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.

Retinal and Ocular Toxicity in Ocular Application of Drugs and Chemicals – Part II: Retinal Toxicity of Current and New Drugs

“…Finally, Kivilcim et al [60] showed that in silicone-filled eyes, the safe dose is up to 200 g, and therefore the vitreous status is important to know before intravitreal administration of 5-FU. In another study, Cardillo et al [61] designed a sustained-release pellet of 1.5 mg naproxen and 5-FU with continuous drug delivery. In this study, there were no drug-related toxic effects evident on histopathological or ERG examination of eyes containing the naproxen/5-FU pellet [61] .…”

“…In another study, Cardillo et al [61] designed a sustained-release pellet of 1.5 mg naproxen and 5-FU with continuous drug delivery. In this study, there were no drug-related toxic effects evident on histopathological or ERG examination of eyes containing the naproxen/5-FU pellet [61] .…”

Animal Models of Proliferative Vitreoretinopathy and Their Use in Pharmaceutical Investigations

“…Therefore, in addition to a clinical indirect microscopic examination, a detailed fundus evaluation of the enucleated eye under a dissecting microscopy is used for PVR grading as follows [86]:…”

Phase I and Phase II Ocular Metabolic Activities and the Role of Metabolism in Ophthalmic Prodrug and Codrug Design and Delivery

“…[65]. Their results suggested that this codrug system effectively inhibits the progression of experimental proliferative vitreoretinopathy (PVR) in a rabbit trauma model that closely resembles PVR in humans [66]. This unique concept of codrug design has also been utilized in our laboratories for codrugs of ethacrynic acid (ECA) covalently linked to either atenolol (ATL) or timolol (TML) via ester bond linkages ( Figure 4) were designed and synthesized to improve ocular delivery, and in addition, to take advantage of the apparent synergistic mechanism of ECA and the two β-adrenergic receptor antagonists [67].…”