Abstract: A nonhuman transgenic mammal is described whose genome comprises a promoter construct operably linked to a heterologous DNA encoding an epithelial sodium channel &bgr; subunit, wherein said promoter construct directs expression of the epithelial sodium channel &bgr; subunit in lung epithelial cells of said animal, and wherein said transgenic mammal has increased lung mucus retention as compared to the corresponding wild-type mammal. The animal is useful in screening compounds for activity in treating lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease.

Abstract: The present invention is directed to a method of stimulating ciliary beat frequency to promote mucociliary or cough clearance of retained mucus secretions from the lungs, sinuses, upper airways, ears, eyes, genito-urinary tract, spermatozoa, ovaries, fallopian tubes, neutrophils, and macrophages of a patient. The method comprises administering uridine triphosphates, adenosine triphosphates, cytidine triphosphates, or dinucleoside tetraphosphates and the derivatives thereof to an affected body of a patient, to treat dysfunction of the mucociliary clearance system as a result of impaired ciliary movement in the patient.

Abstract: Compounds of the general formula P1-L-P2; wherein “P1” is a pyrazinoylguanidine sodium channel blocker, “L” is a linking group, and “P2” is either (i) a pyrazinoylguanidine sodium channel blocker or (ii) a P2Y2 receptor agonist, are disclosed. Pharmaceutical formulations containing the same and methods of use thereof to hydrate mucosal surfaces such as airway mucosal surfaces are also disclosed.

Abstract: Compounds of the general formula P1-L-P2; wherein “P1” is a pyrazinoylguanidine sodium channel blocker, “L” is a linking group, and “P2” is either (i) a pyrazinoylguanidine sodium channel blocker or (ii) a P2Y2 receptor agonist, are disclosed. Pharmaceutical formulations containing the same and methods of use thereof to hydrate mucosal surfaces such as airway mucosal surfaces are also disclosed.

Abstract: The present invention is directed to a method of stimulating ciliary beat frequency to promote mucociliary or cough clearance of retained mucus secretions from the lungs, sinuses, upper airways, ears, eyes, genito-urinary tract, spermatozoa, ovaries, fallopian tubes, neutrophils, and macrophages of a patient. The method comprises administering uridine triphosphates, adenosine triphosphates, cytidine triphosphates, or dinucleoside tetraphosphates and the derivatives thereof to an affected body of a patient, to treat dysfunction of the mucociliary clearance system as a result of impaired ciliary movement in the patient.

Abstract: A method of delivering heterologous nucleic acid (e.g., a gene sequence) into a cell comprises attaching a virus containing a heterologous gene sequence to a G protein coupled receptor (i.e., a seven transmembrane receptor such as the P2Y2 receptor). The virus may be attached to the receptor by means of a bridging antibody, or by binding an antibody specific for the receptor with an antibody specific for the virus, wherein the antibody that specifically binds with the receptor and the antibody that specifically binds to the virus are cross-linked. Alternatively, the virus may express a peptide that specifically binds to the receptor. The receptor may be induced to internalize by means of the addition of a ligand known to trigger internalization of the receptor into the cell.

Abstract: Compounds of the general formula P1-L-P2; wherein “P1” is a pyrazinoylguanidine sodium channel blocker, “L” is a linking group, and “P2” is either (i) a pyrazinoylguanidine sodium channel blocker or (ii) a P2Y2 receptor agonist, are disclosed. Pharmaceutical formulations containing the same and methods of use thereof to hydrate mucosal surfaces such as airway mucosal surfaces are also disclosed.

Abstract: Compounds of the general formula P1-L-P2; wherein “P1” is a pyrazinoylguanidine sodium channel blocker, “L” is a linking group, and “P2” is either (i) a pyrazinoylguanidine sodium channel blocker or (ii) a P2Y2 receptor agonist, are disclosed. Pharmaceutical formulations containing the same and methods of use thereof to hydrate mucosal surfaces such as airway mucosal surfaces are also disclosed.

Abstract: Compounds of the general formula P1-L-P2; wherein “P1” is a pyrazinoylguanidine sodium channel blocker, “L” is a linking group, and “P2” is either (i) a pyrazinoylguanidine sodium channel blocker or (ii) a P2Y2 receptor agonist, are disclosed. Pharmaceutical formulations containing the same and methods of use thereof to hydrate mucosal surfaces such as airway mucosal surfaces are also disclosed.

Abstract: Compounds of Formula I: wherein: X1, and X2 are each independently either O− or S−; X3 and X4 are each independently either —H or —OH, with the proviso that X3 and X4 are not simultaneously —H; R1 is selected from the group consisting of O, imido, methylene and dihalomethylene; R2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxyl, nitro and azido; R3 is selected from the group consisting of H, alkyl, acyl, aryl, and arylalkyl; and R4 is selected from the group consisting of —OR′, —SR′, —NR′, and —NR′R″, wherein R′ and R″ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, with the proviso that R′ is absent when R4 is double bonded from an oxygen or sulfur atom to the carbon at the 4-position of the pyrimidine ring, are used in methods of hydrating lung mucus secr

Abstract: Chronic obstructive airway diseases are treated by administering an osmotically active compound such as a salt, sugar, sugar alcohol, or organic osmolyte to the afflicted airway surface. The compound may be administered as a liquid or dry powder aerosol formulation. Diseases that can be treated by the method include cystic fibrosis, chronic bronchitis, and ciliary dyskinesia. The formulations of the invention can also be used in conjunction with other active agents such as bronchodilators, sodium channel blockers, antibiotics, enzymes, or purinoceptor agonists on airway surfaces.

