CA2226892A1 - Method of detecting lung disease - Google Patents
Method of detecting lung disease Download PDFInfo
- Publication number
- CA2226892A1 CA2226892A1 CA002226892A CA2226892A CA2226892A1 CA 2226892 A1 CA2226892 A1 CA 2226892A1 CA 002226892 A CA002226892 A CA 002226892A CA 2226892 A CA2226892 A CA 2226892A CA 2226892 A1 CA2226892 A1 CA 2226892A1
- Authority
- CA
- Canada
- Prior art keywords
- lung
- acceptable salt
- subject
- pharmaceutically acceptable
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- 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
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P11/10—Expectorants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Dispersion Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Measuring Pulse, Heart Rate, Blood Pressure Or Blood Flow (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
Abstract
A method of facilitating the obtaining of a mucus sample from at least one lung of a subject comprises administering to at least one lung of the subject, in an amount effective to hydrate lung mucus secretions and/or stimulate cilia beat frequency therein, uridine 5'-triphosphate, an active analog thereof, or a pharmaceutically acceptable salt of either thereof, and, optionally, concurrently administering to said at least one lung a physiologically acceptable salt in an amount effective to hydrate lung mucus secretions therein. A sputum or mucus sample is then collected from said at least one lung, which sample can then be analyzed for lung disease. Pharmaceutical compositions useful for carrying out the method comprise UTP or a salt thereof, alone or in combination with a physiologically acceptable salt, or a pharmaceutically acceptable salt of either thereof. The composition may be a liquid/liquid suspension composition or a dry powder composition.
Description
METHOD OF DETECTING LUNG DISEASE
This invention was made with Government support under grant number HL-SPO1-34322 from the National Institutes of Health (NIH). The Government has certain rights to this invention.
Field of the Invention This application concerns lung diagnostic assays in general, and particularly concerns a lung diagnostic assay in which lung mucus secretions are hydrated to facilitate collection thereof.
o Backqround of the Invention The analysis of sputum samples is particularly important in the treatment and diagnosis of many lung disorders, including lung cancer and tuberculosis (TB).
In particular, microbial infections of the lung are a serious problem in patients afflicted with acquired immune deficiency syndrome (AIDS). Two particularly problematic infections are Pneumocystis carinii pneumonia infections and mycobacterial in~ections.
Pneumocystis carinii pneumonia infections are typically referred to as "PCP" infections. It is now estimated that approximately 70 percent of patients afflicted with AIDS wili contract this disease. PCP may be treated with pentamidine isethionate, but an unfortunate W O97/05195 PCT~US96/12377 side effect of this treatment is its toxicity.
Accordingly, there is a continued need for techniques which permit the rapid and convenient screening of AIDS patients for this disease, and for the rapid, early, and accurate diagnosis thereof.
Mycobacteria are a large, diverse, and widely distributed ~amily of aerobic, nonsporulating, nonmotile bacilli that have a high cell-wall lipid content and a slow growth rate. Some Mycobacteria are harmless, while others are significant pathogens. The pathogenic Mycobacterium include M. tuberculosls, responsible for tuberculosis, as well as non-tuberculosis Mycobacteria such as M. avium, responsible for Mycobacterium Avium complex infections.
Sl7m~y of the Invention A first aspect of the present invention is a method of faciltating the obtaining of a mucus sample from at least one lung o~ a subject. The method comprises administering a physiologically acceptable salt to at least one lung of the subject in an amount ef~ective to hydrate lung mucus secretions therein, and concurrently administering to said at least one lung of the subject, in an amount effective to hydrate lung mucous secretions, and/or stimulate mucus secretions therein, and/or stimulate ciliary beat frequency therein, a compound of Formula (I) below, or a pharmaceutically acceptable salt thereo~:
HO- ~ - Rl - O - ~ O - CHz o ,Yl ,Yz ~Y3 ~
H H
OH OH
.
W O 97/05195 PCT~US96/12377 wherein:
Xl, X2, and X3 are each independently selected from the group consisting of OH and SH;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene; and R2 is selected from the group consisting of H
and sr.
The method is accompanied or followed by the step of collecting a mucus sample from said at least one lung of said subject (e.g., by said subject expectorating a sputum sample).
Also disclosed is a method of faciltating the obtaining of a mucus sample from at least one lung of a subject, comprising administering to at least one lung of said subject, in an amount effective to hydrate lung mucous secretions, and/or stimulate mucus secretions therein, and/or stimulate ciliary beat fre~uency therein, a compound of Formula (I) as given above, or a pharmaceutically acceptable salt thereo~, and then collecting a mucus sample from said at least one lung of said subject. The mucus samples collected may then be analyzed for the presence or absence of lung disease (e.g., microbial infection, cancer, etc.) in said subject.
A second aspect of the present invention is pharmaceutical composition useful for facilitating the collecting of a mucus sample from at least one lung of a subject, said composition comprising, alone or in combination, a physiologically acceptable salt in an amount effective to hydrate lung mucus secretions; and a compound of Formula (I) as given above, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucus secretions. The composition may be a li~uid composition or a dry powder ~ composition.
W O 97/05195 PCT~US96/12377 Detailed Description o~ the Invention Compounds illustrative of the compounds of Formula (I) above ~also referred to as "active compounds"
herein) include: ra) uridine 5'-triphosphate (UTP); (b) uridine 5'-0-(3-thiotriphosphate) (UTPrS); and fc) 5-bromo-uridine 5'-triphosphate (5-BrUTP). One preferred compound of Formula (I) above is the UTP analog uridine 5'-0-(3-thiotriphosphate) (or "UTP~S"). These compounds are known or may be made in accordance with known procedures, or variations thereof which will be apparent to those skilled in the art. See generally U.S. Patent Number 5,292,498 to Boucher; N. Cusack and S. Hourani, Annals N. Y. Acad. Sci.
603, 172-181 (G. Dubyak and J. Fedan Eds. 1990). For example, UTP may be made in the manner described in Kenner et al., J. Chem. Soc. 1954, 2288; or Hall and Khorana, J.
Chem. Soc. 76, 5056 (1954). See Merck Index, Monograph No.
9795 (llth Ed. 1989). UTP~S may be made in the manner described in R.S. Goody and F. Eckstein, J. Am. Chem. Soc.
93, 6252 (1971).
For simplicity, Formula I herein illustrates uridine triphosphate active compounds in the naturally occurring D con~iguration, but the present invention also encompasses compounds in the L configuration, and mixtures of compounds in the D and L configurations, unless specified otherwise. The naturally occurring D
configuration is preferred.
The active compounds of Formula ( I) 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 salt, or an ammonium and tetraalkyl ammonium salt, NX4t (wherein X is a C14 alkyl group). Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
Amiloride (also known as 3,5,-diamino-6-chloro-N-(diaminomethylene)pyrazinecarboxamide), benzamil (also W O 97/OSl95 PCTrUS96/12377 knownas3,5-diamino-6-chloro-N-(benzylaminoaminomethylene) pyrazinecarboxamide) and ph--n~m;l (also known as 3,5-diamino-6-chloro-N-(phenylaminoaminomethylene) pyrazinecarboxamide) are known compounds and are disclosed in U.S. Patent No. 3,313,813 to E. Cragoe. The terms "amiloride,""benzamil," and l'phenamil," as used herein (also refered to as "active compounds" herein), include the pharmaceutically acceptable salts thereo~, such as (but not limited to) amiloride hydrochloride, benzamil hydrochloride or phenamil hydrochloride. Amiloride, benzamil or ph~n~m;l used to prepare compositions for the present invention may alternatively be in the form of a pharmaceutically acceptable free base of amiloride, benzamil or phen~m;l.
Because ~he ~ree base of the compound is less soluble than the salt, free base compositions are employed to provide more sustained release of benzamil or phenamil to the lungs.
Physiologically acceptable salts (also sometimes referred to as "active compounds" herein) used to carry out the method o~ the present invention are those that hydrate lung mucus secretions by facilitating the transport of water from lung endothelial cells into the mucu~. Physiologically acceptakle salts are salts that retain the desired biological activity of hydrating lung mucus secretions and do not impart undesired toxicological ef~ects. Physiologically acceptable salts are typically chloride salts, such as sodium chloride, potassium chloride, choline chloride, and N-methyl-D-glucamine chloride. Sodium chloride is currently preferred. These salts may be provided in the form of a dry respirable powder (discussed below) or as an aqueous solution.
The present invention is concerned primarily with the treatment of human subjects. Subjects may or may not be cystic fibrosis patients. The present invention may also be employed for the treatment of other m~mm~l ian subjects, such as dogs and cats, for veterinary purposes.
, The active compounds disclosed herein may be administered to the lung(s) of a subject by any suitable means. As used herein, the word "concurrently" means sufficiently close in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occuring within a short time period - before or after each other). By "at least one lung" is meant that administration of active compounds may be to one or both lungs of the subject, but where administration is to only one lung, then administration of the various active compounds is to the same lung.
Active compounds are preferably administered by administering an aerosol suspension of respirable particles comprised of the active compound or active compounds, which the subject inhales. 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. The respirable particles may be liquid or solid. The particles may optionally contain other therapeutic ingredients such as amiloride, benzamil or phenamil, with the selected compound included in an amount effective to inhibit the reabsorption of water from airway mucous secre~ions, as described in ~.S. Patent No.
