Purpose: Cromakalim prodrug 1 (CKLP1) is a water-soluble ATP-sensitive potassium channel opener that has shown ocular hypotensive properties in ex vivo and in vivo experimental models. To determine its mechanism of action, we assessed the effect of CKLP1 on aqueous humor dynamics and in combination therapy with existing ocular hypotensive agents. Methods: Outflow facility was assessed in C57BL/6 mice by ex vivo eye perfusions and by in vivo constant flow infusion following CKLP1 treatment. Human anterior segments with no trabecular meshwork were evaluated for effect on pressure following CKLP1 treatment. CKLP1 alone and in combination with latanoprost, timolol, and Rho kinase inhibitor Y27632 were evaluated for effect on intraocular pressure in C57BL/6 mice and Dutch-belted pigmented rabbits. Results: CKLP1 lowered episcleral venous pressure (control: 8.9 ± 0.1 mm Hg versus treated: 6.2 ± 0.1 mm Hg, P < 0.0001) but had no detectable effect on outflow facility, aqueous humor flow rate, or uveoscleral outflow. Treatment with CKLP1 in human anterior segments without the trabecular meshwork resulted in a 50% ± 9% decrease in pressure, suggesting an effect on the distal portion of the conventional outflow pathway. CKLP1 worked additively with latanoprost, timolol, and Y27632 to lower IOP, presumably owing to combined effects on different aspects of aqueous humor dynamics. Conclusions: CKLP1 lowered intraocular pressure by reducing episcleral venous pressure and lowering distal outflow resistance in the conventional outflow pathway. Owing to this unique mechanism of action, CKLP1 works in an additive manner to lower intraocular pressure with latanoprost, timolol, and Rho kinase inhibitor Y27632.
Purpose: Cromakalim prodrug 1 (CKLP1) is a water-soluble ATP-sensitive potassium channel opener that has shown ocular hypotensive properties in ex vivo and in vivo experimental models. To determine its mechanism of action, we assessed the effect of CKLP1 on aqueous humor dynamics and in combination therapy with existing ocular hypotensive agents. Methods: Outflow facility was assessed in C57BL/6 mice by ex vivo eye perfusions and by in vivo constant flow infusion following CKLP1 treatment. Human anterior segments with no trabecular meshwork were evaluated for effect on pressure following CKLP1 treatment. CKLP1 alone and in combination with latanoprost, timolol, and Rho kinase inhibitor Y27632 were evaluated for effect on intraocular pressure in C57BL/6 mice and Dutch-belted pigmented rabbits. Results: CKLP1 lowered episcleral venous pressure (control: 8.9 ± 0.1 mm Hg versus treated: 6.2 ± 0.1 mm Hg, P < 0.0001) but had no detectable effect on outflow facility, aqueous humor flow rate, or uveoscleral outflow. Treatment with CKLP1 in human anterior segments without the trabecular meshwork resulted in a 50% ± 9% decrease in pressure, suggesting an effect on the distal portion of the conventional outflow pathway. CKLP1 worked additively with latanoprost, timolol, and Y27632 to lower IOP, presumably owing to combined effects on different aspects of aqueous humor dynamics. Conclusions: CKLP1 lowered intraocular pressure by reducing episcleral venous pressure and lowering distal outflow resistance in the conventional outflow pathway. Owing to this unique mechanism of action, CKLP1 works in an additive manner to lower intraocular pressure with latanoprost, timolol, and Rho kinase inhibitor Y27632.
Authors: Michael Madekurozwa; Ester Reina-Torres; Darryl R Overby; Joseph van Batenburg-Sherwood Journal: Exp Eye Res Date: 2022-05-05 Impact factor: 3.770
Authors: Uttio Roy Chowdhury; Rachel A Kudgus; Bradley H Holman; Tommy A Rinkoski; Cheryl R Hann; Cindy K Bahler; Eric McCloud; Susan E Appt; Joel M Reid; Peter I Dosa; Michael P Fautsch Journal: J Ocul Pharmacol Ther Date: 2021-03-30 Impact factor: 2.850
Authors: Colleen M McDowell; Krishnakumar Kizhatil; Michael H Elliott; Darryl R Overby; Joseph van Batenburg-Sherwood; J Cameron Millar; Markus H Kuehn; Gulab Zode; Ted S Acott; Michael G Anderson; Sanjoy K Bhattacharya; Jacques A Bertrand; Terete Borras; Diane E Bovenkamp; Lin Cheng; John Danias; Michael Lucio De Ieso; Yiqin Du; Jennifer A Faralli; Rudolf Fuchshofer; Preethi S Ganapathy; Haiyan Gong; Samuel Herberg; Humberto Hernandez; Peter Humphries; Simon W M John; Paul L Kaufman; Kate E Keller; Mary J Kelley; Ruth A Kelly; David Krizaj; Ajay Kumar; Brian C Leonard; Raquel L Lieberman; Paloma Liton; Yutao Liu; Katy C Liu; Navita N Lopez; Weiming Mao; Timur Mavlyutov; Fiona McDonnell; Gillian J McLellan; Philip Mzyk; Andrews Nartey; Louis R Pasquale; Gaurang C Patel; Padmanabhan P Pattabiraman; Donna M Peters; Vijaykrishna Raghunathan; Ponugoti Vasantha Rao; Naga Rayana; Urmimala Raychaudhuri; Ester Reina-Torres; Ruiyi Ren; Douglas Rhee; Uttio Roy Chowdhury; John R Samples; E Griffen Samples; Najam Sharif; Joel S Schuman; Val C Sheffield; Cooper H Stevenson; Avinash Soundararajan; Preeti Subramanian; Chenna Kesavulu Sugali; Yang Sun; Carol B Toris; Karen Y Torrejon; Amir Vahabikashi; Janice A Vranka; Ting Wang; Colin E Willoughby; Chen Xin; Hongmin Yun; Hao F Zhang; Michael P Fautsch; Ernst R Tamm; Abbot F Clark; C Ross Ethier; W Daniel Stamer Journal: Invest Ophthalmol Vis Sci Date: 2022-02-01 Impact factor: 4.925
Authors: Uttio Roy Chowdhury; J Cameron Millar; Bradley H Holman; Kjersten J Anderson; Peter I Dosa; Gavin W Roddy; Michael P Fautsch Journal: Invest Ophthalmol Vis Sci Date: 2022-02-01 Impact factor: 4.799
Authors: Uttio Roy Chowdhury; Rachel A Kudgus; Tommy A Rinkoski; Bradley H Holman; Cindy K Bahler; Cheryl R Hann; Joel M Reid; Peter I Dosa; Michael P Fautsch Journal: PLoS One Date: 2020-04-16 Impact factor: 3.240
Authors: Jacques A Bertrand; Martin Schicht; W Daniel Stamer; David Baker; Joseph M Sherwood; Elke Lütjen-Drecoll; David L Selwood; Darryl R Overby Journal: Invest Ophthalmol Vis Sci Date: 2020-03-09 Impact factor: 4.799