Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-07-17
2002-07-16
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S048000, C514S047000
Reexamination Certificate
active
06420347
ABSTRACT:
TECHNICAL FIELD
This invention relates to a method of stimulating ciliary beat frequency to promote mucociliary or cough clearance of retained mucus secretions from the lungs, sinuses, or ears of a patient by administering certain uridine, adenosine, or cytidine triphosphates.
BACKGROUND OF THE INVENTION
Mucociliary clearance is an important defense mechanism of the human airway and middle/inner ear tract. Coordinated beats of cilia in the nose, trachea, bronchi, and middle ear propel the mucous layer toward the pharynx, carrying along with it microorganisms and other particles captured in the mucus. Normal function of this system depends on the frequency and coordination of ciliary beating and the properties of mucus. There are three components of the mucociliary clearance system: (1) the mucin layer, which is formed by secretion of mucins by goblet cells, (2) cilia, which transport the overlying mucin layer by synchronous beating, and (3) the periciliary liquid layer, which surrounds the cilia and is less viscous than the mucin layer, allowing free movement of the cilia. The electrolyte and water concentration of the periciliary layer is regulated by the luminal epithelial cells. (R. Boucher, et al., Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, p. 525-32 entitled “Mechanisms and Therapeutic Actions of Uridine Triphosphates in the Lung” (L. Belardinelli, et al. ed., Alumwer Academic Publishers, Boston 1995)).
Primary ciliary dyskinesia (PCD) is a congenital disease characterized by ultrastructural defects and motility disturbances of cilia, resulting in either absent or abnormal ciliary movement. The most common clinical manifestations of PCD are chronic respiratory disease (e.g., sinusitis, rhinitis, and bronchiectasis) and otitis media. Because PCD patients have either absent or severely impaired mucociliary clearance (MCC), the only available mechanism to clear or move secretions is cough. Cough clearance may be measured in a manner similar to that previously described for MCC. PCD also impairs the propulsion of spermatozoa, resulting in male infertility. (D. Schidlow,
Ann Alergy
73(b), 457-68 (1995)). PCD also results in the impairment of cell motility of certain immune system cells, including neutrophils and macrophages. (N. Valerius,
Eur j Clin Invest
13, 489-94 (1983)). PCD may be responsible for a form of hydrocephalus caused by ciliary malfunction. (M. Greenstone,
Arch Dis Child
59, 481-82 (1984)). The incidence of PCD has been calculated to be one in 16,000 live births, and an estimated 50% of affected individuals also have situs inversus (dextrocardia). The triad of bronchiectasis, sinusitis, and situs inversus (dextrocardia) is referred to as Kartagener's syndrome. (M. Sleigh,
Lancet ii
, 476 (1981)). It has been hypothesized that Kartagener's syndrome is caused by a lack of embryonic ciliary movement, resulting in the random rotation, of the archenteron such that in half the cases there is situs inversus (dextrocardia) and in the other half there is normal cardia situs. (B. Afzelius
Science
193, 317-19 (1976)). The clinical course of PCD is characterized primarily by sinus and ear infections early in life with a progressive change to lung/lower airways diseases in adulthood. Chronic airways infections can lead to chronic obstructive changes in the pulmonary tissue, progressive loss of pulmonary function, and eventually death.
A secondary and more common form of ciliary dyskinesia is the acquired form of the disease. Chronic inflammation caused by severe viral or bacterial respiratory infections, chronic smoking, severe air pollution, chemical or thermal burns to the airways, intubation and mechanical ventilation, and near drowning can result in changes in ciliary structure including disruption of the cellular membrane, loss or incorporation of microtubules, and formation of compound cilia, all of which can result in abnormal or absent ciliary function. (J. Ballenger
Ann Otol Rhinol Laryngol
97 (3 Pt. 1), 253-58 (1988); M. Pedersen
Lung
168 Suppl., 368-76 (1990)). Respiratory infections which often lead to secondary ciliary dyskinesia include influenza, adult respiratory distress syndrome, and ventilator-associated pneumonia (VAP) in intensive care unit (ICU) patients. In some cases acquired ciliary dyskinesia may be reversed with appropriate and timely intervention; however, permanent damage and/or sustained exposure to the above factors may render the ciliary damage irreversible. The clinical manifestations and course would likely appear similar to PCD with respect to chronic lung infections, progressive loss of pulmonary function, and obstructive pulmonary disease.
