Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1996-09-09
2001-06-12
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S145000, C540S470000, C540S122000, C514S461000, C514S184000, C514S501000, C514S502000
Reexamination Certificate
active
06245758
ABSTRACT:
TECHNICAL FIELD
The present invention is for methods of use for the decomposition of peroxynitrite by metal complexes, novel pharmaceutical compositions, and methods of use therefor.
Particularly, the present invention now provides a method for treating selected diseases comprising the decomposition of peroxynitrite with the use of a compound which is a metal complex. This decomposition preferably produces benign agents preventing formation of deleterious decomposition products such as oxygen radicals and which also further prevents inactivation of superoxide dismutase (SOD) by the presence of peroxynitrite. Therefore, the method of use for selected metal complexes of the present invention, as well as novel pharmaceutical compositions for such use is for the treatment of diseases advantageously affected by treatment comprising decomposition of peroxynitrite at a rate accelerated over a natural background rate of decay which comprises administration of an rate-accelerating effective amount of the metal complex in unit dosage form.
In other words, the methods of treatment and novel compositions of this invention provide a twofold benefit in the treatment of diseases (1) accelerated rate of catalytic decomposition of peroxynitrite and (2) protection of SOD against inactivation by peroxynitrite.
Thus, the present invention provides for a method of treatment of human diseases advantageously affected by such decomposition by protection from the deleterious effects resulting from the presence of peroxynitrite in the human body not heretofore known. In addition, since protection against SOD inactivation is provided, such decomposition offers protection against diseases associated with the overproduction of superoxide.
These diseases include ischemic reperfusion injuries such as stroke, head trauma and myocardial ischemia, sepsis, chronic or acute inflammation (such as arthritis and inflammatory bowel disease and the like), adult respiratory distress syndrome, cancer, bronchopulmonary dysplasia, side effects from drug treatment of cancer, cardiovascular diseases, diabetes (not included for treatment by vanadium porphyrin complexes), multiple sclerosis, parkinson's disease, familial amyotrophic lateral sclerosis, and colitis and specific neuronal disorders, preferably ischemic reperfusion, inflammation, sepsis, multiple sclersis, parkinson's disease and stroke.
BACKGROUND ART
Nitric oxide (NO) is known for its dual physiological role as helpful messenger and harmful intermediate. Nitric oxide is shown to be generated in numerous cell types including macrophages, neutrophils, hepatocytes and endothelial cells. See Hibbs et al,
Science,
1987,235,473-476; Rimele et al,
J. Pharmacol. Exp. Ther.,
1988, 245, 102-111; Curran et al,
J. Exp. Med.,
1989, 170, 1769-1774; and Plamer et al,
Nature,
1987, 327, 524-526; respectively. The chemical reaction responsible for the production of NO is catalyzed by a class of enzymes referred to as nitric oxide synthases (NOS) which convert L-arginine to citrulline and NO. Forstermann et al,
Biochemical Pharmacology,
1991,42, 1849-1857. While the role of NO as a signaling molecule in the stimulation of guanylate cyclase is well established, (Monocada et al,
Pharmacological Reviews,
1991, 43, 109-142), the origins of its cytoxicity remained unclear.
Recently a body of compelling evidence surfaced which teaches that NO by itself may not be responsible for cell damage (See Absts. of 1st Annual Mtg. of Oxygen Society, Nov. 12-4, 1993, Charleston, S.C., “Nitric Oxide Requires Superoxide to Exert Bactericidal Activity” by L. Brunnelli and J. S. Beckman). Instead a more reactive species, peroxynitrite, produced by the reaction of superoxide and NO, is found to play a role in the cytotoxicity observed with the over-production of NO. Peroxynitrite is known to decompose via a process which is first order in protons. The rate of proton catalyzed decomposition of peroxynitrite (hereinafter “the natural background rate of decay”) is understood from its study over a variety of pH ranges (see; Keith et al.
J Chem Soc
(A), p.90, 1969). When the pH is 7.4 and the temperature is maintained at 37° C., the observed rate for the decomposition of peroxynitrite is 3.6×10
−1
sec-i (see Beckman et al.