Abstract: A method of stimulating ciliary beat frequency in a subject in need of such treatment is disclosed. The method comprises administering to the airways, ears, eyes, or genito-urinary tract of the subject a triphosphate nucleotide such as uridine 5′-triphosphate (UTP), an analog of UTP, or any other analog, in an amount effective to stimulate ciliary beat frequency. This method is useful for treating patients afflicted with ciliary dyskinesia, Kartagener's syndrome, or any other disease involving dysfunction of ciliary movement, such as male infertility caused by impairment of propulsion of the spermatozoa or immune deficiency caused by impairment of ciliary movement in neutrophils or macrophages. Pharmaceutical formulations and methods of making the same are also disclosed.

Abstract: The present invention relates to P1-(cytidine 5′-)-P-(uridine 5′-)tetraphosphates and its salts, esters and amides, and formulations thereof which are highly stable and selective agonists of the P2Y2 and/or P2Y4 purinergic receptor. The compounds of the invention are useful in the treatment of chronic obstructive pulmonary diseases such as chronic bronchitis, primary ciliary dyskinesia, cystic fibrosis, as well as prevention of pneumonia due to immobility, and the induction of sputum and its expectoration. Furthermore, because of their general ability to clear retained mucus secretions and stimulate ciliary beat frequency, the compounds of the present invention are also useful in the treatment of sinusitis and otitis media.

Abstract: A pharmaceutical formulation comprises, in an amount effective to hydrate lung mucous secretions, a compound of Formula (I): 1

Abstract: A method of hydrating nasal airway surfaces in a subject in need of such treatment comprises topically applying a sodium channel blocker to a nasal airway surface of the subject in an amount effective to inhibit the reabsorption of water by the surface. The channel blocker may be a pyrazinoylguanidine sodium channel blocker, such as benzamil, phenamil, amiloride, or a pharmaceutically acceptable salts thereof. The method may further comprise the step of topically applying a P2Y2 receptor agonist to a nasal airway surface of the subject in an amount effective to stimulate chloride secretion by the nasal airway surface. In a preferred embodiment, the sodium channel blocker is a covalent conjugate of a pyrazinoylguanidine sodium channel blocker and a non-absorbable carrier moiety (e.g., albumin, polyethylene glycol). Such compounds may also be administered to other mucosal surfaces where it is desired to inhibit the reabsorption of water.

Abstract: A method of hydrating nasal airway surfaces in a subject in need of such treatment comprises topically applying a sodium channel blocker to a nasal airway surface of the subject in an amount effective to inhibit the reabsorption of water by the surface. The channel blocker may be a pyrazinoylguanidine sodium channel blocker, such as benzamil, phenamil, amiloride, or a pharmaceutically acceptable salts thereof. The method may further comprise the step of topically applying a P2Y2 receptor agonist to a nasal airway surface of the subject in an amount effective to stimulate chloride secretion by the nasal airway surface. In a preferred embodiment, the sodium channel blocker is a covalent conjugate of a pyrazinoylguanidine sodium channel blocker and a non-absorbable carrier moiety (e.g., albumin, polyethylene glycol). Such compounds may also be administered to other mucosal surfaces where it is desired to inhibit the reabsorption of water.

Abstract: A pharmaceutical formulation comprises, in an amount effective to hydrate lung mucous secretions, a compound of Formula (I): wherein n is from 1 to 6; X is —OH or —SH; A and B are each independently selected from the group consisting of: wherein R is H or Br; or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. A method of hydrating mucous secretions in the lungs of a subject in need of such treatment, comprising administering to the lungs of the subject a compound of Formula I as given above, is also disclosed.

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 mucous 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.

Abstract: A method of promoting clearance of retained mucous secretions in the bronchi, bronchioles and small terminal airways of a subject in need of such treatment is disclosed. The method comprises administering to the bronchi of the subject a uridine phosphate such as uridine 5'-triphosphate (UTP), or P.sup.1,P.sup.4 -di(uridine-5') tetraphosphate (U.sub.2 P.sub.4), an analog of UTP, or any other analog, in an amount effective to promote mucociliary clearance and/or cough clearance of retained fluid in the bronchi, bronchioles and small terminal airways. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: aerosol inhalation, any liquid suspension (including nasal drops or spray), oral form (liquid or pill), injected, intra-operative instillation or suppository form.

Abstract: Compounds of Formula I: ##STR1## wherein: X.sub.1, and X.sub.2 are each independently either O.sup.- or S.sup.- ;X.sub.3 and X.sub.4 are each independently either --H or --OH, with the proviso that X.sub.3 and X.sub.4 are not simultaneously --H;R.sub.1 is selected from the group consisting of O, imido, methylene and dihalomethylene;R.sub.2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxyl, nitro and azido;R.sub.3 is selected from the group consisting of H, alkyl, acyl, aryl, and arylalkyl; andR.sub.4 is selected from the group consisting of --OR', --SR', --NR', and --NR'R", wherein R' and R" are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, with the proviso that R' is absent when R.sub.