Sustained Intraocular Pressure Reduction Research Articles

Latanoprostene Bunod, a Dual-acting Nitric Oxide Donating Prostaglandin Analog for Lowering of Intraocular Pressure

Current topical treatments for glaucoma have limited efficacy in lowering intraocular pressure (IOP) and/or can produce side effects and tolerability problems. At present, IOP remains the only known modifiable risk factor to delay the progression of glaucoma. The novel IOP-lowering treatment latanoprostene bunod (LBN) is a nitric oxide (NO)-donating prostaglandin F2αanalog that is rapidly metabolized in situ to latanoprost acid and butanediol mononitrate, an NO-donating moiety. LBN has a dual action in that it enhances aqueous humor outflow via both the uveoscleral and trabecular meshwork pathways. It is undergoing regulatory review by the Food and Drug Administration (FDA) for the reduction of IOP in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). In the dose-ranging VOYAGER study, LBN 0.024%, the lower of the most effective concentrations evaluated, demonstrated significantly greater IOP lowering and comparable side effects compared with latanoprost 0.005%. The recent APOLLO phase III clinical study (n=420) found LBN 0.024% demonstrated significantly greater reductions in IOP than timolol 0.5% in patients with OAG or OHT at various time points over 3 months. The same study found the proportion of patients with IOP ≤18 mmHg was significantly greater with LBN 0.024% than with timolol 0.5%. In the LUNAR study (n=420), LBN 0.024% was non-inferior to timolol 0.5% over 3 months’ treatment. LBN treatment also resulted in significantly greater IOP lowering than timolol at all time-points with the exception of the first post-baseline assessment. In JUPITER, a study of 130 subjects with OAG or OHT, LBN 0.024% was safe and well tolerated when used for up to a year, and provided significant and sustained IOP reduction. Further, in CONSTELLATION, a study of 25 patients with OHT or OAG, IOP lowering with LBN 0.024% was consistently lower than baseline during both the diurnal/wake and nocturnal/sleep periods whereas timolol 0.5% reduced IOP only during the diurnal period. In addition, LBN 0.024% treatment resulted in a significantly increased diurnal ocular perfusion pressure versus baseline and nocturnal ocular perfusion pressure versus timolol 0.05%. Similarly, in KRONUS, a single-arm, single-center, openlabel study of 24 healthy Japanese subjects, LBN 0.024% significantly lowered mean IOP over a 24-hour period. Across these studies, LBN has demonstrated a favorable safely profile and good ocular tolerability. It is hypothesized that LBN’s dual action on the outflow pathways accounts for the improved efficacy when compared with latanoprost and timolol.

A prospective 3-year follow-up trial of implantation of two trabecular microbypass stents in open-angle glaucoma.

PurposeTo evaluate 3-year safety and intraocular pressure (IOP) following two trabecular microbypass stents in phakic and pseudophakic subjects with open-angle glaucoma (OAG) not controlled on preoperative medication.Patients and methodsIn this prospective pilot study, phakic or pseudophakic subjects with OAG and IOP between 18 mmHg and 30 mmHg on one preoperative topical ocular hypotensive medication underwent medication washout. Thirty-nine qualified subjects with preoperative unmedicated IOP ≥22 mmHg and ≤38 mmHg received two stents. Postoperative examinations were scheduled at Day 1, Week 1, Months 1, 3, 6, and 12, and semiannually through Month 60. Ocular hypotensive medication was considered if postoperative IOP exceeded 21 mmHg. IOP, medication use, and safety were assessed at each visit. Subject follow-up through Month 36 was completed.ResultsThirty-six eyes (92.3%; 95% confidence interval [CI] 79.1%, 98.4%) achieved the primary efficacy end point of Month 12 reduction in IOP ≥20% from baseline (unmedicated IOP) without ocular hypotensive medication. Four subjects required medication during the Month 36 follow-up period. Mean IOP at 36 months for subjects not taking medication was 15.2 mmHg. At 36 months, subjects sustained mean IOP decrease of 9.1±2.7 mmHg (95% CI 8.0 mmHg, 10.14 mmHg), or 37% IOP reduction, from unmedicated baseline IOP. Compared to preoperative medicated IOP, subjects had mean reduction at Month 36 of 5.5±2.7 mmHg (95% CI 4.5 mmHg, 6.6 mmHg), or 26% reduction. Both measures of IOP reduction were highly significant (P<0.001). Other than one case of early postoperative hyphema that resolved at 1 week, no postoperative adverse events were attributed to stent implantation.ConclusionIn a pilot study, two trabecular microbypass stents to treat OAG subjects on one preoperative medication provided statistically significant, sustained, and safe reduction of IOP to ≤15 mmHg without medication through 36 months.

