Mark B. Sherwood

Long-term Morphologic Effects of Antiglaucoma Drugs on the Conjunctiva and Tenon's Capsule in Glaucomatous Patients

Conjunctival and Tenons capsule biopsies from two patient groups were quantitatively analyzed by light microscopy. Group A consisted of 20 patients with a primary glaucoma for whom surgery was a planned primary treatment modality. Group B was comprised of 20 patients with a primary glaucoma who had received at least two types of antiglaucoma topical medication, for a minimum of 1 year (mean, 7.7 years) before surgery. All slides were examined by two masked observers. A significant increase in the number of macrophages, lymphocytes, mast cells, and fibroblasts in the conjunctiva and Tenons capsule and a significant decrease in the number of epithelial goblet cells were seen in the group that received long-term drop therapy. These results suggest that exhaustive medical therapy, before surgery is offered, increases the number of tissue inflammatory cells. It is possible this may enhance the risk of external bleb scarring and filtration surgery failure.

Six-month comparison of Bimatoprost once-daily and twice-daily with timolol twice-daily in patients with elevated intraocular pressure

The efficacy and safety of bimatoprost, a member of a new class of pharmacological agents called prostamides, were compared with the efficacy and safety of timolol in patients with glaucoma or ocular hypertension. Pooled 6-month results from two ongoing, multicenter, randomized, double-masked, clinical trials were analyzed. Patients were randomized in a 2:2:1 ratio to treatment with bimatoprost 0.03% once a day ([QD] n = 474), bimatoprost 0.03% twice a day ([BID] n = 483), or timolol 0.5% BID (n = 241). Scheduled visits were at prestudy, baseline, week 2, week 6, month 3, and month 6. The primary outcome measure was in diurnal intraocular pressure ([IOP] 8 AM, 10 AM, 4 PM, 8 PM). Bimatoprost QD provided significantly greater mean IOP reductions from baseline than timolol at every time of the day and at each study visit (p </=.05). BID dosing of bimatoprost also provided significantly greater mean IOP reductions than timolol at most timepoints, but was not as effective as QD dosing. The IOP lowering provided by bimatoprost QD was sustained for 6 months. At month 6, the mean IOP reduction from baseline at 10 AM was 8.1 mm Hg (33%) with bimatoprost QD, 6.3 mm Hg (26%) with bimatoprost BID, and 5.6 mm Hg (23%) with timolol. Low target pressures were achieved by a significantly higher percentage of patients in the bimatoprost QD group than in the timolol group. At 10 AM (peak timolol effect) at month 6, IOP </= 17 mm Hg was achieved by 63.9% of bimatoprost QD patients, compared with 37.3% of timolol patients (p <.001). Bimatoprost was safe and well-tolerated, with few discontinuations due to adverse events. The most frequent side effect was trace-to-mild conjunctival hyperemia. Changes in iris pigmentation were reported in 1.1% of bimatoprost patients. There were no other significant findings in slit lamp examinations, ophthalmoscopy, visual acuity, or visual fields, and systemic safety parameters were also unaffected. Together these results indicate that bimatoprost QD is statistically and clinically superior to timolol in lowering IOP, and is safe and well-tolerated in patients with glaucoma or ocular hypertension.

Activation and suppression of fibroblast function

The fibroblast is the central player in the wound repair and scarring processes that occur in the anterior segment of the eye. Glaucoma filtration surgery is the ultimate example of the importance of the wound healing process, as this process is the major determinant of the success of this procedure. We highlight the role of the fibroblast, and discuss some of the growth factors stimulating fibro-blast proliferation, migration and extracellular matrix production in the wound environment. We also review current methods of suppressing fibroblast proliferation, the new concepts that have arisen from laboratory studies, and future directions of investigation and treatment.

Results of Intraoperative 5-Fluorouracil Supplementation on Trabeculectomy for Open-angle Glaucoma

The success rate of filtration surgery has been increased by the postoperative subconjunctival injection of 5-fluorouracil, a potent antimetabolite. However, the optimal route of administration has not been determined. Trabeculectomy was performed on one eye each of 14 patients. Topical 5-fluorouracil was applied intraoperatively (50 mg/ml for five minutes) and subconjunctival 5-fluorouracil was injected postoperatively (an average of 5.8 injections) (mean total dose, 29 mg). Seven of the 14 eyes had primary open-angle glaucoma, and seven eyes had open-angle glaucoma with either uveitis, aphakia, or previous failed trabeculectomy. Mean preoperative intraocular pressure was 24.7 mm Hg during treatment with an average of three antiglaucoma medications, and mean final intraocular pressure was 11.9 mm Hg during treatment with an average of 0.2 medication. Thirteen of 14 eyes (93%) had final intraocular pressure of 18 mm Hg or less. Mean follow-up was 6.4 months (range, four to nine months). No remarkable complications occurred. Visual acuity remained stable in 13 of 14 eyes (93%). Intraoperative 5-fluorouracil may be a helpful adjunct in achieving low final intraocular pressure after trabeculectomy.

Latanoprost Treatment for Glaucoma: Effects of Treating for 1 Year and of Switching From Timolol

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.

Change in intraocular pressure during long-term use of loteprednol etabonate.

