Uttio Roy Chowdhury1, Rachel A Kudgus2, Bradley H Holman1, Tommy A Rinkoski1, Cheryl R Hann1, Cindy K Bahler1, Eric McCloud3, Susan E Appt3, Joel M Reid2, Peter I Dosa4, Michael P Fautsch1. 1. Department of Ophthalmology, Mayo Clinic Rochester, Rochester, Minnesota, USA. 2. Department of Oncology Research, Mayo Clinic Rochester, Rochester, Minnesota, USA. 3. Department of Pathology, Section of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. 4. Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota, USA.
Abstract
Purpose: To evaluate pharmacokinetic parameters and ocular hypotensive effects of cromakalim prodrug 1 (CKLP1) in normotensive large animal models. Methods: Optimal CKLP1 concentration was determined by dose response and utilized in short- (5-8 days) and long-term (60 days) evaluation in hound dogs (n = 5) and African Green Monkeys (n = 5). Blood pressure was recorded 3-5 times per week with a tail cuff. Concentrations of CKLP1 and the parent compound levcromakalim were assessed in hound dog plasma and select tissues by LC-MS/MS after bilateral ocular treatment with CKLP1 for 8 days. Pharmacokinetic parameters were calculated from days 1, 4, and 8 data. After necropsy, histology was assessed in 43 tissue samples from each animal. Results: In hound dogs and African Green monkeys, 10 mM CKLP1 (optimal concentration) significantly lowered intraocular pressure (IOP) by 18.9% ± 1.1% and 16.7% ± 6.7%, respectively, compared with control eyes (P < 0.05). During treatment, no significant change in systolic or diastolic blood pressure was observed in either species (P > 0.1). Average values for half-life of CKLP1 was 295.3 ± 140.4 min, Cmax, 10.5 ± 1.6 ng/mL, and area under the concentration vs. time curve (AUClast) 5261.4 ± 918.9 ng·min/mL. For levcromakalim, average values of half-life were 96.2 ± 27 min, Cmax 1.2 ± 0.2 ng/mL, and AUClast 281.2 ± 110.8 ng·min/mL. No significant pathology was identified. Conclusions: CKLP1 lowered IOP in hound dogs and African green monkeys with no effect on systemic blood pressure. Ocular topical treatment of CKLP1 showed excellent tolerability even after extended treatment periods.
Purpose: To evaluate pharmacokinetic parameters and ocular hypotensive effects of cromakalim prodrug 1 (CKLP1) in normotensive large animal models. Methods: Optimal CKLP1 concentration was determined by dose response and utilized in short- (5-8 days) and long-term (60 days) evaluation in hound dogs (n = 5) and African Green Monkeys (n = 5). Blood pressure was recorded 3-5 times per week with a tail cuff. Concentrations of CKLP1 and the parent compound levcromakalim were assessed in hound dog plasma and select tissues by LC-MS/MS after bilateral ocular treatment with CKLP1 for 8 days. Pharmacokinetic parameters were calculated from days 1, 4, and 8 data. After necropsy, histology was assessed in 43 tissue samples from each animal. Results: In hound dogs and African Green monkeys, 10 mM CKLP1 (optimal concentration) significantly lowered intraocular pressure (IOP) by 18.9% ± 1.1% and 16.7% ± 6.7%, respectively, compared with control eyes (P < 0.05). During treatment, no significant change in systolic or diastolic blood pressure was observed in either species (P > 0.1). Average values for half-life of CKLP1 was 295.3 ± 140.4 min, Cmax, 10.5 ± 1.6 ng/mL, and area under the concentration vs. time curve (AUClast) 5261.4 ± 918.9 ng·min/mL. For levcromakalim, average values of half-life were 96.2 ± 27 min, Cmax 1.2 ± 0.2 ng/mL, and AUClast 281.2 ± 110.8 ng·min/mL. No significant pathology was identified. Conclusions: CKLP1 lowered IOP in hound dogs and African green monkeys with no effect on systemic blood pressure. Ocular topical treatment of CKLP1 showed excellent tolerability even after extended treatment periods.
Authors: Patrick C Drayna; Cristina Estrada; Wenli Wang; Benjamin R Saville; Donald H Arnold Journal: Am J Emerg Med Date: 2011-12-12 Impact factor: 2.469
Authors: Uttio Roy Chowdhury; Cindy K Bahler; Bradley H Holman; Peter I Dosa; Michael P Fautsch Journal: PLoS One Date: 2015-11-04 Impact factor: 3.240
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: Cynthia L Pervan-Steel; Uttio Roy Chowdhury; Hemchand K Sookdeo; Ralph A Casale; Peter I Dosa; Thurein M Htoo; Michael P Fautsch; Barbara M Wirostko Journal: Invest Ophthalmol Vis Sci Date: 2022-04-01 Impact factor: 4.925