Comparison of intraocular pressure reduction of initial and adjunct selective laser trabeculoplasty for primary open angle glaucoma in Nigerians

Objective: The objective was to compare the intraocular pressure (IOP) lowering effect of selective laser trabeculoplasty (SLT) as initial and adjunct therapy in primary open angle glaucoma (POAG). Subjects and Methods: Retrospective chart review of POAG patients who had SLT either as initial or adjunct therapy over a period of 1‑year. Each patient had SLT done in 360° of the anterior chamber angle. IOP measurement with the Goldmann applanation tonometer was done at baseline, 60 min post procedure, days 1, 7, 30, 90, and 180. Results: Mean baseline IOP was 15.4 ± 3.5 mmHg and 17.5 ± 5.5 mmHg for initial and adjunct, respectively ( P = 0.153); not significant. Mean IOP at 90 days was 10.5 ± 1.8 mmHg and 16.2 ± 6.3 mmHg for initial and adjunct, respectively ( P = 0.013); statistically significant. Records at 180 days revealed mean IOP of 14.1 ± 3.9 mmHg and 15.7 ± 7.7 mmHg ( P = 0.465) for initial and adjunct, respectively; not significant. The maximal mean IOP reduction in both groups was at 7 days. 70% of patients in the initial had IOP reduction of >20% compared to 63.5% of adjuncts throughout the study period. Initial sustained mean reduction of ≥3 mmHg from day 1 to 90, while the adjunct was till day 30. Conclusion: Initial SLT showed a sustained reduction in IOP, compared to adjunct with marginally lower measurements. Keywords: Adjunct, initial, primary open angle glaucoma, selective laser trabeculoplasty

Cataract surgery in the glaucoma patient

To summarize the role of cataract surgery in the glaucoma patient, in terms of the effect on intraocular pressure (IOP) as well as diagnostic and therapeutic considerations for those with both conditions. Recent evidence suggests that cataract extraction may produce a significant and sustained IOP reduction in individuals with open-angle glaucoma, ocular hypertension, and angle-closure glaucoma. Cataract removal may improve the practitioner's ability to interpret perimetric testing, and re-establishing perimetric and optic nerve imaging baselines is recommended after cataract surgery. The sequence of cataract surgery relative to glaucoma surgery impacts the likelihood of complications and surgical success. There are multiple benefits to perform cataract surgery prior to glaucoma surgery while cataract surgery after trabeculectomy increases the risk of subsequent filtration failure. As “minimally invasive glaucoma surgeries” continue to improve in terms of efficacy, there is an evolving role for combined cataract and glaucoma surgery in patients with early to moderate stages of glaucoma.

Long-term results of up to 12 years of over 700 cases of viscocanalostomy for open-angle glaucoma.

