Alastair Lockwood

Trabeculectomy in the 21st century: a multicenter analysis.

OBJECTIVE To evaluate the efficacy and safety of current trabeculectomy surgery in the United Kingdom. DESIGN Cross-sectional, multicenter, retrospective follow-up. PARTICIPANTS A total of 428 eyes of 395 patients. METHODS Consecutive trabeculectomy cases with open-angle glaucoma and no previous incisional glaucoma surgery from 9 glaucoma units were evaluated retrospectively. Follow-up was a minimum of 2 years. MAIN OUTCOME MEASURES Surgical success, intraocular pressure (IOP), visual acuity, complications, and interventions. Success was stratified according to IOP, use of hypotensive medications, bleb needling, and resuturing/revision for hypotony. Reoperation for glaucoma and loss of perception of light were classified as failures. RESULTS Antifibrotics were used in 400 cases (93%): mitomycin C (MMC) in 271 (63%), 5-fluorouracil (5-FU) in 129 (30%), and no antifibrotic in 28 (7%). At 2 years, IOP (mean ± standard deviation) was 12.4 ± 4 mmHg, and 342 patients (80%) achieved an IOP ≤ 21 mmHg and 20% reduction of preoperative IOP without IOP-lowering medication, whereas 374 patients (87%) achieved an IOP ≤ 21 mmHg and 20% reduction of preoperative IOP overall. An IOP ≤18 mmHg and 20% reduction of preoperative IOP were achieved by 337 trabeculectomies (78%) without IOP-lowering treatment and by 367 trabeculectomies (86%) including hypotensive medication. Postoperative treatments included suture manipulation in 184 patients (43%), resuturing or revision for hypotony in 30 patients (7%), bleb needling in 71 patients (17%), and cataract extraction in 111 of 363 patients (31%). Subconjunctival 5-FU injection was performed postoperatively in 119 patients (28%). Visual loss of >2 Snellen lines occurred in 24 of 428 patients (5.6%). A total of 31 of the 428 patients (7.2%) had late-onset hypotony (IOP <6 mmHg after 6 months). In 3 of these, visual acuity decreased by >2 Snellen lines. Bleb leaks were observed in 59 cases (14%), 56 (95%) of which occurred within 3 months. Two patients developed blebitis. Bleb-related endophthalmitis developed in 1 patient within 1 month postoperatively and in 1 patient at 3 years. There was an endophthalmitis associated with subsequent cataract surgery. CONCLUSIONS This survey shows that good trabeculectomy outcomes with low rates of surgical complications can be achieved, but intensive proactive postoperative care is required.

New developments in the pharmacological modulation of wound healing after glaucoma filtration surgery.

Despite the advent of many new devices for glaucoma surgery, scarring is the main cause of suboptimal pressure control and surgical failure in all forms of surgery. The cytotoxic antimetabolites, 5-flurouracil and mitomycin C both prolong success but with the increased risk of blinding complications. A greater understanding of the cellular mechanisms of the wound healing response has led to the identification and modulation of potential therapeutic targets. These include transforming factor β, inflammatory mediators, the acute phase protein serum amyloid P, vascular endothelial growth factor and the matrix metallaproteinases. While optimal drug delivery is still a major challenge, modulating these effects either directly or through downstream signalling promises to yield anti-scarring efficacy, while minimising side effects.

The PK-Eye: A Novel In Vitro Ocular Flow Model for Use in Preclinical Drug Development

A 2-compartment in vitro eye flow model has been developed to estimate ocular drug clearance by the anterior aqueous outflow pathway. The model is designed to accelerate the development of longer-acting ophthalmic therapeutics. Dye studies show aqueous flow is necessary for a molecule injected into the vitreous cavity to clear from the model. The clearance times of proteins can be estimated by collecting the aqueous outflow, which was first conducted with bevacizumab using phosphate-buffered saline in the vitreous cavity. A simulated vitreous solution was then used and ranibizumab (0.5 mg) displayed a clearance time of 8.1 ± 3.1 days, which is comparable to that observed in humans. The model can estimate drug release from implants or the dissolution of suspensions as a first step in their clearance mechanism, which will be the rate-limiting step for the overall resident time of a candidate dosage form in the vitreous. A suspension of triamcinolone acetonide (Kenalog®) (4.0 mg) displayed clearance times spanning 26-28 days. These results indicate that the model can be used to determine in vitro-in vivo correlations in preclinical studies to develop long-lasting therapeutics to treat blinding diseases at the back of the eye.

Characterisation of Ilomastat for Prolonged Ocular Drug Release

We are developing tablet dosage forms for implantation directly into the subconjunctival space of the eye. The matrix metalloproteinase inhibitor, ilomastat, has previously been shown to be efficacious at suppressing scarring following glaucoma filtration surgery (GFS). We report on the physical characterisation of ilomastat which is being developed for ocular implantation. Since ilomastat is being considered for implantation it is necessary to examine its polymorphs and their influence on aspects of the in vitro drug release profile. X-ray powder diffraction identified two polymorphs of ilomastat from different commercial batches of the compound. Tablets were prepared from the two different polymorphs. Isothermal perfusion calorimetry was used to show that amorphous content is not increased during tablet formulation. The melting points of the two polymorphs are 188 and 208°C as determined by differential scanning calorimetry. Utilising single crystal X-ray diffraction, the structural conformations and packing arrangements of the different polymorphs were determined. The orthorhombic crystal crystallised as a monohydrate while the second monoclinic crystal form is non-solvated. Ilomastat tablets prepared from the two different solid forms exhibited similar drug release profiles in vitro under conditions mimicking the aqueous composition, volume and flow of the subconjunctival space after GFS. This suggests that a reproducible dose at each time point during release after implantation should be achievable in vivo with ilomastat tablets prepared from the two polymorphs identified.