4,501,729 (applicant specifically intends the disclosure of this and all other patent references cited herein be incorporated herein by reference).
The particulate pharmaceutical composition may optionally be combined with a carrier to aid in dispersion or transport. A suitable carrier such as a sugar (i.e., lactose, sucrose, trehalose, mannitol) may be blended with the active compound or compounds in any suitable ratio (e.g., a 1 to 1 ratio by weight).
Particles comprised of active compound for practicing the present invention should include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth or nose and larynx upon inhalation and into the bronchi and alveoli of CA 02226892 l998-0l-l4 the lungs. In general, particles ranging ~rom about 1 to 10 microns in size (more particularly, less than about 5 microns in size) are respirable. Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is preferably m; n; m; zed. For nasal administration, a particle size in the range of 10-500~m is preferred to ensure retention in the nasal cavity.
Liquid pharmaceutical compositions of active compound for producing an aerosol may be prepared by combining the active compound with a suitable vehicle, such as sterile pyrogen free water. The hypertonic saline solutions used to carry out the present invention are preferably sterile, pyrogen-free solutions, comprising from one to ~ifteen percent (by weight) o~ the physiologically acceptable salt, and more preferably from three to seven percent by weight of the physiologically acceptable salt.
Where compounds of Formula (I) or the pharmaceutically acceptable salts thereof are included in the hypertonic saline solution, they are typically included in a concentration ranging from about 10-4M to about 10-1M, and more preferab y in a con-entration ranging from about lG-2M
to about 10 -'M. Other therapeutic compounds such as amiloride, benzamil or phenamil may optionally be included (when such compounds are included, the saline solution is preferably not more than 0.3 percent by weight of the physiologically acceptable salt, and more preferably is 0.12 percent by weiyht of the physiologically acceptable salt).
Solid particulate compositions containing respirable dry particles of micronized active compound may be prepared by grinding dry active compound with a mortar and pestle, and then passing the micronized composition through a 400 mesh screen to break up or separate out large agglomerates. The active compound may be formulated alone (i.e., the solid particulate composition may consist essentially of the active compound) or in combination with a dispersant, diluent or carrier, such as sugars (i.e., lactose, sucrose, trehalose, mannitol) or other acceptable excipients for lung or airway delivery, which may be blended with the active compound in any suitable ratio (e.g., a 1 to 1 ratio by weight). The dry powder solid particulate composition may be obtained by methods known in the art, such as spray-drying, milling, freeze-drying, etc.
Again, other therapeutic compounds such as amiloride, benzamil or phenamil may also be included.
Aerosols of liquid particles comprising the active compound may be produced by any suitable means, such as with a pressure-driven jet nebulizer or an ultrasonic nebulizer. See, e.g., U.S. Patent No. 4,501,729.
Nebulizers are commercially available devices which trans~orm solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of compressed gas, typically air or oxygen, through a narrow venturi ori~ice or by means of ultrasonic agitation. Suitable formulations for use in nebulizers consist of the active ingredient in a liquid carrier, the active ingredient comprising up to 40~ w/w of the ~ormulation, but pre~erably less than 20~ w/w. The carrier is typically water (and most preferably sterile, pyrogen-~ree water) or a dilute aqueous alcoholic solution,preferably made isotonic, but may be hypertonic with body fluids by the addition of, for example, sodium chloride.
Optional additives include preservatives if the formulation is not made sterile, for example, methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants.
Aerosols of solid particles comprising the active compound may likewise be produced with any solid particulate medicament aerosol generator. Aerosol generators for administering solid particulate medicaments to a subject produce particles which are respirable, as explained above, and generate a volume of aerosol containing a predetermined metered dose of a medicament at a rate suitable for human administration. One illustrative r type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by 5 insufflation include finely comminuted powders which may be - delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder (e.g., a metered dose thereof effective to carry out the treatments described herein) is contained in 10 capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely 15 of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w/w of the formulation.
A second type of illustrative aerosol generator comprises 20 a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquified propellant. During use these devices discharge the ~ormulation through a valve adapted to deliver a metered volume, typically from 10 to 200 ~1, to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents, for example, ethanol, surfactants, such as oleic acid or sorbitan trioleate, antioxidants and suitable flavoring agents.
Any propellant may be used in carrying out the present invention, including both chlorofluorocarbon-containing propellants and non-chlorofluorocarbon-W O 97/05195 PCT~US96/12377 containing propellants. Thus, fluorocarbon aerosol propellants that may be employed in carrying out the present invention including fluorocarbon propellants in which all hydrogens are replaced with fluorine, chlorofluorocarbon propellants in which all hydrogens are replaced with chlorine and at least one fluorine, hydrogen-containing fluorocarbon propellants, and hydrogen-containing chlorofluorocarbon propellants. Examples of such propellants include, but are not limited to: CF3-CHF-CF2H; CF3-CH2-CF2H; CF3-CHF-CF3; CF3-CH2-CF3; CF3-CHCl-CF2Cl;
CF3-CHCl-CF3; cy-C(CF2)3-CHCl; CF3-CHCl-CH2Cl; CF3-CHF-CF2Cl;
CF3-CHCl-CFHCl; CF3-CFCl-CFHCl; CF3-CF2-CF2H; CF3-CF2-CH3;
CF2H-CF2-CFH2; CF3-CF2-CFH2; CF3-CF2-CH2Cl; CF2H-CF2-CH3; CF2H-CF2-CH2Cl; CF3-CF2-CF2-CH3; CF3-CF2-CF2-CF2H; CF3-CHF-CHF-CF3;
CF3-O-CF3; CF3-O-CF2H; CF2H-H-0-CF2H; CF2H-O-CFHa; CF3-O-CH3;
CF3-O-CF2-CF2H; CF3-0-CF2-O-CF3; cy-CF2-CF2-0-CF2-; cy-CHF-CF2-O-CF2-; cy-CH2-CF2-O-CF2-; cy-CF2-O-CF2-O-CF2-; CF3-O-CF2-Br;
CF2H-O-CF2-Br; and mixtures thereof, where 'Icy" denotes a cyclic compound in which the end terminal covalent bonds of the structures shown are the same so that the end terminal groups are covalently bonded together. Particularly preferred are hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (propellant i34a) and heptafluoropropane (propellant 227). A stabilizer such as a fluoropolymer may optionally be included in formulations of fluorocarbon propellants, such as described in U.S. Patent No. 5,376,359 to Johnson.
The aerosol, whether formed from solid or liquid particles, may be produced by the aerosol generator at a rate of from about 10 to 150 liters per minute, more preferably from about 30 to 150 liters per minute, and most preferably about 60 liters per minute. Aerosols containing greater amounts of medicament may be ~m; ni stered more rapidly. Typically, each aerosol may be delivered to the patient for a period from about 30 seconds to about 20 minutes, with a delivery period of about five to ten minutes being preferred.
-CA 02226892 l998-0l-l4 W O 97/05195 PCT~US96/12377 The dosage o~ the compound o~ Formula (I), or the pharmaceutically acceptable salt thereof, will vary depending on the condition being treated and the state of the subject, but generally may be an amount sufficient to achieve dissolved concentrations of active compound on the airway surfaces of the subject of from about 10-9 to about 10-2 Moles~liter or even 10~l Moles/liter, more pre~erably ~rom about 10-5 to about 10~1 Moles/liter, and most preferably from about 10-4 to about 10-3 to about 10~1 moles/liter. Depending upon the solubility of the particular formulation of active compound administered, the daily dose may be divided among one or several unit dose administrations.
When the sputum sample is subjected to cytological, bacterial or DNA analysis for detecting infectious microbial species therein, the sputum sample may first be digested with a liquefying agent, such as N-acetyl-L-cystein (NALC) and sodium hydroxide.
As noted above, the present invention is particularly useful for collecting mucus samples which are used for detecting Pneumocystis carinii pneumonia and Mycobacteria infections. The term "Mycobacteria" as used hel-ein has it~ conventional me~n; ng in the art referring to acid-fast, non-motile, rod shaped bacteria. See generally B. Davis et al., Microbiology, 724-742 (~d. Ed. 1980). All generally belong to the family Mycobacteriaceae. By way of example, the mycobacteria include, but are not limited to, Mycobacterium africanum, M. avium, M. bovis, M. bovis-BCG, M. chelonae, M. fortuitum, M. gordonae, M. intracellulae, M. kansasii, M. leprae, M. microti, M. paratuberculosis, M.
scrofulaceum, and M. tuberculosis. The present invention is useful in diagnosing both tuberculosis and non-tuberculosis Mycobacteria, and is useful in diagnosing M.
avium complex infections.
The present invention is explained in greater detail in the following non-limiting Examples.
