Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-05-30
2004-06-01
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S547000
Reexamination Certificate
active
06743821
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to dietary energy supplements, and, in particular, to a novel method and composition beneficial to functioning of the heart, skeletal muscles and other tissues of humans and other mammals with carbohydrate energy forms during exercise stresses and subsequent recovery.
BACKGROUND OF THE INVENTION
The present invention takes advantage of discoveries of the classic (cell-cell, organ-organ) “Lactate Shuttle,” and the “Intracellular Lactate Shuttle” mechanisms by Brooks (1984, 1998). The “Lactate Shuttle Hypothesis” holds that lactate plays a key role in the distribution of carbohydrate potential energy which occurs among various tissue and cellular compartments such as between: cytosol and mitochondria, muscle and blood, blood and muscle, active and inactive muscles, white and red muscles, blood and heart, arterial blood and liver, liver and other tissues such as exercising muscle, intestine and portal blood, portal blood and liver, zones of the liver, skin and blood, and astrocytes and neurons in the brain. Studies on resting and exercising humans indicate that most lactate (70-80%) is disposed of through oxidation, with much of the remainder converted to glucose and glycogen. Studies on canine muscles made to contract in situ also yield the result that lactate is rapidly oxidized (Gladden et al., Zinker et al.). Lactate transport across cellular membranes occurs by means of facilitated exchange along pH and concentration gradients (Roth and Brooks 1990a, 1990b) involving a family of lactate transport proteins now called monocarboxylate transporters (MCT's) (Garcia et al., 1994; Price et al., 1998). Current evidence is that muscle and other cell membrane lactate transporters are abundant with characteristics of high Km and Vmax. There appears to be long-term plasticity in the number of cell membrane transporters, but short-term regulation by allosteric modulation or phosphorylation is not known to occur.
The key to recognition of an “Intracellular Lactate Shuttle” is recognizing that in addition to cell membranes, mitochondria also contain monocarboxylate transporters (mitochondial MCT's or mMCT's) and lactic dehydrogenase (mLDH). Mitochondrial MCT's exist in the mitochondrial inner membrane, and possibly also the outer membrane (FIG.
1
), although presence of an outer mitochondrial membrane MCT is not essential because it is highly permeable. The Intracellular Lactate Shuttle also requires presence of mitochondrial lactate dehydrogenase (mLDH) located on the inner membrane and in the intra-membrane (periplasmic) mitochondrial space. mLDH is necessary to convert lactate, the predominant plasma and intracellular monocarboxylate, to pyruvate, for transport via mMCT into the mitochondrial matrix for catalysis by pyruvate dehydrogenase (PDH) and entry into the tricarboxylic acid (TCA) cycle. Therefore, mitochondrial monocarboxylate uptake and oxidation, rather than translocation of transporters to the cell surfaces, regulate lactate flux in vivo. Key discoveries in basic science are that lactate enters mitochondria, but that pyruvate is oxidized in the mitochondrial matrix.
A. Use of Glycerol-lactate Esters for the Cardiac and Skeletal Muscle Energy
Providing energy sufficient to optimize performance is extremely important for hearts and skeletal muscles under stress of work load. Resting healthy hearts rely on exogenous, blood borne free fatty acids (FFA) as their main energy source with carbohydrate (CHO) derived fuel sources comprised of glucose and lactate playing secondary roles. For instance, in a resting person FFA may provide 80% of energy, glucose 5%, and lactate 15% (Gertz et al., 1988; Wisneski et al., 1987). However, under exercise and other stresses total energy demand increases and the fuel mix changes with the contribution of FFA falling to 40%, glucose use increasing absolutely but remaining at about 5%, and lactate the remainder (55%). During rest lactate is relegated to a minor role as an energy substrate for the heart because arterial lactate concentration is low (≦1.0 mM). However, during physical exercise lactate predominates as the cardiac fuel energy source because production in working muscle and other tissues causes blood lactate concentration to rise to a level (2-20 mM) sufficient to be taken up and oxidized within the heart. As indicated in
FIG. 1
, exogenous lactate gains entry to cardiocytes because of cell membrane lactate transporters. Those transporters facilitate lactate flux down concentration and hydrogen ion (H
+
) gradients. Within cardiocytes, lactate gains entry to mitochondria via another lactate transporter pool, also along concentration and H
+
gradients.
Taking advantage of new knowledge of the role of lactate in cardiac and skeletal muscle metabolism, Kline et al. studied performance and efficiency of hearts removed from rabbits after hemorrhagic shock. When concentrated sodium lactate was added to the isolated working hearts taken from shocked animals, performance was significantly enhanced. This practical demonstration of the use of lactate as a fuel and anaplerotic substrate fort the TCA Cycle in hearts did not address the problem of the sodium load and its consequences imposed from either oral or intravenous administration of concentrated salt solutions.
Realizing that CHO-derived energy sources increase cardiac performance, some investigators have attempted to promote cardiac energy resuscitation after ischaemic attacks by providing glucose, sometimes with insulin and potassium. Currently used cardioplegic solutions containing glucose, insulin and potassium are sometimes referred to as GIK. Other investigators have attempted to provide pyruvate. However, from the physiological perspective such attempts are less than optimal, or misguided, because lactate, not glucose or pyruvate, is the major fuel for the heart under stress.
Recently, results of clinical trials (Ceremuzynski et al., 1999) have not confirmed viability of systemically administered GIK in the management of cardiac episodes. While GIK solutions do positively influence performance of stunned isolated hearts perfused and bathed in artificial solutions, unless GIK is administered into coronary arteries, significant effects on either cardiac performance or survival of ischaemic episodes including MI is not to be expected (Apstein and Opie, 1999). Simply, GIK can not be expected to have much effect because glucose is never the major fuel for the heart. The better approach is to provide lactate in a form that can benefit cardiac metabolism.
U.S. Pat. No. 5,294,641, herein incorporated by reference, is directed to the use of pyruvate to prevent the adverse effects of ischemia in heart muscle. The pyruvate is administered prior to a surgical procedure to increase a patient's cardiac output and heart stroke volume. The pyruvate is administered as a calcium or sodium salt. The pyruvate can alternatively be an ester of pyruvate acid such as ethylamino pyruvate. Pyruvate is used because it is a cellular energy source; but while providing exogenous pyruvate may be potentially efficacious for heart muscle, practically the applicability is limited (vide infra).
With due consideration to growing acceptance of pyruvate as an effective component of reperfusion solution, it has been recognized that traditional pharmacological pyruvate compounds, such as salts of pyruvic acid, are not particularly physiologically suitable. For example, inorganic salts of pyruvate lead to the accumulation of large concentrations of inorganic ions (e.g., potassium, calcium or sodium) in body fluids. Accordingly, while potentially suitable to organ preservation, the salt-pyruvate compounds are not ideally suited to treating an organ or supplementing energy in an active person in vivo, and it is recognized that a need exists to deliver a monocarboxylate (pyruvate-like) compound with is more physiologically appropriate.
In this regard, U.S. Pat. No. 5,283,260, herein incorporated by reference, is directed to treatmen
Pillsbury & Winthrop LLP
Shah Mukund J.
Tucker Zachary C.
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