An Ilomastat-CD Eye Drop Formulation to Treat Ocular Scarring

Purpose The purpose of this study was to develop a topical matrix metalloproteinase inhibitor preparation for antiscarring therapy. Methods The broad spectrum matrix metalloproteinase inhibitor ilomastat was formulated using 2-hydroxypropyl-β-cyclodextrin in aqueous solution. In vitro activity of ilomastat-cyclodextrin (ilomastat-CD) was examined using fibroblasts seeded in collagen. Permeation of ilomastat-CD eye drop through pig eye conjunctiva was confirmed using Franz diffusion cells. Ilomastat-CD eye drop was applied to rabbit eyes in vivo, and the distribution of ilomastat in ocular tissues and fluids was determined by liquid chromatography-mass spectroscopy. Results The aqueous solubility of ilomastat-CD was ∼1000 μg/mL in water and 1400 μg/mL in PBS (pH 7.4), which is greater than ilomastat alone (140 and 160 μg/mL in water and PBS, respectively). The in vitro activity of ilomastat-CD to inhibit collagen contraction in the presence of human Tenon fibroblast cells was unchanged compared to uncomplexed ilomastat. Topically administered ilomastat-CD in vivo to rabbit eyes resulted in a therapeutic concentration of ilomastat being present in the sclera and conjunctiva and within the aqueous humor. Conclusions Ilomastat-CD has the potential to be formulated as an eye drop for use as an antifibrotic, which may have implications for the prevention of scarring in many settings, for example glaucoma filtration surgery.

Shorter Axial Length and Increased Astigmatic Refractive Error are Associated With Socio-Economic Deprivation in an Adult UK Cohort

Purpose: To evaluate whether socio-economic deprivation is associated with ocular axial length and refractive error in a British cohort. Methods: The study population consisted of 7,652 individuals who provided data to the prospective cataract database at Portsmouth Eye unit, UK over a 4 year period (January 2004 to June 2008). Indices of multiple deprivation (IMD) scores measuring both social and economic domains for each patient’s locality were calculated. The association of these measures of deprivation with axial length and refractive error (astigmatic and spherical) were evaluated using regression analyses after adjusting for age and sex. Results: Socio-economically deprived areas (higher IMD scores) were inversely associated with axial lengths and astigmatic refraction. After controlling for age and sex, an inverse linear association was observed between axial length and IMD scores (-0.24mm in highest quintile compared to lowest; 95% confidence intervals: -0.33 to -0.15) and between astigmatic refraction and IMD scores (-0.12 dioptres in highest quintile compared to lowest; 95% confidence intervals: -0.21 to -0.03). There was no association between spherical refraction and IMD scores. Conclusions: Axial length and astigmatic refraction were inversely associated with socio-economic deprivation in this population. Identification of the environmental exposures involved may identify reversible risk factors for impaired vision.

LC–MS analysis to determine the biodistribution of a polymer coated ilomastat ocular implant

ABSTRACT Ilomastat is a matrix metalloproteinase inhibitor (MMPi) that has shown the potential to inhibit scarring (fibrosis) by mediating healing after injury or surgery. A long lasting ocular implantable pharmaceutical formulation of ilomastat is being developed to mediate the healing process to prevent scarring after glaucoma filtration surgery. The ilomastat implant was coated with water permeable and biocompatible phosphoryl choline polymer (PC1059) displayed extended slow release of ilomastat in vitro and in vivo. The ocular distribution of ilomastat from the implant in rabbits at day 30 post surgery was determined by the extraction of ilomastat and its internal standard marimastat from the ocular tissues, plasma, aqueous humour and vitreous fluid followed by capillary‐flow liquid chromatography (cap‐LC), the column effluent was directed into a triple quadrupole mass spectrometer operating in product scan mode. The lower limits of quantification (LLOQs) were 0.3pg/&mgr;L for ocular fluids and plasma, and 3pg/mg for ocular tissues. The extraction recoveries were 90–95% for ilomastat and its internal standard from ocular tissues. Ilomastat was found in ocular fluids and tissues at day 30 after surgery. The level of ilomastat was 18 times higher in the aqueous humour than vitreous humour. The concentration ranking of ilomastat in the ocular tissues was sclera>bleb conjunctiva>conjunctiva (rest of the eye)>cornea. Mass spectrometry analysis to confirm the presence of ilomastat in the ocular tissues and fluids at day 30 post‐surgery establishes the extended release of ilomastat can be achieved in vivo, which is crucial information for optimisation of the ilomastat coated implant.

Acute suprachoroidal haemorrhage post-tenecteplase thrombolysis for myocardial infarction: management considerations.

We report a case of a 63-year-old man who received intravenous tenecteplase as thrombolytic therapy for an inferior ST elevation myocardial infarction. Three hours later he complained of blurred vision in the right eye and on examination had sustained a suprachoroidal haemorrhage. With conservative treatment the haemorrhage resolved, leading to a normalisation of visual acuity. To the authors’ knowledge, no case reports exist of this rare complication following intravenous tenecteplase. We discuss implications for further thrombolysis and anticoagulation.