PHACOVITRECTOMY FOR PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT REPAIR: A Retrospective Review.

PURPOSE: To analyze the single surgery success rate and anterior segment complications related to phacoemulsification and intraocular lens implantation in a series of patients undergoing phacovitrectomy for all types of primary rhegmatogenous retinal detachment. METHODS: We performed a retrospective interventional case series on 302 eyes undergoing phacovitrectomy for primary rhegmatogenous retinal detachment repair between November 1, 2016, and February 2, 2019, in Edmonton, Canada. Primary outcomes included single surgery retinal reattachment rate and anterior segment complications. Secondary outcomes included the effects of proliferative vitreoretinopathy and macula and/or peripheral internal limiting membrane peeling on the rate of surgical success. RESULTS: The single surgery success rate of phacovitrectomy for all types of primary rhegmatogenous retinal detachment was 85.1%. The presence of proliferative vitreoretinopathy was associated with lower surgical success (odds ratio, 0.33; P = 0.01). Macular internal limiting membrane peeling was associated with higher surgical success (odds ratio, 2.4; P = 0.05). Anterior segment complications included posterior capsular opacification (28.8%), posterior synechiae (10.9%), and posterior capsular rupture (2.3%). CONCLUSION: Phacovitrectomy is a safe and effective treatment option for the primary repair of rhegmatogenous retinal detachments. This study provides evidence to support the safe incorporation of phacoemulsification and intraocular lens implantation with retinal surgery.

Are the changes in diagnostic criteria for gestational diabetes mellitus reflected in perinatal outcomes? A retrospective assessment.

BACKGROUND: Gestational diabetes mellitus (GDM) is glucose intolerance first diagnosed during pregnancy not due to overt diabetes. Recent changes to the diagnostic guidelines have been shown to increase the apparent occurrence of GDM. AIM: The aim of this study was to compare retrospectively the neonatal outcomes between groups defined using the new and old criteria to assess the impact of guideline changes on pregnancy outcomes. METHODS: The study was of singleton babies delivered of 641 women, who had oral glucose tolerance testing and pregnancy care at a single tertiary centre between 2011 and 2015. RESULTS: Compared to the population of women not now considered to have GDM by International Association of Diabetes and Pregnancy Study Groups criteria (two-hour glucose concentration ≤8.4 mmol/L), neonates born to women with the new lower fasting criterion (5.1-5.4 mmol/L) and/or the new 60-min group (glucose ≥10 mmol/L) combined were significantly more likely to have birthweight ≥90th percentile (22% vs 5%, P < 0.0001). In contradistinction, there was a significant excess number of small-for-dates babies (birthweight ≤10th percentile) in all subgroups previously diagnosed and treated for GDM by the Australian Diabetes in Pregnancy Society criteria (17% vs 7%, P = 0.001). Rates for lower uterine segment caesarean section, admission to the neonatal intensive care unit / special care nursery and Apgar scores at one and five minutes were not statistically different across all groups. CONCLUSIONS: Outcomes support the lowering of the fasting criterion to extend management of GDM to limit growth of large birthweight neonates. An unexpected outcome was that in women previously treated for GDM, there were increased numbers of low-birthweight neonates.

Protein Engineering on Human Recombinant Follistatin: Enhancing Pharmacokinetic Characteristics for Therapeutic Application.

Follistatin (FS) is an important regulatory protein, a natural antagonist for transforming growth factor-ß family members activin and myostatin. The diverse biologic roles of the activin and myostatin signaling pathways make FS a promising therapeutic target for treating human diseases exhibiting inflammation, fibrosis, and muscle disorders, such as Duchenne muscular dystrophy. However, rapid heparin-mediated hepatic clearance of FS limits its therapeutic potential. We targeted the heparin-binding loop of FS for site-directed mutagenesis to improve clearance parameters. By generating a series of FS variants with one, two, or three negative amino acid substitutions, we demonstrated a direct and proportional relationship between the degree of heparin-binding affinity in vitro and the exposure in vivo. The triple mutation K(76,81,82)E abolished heparin-binding affinity, resulting in ∼20-fold improved in vivo exposure. This triple mutant retains full functional activity and an antibody-like pharmacokinetic profile, and shows a superior developability profile in physical stability and cell productivity compared with FS variants, which substitute the entire heparin-binding loop with alternative sequences. Our surgical approach to mutagenesis should also reduce the immunogenicity risk. To further lower this risk, we introduced a novel glycosylation site into the heparin-binding loop. This hyperglycosylated variant showed a 10-fold improved exposure and decreased clearance in mice compared with an IgG1 Fc fusion protein containing the native FS sequence. Collectively, our data highlight the importance of improving pharmacokinetic properties by manipulating heparin-binding affinity and glycosylation content and provide a valuable guideline to design desirable therapeutic FS molecules.

