Long-term efficacy and safety of bimatoprost for intraocular pressure lowering in glaucoma and ocular hypertension: year 4.

BACKGROUND: Bimatoprost 0.03% has been shown to consistently reduce mean intraocular pressure (IOP) more than timolol 0.5% over 2 years. To further evaluate long-term safety and efficacy, once-daily bimatoprost 0.03% was compared with timolol 0.5% twice daily through year 4. METHODS: In this multicentre, double-masked, randomised, controlled trial, glaucoma and ocular hypertension patients (n = 152) who completed phase III bimatoprost trials through month 36 were enrolled in a study extension through month 48. Patients randomised to bimatoprost once daily (n = 78) or timolol twice daily (n = 35) continued on the same regimen for a fourth year. Patients randomised to bimatoprost twice daily had been switched to bimatoprost once daily dosing at month 24 (bimatoprost twice daily/once daily treatment group), and continued with once daily dosing through month 48 (n = 39). IOP was measured at 08:00 and 10:00 at months 39, 42, 45 and 48. Safety measures included adverse events, biomicroscopy, ophthalmoscopy, visual acuity and visual field. RESULTS: Baseline IOP was comparable among groups. During year 4, mean IOP reductions from baseline were 7.0 to 8.1 mm Hg with bimatoprost once daily and 6.5 to 7.9 mm Hg with bimatoprost twice daily/once daily, significantly greater than with timolol twice daily (3.8 to 5.8 mm Hg, p< or =0.035) at all measurements. Over 4 years, the mean IOP reduction from baseline at 08:00 and 10:00 was 1.9 to 3.9 mm Hg (35% to 100%) greater with bimatoprost once daily than with timolol (p< or =0.013). Low IOPs were achieved by more bimatoprost than timolol patients (p< or =0.042). No safety concerns developed during long-term bimatoprost treatment; two patients in the timolol treatment group discontinued after month 36 because of adverse events. The most common treatment-related adverse event in the bimatoprost treatment groups was conjunctival hyperaemia. CONCLUSION: Bimatoprost once daily provided sustained IOP lowering greater than timolol twice daily and was well tolerated over long-term use.

"Heavy electron" photoelectron spectroscopy: rotationally resolved ion pair imaging of CH3+.

We applied the velocity map imaging technique under high-resolution conditions to study ion pair products of the vacuum ultraviolet photodissociation of methyl chloride. We obtained rotationally resolved kinetic energy release spectra that directly provide vibrational frequencies and rotational constants of the fundamental carbocation, CH3+. The technique is analogous to photoelectron spectroscopy, with the chloride anion playing the role of a "heavy electron." The approach shows promise as a general probe of ionic species not amenable to study by traditional methods.

Apoptotic cell death of cultured salamander photoreceptors induced by cccp: CsA-insensitive mitochondrial permeability transition.

Photoreceptor degeneration is mediated by apoptosis in several animal models, although the underlying mechanisms are yet to be elucidated. We present here an apoptotic model based on a primary cell culture of tiger salamander photoreceptors, in which treatment with carbonyl cyanide m-chlorophenylhydrazone (cccp), a protonophore, induced apoptosis. Cells exposed to cccp showed condensed nuclei and displayed positive TdT-dUTP terminal nick-end labeling (TUNEL). In addition, 10-100 microM cccp rapidly induced a reduction of Delta psi(m) and > or = 30 microM cccp induced a significant leakage of calcein from mitochondria to cytosol and nucleus, indicating a change in mitochondrial inner membrane permeability. Cyclosporin A (CsA), a transition pore blocker, did not prevent the cccp-induced MPT or the cccp-evoked apoptotic cell death, suggesting that cccp-induced apoptotic process was mediated by a CsA-insensitive pathway. This cell model provides an in vitro tool for studying mechanisms of photoreceptor apoptosis in isolated photoreceptors and may provide clues to the etiology of retinal degeneration.

Central corneal thickness of Caucasians and African Americans in glaucomatous and nonglaucomatous populations.