EX~MPLE 1 DeliverY of UTP followed bY Hvpertonic Saline A subject is caused to inhale an aerosol of UTP
solution (10-2M UTP in 0.9~ (by weight) sterile pyrogen-free S saline solution) delivered by a Pari LC Plus nebulizer for 10 minutes. Immediately afterwards, the subject is caused to inhale an aerosol of hypertonic saline solution (3~
sterile pyrogen-free saline solution), delivered by a nebulizer ~or 10 minutes. During inhalation of the aerosols and after inhalation of the aerosols, the subject is encouraged to cough, and all sputum is collected during aerosol inhalation and over a 20 minute interval following cessation of aerosol inhalation. The sputum is captured in a plastic sputum container. The sputum so obtained is analyzed for content pending the clinical requirement, including analyses of cytologies for pulmonarY neoplasm, and the presence of infectious agents, for example, Pneumocystis carinii, by silver staining and immunofluorescence techniques. The technique is applicable for the diagnoses of other micro-organisms in the lower lung, including bacterial, viral, amd microplasma, using culture, immunocytochemical, and molecular (PCR, in situ hybridization) techniques.
E~iMPLE 2 Delivery of UTP with Amiloride This example is carried out in essentially the same manner as example 1 above, except that the UTP is dissolved in a 0.12~ sterile pyrogen-free NaCl solution, and the solution also contains 10-2M amiloride.
EX~MPLE 3 Delivery of Hypertonic Saline followed by UTP
This Example is carried out in essentially the same manner as Example 1 above, except that the hypertonic saline solution is delivered first, and the UTP solution is W O 97/05195 PCT~US96/lZ377 delivered immediately thereafter. Durations of delivery and concentrations remain the same.
E~MPLE 4 Concurrent Deliver~ of UTP in Hypertonic Saline This Example is carried out by modification of Example 1 above, with 10~l UTP being diluted in the hypertonic saline solutiion so that a single solution is delivered to the patient by inhalation of an aerosol generated by a nebulizer for a period of 15 minutes.
E~MPLE 5 Delivery of UTP followed b~ Sample Collection This procedure is carried out in essentially the same manner as Example l above, except that there is no separate administration of a hypertonic saline solution.
A subject is caused to inhale an aerosol of UTP
solution (10-2M UTP in 0.9~ (by weight) sterile pyrogen-free saline solution) delivered by a Pari LC Plus nebulizer for 10 minutes. During inhalation of the aerosol and after inhalation of the aerosol, the subject is encouraged to cough, and all sputum is collected during aerosol inhalation and over a 20 minute interval following cessation of aerosol inhalation. The sputum is captured in a plastic sputum container. The sputum so obtained is analyzed as described in Example 1. The technique is applicable for the diagnoses of other micro-organisms in the lower lung, including bacterial, viral, and mycoplasma, using culture, immunocytochemical, and molecular (PCR, in situ hybridization) techniques.
E~MPLE 6 Delivery of Solid Particulate UTP
This example is carried out in essentially the same manner as Example 5 above, except the subject is administered a respirable dry powder consisting essentially of solid particulate UTP or a pharmaceutically acceptable W O 97/05195 PCT~US96/12377 salt such as trisodium UTP prepared as described above, or as described in U.S. Patent No. 5,292,498 to Boucher. A
sputum sample is collected from the subject as described in Examples 1 and 5 above, and analyzed as described in S Examples 1 and 5 above.
The foregoing examples are illustrative of the present invention, and are not to be construed as limiting thereof. Among other things, volumes, times, and amounts can be varied from those specifically set forth above.
Accordingly, the invention is defined by the following claims, with equivalents of the claims to be included therein.
This invention was made with Government support under grant number HL-SPO1-34322 from the National Institutes of Health (NIH). The Government has certain rights to this invention.
Field of the Invention This application concerns lung diagnostic assays in general, and particularly concerns a lung diagnostic assay in which lung mucus secretions are hydrated to facilitate collection thereof.
o Backqround of the Invention The analysis of sputum samples is particularly important in the treatment and diagnosis of many lung disorders, including lung cancer and tuberculosis (TB).
In particular, microbial infections of the lung are a serious problem in patients afflicted with acquired immune deficiency syndrome (AIDS). Two particularly problematic infections are Pneumocystis carinii pneumonia infections and mycobacterial in~ections.
Pneumocystis carinii pneumonia infections are typically referred to as "PCP" infections. It is now estimated that approximately 70 percent of patients afflicted with AIDS wili contract this disease. PCP may be treated with pentamidine isethionate, but an unfortunate W O97/05195 PCT~US96/12377 side effect of this treatment is its toxicity.
Accordingly, there is a continued need for techniques which permit the rapid and convenient screening of AIDS patients for this disease, and for the rapid, early, and accurate diagnosis thereof.
Mycobacteria are a large, diverse, and widely distributed ~amily of aerobic, nonsporulating, nonmotile bacilli that have a high cell-wall lipid content and a slow growth rate. Some Mycobacteria are harmless, while others are significant pathogens. The pathogenic Mycobacterium include M. tuberculosls, responsible for tuberculosis, as well as non-tuberculosis Mycobacteria such as M. avium, responsible for Mycobacterium Avium complex infections.
Sl7m~y of the Invention A first aspect of the present invention is a method of faciltating the obtaining of a mucus sample from at least one lung o~ a subject. The method comprises administering a physiologically acceptable salt to at least one lung of the subject in an amount ef~ective to hydrate lung mucus secretions therein, and concurrently administering to said at least one lung of the subject, in an amount effective to hydrate lung mucous secretions, and/or stimulate mucus secretions therein, and/or stimulate ciliary beat frequency therein, a compound of Formula (I) below, or a pharmaceutically acceptable salt thereo~:
HO- ~ - Rl - O - ~ O - CHz o ,Yl ,Yz ~Y3 ~
H H
OH OH
.
W O 97/05195 PCT~US96/12377 wherein:
Xl, X2, and X3 are each independently selected from the group consisting of OH and SH;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene; and R2 is selected from the group consisting of H
and sr.
The method is accompanied or followed by the step of collecting a mucus sample from said at least one lung of said subject (e.g., by said subject expectorating a sputum sample).
Also disclosed is a method of faciltating the obtaining of a mucus sample from at least one lung of a subject, comprising administering to at least one lung of said subject, in an amount effective to hydrate lung mucous secretions, and/or stimulate mucus secretions therein, and/or stimulate ciliary beat fre~uency therein, a compound of Formula (I) as given above, or a pharmaceutically acceptable salt thereo~, and then collecting a mucus sample from said at least one lung of said subject. The mucus samples collected may then be analyzed for the presence or absence of lung disease (e.g., microbial infection, cancer, etc.) in said subject.
A second aspect of the present invention is pharmaceutical composition useful for facilitating the collecting of a mucus sample from at least one lung of a subject, said composition comprising, alone or in combination, a physiologically acceptable salt in an amount effective to hydrate lung mucus secretions; and a compound of Formula (I) as given above, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucus secretions. The composition may be a li~uid composition or a dry powder ~ composition.
W O 97/05195 PCT~US96/12377 Detailed Description o~ the Invention Compounds illustrative of the compounds of Formula (I) above ~also referred to as "active compounds"
herein) include: ra) uridine 5'-triphosphate (UTP); (b) uridine 5'-0-(3-thiotriphosphate) (UTPrS); and fc) 5-bromo-uridine 5'-triphosphate (5-BrUTP). One preferred compound of Formula (I) above is the UTP analog uridine 5'-0-(3-thiotriphosphate) (or "UTP~S"). These compounds are known or may be made in accordance with known procedures, or variations thereof which will be apparent to those skilled in the art. See generally U.S. Patent Number 5,292,498 to Boucher; N. Cusack and S. Hourani, Annals N. Y. Acad. Sci.
603, 172-181 (G. Dubyak and J. Fedan Eds. 1990). For example, UTP may be made in the manner described in Kenner et al., J. Chem. Soc. 1954, 2288; or Hall and Khorana, J.
Chem. Soc. 76, 5056 (1954). See Merck Index, Monograph No.
9795 (llth Ed. 1989). UTP~S may be made in the manner described in R.S. Goody and F. Eckstein, J. Am. Chem. Soc.
93, 6252 (1971).
For simplicity, Formula I herein illustrates uridine triphosphate active compounds in the naturally occurring D con~iguration, but the present invention also encompasses compounds in the L configuration, and mixtures of compounds in the D and L configurations, unless specified otherwise. The naturally occurring D
configuration is preferred.
The active compounds of Formula ( I) 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 salt, or an ammonium and tetraalkyl ammonium salt, NX4t (wherein X is a C14 alkyl group). Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
Amiloride (also known as 3,5,-diamino-6-chloro-N-(diaminomethylene)pyrazinecarboxamide), benzamil (also W O 97/OSl95 PCTrUS96/12377 knownas3,5-diamino-6-chloro-N-(benzylaminoaminomethylene) pyrazinecarboxamide) and ph--n~m;l (also known as 3,5-diamino-6-chloro-N-(phenylaminoaminomethylene) pyrazinecarboxamide) are known compounds and are disclosed in U.S. Patent No. 3,313,813 to E. Cragoe. The terms "amiloride,""benzamil," and l'phenamil," as used herein (also refered to as "active compounds" herein), include the pharmaceutically acceptable salts thereo~, such as (but not limited to) amiloride hydrochloride, benzamil hydrochloride or phenamil hydrochloride. Amiloride, benzamil or ph~n~m;l used to prepare compositions for the present invention may alternatively be in the form of a pharmaceutically acceptable free base of amiloride, benzamil or phen~m;l.
