WO1998003177A1 - Method of treating sinusitis with uridine triphosphates and related compounds - Google Patents
Method of treating sinusitis with uridine triphosphates and related compounds Download PDFInfo
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- WO1998003177A1 WO1998003177A1 PCT/US1997/011795 US9711795W WO9803177A1 WO 1998003177 A1 WO1998003177 A1 WO 1998003177A1 US 9711795 W US9711795 W US 9711795W WO 9803177 A1 WO9803177 A1 WO 9803177A1
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- compound
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- 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
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- 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
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Definitions
- This invention relates to a method of removing or preventing the accumulation of retained mucous secretions from the sinus passages of a patient by administering certain uridine. adenosine. or cytidine triphosphates.
- Sinusitis is an inflammation of the paranasal sinuses typically associated with an upper respiratory infection. Sinusitis is this country " s most common health-care complaint, affecting an estimated 31 million people. (A. Moss and V. Parsons. National Center for
- DHHS Publication NO. PHS
- Other less common causes include allergies, air pollution, diving and swimming under water, structural defects of the nose (deviated septum), and as a complication of dental work.
- a common complication of sinusitis is a related middle ear infection (otitis media) due to the close proximity of the sinuses and eustachian tube. (M. Revonta and A. Blokmanis, Can. Fam.
- Uridine 5'-triphosphate (UTP) and adenosine 5 '-tri phosphate (ATP) have been shown to affect the ion transport activity of human airway epithelial cell, as described in U.S. Pat. No. 5,292,498.
- UTP and ATP induce chloride and water secretion in the lung epithelial cells of cystic fibrosis patients, helping to liquefy 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 lungs of cystic fibrosis patients, pneumonia patients, or normal individuals.
- UTP and its related compounds as well as other nucleoside phosphates such as: P 1 ⁇ 4 - di(uridine-5') tetraphosphate (U 2 P 4 ); adenosine 5'-triphosphate (ATP); cytidine 5'-triphosphate (CTP); 1 ,N 6 -ethenoadenosine 5'-triphosphate; adenosine 1 -oxide 5'-triphosphate; 3,N 4 -ethenocytidine 5'-triphosphate; or P !
- UTP and U 2 P 4 are the preferred embodiments of the present invention.
- a method of treating sinusitis in a subject in need of such treatment comprises administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate mucous secretions and stimulate ciliary beat frequency in the luminal epithelial cells of the sinus passages:
- Xi, X 2 , and X 3 are each independently either O “ or S " .
- X 2 . and X 3 are O " .
- R is O, imido, methylene, or dihalomethylene (e.g., dichloromethylene, diflouromethylene).
- R is oxygen or difiuoromethylene.
- R 2 is H or Br.
- R 2 is H.
- Particularly preferred compounds of Formula I are uridine 5'-triphosphate (UTP) and uridine 5'-O-(3-thiotri ⁇ hosphate) [UTP ⁇ S].
- Formula II--P',P 4 di(uridine-5') tetraphosphate [U 2 P 4 ] is also a preferred embodiment of the invention.
- Another compound of Formula II is P',P 4 - di(adenosine-5') tetraphosphate [A 2 P 4 ].
- the method of the present invention can also include administering a compound of Formula HI (adenosine 5'-triphosphate [ATP] or 1,N 6 - ethenoadenosine 5'-triphosphate or adenosine 1 -oxide 5'-triphosphate), or Formula IV (cytidine 5'-triphosphate [CTP] or 3,N 4 -ethenocytidine 5'-triphosphate).
- Formula II
- B is uracil or adenine, attached as shown in Formulae I and III.
- R,, X tract X 2 , and X 3 are defined as in Formula I.
- R 3 and R are H while R 2 is nothing and there is a double bond between N-l and C- (adenine), or
- , X 2 R, and R ⁇ are H while R 7 is nothing and there is a double bond between N-3 and C-4 (cytosine), or,
- a second aspect of the present invention is a pharmaceutical formulation containing the compound of Formula I, II, III or IV in an amount effective to hydrate mucous secretions and stimulate ciliary beat frequency in the luminal epithelial cells of the sinus passages in a patient in need of such treatment.
- 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 and stimulation of ciliary beat frequency in the luminal epithelial cells of the sinus passages in a patient in need of such treatment.
- the method of the present invention may be used to hydrate retained mucous secretions and stimulate ciliary beat frequency in the sinuses of a subject in need of such a treatment.
- the present invention increases mucociliary clearance in three ways: (1) by increasing the ciliary beat frequency of cilia on the surface of luminal epithelial cells, (2) by increasing the secretions of mucins by goblet cells, and (3) by increasing the secretion of water into the periciliary liquid layer as a result of increased secretion of Cl ions by luminal epithelial cells.
