Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
  • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals

Definitions

• 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.
• Otitis media 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.
• 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.
• 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.
• 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.
• UTP and its related compounds 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); l,N 6 -ethenoadosine triphosphate; adenosine 1-oxide triphosphate; 3,N 4 -ethenocytidine triphosphate; tetraphosphate (A 2 P 4 ); or P 1 ,P 4 -di(uridine-5') te raphosphate (U 2 P 4 ) to the site of fluid blockage.
• ATP adenosine 5'-triphosphate
• CTP cytidine 5' -triphosphate
• l,N 6 -ethenoadosine triphosphate adenosine 1-oxide triphosphate
• 3,N 4 -ethenocytidine triphosphate tetraphosphate
• UTP and other nucleoside phosphates induce chloride and water secretion from luminal epithelial cells via activation of the P2Y 2 purinergic receptor.
• the P2Y 2 receptor is part of a family of seven transmembrane spanning, G-protein coupled receptors designated the P2Y receptor family. Most members of the P2Y receptor family, including P2Y 2 , are coupled to the phospholipase C (PLC)-inositol triphosphate (IP 3 ) pathway (J. Simon, et al., Eur. J. Pharmacol., 291, 281- 289 (1995).
• PLC phospholipase C
• IP 3 phospholipase C pathway
• a method of treating otitis media in a subject in need of such treatment 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:
• l 2 and X3 are each independently either O “ or S " .
• X2 and X3 are O".
• Rl is O, imido, methylene, or dihalomethylene (e.g., dichloromethylene, diflouromethylene).
• Ri is oxygen or difluoromethylene.
• R2 is H or Br.
• R2 is H.
• Particularly preferred compounds of Formula I are uridine 5' -triphosphate (UTP) and uridine 5'-0-(3-thiotriphosphate) (UTP ⁇ 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 l,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 tetraphosphate (A 2 P 4 ) or di(uridine-5') tetraphosphate (U 2 P 4 ).
• Formula II adenosine 5' triphosphate [ATP] or l,N 6 -ethenoadenosine triphosphate or adeno
• Ri, Xi, 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 bond between N-l and C-6 (adenine), or
• R 3 and R 4 are H while R 2 is O and there is a double bond between N-l and C-6 (adenine 1 -oxide), or
• Ri, Xi, X 2 , and X 3 are defined as in Formula I.
• R 5 and R ⁇ are H while R 7 is nothing and there is a double bond between N-3 and C-4 (cytosine), or,
• B is adenine or uracil.
• a second aspect of the present invention is a pharmaceutical formulation containing the compound of Formula I, II, HI, or IV in an amount effective to promote fluid drainage from the middle ear by hydrating the mucous secretions in the middle ear and by increasing the ciliary beat frequency in the middle ear and eustachian tube, in a pharmaceutically acceptable carrier.
• a third aspect of the present invention is the use of the active compounds disclosed herein for the manufacture of a medicament for the therapeutic hydration of mucous secretions in the middle ear and for the activation of ciliary beat frequency in the middle ear and eustachian tube of apatient in need of such treatment.
• the method of the present invention may be used to promote drainage of congested fluid from the middle and external ear of a subject in need of such treatment for any reason, including (but not limited to) retained secretions arising from middle and external ear diseases such as otitis media, acute otitis media, otitis media with persistent effusion, serous otitis media (arising from an unresolved acute infection, an allergic reaction, or barotrauma such as from rapid descent in an aircraft), or otitis externa.
• the method of the present invention may also be used to treat inner ear disease, including (but not limited to) Meniere's Disease.
• the present invention induces drainage of middle ear mucous secretions by hydrating the retained secretions and by increasing the ciliary beat frequency of cilia on the surface of the middle ear and eustachian tube. Hydration of the mucous secretions decreases their viscosity, allowing them to be more easily transported from the middle ear and eustachian tube to the nasopharnyx via mucociliary action. Additionally, the present invention accelerates this mucociliary action, further facilitating drainage of retained middle ear secretions into the nasopharnyx.
• the present invention is concerned primarily with the treatment of human subjects, but may also be employed for the treatment of other mammalian subjects, such as dogs and cats, for veterinary purposes.
• Compounds illustrative of the compounds of Formula I above include: (a) uridine 5'-triphosphate (UTP); (b) uridine 5'-0-(3- thiotriphosphate) (UTP ⁇ S); and (c) 5-bromo-uridine 5'-triphosphate (5- BrUTP).
• UDP uridine 5'-triphosphate
• UDP ⁇ S uridine 5'-0-(3- thiotriphosphate)
• 5- BrUTP 5-bromo-uridine 5'-triphosphate
• UTP may be made in the manner described in Kenner, et al., /. Chem. Soc. 1954, 2288; or Hall and Khorana, /. Am. Chem. Soc. 76, 5056 (1954). See Merck Index, Monograph No. 9795 (11th Ed. 1989).
• UTP ⁇ S may be made in the manner described in R. S. Goody and F. Eckstein, /. Am. Chem. Soc. 93, 6252 (1971).
• Formula I herein illustrates uridine triphosphate active compounds in the naturally occuring D configuration, but the present invention also encompasses compounds in the L configuration, and mixtures of compounds in the D and L configurations, unless otherwise specified.
• the naturally occuring D configuration is preferred.
• Compounds illustrative of the compounds of Formula II above include (a) adenosine 5'-triphosphate (ATP) and (b) 1,N 6 - ethenoadenosine triphosphate.
• Compounds illustrative of the compounds of Formula HI above include (a) cytidine 5'-triphosphate and (b) 3,N -ethenocytidine triphosphate. These compounds can be made in accordance with known procedures, or variations thereof which will be apparent to those skilled in the art. For example, phosphorylation of nucleosides by standard methods such as D. Hoard and D. Ott, /. Am. Chem. Soc. 87, 1785-1788 (1965); M.