Because ~he ~ree base of the compound is less soluble than the salt, free base compositions are employed to provide more sustained release of benzamil or phenamil to the lungs.
Physiologically acceptable salts (also sometimes referred to as "active compounds" herein) used to carry out the method o~ the present invention are those that hydrate lung mucus secretions by facilitating the transport of water from lung endothelial cells into the mucu~. Physiologically acceptakle salts are salts that retain the desired biological activity of hydrating lung mucus secretions and do not impart undesired toxicological ef~ects. Physiologically acceptable salts are typically chloride salts, such as sodium chloride, potassium chloride, choline chloride, and N-methyl-D-glucamine chloride. Sodium chloride is currently preferred. These salts may be provided in the form of a dry respirable powder (discussed below) or as an aqueous solution.
The present invention is concerned primarily with the treatment of human subjects. Subjects may or may not be cystic fibrosis patients. The present invention may also be employed for the treatment of other m~mm~l ian subjects, such as dogs and cats, for veterinary purposes.
, The active compounds disclosed herein may be administered to the lung(s) of a subject by any suitable means. As used herein, the word "concurrently" means sufficiently close in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occuring within a short time period - before or after each other). By "at least one lung" is meant that administration of active compounds may be to one or both lungs of the subject, but where administration is to only one lung, then administration of the various active compounds is to the same lung.
Active compounds are preferably administered by administering an aerosol suspension of respirable particles comprised of the active compound or active compounds, which the subject inhales. 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. The respirable particles may be liquid or solid. The particles may optionally contain other therapeutic ingredients such as amiloride, benzamil or phenamil, with the selected compound included in an amount effective to inhibit the reabsorption of water from airway mucous secre~ions, as described in ~.S. Patent No.
4,501,729 (applicant specifically intends the disclosure of this and all other patent references cited herein be incorporated herein by reference).
The particulate pharmaceutical composition may optionally be combined with a carrier to aid in dispersion or transport. A suitable carrier such as a sugar (i.e., lactose, sucrose, trehalose, mannitol) may be blended with the active compound or compounds in any suitable ratio (e.g., a 1 to 1 ratio by weight).
Particles comprised of active compound for practicing the present invention should include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth or nose and larynx upon inhalation and into the bronchi and alveoli of CA 02226892 l998-0l-l4 the lungs. In general, particles ranging ~rom about 1 to 10 microns in size (more particularly, less than about 5 microns in size) are respirable. Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is preferably m; n; m; zed. For nasal administration, a particle size in the range of 10-500~m is preferred to ensure retention in the nasal cavity.
Liquid pharmaceutical compositions of active compound for producing an aerosol may be prepared by combining the active compound with a suitable vehicle, such as sterile pyrogen free water. The hypertonic saline solutions used to carry out the present invention are preferably sterile, pyrogen-free solutions, comprising from one to ~ifteen percent (by weight) o~ the physiologically acceptable salt, and more preferably from three to seven percent by weight of the physiologically acceptable salt.
Where compounds of Formula (I) or the pharmaceutically acceptable salts thereof are included in the hypertonic saline solution, they are typically included in a concentration ranging from about 10-4M to about 10-1M, and more preferab y in a con-entration ranging from about lG-2M
to about 10 -'M. Other therapeutic compounds such as amiloride, benzamil or phenamil may optionally be included (when such compounds are included, the saline solution is preferably not more than 0.3 percent by weight of the physiologically acceptable salt, and more preferably is 0.12 percent by weiyht of the physiologically acceptable salt).
Solid particulate compositions containing respirable dry particles of micronized active compound may be prepared by grinding dry active compound with a mortar and pestle, and then passing the micronized composition through a 400 mesh screen to break up or separate out large agglomerates. The active compound may be formulated alone (i.e., the solid particulate composition may consist essentially of the active compound) or in combination with a dispersant, diluent or carrier, such as sugars (i.e., lactose, sucrose, trehalose, mannitol) or other acceptable excipients for lung or airway delivery, which may be blended with the active compound in any suitable ratio (e.g., a 1 to 1 ratio by weight). The dry powder solid particulate composition may be obtained by methods known in the art, such as spray-drying, milling, freeze-drying, etc.
Again, other therapeutic compounds such as amiloride, benzamil or phenamil may also be included.
Aerosols of liquid particles comprising the active compound may be produced by any suitable means, such as with a pressure-driven jet nebulizer or an ultrasonic nebulizer. See, e.g., U.S. Patent No. 4,501,729.
Nebulizers are commercially available devices which trans~orm solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of compressed gas, typically air or oxygen, through a narrow venturi ori~ice or by means of ultrasonic agitation. Suitable formulations for use in nebulizers consist of the active ingredient in a liquid carrier, the active ingredient comprising up to 40~ w/w of the ~ormulation, but pre~erably less than 20~ w/w. The carrier is typically water (and most preferably sterile, pyrogen-~ree water) or a dilute aqueous alcoholic solution,preferably made isotonic, but may be hypertonic with body fluids by the addition of, for example, sodium chloride.
Optional additives include preservatives if the formulation is not made sterile, for example, methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants.
Aerosols of solid particles comprising the active compound may likewise be produced with any solid particulate medicament aerosol generator. Aerosol generators for administering solid particulate medicaments to a subject produce particles which are respirable, as explained above, and generate a volume of aerosol containing a predetermined metered dose of a medicament at a rate suitable for human administration. One illustrative r type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by 5 insufflation include finely comminuted powders which may be - delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder (e.g., a metered dose thereof effective to carry out the treatments described herein) is contained in 10 capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely 15 of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w/w of the formulation.
A second type of illustrative aerosol generator comprises 20 a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquified propellant. During use these devices discharge the ~ormulation through a valve adapted to deliver a metered volume, typically from 10 to 200 ~1, to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents, for example, ethanol, surfactants, such as oleic acid or sorbitan trioleate, antioxidants and suitable flavoring agents.
Any propellant may be used in carrying out the present invention, including both chlorofluorocarbon-containing propellants and non-chlorofluorocarbon-W O 97/05195 PCT~US96/12377 containing propellants. Thus, fluorocarbon aerosol propellants that may be employed in carrying out the present invention including fluorocarbon propellants in which all hydrogens are replaced with fluorine, chlorofluorocarbon propellants in which all hydrogens are replaced with chlorine and at least one fluorine, hydrogen-containing fluorocarbon propellants, and hydrogen-containing chlorofluorocarbon propellants. Examples of such propellants include, but are not limited to: CF3-CHF-CF2H; CF3-CH2-CF2H; CF3-CHF-CF3; CF3-CH2-CF3; CF3-CHCl-CF2Cl;
CF3-CHCl-CF3; cy-C(CF2)3-CHCl; CF3-CHCl-CH2Cl; CF3-CHF-CF2Cl;
CF3-CHCl-CFHCl; CF3-CFCl-CFHCl; CF3-CF2-CF2H; CF3-CF2-CH3;
CF2H-CF2-CFH2; CF3-CF2-CFH2; CF3-CF2-CH2Cl; CF2H-CF2-CH3; CF2H-CF2-CH2Cl; CF3-CF2-CF2-CH3; CF3-CF2-CF2-CF2H; CF3-CHF-CHF-CF3;
CF3-O-CF3; CF3-O-CF2H; CF2H-H-0-CF2H; CF2H-O-CFHa; CF3-O-CH3;
CF3-O-CF2-CF2H; CF3-0-CF2-O-CF3; cy-CF2-CF2-0-CF2-; cy-CHF-CF2-O-CF2-; cy-CH2-CF2-O-CF2-; cy-CF2-O-CF2-O-CF2-; CF3-O-CF2-Br;
CF2H-O-CF2-Br; and mixtures thereof, where 'Icy" denotes a cyclic compound in which the end terminal covalent bonds of the structures shown are the same so that the end terminal groups are covalently bonded together. Particularly preferred are hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (propellant i34a) and heptafluoropropane (propellant 227). A stabilizer such as a fluoropolymer may optionally be included in formulations of fluorocarbon propellants, such as described in U.S. Patent No. 5,376,359 to Johnson.
The aerosol, whether formed from solid or liquid particles, may be produced by the aerosol generator at a rate of from about 10 to 150 liters per minute, more preferably from about 30 to 150 liters per minute, and most preferably about 60 liters per minute. Aerosols containing greater amounts of medicament may be ~m; ni stered more rapidly. Typically, each aerosol may be delivered to the patient for a period from about 30 seconds to about 20 minutes, with a delivery period of about five to ten minutes being preferred.
-CA 02226892 l998-0l-l4 W O 97/05195 PCT~US96/12377 The dosage o~ the compound o~ Formula (I), or the pharmaceutically acceptable salt thereof, will vary depending on the condition being treated and the state of the subject, but generally may be an amount sufficient to achieve dissolved concentrations of active compound on the airway surfaces of the subject of from about 10-9 to about 10-2 Moles~liter or even 10~l Moles/liter, more pre~erably ~rom about 10-5 to about 10~1 Moles/liter, and most preferably from about 10-4 to about 10-3 to about 10~1 moles/liter. Depending upon the solubility of the particular formulation of active compound administered, the daily dose may be divided among one or several unit dose administrations.
