A twofold thickening of capillary basement membranes of rat retinas resulting from dietary galactose was prevented by sorbinil, an inhibitor of aldose reductase. Since the basement membrane thickening was ultrastructurally similar to that typical of diabetic retinopathy, it may indicate changes in vessel permeability and susceptibility to hemorrhage. Galactosemic rats should be useful models for studying basement membrane-related complications of diabetes and for examining the potential biochemical regulation of basement membrane synthesis by aldose reductase inhibitors.
Age‐related cataract and neurodegeneration has been linked to oxidative stress and increased lenticular levels of Fe and Cu, which can contribute to ROS generated through the Fenton Reaction. Since both antioxidants and chelating agents have both been reported to reduce experimental cataracts, we have synthesized a new class of antioxidants (JHX‐4 and its dimethoxy analog JHX‐8) containing a novel 2‐amino‐4‐hydroxylpyrimidine ring system that selectively chelates Fe and Cu. In vitro studies in human lens epithelial cells and retinal pigment epithelial cells demonstrate that these compounds can reduce ROS generated by H2O2, endoplasmic reticulum (ER) stress, or Fenton’s reaction. In vivo studies demonstrate that these compounds accumulate in the lens and retina after oral administration. In Long‐Evans rats receiving whole head irradiation, these compounds delayed cataract formation proportional to the tissue levels of drug achieved. Compared to untreated rats, treatment with JHX‐4 and ‐8 delayed the formation of PSC punctuate opacities in 50% of animals by 53 and 58 days, respectively and lens PSC opacities by 38 and 47 days, respectively. In vivo neuroprotection studies are currently in progress. Supported by NIH EY016460‐01.
Diabetic dogs rapidly form bilateral sugar cataracts within one year of diagnosis. Similar sugar cataracts also form in galactose‐fed dogs. Since topical KinostatTM has been shown to reverse initial cataract formation in young galactose‐fed dogs, we have conducted a proof of concept masked pilot study with 41 newly diagnosed dogs with diabetes mellitus (DM) to investigate whether KinostatTM can inhibit the progression of cataracts in a clinical setting. After obtaining owner consent to participate in the study, all dogs were randomly assigned a coded vial containing either KinostatTM or vehicle for 1 year with the contents of the vial (drug or placebo) masked from the examiners. Thirty dogs received the active agent while the remainder received the placebo vehicle. Owners were instructed to administer the agent 3 times daily to both eyes and compliance was monitored by recording each time of administration. Ocular examinations on dilated eyes conducted at the initial examination and at 1, 2, 3, 6, and 9 month intervals with slit lamp and indirect ophthalmoscopy indicated that KinostatTM is beneficial in arresting the onset and/or progression of cataracts in dogs with DM. The implications of this study for human sugar cataracts will also be discussed. Supported by NIH SBIR 1R43EY018013‐01A1 Commercial interest
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