Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-23
2003-11-18
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06649615
ABSTRACT:
The present invention relates to a method for inhibiting fibrogenesis, especially liver fibrogenesis, by administering an adrenergic receptor antagonist.
TECHNICAL BACKGROUND
Liver fibrosis is characterized by an excessive deposition of extracellular matrix components in the liver. Several liver cell types participate in matrix deposition, the major types being hepatic stellate cells (HSC) (Friedman et al., 2000) and portal fibroblasts (Tuchweber et al., 1996). During the past decade, a lot of attention has been given to the stimuli responsible for fibrogenic cell activation in the liver. The major focus has been on growth factors and oxidant stress (Friedman et al., 2000). Despite the fact that it is well known that the liver receives an adrenergic innervation (Hsu et al., 1992—Fukuda et al., 1996), only a few studies have focused on the role of this innervation and/or that of secreted catecholamines on liver fibrogenesis. Thus, selective adrenergic denervation with the toxic 6-hydroxydopamine (OHDA) leads to an increase in the number of portal fibroblasts in the dog and in the rabbit (Albino-Teixeira et al., 1990). Furthermore, isolated HSC respond to norepinephrin by increasing their secretion of prostaglandins (Athari et al., 1994). Prostaglandins decrease the proliferation of activated HSC (Mallat et al., 1996) and prostaglandin El treatment decreases liver fibrosis in the bile duct ligation model (Beno et al., 1993). However, it was reported that fibrosis following carbon tetrachloride (CCl
4
) treatment is much more severe in spontaneously hypertensive rats (SHR strain) that exhibit increased concentrations of plasma catecholamines, as compared to control non hypertensive rats (Hsu et al., 1992—Hsu et al., 1995). This article did not however provide quantitative assessment of liver fibrosis.
On the other hand, alpha-adrenergic blocking agents such as prazosin were proposed in the treatment of liver diseases for their vasodilator properties (U.S. Pat. No. 6,174,917).
There was thus a need to clarify the role of the liver adrenergic innervation and catecholamines on the liver fibrogenic process.
SUMMARY OF THE INVENTION
By investigating the effects of noradrenergic antagonism on liver fibrosis, the inventors have shown that treatment with the adrenergic receptor antagonist prazosin strikingly attenuated liver fibrosis by inhibiting liver fibrogenesis.
The invention thus provides a method for inhibiting fibrogenesis, especially liver fibrogenesis, which method comprises administering an effective amount of an adrenergic receptor antagonist to a patient in need of such treatment.
In a particular embodiment, the antagonist prevents the development of liver fibrosis, especially in course of a viral hepatitis, such as chronic hepatitis C.
The adrenergic receptor antagonist may be an antagonist of alpha-1 adrenergic receptor, e.g. prazosin.
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Desmouliere Alexis
Dubuisson Liliane
Rosenbaum Jean
Darby & Darby
Institute National de la Sante et de la Recherche Medicale (INSE
Spivack Phyllis G.
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