Inspire Pharmaceuticals, Inc.

Burroughs Wellcome Co.

Other

Glaxo Wellcome Inc.

The University of North Carolina at Chapel Hill

Janet L Rideout

William Pendergast

Benjamin R Yerxa

Karla M Jacobus

David Walter Barry

Martha H St Clair

Sandra N Lehrman

Phillip A Furman

David J Drutz

Sammy Ray Shaver

Thomas A Krenitsky

Richard C Boucher

Suhaib M Siddiqi

Ward M Peterson

Phillip Allen Furman, Jr

Ben Yerxa

George Walter Koszalka

Robert P Dougherty

George A Freeman

Dallas Croom

Christy L Shaffer

James G Douglass, Iii

Merrick R Almond

Monroe Jackson Stutts

Gertrude B Elion

Charlene L Burns

Arthur C Jones

Michael K James

Jeffrey D Wilson

Eduardo R Lazarowski

Matthew S Cowlen

Cara Geary

Steven A Short

Jon L Collins

Zhen Zhang

Sandra N Lehrmaan

Richard C Evans

Karol K LaCroix

Karol La Croix

Edwardo R Lazarowski

Cary Geary

M Jackson Stutts

Maryse Picher

A method and preparation for the stimulation of tear secretion in a subject in need of such treatment is disclosed. The method comprises administering to the ocular surfaces of the subject a purinergic receptor agonist such as uridine 5'-triphosphate (UTP), dinucleotides, cytidine 5&#x2032;-triphosphate (CTP), adenosine 5&#x2032;-triphosphate (ATP), or their therapeutically useful analogs and derivatives, in an amount effective to stimulate tear fluid secretion and enhance drainage of the lacrimal system. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: topical administration via a liquid, gel, cream, or as part of a contact lens or selective release membrane; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, intra-operative instillation or suppository form.

Method of increasing tear production with purinergic receptor agonists

The present invention provides a method of treating edematous retinal disorders. The method comprises administration of a pharmaceutical formulation comprising a hydrolysis-resistant P2Y receptor agonist to stimulate the removal of pathological extraneous fluid from the subretinal and retinal spaces and thereby reduce the accumulation of said fluid associated with retinal detachment and retinal edema. The P2Y receptor agonist can be administered with therapeutic and adjuvant agents commonly used to treat edematous retinal disorders. The present invention also provides a method of treating cystic fibrosis. The present invention also provides a method of treating sinusitis. The present invention further provides P-(2'-deoxycytidine 5&#x2032;-)P-(uridine 5&#x2032;-)tetraphosphate, tetra-(alkali metal) salts such as tetrasodium, tetralithium, tetrapotassium, and mixed (tetra-alkali metal) salts. The present further provides a pharmaceutical formulation comprising a P-(2&#x2032;-deoxycytidine 5&#x2032;-)P-(uridine 5&#x2032;-)tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier.

P1-(2'-deoxycytidine 5&#x2032;-)P4-(uridine 5&#x2032;-)tetraphosphate, tetra-(alkali metal) salt, for treating sinusitis

Method of treating dry eye disease with purinergic receptor agonists

The present invention provides a method of treating edematous retinal disorders. The method comprises administration of a pharmaceutical formulation comprising a hydrolysis-resistant P2Y receptor agonist to stimulate the removal of pathological extraneous fluid from the subretinal and retinal spaces and thereby reduce the accumulation of said fluid associated with retinal detachment and retinal edema. The P2Y receptor agonist can be administered with therapeutic and adjuvant agents commonly used to treat edematous retinal disorders. The present invention also provides a method of treating cystic fibrosis. The present invention further provides P-(2'-deoxycytidine 5&#x2032;-)P-(uridine 5&#x2032;-) tetraphosphate, tetra-(alkali metal) salts such as tetrasodium, tetralithium, tetrapotassium, and mixed (tetra-alkali metal) salts. The present further provides a pharmaceutical formulation comprising a P-(2&#x2032;-deoxycytidine 5&#x2032;-)P-(uridine 5&#x2032;-) tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier.

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The present invention provides a method of stimulating cervical and vaginal secretions in a mammal by treatment with P2Yand/or P2Ypurinergic receptor agonists. Treatment of vaginal dryness associated with menopause, chemotherapy, and various disease states as well as the treatment of vulvar pain is discussed. Suitable agonists such as UTP, CTP, ATP, dinucleotides and analogs thereof are disclosed.

Method of promoting cervical and vaginal secretions

A method and preparation for enhancing drainage of lacrimal system in a subject in need of such treatment is disclosed. The method comprises administering to the ocular surfaces of the subject a purinergic receptor agonist such as uridine 5'-triphosphate (UTP), dinucleotides, cytidine 5&#x2032;-triphosphate (CTP), adenosine 5&#x2032;-triphosphate (ATP), or their therapeutically useful analogs and derivatives, in an amount effective to stimulate tear fluid secretion and enhance drainage of the lacrimal system. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: topical administration via a liquid, gel, cream, or as part of a contact lens or selective release membrane; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, intra-operative instillation or suppository form.