To study the safety and long-term efficacy of classic viscocanalostomy in patients with open-angle glaucoma (OAG) in different populations. A total of 726 eyes of 726 patients from Europe or South Africa with primary OAG (POAG) and pseudoexfoliative glaucoma (PXFG) were included in this retrospective multicentre study. Complete (qualified) success was defined as an intraocular pressure (IOP) equal to or lower than 21, 18 and 16 mmHg without (with or without) medications, respectively. A failed procedure was defined if IOP was above 21 mmHg, not controllable by laser goniopuncture or medications. The mean IOP before surgery was 42.6 ± 14.2 mmHg for all patients, 29.6 ± 6.6 mmHg for European patients and 48.1 ± 12.9 mmHg for African patients. The follow-up time was 86.2 ± 43.1 months. Mean IOP was 15.4 ± 3.6 mmHg at 5 years, 15.5 ± 4.4 mmHg at 10 years and 16.8 ± 4.2 mmHg at 15 years. The qualified success rate for an IOP of 21, 18 or 16 mmHg or less after 5 years was 92% [95% confidence interval (CI) 0.88-0.96], 70% (95% CI 0.63-0.77) and 43% (95% CI 0.36-0.51) in European patients, and 90% (95% CI 0.87-0.93), 77% (95% CI 0.74-0.81) and 67% (95% CI 0.63-0.72) in African patients, respectively. There was no difference between the success rate for POAG and PXFG for an IOP of 21, 18 or 16 mmHg or less at 5 years (p = 0.64, p = 0.20, p = 0.22, respectively). Laser goniopuncture was performed postoperatively on a total of 127 eyes (17.7%), lowering the pressure from 23.1 ± 1.9 mmHg to 15.0 ± 2.2 mmHg. There were no significant complications, in particular, no blebitis or endophthalmitis. Viscocanalostomy produced a sustained long-term reduction of IOP with a low-risk profile in European and African patients with OAG over 12 years.

Anti-inflammatory Therapy after Selective Laser Trabeculoplasty: A Randomized, Double-Masked, Placebo-Controlled Clinical Trial

To investigate the effect of anti-inflammatory therapy on selective laser trabeculoplasty (SLT) outcomes. Randomized, double-masked, placebo-controlled trial. Patients with primary open-angle or pseudo-exfoliation glaucoma. Patients undergoing SLT were randomized to receive placebo (artificial tears), prednisolone acetate 1%, or ketorolac tromethamine 0.5% eye drops 4 times per day for 5 days commencing immediately after SLT. Change in intraocular pressure (IOP) from baseline to the 1-month post-SLT visit. Mean change in IOP at the 1-month primary outcome time point, as well as all other time points, was not significantly different among groups (P = 0.99). Likewise, a repeated-measures, mixed-effects model did not find significant differences in IOP outcome at the 1-month time point (P = 0.95). The IOP was reduced in all groups at the 1-month post-SLT time point and all other time points, and no significant differences were found between groups using separate unadjusted cross-sectional analyses of variance (P > 0.15 for analyses at all time points). Treatment failure rates were not different among groups (P = 0.75), and at 1 year after SLT, the percentage of patients maintaining a 20% IOP reduction ranged from 18% to 22% in the 3 study groups. Anti-inflammatory therapy after SLT does not seem to substantially influence the IOP-lowering effect of SLT. In this study of patients with low baseline IOP, SLT showed limited efficacy in achieving a sustained reduction in IOP.

Dynamics of outflow easiness coefficient after angular-suprachoroidal drainage in patients with primary glaucoma

Dynamics of outflow easiness coefficient after angular-suprachoroidal drainage in patients with primary glaucoma

Prospective evaluation of microinvasive glaucoma surgery with trabecular microbypass stents and prostaglandin in open-angle glaucoma

