Diabetic macular edema, edema secondary to vein occlusions, central serous chorioretinopathy, cystoid macular edema and subretinal fluid with retinal detachments. These are but some of the conditions in which intraretinal or subretinal fluid leads to vision loss.

Outcomes with todays therapies depend upon the nature of the retinal disorder, but even treatment can often lead to significant loss of visual acuity. Moreover, retinal detachments require surgical intervention, with the attendant morbidity. Thus, we have ample reason to investigate new therapies that might aid in absorption of intraretinal or subretinal fluid.

On the Horizon
Inspire Pharmaceuticals of Durham, N.C., has begun a clinical investigation of a drug for just this purpose. Researchers are studying INS37217, delivered by intravitreous injection, to see if it is safe and effective in removing subretinal fluid in patients with rhegmatogenous retinal detachments (RRD).

INS37217 is a dinucleotide that has agonist activity on P2Y2 receptors. These receptors exist on the retinal-facing membrane of the retinal pigment epithelium (RPE). Activation of the receptors stimulates absorption of fluid from the retina to the choroid. Thus, agents that activate these receptors have the potential to treat conditions that result in an accumulation of intraretinal or subretinal fluid.

Patients with RRD are the first group in whom this drug is being tested. To be included in the study, patients must present with macula-on detachments that are conventionally treatable by pneumatic retinopexy.

The macula-on RRD trial allows investigators to evaluate INS37217 for any safety concerns by testing contrast sensitivity and color vision as well as visual acuity in eyes that should retain excellent vision. These extra tests should enable the investigators to detect any subtle adverse effects.

Patients with other diseases in which INS37217 might be used may already have compromised maculae. This could interfere with the safety analysis of the drug. Future studies may look at some of these other conditions.

Parallel Activity
Endogenous uridine 5-triphosphate (UTP) stimulates the P2Y2 receptor. INS37217 parallels UTPs activity, but lasts longer in the eye by resisting enzymatic degradation.

In vitro studies found INS37217 to produce physiological effects in the RPE comparable with those of UTP. The agent was then tested intravitreally in an in vivo rat retinal bleb model. At 24 hours after administration, there was complete disappearance of four out of six blebs in the INS37217-treated group and no disappearance in the six control blebs.¹ In contrast, UTP was ineffective when given intravitreally, which is consistent with the notion that the retina degrades UTP before it reaches the RPE.

INS37217 was further studied in small retinal detachments in rabbits and large detachments in pigs. In rabbits, INS37217 cut the time to achieve retinal reattachment from more than three hours to approximately 90 minutes.² In pigs the drug reduced that time from 4-5 days to about 36 hours.³

Two centersHunkeler Eye Centers in Kansas City, Mo., and Retinal Consultants in San Diegoare involved in a double-masked, randomized, dose-ranging trial of a single intravitreal injection of INS37217 in subjects with retinal detachments.

Dr. King is affiliated with Hunkeler Eye Centers. He has no financial interests in INS37217 or Inspire Pharmaceuticals.

1. Maminishkis A, et al. Purinoceptor agonists increase fluid clearance out of subretinal space blebs in vivo. IOVS 2000: (suppl.) S136.
2. Meyer CH, et al. The effects of INS37217, a P2Y2 receptor agonist, on the reabsorption rates of subretinal fluid in a rabbit model of retinal detachment. IOVS 2001: (suppl.) S446.
3. Meyer CH, et al. INS37217, a P2Y2 receptor agonist, increases the reabsorption rate of subretinal fluid in pig models of small and large bullous retinal detachments. Deutsche Ophthalmological Society Meeting 2001.