Abstract: The present invention relates to compositions and methods of treatment for cardioprotection through the use of non-peptidic delta opioid receptor agonist compound(s) that mediate cardioprotective effects of ischemic preconditioning. The compounds are used to reduce injury associated with ischemia and reperfusion of cardiac tissue. Further, the compounds may be used in solutions preserving the viability of an isolated organ.

Abstract: The present invention provides new methods for the synthesis of the therapeutic dinucleotide, P1,P4-di(uridine 5′-tetraphosphate), and demonstrates applicability to the production of large quantities. The methods of the present invention substantially reduce the time period required to synthesize diuridine tetraphosphate, preferably to three days or less. The novel tetrammonium and tetrasodium salts of P1,P4-di(uridine 5′-tetraphosphate) (Formula I) prepared by these methods are stable, soluble, nontoxic, and easy to handle during manufacture. wherein: X is Na, NH4 or H, provided that all X groups are not H.

Abstract: Compounds of formula (I) or salts thereof, wherein the dotted Line represents a single or double bond, R1 is alkyl or amino optionally substituted by alkyl, alkanoyl or benzyl group; R2, R3, R4 and R5 are the same or different and each is selected from hydrogen, phenyl, halo, nitro, a group S(O)nR8 wherein n is the integer 0, 1 or 2 and R8 is halo or alkyl or a group NR9R10 wherein R9 and R10 are both hydrogen, a group NR11R12 wherein R11 and R12 are the same or different and each is hydrogen or alkyl, a group OR13 wherein R13 is hydrogen or C1-4 of alkyl optionally substituted by halo; a C1-4 aliphatic group optionally substituted by a group OR14 or NR14R15 wherein R14 and R15 are the same or different and each is hydrogen or alkyl; or two of R2 to R5 are linked together to form a benzo group, or one of R2 to R5 is a group X—Y—R16 wherein X is CH2, NR17, CO or S(O)m and Y is CH2, NR17, O or S(O)m, or X—Y is O, NR17, —CH═CH— or N═N—, are disclosed as pharmacologic

Abstract: The present invention provides new methods for the synthesis of the therapeutic dinucleotide, P1,P4-di(uridine 5′-tetraphosphate), and demonstrates applicability to the production of large quantities. The methods of the present invention substantially reduce the time period required to synthesize diuridine tetraphosphate, preferably to three days or less. The novel tetrammonium and tetrasodium salts of P1,P4-di(uridine 5′-tetraphosphate) (Formula I) prepared by these methods are stable, soluble, nontoxic, and easy to handle during manufacture. Therapeutic uses of Formula I include treatment of sinusitis, otitis media, dry eye, retinal detachment, nasolacrimal duct obstruction, female infertility and irritation due to vaginal dryness, via increased mucus secretions and hydration of the epithelial surface. wherein: X is Na, NH4 or H, provided that all X groups are not H.

Abstract: 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.

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: Compositions and methods for treatment of a urinary tract dysfunction by administering to a subject in need of such treatment a pharmaceutical composition including a delta opioid receptor agonist in an amount effective to reduce the effects of the urinary tract dysfunction. The compositions may further include an additional active agent that is used to treat urinary tract dysfunctions, e.g., alpha-adrenergic agonists, anticholinergics, alpha-adrenergic antagonists and tricyclic antidepressants.

Abstract: Compositions and methods for treatment of sexual dysfunctions by administering to a subject a pharmaceutical composition comprising a delta opioid receptor agonist in an amount effective to delay the onset of ejaculation in the subject during sexual stimulation.

Abstract: 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.

Abstract: Compositions and methods for treatment of depression or other affective mood disorders or pathological mental and/or emotional states, by administration to a subject suffering or susceptible to same, of therapeutically effective delta receptor agonist compound(s), optionally in combination with other mood disorder-combating agents.

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: 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.

Abstract: The present invention provides a method of stimulating cervical and vaginal secretions in a mammal by treatment with P2Y2 and/or P2Y4 purinergic 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.

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: 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′-triphosphate (CTP), adenosine 5′-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.

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 certain novel dinucleotides and formulations thereof which are highly selective agonists of the P2Y2 and/or P2Y4 purinergic 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.

Abstract: 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′-triphosphate (CTP), adenosine 5′-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.

Abstract: 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.