To evaluate the intraocular pressure (IOP) lowering effect of 2 trabecular microbypass stents and postoperative travoprost in patients with open-angle glaucoma (OAG) not controlled on 2 medications preoperatively. S.V. Malayan Ophthalmology Centre, Yerevan, Armenia. Prospective open-label nonrandomized study. This prospective pilot study involved 39 qualified phakic patients with OAG, medicated IOP between 18 mm Hg and 30 mm Hg, and unmedicated baseline (after washout) IOP between 22 mm Hg and 38 mm Hg. Patients received 2 stents (iStent) through a clear corneal incision and were prescribed travoprost starting the night of postoperative day 1. Intraocular pressure, complications, and various safety measures were assessed at examinations through 18 months and planned for every 6 months thereafter until month 60. A washout of medications was performed 13 months postoperatively. All patients achieved an IOP reduction of 20% or more from baseline to 12 months with reduction of 1 medication and with IOP 18 mm Hg or less. Follow-up through 18 months showed that medicated IOP decreased from 22.2 mm Hg ± 2.0 (SD) on 2 medications preoperatively to 14 mm Hg or less on 1 medication at the postoperative visits. The mean unmedicated IOP decreased from 25.3 ± 1.8 mm Hg preoperatively to 17.1 ± 2.2 mm Hg 13 months postoperatively. No intraoperative or serious device-related adverse events occurred. Patients with OAG treated with 2 trabecular microbypass stents and 1 presumptive postoperative medication achieved a significant and sustained reduction in IOP and medication through 18 months. Dr. Katz served as the medical monitor for this study. All authors are consultants to Glaukos Corp.

The impact of cataract surgery on glaucoma care

To summarize the effects of cataract surgery on the management of glaucoma, in terms of the effect on both the intraocular pressure (IOP) and postoperative diagnostic as well as therapeutic considerations. Recent evidence corroborates prior data demonstrating significant and sustained IOP reduction after cataract extraction, particularly in closed-angle variants of glaucoma, but also in individuals with open-angle glaucoma or ocular hypertension. Performing cataract surgery after trabeculectomy increases the odds of filtration failure with the likelihood of this adverse effect being inversely proportional to the duration between the glaucoma and cataract procedures. Although cataract has a significant effect on the results of visual field testing, the Visual Field Index may be less influenced than other parameters such as the mean and pattern deviation. The accuracy of time-domain ocular coherence tomography and spectral-domain ocular coherence tomography are also negatively impacted by cataract. Considering cataract surgery as an IOP-lowering procedure may be appropriate in select patients. Performing cataract extraction prior to glaucoma surgery has numerous benefits. The sequence of the procedures performed has implications in terms of complications, surgical success, and diagnostics. Reestablishing perimetric and structural baselines with imaging modalities is appropriate after cataract surgery is performed in glaucoma patients.

5-Fluorouracil Augmented Needle Revision of Trabeculectomy

To determine whether the outcome of needle revision of trabeculectomy is influenced by the presumed anatomic location of resistance to aqueous outflow. Retrospective case note review. Thirty-four eyes of 30 consecutive patients undergoing their first needle revision of trabeculectomy. We compared 2 types of needle revision: "type-1 needling," limited to breaking down fibrosis in the subconjuctival-subtenon space, and "type-2 needling," which additionally involved needling underneath the scleral flap. Unqualified success was defined as a postneedling intraocular pressure (IOP) >4 mm Hg and ≤21 mm Hg at the most recent follow-up without further surgery, medications, or repeat needling. Qualified success was defined as a successful patient who required medications or repeat needling. The mean follow-up period was 2.1 ± 0.1 years (range, 1.0 to 3.8 y). Sixteen type-1 and 18 type-2 procedures were performed at a median of 124 days (22 d to 14 y) after trabeculectomy. IOP decreased from a mean of 28.2±1.3 mm Hg (19 to 52 mm Hg) preneedling to 6.7±0.8 mm Hg (2 to 22 mm Hg) on the first postoperative visit and 15.1±0.7 mm Hg (8 to 27 mm Hg) at the most recent follow-up. The overall success rate was 82.4% (47.1% unqualified and a further 35.3% qualified). There was no significant difference in the success rates between type-1 (14/16) and type-2 (14/18) needle revisions (Fisher exact test, P=0.66). Similar proportions of eyes undergoing type-1 and type-2 needling underwent a second needling procedure. There was no significant difference in the IOP reduction between type-1 and type-2 needling (Mann-Whitney U test, P=0.78). Needle revision is an effective technique for trabeculectomy bleb remodeling and can result in a sustained reduction in IOP. The location of the obstruction did not influence outcome, with type-1 and type-2 needle revisions equally likely to succeed.