When the sputum sample is subjected to cytological, bacterial or DNA analysis for detecting infectious microbial species therein, the sputum sample may first be digested with a liquefying agent, such as N-acetyl-L-cystein (NALC) and sodium hydroxide.
As noted above, the present invention is particularly useful for collecting mucus samples which are used for detecting Pneumocystis carinii pneumonia and Mycobacteria infections. The term "Mycobacteria" as used hel-ein has it~ conventional me~n; ng in the art referring to acid-fast, non-motile, rod shaped bacteria. See generally B. Davis et al., Microbiology, 724-742 (~d. Ed. 1980). All generally belong to the family Mycobacteriaceae. By way of example, the mycobacteria include, but are not limited to, Mycobacterium africanum, M. avium, M. bovis, M. bovis-BCG, M. chelonae, M. fortuitum, M. gordonae, M. intracellulae, M. kansasii, M. leprae, M. microti, M. paratuberculosis, M.
scrofulaceum, and M. tuberculosis. The present invention is useful in diagnosing both tuberculosis and non-tuberculosis Mycobacteria, and is useful in diagnosing M.
avium complex infections.
The present invention is explained in greater detail in the following non-limiting Examples.
EX~MPLE 1 DeliverY of UTP followed bY Hvpertonic Saline A subject is caused to inhale an aerosol of UTP
solution (10-2M UTP in 0.9~ (by weight) sterile pyrogen-free S saline solution) delivered by a Pari LC Plus nebulizer for 10 minutes. Immediately afterwards, the subject is caused to inhale an aerosol of hypertonic saline solution (3~
sterile pyrogen-free saline solution), delivered by a nebulizer ~or 10 minutes. During inhalation of the aerosols and after inhalation of the aerosols, the subject is encouraged to cough, and all sputum is collected during aerosol inhalation and over a 20 minute interval following cessation of aerosol inhalation. The sputum is captured in a plastic sputum container. The sputum so obtained is analyzed for content pending the clinical requirement, including analyses of cytologies for pulmonarY neoplasm, and the presence of infectious agents, for example, Pneumocystis carinii, by silver staining and immunofluorescence techniques. The technique is applicable for the diagnoses of other micro-organisms in the lower lung, including bacterial, viral, amd microplasma, using culture, immunocytochemical, and molecular (PCR, in situ hybridization) techniques.
E~iMPLE 2 Delivery of UTP with Amiloride This example is carried out in essentially the same manner as example 1 above, except that the UTP is dissolved in a 0.12~ sterile pyrogen-free NaCl solution, and the solution also contains 10-2M amiloride.
EX~MPLE 3 Delivery of Hypertonic Saline followed by UTP
This Example is carried out in essentially the same manner as Example 1 above, except that the hypertonic saline solution is delivered first, and the UTP solution is W O 97/05195 PCT~US96/lZ377 delivered immediately thereafter. Durations of delivery and concentrations remain the same.
E~MPLE 4 Concurrent Deliver~ of UTP in Hypertonic Saline This Example is carried out by modification of Example 1 above, with 10~l UTP being diluted in the hypertonic saline solutiion so that a single solution is delivered to the patient by inhalation of an aerosol generated by a nebulizer for a period of 15 minutes.
E~MPLE 5 Delivery of UTP followed b~ Sample Collection This procedure is carried out in essentially the same manner as Example l above, except that there is no separate administration of a hypertonic saline solution.
A subject is caused to inhale an aerosol of UTP
solution (10-2M UTP in 0.9~ (by weight) sterile pyrogen-free saline solution) delivered by a Pari LC Plus nebulizer for 10 minutes. During inhalation of the aerosol and after inhalation of the aerosol, the subject is encouraged to cough, and all sputum is collected during aerosol inhalation and over a 20 minute interval following cessation of aerosol inhalation. The sputum is captured in a plastic sputum container. The sputum so obtained is analyzed as described in Example 1. The technique is applicable for the diagnoses of other micro-organisms in the lower lung, including bacterial, viral, and mycoplasma, using culture, immunocytochemical, and molecular (PCR, in situ hybridization) techniques.
E~MPLE 6 Delivery of Solid Particulate UTP
This example is carried out in essentially the same manner as Example 5 above, except the subject is administered a respirable dry powder consisting essentially of solid particulate UTP or a pharmaceutically acceptable W O 97/05195 PCT~US96/12377 salt such as trisodium UTP prepared as described above, or as described in U.S. Patent No. 5,292,498 to Boucher. A
sputum sample is collected from the subject as described in Examples 1 and 5 above, and analyzed as described in S Examples 1 and 5 above.
The foregoing examples are illustrative of the present invention, and are not to be construed as limiting thereof. Among other things, volumes, times, and amounts can be varied from those specifically set forth above.
Accordingly, the invention is defined by the following claims, with equivalents of the claims to be included therein.
Claims (29)
1. A method of faciltating the obtaining of a mucus sample from at least one lung of a subject, comprising:
administering a physiologically acceptable salt to at least one lung of said subject in an amount effective to hydrate lung mucus secretions and/or stimulate cilia beat frequency therein, and concurrently administering to said at least one lung of said subject, in an amount effective to hydrate lung mucous secretions therein, a compound of Formula (I) below, or a pharmaceutically acceptable salt thereof:
wherein:
X1, X2, and X3 are each independently selected from the group consisting of OH and SH;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene; and R2 is selected from the group consisting of H
and Br.
administering a physiologically acceptable salt to at least one lung of said subject in an amount effective to hydrate lung mucus secretions and/or stimulate cilia beat frequency therein, and concurrently administering to said at least one lung of said subject, in an amount effective to hydrate lung mucous secretions therein, a compound of Formula (I) below, or a pharmaceutically acceptable salt thereof:
wherein:
X1, X2, and X3 are each independently selected from the group consisting of OH and SH;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene; and R2 is selected from the group consisting of H
and Br.
2. A method according to claim 1, wherein said physiologically acceptable salt is administered by administering an aqueous solution containing both said salt and said compound of Formula (I) or said pharmaceutically acceptable salt thereof.
3. A method according to claim 1, wherein said compound of Formula (I), or said pharmaceutically acceptable salt thereof, is administered in an amount sufficient to achieve concentrations thereof on the airway surfaces of said subject of from about 10-9 to about 10-1 Moles/liter.
4. A method according to claim 1, further comprising concurrently administering a compound selected from the group consisting of amiloride, benzamil and phenamil, and pharmaceutically acceptable salts thereof, to said subject in an amount effective to inhibit the reabsorption of water from lung mucous secretions.
5. A method according to claim 1, wherein X2 and X3 are OH.
6. A method according to claim 1, wherein R1 is oxygen.
7. A method according to claim 1, wherein R2 is H.
8. A method according to claim 1, wherein said compound is selected from the group consisting of uridine 5'-triphosphate, uridine 5'-O-(3-thiotriphosphate), and the pharmaceutically acceptable salts thereof.
9. A method according to claim 1, wherein said physiologically acceptable salt is selected from the group consisting of sodium chloride, potassium chloride, choline chloride, and N-methyl-D-glucamine chloride.
10. A method according to claim 1, wherein said physiologically acceptable salt is sodium chloride.
11. A method according to claim 1, further comprising the step of collecting a mucus sample from said at least one lung of said subject.
12. A method according to claim 1, wherein said physiologically acceptable salt and said compound of Formula (I) or said pharmaceutically acceptable salt thereof are delivered by administering an aerosol suspension of respirable particles comprised thereof to the said at least one lung of said subject.
13. A method of faciltating the obtaining of a mucus sample from at least one lung of a subject, comprising:
administering to said at least one lung of said subject, in an amount effective to hydrate lung mucous secretions and/or stimulate cilia beat frequency therein, a compound of Formula (I) below, or a pharmaceutically acceptable salt thereof:
wherein:
X1, X2, and X3 are each independently selected from the group consisting of OH and SH;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene; and R2 is selected from the group consisting of H
and Br; and then collecting a mucus sample from said at least one lung of said subject.
administering to said at least one lung of said subject, in an amount effective to hydrate lung mucous secretions and/or stimulate cilia beat frequency therein, a compound of Formula (I) below, or a pharmaceutically acceptable salt thereof:
wherein:
X1, X2, and X3 are each independently selected from the group consisting of OH and SH;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene; and R2 is selected from the group consisting of H
and Br; and then collecting a mucus sample from said at least one lung of said subject.
14. A method according to claim 13, further comprising the step of:
analyzing said mucus sample to detect the presence or absence of lung disease in said subject.
analyzing said mucus sample to detect the presence or absence of lung disease in said subject.
15. A method according to claim 13, wherein said physiologically acceptable salt is administered by administering an aqueous solution containining both said salt and said compound of Formula (I) or said pharmaceutically acceptable salt thereof.
16. A method according to claim 13, wherein said compound of Formula (I), or said pharmaceutically acceptable salt thereof, is administered in an amount sufficient to achieve concentrations thereof on the airway surfaces of said subject of from about 10-9 to about 10-3 Moles/liter.
