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In a chronic disease such as glaucoma, a therapy that provides a long lasting local effect with minimal systemic side effects, while circumventing the issue of patient compliance, is very attractive. The field of gene therapy is growing rapidly and ocular applications are expanding. Our understanding of the molecular pathogenesis of glaucoma is leading to greater specificity in ocular tissue targeting. Improvements in gene delivery techniques, refinement of vector construction methods, and development of better animal models combine to bring this potential therapy closer to reality.

A decade has passed since the first topical prostaglandin analog was prescribed to reduce intraocular pressure (IOP) for the treatment of glaucoma. Now four prostaglandin analogs are available for clinical use around the world and more are in development. The three most efficacious of these drugs are latanoprost, travoprost, and bimatoprost, and their effects on IOP and aqueous humor dynamics are similar. A consistent finding is a substantial increase in uveoscleral outflow and a less consistent finding is an increase in trabecular outflow facility. Aqueous flow appears to be slightly stimulated as well. Prostaglandin receptors and their associated mRNAs have been located in the trabecular meshwork, ciliary muscle, and sclera, providing evidence that endogenous prostaglandins have a functional role in aqueous humor drainage. Earlier evidence found that topical PG analogs release endogenous prostaglandins. One well-studied mechanism for the enhancement of outflow by prostaglandins is the regulation of matrix metalloproteinases and remodeling of extracellular matrix. Other proposed mechanisms include widening of the connective tissue-filled spaces and changes in the shape of cells. All of these mechanisms alter the permeability of tissues of the outflow pathways leading to changes in outflow resistance and/or outflow rates. This review summarizes recent (since 2000) animal and clinical studies of the effects of topical prostaglandin analogs on aqueous humor dynamics and recent cellular and molecular studies designed to clarify the outflow effects.

Topical treatments with certain prostaglandins (PGs), including FP receptor agonists, lower intraocular pressure by increasing uveoscleral outflow. Although the precise mechanism for the increased uveoscleral outflow is not known, there appears to be activation of a molecular transduction cascade and an increase in the biosynthesis of certain metalloproteinases. This leads to reduction of extracellular matrix components within the ciliary muscle, iris root, and sclera. It is possible that this reduction of extracellular matrix present within portions of the uveoscleral pathway may contribute to the mechanism of increased uveoscleral outflow. Additional mechanisms that may contribute to the PG-mediated increase of uveoscleral outflow include relaxation of the ciliary muscle, cell shape changes, cytoskeletal alteration, or compaction of the extracellular matrix within the tissues of the uveoscleral outflow pathway. Future studies should clarify the importance of these various responses that may contribute to increased uveoscleral outflow. At present, there is no compelling evidence for a substantial facility-increasing effect on the trabecular meshwork outflow for any of these compounds.

Gene therapy in the anterior and posterior segment tissues may have the potential to favorably influence aqueous hydrodynamics and retinal ganglion cell biology, thereby preventing, delaying, or minimizing glaucomatous damage to the optic nerve. We demonstrated the feasibility of using a herpes viral vector (ribonucleotide reductase defective HSV-1, hrR3) to deliver the lacZ reporter gene to living cat and rat eyes. Cats received injections into the anterior chamber and rats into the vitreous cavity. In cats, lacZ expression was detectable at 1 to 2 days in the anterior outer portion of the ciliary muscle and the lining of the intertrabecular spaces of the corneoscleral and uveal meshwork. Rat eyes showed lacZ expression in the retinal pigment epithelium and photoreceptor outer segments 2 days after injection.

Purpose: To determine the efficacy and safety of latanoprost treatment for 1 year in glaucoma patients, and to evaluate the effects of switching from timolol to latanoprost therapy., Methods: Latanoprost 0.005% was topically applied once daily without masking for 6 months in 223 patients with elevated intraocular pressure after previous treatment with latanoprost once daily or 0.5% timolol twice daily for 6 months in a multicenter, randomized, double-masked, parallel group study., Results: Compared with baseline values before treatment, a significant (P < .0001) diurnal reduction in intraocular pressure of 6 to 8 mm Hg was maintained with minimal fluctuation for the duration of treatment. When treatment was switched from timolol to latanoprost, intraocular pressure was reduced by 1.5 +/- 0.3 mm Hg (mean +/- SEM; 8% change in intraocular pressure; 31% of the intraocular pressure reduction produced by timolol; P < .001) compared with the change in intraocular pressure in patients remaining on latanoprost therapy. Of the patients initially enrolled, 95% successfully completed treatment. There was a slight overall increase in conjunctival hyperemia in patients who switched from timolol to latanoprost, but no change in those who continued latanoprost. The timolol-induced reduction of resting heart rate returned to baseline levels after switching to latanoprost. Of the 247 patients treated with latanoprost during the masked and/or open-label studies, 12 (5%) demonstrated a definite (n = 4) or possible (n = 8) increase in iris pigmentation., Conclusions: Latanoprost is a well-tolerated ocular hypotensive agent that appears to be more effective than timolol in reducing intraocular pressure. The increase in iris pigmentation appears to be harmless but requires further investigation.

One hundred twenty-nine patients thought to be at risk for developing angle-closure glaucoma underwent a baseline examination, which included gonioscopy, refraction, anterior chamber pachymetry, ultrasound biometry, and an angle-closure provocative test. Patients were then followed up with no treatment. Mean follow-up was 2.7 years with a range up to six years. Twenty-five patients developed angle closure in at least one eye during the follow-up period, but in most (17 of the 25 patients), the angle closure was nonacute (that is, no clinical signs or symptoms and no increase in intraocular pressure). None of the test factors studied showed a high sensitivity or positive predictive accuracy in detecting the eyes that later developed angle closure.

