tretinoin and Vitreoretinopathy--Proliferative

Proliferative vitreoretinopathy (PVR) is a complex process. It causes contractile fibrocellular membranes that may prevent retinal reattachment. PVR therefore remains one of the most severe complications of rhegmatogenous retinal detachment (RD), with an incidence of 5-11%, and is among the most frequent causes of surgical failure (50-75%). Its severity derives from the complexity of the surgery required to treat patients and from its uncertain anatomic and functional prognosis. The first step in preventing PVR is to identify patients at risk by means of clinical and/or biological factors such as the characteristics of retinal tears (large size, number) and detachment (preexisting PVR, extent), and the use of cryotherapy. Surgeons must therefore adapt their surgical approach to the risk of PVR. The study of animal models and the natural history of the condition in humans demonstrate the importance of early antiproliferative treatment in the early stage of the disease. Combining 5-fluoro-uracil and heparin in the vitrectomy infusion lowers the rate of postoperative PVR onset in patients with PVR risk factors. The evaluation of new molecules and new dosages will lead to a decisive step in the fight against PVR.

Topics: Antibiotics, Antineoplastic; Colchicine; Daunorubicin; Fibrinolytic Agents; Fluorouracil; Glucocorticoids; Heparin; Humans; Immunosuppressive Agents; Intravitreal Injections; Keratolytic Agents; Retinal Detachment; Tretinoin; Tubulin Modulators; Vitreoretinopathy, Proliferative

Pharmacotherapy were the mainstream methods for the treatment of proliferative vitreoretinopathy (PVR), one of the leading causes of blindness. Due to the negligible side-effects, retinoic acid (RA) was considered to be a promising candidate drug. However, it was still a challenge to deliver drugs into vitreous with both long-term efficiency and biosafety. Sodium alginate was considered to be an excellent drug carrier owing to its controlled size, good biocompatibility and degradability. Based on a one-time synthetic strategy of preparing RA-sodium alginate microspheres, the study was aimed to establish a non-toxic and effective RA slow release platform. The prepared microspheres were smoothly round and relatively homogenous with an average diameter of 95.7±9.6μm. RA release rate from RA-MS was assessed in vitro by UV spectrometry and in vivo by high performance liquid chromatography, achieving a steady, long-term and effective level of RA. The biocompatibility of RA-MS was further confirmed through histology using HE staining and fundus microscope, finding no inflammation and other toxic response. Collectively, it could be concluded that RA-MS possessed a great potential in retinal PVR treatment.

Topics: Alginates; Animals; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Glucuronic Acid; Hexuronic Acids; Intravitreal Injections; Microspheres; Particle Size; Rabbits; Spectrophotometry, Ultraviolet; Tretinoin; Vitreoretinopathy, Proliferative

In a number of cases of retinal detachment, treatment may require the removal of the vitreous humour within the eye and replacement with silicone oil to aid healing of the retina. The insertion of silicone oil offers the opportunity to also deliver drugs to the inside of the eye; however, drug solubility in silicone oil is poor and release from this hydrophobic drug reservoir is not readily controlled. Here, we have designed a range of statistical graft copolymers that incorporate dimethylsiloxane and ethylene glycol repeat units within the side chains, allowing short chains of oligo(ethylene glycol) to be solubilised within silicone oil and provide hydrogen bond acceptor sites to interact with acid functional drug molecules. Our hypothesis included the potential for such interactions to be able to delay/control drug release and for polymer architecture and composition to play a role in the silicone oil miscibility of the targeted polymers. This strategy has been successfully demonstrated using both ibuprofen and all-trans retinoic acid; drugs with anti-inflammatory and anti-proliferation activity. After the copolymers were shown to be non-toxic to retinal pigment epithelial cells, studies of drug release using radiochemical approaches showed that the presence of 10v/v% of a linear graft copolymer could extend ibuprofen release over three-fold (from 3days to >9days) whilst the release of all-trans retinoic from the silicone oil phase was extended to >72days. These timescales are highly clinically relevant showing the potential to tune drug delivery during the healing process and offer an efficient means to improve patient outcomes.

Topics: Administration, Ophthalmic; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Dimethylpolysiloxanes; Drug Carriers; Drug Liberation; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Ibuprofen; Polyethylene Glycols; Retinal Pigment Epithelium; Silicone Oils; Solvents; Tretinoin; Vitreoretinopathy, Proliferative