Translating slow-binding inhibition kinetics into cellular and in vivo effects.

Many drug candidates fail in clinical trials owing to a lack of efficacy from limited target engagement or an insufficient therapeutic index. Minimizing off-target effects while retaining the desired pharmacodynamic (PD) response can be achieved by reduced exposure for drugs that display kinetic selectivity in which the drug-target complex has a longer half-life than off-target-drug complexes. However, though slow-binding inhibition kinetics are a key feature of many marketed drugs, prospective tools that integrate drug-target residence time into predictions of drug efficacy are lacking, hindering the integration of drug-target kinetics into the drug discovery cascade. Here we describe a mechanistic PD model that includes drug-target kinetic parameters, including the on- and off-rates for the formation and breakdown of the drug-target complex. We demonstrate the utility of this model by using it to predict dose response curves for inhibitors of the LpxC enzyme from Pseudomonas aeruginosa in an animal model of infection.

Cataract surgery and age-related macular degeneration.

PURPOSE OF REVIEW: The following review describes the recent evidence regarding the effect of cataract surgery on age-related macular degeneration (AMD). RECENT FINDINGS: For patients with both visually significant cataracts and AMD, recent evidence supports the role of cataract surgery with reports demonstrating improved visual acuity, absence of significant disease progression, and improved quality of life. SUMMARY: Recent evidence does not find cataract surgery to cause or worsen AMD.

Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914.

We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drug-resistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467-474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of supercoiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of supercoiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases α and ß.

Untargeted Metabolomics To Ascertain Antibiotic Modes of Action.

Deciphering the mode of action (MOA) of new antibiotics discovered through phenotypic screening is of increasing importance. Metabolomics offers a potentially rapid and cost-effective means of identifying modes of action of drugs whose effects are mediated through changes in metabolism. Metabolomics techniques also collect data on off-target effects and drug modifications. Here, we present data from an untargeted liquid chromatography-mass spectrometry approach to identify the modes of action of eight compounds: 1-[3-fluoro-4-(5-methyl-2,4-dioxo-pyrimidin-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea (AZ1), 2-(cyclobutylmethoxy)-5'-deoxyadenosine, triclosan, fosmidomycin, CHIR-090, carbonyl cyanidem-chlorophenylhydrazone (CCCP), 5-chloro-2-(methylsulfonyl)-N-(1,3-thiazol-2-yl)-4-pyrimidinecarboxamide (AZ7), and ceftazidime. Data analysts were blind to the compound identities but managed to identify the target as thymidylate kinase for AZ1, isoprenoid biosynthesis for fosmidomycin, acyl-transferase for CHIR-090, and DNA metabolism for 2-(cyclobutylmethoxy)-5'-deoxyadenosine. Changes to cell wall metabolites were seen in ceftazidime treatments, although other changes, presumably relating to off-target effects, dominated spectral outputs in the untargeted approach. Drugs which do not work through metabolic pathways, such as the proton carrier CCCP, have no discernible impact on the metabolome. The untargeted metabolomics approach also revealed modifications to two compounds, namely, fosmidomycin and AZ7. An untreated control was also analyzed, and changes to the metabolome were seen over 4 h, highlighting the necessity for careful controls in these types of studies. Metabolomics is a useful tool in the analysis of drug modes of action and can complement other technologies already in use.

Cell therapy for retinal disease.

