Intravitreal administration of known phototoxicants in the rabbit fails to produce phototoxicity: implications for phototoxicity testing of intravitreally administered small molecule therapeutics.

CONTEXT: Intravitreal (ITV) dosing has become a clinically important route of administration for the treatment of uveitis, endophthalmitis, retinal vein occlusion, diabetic macular edema and age-related macular degeneration. Despite this, there are no validated non-clinical models of phototoxicity for ITV products. OBJECTIVE: The objective of this study was to develop an ITV rabbit model of phototoxicity for use in assessing the photosafety of small molecules therapeutics. MATERIALS AND METHODS: Dutch Belted rabbits were intravitreally injected bilaterally with four known phototoxicants: 8-methoxypsoralen, lomefloxacin, doxycycline and stannsoporfrin. Triescence(®), a non-phototoxic triamcinolone acetonide steroid formulation designed for ITV administration, was used as a negative control. One eye was then irradiated with solar-simulated ultraviolet radiation for 30 min, 1 h after dosing, while the other eye was occluded, serving as a non-irradiated control. RESULTS: Despite the direct administration of known phototoxicants into the vitreous, no evidence of ocular phototoxicity was observed in any dose group. Direct (non-phototoxic) retinal toxicity was observed in the doxycycline dose group only. CONCLUSION: These data suggest that the posterior segment of the rabbit eye is protected against phototoxicity by anatomical and/or physiological mechanisms, and is not a useful model for the assessment of phototoxicity of intravitreally administered molecules.

Effects of topically applied heterologous serum on reepithelialization rate of superficial chronic corneal epithelial defects in dogs.

OBJECTIVE To assess the effects of topical application of undiluted heterologous serum on time to corneal reepithelialization in dogs with superficial chronic corneal epithelial defects (SCCEDs). DESIGN Multicenter, randomized, double-masked, controlled clinical trial. ANIMALS 41 client-owned dogs. PROCEDURES After collection of baseline clinical and historical data, dogs were randomly assigned to receive topically applied undiluted heterologous serum (n = 22) or isotonic saline (0.9% NaCl) solution (19) along with tobramycin and atropine. Epithelial debridement (at all visits) and grid keratotomy (at visits 2, 3, and 4) of SCCEDs were performed. Ophthalmic examination including fluorescein application was performed once weekly for 4 weeks or until corneal reepithelialization. Clinicians and owners were masked to treatment group. RESULTS No differences in baseline data were detected between treatment groups. No difficulties with medication administration, noncompliance, or adverse reactions were noted. All SCCEDs in both groups healed by 4 weeks after treatment began. Median time to reepithelialization (2 weeks) was not significantly different between serum-treated and placebo-treated eyes. Irrespective of treatment group, median time to reepithelialization was not significantly different for Boxers versus non-Boxer breeds. Direct correlations were detected between time to reepithelialization and vascularization score at study entry, vascularization score at time of reepithelialization, and ulcer area at study entry in both groups. Time to reepithelialization was not correlated with age, sex, or duration of signs in either group. CONCLUSIONS AND CLINICAL RELEVANCE Topical application of undiluted heterologous serum was well tolerated by dogs with SCCEDs but, as an adjunct to standard treatment, did not reduce time to corneal reepithelialization.

Dynamic confirmation of fixation techniques of the tibial tubercle osteotomy.

The tibial tubercle osteotomy is gaining popularity for revision total knee arthroplasty; however, the potential for tubercle displacement has been a concern. This study compared the mechanical behavior of the tibial tubercle osteotomy after screw and cerclage wire fixation. Tibial tubercle osteotomy was done on 40 tibias from cadavers with equal numbers fixed by either screws or wires. Specimens were loaded cyclically to simulate straight leg raises and then loaded to failure with the patellar tendon oriented 0 degrees or 25 degrees from the tibial axis. Tibial tubercle osteotomy cyclic displacement was greater for wire constructs at 25 degrees than all other constructs. Failure loads were greater for screw constructs at 25 degrees than both wire constructs. Screw constructs failed at 1429 +/- 348 N (0 degrees) and at 1925 +/- 982 N (25 degrees). Wire constructs failed at 1072 +/- 260 N (0 degrees) and at 893 +/- 293 N (25 degrees). Bone mineral density correlated positively with failure loads. Straight leg raise (400 N) and knee extension (250 N) against gravity during rehabilitation should be feasible with either screw or wire fixation after tibial tubercle osteotomy. Special care should be taken for the large patient and patients with decreased bone density.