17. A method according to claim 13, further comprising concurrently administering a compound selected from the group consisting of amiloride, benzamil and phenamil, and pharmaceutically acceptable salts thereof, to said subject in an amount effective to inhibit the reabsorption of water from lung mucous secretions.
18. A method according to claim 13, wherein X2 and X3 are OH.
19. A method according to claim 13, wherein R1 is oxygen.
20. A method according to claim 13, wherein R2 is H.
21. A method according to claim 13, wherein said compound is selected from the group consisting of uridine 5'-triphosphate, uridine 5'-O-(3-thiotriphosphate), and the pharmaceutically acceptable salts thereof.
22. A method according to claim 13, wherein said compound of Formula (I) or said pharmaceutically acceptable salt thereof is delivered by administering an aerosol suspension of respirable particles comprised thereof to the said at least one lung of said subject.
23. A pharmaceutical composition useful for facilitating the collecting of a mucus sample from at least one lung of a subject, said composition comprising, in combination, a physiologically acceptable salt in an amount effective to hydrate lung mucus secretions; and a compound of Formula (I) below, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucus secretions and/or stimulate cilia beat frequency:
wherein:
X1, X2, and X3 are each independently selected from the group consisting of OH and SH;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene; and R2 is selected from the group consisting of H
and Br.
wherein:
X1, X2, and X3 are each independently selected from the group consisting of OH and SH;
R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene; and R2 is selected from the group consisting of H
and Br.
24. A composition according to claim 23, wherein said composition is a dry powder comprised of respirable particles.
25. A composition according to claim 23, wherein said composition is a saline solution.
26. A composition according to claim 25, wherein said saline solution is a hypertonic saline solution.
27. A composition according to claim 23, said solution further containing a compound selected from the group consisting of amiloride, benzamil and phenamil, and pharmaceutically acceptable salts thereof, in an amount effective to inhibit the reabsorption of water from lung mucous secretions.
28. A composition according to claim 23, wherein said physiologically acceptable salt is selected from the group consisting of sodium chloride, potassium chloride, choline chloride, and N-methyl-D-glucamine chloride.
29. A method according to claim 23, wherein said physiologically acceptable salt is sodium chloride.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/509,052 US5628984A (en) | 1995-07-31 | 1995-07-31 | Method of detecting lung disease |
US08/509,052 | 1995-07-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2226892A1 true CA2226892A1 (en) | 1997-02-13 |
Family
ID=24025091
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002226892A Abandoned CA2226892A1 (en) | 1995-07-31 | 1996-07-24 | Method of detecting lung disease |
Country Status (17)
Country | Link |
---|---|
US (4) | US5628984A (en) |
EP (1) | EP0841900B1 (en) |
JP (2) | JP3623237B2 (en) |
KR (1) | KR100283306B1 (en) |
CN (1) | CN1121441C (en) |
AT (1) | ATE276740T1 (en) |
AU (1) | AU705528B2 (en) |
BR (1) | BR9610059A (en) |
CA (1) | CA2226892A1 (en) |
DE (1) | DE69633449T2 (en) |
ES (1) | ES2229281T3 (en) |
IL (1) | IL122803A0 (en) |
MX (1) | MX9800933A (en) |
NO (1) | NO980279D0 (en) |
NZ (1) | NZ313864A (en) |
WO (1) | WO1997005195A1 (en) |
ZA (1) | ZA966425B (en) |
Families Citing this family (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5948768A (en) * | 1995-04-13 | 1999-09-07 | Milkhaus Laboratory | Treatment of otitis media by sublingual administration of DNA |
AU716486B2 (en) * | 1995-04-13 | 2000-02-24 | Milkhaus Laboratory, Inc. | Methods for treating respiratory disease |
US6096721A (en) * | 1995-04-13 | 2000-08-01 | Milkhaus Laboratory, Inc. | Method for treating mucositis by sublingual administration of DNA |
US5635160A (en) | 1995-06-07 | 1997-06-03 | The University Of North Carolina At Chapel Hill | Dinucleotides useful for the treatment of cystic fibrosis and for hydrating mucus secretions |
US5628984A (en) * | 1995-07-31 | 1997-05-13 | University Of North Carolina At Chapel Hill | Method of detecting lung disease |
US6319908B1 (en) | 1996-07-03 | 2001-11-20 | Inspire Pharmaceuticals, Inc. | Method for large-scale production of di(uridine 5′-tetraphosphate) and salts thereof |
US5968913A (en) * | 1996-07-03 | 1999-10-19 | Inspire Pharmaceuticals, Inc. | Pharmaceutical compositions of uridine triphosphate |
US5763447C1 (en) | 1996-07-23 | 2002-05-07 | Inspire Pharmaceuticals | Method of preventing or treating pneumonia in immobilized patients with uridine triphosphates and related compounds |
US6159952A (en) * | 1996-11-07 | 2000-12-12 | Inspire Pharmaceuticals, Inc. | Method of treating bronchitis with uridine triphosphate and related compounds |
US6998121B2 (en) | 2003-01-23 | 2006-02-14 | Milkhaus Laboratory, Inc. | Method of treatment of connective tissue disorders by administration of streptolysin O |
DE69822482T2 (en) | 1997-07-25 | 2005-03-03 | Inspire Pharmaceuticals, Inc. | SALTS OF DI (URIDINE 5'-TETRAPHOSPHATE), METHOD OF PREPARING THEREOF AND USES THEREOF |
TW593331B (en) | 1997-07-25 | 2004-06-21 | Inspire Pharmaceuticals Inc | Method for large-scale production of di(uridine 5')-tetraphosphate and salts thereof |
US6872710B2 (en) * | 1997-07-25 | 2005-03-29 | Inspire Pharmaceuticals, Inc. | Di(uridine 5′)-tetraphosphate and salts thereof |
KR20010023359A (en) * | 1997-08-29 | 2001-03-26 | 인스파이어 파마슈티컬즈 | Use of uridine 5'-diphosphate and analogs thereof for the treatment of lung diseases |
US6926911B1 (en) * | 1998-12-22 | 2005-08-09 | The University Of North Carolina At Chapel Hill | Compounds and methods for the treatment of airway diseases and for the delivery of airway drugs |
AU771984B2 (en) * | 1998-12-22 | 2004-04-08 | University Of North Carolina At Chapel Hill, The | Compounds and methods for the treatment of airway diseases and for the delivery of airway drugs |
ATE281837T1 (en) * | 1999-02-26 | 2004-11-15 | Inspire Pharmaceuticals | USE OF DINUCLEOTIDE TRIPHOSPHATES, CYTIDINE DIPHOSPHATES AND ADENINE DIPHOSPHATES FOR THE PRODUCTION OF A PHARMACEUTICAL PREPARATION FOR PROMOTING MUCCUS UTHYDRATION |
WO2000075365A2 (en) * | 1999-06-08 | 2000-12-14 | University Of Iowa Research Foundation | Compounds and methods to enhance raav transduction |
US7241447B1 (en) * | 1999-10-07 | 2007-07-10 | University Of Iowa Research Foundation | Adeno-associated virus vectors and uses thereof |
US7115585B2 (en) | 2000-08-21 | 2006-10-03 | Inspire Pharmaceuticals, Inc. | Compositions for treating epithelial and retinal tissue diseases |
US7452870B2 (en) * | 2000-08-21 | 2008-11-18 | Inspire Pharmaceuticals, Inc. | Drug-eluting stents coated with P2Y12 receptor antagonist compound |
US7018985B1 (en) | 2000-08-21 | 2006-03-28 | Inspire Pharmaceuticals, Inc. | Composition and method for inhibiting platelet aggregation |
WO2003000056A1 (en) | 2001-06-25 | 2003-01-03 | Inspire Pharmaceuticals, Inc. | Joint lubrication with p2y purinergic receptor agonists |
JP3823162B2 (en) * | 2001-07-31 | 2006-09-20 | 株式会社エイアンドティー | Clinical laboratory analyzer, clinical laboratory analysis method, and clinical laboratory analysis program |
WO2003039473A2 (en) * | 2001-11-06 | 2003-05-15 | Inspire Pharmaceuticals, Inc. | Method for treating or preventing inflammatory diseases |
US20060196365A1 (en) * | 2001-12-11 | 2006-09-07 | Garman Michael H | Combined water cooler and hot beverage maker |
US6858615B2 (en) | 2002-02-19 | 2005-02-22 | Parion Sciences, Inc. | Phenyl guanidine sodium channel blockers |