Topical silver nanoparticles result in improved bleb function by increasing filtration and reducing fibrosis in a rabbit model of filtration surgery.

To compare the effects of silver nanoparticles (AgNPs) and mitomycin C (MMC) on intraocular pressure (IOP) and external, histologic, and immunohistochemical bleb characteristics in a rabbit model of filtration surgery. Filtration surgery with concurrent topical application of either AgNPs or MMC was performed on 14 pigmented Dutch Belted rabbits. IOP and bleb characteristics were compared on postoperative day 1 and at weeks 1 through 6. Hematoxylin and eosin staining and smooth muscle actin (SMA) immunohistochemistry were performed at postoperative week 6. Average IOP across all time points was reduced 5.8 and 3.8 mm Hg in AgNP- and MMC-treated eyes, respectively. At week 6, IOP was reduced 4.1 and 0.2 mm Hg in AgNP- and MMC-treated eyes, respectively. Blebs were smaller, thicker, and less ischemic in AgNP-treated eyes. AgNP-treated eyes showed less fibrosis and more stromal edema, suggesting increased filtration, and also had fewer SMA-positive myofibroblasts, suggesting reduced bleb contraction. AgNP-treated eyes showed more lymphocytes than MMC-treated eyes. There were few complications in both groups. In a rabbit model of filtration surgery, AgNPs are a reasonable alternative to MMC as adjunctive therapy. Compared to MMC, AgNPs result in an improved and sustained reduction of IOP and promote blebs with decreased fibrosis and ischemia as well as increased filtration despite a smaller overall size. This combination may offer an opportunity to promote long-term surgical IOP reduction with an improved complication profile.

Circumferential viscocanalostomy with suture tensioning in Schlemm canal (canaloplasty) – One year experience

PurposeTo study the efficacy and the safety of ultrasound biomicroscopy assisted canaloplasty in the treatment of open-angle glaucoma (OAG) MethodsA prospective study of uncontrolled open-angle glaucoma patients, or patients with cataracts associated with controlled or uncontrolled OAG under maximal medical therapy who had been subjected to canaloplasty alone or combined with cataract surgery, respectively. Complications, Goldmann intraocular pressure (IOP) and mean number of drugs (ND) were evaluated at 1 day, 1 week, 1 month, and every 3 months. ResultsThirty five surgeries were performed (11 canaloplasties, 24 phaco-canaloplasties). The mean IOP (mmHg) dropped from 24.5±5.1, in canaloplasty, and from 19.8±6.4, in phacocanaloplasty, preoperatively, to medium-low levels at all follow-up periods (13.5±1.0 and 11.0±4.2, at 1 year in canaloplasty and phaco-canaloplasty, respectively). The number of grugs used dropped from 3.3±0.5 before surgery to less than of 1 in all follow-up periods (0.5±0.8 at 1 year). The complications were 2 microruptures of the trabeculodescemetic window, 5 entries in the collector channels, 5 choroidal space/anterior chamber passages, 10 hyphemas, 3 hypotonies, one peripheral Descemet detachment, one intracorneal hematoma, two peripheral anterior synechia, one internal iris prolapse, and two suture extrusions to the anterior chamber. ConclusionsUltrasound biomicroscopy assisted Canaloplasty, alone or combined, provided a sustained IOP reduction to medium-low levels, led to a decrease in the number of drugs and had a good safety profile, making this a good alternative to trabeculectomy.

Viscocanalostomía circunferencial con sutura de tensión en el canal de Schlemm (canaloplastia): un año de experiencia

PurposeTo study the efficacy and the safety of ultrasound biomicroscopy assisted canaloplasty in the treatment of open-angle glaucoma (OAG) MethodsA prospective study of uncontrolled open-angle glaucoma patients, or patients with cataracts associated with controlled or uncontrolled OAG under maximal medical therapy who had been subjected to canaloplasty alone or combined with cataract surgery, respectively. Complications, Goldmann intraocular pressure (IOP) and mean number of drugs (ND) were evaluated at 1 day, 1 week, 1 month, and every 3 months. ResultsThirty five surgeries were performed (11 canaloplasties, 24 phaco-canaloplasties). The mean IOP (mmHg) dropped from 24.5±5.1, in canaloplasty, and from 19.8±6.4, in phacocanaloplasty, preoperatively, to medium-low levels at all follow-up periods (13.5±1.0 and 11.0±4.2, at 1 year in canaloplasty and phaco-canaloplasty, respectively). The number of grugs used dropped from 3.3±0.5 before surgery to less than of 1 in all follow-up periods (0.5±0.8 at 1 year). The complications were 2 microruptures of the trabeculodescemetic window, 5 entries in the collector channels, 5 choroidal space/anterior chamber passages, 10 hyphemas, 3 hypotonies, one peripheral Descemet detachment, one intracorneal hematoma, two peripheral anterior synechia, one internal iris prolapse, and two suture extrusions to the anterior chamber. ConclusionsUltrasound biomicroscopy assisted Canaloplasty, alone or combined, provided a sustained IOP reduction to medium-low levels, led to a decrease in the number of drugs and had a good safety profile, making this a good alternative to trabeculectomy.

Sustained intraocular pressure reduction throughout the day with travoprost ophthalmic solution 0.004%

BackgroundThe purpose of this study was to characterize intraocular pressure (IOP) reduction throughout the day with travoprost ophthalmic solution 0.004% dosed once daily in the evening.MethodsThe results of seven published, randomized clinical trials including at least one arm in which travoprost 0.004% was dosed once daily in the evening were integrated. Means (and standard deviations) of mean baseline and on-treatment IOP, as well as mean IOP reduction and mean percent IOP reduction at 0800, 1000, and 1600 hours at weeks 2 and 12 were calculated.ResultsFrom a mean baseline IOP ranging from 25.0 to 27.2 mmHg, mean IOP on treatment ranged from 17.4 to 18.8 mmHg across all visits and time points. Mean IOP reductions from baseline ranged from 7.6 to 8.4 mmHg across visits and time points, representing a mean IOP reduction of 30%. Results of the safety analysis were consistent with the results from the individual studies for travoprost ophthalmic solution 0.004%, with ocular hyperemia being the most common side effect.ConclusionTravoprost 0.004% dosed once daily in the evening provides sustained IOP reduction throughout the 24-hour dosing interval in subjects with ocular hypertension or open-angle glaucoma. No reduction of IOP-lowering efficacy was observed at the 1600-hour time point which approached the end of the dosing interval.

Regulation of ocular adrenoceptor genes expression by 5-MCA-NAT

We have demonstrated that 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), reduces intraocular pressure (IOP) in rabbits. In addition, we have reported a link between hypotensive effect of 5-MCA-NAT and sympathetic nervous system. Moreover, it is known that aqueous humour production is controlled by the activation of adrenoceptors (ADRs) present in the ocular ciliary epithelium. Thus, the aim of this study is to investigate if the hypotensive effect of 5-MCA-NAT is due to a regulation of ciliary ADR genes expression. To confirm this we followed the effect of 5-MCA-NAT on rabbit IOP for 144 consecutive hours. A sustained IOP reduction for up to 72 h (P<0.01) was seen. In addition, changes in ADRB2 and ADRA2A mRNA were measured in cultured rabbit nonpigmented ciliary epithelial cells. After 5-MCA-NAT treatment, a significant downregulation of ADRB2 and upregulation of ADRA2A was observed. These results provide the regulation of ADRs mRNA by 5-MCA-NAT.