OBJECTIVE: To determine whether there is a difference in central corneal thickness between African American and Caucasian patients. If present, a difference might alter the measurement of intraocular pressure and potentially the assessment and management of glaucoma in these populations. METHODS: Central corneal thickness was measured by means of ultrasound pachymetry in African American (n = 56) and Caucasian (n = 32) patients with suspected or confirmed glaucoma and control populations of African American (n = 26) and Caucasian (n = 51) subjects in whom there was no evidence of elevated intraocular pressure or glaucomatous optic nerve damage. Measurements of central corneal thickness were then compared between different subpopulations by means and population distribution analysis. RESULTS: A statistically significant difference was noted between the mean (+/-SD) central corneal thickness of all African American (including those with and without glaucoma) (right eye, 531.0 +/- 36.3 microm; left eye, 530.0 +/- 34.6 microm) and all Caucasian (including those with and without glaucoma) (right eye, 558.0 +/- 34.5 microm; left eye, 557.6 +/- 34.5 microm) patients. Similar results were found when subpopulations were tested. Distribution analysis of central corneal thickness measurements noted the largest cluster of African American patients around 520 to 540 microm, whereas the largest cluster of Caucasian patients was between 580 and 600 microm. CONCLUSIONS: African Americans were found to have thinner central cornea thickness measurements than Caucasians. This finding in African Americans may lead to lower applanation intraocular pressure readings compared with those of Caucasians, potentially resulting in an underestimation of the actual level of intraocular pressure.

[Implant in Schlemm's canal. A new method for regulating intraocular pressure in patients with primary open-angle glaucoma?]. / Implantat in den Schlemm-Kanal. Eine neue Methode, den intraokularen Druck bei Patienten mit primärem Offenwinkelglaukom zu regulieren?

BACKGROUND: A surgical technique was developed using a Schlemm's canal implant to bypass the obstruction of outflow of the juxtacanalicular trabecular meshwork in patients with primary open-angle glaucoma. The implant device should also bridge healing processes after trabeculotomy and laser techniques. PATIENTS AND METHODS: An 8- to 15-mm-long silicone tube was implanted in each of two human autopsy eyes connecting the anterior chamber directly with Schlemm's canal. Serial sectioning was performed at two sections of 1-mm length. RESULTS: Implantation of the tube was technically uneventful. Histological examination showed no evidence of mechanical disruption of the endothelial lining of the inner wall of Schlemm's canal. CONCLUSION: These preliminary results demonstrate the possibility of shunting aqueous directly into Schlemm's canal using a silicone tube. A clinical study in a selected group of patients is planned.

Effects of atropine on anterior chamber depth and anterior chamber inflammation after primary trabeculectomy.

PURPOSE: To investigate the effects of postoperative atropine on central and peripheral anterior chamber depth and anterior chamber inflammation in patients undergoing primary trabeculectomy. METHODS: Two separate groups of patients who were phakic without previous intraocular surgery undergoing primary trabeculectomy were prospectively randomized to atropine or no atropine. In the first group of patients, 24 eyes of 21 patients undergoing primary trabeculectomy were prospectively randomized to atropine or no atropine, and their anterior chamber depth was measured. Central and peripheral chamber depths were measured using the EAS-1000 anterior segment analysis system (Nidek, Tokyo, Japan) before surgery and on postoperative days 1, 3, 7, 14, and 30. In the second group, 34 patients undergoing primary trabeculectomy were prospectively randomized to atropine or no atropine, and their anterior chamber reaction was documented. The amount of cells and flare was measured using the Kowa laser flare meter (FM-500) and cell counter (LC-500) (Kowa Electronics and Optics, Tokyo, Japan) preoperatively and on postoperative day 1, 7, and 30. RESULTS: Compared with preoperative measurements, a small (approximately 0.1 mm) but statistically significant deepening of the central and peripheral anterior chamber depth on days 1, 7, 14, and 30 was found in patients who used atropine. In the nonatropine group, no statistically significant change was found in central or peripheral anterior chamber depths at any time as compared with preoperative values. There was no statistically significant difference in the cell or flare counts between the atropine and nonatropine groups at any time. CONCLUSIONS: This study showed a small but statistically significant deepening of the anterior chamber with atropine. No statistically significant differences were observed in the cell or flare counts between atropine and nonatropine groups. Routine atropine use after trabeculectomy may not be necessary to reduce postoperative complications, such as shallowing of the anterior chamber or anterior chamber inflammation. In patients with a shallow anterior chamber, however, atropine would be expected to deepen the chamber.

Incidence of brimonidine allergy in patients previously allergic to apraclonidine.