US7435724B2 (en) | 2002-02-27 | 2008-10-14 | Inspire Pharmaceutical, Inc. | Degradation-resistant mononucleoside phosphate compounds |
AU2003243191B2 (en) | 2002-05-02 | 2007-09-20 | President And Fellows Of Harvard College | Formulations limiting spread of pulmonary infections |
US20050220720A1 (en) * | 2002-05-02 | 2005-10-06 | David Edwards | Formulations limiting spread of pulmonary infections |
US7629312B2 (en) | 2003-01-23 | 2009-12-08 | Milkhaus Laboratory, Inc. | Method of treatment of tendonitis by administration of streptolysin O |
EP1608763A2 (en) * | 2003-03-31 | 2005-12-28 | University Of Iowa Research Foundation | Compounds and methods to enhance raav transduction |
WO2004112687A2 (en) * | 2003-06-26 | 2004-12-29 | Biotron Limited | Antiviral acylguanidine compounds and methods |
US20090253714A1 (en) * | 2003-08-20 | 2009-10-08 | Johnson Michael R | Methods of reducing risk of infection from pathogens |
US7745442B2 (en) | 2003-08-20 | 2010-06-29 | Parion Sciences, Inc. | Methods of reducing risk of infection from pathogens |
CA2547972A1 (en) * | 2003-11-24 | 2005-06-09 | Georgia State University Research Foundation, Inc. | Fused ring dicationic anti-protozoan agents and their prodrugs |
US20050207983A1 (en) * | 2004-03-05 | 2005-09-22 | Pulmatrix, Inc. | Formulations decreasing particle exhalation |
WO2005086754A2 (en) * | 2004-03-08 | 2005-09-22 | Georgia State University Research Foundation, Inc. | Dicationic compounds for activity against trichomonas vaginalis |
US20070099968A1 (en) * | 2004-06-26 | 2007-05-03 | Biotron Limited | Antiviral compounds and methods |
GB0417886D0 (en) * | 2004-08-11 | 2004-09-15 | Univ Cardiff | Method and means for enhanced pulmonary delivery |
US20060199768A1 (en) * | 2005-03-07 | 2006-09-07 | University Of North Carolina At Chapel Hill | Inhibitors of RecA activities for control of antibiotic-resistant bacterial pathogens |
AU2006201739A1 (en) * | 2005-05-05 | 2006-11-23 | The University Of North Carolina At Chapel Hill | Synthesis and antiprotozoal activity of dicationic 3,5-diphenylisoxazoles |
EP2402001A1 (en) * | 2005-05-18 | 2012-01-04 | Pulmatrix, Inc. | Formulations for alteration of biophysical properties of mucosal lining |
US7964619B2 (en) | 2005-06-03 | 2011-06-21 | The University Of North Carolina At Chapel Hill | Teraryl components as antiparasitic agents |
US8101636B2 (en) | 2005-06-03 | 2012-01-24 | The University Of North Carolina At Chapel Hill | Linear dicationic terphenyls and their aza analogues as antiparasitic agents |
US20100249175A1 (en) * | 2005-12-02 | 2010-09-30 | Wilson W David | Dicationic compounds which selectively recognize G-quadruplex DNA |
US20090017062A1 (en) * | 2006-04-28 | 2009-01-15 | Iowa Research Foundation Iowa Centers For Enterpri | Methods and compounds to alter virus infection |
US20080260863A1 (en) * | 2007-04-20 | 2008-10-23 | Pre Holding, Inc. | Compositions for mucociliary clearance and methods for administering same |
JP2010531304A (en) | 2007-06-18 | 2010-09-24 | ユニバーシティ オブ ルイビル リサーチ ファウンデーション、インコーポレイテッド | PFKFB3 inhibitor family with antineoplastic activity |
WO2009045536A2 (en) * | 2007-10-05 | 2009-04-09 | The University Of North Carolina At Chapel Hill | Receptor targeted oligonucleotides |
US8551534B2 (en) | 2007-10-10 | 2013-10-08 | Parion Sciences, Inc. | Inhaled hypertonic saline delivered by a heated nasal cannula |
WO2009051796A2 (en) * | 2007-10-17 | 2009-04-23 | The University Of North Carolina At Chapel Hill | 2,5-diaryl selenophene compounds, aza 2,5-diaryl thiophene compounds, and their prodrugs as antiprotozoal agents |
CA2721082A1 (en) | 2008-04-09 | 2009-10-15 | The University Of North Carolina At Chapel Hill | Methods of regulating actin cytoskeletal rearrangement and intercellular gap formation |
JP2012504646A (en) * | 2008-10-01 | 2012-02-23 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル | Protection of the hematopoietic system against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors |
JP2012504645A (en) * | 2008-10-01 | 2012-02-23 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル | Pharmaceutical composition for reducing or preventing the influence of ionizing radiation on healthy cells |
JP5671001B2 (en) | 2009-03-26 | 2015-02-18 | パルマトリックス,インコーポレイテッド | Dry powder formulation and method for treating lung disease |
JP2012526850A (en) | 2009-05-13 | 2012-11-01 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル | Cyclin-dependent kinase inhibitors and uses thereof |
CA2768154C (en) | 2009-07-13 | 2018-02-13 | Irix Pharmaceuticals | Synthesis of prostanoids |
CA2768582C (en) | 2009-07-24 | 2017-02-14 | University Of Tennessee Research Foundation | Spectinamides as anti-tuberculosis agents |
EP2464278B1 (en) * | 2009-08-10 | 2015-09-16 | P2-Science Aps | Utp for the diagnosis of stenoses and other conditions of restricted blood flow |
WO2011161212A1 (en) * | 2010-06-23 | 2011-12-29 | P2-Science Aps | Combined flow directed intraarterial microcatheter for the infusion of hyperemic agent and concomitant pressure measurements for diagnostic purposes |
EP2611438B1 (en) | 2010-08-30 | 2020-04-01 | Pulmatrix Operating Company, Inc. | Dry powder formulations and methods for treating pulmonary diseases |
EP2448571B1 (en) | 2010-08-30 | 2013-06-12 | Pulmatrix, Inc. | Respirably dry powder comprising calcium lactate, sodium chloride and leucine |
MX354828B (en) | 2010-09-29 | 2018-03-22 | Pulmatrix Operating Co Inc | Monovalent metal cation dry powders for inhalation. |
DK3470057T3 (en) | 2010-09-29 | 2021-11-22 | Pulmatrix Operating Co Inc | CATIONIC DRY POWDER INCLUDING MAGNESIUM SALT |
WO2012068381A2 (en) | 2010-11-17 | 2012-05-24 | The University Of North Carolina At Chapel Hill | Protection of renal tissues from schema through inhibition of the proliferative kisses cdk4 and cdk6 |
CA2838529C (en) | 2011-06-07 | 2020-03-24 | Parion Sciences, Inc. | Methods of treatment |
US8945605B2 (en) * | 2011-06-07 | 2015-02-03 | Parion Sciences, Inc. | Aerosol delivery systems, compositions and methods |
AR086745A1 (en) | 2011-06-27 | 2014-01-22 | Parion Sciences Inc | 3,5-DIAMINO-6-CHLORINE-N- (N- (4- (4- (2- (HEXIL (2,3,4,5,6-PENTAHYDROXIHEXIL)) AMINO) ETOXI) PHENYL) BUTIL) CARBAMIMIDOIL) PIRAZINA -2-CARBOXAMIDE |
CN107596518B (en) | 2012-02-29 | 2021-04-23 | 普马特里克斯营业公司 | Inhalable dry powder |
US9833207B2 (en) | 2012-08-08 | 2017-12-05 | William Harrison Zurn | Analysis and clearing module, system and method |
RU2018138195A (en) | 2012-12-17 | 2018-12-18 | Пэрион Сайенсиз, Инк. | COMPOUNDS 3,5-DIAMINO-6-CHLORO-N- (N- (4-Phenylbutyl) Carbamimidoyl) Pyrazine-2-Carboxamide |
PE20151054A1 (en) | 2012-12-17 | 2015-08-07 | Parion Sciences Inc | CHLORINE-PIRAZINE CARBOXAMIDE DERIVATIVES WITH BLOCKING ACTIVITY ON THE EPITHELIAL SODIUM CHANNELS |
US9962533B2 (en) | 2013-02-14 | 2018-05-08 | William Harrison Zurn | Module for treatment of medical conditions; system for making module and methods of making module |
CN105407889B (en) | 2013-03-15 | 2018-06-01 | G1治疗公司 | For the regulated treatments of HSPC of Rb positive abnormal cell proliferations |
JP6435315B2 (en) | 2013-03-15 | 2018-12-05 | ジー1、セラピューティクス、インコーポレイテッドG1 Therapeutics, Inc. | Highly active antineoplastic and antiproliferative agents |
WO2014165303A1 (en) | 2013-04-01 | 2014-10-09 | Pulmatrix, Inc. | Tiotropium dry powders |
CN105592851A (en) | 2013-09-30 | 2016-05-18 | 帕西昂Api服务公司 | Novel synthesis routes for prostaglandins and prostaglandin intermediates using metathesis |
US9102633B2 (en) | 2013-12-13 | 2015-08-11 | Parion Sciences, Inc. | Arylalkyl- and aryloxyalkyl-substituted epithelial sodium channel blocking compounds |
WO2015161283A1 (en) | 2014-04-17 | 2015-10-22 | G1 Therapeutics, Inc. | Tricyclic lactams for use in hspc-sparing treatments for rb-positive abnormal cellular proliferation |
