Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-12-22
2004-03-09
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S043000, C514S04400A, C514S045000, C514S046000, C514S048000, C514S049000, C514S050000, C514S051000, C514S052000, C514S265100, C514S849000, C514S851000, C514S853000, C514S855000
Reexamination Certificate
active
06703376
ABSTRACT:
TECHNICAL FIELD
This invention relates to a method of removing or preventing the accumulation of retained mucous secretions from the lungs and bronchi of immobilized or bedridden patients, including those whose breathing is assisted by mechanical ventilation.
BACKGROUND OF THE INVENTION
Bedrest or immobility can result from a variety of health problems, both acute and chronic in nature. A primary concern in caring for persons who are immobilized or placed on bedrest is that of prevention of pneumonia and other respiratory problems. Once pneumonia develops in these patients, morbidity and mortality can be significant. Because of the immobility it may be difficult for patients to cough and mobilize secretions. Immobile patients include patients confined to either beds or wheelchairs. In addition to complications arising from the immobility, the underlying health problem may place patients at increased risk for infection. Factors or disease states which predispose for high risk for pneumonia development include: altered conciousness (from head injury, anesthesia, drug overdose or other serious illness), tracheal intubation (via endotracheal, nasotracheal, or tracheostomy tubes), mechanical ventilation, and other procedures or treatments including intra-aortic balloon pump, hemo- or ultrafiltration, chronic disease states such as cancer, progressive neuromuscular disorders (multiple sclerosis, amytropic lateral sclerosis, etc.), heart disease, diabetes mellitus, acute neurological disorders (stroke, seizures, Guillain-Barre' syndrome, spinal cord injury), and rehabilitation from injuries or surgeries (bedrest, traction, etc.). (p. 502 “Medical-Surgical Nursing: Assessment and Management of Clinical Problems” by S. Lewis and I. Collier, 2nd ed. 1987, McGraw-Hill, New York).
Mechanical ventilation is indicated for respiratory failure or compromise resulting from a variety of pulmonary disorders and complications. It has been estimated that over 100,000 patients require mechanical ventilation in the U.S. every year (I. Kappstein, et al., Eur. J. Clin. Microbiol. Infect. Dis. 11(6), 504-8 (1992)). Morbidity and mortality from the underlying disorders can be high, and the addition of mechanical ventilation further increases risk. Complications resulting from mechanical ventilation may include: ventilator-associated pneumonia (VAP), pneumothorax, pulmonary embolus, right mainstem bronchus intubation, accidental extubation, aspiration of gastric contents, sepsis, fluid overload/heart failure, hypotension, and death (B. deBoisblanc, et al., Chest 103, 1543-7 (1993)). One of the most common complications is VAP, with an incidence conservatively estimated at 25%, with greater than 12,000 deaths per year due to VAP (D. Craven, et al., Am. Rev. Respir. Dis. 133, 792-6 (1986). Increased vigilance by nursing or other health care professionals, invasive monitoring, use of vasoactive medications, and frequent overall assessments greatly increase the cost of care for mechanically ventilated patients. A conservative estimate for total cost of these mechanically ventilated patients approaches $1.5 billion per year in the U.S. alone (I. Kappstein, supra).
Patients who are intubated and on mechanical ventilation are at several-fold higher risk for developing pneumonia and other pulmonary complications than non-intubated patients, due to the impairment or absence of several aspects of the normal pulmonary defense mechanisms (T. Inglis, J. Hosp. Infect. 30, 409-13 (1995)). Normal defense mechanisms consist of: 1) filtration, warming, and humidification of air; 2) epiglottis closure over the trachea; 3) cough reflex; 4) mucociliary escalator system; 5) immunoglobulins A and G; and 6) activity of alveolar macrophages. Airways distal to the larynx are normally sterile, but with intubation, the cough reflex is impaired and closure of the epiglottis cannot occur, allowing contamination of the lower airways. Because clinical practice guidelines generally do not advocate the maintenance of a complete airway seal in the trachea by the endotracheal cuff, some leakage of nasopharyngeal secretions below the epiglottis may occur, therefore increasing risk for infection in the lower airways (P. Mahul, et al., Intensive Care Med. 18, 20-5 (1992)).
