Topical Ketotifen Fumarate Inhibits Choroidal Mast Cell Degranulation and Loss of Retinal Pigment Epithelial Cells in Rat Model for Geographic Atrophy.

Purpose: This study evaluates whether topical ketotifen fumarate (KTF) can prevent geographic atrophy (GA)-like phenotypes in a rat model. Methods: Pharmacokinetics (PKs) of KTF after topical administration twice daily for 5 days was analyzed in rat retina, retinal pigment epithelium (RPE)/choroid/sclera, and in plasma by an liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Rats were then given hydrogel implants +/- 48/80 in the superior subconjunctival space and topically treated with 1% and 0.25% of KTF or phosphate buffer saline (PBS) twice daily. Rats were euthanized at 1, 2, 4, and 8 weeks postinjection. Choroidal mast cells (MCs) were stained with nonspecific esterase and the RPE monolayer was labeled with RPE65 and ZO-1 in whole mount choroids. Retinal and choroidal areas were determined in cryosections stained with picrosirius red. Dark-adapted electroretinogram (ERG) was also performed to evaluate retinal function. Results: PK results showed the highest level of KTF (average 5.6 nM/mg) in the RPE/choroid/sclera in rats given topical 1% KTF. Topical 1% KTF significantly reduced choroidal MC degranulation at 1 week and 2 weeks (both P < 0.001) and RPE loss at 4 weeks (P < 0.001) as well as retinal and choroidal thinning (both P < 0.001) and reduction in ERG amplitude at 8 weeks (P < 0.05) compared to PBS. Similar results were obtained with 0.25% KTF. Conclusions: Both 1% and 0.25% KTF eye drops effectively reduced MC degranulation, RPE loss, and retinal and choroidal thinning while preventing the decline of ERG amplitude in a GA-like rat model. These data suggest that topical KTF might be a new therapeutic drug for treating GA. Translational Relevance: The results of this study demonstrate that topical KTF successfully reduced GA-like phenotypes in a rat model and may provide a novel therapy for GA.

Heat effects on the retina.

BACKGROUND AND OBJECTIVE: To study the heat and power dissipation effect of anintraocular electronic heater on the retina. The determination of thermal parameters that are nonharmful to the retina will aid in the development of an implantable intraocular electronic retinal prosthesis. MATERIALS AND METHODS: In dogs, five different retinal areas were touched with a custom intraocular heater probe (1.4 x 1.4 x 1.0 mm) for 1 second while the heater dissipated 0 (control), 10, 20, 50, or 100 mW. In a second protocol, the heater was mechanically held in the vitreous cavity while dissipating 500 mW for 2 hours while monitoring intraocular temperature. The animals were observed for 4 weeks with serial fundus photography and electroretinography. The procedure was then repeated in the fellow eye. The dogs were killed and both eyes were enucleated and submitted for histology. RESULTS: In experiments using protocol 1, heater settings of 50 mW or higher caused an immediate visible whitening of the retinal tissue. Histologically, this damage was evident only if the eyeswere immediately enucleated. Permanent damage was caused by heater settings of 100 mW or higher. Under protocol 2, no ophthalmologic, electroretinography, or histologic differences were noted between the groups. Temperature increases of 5 degrees C in the vitreous and 2 degrees C near the retina were noted. CONCLUSIONS: The liquid environment of the eye acts as a heat sink that is capable of dissipating a significant amount of power. An electronic chip positioned away from the retina can run at considerably higher powers than a chip positioned on the retinal surface.