PURPOSE: This study was performed to determine the incidence of allergic reaction to brimonidine in patients who have previously demonstrated an allergic reaction to apraclonidine. METHODS: A retrospective chart review was performed to identify patients who had demonstrated an allergic reaction to apraclonidine of sufficient severity to result in drug discontinuation. Within this group, those patients subsequently treated with brimonidine were isolated and analyzed, and the incidence of allergy to brimonidine was determined. RESULTS: Forty-five patients were identified with a significant allergic reaction to apraclonidine that resulted in drug discontinuation. Of these patients, 22 subsequently received brimonidine. Follow-up on all patients was obtained for at least 15 months. All but two of the 22 patients were taking additional topical glaucoma medications, ranging from one to three additional agents with an average of 1.8+/-0.8 medications. Seventeen patients incurred no allergic reaction to brimonidine. Only five patients (22.7%) previously allergic to apraclonidine developed an allergic reaction to brimonidine. Three of these patients demonstrated only a follicular conjunctival reaction, one had conjunctival hyperemia, and one patient developed a periocular dermatitis. The allergic reactions developed at 8.2+/-1.2 months after initiation of brimonidine therapy. CONCLUSIONS: In this study, the risk of developing an allergic reaction to brimonidine in patients known to be allergic to apraclonidine is 22.7%. This lack of a strong cross-reactive allergic response possibly suggests different allergic mechanisms for these two medications. Therefore, brimonidine therapy in patients previously identified as being allergic to apraclonidine is safe and does not result in a cross-reactive response in the great majority of patients (or in nearly four of five patients).

Effects of betaxolol on light responses and membrane conductance in retinal ganglion cells.

PURPOSE: To examine the physiological effects of betaxolol, a beta1-adrenergic receptor blocker commonly used in the treatment of glaucoma, on retinal ganglion cells and to evaluate its potential to elicit responses consistent with a neuroprotective agent against ganglion cell degeneration. METHODS: Single-unit extracellular recording, electroretinogram (ERG), intracellular and whole-cell patch-clamp recording techniques were made from flatmounted, isolated retina, superfused eyecup, and living retinal slice preparations of the larval tiger salamander. RESULTS: Bath application of 20 microM betaxolol reduced the glutamate-induced increase of spontaneous spike rate in retinal ganglion cell by approximately 30%. The glutamate-induced postsynaptic current recorded under voltage-clamp conditions was reduced by 50 microM betaxolol, and the difference current-voltage (I-V) relation (I(Control)-I(betaxolol)) was N-shaped and AP5-sensitive, characteristic of N-methyl-D-aspartate receptor-mediated current. Application of 50 microM betaxolol reversibly reduced the voltage-gated sodium and calcium currents by approximately one third of their peak amplitudes. The times-to-action of betaxolol on ganglion cells are long (15-35 minutes for 20-50 microM betaxolol), indicative of modulation through slow biochemical cascades. Betaxolol, up to 100 microM, exerted no effects on horizontal cells or the ERG, suggesting that the primary actions of this beta1 blocker are restricted to retinal ganglion cells. CONCLUSIONS: These physiological experiments provide supporting evidence that betaxolol acts in a manner consistent with preventing retinal ganglion cell death induced by elevated extracellular glutamate or by increased spontaneous spike rates under pathologic conditions. The physiological actions of betaxolol lead to reducing neurotoxic effects in ganglion cells, which are the most susceptible retinal neurons to glutamate-induced damages under ischemic and glaucomatous conditions. Therefore, betaxolol has the potential to be a neuroprotective agent against retinal degeneration in patients with disorders mediated by such mechanisms.

Retinal ganglion cell dysfunction induced by hypoxia and glutamate: potential neuroprotective effects of beta-blockers.

The objective of this study was to examine the effects of hypoxia, glutamate, and beta-blockers on the electrical activities of retinal ganglion cells. Single-unit extracellular and whole-cell voltage clamp recording techniques were used to record electrical activities from ganglion cells in the tiger salamander retina. This was performed under physiologic conditions, hypoxia, or elevated exogenous or endogenous glutamate levels. Light-evoked spike activities, glutamate-induced currents, and voltage-gated sodium and calcium currents were measured in the presence of the beta-1 selective antagonist betaxolol or the nonselective antagonist timolol. Hypoxia resulted in suppressing or blocking the OFF responses in the majority of ON-OFF ganglion cells tested, whereas the ON responses were only slightly affected. The presence of increased glutamate had similar findings and demonstrated an increase in the spontaneous firing rate of retinal ganglion cells. Betaxolol (2-50 microM) reduced the rate of spontaneous firing of retinal ganglion cells induced by glutamate. At 2 to 50 microM, betaxolol reversibly reduced the voltage-gated sodium currents and calcium currents in retinal ganglion cells. Timolol (up to 100 microM) did not demonstrate any detectable action on these currents. The physiologic responses of retinal ganglion cells to hypoxia or elevated glutamate levels in this animal model appear to be very similar. Although short-term exposure to hypoxia and glutamate used in this study exerts reversible actions on ganglion cells and does not induce permanent cell damage, such initial physiologic actions are likely to be precursors of permanent cell damage. Thus, hypoxia and elevated glutamate levels in the retina may represent a final pathway in diseases affecting retinal ganglion cells, such as glaucoma. Similar damage could result from different factors, such as decreased perfusion-induced ischemia or anomalous neuronal processing of glutamate. Betaxolol exerts its primary neuronal actions on retinal ganglion cells. It reversibly blocked voltage-gated calcium current and reduced the spontaneous firing rate by suppressing glutamate-gated currents and sodium currents in ganglion cells. These actions may protect ganglion cells from damage caused by ischemia or elevated glutamate levels.