PURPOSE OF REVIEW: The following review will provide an update on stem cell therapy with a focus on completed and ongoing human trials. RECENT FINDINGS: Significant progress has brought stem cell therapy from proof-of-concept animal models to human clinical trials. Although in its infancy, valuable safety and efficacy data are starting to emerge from trials looking at cell therapies for age-related macular degeneration, Stargardt's macular dystrophy, retinitis pigmentosa, and ischemic retinopathies. SUMMARY: Although clinical trials continue to enroll and evaluate stem cell therapy in patients with retinal diseases, preliminary results using both cellular replacement and trophic models have provided initial support for this exciting therapy. Results of these pivotal trials will form a key foundation for moving forward toward the ultimate goal of preventing blinding disease.

Target-based resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a novel bacterial type II topoisomerase inhibitor.

In a previous report (T. J. Dougherty, A. Nayar, J. V. Newman, S. Hopkins, G. G. Stone, M. Johnstone, A. B. Shapiro, M. Cronin, F. Reck, and D. E. Ehmann, Antimicrob Agents Chemother 58:2657-2664, 2014), a novel bacterial type II topoisomerase inhibitor, NBTI 5463, with activity against Gram-negative pathogens was described. First-step resistance mutations in Pseudomonas aeruginosa arose exclusively in the nfxB gene, a regulator of the MexCD-OprJ efflux pump system. The present report describes further resistance studies with NBTI 5463 in both Pseudomonas aeruginosa and Escherichia coli. Second-step mutations in P. aeruginosa arose at aspartate 82 of the gyrase A subunit and led to 4- to 8-fold increases in the MIC over those seen in the parental strain with a first-step nfxB efflux mutation. A third-step mutant showed additional GyrA changes, with no changes in topoisomerase IV. Despite repeated efforts, resistance mutations could not be selected in E. coli. Genetic introduction of the Asp82 mutations observed in P. aeruginosa did not significantly increase the NBTI MIC in E. coli. However, with the aspartate 82 mutation present, it was possible to select second-step mutations in topoisomerase IV that did lead to MIC increases of 16- and 128-fold. As with the gyrase aspartate 82 mutation, the mutations in topoisomerase IV did not by themselves raise the NBTI MIC in E. coli. Only the presence of mutations in both targets of E. coli led to an increase in NBTI MIC values. This represents a demonstration of the value of balanced dual-target activity in mitigating resistance development.

Molecular mechanisms of sulbactam antibacterial activity and resistance determinants in Acinetobacter baumannii.

Sulbactam is a class A ß-lactamase inhibitor with intrinsic whole-cell activity against certain bacterial species, including Acinetobacter baumannii. The clinical use of sulbactam for A. baumannii infections is of interest due to increasing multidrug resistance in this pathogen. However, the molecular drivers of its antibacterial activity and resistance determinants have yet to be precisely defined. Here we show that the antibacterial activities of sulbactam vary widely across contemporary A. baumannii clinical isolates and are mediated through inhibition of the penicillin-binding proteins (PBPs) PBP1 and PBP3, with very low frequency of resistance; the rare pbp3 mutants with high levels of resistance to sulbactam are attenuated in fitness. These results support further investigation of the potential clinical utility of sulbactam.

Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy.

The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R(2) = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated ß-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.

Avibactam is a covalent, reversible, non-ß-lactam ß-lactamase inhibitor.

Avibactam is a ß-lactamase inhibitor that is in clinical development, combined with ß-lactam partners, for the treatment of bacterial infections comprising gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a ß-lactam core but maintains the capacity to covalently acylate its ß-lactamase targets. Using the TEM-1 enzyme, we characterized avibactam inhibition by measuring the on-rate for acylation and the off-rate for deacylation. The deacylation off-rate was 0.045 min(-1), which allowed investigation of the deacylation route from TEM-1. Using NMR and MS, we showed that deacylation proceeds through regeneration of intact avibactam and not hydrolysis. Other than TEM-1, four additional clinically relevant ß-lactamases were shown to release intact avibactam after being acylated. We showed that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among ß-lactamase inhibitors.

Kinetics of avibactam inhibition against Class A, C, and D ß-lactamases.