Proc. Natl. Acad. Sci. USA Vol
87
,
pp1620-1624, 1990). Beckman shows that peroxynitrite decomposition generates a strong oxidant with reactivity similar to hydroxyl radical, as assessed by the oxidation of deoxyribose or dimethyl sulfoxide with the further suggestion that superoxide dismutase protects vascular tissue stimulated to produce superoxide and NO under pathological conditions by preventing the formation of peroxynitrite. See Beckman et al, “Apparent Hydroxyl Radical Production by Peroxynitrite: Implications for Endothelial Injury from Nitric Oxide and Superoxide” in
Proc. Natl. Acad. Sci. USA
, Vol. 87, pp 1629-1624, February 1990.
Further, it is well established that peroxynitrite decomposes to give the hydroxyl radical and nitrogen dioxide, a potent nitrating agent. Both of these species are potent oxidants shown to react with lipid membrane and sulfhydryl moieties (See Radi et al “Peroxynitrite Oxidation of Sulfhydryls” in
The Journal of Biological Chemistry
, Vol. 266, No. 7 March 5, pp 4244-4250, 1991).
Hardy et al suggest the interaction of O
2−
with nitric oxide forms peroxynitrite or the protonation of O
2−
to form perhydroxyl radical is involved in the neutrophil-meditated killing of HAE cells (FASEB Meeting on Apr. 5-9, 1992 in Anaheim, Calif.) and further Hardy et al suggest a role for peroxynitrite in oxidative damage of human endothelial cells (Abstract in the “Experimental Biology” section of FASEB on Mar. 28-Apr. 1, 1993 in New Orleans, La.).
In other words, harmful products from peroxynitrite decomposition is specifically taught by many references.
In addition, it has been shown that the reaction of peroxynitrite with Mn and Fe SOD results in inactivation of the enzyme (See also Radi et al,
Arch. Biochem. Biophys.,
1991, 288, 481-487). It is now known that peroxynitrite will also inactivate CuZn SOD.
Thus, the effects of the decomposition of peroxynitrite; whether by the generation of damaging decomposition products or inactivation of SOD, in a wide variety of diseases are well documented.
For example, a study assessing the deleterious effects of peroxynitrite on the rat colon is reported by Rachmilewitz et al in “Peroxynitrite-induced Rat Colitis: A New Model of Colonic Inflammation” from Gastroenterology 105 (6) 1993.
Beckman et al in PCT/US91/07894 (corresponding to U.S. Pat. No. 5,277,908) teach, specifically that peroxynitrite is formed by the reaction of superoxide (O
2−
) and nitric oxide in tissues subjected to ischemic, inflammatory or septic conditions. Beckman et al link SOD deficiencies and peroxynitrite to amyotrophic lateral sclerosis (ALS) in
Nature
, Vol 364, 12 August 1993 and Hogg et al and Beckman et al., respectively, present a relationship between peroxynitrite and atherosclerosis in
Biochemical Society Transactions
, Vol. 21, received Dec. 22, 1992 and in “Extensive Nitration of Protein Tyrosines in Human Atherosclerosis Detected by Immunohistochemistry”,
Biol Chem. Hoppe-Sevler, Vol.
375, pp 81-88, February 1994. Further, the involvement of peroxynitrite in various disease states is found for lung diseases attributed to cigarette smoke, atherosclerosis, amyotrophic lateral sclerosis, cold-induced brain edema in
Chem. Res. Toxicol.
, Vol. 5, No. 3, 1992 pp 425-431. See also “Cold-induced Brain Edema in Mice” in
The Journal of Biological Chemistry
, Vol.268, No. 21 Issue of July 25, pp
15394-15398, 1993.
More recently a spinal neuron toxicity assay has been developed by Scherch et al to screen for drugs which block peroxynitrite toxicity. (23rd Annual Meeting of the Society for Neuroscience, Washington, D. D., Nov. 7-12, 1993 and abstracted in
Society for Neuroscience Abstracts
19 (1-3) 1993 and
Biosis
94:4951.
Further, by preventing inactivation of SOD by reducin
Salvemini Daniela
Stern Michael K.
Monsanto Company
Raymond Richard L.
Sripada Pavanaram K
LandOfFree
Methods of use for peroxynitrite decomposition catalysts,... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods of use for peroxynitrite decomposition catalysts,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods of use for peroxynitrite decomposition catalysts,... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2435117