Pharmacological Profile and Ocular Hypotensive Effects of Cromakalim Prodrug 1, a Novel ATP-Sensitive Potassium Channel Opener, in Normotensive Dogs and Nonhuman Primates
| Autor: | Michael P. Fautsch, Eric McCloud, Uttio Roy Chowdhury, Cheryl R. Hann, Bradley H. Holman, Cindy K. Bahler, Tommy A. Rinkoski, Peter I. Dosa, Joel M. Reid, Rachel A. Kudgus, Susan E. Appt |
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| Rok vydání: | 2021 |
| Předmět: |
Primates
Cromakalim ATP-sensitive potassium channel Administration Topical Administration Ophthalmic Blood Pressure Pharmacology chemistry.chemical_compound Dogs Pharmacokinetics KATP Channels Chlorocebus aethiops Animals Pharmacology (medical) Prodrugs Antihypertensive Agents Intraocular Pressure Dose-Response Relationship Drug Chemistry Original Articles Prodrug Ophthalmology Area Under Curve Models Animal Female Autopsy Large animal Half-Life |
| Zdroj: | J Ocul Pharmacol Ther |
| ISSN: | 1557-7732 |
| Popis: | 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 0.1). Average values for half-life of CKLP1 was 295.3 ± 140.4 min, C(max,) 10.5 ± 1.6 ng/mL, and area under the concentration vs. time curve (AUC(last)) 5261.4 ± 918.9 ng·min/mL. For levcromakalim, average values of half-life were 96.2 ± 27 min, C(max) 1.2 ± 0.2 ng/mL, and AUC(last) 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. |
| Databáze: | OpenAIRE |
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