| Cardiac glycosides to treat cystic fibrosis and other il-8 dependent disorders -> Monitor Keywords |
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  Cardiac glycosides to treat cystic fibrosis and other il-8 dependent disordersRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Cyclopentanohydrophenanthrene Ring SystemThe Patent Description & Claims data below is from USPTO Patent Application 20060234955. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority from U.S. Provisional Application Ser. No. 60/383,117, filed May 28, 2002. The entirety of that provisional application is incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates generally to the use of cardiac glycosides such as oleandrin to inhibit the secretion of IL-8 from cells secreting elevated levels of IL-8. [0004] 2. Background of the Technology [0005] Cystic fibrosis is the most common autosomal recessive lethal disease in the United States (Welsh, et al. (1995)). Approximately 5% of the population carries one mutant CFTR gene (Rommens, et al. (1989); Riordan, et al. (1989); Kerem, et al. (1989)), and the disease occurs in a frequency of 1 in 2500 live births. Statistically, death occurs in the majority of patients by age 28. At the present time the respiratory difficulties and ensuing complications of inflammation and lung infection are directly responsible for the eventual death of over 90% of CF patents. In control individuals, inflammation is regulated by well-characterized signaling pathways. However, in CF inflammation is out of control, eventually causing destruction of the lung. The consequences are terminal if a lung cannot be found for transplantation. [0006] The CF lung has been described as microscopically normal at birth, with subtle abnormalities in mucus secretion appearing very early (Pilewski, et al. (1999)). Bacterial infection and objective evidence of inflammation occur at later times, with a clear temporal evolution of different principal bacterial pathogens. For example, Staphylococcus aureus and Hemophilus influenzae take up residence in the CF airway early, the mean age of positive culture being 12.4 months (Abman, et al., 1991). By comparison, Pseudomonas aeruginosa infection follows at a substantially later time, the mean age of first positive culture being 20.8 months. Persistent colonization by P. aeruginosa characterizes the older CF patient, and profound, persistent cellular evidence of inflammation accompanies persistent infection as the patient approaches the terminal phases of the disease. [0007] As the CF patient ages, the CF lung becomes characterized by elevated levels of white cells. These include polymorphonuclear leukocytes, macrophages, monocytes, lymphocytes and eosinophils. It is hypothesized that these cells are attracted from the circulation into the airway by the high levels of interleukin-8 (IL8) and other pro-inflammatory factors such as IL-1.beta., IL-6, leukotriene B.sub.4, RANTES, and TNF.alpha.. These factors mark the character of the CF lumenal milieu (Bonfield, et al. (1995a); ibid (1995b)). Among these factors, IL-8 ranks as the most prevalent and potent. IL-8 is an 8 kDa chemokine protein which is a principal chemotactic agent for neutrophils and T cells (Cruse, et al. (1995)). This chemokine is of specific importance for cystic fibrosis because it is profoundly elevated in bronchoalveolar lavage fluids, sputum, and serum from CF patients (Dean, et al. (1993); Richman-Eisenstat, et al. (1993); Francoeur, et al. (1995); Armstrong, et al. (1997)). It had been considered possible that high IL-8 levels might be secondary to chronic or persistent infections. However, both IL8 message and protein are elevated in bronchoalveolar lavage fluids from infants with CF as early as 4 weeks of age (Khan, et al. (1995)). Importantly, hypersecretion of IL-8 occurs prior to objective evidence of infection by viruses, fungi or common CF pathogenic bacteria (Khan, et al (1995)). The concept of the generality of a pro-inflammatory state for CF epithelia is further manifest by the fact that fecal IL-8 levels in CF children are approximately 1000-fold elevated over non-CF controls (Briars, et al. (1995)). Fecal IL-8 levels are correlated with lung function (FEV1, forced expiratory volume in one second), and only to some extent with established Pseudomonas infection. A recent study with bronchial biopsies from CF patients undergoing lung transplant has demonstrated consistent up-regulation of IL-8 expression in submucosal gland cells (Tabary, et al. (1998)). Thus, based on these clinical criteria, high IL8 levels would appear to be intrinsic to the CF lung. [0008] Consistently, airway epithelial cells isolated from CF patients secrete more IL-8 than do cells cultured from patients without CF (Bedard, et al. (1993); Ruef, et al. (1993); Dimango, et al. (1998)). Interestingly, cells cultured from much higher in the