The leading cause of VAP is thought to be aspiration of colonized gastric secretions via the incompletely closed glottis (P. Mahul, et al., supra). Colonization of the lower respiratory tract, especially with gram-negative bacteria is an early stage in the development of VAP. In addition, the use of suction catheters via the endotracheal tube to clear lower airway secretions, as well as other manipulations of the ventilatory system, significantly increase the chance for nosocomial infection, especially pneumonia. The normal warming, humidification, and filtration mechanisms for distal airways are non-functional for intubated patients, and the underlying conditions of the patient, i.e., malnutrition, fluid and/or electrolyte imbalance, and infections, may further complicate a patient's prognosis.
Mucociliary transport velocity has been shown to be impaired in patients who are intubated and receiving mechanical ventilation (F. Konrad, et al., Intensive Care Med. 21, 482-89 (1995); F. Konrad, et al., Chest 105(1), 237-41 (1994); F. Konrad, et al., Chest 102(5), 1377-83 (1992)). Because movement and clearance of secretions is an important lung defense mechanism, any impairment of this function, in addition to the introduction of artificial airways, mechnical ventilation, and the underlying disease state, can severely compromise the pulmonary host defense mechanisms.
Agents that can obviate the need for intubation and mechanical ventilation, or reduce time on mechanical ventilation, thereby decreasing the incidence of complications such as VAP, would certainly have a significant impact in the critical care setting, both in terms of the health of the patient and the costs associated with treatment. Applicants have discovered that uridine 5′-triphosphate (UTP) and related nucleotide compounds modulate specific activities of human airway epithelial cells that are components of the mucociliary escalator. Transport of foreign particles out of the lungs via the mucociliary escalator relies on the integrated action of: 1) mucus secretion by goblet cells and submucosal glands which traps foreign particles; 2) cilia to propel the mucus out of the lungs; and 3) epithelial ion transport systems which maintain the ionic milieu of, and hence the viscosity of, airway surface liquid to allow effective ciliary beating. Application of extracellular UTP to the apical surface of normal human nasal epithelial cells in primary culture causes increased Cl- secretion in a concentration-dependent manner (S. Mason, et al., Br. J. Pharmacol. 103, 1649-56 (1991); M. Knowles, et al., N. Engl. J. Med. 325, 533-8 (1991)). This response was also observed in cultured nasal epithelial cells from cystic fibrosis (CF) patients (R. Benali, et al., Am. J. Respir. Cell Mol. Biol. 10, 363-8 (1994)). This increased Cl- transport has been associated with increased fluid transport across the epithelium (C. Jiang, et al., Science 262, 424-7 (1993)). In addition to these effects on Cl- and fluid transport, UTP has been shown to produce an increase in cilia beat frequency in cultured human epithelial cells from normal adult humans and CF patients (D. Drutz, et al., Drug Dev Research 1996; 37(3):185 “Uridine 5′ Triphosphate (UTP) Regulates Mucociliary Clearance Via Purinergic Receptor Activation”, presented at “Purines '96” conference held in Milan, Italy, Jul. 6-9, 1996). These actions of UTP have been associated with an increase in intracellular calcium ion (Ca++) due to stimulation of phospholipase C by the P
2
Y
2
receptor (H. Brown, et al., Mol. Pharmacol. 40, 648-55 (1991)). UTP has also been shown to increase the rate and total amount of mucin secretion by goblet cells in human airway epithelial explants (M. Lethem, et al., Am. J. Respir. Cell Mol. Biol. 9, 315-22 (1993)). These
Jacobus Karla M.
Leighton H. Jeff
Halluin Albert P.
Howrey Simon Arnold & White , LLP
Inspire Pharmaceuticals Inc.
Kung Viola T.
Pak John
LandOfFree
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