Method of enhancing drainage of lacrimal system with purinergic receptor agonists

The present invention provides a method of treating edematous retinal disorders. The method comprises administration of a pharmaceutical formulation comprising a hydrolysis-resistant P2Y receptor agonist to stimulate the removal of pathological extraneous fluid from the subretinal and retinal spaces and thereby reduce the accumulation of said fluid associated with retinal detachment and retinal edema. The P2Y receptor agonist can be administered with therapeutic and adjuvant agents commonly used to treat edematous retinal disorders. The pharmaceutical formulation useful in this invention comprises a P2Y receptor agonist with enhanced resistance to extracellular hydrolysis, such as dinucleoside polyphosphate compounds, or hydrolysis-resistant mononucleoside triphosphate salts. The present invention also provides P-(2'-deoxycytidine 5&#x2032;-)P-(uridine 5&#x2032;-)tetraphosphate, tetra-(alkali metal) salts such as tetrasodium, tetralithium, tetrapotassium, and mixed (tetra-alkali metal) salts. The present further provides a pharmaceutical formulation comprising a P-(2&#x2032;-deoxycytidine 5&#x2032;-)P-(uridine 5&#x2032;-)tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier.

Pharmaceutical formulation comprising dinucleoside polyphosphates and salts thereof

The present invention relates to certain novel dinucleotides and formulations thereof which are highly selective agonists of the P2Yand/or P2Ypurinergic receptor. They are useful in the treatment of chronic obstructive pulmonary diseases such as chronic bronchitis, PCD, cystic fibrosis, as well as prevention of pneumonia due to immobility. 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, otitis media and nasolacrimal duct obstruction. They are also useful for treatment of dry eye disease and retinal detachment as well as facilitating sputum induction and expectoration.

Certain dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency

A method and preparation for the stimulation of tear secretion in a subject in need of such treatment is disclosed. The method comprises administering to the ocular surfaces of the subject a purinergic receptor agonist such as uridine 5'-triphosphate [UTP], dinucleotides, cytidine 5&#x2032;-triphosphate [CTP], adenosine 5&#x2032;-triphosphate [ATP], or their therapeutically useful analogs and derivatives, in an amount effective to stimulate tear fluid secretion and enhance drainage of the lacrimal system. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: topical administration via a liquid, gel, cream, or as part of a contact lens or selective release membrane; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, intra-operative instillation or suppository form.

The present invention relates to certain novel dinucleoside polyphosphates of general Formulae I, II and III, and formulations thereof which are selective ligands of the P2Y purinergic receptors. Applicants have discovered that dinucleoside polyphosphates of general Formulae I, II and III are effective in clearing retained mucous secretions, balancing tissue hydration and fluid secretion, and/or inhibiting or preventing early stages of platelet activation, platelet degranulation, and platelet aggregation.

Dinucleoside polyphosphate compositions and their therapeutic use

This invention is directed to a method of stimulating tear secretion and mucin production in eyes. The method comprises the step of administering to the eyes of a subject a composition comprising a compound of Formula I, II, III, or IV and its pharmaceutically acceptable salts, in an amount effective to stimulate tear fluid secretion. The method of the present invention may be used to increase tear production for any reason, including, but not limited to, treatment of dry eye disease and corneal injury. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: topical administration via a liquid, gel, cream, or as part of a contact lens or selective release membrane; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, intra-operative instillation or suppository form.

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.

Method of treating ciliary dyskinesia with dinucleoside polyphosphate compounds or UTP analogues

The invention provides a method of regulating water and mucin secretions and fluid transport in the gastrointestinal tract. The invention also provides a method for treating a gastrointestinal disease in which the mucosal barrier of the gastrointestinal system is impaired. The invention additionally provides a method for correcting disorders of fluid secretion or absorption in the gastrointestinal system. The method comprises administering to a patient a pharmaceutical composition comprising a purinergic P2Y receptor agonist, in an amount effective to regulate water and mucin secretions or to correct abnormal fluid transport in the gastrointestinal tract. The pharmaceutical composition used in this invention comprises a P2Y purinergic receptor agonist such as uridine 5&prime;-diphosphate (UDP), uridine 5&prime;-triphosphate (UTP), cytidine 5&prime;-diphosphate (CDP), cytidine 5&prime;-triphosphate (CTP), adenosine 5&prime;-diphosphate (ADP), adenosine 5&prime;-triphosphate (ATP), and their analogs; and dinucleotide polyphosphate compounds of general Formula (IV). Said compound is prepared in an oral form, an injectable form, or a suppository form, and administered to a patient.

Method of treating gastrointestinal tract disease with purinergic receptor agonists

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Fuquay-Varina, NC, United States of America

Janet L Rideout