airway, such as those from the nasal epithelium, do not show this disparity between control and CF patients (Black, et al. (1998)). In addition, CF respiratory epithelial cells are hyper-responsive in terms of IL-8 secretion to Pseudomonas cells and toxins (Massion, et al. (1994); Dimango, et al. (1998)), or to a combination of TNF.alpha. and INF.gamma. (Schweibert, et al. (1999)). CFTR levels in human lung are highest in submucosal glands. High levels of IL-8 mRNA and protein have been shown in these tissues from CF patients, both in vitro and in vivo (Tabary, et al. (1998)). In the latter study, other pro-inflammatory cytokines such as IL-1.beta. and IL-6 were unaffected by the CF condition. The high levels of IL-8 production by CF epithelial cells have been proposed to be due to retention of mutant CFTR in the endoplasmic reticulum, which, by an unknown mechanism, activates NF.kappa.B via activation of I.kappa.B (DiMango, et al. (1998)). Attention is drawn to the NF.kappa.B system because it is known that transcription of the IL-8 gene is activated in normal epithelial cells when activated NF.kappa.B migrates from the cytosol to the nucleus and binds to the IL-8 promotor. An adenovirus hyperexpressing IkB.alpha. has been employed to suppress IL-8 secretion both from a CF cell line ("CFTE"), as well as from mouse lung (as MIP2), when instilled simultaneously with an infectious dose of P. aeruginosa (Griesenbach, et al. (1999); ibid (2000). [0009] It would be desirable to develop compositions that reduce the secretion of IL-8 and other pro-inflammatory cytokines from cells secreting elevated levels of these compounds. These compositions could be useful in the treatment of disease conditions characterized by elevated levels of these compounds. BRIEF DESCRIPTION OF THE DRAWINGS [0010] The present invention may be better understood by reference to the accompanying drawings in which: [0011] FIG. 1 illustrates the NF.kappa.B activation pathway leading to synthesis of IL-8; [0012] FIG. 2 illustrates the Activation of IL-8 promoter by NFkB and other cis acting transcription factors; [0013] FIG. 3 is a graph showing the effect of oleandrin on IL-8 secretion from cystic fibrosis lung epithelial cell IB-3; [0014] FIG. 4A illustrates the nuclear magnetic resonance (NMR) spectrum of oleandrin used in these experiments; [0015] FIG. 4B illustrates the mass spectrum of oleandrin used in these experiments; and [0016] FIGS. 5A and 5B illustrate the structures of various oleandrin analogues. SUMMARY OF THE INVENTION [0017] According to a first aspect of the invention, a method of inhibiting the secretion of IL-8 from a cell secreting elevated levels of IL-8 comprising contacting the cell with a composition comprising a cardiac glycoside is provided. According to this aspect of the invention, the cell can be a CF lung epithelial cell. Also according to this aspect of the invention, the cardiac glycoside can be selected from the group consisting of oleandrin, digitoxin, digoxin, ouabain, digoxigenen, digitoxigenen, and acetyl-stropanthidin. [0018] According to a second aspect of the invention, a method of treating disease conditions characterized by elevated levels of IL-8 comprising administering to a mammal suffering from the disease a composition comprising an effective amount of a cardiac glycoside is provided. According to this aspect of the invention, the mammal can be a human. Also according to this aspect of the invention, the elevated levels of IL-8 can result from a condition selected from the group consisting of: cardiopulmonary bypass surgery; cardiopulmonary arrest; inflammatory bowel disease; lung disorders and lung conditions; traumatic brain injury; stroke; transplant graft rejection; Alzheimer's disease; Parkinson's disease; HIV; viral infections; and fevers resistant to cyclooxygenase inhibitors. [0019] According to a third aspect of the invention, a method of treating conditions characterized by elevated levels of IL-8 in a human suffering from cystic fibrosis comprising administering to the human an effective amount of a composition comprising a cardiac glycoside is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0020] IL-8 secretion by the CF tracheal epithelial cell line IB-3 is elevated compared to IL-8 secretion by the same cell line corrected with wildtype CFTR (Eidelman, et al. (2001a)). Therefore, elevated levels of IL-8 secretion may be caused by mutant CFTR and a drug or gene able to correct the trafficking defect of .DELTA.F508-CFTR may also lower IL-8 secretion. Continue reading... Full patent description for Cardiac glycosides to treat cystic fibrosis and other il-8 dependent disorders Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Cardiac glycosides to treat cystic fibrosis and other il-8 dependent disorders patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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