Ocular Hypotensive Response in Nonhuman Primates of (8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a Selective 5-HT2 Receptor Agonist.

Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochemical and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clinical evaluation of this compound. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclinical evaluation as a candidate for proof-of-concept studies in humans.

Safety of moxifloxacin as shown in animal and in vitro studies.

Topical treatment of ocular bacterial infection is practiced widely, and the choice of the antibacterial agent depends on the nature of the infection, including the susceptibility of the organism, the tissue affected, and the safety profile of the agent. Moxifloxacin is a fourth-generation fluoroquinolone approved for ophthalmic use as moxifloxacin ophthalmic solution 0.5% (VIGAMOX, Alcon, Fort Worth, TX). Moxifloxacin ophthalmic solution 0.5% is self-preserved at a near-neutral pH of 6.8. In treating ocular infection, the three important aspects of therapeutic control are potency, penetration of the drug to the target site, and safety of the drug and the drug product. Moxifloxacin ophthalmic solution 0.5% provides antibacterial potency and high penetration of target ocular tissues. The ocular and systemic safety profile of moxifloxacin compares favorably with those of other fluoroquinolone antimicrobial agents, with a low risk of recognized quinolone-related toxicity. In vitro studies of fluoroquinolones with human or rabbit corneal epithelial cells or keratocytes suggest that moxifloxacin is similar in cytotoxicity potential to other drugs of this family. Specialized in vivo corneal wound-healing studies draw little distinction between moxifloxacin-treated eyes and those treated with other fluoroquinolones. Repeated-dose topical ocular studies in rabbits and monkeys, with high concentrations (up to 3%) of moxifloxacin and at treatment durations and regimens well in excess of label-prescribed use, demonstrated a high safety margin for ocular and extraocular tissues. Cornea, the tissue with highest exposure, was found to be unaffected by these high exposures, with slit-lamp biomicroscopy, corneal thickness measurement, intraocular pressure, and specular microscopy of the corneal endothelium (monkeys only), and histologic evaluation showing no effects, as compared with controls. Moxifloxacin ophthalmic solution 0.5% affords superior efficacy and ocular tissue penetration, with a favorable safety profile.

Neural losses correlated with visual losses in clinical perimetry.

PURPOSE: The validity of clinical perimetry for evaluation of the pathology of glaucoma is based on correlated losses in retinal ganglion cells and visual sensitivity, but procedures to quantify neural losses from visual field defects have not been developed. The purpose of the present study was to investigate the neural and sensitivity losses from experimental glaucoma to establish the framework for a quantitative model for the structure-function relationships of standard clinical perimetry. METHODS: Perimetry, by behavioral testing, and retinal histology data were obtained from rhesus monkeys with significant visual field defects caused by experimental glaucoma. Ganglion cell densities were obtained from sections of retina that corresponded to 16 perimetry test locations. Perimetry sensitivity as a function of ganglion cell density at corresponding retina/visual field locations was analyzed. RESULTS: The structure-function relationships were linear on log-log coordinates, with parameters that varied systematically with eccentricity. The slope value varied from 1.25 dB/dB at 4.2 degrees from fixation to a value of 2.32 dB/dB at 24 degrees from fixation, whereas the intercept value varied from -25.2 dB to -55.7 dB over the same range of eccentricities. The structure-function relationships produced a model to predict the ganglion cell density underlying a given level of visual sensitivity and location in the visual field. The model, with no free parameters, produced an accurate and relatively precise quantification of retinal ganglion cell losses caused by experimental glaucoma in monkeys. However, because the early detection of glaucoma is limited by intersubject variability, ganglion cell losses of 40% to 50% were necessary before visual sensitivity losses exceeded the normal 95% confidence limits. CONCLUSIONS: With retinal eccentricity as a factor, the neural losses from glaucoma are predictable from visual sensitivity measurements by clinical perimetry. The relationships derived from experimental glaucoma in monkeys also accurately predict the rate of age-related losses of retinal ganglion cells in humans, based on the normative perimetry data for age-related reductions in visual sensitivity. The success of the model in this study suggested that it is potentially applicable to the clinical interpretation of the state of glaucomatous optic neuropathy.