J.N. Ver Hoeve

Effect of H-7 and Lat-B on Retinal Physiology

Purpose: To investigate the effects of H-7 and Latrunculin B (Lat-B) on retinal vascular permeability and electrophysiology at concentrations that increase outflow facility in monkeys. Methods: One eye of 1 rhesus and 22 cynomolgus monkeys received an intravitreal bolus injection of H-7 or Lat-B; the opposite eye received vehicle. Multifocal electroretinograms (mfERGs), and photopic and scotopic full-field electroretinograms (ffERGs, sERGs) were recorded in subsets of monkeys at baseline and at multiple time-points post-H-7 or Lat-B. Vitreous fluorophotometry (VF) and fluorescein angiography (FA) were also performed. Results: No differences between the H-7 or Lat-B treated and control eyes were found in ffERGs, mfERGs, sERGs, or in FAs in any monkey. No significant difference was found in vitreous fluorescein levels between H-7 treated or Lat-B treated vs. control eyes. Conclusions: No effect on retinal vascular permeability or retinal electrophysiology was apparent after intravitreal administration of H-7 or Lat-B at doses that increase outflow facility and lower IOP when given intracamerally.

Implications of retinal effects observed in chronic toxicity studies on the clinical development of a CNS-active drug candidate

The development path described for JNJ-26489112 provides perspectives on interpretation of retinal effects observed in nonclinical studies and their implications for clinical development. JNJ-26489112 is a CNS-active investigational drug that has potential as a novel treatment for treatment-resistant and bipolar depression, epilepsy, and neuropathic/inflammatory pain. In a 6-month toxicity study in albino rats, retinal atrophy was observed at supratherapeutic exposures to JNJ-26489112. The histopathological changes and topography of the lesions were characteristic of light-induced damage specific to albino rats. The species/strain specificity is supported by an absence of any ocular effects in dogs and in pigmented and albino rats, housed under standard and reduced lighting, respectively. To further evaluate its potential to cause ocular effects, in vivo functional and structural ocular analyses were included in a 9-month monkey toxicity study. Reductions in rod- and cone-mediated electroretinograms were observed at supratherapeutic exposures but without any histopathologic changes. These data suggested that the effects of JNJ-26489112 in monkeys were neuromodulatory and not neurotoxic. Taken together, data related to the light-induced atrophy in albino rats and reversible neuromodulatory effects in monkeys, supported the safe evaluation of JNJ-26489112 in a clinical proof-of-concept study that included comprehensive functional and structural ocular monitoring.

Effect of orientation on spatiotemporal contrast sensitivity in multiple sclerosis

Spatiotemporal contrast sensitivity at three orientations, vertical, horizontal and oblique, was studied in 18 patients with clinically definite and laboratory-confirmed definite multiple sclerosis (MS). Nineteen age-matched control subjects were also studied under identical experimental conditions. Contrast thresholds for detecting steady and counterphase modulated (5 Hz) gratings ranging in spatial frequency from 0.5 to 12 c/deg were measured by a modified psychophysical method of limits. With the exception of two patients (three eyes) whose Snellen acuity scores were 20/70, all observers had acuity scores of 20/30 or better. All subjects were corrected for astigmatism. Orientation, spatial frequency and temporal frequency interacted differently in determining contrast sensitivity in the two groups of observers. For the controls, an oblique effect was present for both the steady and counterphase modulated gratings of high spatial frequencies, and there was no orientation-dependent loss of sensitivity for low spatial frequencies. For the observers with MS, there was no oblique effect, but sensitivity was dependent on orientation for the low spatial frequencies. Most patients with MS had reduced contrast sensitivity, compared to the controls, at one or more orientations. Counterphase modulation increased sensitivity to the low spatial frequencies and decreased sensitivity to the high spatial frequencies for both normal controls and patients with MS. In patients with MS this effect of temporal modulation on contrast sensitivity was markedly enhanced.

Dynamics of adaptation for vision with a stabilized image.

The addition of a uniform increment of light to a high-contrast image that has been stabilized on the retina reveals marked perceptual nonlinearities. When the increment is small, the pattern appears in its original phase (OP), large increments produce an apparent phase reversal (APR), and intermediate increments may yield an apparently blank field or an oscillation of the apparent phase. In the present series of studies the threshold values used to produce a stable OP and APR were determined as a function of adaptation time before the application of the increment. The stabilized target had a luminance profile consisting of the difference of two Gaussians. A model of detection incorporating a multiplicative gain controlled by a filtered version of the stimulus was used to account for the occurrence of the OP and the APR and the transitory phenomena following the uniform increment. It is argued that the midpoint of the transition zone between the OP and APR, corresponding to blanking, enables us to estimate the shape of the step response function of the gain filter independently of the subsequent detection processes.