Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-05-21
2004-04-06
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S738000
Reexamination Certificate
active
06716819
ABSTRACT:
BACKGROUND OF THE INVENTION
Cystic fibrosis (CF) is a human genetic disease of epithelia. Although the survival rate of those suffering with cystic fibrosis has improved in recent years, the median age for patient survival is still only about 25-30 years despite intensive supportive and prophylactic treatment. Today cystic fibrosis remains the most common congenital disease among Caucasians, where it has a prevalence of about 1 in 2,000 live births and is uniformly fatal. Nearly all patients suffering from the disease develop chronic progressive disease of the respiratory system, the most common cause of death being pulmonary disease. In the majority of cases, pancreatic dysfunction occurs; hepatobiliary and genitourinary disease are also frequent. Because of the multi-system clinical manifestations of the disease, current methods of treatment for the disease have focused on therapeutic approaches to reduce the symptoms of cystic fibrosis.
It is now known that the disease is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a phosphorylation-regulated Cl
−
channel located in the apical membrane of involved epithelia. Also, much has been discovered about how CF-associated mutations disrupt protein function, thereby disrupting Cl
−
transport across CF epithelia.
Despite any advances, the pathogenesis of CF lung disease is still not understood. Lung disease is characterized by bacterial colonization and chronic airway infection. Many organisms can be involved, but
Pseudomonas aeruginosa
and
Staphylococcus aureus
are particularly prominent. Chronic bacterial infections progressively destroy the lung, and may ultimately lead to respiratory failure.
Airway infections currently cause most of the morbidity and mortality in cystic fibrosis (CF) (Taussig, L. M. 1984. Cystic Fibrosis. Georg Thieme Verlag Stuttgart, N.Y.; Davis, P. B. 1993. Pathophysiology of the Lung Disease in Cystic Fibrosis. In Cystic Fibrosis. P. B. Davis, editor. Marcel Dekker, Inc., New York. 193-218; Welsh, M. J., L. -C. Tsui, T. F. Boat and A. L. Beaudet. 1995. Cystic Fibrosis. In The Metabolic and Molecular Basis of Inherited Disease. C. R. Scriver, A. L. Beaudet, W. S. Sly and D. Valle, editors. McGraw-Hill, Inc., New York. 3799-3876; Burns, J. L., B. W. Ramsey, and A. L. Smith. 1993. Clinical manifestations and treatment of pulmonary infections in cystic fibrosis.
Adv. Pediatr. Infect. Dis.
8:53-56). Infections begin early in the course of disease, are nearly impossible to eradicate, and together with the resulting exuberant inflammation destroy the lung. The pathogenesis of CF airway infection involves a host defense defect that is restricted to the airways; other organs are not infected, and when non-CF lungs are transplanted into a CF patient, they do not become infected (Taussig, L. M. 1984. Cystic Fibrosis. Georg Thieme Verlag Stuttgart, New York; Davis, P. B. 1993. Pathophysiology of the Lung Disease in Cystic Fibrosis. In Cystic Fibrosis. P. B. Davis, editor. Marcel Dekker, Inc., New York. 193-218; Welsh, M. J., L. C. Tsui, T. F. Boat, and A. L. Beaudet. 1995. Cystic Fibrosis. In The Metabolic and Molecular Basis of Inherited Disease. C. R. Scriver, A. L. Beaudet, W. S. Sly and D. Valle, editors. McGraw-Hill, Inc., New York. 3799-3876; Davis, P. B., M. Drumm and M. W. Konstan. 1996, Cystic Fibrosis.
Am. J. Respir. Crit. Care Med.
154:1229-1256; Wine, J. J. 1999. The genesis of cystic fibrosis lung disease.
J. Clin. Invest.
103:309-312; Pilewski, J. M., and R. A. Frizzel. 1999. Role of CFTR in Airway Disease.
Physiol Rev.
79:S215-S255; Quinton, P. 1999. Physiological basis of cystic fibrosis: a historical perspective.
Physiol. Rev.
79:S3-S22; Accurso, F. J. 1997. Early pulmonary disease in cystic fibrosis.
Curr. Opin. Pulm. Med.
3:400-403). Early in the disease, many different organisms infect the airways, but with time
Staphylococcus aureus
and
Pseudomonas aeruginosa
predominate (Burns, J. L., J. Emerson, J. R. Stapp, D. L. Yim, J. Krzewinski, L. Louden, B. W. Ramsey and C. R. Clausen. 1998. Microbiology of sputum from patients at cystic fibrosis centers in the United States.
