Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-04-05
2003-03-11
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06531457
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for preventing tissue injury, i.e., due to inflammatory activity.
BACKGROUND OF THE INVENTION
The inflammatory response serves the purpose of eliminating harmful agents from the body. There is a wide range of pathogenic insults that can initiate an inflammatory response including infection, allergens, autoimmune stimuli, immune response to transplanted tissue, noxious chemicals, and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal trauma. Inflammation normally is a very localized action which serves in expulsion, attenuation by dilution, and isolation of the damaging agent and injured tissue. The body's response becomes an agent of disease when it results in inappropriate injury to host tissues in the process of eliminating the targeted agent, or responding to a traumatic insult.
As examples, inflammation is a component of pathogenesis in several vascular diseases or injuries. Examples include: ischemia/reperfusion injury (N. G. Frangogiannis et al., in
Myocardial Ischemia: Mechanisms, Reperfusion, Protection,
M. Karmazyn, ed., Birkhuser Verlag (1996) at 236-284; H. S. Sharma et al.,
Med. of Inflamm.,
6, 175 (1987)), atherosclerosis (R. Ross,
Nature,
362, 801 (1993)), inflammatory aortic aneurysms (N. Girardi et al.,
Ann. Thor. Surg.,
64, 251 (1997); D. I. Walker et al.,
Brit. J. Surg.,
59, 609 (1972); R. L. Pennell et al.,
J. Vasc. Surg.,
2, 859 (1985)), and restenosis following balloon angioplasty (see, R. Ross cited above). The cells involved with inflammation include leukocytes (i.e., the immune system cells - neutrophils, eosinophils, lymphocytes, monocytes, basophils, macrophages, dendritic cells, and mast cells), the vascular endothelium, vascular smooth muscle cells, fibroblasts, and myocytes.
The release of inflammatory cytokines such as tumor necrosis factor-alpha (TNF&agr;) by leukocytes is a means by which the immune system combats pathogenic invasions, including infections. TNF&agr; stimulates the expression and activation of adherence factors on leukocytes and endothelial cells, primes neutrophils for an enhanced inflammatory response to secondary stimuli and enhances adherent neutrophil oxidative activity. See, Sharma et al., cited above. In addition, macrophages/dendritic cells act as accessory cells processing antigen for presentation to lymphocytes. The lymphocytes, in turn, become stimulated to act as pro-inflammatory cytotoxic cells.
Generally, cytokines stimulate neutrophils to enhance oxidative (e.g., superoxide and secondary products) and nonoxidative (e.g., myeloperoxidase and other enzymes) inflammatory activity. Inappropriate and over-release of cytokines can produce counterproductive exaggerated pathogenic effects through the release of tissue-damaging oxidative and nonoxidative products (K. G. Tracey et al.,
J. Exp. Med.,
167, 1211 (1988); and D. N. Mäannel et al.,
Rev. Infect. Dis.,
9 (suppl. 5), S602-S606 (1987)). For example, TNF&agr; can induce neutrophils to adhere to the blood vessel wall and then to migrate through the vessel to the site of injury and release their oxidative and non-oxidative inflammatory products.
Although monocytes collect slowly at inflammatory foci, given favorable conditions, the monocytes develop into long-term resident accessory cells and macrophages. Upon stimulation with an inflammation trigger, monocytes/macrophages also produce and secrete an array of cytokines (including TNF&agr;), complement, lipids, reactive oxygen species, proteases and growth factors that remodel tissue and regulate surrounding tissue functions.
For example, inflammatory cytokines have been shown to be pathogenic in: arthritis (C. A. Dinarello,
Semin. Immunol.,
4, 133 (1992)); ischemia (A. Seekamp et al.,
Agents
-
Actions
-
Supp.,
41, 137 (1993)); septic shock (D. N. Männel et al.,
Rev. Infect. Dis.,
9 (suppl. 5), S602-S606 (1987)); asthma (N. M. Cembrzynska et al.
, Am. Rev. Respir. Dis.,
147, 291 (1993)); organ transplant rejection (D. K. Imagawa et al.,
Transplantation,
51, 57 (1991); multiple sclerosis (H. P. Hartung,
Ann. Neurol.,
33, 591 (1993)); AIDS (T. Matsuyama et al.,
AIDS,
5, 1405 (1991)); and in alkali-burned eyes (F. Miyamoto et al.,
Opthalmic Res.,
30, 168 (1997)). In addition, superoxide formation in leukocytes has been implicated in promoting replication of the human immunodeficiency virus (HIV) (S. Legrand-Poels et al.,
AIDS Res. Hum. Retroviruses,
6, 1389 (1990)).
