Therapeutic use of nucleotides in respiratory and ophthalmic diseases

Nucleotide agonists of P2Y(2) receptors are potentially useful therapeutics for treating respiratory diseases such as chronic bronchitis and cystic fi brosis, and for treating ophthalmic indications such as dry eye and retinal detachment. INS365 is a chemically stable nucleotide P2Y(2) agonist that, when inhaled, enhances mucociliary clearance of the airways and thus may be useful for treating chronic bronchitis in which retained mucus is a hallma rk. On the ocular mucosa, P2Y(2) agonists stimulate the secretion of salt, water, and mucus. This mechanism of basal tear secretion forms the scientif ic basis for the clinical investigation of INS365 as a tear film secretagog ue for the treatment of dry eye disease. INS365 ophthalmic solution is curr ently in Phase II clinical trials in the US. INS37217, a next-generation nu cleotide P2Y(2) agonist with enhanced metabolic stability and a potentially longer duration of action, is being developed for the treatment of cystic fibrosis and retinal detachment. In cystic fibrosis, P2Y(2) agonists activa te an alternative chloride channel, thereby restoring hydration of the airw ay surface and promoting mucociliary clearance. in experimental models of r etinal detachment, INS37217 injected into the back of the eye activates P2Y (2) receptors on the retinal pigmented epithelium, promoting fluid absorpti on in the subretinal space and thus facilitating retinal reattachment. Sinc e receptor for nucleotides are found throughout the body, nucleotides and t heir analogs have great therapeutic promise when administered locally to th e desired site of action. Drug Dev. Res. 52:196-201, 2001. (C) 2001 Wiley-L iss, Inc.