Pharmacological Profile and Ocular Hypotensive Effects of Cromakalim Prodrug 1, a Novel ATP-Sensitive Potassium Channel Opener, in Normotensive Dogs and Nonhuman Primates.

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.

Within-plant relationships among wounding, jasmonic acid, and nicotine implications for defence in Nicotiana sylvestris.

In Nicotiana sylvestris Spegazzini and Comes (Solanaceae), we examined the relationships among wounding, endogenous leaf jasmonic acid (JA) pools, and whole-plain (WP) nicotine accumulation over a range of wounding intensities and spatial distributions, in order to explore optimal defence (OD) theory predictions. We quantitatively wounded one or four leaves and then quantified: (1) JA in damaged and undamaged leaves 90 min after wounding; (2) WP nicotine concentration after 5 d (the times when JA and nicotine attain the largest wound-induced concentrations). We find: (1) statistically significant, positive relationships on a leaf-by-leaf basis among the number of leaf punctures, endogenous leaf JA, and WP nicotine accumulation; (2) that young, undamaged leaves have a higher concentration of JA than do older, undamaged leaves, and produce a greater amount of JA per puncture than older leaves, but that all leaves have the same JA content (ng JA per leaf); and (3) that a damaged leaf produces less JA when other leaves in the canopy are wounded than when it is the onh wounded leaf in the canopy, but that when it is the only wounded leaf, the phylotactically adjacent, undamaged leaves do not increase their JA concentrations. The observation that younger leaves produce more JA per puncture than do older leaves is consistent with OD theory predictions. The observation that a small amount of damage localized to a single leaf is as effective as a larger amount of damage dispersed across the canopy in increasing leaf JA and WP nicotine accumulation shows the plant's ability to differentiate between dispersed and localized damage. Because the quantity of JA in a wounded leaf 90 min after wounding is a reliable indicator of the WP nicotine response to wounding, this trait provides insight into how plants integrate information about environmental insults and tailor their defence responses.