Clin. Infect. Dis.
27:158-163).
The pathogenesis of CF airway infections and link mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) Cl
−
channel to the propensity for infection may be explained as follows (Smith, J. J., S. M. Travis, E. P. Greenberg and M. J. Welsh. 1996. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.
Cell
. 85:229-236; and erratum 287(222)). The thin layer of airway surface liquid (ASL) contains many antimicrobial substances including lysozyme, lactoferrin, secretory leukoproteinase inhibitor (SLPI), human beta defensins 1 and 2, secretory phospholipase A2, and the cathelicidin LL-37 (Arnold, R. R., M. Brewer and J. J. Gauthier. 1980. Bactericidal activity of human lactoferrin: Sensitivity of a variety of microorganisms.
Infect. Immun.
28:893-898; Jacquot, J., J. M. Tournier, T. G. Carmona, E. Puchelle, J. P. Chazalette and P. Sadoul. 1983. Proteins of bronchial secretions in mucoviscidosis. Role of infection.
Bull. Eur. Physiopathol. Respir.
19:453-458; Thompson, A. B., T. Bohling, F. Payvandi, and S. I. Rennard. 1990. Lower respiratory tract lactoferrin and lysozyme arise primarily in the airways and are elevated in association with chronic bronchitis.
J. Lab. Clin. Med.
115:148-158; Hiemstra, P. S., R. J. Maassen, J. Stolk, R. Heinzel-Wieland, G. J. Steffens, and J. H. Dijkman. 1996. Antibacterial activity of antileukoprotease.
Infect. Immun.
64:4520-4524; Zhao, C., I. Wang, and R. I. Lehrer. 1996. Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells.
FEBS Lett.
396:319-322; McCray, P. B. and L. Bentley. 1997. Human airway epithelia express a &bgr;-defensin.
Am. J. Respir. Cell. Mol. Biol.
16:343-349; Goldman, M. J., G. M. Anderson, E. D. Stolzenberg, U. P. Kari, M. Zasloff, and J. M. Wilson. 1997. Human &bgr;-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis.
Cell.
88:553-560; Bals, R., X. Wang, Z. Wu, T. Freeman, V. Bafna, M. Zasloff and J. M. Wilson. 1998. Human &bgr;-defensin-2 is a salt-sensitive peptide antibiotic expressed in human lung.
J Clin Invest.
102; Diamond, G., and C. L. Bevins. 1998. Beta-defensins: endogenous antibiotics of the innate host defense response.
Clin. Immunol. Immunopath.
88:221-225; Bals, R., X. Wang, M. Zasloff and J. M. Wilson. 1998. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface.
Proc. Nat'l. Acad. Sci. USA.
95:9541-9546; Travis, S. M., B. A. D. Conway, J. Zabner, J. J. Smith, N. N. Anderson, P. K. Singh, E. P. Greenberg, and M. J. Welsh. 1999. Activity of Abundant Antimicrobials of the Human Airway.
Am. J. Respir. Cell Mol. Biol.
20:872-879; Singh, P. K., H. P. Jia, K. Wiles, J. Hesselberth, L. Liu, B. D. Conway, E. Valore, M. J. Welsh, T. Ganz, B. F. Tack and P. B. J. McCray. 1998. Constitutive and inducible expression of &bgr;-defensin antimicrobial peptides by human airway epithelia. Unpublished.). These agents acting alone and synergistically form part of the local pulmonary host defense system, killing the small numbers of bacteria that are constantly being deposited on the airway surface. Importantly, an increase in salt concentration inhibits the antibacterial activity of nearly all these agents and attenuates synergy between agents (Goldman, M. J., G. M. Anderson, E. D. Stolzenberg, U. P. Kari, M. Zasloff, and J. M. Wilson. 1997. Human &bgr;-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis.
Cell.
88:553-560; Bals, R., X. Wang, Z.Wu, T. Freeman, V. Bafna, M. Zasloff and J. M. Wilson. 1998. Human &bgr;-defensin-2 is a salt-sensitive peptide antibiotic expressed in human lung.
J. Clin. Invest.
102; Travis, S. M., B. A. D. Conway, J. Zabner
Welsh Michael J.
Zabner Joseph
Delacroix-Muirheid C.
McKee Voorhees & Sease, P.L.C.
Spivack Phyllis G.
University of Iowa Research Foundation
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