- UTP increases surfactant phospholipid production and secretion by type II aveolar cells in vitro.
- the mucins secreted by goblet cells form a layer on top of the cilia and capture foreign particles, including viruses and bacteria; the mucin layer is transported by the wave-like action of cilia; and the movement of cilia is facilitated by the hydration of the periciliary liquid layer surrounding the cilia.
- 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.
- uridine 5'- triphosphate UTP
- uridine 5'-O-(3-thiotriphosphate) UTP ⁇ S
- 5-bromo-uridine 5'-triphosphate 5-BrUTP
- UTP may be made in the manner described in Kenner, et al., J. Chem. Soc.
- Formulae I-IV herein illustrate the active compounds in the naturally occurring 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 occurring D-configuration is preferred.
- Compounds illustrative of the compounds of Formula II include (P'.P 4 -di(adenosine- 5') tetraphosphate (A 2 P 4 ) or P',P -di(uridine-5') tetraphosphate (UJ- 4 ). These compounds can be made in accordance with known procedures, or variations thereof which will be described by: P. Zamecnik, et al., Proc. Natl. Acad. Sci.
- U 2 P 4 can be prepared by methods similar to that described in C. Vallejo, et al., Biochem. Biophys. Ada 438, 304-09 (1976).
- Compounds illustrative of the compounds in Formula III above include (a) adenosine 5'-triphosphate (ATP) and (b) 1 ,N 6 -ethenoadenosine 5'-triphosphate.
- Compounds illustrative of the compounds of Formula IV above include (a) cytidine 5'-triphosphate and (b) 3,N 4 - ethenocytidine 5'-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, J. Am. Chem. Soc. 87, 1785-1788 (1965); M.
- Compounds of Formulas I, III, or IV where R, is CC1 2 and CF 2 can be prepared by methods similar to that described in G. Blackburn, et al., J. Chem. Soc. Perkin Trans. 1, 1119- 25 (1984).
- Compounds of Formula I, II, III where R, is CH 2 can be prepared by methods similar to that described in T. Myers, et al., J. Am. Chem. Soc. 85, 3292-95 (1963).
- UTP, ATP, CTP, A 2 P 4 , 3,N 4 -ethenocytidine triphosphate, 1,N - ehtenoadenine 5'-triphosphate, adenosine 1 -oxide 5'-triphosphate, ATP ⁇ S, ATP ⁇ S, ATP ⁇ S, AMPPCH2P, AMPPNHP, N 4 -ethenocytidine and 1 ,N 6 -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, or an ammonium and tetraalkyl ammonium salts,
- 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 lungs, sinuses, ears or eyes by a variety of suitable means, but -ire 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, or eye 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, or eye drops of a liquid formulation
- Liquid pharmaceutical compositions of the active compound for producing a nasal spray or nasal powder, or nasal or eye 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 hydrate mucous secretions and stimulate ciliary beat frequency in the sinuses will vary depending on the state of the subject, but generally an effective amount is the amount sufficient to achieve concentrations of active compound on the sinus passages of the subject of from about 10 "7 moles/liter (e.g., for UTP 0.00001 mg/mL) to about 10 " ' moles/liter (e.g., for UTP, 52 mg/mL), and more preferably from about 10-6 moles/liter (e.g., for UTP, 0.001 mg/mL) to about 10 " ' moles/liter (e.g., for UTP, 50 mg/,L).
- an effective amount is the amount sufficient to achieve concentrations of active compound on the sinus passages of the subject of from about 10 "7 moles/liter (e.g., for UTP 0.00001 mg/mL) to about 10 " ' moles/liter (e.g., for UTP, 52 mg/mL), and more preferably from about 10-6 mo
- the daily dose to promote fluid drainage may be divided among one or several unit dose administrations.
- the daily dose schedule is no more than four times per day.
- Another means of administering the active compound to the sinuses of the patient to promote fluid/secretion 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.
- the active compound can be aerosolized in a variety of forms, such as, but not limited to, dry powder inhalants, metered dose inhalants, or liquid/liquid suspensions.
- dry powder delivery the UTP may be formulated alone or in combination with diluent or carrier, such as sugars (i.e., lactose, sucrose, trehalose, mannitol) or other acceptable excipients for lung or airway delivery.
- the dry powder may be obtained by methods known in the art, such as spray-drying, milling, freeze-drying, etc.
- Another means of administering the active compound to the sinuses would involve an injected form of the active compound, injected from the nose or sinus area of the face directly into the sinus passageways.
- Additional means of administering the active compound to the sinuses would involve a suppository form of the active compound, such that a therapeutically effective amount of the compound reaches the sinuses via systemic absorption and circulation.
- Another means of administering the active compound would involve intra-operative instillation of a gel, cream, powder, foam, crystal or liquid suspension form of the active compound such that a therapeutically effective amount reaches the sinuses.
