An intravitreal biodegradable sustained release naproxen and 5-fluorouracil system for the treatment of experimental post-traumatic proliferative vitreoretinopathy

Abstract

Background/aims: To determine the potential of an intravitreal sustained release naproxen and 5-fluorouracil (NA/5-FU) codrug for the treatment of experimental proliferative vitreoretinopathy (PVR) in a model for trauma associated tractional retinal detachment (TRD).

Methods: Sustained release pellets were prepared by covalently linking naproxen to 5-fluorouracil. Drug release was tested in vitro and toxic effects were evaluated by electroretinography and light microscopy. Traumatic PVR was induced in pigmented rabbits by performing a scleral laceration, followed by repair and intravitreal injection of 0.4 ml of autologous blood. Thirty six eyes were treated with a sustained release implant containing 1.5 mg NA/5-FU as a codrug and 36 control eyes were submitted to surgery alone. Eyes were evaluated for TRD by serial indirect ophthalmoscope examination at different time points followed by postmortem fundus evaluation of the enucleated eye

Results: The NA/5-FU pellets were found to provide linear release of 5-FU and naproxen over the 30 day duration of the in vitro release test. Both the severity of PVR grade and the percentage of eyes with moderate or worse tractional detachment were significantly lower in eyes treated with the codrug pellet. There were no drug related toxic effects evident on histopathological or electroretinograph examination of eyes containing the NA/5-FU pellet.

Conclusions: The results suggest that this NA/5-FU codrug device effectively inhibits the progression of PVR in a rabbit trauma model that closely resembles PVR in humans. Additional studies to add knowledge to these initial findings and to clarify the potential of the codrug device for the treatment of human PVR are warranted.

Figure 1

In vitro release of naproxen and 5-fluorouracil from NA/5-FU codrug pellets placed in 50% human plasma and 50% phosphate buffer, pH 7.4. Data represent mean (SD); n = 3 at each time point.

Figure 2

Median clinical grade of proliferative vitreoretinopathy as a function of time. Median grade was 0 at time points that do not show a data bar.

Figure 3

Percentage of eyes with moderate or worse tractional detachment as a function of time. The percentage of eyes with moderate tractional detachment was 0 at time points that do not show a data bar.

Figure 4

Fundus evaluation of a radial section of the enucleated eye, 30 days after the triggering event. (A) The finding in the control eye where typically 50%–100% of the retina was detached (severe retinal detachment), usually associated with an open funnel configuration. Fibrous ingrowth from the wound and the peripheral retina and ray drawn towards the fibrous mass can be observed. (B) A treated eye with the retina attached with minimal traction elevation confined to the posterior pole. Note that at day 30 the NA/5-FU pellet showed only partial absorption.

Figure 5

Representative scotopic electroretinography in eye receiving a 1.5 mg NA/5-FU codrug pellet. The ratios of the electroretinographic b-wave amplitude of the implanted (right) to the left eye (control) were not statistically different when preinjection values (left) were compared with postimplantation values (right) at day 60 (p = 0.27).