Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-12-14
2002-12-31
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S077000, C514S075000, C514S025000
Reexamination Certificate
active
06500810
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the use of phospholipid compositions to attenuate inflammation.
The inflammatory response is characterized by increased leukocyte rolling, adherence and transmigration following an inflammatory stimulus. The early hallmark of endothelial dysfunction is reduced release of nitric oxide (NO), which not only regulates vascular tone, but also modulates leukocyte-endothelium interaction. Leukocyte-endothelium interaction represents a multistep process involving sequential activation of specific cell adhesion glycoproteins such as integrins, immunoglobulin superfamily members and selectins (Bevilacqua & Nelson, 1993; McEver, 1992). Two of these adhesion molecules are particularly important in the regulation of cell-to-cell interaction (i.e., P-selectin on the microvascular endothelium and CD18 on circulating neutrophils).
In particular, P-selectin, a member of the selectin family of adhesion glycoproteins, is rapidly translocated from the Weibel-Palade bodies to the endothelial cell surface upon hypoxia-reoxygenation or activation with inflammatory mediators such as thrombin, histamine, or oxygen-derived free radicals (Lorant et al., 1991; McEver et al., 1989; Patel et al., 1991). P-selectin is believed to play a significant role in the initial phase of leukocyte capture, which is rolling of leukocytes along the vascular endothelial surface (McEver et al., 1989; Davenpeck et al., 1994). PMN rolling serves to tether the unstimulated neutrophil to the activated endothelium, thus bringing the neutrophil in closer contact with the endothelial cells, allowing firm adherence to occur (Lorant et al., 1991; Davenpeck et al., 1994). Rolling PMNs are able to engage in firm adhesion to the endothelium mainly by &bgr;
2
-integrin interacting (i.e., CD11/CD18) with intercellular adhesion molecule-1 (CAM-1)(Butcher, 1991). Following adhesion, PMNs are further activated, change their shape, and some undergo transendothelial migration mediated in large part by PECAM-1 (Vaporciyan et al., 1993). Finally, activated leukocytes can release superoxide radicals, which can directly quench endogenous NO released by endothelial cells (Rubanyi & Vanhoutte, 1986; Ma et al., 1993), a process known to exacerbate endothelial dysfunction.
A functional relationship between the loss of endothelium-derived NO and the expression of P-selectin has been established (Davenpeck et al., 1994). Similarly, it has been shown that blocking NO synthesis via N
G
-monomethy-[-L-arginine or N
G
-nitro-LCarginine methyl ester (L-NAME) increases leukocyte adherence and emigration in the mesenteric microcirculation (Scalia & Leer, 1998) as well as enhances microvascular permeability (Kubes & Granger, 1992).
Thus, a need exists for methods of attenuating the inflammation process by modulating the expression of adhesion molecules in endothelial cells or circulating neutrophils. The present invention satisfies this needs and provides related advantages as well.
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“Lysophosphatidylcholine stimulates leukocyte rolling and adherence in rat mesenteric microvasculature”, Lefer et al., American Journal of Physiology, 1997, vol. 272., No. 6 Part 2, pp. H2584-H2590, abstract.*
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Goddard J. Graham
Lefer Allan M.
Fay Zohreh
Kwon Brian-Yong S.
Sheridan & Ross P.C.
Sky High, LLC
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