The Intraocular Pressure Lowering Effect of a Dual Kinase Inhibitor (ITRI-E-(S)4046) in Ocular Hypertensive Animal Models.

Purpose: The purpose of this study was to develop a preclinical compound, ITRI-E-(S)4046, a dual synergistic inhibitor of myosin light chain kinase 4 (MYLK4) and Rho-related protein kinase (ROCK), for reducing intraocular pressure (IOP). Methods: ITRI-E-(S)4046 is an amino-pyrazole derivative with physical and chemical properties suitable for ophthalmic formulation. In vitro kinase inhibition was evaluated using the Kinase-Glo Luminescent Kinase Assays. A comprehensive kinase selectivity analysis of ITRI-E-(S)4046 was performed using the KINOMEscan assay from DiscoverRx. The IOP reduction and tolerability of ITRI-E-(S)4046 were assessed in ocular normotensive rabbits, ocular normotensive non-human primates, and ocular hypertensive rabbits. In vivo studies were conducted to assess drug concentrations in ocular tissue. The adverse ocular effects of rabbit eyes were evaluated following the OECD405 guidelines. Results: ITRI-E-(S)4046 showed highly selective kinase inhibitory activity against ROCK1/2, MYLK4, and mitogen-activated protein kinase kinase kinase 19 (MAP3K19), with high specificity against protein kinase A, G, and C families. In ocular normotensive rabbits and non-human primates, the mean IOP reductions of 0.1% ITRI-E-(S)4046 eye drops were 29.8% and 28.5%, respectively. In hypertonic saline-induced and magnetic beads-induced ocular hypertensive rabbits, the mean IOP reductions of ITRI-E-(S)4046 0.1% eye drops were 46.9% and 22.0%, respectively. ITRI-E-(S)4046 was well tolerated with only temporary and minor signs of hyperemia. Conclusions: ITRI-E-(S)4046 is a novel type of highly specific ROCK1/2 and MYLK4 inhibitor that can reduce IOP in normotensive and hypertensive animal models. It has the potential to become an effective and well-tolerated treatment for glaucoma.

Promoting bone health management in women diagnosed with breast cancer: a pilot randomized controlled trial.

This study investigates, in women diagnosed with breast cancer, the feasibility of evaluating the effects of educational material and its delivery method, on bone health management. The study results suggest educational material may improve rates of bone mineral density testing. INTRODUCTION: Educational materials improve bone mineral density (BMD) testing rates in high-risk patients, but the effect is unknown in women diagnosed with breast cancer. Methods of delivering educational materials may also affect testing rates. The purposes of this study were to determine the feasibility of the protocol and to pilot-test the effects of educational material and its delivery methods on BMD testing rates. METHOD: Pilot randomized controlled trial with block randomization. Fifty-four women (aged 65-75 and diagnosed with breast cancer ≥ 3 years ago (2010-2012) and not taking osteoporosis medication) were recruited from February to May 2016 and randomized to three groups: control without educational material, educational material delivered by postal mail, and educational material delivered by patient choice of postal mail, email, or text messaging. Outcome measures were primarily evaluated using self-report questionnaires. RESULTS: The participation rate, defined as the proportion of eligible participants who consented to participate, was 39.1%. Primary outcome measure was obtained for 98% of the recruited women. During the 6-month follow-up period, BMD testing rates were significantly higher in the groups receiving educational materials by mail (26%, 95%CI = 10 to 49) and by patient choice (18%, 95%CI = 5 to 41), when compared with the control group (6%, 95%CI = 0.3 to 25). Educational material was associated with a 17% higher BMD testing rate. CONCLUSIONS: The study protocol is feasible for a large-scale study. The educational material intervention is broadly accepted by the study participants with a promising positive effect on BMD testing rates.