Drugs Acting on the ECM

Drugs which act on the interface between cells and the ECM have the potential to inhibit intraretinal scarring at a relatively earlier step than simple proliferation. Heparin and related peptides have a multitude of effects on cells and their interaction with the ECM. Heparin is a glycosaminoglycan derived from heparin sulfate, which binds to several ECM proteins, including fibronectin, laminin, and vitronectin [48]. In addition to its antithrombotic properties, for which it was first discovered and processed, heparin clearly has important effects on a variety of growth factors. It actively binds fibroblast growth factor, platelet-derived growth factor, and endothelial-cell growth factor. Soluble heparin causes an increase in cell spreading and produces changes in the cytoskeleton of smooth muscles. It also inhibits the polymerization of type-1 collagen and reduces cell-mediated contraction of collagen gels when cultured fibroblasts or RPE cells are interspersed within a collagen matrix. This may be a process analogous to hypocellular gel contraction, an important attack point in the prevention of PVR [15,48].

Because heparins have significant anticoagulant affects, they may result in hemorrhagic complications, and this stimulated the search for compounds with heparin-like qualities on growth factors, but without the potential hemorrhagic issues. It is known that fractionation of longer chains of heparin into smaller molecular weight fragments causes loss of some of the anticoagulant activity while preserving the ECM effects. As a result, low-molecular-weight fractions of heparin with a molecular weight of 5000 or less retain their ability to catalyze the inhibition of Factor Xa, but lose their ability to directly inhibit thrombin [49]. When low-molecular-weight heparin was introduced into the infusate during vitrectomy in an animal model, fibrin formation was markedly reduced without any coincident increase in intraocular hemorrhage [50]. Use of 5 IU/ml of low-molecular-weight heparin in the infusate during creation of an experimental model of proliferative vitreoretino-pathy reduced the rate of traction detachment from 77% to 28% at 3 months [51]. These encouraging results led to the inclusion of low-molecular-weight heparin in the infusate, along with 5-FU, which was studied in the prevention of PVR in humans [15,42,50,51].

In another important PVR trial, when conventional heparin (1 IU/ml) was combined with a steroid dexamethasone (5 mg/ml) in the infusate, there was a slight increase in the retinal reattachment rate compared with controls from 65% to 80% in addition to a reduction in the rate of reproliferation from 26.5% to 16%. A mild increase in the rate of hyphema and vitreous hemorrhage was seen, although it was not judged to be clinically significant [33].

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