The study was designed to better understand how retinoic acid (RA) influenced the migration and invasion abilities of retinal pigment epithelial cells (RPE) in vitro and how the related genes of the extracellular matrix (ECM) were expressed. The inhibition effects of RA on proliferative vitreoretinopathy (PVR) formation induced by RPE cells were studied in rabbits. Wound healing and Boyden chamber assays were used to show the abilities of migration and invasion of RPE. Microarray, real-time quantitative PCR (qPCR) and Western blotting showed how RA regulated the ECM genes. RA (10(-5) M) significantly (P < 0.05) inhibited PVR membrane and traction retinal detachment formation (80%). Moreover, RA treatment significantly inhibited the migration (80%) and invasion (65%) behaviors of human RPE cells (P < 0.05) by wound healing and Boyden chamber assays, respectively. Microarray and q PCR analysis showed RA treatment did inhibit the motility of human RPE cells by inhibition of metalloproteinases (MMP) 1, 2, 9, fibronectin-1, transforming growth factor beta, thrombospondin-1, tenascin C, most collagen, integrin, laminin molecules and along enhancing E-cadherin and MMP3 genes expression. And Western blotting indicated the coincident results on protein level of MMP1, 2, 3, 9, 14; fibronectin-1; integrinαM, β2 and E-cadherin. In conclusions, RA is a vital drug to inhibit the abilities of migration and invasion of RPE and to hamper the PVR formation by regulating some genes expression of ECM.

Topics: Adult; Animals; Antineoplastic Agents; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Cells, Cultured; Cytoskeleton; Disease Models, Animal; Extracellular Matrix; Extracellular Matrix Proteins; Gene Expression; Humans; Oligonucleotide Array Sequence Analysis; Rabbits; Retinal Pigment Epithelium; RNA, Messenger; Tretinoin; Vitreoretinopathy, Proliferative; Wound Healing

To evaluate the antiproliferative effect of an all-trans retinoic acid (at-RA) drug delivery system (DDS) on experimental proliferative vitreoretinopathy (PVR).. PVR was induced in rabbits with core vitrectomy and fibroblast injection. The DDS containing 420 microg, 650 microg, and 1,070 microg of at-RA was implanted into the vitreous of treated groups B, C, and D, respectively. Group A with no DDS and group E with nonmedicated DDS served as controls. The intravitreal at-RA concentration was measured with high-pressure liquid chromatography. The drug toxicity was evaluated histologically.. The severity of PVR was significantly reduced in groups C and D but not in groups A, B, and E. The drug release peaked at 6 weeks to 7 weeks. No signs of retinal toxicity were found in the DDS groups.. Intravitreal implantation of at-RA DDS appears effective in inhibiting the development of PVR and is well tolerated in rabbit eyes.

Topics: Absorbable Implants; Animals; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Delivery Systems; Drug Implants; Fibroblasts; Lactic Acid; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rabbits; Tretinoin; Vitrectomy; Vitreoretinopathy, Proliferative; Vitreous Body

It has been reported that retinoic acid (RA) may inhibit the growth of RPE and be used in the treatment of proliferative vitreoretinopathy (PVR). However, previous reports in this field have been conflicting. The main reason for these contradictory findings is that different methods for evaluating the effects of RA on RPE from different species have been used. In human specimens, only RPE from the donor eye (stationary) but not RPE from the PVR membrane (already at active proliferation status) have been tested. This study tested the effects of RA on the growth of RPE using a novel in vitro model: RPE from the PVR membranes, which simulates the in vivo situation of PVR patients better than RPE from the donor eyes. This study also used various methods to solve the conflicting results reported previously. We found that both all transretinoic acid (all-RA) and 13-cis-retinoic acid (cis-RA) can promptly (though not completely) inhibit proliferation of RPE (inhibition rate of 89%-90%) over a very wide range of concentrations (10(-9)-10(-5) M) and various lengths of periods (2-12 days) in a dose-dependent and time-dependent manner and without evident cytotoxic effects. Previously reported disadvantages discovered from the study of RPE from donor eyes, e.g., the absence of inhibitory effects on the early passages of cultured cells and inhibition occurring only after long-term treatment, do not present in RPE cells from the PVR membrane. The proliferation of RPE recovered from the inhibition by RA rapidly after the discontinuation of treatment, indicating that a continuous supply of the drug over a long period, i.e., until the breakdown of the blood-retinal barrier has been repaired, is essential for the success of drug treatment of PVR.

Topics: Basement Membrane; Bromodeoxyuridine; Cell Count; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Keratins; Pigment Epithelium of Eye; S100 Proteins; Time Factors; Tretinoin; Vitreoretinopathy, Proliferative

To investigate the antiproliferative effect of different concentration of all-trans retinoic acid (atRA) in a drug delivery system (DDS) in an experimental proliferative vitreoretinopathy (PVR) model.. The PVR animal model was induced by central vitrectomy and homologous fibroblasts injected at the same time in pigmented rabbits. Fifty rabbits underwent the surgery. These rabbits were divided into 5 groups of 10 rabbits at random. Group A was the control group. In group B, C, and E, one DDS device was implanted into the vitreous cavity after the vitrectomy, each DDS contained atRA 420 microg, 650 microg and no drug, respectively. In group D, two DDS devices were placed into the vitreous cavity, the total atRA content was 1,070 microg (420 microg + 650 microg). Each group was observed for 8 weeks. The development and the severity of PVR were observed and recorded. The vitreous cavity fluid was aspirated each week for measurement of the concentration of the atRA, in order to estimate the relationship between PVR and concentration of atRA. After 8 weeks, the retinal toxicity was evaluated by histopathology. Statistical analyses were performed at the end of the experiment.. Eight weeks after the operation, the incidence of PVR was lower in group C and group D, and there was a significantly statistical difference between these two groups and other groups. No intraocular toxicity was found by the histopathology examination.. atRA DDS is a safe and convenient mode for intraocular administration. DDS containing 650 microg and 1,070 microg atRA can inhibit the cell proliferation in the vitreous cavity effectively after surgery. atRA at a lower concentration cannot eliminate the cell proliferation but may delay the occurrence of PVR.

Topics: Animals; Cell Division; Delayed-Action Preparations; Drug Implants; Female; Male; Rabbits; Tretinoin; Vitreoretinopathy, Proliferative; Vitreous Body

To investigate the relationship between the level of retinoic acid (RA) in the subretinal fluid (SRF) and the extent of the vitreoretinopathy in 56 patients with rhegmatogenous retinal detachment, we studied the levels of RA in both SRF and serum using high liquid chromatography and also examined those levels in part of patients who took oral vitamin A 150,000 U.d-1. The results were that the level of RA in the SRF increased with the grade of the proliferative vitreoretinopathy (PVR); the levels of RA in both SRF and serum were significantly higher in the cases with vitamin A than those without. We conclude that retinoic acid metabolism between retinal pigment epithelial cells and neural epithelia was unbalanced after retinal detachment. Oral vitamin A is helpful to inhibit the genesis and development of the proliferative vitreoretinopathy.

Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Random Allocation; Retina; Retinal Detachment; Tretinoin; Vitamin A; Vitreoretinopathy, Proliferative

The pathobiology in proliferative vitreoretinopathy (PVR) is complex. The mechanism of the release of retinal cells from their cellular bond is unknown. The metalloproteinase stromelysin cleaves proteins of the extracellular matrix (ECM). This may liberate retinal cells. The expression of stromelysin in human RPE cells has been demonstrated. Here, stromelysin gene expression under all-trans-Retinal (atR) was investigated.. Human RPE-cells were used from passage 2 to 5. The expression of the human stromelysin gene was determined by reverse transcriptase-polymerase chain reaction using specific oligonucleotides. RPE-cells were incubated with 162 nmol/l tetraphorbolester (TPA) alone or simultaneous with 1 mumol/l atR.. TPA increased the expression of stromelysin in RPE cells. Incubation with TPA and atR lowered this increase. The decrease of expression was calculated semiquantitatively.. The expression of stromelysin in RPE cells is lowered after incubation with 1 mumol/l atR. The dedifferentiation of RPE-cells may decrease intracellular atR levels. This could turn an inhibition of stromelysin gene expression to an increase. This may then release retinal cells from their cellular bond and therefore be one of the initial steps in the development of PVR.

Topics: Cells, Cultured; Gene Expression Regulation, Enzymologic; Humans; Matrix Metalloproteinase 3; Matrix Metalloproteinase Inhibitors; Pigment Epithelium of Eye; Tretinoin; Vitreoretinopathy, Proliferative

To determine the antiproliferative activity in intravitreous retinoic acid (RA) dispersed in 1% sodium hyaluronate (HA).. Six groups of pigmented rabbits underwent gas-compression vitrectomy. Four days later, gas/HA or gas/balanced salt solution (BSS) exchange (1.0 m1) was performed in all rabbits. Groups A (n = 10) and B (n = 5) received intravitreous RA dissolved in 0.01 m1 of ethanol and dispersed in 1% HA (10 and 15 micrograms RA/m1, respectively). Group C (n = 10) received intravitreous RA dissolved in ethanol and dispersed in BSS (10 micrograms RA/m1). Groups D (n = 5) and F (n = 4) received 1 m1 of HA with ethanol; group E (n = 5) received 1 m1 of HA without ethanol. All groups except group F also received homologous fibroblasts and autologous, platelet-rich plasma intravitreously. The eyes were examined ophthalmoscopically for 1 month. Proliferative vitreoretinopathy (PVR) findings were graded according to the classification of Fastenberg et al. all group F eyes also were examined by light and electron microscopy.. RA in HA lessened PVR progression within 1 month when compared with HA injection controls and within 2 weeks when compared with the RA in BSS treatment group (both, p < 0.05). NO specific change attributable to ethanol was observed histopathologically.. RA dissolved in ethanol and dispersed in HA could be useful to treat PVR when silicone oil is unnecessary.

Topics: Animals; Blood Transfusion; Cell Division; Disease Models, Animal; Ethanol; Female; Fibroblasts; Hyaluronic Acid; Male; Osmolar Concentration; Plasma; Platelet Transfusion; Rabbits; Sodium Chloride; Solutions; Tretinoin; Vitreoretinopathy, Proliferative

The purpose of this study was to evaluate the effect of 13-cis-Retinoic Acid (RA) in Silicone-Fluorosilicone Copolymer Oil (SiFO) in a rabbit model of proliferative vitreoretinopathy (PVR). Rabbits underwent gas-compression vitrectomy. During gas-SiFO exchange, group 1 was injected with 1 ml (10 microg ml-1) 13-cis-RA in SiFO, group 2 with 1.5 ml (9 microg 1.5 ml-1) all-trans-RA in SiFO, group 3 with 1 ml SiFO alone, and group 4 with balanced salt solution (BSS). Groups 1-4 were also injected with 0.1 ml suspension of fibroblasts (75,000 0.1 ml-1) and 0.05 ml platelet rich plasma (70,000 0.1 ml-1), and were observed for 4 weeks. Group 5 was injected with SiFO alone, group 6 with 1 ml (10 microg ml-1) 13-cis-RA in SiFO, group 7 with 1.5 ml (9 microg 1.5 ml-1) all-trans-RA in SiFO, and group 8 with BSS. After 4 weeks, groups 5-7 underwent SiFO-BSS exchange. ERG and histopathology were performed to test for retinal toxicity in groups 5-8. The incidence of traction retinal detachment at 4 weeks was: group 1, 42.9%; group 2, 36.4%; group 3, 87.5%; and group 4, 88.9%. A significant difference in the incidence of PVR was noted between treated eyes (groups 1 and 2) and control eyes (groups 3 and 4) at 2, 3, and 4 weeks (P<0.05). No significant difference in the incidence of PVR was found between groups 1 and 2 during the same observation periods. ERG and histopathological studies showed no differences between the treated and the control fellow eyes (group 5-7) after 4 weeks. 13-cis-RA in SiFO (10 microg ml-1) is as effective as all-trans-RA in SiFO (9 microg 1.5 ml-1) in controlling the incidence of PVR when used for short term retinal tamponade and does not appear to be associated with retinal toxicity.

Topics: Animals; Electroretinography; Intraocular Pressure; Isotretinoin; Polymers; Rabbits; Retina; Retinal Detachment; Silicones; Tretinoin; Vitreoretinopathy, Proliferative

The authors evaluated the effect of retinoic acid (RA) in silicone oil (SiO) and in silicone-fluorosilicone (SiFO) copolymer oil in a new rabbit model of proliferative vitreoretinopathy (PVR).. To create the PVR model, three groups of rabbits were administered vitreous injections of approximately 100,000 homologous fibroblasts, 75,000 platelet-rich plasma (PRP), and fibroblasts + PRP, respectively. These rabbits were followed up ophthalmoscopically and histopathologically for as long as 2 months. Five additional groups of rabbits underwent gas-compression vitrectomy in one eye. Four days later, group 1 was administered intravitreous RA in SiFO (9 micrograms/ml) with approximately 150,000 fibroblasts and 70,000 PRP. Group 3 was administered the same amount of fibroblasts and PRP as group 1 with RA in SiO (9 micrograms/ml). Groups 2, 4, and 5 were administered the same amount of fibroblasts and PRP as groups 1 and 3 with 1 ml of SiFO, SiO, or balanced salt solution only, respectively. To evaluate RA toxicity, RA was injected in SiO (15 and 20 micrograms/ml) and RA in SiFO (10 micrograms/ml).. All eyes that were administered fibroblasts or PRP developed vitreous membranes, but those with PRP alone did not develop proliferative changes or retinal detachment; fibroblasts alone produced proliferative changes and retinal detachment after 2 to 3 weeks; fibroblasts + PRP produced similar changes within 3 days of injection. Retinoic acid (15 micrograms/ml) in SiO and RA (10 micrograms/ml) in SiFO was well tolerated. Retinal atrophic changes were found in eyes with 20 micrograms/ml RA in SiO. The retinal detachment rate was lower (P < 0.05) in the eyes that were administered fibroblasts + PRP and RA than in the controls. Significant differences were found in the degrees of PVR among the groups.. RA could be useful in PVR treated with SiO or for eyes treated intraoperatively with heavier-than-water SiFO when it is used as a short-term retinal tamponade.

Topics: Animals; Blood Platelets; Disease Models, Animal; Drug Carriers; Fibroblasts; Injections; Rabbits; Random Allocation; Retina; Retinal Detachment; Silicone Oils; Tretinoin; Vitreoretinopathy, Proliferative; Vitreous Body