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Editors Selection IGR 16-4

Medical treatment: ROCK inhibition

Comment by Paul Kaufman on:

20766 Intraocular Pressure-Lowering Effects and Safety of Topical Administration of a Selective ROCK Inhibitor, SNJ-1656, in Healthy Volunteers, Tanihara H; Inatani M; Honjo M et al., Archives of Ophthalmology, 2008; 126: 309-315

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Tanihara et al. (376) present an interesting preliminary clinical study of ROCK inhibition and IOP lowering. Their IOP effect, albeit modest, validates pre-clinical physiological, morphological and cell biological data indicating that the Rho/ROCK cascade regulation of cellular contractility/relaxation, cell adhesion, cell shape and overall structural tension in the TM are: 1) important regulatory mechanisms for the physiological control of outflow facility; and 2) potentially important and clinically useful targets for therapeutic reduction of intraocular pressure. The starting IOP was only about 14 mmHg in their young, normal subjects, so the small magnitude of the effect may not be predictive either way of what might occur in an elderly glaucomatous eye. Clinical/physiologic studies in human subjects confirming that the IOP lowering derives from increased conventional outflow facility would be reassuring.

Their IOP effect, albeit modest, validates pre-clinical physiological, morphological and cell biological data

The conjunctival hyperemia noted is not surprising and likely to be mechanism-related; clinical utility of this approach may require better structure-activity or pharmacokinetic approaches to separating ocular surface from trabecular meshwork effects. We cannot be sure that the absence of corneal or other anterior segment adverse effects by conventional slit lamp examination after only one week of topical drug administration in these young healthy eyes is predictive of what might occur in elderly, glaucomatous eyes that have been assaulted by decades of topical drug therapy/vehicles and in some cases prior intraocular surgery. Potential effects on the corneal endothelium are of special concern, since endothelial cells are lost and less functional with age. No data on corneal thickness, endothelial cell counts or cell shape/size were presented although the statement was made that there were no effects on these parameters. However, the authors statements such as "…few adverse effects" and that "the adverse effects of its administration did not matter" are premature. These are not criticisms of a well-done and appropriately targeted initial short-term dose ranging clinical trial of a promising therapeutic strategy with a solid scientific base. Rather, these are cautions and suggestions for proceeding in a clinically prudent and scientifically rigorous development pathway for an exciting, potentially important new approach. None of our commonly used glaucoma drug classes are directed at the conventional outflow pathway ‐ presumably the site of outflow obstruction in most primary and secondary glaucomas.

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