WO2016040858A1 (en) | 2014-09-12 | 2016-03-17 | G1 Therapeutics, Inc. | Combinations and dosing regimes to treat rb-positive tumors |
WO2016040848A1 (en) | 2014-09-12 | 2016-03-17 | G1 Therapeutics, Inc. | Treatment of rb-negative tumors using topoisomerase inhibitors in combination with cyclin dependent kinase 4/6 inhibitors |
CN104306028B (en) * | 2014-09-26 | 2016-08-17 | 张清玲 | A kind of sputum collecting method for the detection of respiratory tract bacterial 16 S rRNA gene order |
WO2017035405A1 (en) | 2015-08-26 | 2017-03-02 | Achillion Pharmaceuticals, Inc. | Amino compounds for treatment of immune and inflammatory disorders |
WO2017035401A1 (en) | 2015-08-26 | 2017-03-02 | Achillion Pharmaceuticals, Inc. | Amide compounds for treatment of immune and inflammatory disorders |
WO2017139381A1 (en) | 2016-02-08 | 2017-08-17 | University Of Iowa Research Foundation | Methods to produce chimeric adeno-associated virus/bocavirus parvovirus |
MX2018010842A (en) | 2016-03-07 | 2019-07-04 | Univ Iowa Res Found | Aav-mediated expression using a synthetic promoter and enhancer. |
CN109789143A (en) | 2016-07-01 | 2019-05-21 | G1治疗公司 | Antiproliferative based on pyrimidine |
US10413583B2 (en) | 2016-11-30 | 2019-09-17 | The University Of Chicago | Synthetic substrates for enzymes that catalyze reactions of modified cysteines and related methods |
EP3589628A4 (en) | 2017-03-01 | 2021-03-31 | Achillion Pharmaceuticals, Inc. | Aryl, heteroary, and heterocyclic pharmaceutical compounds for treatment of medical disorders |
WO2018160891A1 (en) | 2017-03-01 | 2018-09-07 | Achillion Pharmaceutical, Inc. | Pharmaceutical compounds for treatment of medical disorders |
GB2604314A (en) * | 2017-09-22 | 2022-09-07 | Nerudia Ltd | Device, system and method |
US11439608B2 (en) | 2017-09-25 | 2022-09-13 | Qun Lu | Roles of modulators of intersectin-CDC42 signaling in Alzheimer's disease |
US11541120B2 (en) | 2017-12-05 | 2023-01-03 | Anthos Partners, Lp | Phosphonium-based ionic drug conjugates |
EP3846803A4 (en) | 2018-09-06 | 2022-08-10 | Achillion Pharmaceuticals, Inc. | Macrocyclic compounds for the treatment of medical disorders |
BR112021004263A2 (en) | 2018-09-06 | 2021-05-25 | Achillion Pharmaceuticals, Inc. | morphic forms of danicopane |
MX2021003425A (en) | 2018-09-25 | 2021-07-16 | Achillion Pharmaceuticals Inc | Morphic forms of complement factor d inhibitors. |
US10988479B1 (en) | 2020-06-15 | 2021-04-27 | G1 Therapeutics, Inc. | Morphic forms of trilaciclib and methods of manufacture thereof |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1055465A (en) * | 1962-09-27 | 1967-01-18 | Vantorex Ltd | Allergenic aerosol compositions |
BE639386A (en) * | 1962-10-30 | |||
US4132600A (en) * | 1977-06-01 | 1979-01-02 | Massachusetts Institute Of Technology | Enzymatic noninvasive method for detecting cancer |
US4501729A (en) * | 1982-12-13 | 1985-02-26 | Research Corporation | Aerosolized amiloride treatment of retained pulmonary secretions |
FR2571257A1 (en) * | 1984-08-06 | 1986-04-11 | Gros Pierre | Composition for humidifying the rhinopharyngeal mucosa |
US5470838A (en) * | 1987-10-28 | 1995-11-28 | Pro-Neuron, Inc. | Method of delivering exogenous uridine or cytidine using acylated uridine or cytidine |
US4950477A (en) * | 1988-08-23 | 1990-08-21 | Memorial Hospital For Cancer And Allied Dieseas | Method of preventing and treating pulmonary infection by fungi using aerosolized polyenes |
GB9027968D0 (en) * | 1990-12-22 | 1991-02-13 | Fisons Plc | Method of treatment |
EP0517573A1 (en) * | 1991-06-05 | 1992-12-09 | Synthelabo | Pharmaceutical compositions for the treatment of airway disorders |
US5292498A (en) * | 1991-06-19 | 1994-03-08 | The University Of North Carolina At Chapel Hill | Method of treating lung disease with uridine triphosphates |
US5567689A (en) * | 1993-08-13 | 1996-10-22 | The Uab Research Foundation | Methods for increasing uridine levels with L-nucleosides |
US5656256A (en) * | 1994-12-14 | 1997-08-12 | The University Of North Carolina At Chapel Hill | Methods of treating lung disease by an aerosol containing benzamil or phenamil |
US5628984A (en) * | 1995-07-31 | 1997-05-13 | University Of North Carolina At Chapel Hill | Method of detecting lung disease |
-
1995
- 1995-07-31 US US08/509,052 patent/US5628984A/en not_active Expired - Lifetime
-
1996
- 1996-07-24 IL IL12280396A patent/IL122803A0/en unknown
- 1996-07-24 NZ NZ313864A patent/NZ313864A/en unknown
- 1996-07-24 DE DE69633449T patent/DE69633449T2/en not_active Expired - Fee Related
- 1996-07-24 BR BR9610059A patent/BR9610059A/en not_active Application Discontinuation
- 1996-07-24 AT AT96926158T patent/ATE276740T1/en not_active IP Right Cessation
- 1996-07-24 KR KR1019980700675A patent/KR100283306B1/en not_active IP Right Cessation
- 1996-07-24 CA CA002226892A patent/CA2226892A1/en not_active Abandoned
- 1996-07-24 EP EP96926158A patent/EP0841900B1/en not_active Expired - Lifetime
- 1996-07-24 AU AU66399/96A patent/AU705528B2/en not_active Ceased
- 1996-07-24 MX MX9800933A patent/MX9800933A/en not_active IP Right Cessation
- 1996-07-24 CN CN96195803A patent/CN1121441C/en not_active Expired - Fee Related
- 1996-07-24 US US08/776,772 patent/US6133247A/en not_active Expired - Lifetime
- 1996-07-24 ES ES96926158T patent/ES2229281T3/en not_active Expired - Lifetime
- 1996-07-24 WO PCT/US1996/012377 patent/WO1997005195A1/en active IP Right Grant
- 1996-07-24 JP JP50781797A patent/JP3623237B2/en not_active Expired - Fee Related
- 1996-07-29 ZA ZA9606425A patent/ZA966425B/en unknown
- 1996-12-30 US US08/777,026 patent/US5902567A/en not_active Expired - Lifetime
-
1998
- 1998-01-21 NO NO980279A patent/NO980279D0/en not_active Application Discontinuation
-
1999
- 1999-11-04 US US09/433,757 patent/US6214536B1/en not_active Expired - Lifetime
-
2002
- 2002-08-05 JP JP2002227140A patent/JP2003073280A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
EP0841900B1 (en) | 2004-09-22 |
EP0841900A4 (en) | 1998-06-10 |
JPH11509759A (en) | 1999-08-31 |
NO980279L (en) | 1998-01-21 |
WO1997005195A1 (en) | 1997-02-13 |
US5628984A (en) | 1997-05-13 |
JP2003073280A (en) | 2003-03-12 |
BR9610059A (en) | 1999-03-02 |
KR19990036011A (en) | 1999-05-25 |
ES2229281T3 (en) | 2005-04-16 |
ZA966425B (en) | 1997-02-19 |
DE69633449T2 (en) | 2006-04-27 |
JP3623237B2 (en) | 2005-02-23 |
AU6639996A (en) | 1997-02-26 |
US6214536B1 (en) | 2001-04-10 |
US5902567A (en) | 1999-05-11 |
NZ313864A (en) | 2000-04-28 |
US6133247A (en) | 2000-10-17 |
IL122803A0 (en) | 1998-09-16 |
EP0841900A1 (en) | 1998-05-20 |
CN1191553A (en) | 1998-08-26 |
AU705528B2 (en) | 1999-05-27 |
DE69633449D1 (en) | 2004-10-28 |
CN1121441C (en) | 2003-09-17 |
ATE276740T1 (en) | 2004-10-15 |
KR100283306B1 (en) | 2001-03-02 |
NO980279D0 (en) | 1998-01-21 |
MX9800933A (en) | 1998-05-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0841900B1 (en) | Pharmaceutical composition for detecting lung disease | |
US5849706A (en) | Method of treating retained asthma pulmonary secretions | |
EP0941099B1 (en) | Treatment of bronchitis with diuridine tetraphosphate | |
TW200817343A (en) | Method of enhancing mucosal hydration and mucosal clearance by treatment with sodium channel blockers and osmolytes | |
US7851456B2 (en) | P2Y6 receptor agonists for treating lung diseases | |
JP2002532430A (en) | Treatment of severe chronic bronchitis (bronchiectasis) using aerosolized antibiotics | |
CN1143672C (en) | Novel pharmaceutical compositions of uridine triphosphate | |
WO1999001138A1 (en) | A pharmaceutical formulation of uridine triphosphate suitable for administration in a small volume | |
WO2022047292A1 (en) | Methods for treating newly diagnosed mycobacterium avium complex lung infections |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |