3 résultats d'études révélés dimanche et mardi : kronus ( phase I ) , constellation( phase II ) et une autre inconnue au bataillon ( la 1ere)
Dimanche 4 mai :
TITLE: NO-induced Regulation of Primary Human Trabecular Meshwork Cell Contractility by Latanoprostene Bunod
AUTHORS (LAST NAME, FIRST NAME): Cavet, Megan E.1; Vollmer, Thomas R.1; Harrington, Karen1; VanDerMeid, Karl1; Richardson, Mary1
INSTITUTIONS (ALL): 1. Pharmaceutical R&D, Bausch & Lomb, Rochester, NY, United States.
Purpose: Prior in vivo studies demonstrated that latanoprostene bunod (LBN), a nitric oxide (NO)-donating latanoprost, results in greater IOP lowering than latanoprost (Xalatan). This study determined the effect of LBN on primary human trabecular meshwork cell (HTMC) contractility and underlying signaling pathways, to assess whether LBN may mediate this additional IOP lowering via the conventional outflow pathway.
Methods: The effect of LBN (1 - 100 µM) on HTMC cGMP levels was determined by ELISA ± the soluble guanylate cyclase (sGC) inhibitor ODQ. Endothelin-1 (100 nM) was used to induce HTMC contractility. To determine the effect of LBN on myosin light chain-2 (MLC-2) phosphorylation, HTMC were pre-treated with 10 - 60 µM LBN for 1 h and then endothelin-1 for 5 min. MLC-2 phosphorylation was determined by western blotting. The effects of LBN (30 and 45 µM) on endothelin-induced actin cytoskeletal stress fibers and the focal adhesion associated protein vinculin were determined by confocal microscopy. Endothelin-1 induced HTMC monolayer resistance in the presence of LBN (1 - 45 µM) was determined by electrical cell substrate impedance sensing, as an indicator of cell contractility. Latanoprost was used as a comparator in all studies.
Results: LBN (1 - 100 µM) significantly increased cGMP levels in a dose dependent manner with an EC50 of 1.54 ± 1.33 µM, while latanoprost caused a minimal increase in cGMP at 100 µM only. The cGMP elevation was abolished by ODQ and was therefore sGC dependent. Effects of LBN on endothelin-1-induced MLC-2 phosphorylation were significantly greater than those of latanoprost. LBN caused a dramatic reduction in endothelin-1 induced actin stress fibers and vinculin localization at focal adhesions, while latanoprost was without effect. LBN significantly reduced endothelin-1 induced HTMC monolayer resistance increases to a greater extent than latanoprost over the dose range studied, indicating a greater reduction in cell contractility with LBN.
Conclusions: Data suggest that LBN mediates HTMC relaxation through activation of the cGMP signaling pathway and a subsequent reduction in MLC-2 phosphorylation. In all cases, effects observed with LBN were of a greater magnitude than those observed with latanoprost. This mechanism may underlie the additional IOP lowering effects of LBN over latanoprost observed in in vivo studies.
TITLE: Efficacy of Latanoprostene Bunod Ophthalmic Solution, 0.024%, in Lowering Intraocular Pressure Over 24-Hours in Normal Japanese Subjects (KRONUS)
AUTHORS (LAST NAME, FIRST NAME): Araie, Makoto1, 2; Ong, Tuyen3; Scassellati-Sforzolini, Baldo3; Ngumah, Quintus3; Vittitow, Jason L.3; Weinreb, Robert N.4
INSTITUTIONS (ALL): 1. Kanto Central Hospitals, Mutual Aid Assoc of Public Sch Teachers, Setagaya-Ku, Tokyo, Japan.
2. Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
3. Clinical Affairs, Bausch+Lomb, Bridgewater, NJ, United States.
4. Ophthalmology and Hamilton Glaucoma Center, University of California, San Diego, La Jolla, CA, United States.
Purpose: To evaluate the effect of latanoprostene bunod, 0.024% in reducing and maintaining IOP over 24 hours in normal Japanese subjects. In Phase 2 dose-ranging studies in USA (VOYAGER) and Japan, 0.024% latanoprostene bunod was the safest and most efficacious dose, demonstrating significantly greater IOP reduction compared with latanoprost, 0.005%.
Methods: This was a single-arm, single-center, open-label, clinical study of 24 healthy Japanese male volunteers. A baseline IOP profile was established in both eyes in the sitting position at 8 PM, 10 PM, 12 AM, 2 AM, 4 AM, 8 AM, 10 AM, 12 PM and 4 PM using a Goldmann applanation tonometer. Following the baseline visit, both eyes were treated with 0.024% latanoprostene bunod QD at approximately 8 PM for 14 days. For each subject's right eye, the change and change from baseline in sitting IOP at each time point was assessed on Day 14. A one-sampled paired t-test was used to determine statistical significance.
