Effect of Cromakalim Prodrug 1 (CKLP1) on Aqueous Humor Dynamics and Feasibility of Combination Therapy With Existing Ocular Hypotensive Agents

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dc.creatorRoy Chowdhury, Uttio
dc.creatorRinkoski, Tommy A.
dc.creatorBahler, Cindy K.
dc.creatorMillar, J. Cameron
dc.creatorBertrand, Jacques A.
dc.creatorHolman, Bradley H.
dc.creatorSherwood, Joseph M.
dc.creatorOverby, Darryl R.
dc.creatorStoltz, Kristen L.
dc.creatorDosa, Peter I.
dc.creatorFautsch, Michael P.
dc.date.accessioned2022-10-14T14:32:31Z
dc.date.available2022-10-14T14:32:31Z
dc.date.issued2017-11-01
dc.description.abstractPurpose: 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.
dc.description.sponsorshipSupported by National Institutes of Health Grants EY21727 (MPF), EY26490 (MPF), and EY022359 (DRO); Minnesota Partnership for Biotechnology and Medical Genomics No. 12.06 (MPF, PID); Minnesota Partnership for Biotechnology and Medical Genomics TPDF No. 15.01 (MPF, PID); National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114 (PID); Fight for Sight (UK) No. 1858 (DRO); Research to Prevent Blindness (URC, TAR, CKB, BHH, MPF); and Mayo Foundation (MPF).
dc.identifier.citationRoy Chowdhury, U., Rinkoski, T. A., Bahler, C. K., Millar, J. C., Bertrand, J. A., Holman, B. H., Sherwood, J. M., Overby, D. R., Stoltz, K. L., Dosa, P. I., & Fautsch, M. P. (2017). Effect of Cromakalim Prodrug 1 (CKLP1) on Aqueous Humor Dynamics and Feasibility of Combination Therapy With Existing Ocular Hypotensive Agents. Investigative ophthalmology & visual science, 58(13), 5731-5742. https://doi.org/10.1167/iovs.17-22538
dc.identifier.issn1552-5783
dc.identifier.issue13
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31852
dc.identifier.volume58
dc.publisherARVO Journals
dc.relation.urihttps://doi.org/10.1167/iovs.17-22538
dc.rights.holderCopyright 2017 The Authors
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceInvestigative Ophthalmology & Visual Science
dc.subject.meshAmides / therapeutic use
dc.subject.meshAnimals
dc.subject.meshAnterior Eye Segment / drug effects
dc.subject.meshAntihypertensive Agents / therapeutic use
dc.subject.meshAqueous Humor / physiology
dc.subject.meshCromakalim / therapeutic use
dc.subject.meshDrug Synergism
dc.subject.meshDrug Therapy, Combination
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshIntraocular Pressure / drug effects
dc.subject.meshLatanoprost
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMiddle Aged
dc.subject.meshOphthalmic Solutions
dc.subject.meshProdrugs / therapeutic use
dc.subject.meshProstaglandins F, Synthetic / therapeutic use
dc.subject.meshPyridines / therapeutic use
dc.subject.meshRabbits
dc.subject.meshSclera / blood supply
dc.subject.meshTimolol / therapeutic use
dc.subject.meshTonometry, Ocular
dc.subject.meshVenous Pressure / drug effects
dc.titleEffect of Cromakalim Prodrug 1 (CKLP1) on Aqueous Humor Dynamics and Feasibility of Combination Therapy With Existing Ocular Hypotensive Agents
dc.typeArticle
dc.type.materialtext

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