Prostaglandin Pathway Gene Therapy for Sustained Reduction of Intraocular Pressure

Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostaglandin (PG) biosynthesis. In the eye, loss of COX-2 expression in aqueous humor-secreting cells has been associated with primary open-angle glaucoma (POAG). Reduction of intraocular pressure (IOP) is the main treatment goal in this disease. We used lentiviral vectors to stably express COX-2 and other PG biosynthesis and response transgenes in the ciliary body epithelium and trabecular meshwork (TM), the ocular suborgans that produce aqueous humor and regulate its outflow, respectively. We show that robust ectopic COX-2 expression and PG production require COX-2 complementary DNA (cDNA) sequence optimization. When COX-2 expression was coupled with a similarly optimized synthetic PGF2alpha receptor transgene to enable downstream signaling, gene therapy produced substantial and sustained reductions in IOP in a large animal model, the domestic cat. This study provides the first gene therapy for correcting the main cause of glaucoma.

The effect of cataract extraction on intraocular pressure

To review the current ophthalmic literature regarding the impact of modern cataract surgery on intraocular pressure (IOP). Many articles in the literature demonstrate a modest, long-lasting decrease in IOP following phacoemulsification and posterior chamber intraocular lens implantation in patients with primary open-angle glaucoma and ocular hypertension. The mechanism of this average pressure-lowering effect has yet to be elucidated. The IOP reductions obtained in patients with angle closure glaucoma are often more pronounced than those seen in patients with open angles. Patients with higher levels of preoperative IOP obtain greater average reductions in IOP, although this phenomenon may partially be explained by a statistical effect known as regression to the mean. Although it is well recognized that phacoemulsification may result in a modest sustained reduction in IOP, there are several limitations in the studies that have assessed the magnitude of this effect. The implications of such IOP reduction with cataract surgery on the medical and surgical algorithms for care in patients with open-angle glaucoma and coexistent cataract remain unclear. In contrast, the substantial benefits of cataract surgery in patients with acute and chronic angle-closure glaucoma have been well studied and are generally widely accepted. An improved understanding of the pathophysiological mechanisms of IOP lowering after cataract extraction may help us better predict which patients are most likely to benefit from simple cataract extraction, obviating the need for combined cataract and glaucoma surgical procedures in such circumstances.

Bimatoprost

Bimatoprost (Lumigan) is a synthetic prostamide that reduces intraocular pressure (IOP) by increasing the outflow of aqueous humour. In patients with open-angle glaucoma or ocular hypertension, long-term treatment (for up to 48 months) with once-daily bimatoprost 0.03% ophthalmic solution was more effective than timolol twice daily in providing a sustained and stable reduction in IOP. Bimatoprost 0.03% ophthalmic solution demonstrated efficacy similar to, or greater than, the prostaglandin analogues latanoprost and travoprost in reducing IOP and achieving target IOP levels. Switching to bimatoprost was as effective in maintaining diurnal IOP control as switching to a fixed combination of latanoprost/timolol (in patients with IOP levels controlled with a nonfixed combination of latanoprost plus timolol), and similarly, or more, effective in lowering IOP and providing overall diurnal IOP control than switching to a combination of dorzolamide/timolol (in patients with IOP inadequately controlled with other antiglaucoma agents including timolol). Treatment with bimatoprost was generally well tolerated, with conjunctival hyperaemia (mostly mild), growth of eyelashes and ocular pruritus being commonly reported. Other adverse events included increases in the pigmentation of the iris, perorbital areas and eyelashes.

