Stephen Kim, MD, Associate Professor of Ophthalmology and Visual Sciences at Vanderbilt, Nashville, TN, discussed the pathologic role of prostaglandins in AMD and DR and the therapeutic application of NSAIDs.
NSAIDS are one of the most commonly prescribed classes of medications worldwide due to their established analgesic, antipyretic, and anti-inflammatory therapeutic effects. Approximately 1 in 6 individuals in the United States are prescribed a NSAID and many more use over the counter ones. NSAIDs are potent inhibitors of cyclooxygenase (COX) enzyme, and thereby all downstream production of pro-inflammatory prostaglandins. Within the eye, it is well established that prostaglandins cause vasodilation, increase vascular permeability, facilitate leukocyte migration, and promote angiogenesis.
7 Consequently, their inhibition has favorable clinical effects on ocular inflammation and cystoid macular edema (CME).
In addition to their established therapeutic effects, a growing body of scientific evidence indicates that prostaglandins play a pathologic role in the progression of AMD and recent years have seen more studies examining a therapeutic role of NSAIDs in slowing progression.
8 While anti-VEGF inhibitors have been an important advance in the treatment of exudative AMD, they do not slow down the underlying disease process. Moreover, VEGF is essential for normal homeostasis of retinal cells and its chronic inhibition may be undesirable. In addition, solely inhibiting VEGF does not address the underlying cause of VEGF induction. In this regard, COX can be detected in human choroidal neovascular membranes and considerable scientific evidence indicates that COX is a promoter of angiogenesis. Pharmacologic inhibition of COX appears to reduce VEGF expression in cultured human cells and suppresses VEGF in animal models of retinal angiogenesis. Published work from Kim's lab has demonstrated that both pharmacologic inhibition and genetic deletion of COX reduces laser-induced CNV in animal models.
9,10 While results from clinical studies investigating a therapeutic benefit of NSAIDs for AMD have been inconsistent, two recent prospective, randomized, controlled clinical studies reported favorable effects of topical bromfenac with respect to retinal thickness and reduced number of anti-VEGF treatments in patients with exudative AMD.
8
DR is the most frequent cause of legal blindness among working-aged individuals in developed countries.
3 DME is the most common cause of vision loss in diabetic patients, affecting about 75,000 new patients in the United States every year.
4 Proven preventable measures for DR include lowering of high blood pressure and strict control of blood glucose, but a growing body of scientific evidence supports a pathogenic role of inflammation.
8 In support of this, a number of pro-inflammatory cytokines, including prostaglandin E
2 (PGE
2) and VEGF, are consistently elevated in the vitreous of patients with advanced stages of DR and DME and treatment with NSAIDs prevents or delays DR progression in animal models. Kim presented work from his group that demonstrated elevated levels of prostaglandin PGE
2 in vitreous samples taken from patients with advanced DR that correlated with vitreous levels of VEGF.
11 Kim also presented results from a prospective, randomized clinical study that demonstrated significant intraocular reduction of interleukin 8 (IL-8) and platelet-derived growth factor (PDGF)-AA levels in eyes with advanced DR treated with topical ketorolac 0.45%.
12 Kim reported that meaningful inhibition of PGE
2 and other inflammatory cytokines implicated in the pathogenesis of DR may prevent or delay progression of DME (
Fig. 2).
Despite scientific evidence that inhibition of prostaglandins may delay the progression of AMD and DR, Kim emphasized that topical or oral application of NSAIDs does not result in sufficient retinal drug levels to meaningfully reduce retinal prostaglandin levels. Intraocular injection, on the other hand, provides considerably higher retinal drug levels while minimizing systemic exposure. Previous work from Kim's lab has demonstrated that intravitreal ketorolac results in therapeutic retinal drug levels 100 to 1000 times greater than after topical application and significantly reduces intraocular inflammation and PGE
2 levels in an animal model of uveitis.
13,14 However, ketorolac has a short intraocular half-life, which greatly limits its therapeutic effect.
Kim presented new data on the safety, pharmacokinetics, and efficacy of intraocular celecoxib. Celecoxib is a selective COX-2 inhibitor used in the treatment of inflammatory arthritis. It is more than 300 times more selective for COX-2 than COX-1. COX-2 is the inducible isoform of COX and predominately involved in inflammatory responses and its preferential inhibition may minimize toxicity. Celecoxib is also relatively insoluble in vitreous, which may translate into more sustained delivery after intraocular injection. Escalating doses of celecoxib were intravitreally injected into rabbit eyes and were found to be nontoxic to the retina and resulted in sustained retinal drug levels out to 8 weeks. Intraocular celecoxib significantly reduced intraocular inflammation and PGE2 in an animal model of uveitis. Despite the observation of cataract formation at higher doses, there was no increase in intraocular pressure and the drug was well tolerated with no other evident adverse effects.
Kim concluded that despite increasing rationale to test the efficacy of NSAIDs to slow progression and prevent vision-threatening complications of AMD and DR, there is no convincing evidence that topical or systemic NSAIDs achieve measurable retinal drug levels. In contrast, intravitreal administration of celecoxib results in considerably higher retinal drug levels and sustained intraocular delivery.