• Derivatives with alpha, beta and gamma thiophosphorus groups can be derived by the following or by adapting methods of: J. Ludwig and F. Eckstein, /. Org. Chem. 54, 631-35 (1989); F. Eckstein and R. Goody, Biochemistry 15, 1685 (1976); R. Goody and F. Eckstein, /. Am. Chem. Soc. 93, 6252 (1971).
• Compounds of Formulas I, II, or III where Ri is CC1 2 and CF 2 can be prepared by methods similar to that described in G. Blackburn, et al., /. Chem. Soc. Perkin Trans. I, 1119-25 (1984).
• Compounds of Formula I, II, in where Ri is CH 2 can be prepared by methods similar to that described in T. Myers, et al., /. Am. Chem. Soc. 85, 3292-95 (1963).
• Compounds illustrative of the compounds of Formula IV include tetraphosphate (A 2 P 4 ) or di(uridine-5') tetraphosphate (U 2 P 4 ).
• UTP, ATP, CTP, A 2 P 4 , 3,N -ethenocytidine triphosphate, 1,N -ethenoadenine triphosphate, adenosine 1 -oxide triphosphate, ATP ⁇ S, ATP ⁇ S, ATP ⁇ S, AMPPCH 2 P, AMPPNHP, N 4 - ethenocytidine and 1,N -ethenoadenosine are commercially available, for example, from Sigma Chemical Company, PO Box 14508, St. Louis, MO 63178.
• the active compounds of Formulae I - IV may be administered by themselves or in the form of their pharmaceutically acceptable salts, e.g., an alkali metal salt such as sodium or potassium, an alkaline earth metal salts such as manganese, magnesium and calcium or an ammonium and tetraalkyl ammonium salts, NX 4 + (wherein X is . 4 ).
• pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
• the active compounds disclosed herein may be administered to the middle ear of a patient to promote fluid drainage in otitis media by a variety of suitable means, but are preferably administered by administering a liquid /liquid suspension (either a nasal spray of respirable particles which the subject inhales, or nasal drops of a liquid formulation) comprised of the active compound.
• a liquid /liquid suspension either a nasal spray of respirable particles which the subject inhales, or nasal drops of a liquid formulation
• Liquid pharmaceutical compositions of the active compound for producing a nasal spray or nasal drops may be prepared by combining the active compound with a suitable vehicle, such as sterile pyrogen free water or sterile saline by techniques known to those skilled in the art.
• the dosage of active compound to promote fluid drainage will vary depending on the condition being treated and the state of the subject, but generally an effective amount is the amount sufficient to achieve concentrations of active compound on the middle ear surfaces of the subject of from about 10" 7 to about 10" 2 Moles /liter, and more preferable from about 10" 6 to about 3 x 10" 4 Moles /liter.
• the daily dose to promote fluid drainage may be divided among one or several unit dose administrations.
• the daily dose is no more than two times per day.
• Another means of administering the active compound to the middle ear of the patient to promote fluid drainage may include any oral form of the active compound, administered to the patient either by means of a liquid suspension of the active compound which is poured into the mouth of the patient, or by means of a pill form swallowed by the patient.
• Another means of administering an effective amount of the active compound to the middle and inner ear would involve the patient inhaling a nebulized form of the active compound into their respiratory tract, such that the active compound enters the nasopharnyx and subsequently enters the inner and middle ear of the patient.
• Another means of administering the active compound to the middle ear would include any topical form of the active compound, administered as a cream or gel to the outer ear, which would subsequently permeate through the tympanic membrane into the middle ear of the patient.
• Another means of administering the active compound to the middle ear would involve an injected form of the active compound, injected from the outer ear directly through the tympanic membrane into the middle ear, or injected indirectly through the upper neck region into the middle ear.
• Another means of administering the active compound to the middle ear would involve a suppository form of the active compound, such that a therapeutically effective amount of the compound reaches the middle ear via systemic absorption.
• An additional means of administering the active compound would involve intra-operative instillation of the active compound into the middle, inner or outer ear via a gel, cream, or ⁇ 2
• liquid suspension form of the active compound such that a therapeutically effective amount reaches the middle, inner or outer ear.
• UTP and compounds of Formulae I - IV also have therapeutic benefit when used in combination with other agents used to treat otitis media, such as, but not limited to: antibiotics like penicillin, penicillan plus beta-lactam, erythromycin plus sulisoxazole, ephalosporin, trimethodprim, trimethodprim plus sulfamethoxazole, macrolides, and oxazolidinones; vaccines; antihistamines, decongestants, mucolytic agents; nonsteroidal antiinflammatory agents; and corticosteroids.
• UTP may also be used in combination with agents under development, such as NE-1530-a naturally occuring airway oligosaccharide (Neose Technologies, Inc.), and gene therapy.
• Figure 1 is the in situ hybridization of human P2Y 2 receptor using a 600 bp antisense probe.
• Figure 2 is the in situ hybridization of human P2Y 2 using, as a control, a 600 bp sense probe. Comparison of antisense and sense probes reveals more radioautographic signal with antisense probe, consistent with expression of P2Y 2 receptor in the Eustachian tube.

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• 1996
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  • 1997-02-14 WO PCT/US1997/002299 patent/WO1997029756A1/en not_active Ceased
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