Collagen type I and III synthesis by Tenon's capsule fibroblasts in culture: individual patient characteristics and response to mitomycin C, 5-fluorouracil, and ascorbic acid.

PURPOSE: This study was performed to better understand the differences between patients in specific components of wound healing as it may pertain to glaucoma filtration surgery, including the use of antimetabolites. METHODS: Human Tenon's capsule fibroblasts were obtained at the time of glaucoma filtering surgery and established in individual cell cultures from 35 glaucoma patients. The dose-response to 5-fluorouracil (5FU) and mitomycin C (MMC) was determined. The individual cell lines were exposed to the antimetabolites and ascorbic acid with measurement of collagen type I and III production by an ELISA-type dot blot assay. These results were then statistically compared to the individual patient characteristics including age, race, previous surgery and medications, and type of glaucoma. RESULTS: 5-FU had little effect on collagen type I and III production or protein synthesis. MMC had an inhibitory effect on collagen secretion and total protein synthesis with increasing concentration. Photomicrographs of the cells after each treatment condition revealed characteristic morphologic changes when compared to controls. There was a large range of collagen type I and III production with correlation between the amounts of each collagen type secreted in response to the antimetabolites. However, there was no correlation with accepted risk factors for filtration failure. CONCLUSION: These antimetabolites act similarly on different cell lines in a nonspecific manner. The results suggest that the increased risk of filtration failure due to age, race, diagnosis, and previous conjunctival surgery is not due to differences in secretion of collagen types I and III by Tenon's capsule fibroblasts.

Clinical experience with apraclonidine 0.5%.

PURPOSE: This study describes our long-term experience with apraclonidine 0.5% in the treatment of chronic glaucoma in clinical practice. METHODS: A retrospective review was performed of all consecutive patients treated with apraclonidine 0.5%, specifically studying the magnitude of IOP reduction, incidence of allergic reaction, frequency of ineffectiveness, and its additivity to other anti-glaucoma medications. Patients previously treated with this agent or in whom multiple simultaneous medication changes were made were excluded. RESULTS: A total of 174 patients were included in this study and followed up to 24 months. For 38 patients (21%), the drug was found to be ineffective at some point during the study. A similar number of patients developed an allergic reaction to the medication. Intraocular pressure lowering ranged from 19 to 26% overall, and 22.5 to 29% in those responding to apraclonidine 0.5%. CONCLUSION: In this study, apraclonidine 0.5% was shown to be effective in reducing intraocular pressure, both for short-term situations and for longer periods of treatment, up to 24 months.

Levobunolol 0.5% and timolol 0.5% to prevent intraocular pressure elevation after neodymium:YAG laser posterior capsulotomy.

PURPOSE: To evaluate the prophylactic effect of levobunolol 0.5%, timolol 0.5%, or vehicle in reducing the incidence of postoperative intraocular pressure (IOP) spikes of 5 and 10 mm Hg or more in patients having neodymium:YAG (Nd:YAG) laser posterior capsulotomy. SETTING: Miami Vision Center, Coral Gables, Florida; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; Cincinnati Eye Institute, Cincinnati, Ohio; South Texas Cataract and Glaucoma Center, San Antonio, Texas; Mid-South Eye Foundation, Memphis, Tennessee, USA. METHODS: This prospective, double-masked, randomized study comprised 144 patients having Nd:YAG laser posterior capsulotomy in one eye. One drop of the test medication was administered preoperatively and one drop on the evening after surgery; IOP was measured preoperatively and 1,2,3 and 24 hours postoperatively. RESULTS: Intraocular pressure elevations of 5 mm Hg or more were seen in 1 of 60 patients (2%) in the levobunolol group, 4 of 54 (7%) in the timolol group, and 10 of 28 (36%) in the vehicle group. These elevations occurred significantly more frequently in the vehicle group than in the levobunolol (P < .001) or timolol (P < .004) groups. Elevations of 10 mm Hg or more were found in 2 of 28 patients (7%) treated with vehicle but were not observed in the patients treated with levobunolol or timolol. CONCLUSIONS: Levobunolol 0.5% or timolol 0.5% administered preoperatively and again in the evening after Nd:YAG laser capsulotomy effectively blunted the IOP rise that frequently follows laser surgery.

