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Vol. 302, Issue 3, 871-880, September 2002
Inspire Pharmaceuticals, Inc., Durham, North Carolina (B.R.Y.,
A.C.J., M.C., R.D., J.B.); University of Miami, Mount Sinai Medical
Center, Miami Beach, Florida (J.R.S., W.M.A.); and Cystic
Fibrosis/Pulmonary Research and Treatment Center, School of Medicine,
University of North Carolina, Chapel Hill, North Carolina (C.W.D.,
M.J.S., M.L.-F., M.P., R.C.B.)
INS37217 [P1-(uridine 5')-P4-(2'-deoxycytidine
5')tetraphosphate, tetrasodium salt] is a deoxycytidine-uridine
dinucleotide with agonist activity at the P2Y2 receptor. In
primate lung tissues, the P2Y2 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 P2Y2 agonists in the
treatment of diseases such as cystic fibrosis.
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