CORNEA EWAP DECEMBER 2023 41 corneal fibrosis but also that it could work in a cornea where the epithelium and epithelial basement membrane are intact.” Dr. Wilson said there are dozens of companies that have brainstormed ideas for drugs that will impact corneal fibrosis when given topically. Many have reached out for his opinion, and Dr. Wilson said the first question he asks is if it penetrates the epithelium and epithelial basement membrane. The answer is almost always no, but now it’s been proven that losartan does. Dr. Wilson’s work includes five studies in rabbits, three of which are published, one that is in review, and another that is being prepared for publication. One study was for descemetorhexis, one was for alkali burns, 3 and a third was in PRK in rabbits. “One study simulated a blast injury to the cornea, and we used that with an irregular excimer laser ablation that simulates a very rough corneal surface, while the last study investigated the effect of losartan on incisions in rabbit corneas,” he said. The Cleveland Clinic has submitted a patent covering losartan and all the other drugs in that group, Dr. Wilson said, adding that there are at least eight other angiotensin II receptor blockers. Losartan was the drug that was initially focused on because it has shown several advantages, with the first being that it’s soluble in basic buffers like balanced salt solution or normal saline. Most other drugs in that group are not soluble in aqueous solutions, so you’d have to use special vehicles. This adds more complexity for formulating it for patients. Losartan is also one of the most widely used oral drugs in the world, so the safety is assured, he said. It’s now been used topically by hundreds of ophthalmologists throughout the world. Dr. Wilson has trained a number of Brazilian corneal and refractive surgeons and noted that the first in-human case report using losartan for a refractive surgery complication came from Renato Ambrosio, Jr., MD, PhD, who contacted Dr. Wilson about one of his patients who he thought would benefit from this. 4 Since this first case, Dr. Wilson said he has heard from many other ophthalmologists with cases where they think losartan could be used. Dr. Wilson noted that a critical piece is that “you can’t stop after 1 month of treatment and think that the patient failed.” Some patients will start responding by 2 or 3 months. “In the vast majority, especially the more severe scarring fibrosis, it’s going to take 4–6 months before you see that it’s working,” he said. He noted that patients may notice an improvement in vision before physicians see it at the slit lamp. It’s important to get a commitment from the patient to try this option for 6 months before giving up. Dr. Wilson noted that of the few patients who have been using it for almost a year, there have been no reports of toxicity. However, he cautioned that those interested in exploring this treatment option stick to the recommended and proven dosage of 0.8 mg/mL. While many have asked if it would make sense to increase the dosage for the treatment to work faster, this could cause complications because you start interfering with normal functions that transforming growth factor beta controls in the cornea. “I encourage physicians not to use more than 0.8 mg/mL until animal studies show that higher concentrations are safe and effective. It’s working so well now,” he said. His research has shown that losartan is soluble up to more than 400 mg/mL in balanced salt solution, but when you get up to this amount, it becomes viscous like hyaluronic acid-containing solutions. “I don’t want physicians applying that to corneas before higher doses have been tried in animals. My biggest concern is that people will start using higher concentrations with no data and end up with complications that have not been reported with the 0.8 mg/mL dosage since transforming growth factor beta also regulates normal cellular functions in corneas,” he said, emphasizing that he has yet to have any reports of complications in patients using it 6 times a day for months. Dr. Wilson pointed out that animal studies that have been done have so far have been prophylactic. But the human studies are in patients who already have the fibrosis and start treatment. This proves that the treatment could work either way. “It works prophylactically because transforming growth factor beta is required for the precursor cells to develop into myofibroblasts,” he said. “Or it works if the fibrosis is already there because the myofibroblasts that maintain the fibrosis are still dependent on an ongoing adequate supply of transforming growth factor beta signaling. If you cut that off with losartan, you’ll cause those cells to undergo apoptosis, and when that happens, normal keratocytes and corneal fibroblasts can repopulate that area of the cornea and restore the normal transparent arrangement of the stromal tissue.” This will require further
RkJQdWJsaXNoZXIy Njk2NTg0