The typical mammalian respiratory epithelial cell contains about 200 cilia. Each cilium has nine peripheral microtubular doublets and two central tubules. Each peripheral doublet contains an A subunit and a B subunit, and each A subunit has a set of curved arms attached to it called the inner and outer dynein arms. These dynein arms contain ATPase-an enzyme which breaks down adenosine triphosphate (ATP), providing the energy for ciliary movement. Because the most common ultrastructural abnormality associated with primary ciliary dyskinesia is the total absence of dynein arms (B. Afzelius, et al.,
J Cell Biol
66, 225-32 (1975)), researchers began investigating whether extracellular application of ATP and ATPase could activate immotile cilia in vitro. (J. Forrest, et al.,
Am Rev Resp Dis
120, 511-15 (1979)). Although the results appeared positive, the findings have not been consistently reproduced by others. It was later discovered that extracellular application of Ca
2+
and cAMP could increase the beat frequency of respiratory tract cilia. (A. Lansley, et al.,
Am J. Physiol
263, L232-42 (1992)). It has not been definitively established that any therapy will stimulate cilia beat in cases where complete ciliary immotility has been demonstrated. In such cases, it might be of therapeutic benefit to increase hydration of the viscous mucous secretions.
Applicant has discovered that extracellular triphosphate nucleotides, especially uridine 5′-triphosphate (UTP) modulates all three components of the mucociliary transport system. UTP stimulates ciliary beat frequency (R. Boucher, et al., supra); UTP stimulates mucin secretion by goblet cells (M. Lethem, et al.,
Am J Respir Cell Mol Biol
9, 315-22 (1993)); and UTP stimulates Cl- secretion in airway epithelial cells, which increases hydration of the periciliary liquid layer (M. Knowles, et al., N
Eng j. Med
325, 533-38 (1991)). Applicant has also demonstrated that UTP is safe and improves cough clearance in PCD patients. (P. Noone, et al., abstract submitted to the 1996 International Conference of The American Thoracic Society).
In summary, a variety of clinical manifestations of ciliary dyskinesia, such as absent or impaired mucociliary clearance in the respiratory and middle/inner ear tract, impaired propulsion of spermatozoa, and impaired motility of neutrophils and macrophages can be improved or alleviated by administering UTP and its related compounds, as well as other nucleoside phosphates such as: adenosine 5′-triphosphate (ATP); cytidine 5′-triphosphate (CTP); 1,N
6
-ethenoadenosine triphosphate; adenosine 1-oxide triphosphate; 3,N
4
-ethenocytidine triphosphate; P
1
,P
4
-di(adenosine-5′) tetraphosphate (A
2
P
4
); or P
1
, P
4
-di(uridine-5′) tetraphosphate (U
2
P
4
) to the affected part of the body.
SUMMARY OF THE INVENTION
A method of treating ciliary dyskinesia in a subject in need of such treatment is disclosed. The method comprises administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount effective to stimulate ciliary beat frequency, where possible, in the luminal epithelial cells of the lung or middle/inner ear, eyes, genito-urinary tract; spermatozoa cells; or certain cells of the immune system, including neutrophils and macrophages:
wherein:
X
1
, X
2
, and X
3
are each indepe
Boucher, Jr. Richard C.
Drutz David J.
Geary Cary
Jacobus Karla M.
James Michael K.
Chiang Robin C.
Crane Lawrence E
Geist Gary
Halluin Albert P.
Inspire Pharmaceuticals Inc.
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