Total outflow facility was determined in cynomolgus monkeys by two-level constant pressure perfusion. Topical epinephrine increased facility by 30% to 35% three to four hours after dosing, whether given as a single 600-micrograms dose or as twice daily 600-micrograms doses for three days. A single 5.5-micrograms intracameral dose of epinephrine or norepinephrine increased facility by 65% to 70% three to four hours after dosing. A single 180-micrograms topical dose of timolol or betaxolol had no effect on facility three to four hours later. Timolol pretreatment prevented the facility-increasing effect of both topical epinephrine and intracameral norepinephrine, but betaxolol pretreatment prevented neither. These findings indicate that no cumulative facility-increasing effect of epinephrine, beyond the acute (three hour) facility-increasing effect, develops within three days; there may be a facility-decreasing effect of large topical epinephrine doses on the vascular structures external to the trabecular meshwork; there is no, or only subthreshold, facility-affecting ambient beta-adrenergic tone in the meshwork; and the facility-increasing effect of both epinephrine and norepinephrine is mediated by beta 2-adrenergic receptors in the trabecular endothelium.

Twelve subjects with glaucoma or ocular hypertension underwent measurement of visual fields (Humphrey perimeter and the Henson CFS2000 perimeter), contrast sensitivity (Vistech wall charts), and perimacular leukocyte velocity (Oculix BFS-1000 blue field entoptic technique). Significant positive correlations were seen between asymmetry of visual function and asymmetry of retinal leukocyte velocity in the study population. The eye with the higher velocity of retinal leukocyte flow tended to have better visual function as measured by Humphrey mean deviation (P less than .05), Henson Score (P less than .06), and Vistech contrast sensitivity score at 6 cycles/degree (P less than .001). An association of borderline significance was found between the asymmetries of intraocular pressure and retinal leukocyte velocity (P = .06). No significant intraocular pressure:visual field correlations were found on asymmetry analysis, although the inverse relationship between intraocular pressure and contrast sensitivity was significant (P less than .05). Significant correlations were obtained between visual field scores derived from the Henson data and Humphrey parameters mean deviation (P less than .001) and corrected pattern standard deviation (P less than .05) on both asymmetry and single eye analysis.

A 57-year-old alcoholic man sustained permanent bilateral blindness and optic atrophy as a complication of hemorrhage from peptic ulcer disease. Post-hemorrhagic visual loss occurs in middle-aged, debilitated persons a short time after repeated episodes of hemorrhage from any site.

A 53-year-old man, to our knowledge the first person described with unilateral Rieger's anomaly, had a prominent anteriorly displaced Schwalbe's ring, broad iris strands inserting into Schwalbe's ring, anterior stromal iris hypoplasia, mild microcornea, and marked astigmatism in his right eye. His left eye was entirely normal.

I treated cynomolgus monkeys with topical echothiophate iodide twice daily for several months. Accommodative responses to topical or intramuscular pilocarpine were determined after ciliary ganglion or cholinergic nerve blockade. During echothiophate treatment, there was little or no accommodative response to intramuscular pilocarpine doses which were near maximal in nonechothiophate-treated eyes. Similarly, echothiophate-treated eyes demonstrated little or no response to topical pilocarpine doses that were more than 50 times supramaximal in nontreated eye. Within two weeks after stopping echothiophate, accommodative responses to intramuscular pilocarpine had returned noticeably, and by seven weeks after stopping echothiophate, sensitivity to intramuscular pilocarpine had increased to 30 to 50% of control levels. The findings are compatible with acetylcholine-induced cholinergic subsensitivity of the ciliary muscle.

In a double-masked randomized prospective study, 19 adult white subjects with primary open-angle glaucoma or ocular hypertension were treated twice daily with drops of 0.25% betaxolol (a relatively selective beta 1-adenoceptor antagonist) or placebo for six weeks. The nine betaxolol-treated subjects demonstrated a statistically significant average decrease in intraocular pressure of 3.8 +/- 5 mm Hg, evident after one week and persisting throughout the entire six-week treatment period. The ten placebo-treated subjects exhibited a statistically nonsignificant increase in intraocular pressure of 0.4 +/- 2.4 mm Hg. Mean systemic arterial blood pressure, pulse rate, corneal sensitivity, pupil diameter, and basal tear secretion remained unchanged in both groups. Transient stinging upon instillation of the eyedrops was the only side effect in the betaxolol-treated subjects but in no case did it necessitate cessation of therapy.

A 67-year-old woman and a 75-year-old woman taking carbonic anhydrase inhibitors for therapy of glaucoma and high doses of aspirin for therapy of arthritis developed severe acid-base imbalance and salicylate intoxication. Neither patient exhibited ill effects when taking high aspirin doses without carbonic anhydrase inhibitor. Carbonic anhydrose inhibitor-induced acidemia increases the risk of developing salicylate intoxication in patients receiving high aspirin doses.

Cynomolgus and vervet monkeys were treated unilaterally with topical echothiophate iodide twice daily for eight to 25 weeks. The effect of intracameral pilocarpine on outflow facility was determined in the ganglionic-blocked animal during and after echothiophate treatment. The echothiophate-treated eyes demonstrated marked subsensitivity to pilocarpine, and required several weeks to months to recover normal pilocarpine sensitivity.