accumulates in the cytosol, degradative enzymes become activated and begin to further affect the cell's ability to regulate calcium. Calcium activated enzymes, e.g., phospholipases, break down the cell's membranes, making them even “leakier” to calcium. Additional enzymes, e.g., proteases, also attack the molecular pumps. When oxygen is restored to the tissue, free radical oxygen species are produced that can further damage these systems.
If the combined effects of the enzymes and the free radical oxygen species becomes severe enough, the cell will not recover and maintain acceptable levels of calcium, even if it successfully re-energizes when circulation is reestablished. The cell has become irreversibly damaged and will ultimately die from an overload of calcium. This pathogenic sequence might be repeated millions of times in the first several hours following a transient interruption in blood supply to the heart or brain.
Neuron damage, following a stroke or cardiac arrest, and myocyte damage, following coronary artery occlusion, are two examples of such cell damage. When essential cellular constituents leak out of such damaged cells, the cell is referred to as lysed and, of course, is irreparable.
Various treatments have been studied for treating or preventing calcium mediated cellular damage to reduce the likelihood of cell lysis during and following a transient period of oxygen deprivation. The most common treatments involve administering chemical compounds that either limit entry of calcium ions into the cell (i.e., plasma membrane channel blockers) or antagonize the calcium activated enzymes by binding to intracellular proteins like calmodulin. These treatments, however, are not restricted to the damaged cells. They can affect the function of normal, healthy cells and cause a number of adverse side effects. More selective methods are, therefore, needed to treat or prevent calcium mediated damage in cells deprived of oxygen, while avoiding these adverse side effects.
SUMMARY OF THE INVENTION
It is an object of the present invention to treat or prevent the pathogenic effects in a mammal caused by intracellular calcium overload. It is another object to prevent irreversible cell damage or hypoxic or post-hypoxic cell lysis in a mammal that has suffered from a disease condition associated with or resulting from insufficient tissue oxygenation.
It is a more specific object of the present invention to provide methods and compositions for preventing lysis of such cells and reducing the extent of organ damage in a mammal that has suffered from anoxia, hypoxia or ischemia, such as that which occurs in cardiac arrest, pulmonary embolus, renal artery occlusion, coronary artery occlusion, occlusive stroke, hemorrhagic stroke, adult respiratory distress syndrome, neonatal respiratory distress syndrome, suffocation, or profound anemia.
Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of instrumentalities and combinations particularly pointed out in the appended claims.
To achieve the objects and in accordance with the purpose of the invention, as embodied and broadly described herein, the invention comprises a method for treating or preventing pathogenic effects in a mammal caused by intracellular calcium overload comprising administering to the mammal a mixture of sodium co-transport dependent amino carboxylic acids or their physiologically acceptable salts in an amount sufficient to substantially saturate the sodium dependent amino carboxylic acid transport mechanisms of a mammalian cell's plasma membrane. The present invention also relates to a pharmaceutical composition for treating or preventing pathogenic effects in a mammal caused by intracellular calcium overload that comprises a mixture of sodium co-transport dependent amino carboxylic acids or their physiologically acceptable salts in an amount sufficient to substantially saturate the sodium dependent transport mechanisms of a mammalian cell's plasma membrane to treat or prevent these pathogenic effects, together with a pharmaceutically acceptable carrier.
As used in the present invention, the terms “saturate” and “saturating concentrations” denote the accepted biochemical kinetic definition, i.e., those concentrations of substrate or ligand that maximally activate (V
max
) their respective enzyme(s), transport mechanism(s), or receptor(s).
Reference will now be made in detail to preferred embodiments of the invention.
DETAILED DESCRIPTION OF THE INVENTION
An aspect of the present invention contemplates treating a mammal suffering with a disease condition resulting from insufficient tissue oxygenation by administrating a mixture of therapeutic amino carboxylic acid agents to alleviate the toxic effects of calcium overload on hypoxic and/or post hypoxic cells, anoxic and/or postanoxic cells, and ischemic and/or postischemic cells. The therapeutic amino carboxylic acids of the present invention can treat such cells by entering the cell's interiors. They are referred to as sodium co-transport dependent amino carboxylic acids. To be sodium co-transport dependent means that these amino carboxylic acids are obligatorily transported into the cell in association with sodium through sodium dependent, plasma membrane transport systems.
Without being bound to any particular theory, it is believed that when the amino carboxylic acids of the present invention enter the cell with the sodium ions they cause a partial discharge of the cell membrane's sodium electrochemical gradient. This disturbance in the gradient prevents rapid re-alkalinization of the cell, thereby inactivating pH-sensitive calcium dependent cytolytic enzymes and minimizing or eliminating the cytotoxic effects of calcium overload. All of the therapeutic amino carboxylic acid agents of the present invention are selective for identified sodium-dependent transport (“symport”) proteins. The sodium dependent transport systems are known to those skilled in the art to include the GLY, A, ASC, and N transporters.
In a primary embodiment of the present invention, a pharmaceutical composition is provided containing saturating concentrations of:
(a) one or more substrates for the GLY transport system;
(b) one or more substrates for the A transport system;
(c) one or more substrates for the ASC transport system;
(d) one or more substrates for the N transport system; and
(e) at least one stimulator or activator of the hepatic urea cycle.
A preferred composition of these substrates comprises a mixture of glycine, proline, histidine, serine, alanine, glutamic acid, glutamine, and arginine.
As indicated, in this embodiment, one or more administered therapeutic agents are substrates for the “GLY” transport system. The GLY transport system is a sodium-dependent amino carboxylic acid transport protein widely expressed in terminally differentiated mammalian cells. See H. N. Christensen, Physiological Reviews, Volume 70, p. 43-77, 1990, hereby incorporated by reference. The preferred sub
Kramer Richard S.
Pearlstein Robert D.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Kumar Shailendra
Leigh Biotechnology, Inc.
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