- No drug can reverse cortical cataracts once they have formed — only surgery can remove cataracts.
- Experimentally, aldose reductase inhibitors have been shown to prevent the development/progression of “sugar” cataracts in diabetic or galactosemic animals.
- Kinostat is a topical aldose reductase inhibitor being developed for the prevention of blinding cortical cataracts in dogs with diabetes mellitus.
What Are Sugar Cataracts?
Diabetic (sugar) cataracts are osmotically induced by the intracellular accumulation of sorbitol from glucose that is catalyzed by aldose reductase. Physiologically, sorbitol is produced by aldose reductase in the metabolically active lens cells as a protective response to an increased hyperosmotic environment produced by hyperglycemia. The accumulation of sorbitol increases the intracellular osmolarity to protect the cell from dehydrating. The osmolyte sorbitol is a polar sugar alcohol that does not readily pass through membranes. When the hyperglycemic environment is reduced, the intracellular osmolarity suddenly becomes higher than its surrounding environment. As a result, the cells swell because sorbitol cannot be rapidly removed from the cell. This swelling initiates both cellular membrane permeability changes and biochemical changes (induction of oxidative stress that alters membranes and causes protein aggregation) that result in lens cell degeneration that leads to cataract formation. The development of sugar cataracts begins with suture accentuation as lens fibers, which attach at the suture area, swell. This is followed by vacuole formation initially at the superficial equatorial areas that progress to encompass the entire equatorial area. Eventually cortical opacities appear as a result of increased light scattering due to lens fibers degeneration, membrane alterations, and protein aggregation. Cortical opacities are the first sign of diabetic cataract that can be clinically observed without the aid of mydriatic dilation and biomicroscopy. This is the endpoint of our clinical trial. Cortical opacities result in blindness and require cataract surgery. However, cortical cataracts can progress to mature or hypermature cataracts that can contribute to the development of uveitis or glaucoma. Because aldose reductase has broad substrate specificity, the same process occurs in naturally galactosemic animals.
What Factors Affect Sugar Cataract Development?
The onset and rate of progression of sugar cataracts is dependent on a number of factors that include the general health of the dog and the control of its hyperglycemia, the presence or absence of ocular disease not associated with diabetes mellitus, and lenticular aldose reductase activity. Of these, the levels of hyperglycemia and aldose reductase activity appear to be the most important. Lenticular aldose reductase activity is induced by hyperglycemia and is higher in younger versus older dogs. As a result, the progression of sugar cataracts is faster and the lens changes are more severe in younger dogs. Lens changes associated with sugar cataract formation are documented in dilated eyes by slit lamp and/or retroillumination photography below:
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1) Unchanged/No Cataract Formation
2) Equatorial Vacuoles Encompassing Less Than 360°
3) Equatorial Vacuoles Encompassing the Entire Equatorial Region (360°) and Cortical
4) Late Immature to Mature Cataract With/Without Vision Loss
In diabetic dogs, cortical opacities are the first clinical sign of cataract generally observed by veterinarians. This is because changes up to the cortical opacity stage are generally not observed without mydriatic dilation and biomicroscopy. Approximately 21% of dogs have been reported to have cataracts at the time of diagnosis of diabetes mellitus by veterinarians. The remaining 79% are classified as a “clear, not cataractous lens”. However, this does not mean that this remaining 79% of the dogs are free of lens changes and, therefore, suitable for Kinostat treatment. In our experience, vacuoles are absent in only half of the remaining “clear eyed” dogs diagnosed by veterinarians because vacuoles are primarily only visible in dilated eyes.Why is vacuole formation important? Suture accentuation and vacuole formation represent hydration changes that are directly linked to sorbitol-associated osmotic stress. The appearance of vacuoles indicates the presence of intracellular sorbitol accumulation. While sorbitol accumulation increases intracellular osmolarity in response to extracellular osmotic stress, the presence of intracellular sorbitol levels can only be gradually decreased because sorbitol cannot be readily removed from the lens cells by diffusion. Kinostat cannot remove intracellular sorbitol levels – it can only prevent the further formation of sorbitol. The initial presence of vacuoles can wax and wane as the extracellular osmolarity is increased and decreased in response to hyperglycemic control through insulin administration. However, as the number of vacuoles increase to the intermediate or advanced stage, they no longer wax and wane, and large swings in hyperglycemia (especially in rapid reductions after insulin administration) become especially deleterious. This can result in overnight cortical cataracts as clinically described in humans. Large swings in hyperglycemia especially occur in the first few months after diagnosis because regulating insulin dosages and blood glucose levels requires extensive communication between the owner and veterinarian. That is why cataracts have been reported to develop within the first 100 days in 41% of newly diagnosed diabetic dogs.
How Does Kinostat Work?
Kinostat is an aldose reductase inhibitor that in the lens prevents the conversion of glucose to sorbitol that results in the lens changes described above. Proper administration of Kinostat only reduces the levels of sorbitol formed in the lens; therefore, the degree of equatorial vacuoles present (i.e., intracellular sorbitol present) at the initiation of Kinostat treatment clearly affects the “observed efficacy” of this drug. At what level of lens changes is Kinostat no longer effective in preventing the development of cortical cataracts in dogs? There is a point in vacuole development where intervention no longer arrests the subsequent development of cortical cataracts. Studies suggest that the development of cortical cataract can only be halted when lenses are treated with the aldose reductase inhibitor prior to the development of a complete ring of equatorial vacuoles. In our initial clinical study of 40 dogs where Kinostat was administered to dogs with no lens changes or only minimal vacuoles present, a significant decrease in cortical cataract formation was observed. (Click here to see paper.)
An FDA Regulated Trial Has Been Completed
A Placebo-Controlled Double-Masked, Multicenter Trial has been completed at the following locations:
Kelley Corcoran, DVM, DACVO
4103 Rust Road
Fairfax, VA 22030
Toll Free: 888-278-1299
Thomas Miller, DVM, MS, DACVO
Tampa Bay Veterinary Specialists
1501A Belcher Road South, Suite 1A
Largo, FL 33771
E. Dan Wolf, DVM, DACVO
Southern Eye Clinic for Animals
5406 Hoover Blvd., Ste 20
Tampa, FL 33634
Jennifer Hyman, VMD, MA, DACVO
Eye Care For Animals
808 Bestgate Road
Annapolis, MD 21401
Phone: 410-224-4470 or 1-877-409-3937
Tonya McIlnay, DVM, MS, DACVO
Veterinary Eye Specialists of Nebraska
10371 Ellison Circle
Omaha, NE 68134
Terah Webb, DVM, DACVO
MedVet Medical and Cancer Center for Pets
300 E. Wilson Bridge Rd.
Worthington, OH 43085
Mary Belle Glaze, DVM, MS, DACVO
Gulf Coast Animal Eye Clinic
1551 Campbell Road, Suite V
Houston, TX 77055
Robert Munger, DVM, MS, DACVO
Animal Ophthalmology Clinic, Ltd.
4444 Trinity Mills Road, Ste 201
Dallas, TX 75287
Reuben Merideth, DVM, DACVO
Eye Care for Animals
175 E. Fort Lowell Road
Tucson, AZ 85705
Toll Free: 877-762-9838
Eye Care for Animals
5040 Convoy Street, Suite B
San Diego, CA 92111
Randy Scagliotti, DVM, MS, DACVO
Eye Care for Animals
3025 Edinger Ave.
Tustin, CA 92780
Kinostat is currently not available for sale. We have filed our final report to the FDA and are eagerly awaiting their anticipated approval. Thank you for your interest in our product. We are striving to make this available as soon as possible to meet your diabetic dog’s needs.