Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-06-07
2002-12-17
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S886000, C514S825000, C514S944000, C514S962000, C554S115000, C554S121000, C554S224000
Reexamination Certificate
active
06495596
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a group of compounds and a method for inhibiting certain enzyme systems that mediate a variety of physiological responses in mammals. More particularly, the present invention relates to a compound and method for inhibition of phospholipase A
2
, and cyclooxygenase-2, which are enzymes that catalyze a cascade of biochemical reactions that lead to the mediation of pain, fever, inflammation and other functions.
BACKGROUND OF THE INVENTION
Human beings and other mammals spend energy continuously defending against a vast array of invasive pathogenic organisms including bacteria, viruses, fungi and other intracellular and extra-cellular parasites in addition to other potentially harmful agents that are capable of upsetting homeostasis. In response, humans and other mammals maintain many mechanisms capable of processing and defending against such antigens and agents. The biological response to attack and injury is mediated through the formation of a series of structurally related compounds called eicosanoids, which include the prostaglandins, the leukotrienes, and the thromboxanes. Master enzymes known as phospholipase A
2
and phospholipase C regulate the formation of these highly potent compounds.
Phospholipase A
2
is a heat-stable, calcium dependent enzyme that catalyses the hydrolysis of the 2-acyl bond of 3-n-phosphoglycerides. It has a molecular weight of about 30,000 Daltons. Phospholipase A
2
has been found in many human tissues including platelets, chondrocytes, placenta, cartilage, peritoneal calls and peritoneal fluid and spleen. (Vades, p., Puzanski, W., Soluble phospholipase A
2
in human pathology: clinical-laboratory interface. Biochemistry, molecular biology, and physiology of phospholipase A
2
and its regulatory factors. Ed AB Mukherjee, Plenum Press, New York, 1990.) High levels of phospholipase A
2
are found in synovial tissue and it has been shown that activity of rheumatoid arthritis significantly correlated to the levels of serum phospholipase A
2
. (Vadas, P., Pruzanski, W. and Stefanski, E., Characterization of extracellular phospholipaseA2 in human synovial fluids. Life Sci. 36: 579, 1985.)
Substantial evidence has been found (above reference) that excessive concentrations of extra-cellular phospholipase A
2
may initiate and propagate inflammation and cause cellular damage. In addition phospholipase A
2
was also found to modulate various aspects of phagocytic activity, vascular tone and permeability. A strong correlation between phospholipase A
2
activity and certain human diseases have also been identified. A few such diseases are listed in table 1 below.
DISEASE
LOCATION OF PHOSPHOLIPASE A
2
Rheumatoid arthritis
Serum, synovial fluid
Osteoarthritis
Synovial fluid
Psoriasis
Synovial fluid
Monoarthritis
Synovial fluid
Gout
Synovial fluid
Collagen Vascular Disease
Serum
Pancreatitis
Serum
Peritonitis
Peritoneal fluid
Sepsis and Shock
Serum
Renal Failure
Serum
FIG. 1
illustrates the key role that phospholipase A
2
and cyclooxygenase-2 are currently understood to play in the formation of potent, biologically active substances that mediate a variety of conditions and disease states. The process of the formation of prostaglandin's, leukotrienes, lipoxins, and thromboxanes in addition to lysosomal enzyme release, bactericidal activity, pro-inflammatory eicosanoids, PAF and lysophosphatides and reactive oxygen species, begins on the surface of specialized cells including osteoblasts, endothelial cells, chondrocytes, synoviocytes, and renal mesangial cells. The major constituents of these, and all other, cell membranes are phospholipids. The biochemical conversion of these important molecules to arachidonic acid is catalyzed by phospholipase A
2
. Arachidonic acid is further converted to leukotrienes, lipoxins, thromboxanes and prostaglandins. The latter two species are formed by way of chemical conversion catalyzed by two other important enzymes known as cyclo-oxygnease-1 and cyclooxygenase-2. The arachidonic acid cascade is a well know pathway leading to the mediation of pyrogenicity, vasoconstriction, increased vascular permeability, contraction of smooth muscle, inflammation, and pain.
Found in every cell of the human body, albeit to varying degrees, prostaglandins have profound physiologic effects including mediation of pain and inflammation. The prostaglandins (PG) are a family of lipid-soluble hormone-like molecules produced by different cell types in the body. For example, macrophages and monocytes are large producers of both PGE2 and PGF2, neutrophils produce moderate amounts of PGE2, and masts cells produce PGD2. It is important to note that, unlike histamine, prostaglandins do not exist free in tissues vacuoles, but have to be synthesized and released in response to an appropriate stimulus. This synthesis is dependent on phospholipase A
2
and cyclooxygenase-2.
Thromboxanes are produced by monocytes and macrophages, as well as by platelets. Thromboxanes are involved in causing platelets to aggregate and constrict blood vessels and airways. These effects are some what opposed by the action of prostacyclin (PGI2), which is a potent vasodilator.
Leukotrienes (LT) exist in a number of varieties, and cause the chemotaxis (directed locomotion) and/or chemokinesis (general cell movement) of a number of cell types including neutrophils. The synthesis of LTB4 is inhibited by colchicines, an anti-flammatory agent used for treatment of gout. The mixture of LTC4, LTD4 and LTE4 originally called slow reacting substance of anaphylaxis is produced by a wide variety of smooth muscle, mainly in the bronchus, and have effects on mucous secretions. Inhibition of the formation of these substances is a useful therapeutic modality in asthma.
Lipoxins (LX) are a family of molecules that are thought to stimulate changes in microcirculation. For example, LXA4 induces rapid arteriolar dilation and can also antagonize LTD4-induced vasoconstriction. This suggests that LXA4 may regulate the action of vasoconstrictor leukotrienes. LXA4 can block neutrophil chemotaxis induced both LTB4 and N-formyl-oligopeptieds. Both LXA4 and LXB4 inhibit cytoxicity of natural killer T cells and thus there inhibition can be useful in allowing the immune system to remain intact while fighting infections and cancer.
Inflammation is a complex response of the body in response to damage of its cells and vascular tissues. The elucidation of the detailed processes of inflammation has revealed a close relationship between inflammation and the immune response.
Basic symptoms of inflammation include redness, swelling, heat, pain, and deranged function. These signs and symptoms are thought to be due to extravasation of plasma and infiltration of leukocytes into the site of inflammation, as a result of cell damage. Early investigators considered inflammation a primary host defense system. Indeed inflammation is the key reaction of the immune response, but in fact, inflammation is more than this, since it can lead to death, as anaphylactic shock, or debilitating diseases, as in arthritis or gout.
What is needed is a novel lipid compound that is capable of reducing inflammation and certain related disease conditions, while avoiding disadvantages of the prior art, preferably without unacceptable side effects.
SUMMARY OF THE INVENTION
The present invention comprises a group of related lipid molecules, and methods for using the group of related lipid molecules, for inhibiting certain enzyme systems including phospholipase A
2
and cyclooxygenase-2, for the mediation of pain, fever, inflammation and other functions including phospholipase A
2
and cyclooxygenase-2. The ability of the group of related lipids of the invention to inhibit enzyme systems including phospholipase A
2
and cyclooxygenase-2 was surprising and unexpected. The group of related lipid molecules of the invention may be characterized by specific structural characteristics, or by specific biological activity, including inhibition of the previously listed enzymes. The group of relate
Biozibe Laboratories, Inc.
Carr Deborah D.
Gregory Smith & Associates
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