It is well known that adenosine and some analogs of adenosine that nonselectively activate adenosine receptor subtypes decrease neutrophil production of inflammatory oxidative products (B. N. Cronstein et al.,
Ann. N.Y. Acad. Sci.,
451, 291 (1985); P. A. Roberts et al.,
Biochem. J.,
227, 669 (1985); D. J. Schrier et al.,
J. Immunol.,
137, 3284 (1986); B. N. Cronstein et al.,
Clinical Immunol. and Immunopath.,
42, 76 (1987); M. A. Iannone et al., in
Topics and Perspective in Adenosine Research,
E. Gerlach et al., eds., Springer-Verlag, Berlin, p. 286 (1987); S. T. McGarrity et al.,
J. Leukocyte Biol.,
44, 411421 (1988); J. De La Harpe et al.,
J. Immunol.,
143, 596 (1989); S. T. McGarrity et al.,
J. Immunol.,
142, 1986 (1989); and C. P. Nielson et al.,
Br. J. Pharnacol.,
97, 882 (1989)). For example, adenosine has been shown to inhibit superoxide release from neutrophils stimulated by chemoattractants such as the synthetic mimic of bacterial peptides, f-met-leu-phe (fMLP), and the complement component C
5
a (B. N. Cronstein et al.,
J. Immunol.,
135, 1366 (1985)). Adenosine can decrease the greatly enhanced oxidative burst of PMN (neutrophil) first primed with TNF-&agr; and then stimulated by a second stimulus such as f-met-leu-phe (G. W. Sullivan et al.,
Clin.Res.,
41, 172A (1993)). Additionally, it has been reported that adenosine can decrease the rate of HIV replication in a T-cell line (S. Sipka et al.,
Acta. Biochim. Biopys. Hung.,
23, 75 (1988)). However, there is no evidence that
in vivo
adenosine has anti-inflammatory activity (G. S. Firestein et al.,
Clin. Res.,
41, 170A (1993); and B. N. Cronstein et al.,
Clin. Res.,
41, 244A (1993)).
It has been suggested that there is more than one subtype of adenosine receptor on neutrophils that can have opposite effects on superoxide release (B. N. Cronstein et al.,
J. Clin. Invest.,
85, 1150 (1990)). The existence of A
2A
receptor on neutrophils was originally demonstrated by Van Calker et al. (D. Van Calker et al.,
Eur. J. Pharmacology,
206, 285 (1991)).
There has been progressive development of compounds that are more and more potent and/or selective as agonists of A
2A
adenosine receptors (AR) based on radioligand binding assays and physiological responses. Initially, compounds with little or no selectivity for A
2A
receptors were developed, such as adenosine itself or 5′-carboxamides of adenosine, such as 5′-N-ethylcarboxamidoadenosine (NECA) (B. N. Cronstein et al.,
J. Immunol.,
135,1366 (1985)). Later, it was shown that addition of 2-alkylamino substituents increased potency and selectivity, e.g., CV1808 and CGS21680 (M. F. Jarvis et al.,
J. Pharmacol. Exp. Ther.,
251, 888 (1989)). 2-Alkoxy-substituted adenosine derivatives such as WRC-0090 are even more potent and selective as agonists at the coronary artery A
2A
receptor (M. Ueeda et al.,
J. Med. Chem.,
34, 1334 (1991)). The 2-alklylhydrazino adenosine derivatives, e.g., SHA 211 (also called WRC-0474) have also been evaluated as agonists at the coronary artery A
2A
receptor (K. Niiya et al.,
J. Med. Chem.,
35, 4557 (1992)).
There is one report of the combination of relatively nonspecific adenosine analogs, R-phenylisopropyladenosine (R-PIA) and 2-chloroadenosine (Cl-Ado) with a phosphodiesterase (PDE) inhibitor resulting in a lowering of neutrophil oxidative activity (M. A. lannone et al.,
Topics and Perspectives in Adenosine Research,
E. Garlach et al., eds., Springer-Verlag, Berlin, pp. 286-298 (1987)). However, R-PIA and Cl-Ado analogs are actually more potent activato
Kron Irving L.
Linden Joel M.
MacDonald Timothy
Okusa Mark
Sarembock Ian J.
Jarvis William R. A.
Schwegman, Lunderberg, Woessner & Kluth, P.A.
University of Virginia
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