Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1996-02-21
2002-07-23
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S047000, C424S437000, C424S465000
Reexamination Certificate
active
06423694
ABSTRACT:
TECHNICAL FIELD
This invention relates to a method of removing or preventing the accumulation of retained mucous secretions from the middle ear of a patient by administering certain uridine, adenosine, or cytidine triphosphates.
BACKGROUND OF THE INVENTION
Otitis media (OM) is a viral or bacterial infection of the middle ear primarily, but not exclusively, afflicting children under three years of age. It is characterized by the presence of congested fluid in the middle ear and is usually precipitated by an infection in the respiratory tract which spreads into the middle ear via the nasopharnyx and eustachian tube. The incidence of OM is increasing—annual physician's office visits for OM have increased 150% from 1975 through 1990 (L. McCraig and J. Hughes,
JAMA
273(3), 214-19 (1995)). This is most likely due to increased use of large-group day care facilities, where children are exposed to more respiratory pathogens. Approximately 25-40 million office visits are made each year for diagnosis and treatment of OM, and by age three, approximately 75% of children will have had at least one episode of acute OM (with the maximum incidence in children 6-24 months of age) (J. Klein,
Clin Infect Dis
19, 823-33 (1994)). Anatomically, the eustachian tubes in infants are shorter, wider, and lie more horizontally than in older children and adults, facilitating the spread of pathogens from the nasopharnyx to the middle ear (L. Schwartz and R. Brown,
Arch Intern Med
152, 2301-04 (1992)). The infection evokes an inflammatory response in the mucosal tissue of the eustachian tube and middle ear, resulting in fluid effusion in the middle ear. The resulting fluid is viscous and pus-filled, making normal mucociliary movement of the fluid difficult, and inflammation of the eustachian tube at its narrowest point, the isthmus, effectively blocks drainage of the fluid into the nasopharnyx (J. Klein, supra (1994)). Middle ear congestion can be expected to cause significant pain, dizziness, and hearing impairment in the patient; the average hearing loss from the fluid accumulation is 25 decibels. This is of particular concern in very young children because impairment of hearing could delay or seriously impede aspects of normal cognitive development which are dependent upon exposure to language and social interaction (D. Teele, et al.
J. Infect Dis
1621, 685-94 (1990)). Other potential (but uncommon) sequelae of OM include mastoiditis, meningitis, extradural abscess, subdural empyema, brain abscess, and lateral sinus thrombosis.
About 80-90% of OM effusions eventually resolve spontaneously following antibiotic therapy; the process may take as long as three months. However, congestion in the middle ear may persist for weeks or even months beyond sterilization of this fluid with antibiotics due to a continued hypersecretory state of the mucous-producing cells. (S. Wintermeyer and M. Nahata,
Annals of Pharmocotherapy
28, 1089-99 (1994)). The cause of this persistent hypersecretory state is not well understood but may relate to unrelieved underlying eustacian tube obstruction. As a further impediment to treatment, the effectiveness of antibiotic therapy is decreasing on account of growing bacterial resistance to antibiotics (M. Poole,
Pediatr Infect Dis J.
14(4), 523-26 (1995)). If middle ear congestion persists for more than three months, surgery is commonly performed to insert a typanostomy tube to ventilate the middle ear of the patient (K. Grundfast,
Arch Otolaryngol Head Neck Surg,
120, 797-98 (1994)). Tympanostomy surgery is now the second most frequent surgical procedure in children (after circumcision) (J. Klein, supra (1994)). The tube allows drainage of the fluid out of the ear and eventual resolution of the disease in a vast majority of chronic cases. However, the surgery is costly (>$2,000), and requires administering general anesthesia, a particular concern in infant patients. Furthermore, potential (but uncommon) sequelae of the surgery include persistent otorrhea, permanent perforation or scarring of the tympanic membrane, and cholesteatoma (a cyst-like sac filled with keratin debris that can occlude the middle ear and erode surrounding structures) (J. Klein, supra (1995)).
Thus, as a result of the decreasing effectiveness of antibiotic therapy due to bacterial resistance and the high costs and risks associated with typanostomy surgery, medical researchers have sought to develop other effective therapies for this increasingly prevalent disease. A French biotechnology company, Laboratoires SYNTHELABO FRANCE, has developed a method of treating nasal mucous fluid congestion under the trademark name rhinATP™ which uses adenosine triphosphate (ATP) as the active compound. This technology was licensed under U.S. Pat. No. 5,420,116 (applicant intends the disclosure of this and all other patent references and publications cited herein be incorporated herein by reference). Their method of treatment comprises administering ATP to the nasal cavity via nasal spray or nasal drops. Uridine triphosphate (UTP) and adenine triphosphate (ATP) have also been shown to effect the ion transport activity of human airway epithelial cells, as described in U.S. Pat. No. 5,292,498. Specifically, UTP and ATP induce chloride and water secretion by the lung epithelial cells of cystic fibrosis patients, helping to liquify and facilitate transport of the highly viscous airway surface mucus that characterizes this disease. It has also been found that UTP and ATP stimulate the ciliary beat frequency in lung epithelial cells, further facilitating the transport of mucus from the lungs of cystic fibrosis patients. See, R. Boucher, et al., Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, p. 525-532 entitled “Mechanisms and Therapeutic Actions of Uridine Triphosphates in the Lung” (L. Belardinelli, et al. ed., Alumwer Academic Publishers, Boston 1995); see also, L. Gheber, et al.,
J. Membrane Biol.
147, 83-93 (1995). Applicant has discovered that the high viscosity of the retained middle ear fluid in OM patients can be 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
-ethenoadosine 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(uridine5′) tetraphosphate (U
2
P
4
) to the site of fluid blockage.
SUMMARY OF THE INVENTION
A method of treating otitis media in a subject in need of such treatment is disclosed. The method comprises administering to the middle ear of the subject a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount effective to promote fluid drainage from the middle ear by hydrating mucous secretions in the middle ear and by increasing ciliary beat frequency in the middle ear and eustachian tube:
wherein:
X
1
, X
2
, and X
3
are each independently either O
−
or S
−
. Preferably, X
2
and X
3
are O
−
.
R
1
is O, imido, methylene, or dihalomethylene (e.g., dichloromethylene, diflouromethylene). Preferably, R
1
is oxygen or difluoromethylene.
R
2
is H or Br. Preferably, R
2
is H. Particularly preferred compounds of Formula I are uridine 5′-triphosphate (UTP) and uridine 5′-O-(3-thiotriphosphate) (UTP&ggr;S).
Formula I is the preferred embodiment of the compound, however, the method of the present invention can also include administering a compound of Formula II (adenosine 5′ triphosphate [ATP] or 1,N
6
-ethenoadenosine triphosphate or adenosine 1-oxide triphosphate), or Formula III (cytidine 5′ triphosphate [CTP] or 3,N
4
-ethenocytidine triphosphate), or Formula IV (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
).
wherein:
R
1
, X
1
, X
2
, and X
3
are defined as in Formula I.
R
3
and R
4
are H while R
2
is nothing and there is a double bon
Drutz David J.
Jacobus Karla M.
Rideout Janet L.
Chiang Robin C.
Crane Lawrence E.
Geist Gary
Halluin Albert P.
Howrey Simon Arnold & White , LLP
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