Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-02-22
2000-08-01
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3140
Patent
active
060967773
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a new method of treatment using compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting the expression of Fas, a cell surface protein.
BACKGROUND OF THE INVENTION
Cell proliferation, differentiation, and survival are often regulated by growth, differentiation, and survival factors, respectively, which are collectively called cytokines. Cytokines bind to their complementary receptors, which transduce the extracellular signal into an intracellular signaling cascade. Fas ligand (FasL) is a cytokine. It is one of the few known cytokines that is a death factor. This ligand binds to its receptor, Fas, a cell-surface protein, and induces apoptosis (cell death). Many tissues and cell lines weakly express Fas, but abundant expression has been found in mouse heart, liver, lung, kidney, ovary and thymus (R. Watanabe-Fukunaga, et al., J. Immunol., 148, 1274-1279 (1992)). In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction (S. Nagata, et al., Science, 267, 1449-1456 (1995)).
Surprisingly, it has been found that carvedilol, a dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonist, inhibits the expression of Fas. This inhibition may mean that carvedilol and related Formula I compounds are useful for diseases wherein inhibition of Fas-mediated apoptosis is indicated. Particularly, this inhibition may mean that carvedilol and related Formula I compounds are useful for blocking ischemia-induced apoptosis in cardiac cells, for preventing or inhibiting tissue remodeling, in particular in cardiac tissue and blood vessels, for treating autoimmune diseases, and for inhibiting tumor growth and metastasis.
SUMMARY OF THE INVENTION
The present invention relates to a new method of treatment using compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists, in particular the carbazoiyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting the expression of Fas. The invention also relates to a method of treatment using compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting apoptosis. Furthermore, this invention relates to a method of treatment using compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for diseases wherein inhibition of Fas-mediated apoptosis is indicated. In particular, this invention is directed to the use of Formula I compounds, preferably carvedilol, to specifically induce Fas-mediated apoptosis of undesirable cells, such as cancer or autoreactive immune cells. Additionally, when control of aberrant forms of Fas activation is desired, the Formula I compounds, preferably carvedilol, are used to prevent cell depletion in AIDS or neurodegenerative diseases.
This invention also relates to a method of treatment using compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for preventing or inhibiting tissue remodeling, in particular in cardiac tissue and blood vessels. The present method includes the use of compounds which are dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolarnine compounds of Formula I, preferably carvedilol, to block ischemia-ind
REFERENCES:
patent: 4503067 (1985-03-01), Wiedemann et al.
J. of Cardiovascular Pharm; Senior, et al., "Effects of Carvedilol on Ventricular Arrhythmias", 1992, vol. 19, (Suppl. 1): pp. S117-S121.
J. of Cardiovascular Pharm; DasGupta, et al., "The Effects of Intravenous Carvedilol, A New Multiple Action Vasodilatory .beta.-Blocker, in Congestive Heart Failure", 1991, vol. 18, (Suppl. 1): pp. S12-S16.
Vacek, et al., Vnitr. Lek., 1994, vol. 40, No. 4, Doc. No. 124:250307.
Feuerstein, et al., Drugs Today, 1995, vol. 31, Suppl. F, Doc. No. 124:75193.
American J. of Cardiology; DasGupta, et al., "Value of Carvedilol in Congestive Heart Failure Secondary to Coronary Artery Disease", 1990, vol. 66, pp. 1118-1123.
Z. Kardiol; A. Buchwald, et al., "Acute Hemodynamic Effects of the Beta-blocker Carvedilol in Heart Failure", 1990, vol. 79, No. 6, pp. 424-428.
JACC; DiLenarda, et al., "Acute Hemodynamic Effects of Carvedilol Versus Metoprolol In Idiopathic Dilated Cardiomyopathy", 1991, vol. 17, No. 2, Absrtact 142A.
Frontiers in CHF;D. Tepper, "Multicenter Oral Carvedilol Heart Failure Assesments", 1996, vol. 2, No. 1, pp. 39-40.
J. of Cardiovascular Pharm; DasGupta, et al., 1990, vol. 19, (Suppl. 1): pp. 562-567.
J. of Hypertension; C. Rosendorff, "Beta-blocking agents with vasodilator activity", 1993, vol. 11, (Suppl. 4): pp. S37-S40.
Cardiology; J. Lessem, et al., "Development of a Multiaction Beta-blocker", 1993, vol. 82, (Suppl. 3): pp. 50-58.
Drug Safety; W.J. Louis, et al., "A Risk-Benefit Assessment of Carvedilol in the Treatment of Cardiovascular Disorders", 1994, vol. 11, No. 2, pp. 86-93.
Drugs; McTavish, et al., "Carvedilol--A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therepeutic Efficacy", 1993, vol. 45, No. 2, pp. 232-258.
Circulation; H. Krum, et al., "Effects of Carvedilol, a Vasodilator-.beta.-Blocker, in Patients with Congestive Heart Failure Due to Ischemic Heart Disease", 1995, vol. 92, No. 2, pp. 212-218.
CBS-TV; CBS Evening News, Transcript, Jan. 27, 1993, 6:30-7:00pm.
CNBC; Steals and Deals, Transcript, Jan. 29, 1993, 8:30pm.
Circulation; DasGupta, et al., 1989, vol. 80, No. 4, (Suppl. II): pp. 116-117.
Drugs to Today; Ruffolo, et al., "Carvedilol(Kredex ): A Novel Multiple Action Cardiovascular Agent", 1991, vol. 27, No. 7, pp. 465-492.
Cardiovascular Drug Review; Ruffolo, et al., Carvedilol: "A Novel Cardiovascular Drug with Multiple Actions", 1992, vol. 10, No. 2, pp. 127-157.
Feuerstein Giora Zeev
Yue Tian-Li
Boehringer Mannheim Pharmaceuticals Corporation
Henley III Raymond
Kinzig Charles M.
McCarthy Mary E.
SmithKline Bechman Corporation Limited Partnership No. 1
LandOfFree
Method for inhibiting the expression of Fas does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for inhibiting the expression of Fas, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for inhibiting the expression of Fas will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-664476