Effects of an intravitreal daunomycin implant on experimental proliferative vitreoretinopathy: simultaneous pharmacokinetic and pharmacodynamic evaluations.
Intravitreal daunomycin (D) effectively suppresses cellular proliferation in experimental proliferative vitreoretinopathy (PVR) but has a narrow therapeutic safety range. Studies were undertaken to reduce toxicity of D by preparing a slow-release implant using polysulfone capillary fiber (PCF). Fabrication of the implant involved loading PCF with 1% D in tristearin (w/w), an excipient with diffusion-retardant properties. Two dose levels of the PCF-D device (15 micrograms and 30 micrograms/device) were prepared and sterilized prior to use. To examine the kinetics and efficacy of the device, rabbits were randomized and eyes were implanted as follows: 1) control group (PCF vehicle); 2) PCF-D (15 micrograms/device); 3) PCF-D (30 micrograms/device). Immediately after implantation, all eyes received an intravitreal injection of 2.5 x 10(5) retinal pigmented epithelial (RPE) cells. Thereafter, tractional retinal detachments (TRD) were graded by ophthalmoscopic examination. Also, fluorophotometry scanning from the retina to the anterior chamber was performed to determine the intraocular bioavailability of D. Results showed a therapeutically sustained level of D up to 21 days after device implantation. Midvitreous concentration of D was greater in group 3 than group 2 at all time points examined, indicating a dose-proportional increase in D release. Results of the PVR study showed that by 7 days after treatment, all eyes implanted with the PCF vehicle developed stage 2 TRD or greater; only 1 eye in each of groups 2 and 3 developed stage 2. By 2 weeks, most eyes in groups 2 and 3 remained in stages 1 and 2 with only 2 eyes progressing to stages 3 and 4 TRD. By 5 weeks, all eyes in group 1 showed stages 4 and 5 TRD, while most eyes in groups 2 and 3 remained in stages 1 and 2. The device with 30 micrograms D was more effective in preventing TRD. In conclusion, these data indicate that PCF can reduce the toxicity of D and may be a useful implant for treatment of PVR.
Rahimy
M H
MH
Pharmacia, Inc., Columbus, Ohio.
Peyman
G A
GA
Fernandes
M L
ML
el-Sayed
S H
SH
Luo
Q
Q
Borhani
H
H
D000818:Animals; D001682:Biological Availability; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003630:Daunorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004343:Drug Implants; D015590:Fluorophotometry; D010857:Pigment Epithelium of Eye / Q000254:growth & development; D011817:Rabbits; D011897:Random Allocation; D012163:Retinal Detachment / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014822:Vitreous Body / Q000378:metabolism*
D004337:Drug Carriers; D004343:Drug Implants; D003630:Daunorubicin