Effect of cromakalim prodrug 1 (CKLP1) on aqueous humor dynamics and feasibility of combination therapy with existing ocular hypotensive agents

Uttio Roy Chowdhury, Tommy A. Rinkoski, Cindy K. Bahler, John Cameron Millar, Jacques A. Bertrand, Bradley H. Holman, Joseph M. Sherwood, Darryl R. Overby, Kristen L. Stoltz, Peter I. Dosa, Michael P. Fautsch

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2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5731-5742
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number13
DOIs
StatePublished - 1 Nov 2017

Fingerprint

Cromakalim
Aqueous Humor
Prodrugs
latanoprost
Timolol
Intraocular Pressure
Trabecular Meshwork
Therapeutics
rho-Associated Kinases
Venous Pressure
Inbred C57BL Mouse
Pressure
KATP Channels
Theoretical Models
Perfusion

Keywords

  • ATP-sensitive potassium channel
  • Distal outflow
  • Glaucoma medications
  • Intraocular pressure
  • Ocular hypertension

Cite this

Chowdhury, Uttio Roy ; Rinkoski, Tommy A. ; Bahler, Cindy K. ; Millar, John Cameron ; Bertrand, Jacques A. ; Holman, Bradley H. ; Sherwood, Joseph M. ; Overby, Darryl R. ; Stoltz, Kristen L. ; Dosa, Peter I. ; Fautsch, Michael P. / Effect of cromakalim prodrug 1 (CKLP1) on aqueous humor dynamics and feasibility of combination therapy with existing ocular hypotensive agents. In: Investigative Ophthalmology and Visual Science. 2017 ; Vol. 58, No. 13. pp. 5731-5742.
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title = "Effect of cromakalim prodrug 1 (CKLP1) on aqueous humor dynamics and feasibility of combination therapy with existing ocular hypotensive agents",
abstract = "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.",
keywords = "ATP-sensitive potassium channel, Distal outflow, Glaucoma medications, Intraocular pressure, Ocular hypertension",
author = "Chowdhury, {Uttio Roy} and Rinkoski, {Tommy A.} and Bahler, {Cindy K.} and Millar, {John Cameron} and Bertrand, {Jacques A.} and Holman, {Bradley H.} and Sherwood, {Joseph M.} and Overby, {Darryl R.} and Stoltz, {Kristen L.} and Dosa, {Peter I.} and Fautsch, {Michael P.}",
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Chowdhury, UR, Rinkoski, TA, Bahler, CK, Millar, JC, Bertrand, JA, Holman, BH, Sherwood, JM, Overby, DR, Stoltz, KL, Dosa, PI & Fautsch, MP 2017, 'Effect of cromakalim prodrug 1 (CKLP1) on aqueous humor dynamics and feasibility of combination therapy with existing ocular hypotensive agents', Investigative Ophthalmology and Visual Science, vol. 58, no. 13, pp. 5731-5742. https://doi.org/10.1167/iovs.17-22538

Effect of cromakalim prodrug 1 (CKLP1) on aqueous humor dynamics and feasibility of combination therapy with existing ocular hypotensive agents. / Chowdhury, Uttio Roy; Rinkoski, Tommy A.; Bahler, Cindy K.; Millar, John Cameron; Bertrand, Jacques A.; Holman, Bradley H.; Sherwood, Joseph M.; Overby, Darryl R.; Stoltz, Kristen L.; Dosa, Peter I.; Fautsch, Michael P.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 13, 01.11.2017, p. 5731-5742.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effect of cromakalim prodrug 1 (CKLP1) on aqueous humor dynamics and feasibility of combination therapy with existing ocular hypotensive agents

AU - Chowdhury, Uttio Roy

AU - Rinkoski, Tommy A.

AU - Bahler, Cindy K.

AU - Millar, John Cameron

AU - Bertrand, Jacques A.

AU - Holman, Bradley H.

AU - Sherwood, Joseph M.

AU - Overby, Darryl R.

AU - Stoltz, Kristen L.

AU - Dosa, Peter I.

AU - Fautsch, Michael P.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

KW - ATP-sensitive potassium channel

KW - Distal outflow

KW - Glaucoma medications

KW - Intraocular pressure

KW - Ocular hypertension

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U2 - 10.1167/iovs.17-22538

DO - 10.1167/iovs.17-22538

M3 - Article

VL - 58

SP - 5731

EP - 5742

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 13

ER -