PURPOSE Loteprednol etabonate is a novel site-active corticosteroid synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. In double-masked studies, loteprednol etabonate was effective in the treatment of giant papillary conjunctivitis, seasonal allergic conjunctivitis, postoperative inflammation, and uveitis. The objective of this analysis was to determine the incidence of clinically significant elevations in intraocular pressure (IOP) with long-term use of loteprednol etabonate. PATIENTS AND METHODS All subjects (healthy volunteers or patients with inflammation or allergy) in all sponsored loteprednol etabonate studies in the United States were evaluated. A clinically significant elevation in IOP was defined as > or = 10 mmHg at any visit, and long-term use was defined as > or = 28 days. Of the 2,210 subjects, 1,648 were treated for 28 days or longer with loteprednol etabonate (0.2% or 0.5%), prednisolone acetate 1%, or vehicle. RESULTS IOP elevation > or = 10 mmHg occurred in 1.7% (15/901) of patients taking long-term loteprednol etabonate, 0.5% (3/583) of those taking vehicle, and 6.7% (11/164) of those taking prednisolone acetate. Excluding patients who wore contact lenses, the incidence was 0.6% (4/624), 1.0% (3/304), and 6.7% (11/164) for loteprednol etabonate, vehicle, and prednisolone acetate, respectively. The incidence of IOP elevations with 0.2% loteprednol etabonate was 0.8% (1/133), similar to that for vehicle (0.7%, 1/135). CONCLUSION The results of this analysis in a large population of subjects undergoing long-term therapy and of a previously published controlled, double-masked study in corticosteroid responders suggest that loteprednol etabonate has less propensity to cause clinically significant elevations in IOP than prednisolone acetate.

Intraoperative and post operative treatment with 5-Fluorouracil and mitomycin-c: long term effects in vivo on subconjunctival and scleral fibroblasts

Rabbits undergoing full thickness glaucoma filtering surgery were exposed to one of 4 treatments. Group 1 received intraoperative distilled water, group 2 received intraoperative mitomycin-c 0.2 mg/ml for 5 minutes, group 3 received 5 post operative injections of 5-Fluorouracil (5-FU) 5 mg in 0.1 ml, and group 4 received intraoperative 5-FU 50 mg/ml followed by 5 post operative injections of 5-FU. 30 days after the operation tissue biopsies were taken from the subconjunctival and scleral tissue at the treated area and 90 and 180 degrees from the treated area. The biopsies were then placed in tissue culture media and the outgrowths quantitated. The fibroblast outgrowths from all areas did not differ significantly from each other except for the outgrowths from the areas directly treated with mitomycin 0.2 mg/ml which were significantly smaller. In addition then cells were morphologically abnormal although there were foci of normal cells which appeared to be growing from localised areas in the tissue biopsies. The outgrowths from the areas 90 and 180 degrees from the treated area were normal. Intraoperative treatments with mitomycin-c result in long term inhibition of fibroblast proliferation limited to the treated area, when compared with intraoperative and postoperative treatment with 5-FU. Failure of filtration surgery in eyes treated with intraoperative mitomycin may in part be due to unaffected cells reproliferating.

A primate model for age related macular drusen.

A closed colony of semi-free-ranging rhesus monkeys maintained in isolation since 1938 by the Caribbean Primate Research Center (CPRC) is being studied as a model for age related macular drusen. Of examined colony animals 57.7% of the monkeys and 47.3% of their eyes have drusen. The prevalence and severity of drusen are linearly related to increasing age and are significantly higher in specific maternal lineages (matrilines). An electrophysiological estimate indicates loss of function associated with drusen. Prevalence of drusen in CPRC females is almost twice that of males, while the prevalence among CPRC animals in general appears to be several times that of monkeys from continental US facilities. Evidence suggests that the frequency of endstage lesions is also similar to that in human populations. The CPRC matriline monkeys appear to provide the best model yet reported for human age related macular drusen.

Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa.

Abstract Proof of concept for MERTK gene replacement therapy has been demonstrated using different viral vectors in the Royal College of Surgeon (RCS) rat, a well characterized model of recessive retinitis pigmentosa that contains a mutation in the Mertk gene. MERTK plays a key role in renewal of photoreceptor outer segments (OS) by phagocytosis of shed OS tips. Mutations in MERTK cause impaired phagocytic activity and accumulation of OS debris in the interphotoreceptor space that ultimately leads to photoreceptor cell death. In the present study, we conducted a series of preclinical potency and GLP-compliant safety evaluations of an adeno-associated virus type 2 (AAV2) vector expressing human MERTK cDNA driven by the retinal pigment epithelium-specific, VMD2 promoter. We demonstrate the potency of the vector in RCS rats by improved electroretinogram (ERG) responses in treated eyes compared with contralateral untreated controls. Toxicology and biodistribution studies were performed in Sprague-Dawley (SD) rats injected with two different doses of AAV vectors and buffer control. Delivery of vector in SD rats did not result in a change in ERG amplitudes of rod and cone responses relative to balanced salt solution control-injected eyes, indicating that administration of AAV vector did not adversely affect normal retinal function. In vivo fundoscopic analysis and postmortem retinal morphology of the vector-injected eyes were normal compared with controls. Evaluation of blood smears showed the lack of transformed cells in the treated eyes. All injected eyes and day 1 blood samples were positive for vector genomes, and all peripheral tissues were negative. Our results demonstrate the potency and safety of the AAV2-VMD2-hMERTK vector in animal models tested. A GMP vector has been manufactured and is presently in clinical trial.

Wound modulation after filtration surgery.

Filtration surgery is the standard invasive procedure for the management of intraocular pressure in advanced glaucoma. The key to a successful outcome is to modulate the normal wound healing cascade that leads to closure of the newly created aqueous outflow pathway. Antifibrotic agents such as mitomycin C and 5-fluorouracil have been increasingly used to modulate the wound healing process and increase surgical success. Although these agents have proven efficacy, they also increase the risk of complications. Efforts have centered on the identification of novel agents and techniques that can influence wound modulation without these complications. We detail new agents and methods under investigation to control wound healing after filtration surgery.