Pharmacologic inhibition of experimental proliferative vitreoretinopathy (PVR) using a triamcinolone/5-fluorouracil codrug sustained release pellet
Purpose: We have previously evaluated the efficacy of a novel dexamethasone/5-fluorouracil (5-FU) codrug pellet in the treatment of PVR. This prepararion was not fully effective because of the drug's high solubility and relatively fast release rate. In this study we evaluated the efficacy and in vitro pharmacokinetics of a triamcinolone (TA)/ 5-FU pellet, a less soluble and longer acting preparation in the treatment of experimental PVR. Methods: Thirty New Zealand White Rabbits underwent two-port lensectomy, core vitrectomy and retinal endodiathermy to create PVR, according to a modification of the method of Iverson et al [IOVS,1992(suppl.)]. No drug was placed in 9 control animals. One 2.5 mg pellet of the TA/5-FU codrug was placed in each of 11 eyes and three pellets (total 10 mg) were placed in 10 eyes. Severity of PVR, presence or absence of retinal detachment (RD) and corneal neovascularization (NV) were graded weekly by two masked observers for 8 weeks. For pharmacokinetic analysis, 1, 4 and 8 mg pellets were immersed in 1 ml of phosphate buffer and samples analyzed every 24 hours for TA, 5-FU and intact codrug. Results: Both the severity of PVR and the number of RDs were significantly less in the 10 mg codrug group than in controls by week 3. This difference remained statistically significant throughout eight weeks of follow-up (p<0.02). In the 2.5 mg pellet group the severity of PVR and number of RDs were less than in controls but this difference was not statistically significant. At eight weeks, significant corneal NV was present in 7/9 control animals, 0/11 in the 2.5 mg and in 1/10 in the 10 mg pellet group (p≤0.01). Release from each pellet was found to be constant (ie. zero order) and increased with increasing surface area of the pellet. Conclusions: The increased surface area afforded by the 10 mg co-drug pellet compared to the 2.5 mg pellet accounted for its more rapid in vitro release rate and was a significant advantage in the treatment of experimental PVR. The TA/5-FU codrug pellet is a promising new agent for the management of PVR.
Khawly, JA; Yang, DCS; Cynkowski, T; Cynkowska, A; Crooks, PA; Ashton, P; Jaffe, GJ
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