title: Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits.
abstract: OBJECTIVE
  To evaluate the topical instillation of K-115, a selective Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, on intraocular pressure (IOP), ocular distribution, and aqueous humor dynamics in experimental animals.
  
  
  METHODS
  Kinase inhibition by K-115 was measured by biochemical assay. IOP was monitored using a pneumatonometer in albino rabbits and monkeys after topical instillation of K-115. The ocular distribution of [(14)C]K-115 was determined by whole-head autoradiography. The aqueous flow rate was determined by fluorophotometry. The total outflow facility and uveoscleral outflow were measured by two-level constant pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively.
  
  
  RESULTS
  Biochemical assay showed that K-115 had selective and potent inhibitory effects on ROCKs. In rabbits, topical instillation of K-115 significantly reduced IOP in a dose-dependent manner. Maximum IOP reduction was observed 1 h after topical instillation, which was 8.55 ± 1.09 mmHg (mean ± SE) from the baseline IOP at 0.5%. In monkeys, maximum IOP reduction was observed 2 h after topical instillation, which was 4.36 ± 0.32 mmHg from the baseline IOP at 0.4%, and was significantly stronger than that of 0.005% latanoprost. Whole-head autoradiography showed that the radioactivity level was maximum at 15 min after instillation of [(14)C]K-115 in the ipsilateral eye. Single instillation of 0.4% K-115 showed no effect on aqueous flow rate or uveoscleral outflow, but significantly increased conventional outflow facility by 2.2-fold compared to vehicle-treated eyes in rabbits.
  
  
  CONCLUSIONS
  These results indicated that K-115 ophthalmic solution, a selective and potent ROCK inhibitor, is a novel and potent antiglaucoma agent.
authors: Tokyo New Drug Research Laboratories, Kowa Co., Ltd. , Tokyo , Japan.
authors: Tomoyuki
authors: T
authors: Isobe
authors: Ken
authors: K
authors: Mizuno
authors: Yoshio
authors: Y
authors: Kaneko
authors: Masayuki
authors: M
authors: Ohta
authors: Takashi
authors: T
authors: Koide
authors: Sohei
authors: S
authors: Tanabe
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D015590:Fluorophotometry; D005500:Follow-Up Studies; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007429:Intraocular Pressure / Q000187:drug effects / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009883:Ophthalmic Solutions; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007546:Isoquinolines; C584679:K-115; D009883:Ophthalmic Solutions; D013449:Sulfonamides; D054460:rho-Associated Kinases
keywords: Aqueous humor dynamics; K-115; ROCK; glaucoma; intraocular pressure