denufosol-tetrasodium and Brain-Neoplasms

INS37217 [P(1)-(uridine 5')-P(4)-(2'-deoxycytidine 5')tetraphosphate, tetrasodium salt] is a deoxycytidine-uridine dinucleotide with agonist activity at the P2Y(2) receptor. In primate lung tissues, the P2Y(2) receptor mRNA was located by in situ hybridization predominantly in epithelial cells and not in smooth muscle or stromal tissue. The pharmacologic profile of INS37217 parallels that of UTP, leading to increased chloride and water secretion, increased cilia beat frequency, and increased mucin release. The combined effect of these actions was confirmed in an animal model of tracheal mucus velocity that showed that a single administration of INS37217 significantly enhanced mucus transport for at least 8 h after dosing. This extended duration of action is consistent with the ability of INS37217 to resist metabolism by airway cells and sputum enzymes. The enhanced metabolic stability and resultant increased duration of improved mucociliary clearance may confer significant advantages to INS37217 over other P2Y(2) agonists in the treatment of diseases such as cystic fibrosis.

Topics: Animals; Astrocytoma; Brain Neoplasms; Calcium; Chlorides; Cilia; Cystic Fibrosis; Deoxycytosine Nucleotides; Epithelial Cells; Humans; In Situ Hybridization; In Vitro Techniques; Indicators and Reagents; Macaca mulatta; Mucins; Mucociliary Clearance; Ophthalmic Solutions; Polyphosphates; Purinergic P2 Receptor Agonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y2; Reverse Transcriptase Polymerase Chain Reaction; Sheep; Tumor Cells, Cultured; Uracil Nucleotides; Uridine