Visual function following trabeculectomy: effect on corneal topography and contrast sensitivity.

PURPOSE: This study was to determine the role of changes in refractive error, contrast sensitivity, and corneal topography in transient changes in visual function following trabeculectomy. METHODS: We performed a prospective study evaluating these factors in 13 consecutive patients undergoing a standardized trabeculectomy. Preoperatively, and at 1, 4, and 12 weeks postoperatively, we measured best-corrected visual acuity, refractive error, and contrast sensitivity and analyzed computerized video-keratographic studies including estimated corneal visual acuity. RESULTS: One week postoperatively, best-corrected visual acuity decreased at least one line in 8 of 13 patients, whereas no eyes had decreased contrast sensitivity. Mean central corneal astigmatism increased 1.4 diopters along the surgical meridian. By 12 weeks, visual acuity returned to preoperative levels in all patients and the corneal topographic changes returned to within 1 diopter of preoperative values in 12 of 13 patients. Postoperative changes in estimated corneal visual acuity were similar to those in best-corrected visual acuity with no statistically significant difference. CONCLUSIONS: Corneal topographic changes appear to contribute to visual acuity reduction following trabeculectomy. In most cases this is transient with return to preoperative topography within 12 weeks.

Ascorbate stimulates type I and type III collagen in human Tenon's fibroblasts.

PURPOSE: To better understand wound healing after glaucoma filtration surgery by measuring the production of type I and type III collagen in cultured Tenon's fibroblasts and determine the effect of ascorbic acid on collagen subtype production. METHODS: An ELISA-type dot blot assay was used to directly measure the production of types I and III collagen by subconfluent cultures of fibroblasts from human Tenon's capsule. Because ascorbic acid is both high in aqueous humor and necessary for the production of collagen, we measured the dose response of type I and type III collagen production to ascorbic acid. RESULTS: Ascorbic acid stimulated an increase in collagen production that reached a maximum level at 100 micrograms/ml. This is approximately half of the ascorbic acid concentration found in human aqueous humor. Unlike previous reports, we found no toxic effects from ascorbic acid at concentrations as high as 250 micrograms/ml over a 24-hour period. The lack of toxicity may result from the use of serum-free media in the assay. CONCLUSIONS: This culture system will be useful for exploring factors that may alter collagen production and could potentially affect wound healing.

Picosecond neodymium:yttrium lithium fluoride (Nd:YLF) laser peripheral iridotomy.

PURPOSE: We evaluated the picosecond neodymium:yttrium lithium fluoride (Nd:YLF) laser for performing peripheral iridotomies of predetermined size and shape in various types of irides. METHODS: In the first part of the study, we determined operating parameters from performing 60 iridotomies in human cadaver eyes. Subsequently, using the parameters obtained in cadaver eyes, iridotomies were created in eyes of patients with primary angle-closure glaucoma. RESULTS: In the cadaver eyes, the optimal parameters were a rectangular cutting pattern of 0.3 x 0.3 mm, 500-microns cutting depth, 50-microns spot separation, 200 to 400 microJ of energy per pulse, 200 to 400 pulses per second, and no focal offset distance. In 18 eyes of 11 patients, iridotomies with well-defined margins and size were created. Minimal hemorrhage occurred intraoperatively in ten of 18 eyes (55.6%), which did not affect the outcome of the procedure. Increases of postoperative intraocular pressure at one hour averaged 3.5 +/- 5.1 mm Hg, with an increase of more than 10 mm Hg in three eyes (16.7%), and a maximum of 12 mm Hg. We observed no corneal or retinal damage. CONCLUSION: The picosecond Nd:YLF laser seems to be an effective instrument for reliably performing peripheral iridotomies of precise size and shape using low energy per pulse levels. This laser, unlike the argon laser, is successful independent of iris thickness or color and can easily make a larger iridotomy than is often possible with the Nd:YAG laser.

Gonioscopic ab interno Nd:YLF laser sclerostomy in human cadaver eyes.

We explored the potential of the picosecond Nd:YLF laser to perform gonioscopic ab interno sclerostomy in human cadaver eyes. Full-thickness sclerostomies were created in 12 such eyes and confirmed by external scleral and histopathologic examination. Optimum parameters for successful completion of a sclerostomy were: a rectangular pattern of 0.3 mm by 0.3 mm, a repetition rate of 1000 pulses per second, an energy-per-pulse of 400 mJ, and a spot separation between 10 and 50 microns, with no focal offset. The Nd:YLF laser reliably created successful gonioscopic sclerostomies with minimal adjacent thermal damage in human cadaver eyes.