ANTI-FIBROSIS AGENTS IN GLAUCOMA

 

INTRODUCTION:

“Early” bleb failure after glaucoma filtering surgery (GFS) shows a hypercellular appearance, while “late” failure is associated with thicker collagen deposition.

Inhibition of scarring can be achieved at various levels by both physical and pharmacologic methods.

Decreasing the size of the operative site and careful hemostasis (which avoids excessive fibrin and thermal tissue injury) reduce the scope of the initial, intra-operative injury and subsequent fibrosis-stimulating inflammation.

Avoiding other sources of inflammation, such as combined surgical procedures, have the same effect. Successful egress of aqueous through the sclerostomy serves to keep the patency of the fistula for a prolonged time.

Characteristics of patients with increased risk for scarring include:

• Young age
• Black race
• Previous unsuccessful GFS
• Aphakia and pseudophakia
• Neovascular glaucoma
• Uveitic glaucoma
• Iridocorneal endothelial syndrome
• Previous prolonged topical glaucoma therapy
• Conjunctival scarring from conditions such as alkali burns or pseudopemphigoid.

 

PHARMACOLOGIC AGENTS

Drugs used in inhibiting fibrosis in the GFS bleb can be categorized into the following groups=

1.        ANTI-INFLAMMATORY AGENTS	Corticosteroids	Non-steroidal anti-inflammatory drugs
2.       ANTI-NEOPLASTIC AGENTS	5-Fluorouracil (5-FU)		Mitomycin C (MMC)
3.       OTHER ANTINEOPLASTIC AGENTS	Antibiotics		Pyrimidine analogs	Alkaloids
4.       OTHER ANTIFIBROSIS AGENTS	Interferon-α, calcium ionophore A23187, β-aminoproprionitrile (BAPN), and D-penicillamine (DPA)

 

1.      ANTI-INFLAMMATORY AGENTS

(a) Corticosteroids:

Sugar, first noted the beneficial effect of topical corticosteroids in prevention of bleb scarring.

Systemic steroids did not have any additional effects.

Subconjunctival steroids have been used at the conclusion of the GFS procedure.

The presumed mechanism of the anti-fibrosis activity of corticosteroids in GFS is the inhibition of the inflammatory response, mediated via blockage of the lipo-oxygenase and cyclo-oxygenase pathways by direct inhibition of phospholipase A2.

This results in decreased capillary permeability, chemotaxis inhibition, and suppression of fibrin deposition.

Decreased fibroblast proliferation occurs at higher concentrations while a stimulatory effect may be seen at lower concentrations.

(b) Non-steroidal anti-inflammatory drugs:

NSAIDs, inhibitors of both lipoxygenase and cyclooxygenase pathways, have demonstrated suppression of human ocular fibroblast proliferation.

However, in clinical trials, topical post-operative flurbiprofen 0.03% after GFS resulted in higher rate of encapsulated blebs and higher final IOP.

2.     ANTI-NEOPLASTIC AGENTS

Many pharmacologic agents hinder the scarring process via antimetabolic activity, typically interfering with one or more phases of the cell replication cycle of fibroblasts.

(a) 5-Fluorouracil (5-FU)=

5-Fluororidine (5-FUR) and 5-FU are pyrimidine nucleotide analogs. Similar to the pyrimidine analogs, they owe their anti-neoplastic activity to small structural dissimilarities from endogenous pyrimidines.

These agents require metabolic conversion to nucleotides to exert cytotoxicity. Simultaneous catabolism can inactivate these drugs.

5-FU is a fluorinated pyrimidine with a molecular weight of 130.08.

It undergoes intracellular conversion to the active deoxynucleotide, 5-fluro-2’-deoxyuridine 5’-monophosphate (FdUMP).

FdUMP causes competitive inhibition of thymidylate synthetase in the S-phase of the cell-replication cycle. This hampers the conversion of deoxyuridylic acid to thymidylic acid, thus impeding DNA synthesis.

FdUMP is also incorporated directly into DNA molecules after conversion by intracellular kinases to a triphosphate. Such DNA, with fluorouracil substituted for thymine, may be more unstable than native DNA.

It also interferes with RNA processing and function after its conversion to the ribonucleotide, fluouridine monophosphate (FUMP).

In GFS, this agent has been used mostly as post-operative subconjunctival injections.

The usual single dose is 5 mg (0.1 ml of undiluted bolus at 50 mg/ml).

The subconjunctival injection is performed 90 to 180 degrees away from the bleb. A tuberculin syringe with 30-gauge needle is used by going tangentially to the globe, bevel away from the sclera.

Avoid the conjunctival vessels to minimize bleeding.

Subconjunctival diffusion around the wound site may occur, especially through the needle track.

This elution of the drug into the tear film may encourage epithelial toxicity.

Leakage can be reduced by tamponade of the injection site with a cotton applicator; light massage to move the drug from the track and irrigation of residual undiluted 5-FU from the conjunctiva and eyelids with saline.

The number of injections can be adjusted by the clinical response and other factors such as patient access, acceptance, affordability, and compliance.

Intra-operative 5-FU implantation using a purified collagen sponge containing 100 µgm of 5-FU in the quadrant of surgery has also been reported. This leads to a slow release of the agent and potentially less epithelial toxicity.

Undiluted 5-FU (50 mg/ml) has been used intraoperatively using drug-soaked cellulose sponges placed under and over the scleral flap and sub-conjunctivally for a 5-minute period followed by copious balanced salt solution (BSS) irrigation.