Seven-year follow-up of combined cataract extraction and viscocanalostomy

To investigate the long-term success and complications of phacoemulsification combined with viscocanalostomy (phacoviscocanalostomy) in eyes with coexisting cataract and medically uncontrolled glaucoma. Department of Ophthalmology, Warrington Hospital, Warrington, United Kingdom. A prospective nonrandomized study evaluated 165 consecutive eyes (114 patients) that had phacoviscocanalostomy. The main outcome measures were intraocular pressure (IOP), visual acuity, requirement for topical antiglaucoma medication, and the presence or absence of drainage blebs or bleb complications. The mean follow-up was 38.7 months +/- 19.3 (SD) (range 12 to 90 months). There was a statistically significant decrease in IOP, from 24.1 +/- 5.1 mm Hg preoperatively to 13.8 +/- 8.1 mm Hg 1 day after surgery (P<.001), 16.0 +/- 4.1 mm Hg at 5 years (P<.001), and at all evaluations to the last follow-up. The mean number of medications per eye decreased significantly from 2.5 +/- 0.9 before surgery to 0.1 +/- 0.5 at last follow-up (P<.001). At the final follow-up, IOP was reduced by 33.2% (16.2 mm Hg versus 24.1 mm Hg). Complete success, defined as an IOP reduction of more than 30% from preoperative level without medications, was achieved in 48.5% of eyes, with 42% of eyes having an IOP of less than 16 mm Hg. The percentage fall in IOP was linearly related to the preoperative IOP level (P<.001). No eye developed a trabeculectomy-type bleb, and there were no bleb-related complications. Phacoviscocanalostomy was safe and effective for the management of eyes with coexisting cataract and medically uncontrolled glaucoma. It provided a stable and sustained reduction in IOP with a minimum requirement for topical medication.

463. COX-2-Based Gene Therapy: Reduction of Intraocular Pressure in a Glaucoma Gene Therapy Animal Model with Lentiviral Vectors Expressing COX-2, a Prostaglandin Synthase, or a Prostaglandin Receptor

BACKGROUND: Cyclooxygenase-2 (COX-2), an inducible enzyme in the prostaglandin (PG) biosynthesis cascade, is important in medically significant disease states, including glaucoma and cancer. Most recently, COX-2 inhibitors have been implicated in adverse cardiovascular outcomes. Durable COX-2 expression by exogenous genes has not been previously achieved. We hypothesized that the inducible PG biosynthetic and response pathways could be manipulated via a gene therapy approach with lentiviral vectors. Since PGF2α analogs are the most effective glaucoma drugs, we further hypothesized that these vectors could be used to durably reduce intraocular pressure (IOP) in a large animal model we developed. Glaucoma is an appealing candidate for lentiviral vector therapy, since the causative IOP elevation results from pathophysiology that is (i) chronic; (ii) frequently refractory to conventional therapies; (iii) anatomically confined to a discrete anterior chamber region that is targetable by transcorneal injection. Therapeutic transgenes have not been described for glaucoma, which remains the leading cause of irreversible blindness. METHODS: We constructed lentiviral vectors expressing cDNAs for human COX- 2 or other relevant proteins (PGF synthase, and the PGF receptor). mRNA and protein levels were measured by Northern & Western blotting. PGF2α production was assayed. Anterior chambers of 15 domestic cats were injected with lentiviral vectors. Left eyes were injected with 107–108 TU of a control eGFP vector, while right eyes received equivalent doses of one or more therapeutic vectors. Animals were monitored serially for IOP and clinical effects. RESULTS: COX-2 mRNA proved highly unstable even with a minimal cDNA lacking the known destabilizing 3′ UTR. We then observed that the human COX-2 cDNA has highly skewed codon use very similar in composition to that of lentiviral structural genes. We therefore codon-optimized the cDNA, which enabled robust, sustained expression for the first time. Increased synthesis of PGF2α up to 0.9 × 104 –fold greater than control, was observed. In the animals, vectors were well-tolerated and produced marked, sustained (2 months at present, with all animals under ongoing observation), and highly significant IOP decreases (mean over entire two months = 4.2 mm Hg, p < 0.002) compared to control eyes were achieved by this gene therapy manipulation of prostaglandin production or receptor response. A combination of the COX-2 and PGF receptor vectors produced the largest IOP decrease (mean = 5.6 mm Hg, 38% reduction, p < 3 × 10-9). CONCLUSIONS: Major prostaglandin biosynthetic and response pathways can be manipulated by gene therapy. Codon optimization of the COX-2 coding region profoundly augments mRNA stability. Sustained, substantial, highly statistically significant decreases in IOP were achieved in a large animal model developed for glaucoma studies. This is the first gene therapy study to demonstrate sustained IOP reduction, defining a first therapeutic transgene possibility. Investigations of other COX-2-and PG-related processes and diseases will also be enabled by these findings.