Results: The mean age of the volunteers was 26.8 (range 20-39) years. Mean IOPs (± SD) on Day 0 were: 14.4mmHg (1.7), 13.9mmHg (1.5), 13.4mmHg (1.4), 13.0mmHg (1.3), 13.2mmHg (1.6), 14.0mmHg (1.7), 13.7mmHg (1.5), 13.5mmHg (1.7) and 13.4mmHg (1.6) with a 24-hour mean IOP of 13.6 mmHg (1.6). On Day 14 pressures were: 11.5mmHg (1.8), 9.8mmHg (1.4), 9.8mmHg (1.2), 9.9mmHg (1.2), 9.9mmHg (1.5), 9.8mmHg (1.7), 9.6mmHg (1.3), 9.4mmHg (1.3) and 10.1mmHg (1.1) with a 24-hour mean IOP of 10.0 mmHg (1.5). Intraocular pressures were taken at 8 PM, 10 PM, 12 AM, 2 AM, 4 AM, 8 AM, 10 AM, 12 PM and 4 PM, respectively. 14-day QD treatment with 0.024% Latanoprostene bunod reduced IOP at all time points (p < 0.001) with a mean 24-hour reduction of 3.6mmHg (1.5) or 26% from the baseline. Peak and trough IOP lowering occurred at 8 AM and 8 PM (12 and 24 hours following instillation) with a mean reduction of 4.2mmHg (1.8) or 30% and 2.8mmHg (2.2) or 20%, respectively. No significant adverse events were encountered.
Conclusions: Latanoprostene bunod, 0.024% dosed QD for 14 days significantly lowered IOP in normal Japanese subjects during the entire 24 hour period from 13.6 to 10.0 mmHg, corresponding to 27% reduction in mean 24-hour IOP. The current result suggests potential of this compound in providing sustained 24-hour IOP reduction to glaucoma patients not only with elevated, but also with normal IOP.
Mardi 6 mai :
TITLE: Efficacy of Latanoprostene Bunod Ophthalmic Solution 0.024% Compared With Timolol Maleate Ophthalmic Solution 0.5% in Lowering IOP over 24 hours in Subjects With Open Angle Glaucoma or Ocular Hypertension (CONSTELLATION)
AUTHORS (LAST NAME, FIRST NAME): Liu, John H.1; Vittitow, Jason L.2; Ngumah, Quintus2; Weinreb, Robert N.1
INSTITUTIONS (ALL): 1. Dept of Ophthalmology and Hamilton Glaucoma Center, Univ of California, San Diego, La Jolla, CA, United States.
2. Bausch & Lomb, Madison, NJ, United States.
Purpose: To compare the effect of latanoprostene bunod (LBN) 0.024% QD with timolol maleate 0.5% BID in reducing 24-hour intraocular pressure (IOP) in subjects with open angle glaucoma (OAG) or ocular hypertension (OHT).
Methods: This was a randomized, single-center, open-label, 2-period, 8-week study with crossover at 4 weeks. Twenty subjects (43-82 years) with a baseline IOP at least 22 mmHg in at least 1 eye and less than 36 mmHg in both eyes and a diagnosis of OAG or OHT were included. Subjects were housed in a sleep laboratory for 24 hours and a baseline IOP profile was created. IOP of both eyes was measured with a pneumatonometer every two hours in the sitting and supine positions from 8AM to 10PM, and in the supine position only from 12AM to 6AM. During the first period of the study subjects were randomized 1:1 to either of 2 treatment sequences: LBN 0.024% instilled in both eyes at 8PM or timolol maleate 0.5% instilled twice a day at 8AM and 8PM. After four weeks of treatment, subjects were housed in the sleep laboratory for a second 24 hour period IOP measurement. At the end of the 24 hours, subjects were crossed over to receive the comparator treatment, which initiated period 2. After four weeks of the period 2 treatment, subjects were housed in the sleep laboratory for a third 24 hour IOP measurement. The mean IOP from both periods for the 2 treatment groups (LBN 0.024% QD and timolol maleate 0.5% BID) were compared using a Mixed Model Repeated Measures analysis of variance (ANOVA) model, during the diurnal, nocturnal, and 24 hour periods.
Results: Mean change from baseline in IOP (mmHg) was 3.9±0.28 for latanoprostene bunod treated eyes and 2.4±0.29 for timolol treated eyes during the diurnal period; 2.75 ± 0.45 for latanoprostene bunod and 0.2±0.46 for timolol during the nocturnal period; and 3.5 ± 0.24 for latanoprostene bunod and 1.7±0.25 for timolol during the entire 24 hour period.
Conclusions: In this group of open angle glaucoma/ocular hypertensive patients, LBN 0.024% was shown to be superior to timolol with regard to IOP lowering during the entire 24 hour period measured (p<0.05), suggesting that treatment with LBN 0.024% may provide more effective and better sustained diurnal and nocturnal IOP reduction.
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