Toxicity:

Systemic toxicity is rare as hardly 1-3% of the dose used in anti-cancer therapy enters the general circulation following ocular 5-FU usage.

Most of the drug is metabolized through hepatic clearance and elimination by respiration as carbon dioxide or renal excretion in the form of metabolites or free drug.

Ocular toxicity occurs as a consequence of its effect on rapidly dividing epithelial cells of the cornea and conjunctiva.

The Fluorouracil Filtering Surgery Study (FFSS) group reported punctate corneal epitheliopathy in 98% of patients, conjunctival epithelial defects, and corneal epithelial defects (64%). This toxicity was also responsible for a large number of conjunctival wound leaks.

Other corneal complications were: filamentary keratitis, keratinized corneal plaques, infectious corneal ulcers, and striate melanokeratosis (attributed to centripetal migration of pigment-laden stem cells from the limbus).

5-FU was also associated with punctal-canalicular stenosis, cicatricial ectropion due to lower lid dermatitis, contact dermatitis, and increased pigmentation of periocular skin.

The most devastating complications of 5-FU have been the occurrence of thin, cystic blebs, with an increased frequency of late bleb leaks, late endophthalmitis, and hypotonic maculopathy (also choroidal effusion and persistent shallow chambers).

5-FU should be avoided in patients with known corneal diseases that increase the risk of complications. Such conditions include bullous keratopathy, severe-dry eye syndrome, preexisting corneal epithelial defects, recurrent erosion syndrome, corneal melting syndrome, preexisting dellen, and conditions associated with decreased limbal stem cells such as Stevens-Johnson syndrome, pemphigoid, pseudopemphigoid, and old alkali burns.

Epithelial defects and wound leaks appear dose-related.

Careful closure of the conjunctival wound is critical to the prevention of early postoperative wound leaks.

Suturing with small taper point (round-bodied) needles with 8/0-10/0 sutures and employing a running mattress closure may prevent bleb leaks appreciably.

In general, antimetabolites are more commonly associated with hypotonic maculopathy in young and myopic patients.

The FFSS reported that 5-FU reduced the failure rates of GFS to 49% postoperatively, compared to 74% in control eyes.

(b) Mitomycin C (MMC)=

MMC was isolated by Wakaki and colleagues from Streptomyces caespitosus.

It undergoes enzyme activation in tissues and functions as an alkylating agent, cross-linking DNA.

Although it is cell-cycle phase non-specific, it is most active in the G and S phases of cell division.

MMC is used to treat neoplasms of the stomach, pancreas, bladder, colon, rectum, lung, cervix and breast.

In GFS it is used to prevent the replication of fibroblasts.

Studies have shown subconjunctival fibroblast proliferation inhibition to be dependent on the dose and exposure time.

The potency of MMC is 100 times greater than 5-FU.

MMC impedes the future replication of even those cells which are not synthesizing DNA at the time of exposure.

The markedly hypovascular blebs following the use of MMC are probably due to toxicity to vascular endothelium and contribute to the decreased scarring.

Toxic damage to the ciliary body and resulting decreased aqueous production could also contribute to the lowered IOP.

MMC has been used in a concentration between 0.1-0.5 mg/ml. it remains stable for 7 days at room temperature and for 14 days when refrigerated.

Non-preserved MMC should be used within 24 hours.

MMC is placed on the scleral bed after conjunctival dissection, either before or after the scleral flap has been fashioned. However, it should never be used once the coats of the eyeball have a full-thickness entry.

Some surgeons prefer to place the sponge over the scleral flap.

Care should be taken to avoid touching the edges of the conjunctival flap to the sponge, which might encourage postoperative wound leaks.

Toxicity:

MMC should be avoided during pregnancy due to its potential teratogenic effects.

It has significant corneal endothelial toxicity.

Scleral thinning and necrosis have not been reported following the use of MMC as described here.

MMC has fewer rates of corneal epithelial toxicity as compared to 5-FU.

Conjunctival wound leaks and hypotonic maculopathy is dependent on exposure times.

Treatment options for hypotonic maculopathy include autologous blood injection into the bleb, cryotherapy, and topical application of trichloracetic acid.

3.     OTHER ANTINEOPLASTIC AGENTS

 (a) Antibiotics=

Bleomycin, daunorubicin, doxorubicin, and mithramycin are antineoplastic antibodies extracted from Streptomyces. These agents have been found to inhibit fibroblasts.

(b) Pyrimidine analogs=

Cytosine arabinoside (Ara-C), trifluorothymidine, 5-fluoroorotate and metabolites of 5-FU have antiproliferative actions. They inhibit DNA polymerase and impede DNA synthesis.

(c)  Alkaloids=

Some alkaloids extracted from plants have been found to inhibit fibroblasts. These include vincristine, vinblastine and taxol.

4.     OTHER ANTIFIBROSIS AGENTS IN GLAUCOMA SURGERY

Interferon-α, calcium ionophore A23187, β-aminoproprionitrile (BAPN), and D-penicillamine (DPA) have been studied for their ability to inhibit cellular proliferation, collagen synthesis, and maturation.

Interferon-α inhibits collagen production, fibroblast proliferation, and chemotaxis.

Calcium ionophore A23187 also inhibits collagen synthesis.

DPA and BAPN inhibit collagen fibril cross-linking after synthesis, thus, decreasing the tensile strength of scar tissue.

Tissue plasminogen activators (TPA) is an enzyme that converts plasminogen to plasmin, which is fibrinolytic. TPA may enhance GFS.

Similarly, heparin also inhibits the proliferation of human scleral fibroblasts. However, it requires frequent exposure.