- the preferred embodiments of the present invention-UTP and U 2 P 4 , as well as the other compounds for Fomiulae I - IV also have therapeutic benefit when used in combination with other agents used to treat sinusitis, such as, but not limited to: antibiotics; antiviral agents; antihistamine/decongestant agents; steam inhalation; ucolytic agents; nonsteroidal anti-inflammatory agents; steroids; and warm compresses applied over the sinus area of the face.
- Digitized output signals were conditioned and analyzed in the frequency domain using a fast Fourier transform program. That frequency associated with the greatest power by the above program will be defined as the best frequency and recorded.
- the product of Formulation II (8.3 and 82.5 mg/ml) increased cilia beat frequency to 18.3 ⁇ 1.3 beats/min. (mean ⁇ SD) and 18.0 ⁇ 0.45 beats/min. from a baseline value of 12.0 ⁇ 1.1 beats/min.
- Uridine 5'-triphosphate (UTP) or P',P 4 di(uridine-5')-tetraphosphate (U 2 P 4 ) is administered to patients diagnosed with acute sinusitis.
- UTP is administered via nasal drops or nasal spray, 2 - 3 times a day, for a total of 3 - 5 days during an acute episode of sinusitis.
- the concentration of UTP is in the range of 10 "7 to 10 "1 moles/liter (e.g.. for UTP, 0.001 to 50 mg/mL).
- Treatment with UTP begins as soon as the presumptive diagnosis of sinusitis is made; not necessarily after antibiotic therapy is initiated.
- the length of treatment for each patient is one week (or as long as symptoms persist).
- UTP effectiveness of UTP in promoting the drainage of blocked sinus fluid is measured by a decrease in symptomatic complaints as well as by the results of physical examinations.
- the safety of UTP is assessed by standard safety measures of vital signs— heart rate, respiratory rate, blood pressure, electrocardiogram and laboratory blood tests (e.g., blood chemistries and complete blood count), as well as any adverse events observed/reported.
- the subject methods and compounds described herein provide a means for inducing drainage of mucous secretions from the sinus passageways in a patient afflicted with sinusitis.
- the method comprises administering to the sinuses of the subject a uridine triphosphate such as uridine 5'-triphosphate (UTP), U 2 P 4 , or any analog of UTP in an amount effective to hydrate mucous secretions or stimulate ciliary beat frequency in the sinuses.
- a uridine triphosphate such as uridine 5'-triphosphate (UTP), U 2 P 4 , or any analog of UTP in an amount effective to hydrate mucous secretions or stimulate ciliary beat frequency in the sinuses.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10506966A JP2000514461A (en) | 1996-07-03 | 1997-07-03 | Method for treating sinusitis with uridine triphosphate and related compounds |
EP97942376A EP0939637A4 (en) | 1996-07-03 | 1997-07-03 | Method of treating sinusitis with uridine triphosphates and related compounds |
NZ333983A NZ333983A (en) | 1996-07-03 | 1997-07-03 | Method of treating sinusitis with uridine triphosphates and related compounds |
AU44089/97A AU728504B2 (en) | 1996-07-03 | 1997-07-03 | Method of treating sinusitis with uridine triphosphates and related compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08/675,620 US5789391A (en) | 1996-07-03 | 1996-07-03 | Method of treating sinusitis with uridine triphosphates and related compounds |
US08/675,620 | 1996-07-03 |
Publications (1)
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WO1998003177A1 true WO1998003177A1 (en) | 1998-01-29 |
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PCT/US1997/011795 WO1998003177A1 (en) | 1996-07-03 | 1997-07-03 | Method of treating sinusitis with uridine triphosphates and related compounds |
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US (4) | US5789391A (en) |
EP (1) | EP0939637A4 (en) |
JP (1) | JP2000514461A (en) |
KR (1) | KR20000067852A (en) |
CN (1) | CN1227491A (en) |
AU (1) | AU728504B2 (en) |
CA (1) | CA2259552A1 (en) |
NZ (1) | NZ333983A (en) |
WO (1) | WO1998003177A1 (en) |
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Also Published As
Publication number | Publication date |
---|---|
US5958897A (en) | 1999-09-28 |
CN1227491A (en) | 1999-09-01 |
EP0939637A1 (en) | 1999-09-08 |
US5789391A (en) | 1998-08-04 |
CA2259552A1 (en) | 1998-01-29 |
US5981506A (en) | 1999-11-09 |
KR20000067852A (en) | 2000-11-25 |
AU728504B2 (en) | 2001-01-11 |
AU4408997A (en) | 1998-02-10 |
JP2000514461A (en) | 2000-10-31 |
US5972904A (en) | 1999-10-26 |
EP0939637A4 (en) | 2001-09-26 |
NZ333983A (en) | 2000-09-29 |
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