Avibactam is a non-ß-lactam ß-lactamase inhibitor with a spectrum of activity that includes ß-lactamase enzymes of classes A, C, and selected D examples. In this work acylation and deacylation rates were measured against the clinically important enzymes CTX-M-15, KPC-2, Enterobacter cloacae AmpC, Pseudomonas aeruginosa AmpC, OXA-10, and OXA-48. The efficiency of acylation (k2/Ki) varied across the enzyme spectrum, from 1.1 × 10(1) m(-1)s(-1) for OXA-10 to 1.0 × 10(5) for CTX-M-15. Inhibition of OXA-10 was shown to follow the covalent reversible mechanism, and the acylated OXA-10 displayed the longest residence time for deacylation, with a half-life of greater than 5 days. Across multiple enzymes, acyl enzyme stability was assessed by mass spectrometry. These inhibited enzyme forms were stable to rearrangement or hydrolysis, with the exception of KPC-2. KPC-2 displayed a slow hydrolytic route that involved fragmentation of the acyl-avibactam complex. The identity of released degradation products was investigated, and a possible mechanism for the slow deacylation from KPC-2 is proposed.

NBTI 5463 is a novel bacterial type II topoisomerase inhibitor with activity against gram-negative bacteria and in vivo efficacy.

The need for new antibiotics that address serious Gram-negative infections is well recognized. Our efforts with a series of novel bacterial type II topoisomerase inhibitors (NBTIs) led to the discovery of NBTI 5463, an agent with improved activity over other NBTIs against Gram-negative bacteria, in particular against Pseudomonas aeruginosa (F. Reck, D. E. Ehmann, T. J. Dougherty, J. V. Newman, S. Hopkins, G. Stone, N. Agrawal, P. Ciaccio, J. McNulty, H. Barthlow, J. O'Donnell, K. Goteti, J. Breen, J. Comita-Prevoir, M. Cornebise, M. Cronin, C. J. Eyermann, B. Geng, G. R. Carr, L. Pandarinathan, X. Tang, A. Cottone, L. Zhao, N. Bezdenejnih-Snyder, submitted for publication). In the present work, NBTI 5463 demonstrated promising activity against a broad range of Gram-negative pathogens. In contrast to fluoroquinolones, the compound did not form a double-strand DNA cleavable complex with Escherichia coli DNA gyrase and DNA, but it was a potent inhibitor of both DNA gyrase and E. coli topoisomerase IV catalytic activities. In studies with P. aeruginosa, NBTI 5463 was bactericidal. Resistant mutants arose at a low rate, and the mutations were found exclusively in the nfxB gene, a regulator of the MexCD-OprJ efflux system. Levofloxacin-selected resistance mutations in GyrA did not result in decreased susceptibility to NBTI 5463. Animal infection studies demonstrated that NBTI 5463 was efficacious in mouse models of lung, thigh, and ascending urinary tract infections.

Optimization of physicochemical properties and safety profile of novel bacterial topoisomerase type II inhibitors (NBTIs) with activity against Pseudomonas aeruginosa.

Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.

Novel heterozygous PRPH2 variant identified in a patient with spinocerebellar ataxia type 14 and macular dystrophy.

PURPOSE: To report on a patient with spinocerebellar ataxia type 14 (SCA14) and macular dystrophy with identification of a novel PRPH2 variant. METHODS: Case report. RESULTS: A 63-year-old female with molecularly confirmed SCA14 presented with symmetric pigmentary disturbances in a perifoveal distribution resembling a pattern macular dystrophy. She had no history of using medications with recognized toxic macular effects. Subsequent genetic testing confirmed a novel heterozygous missense variant of unknown significance in PRPH2 (PRPH2: c.694 G>A, p.(Ala232Thr)). CONCLUSIONS: To our knowledge, this is the first case of macular dystrophy identified in a patient with SCA14. While it is possible that the macular dystrophy observed in this patient might be an under-reported phenotype associated with SCA14, the pattern of macular changes is consistent with PRPH2-related disorders. The identified missense variant is predicted to be damaging by most in silico models, and the residue is highly conserved, adding support to a dual genetic diagnosis in this case.

Effect of Macular Internal Limiting Membrane Peeling on Single Surgery Success Rates of Vitrectomy for Uncomplicated, Primary Macula-Off Retinal Detachment.

Purpose: To determine the anatomic and visual outcomes of pars plana vitrectomy for uncomplicated, primary macula-off rhegmatogenous retinal detachment (RRD) with and without internal limiting membrane (ILM) peeling. Methods: This retrospective chart review comprised 129 patients with uncomplicated, primary macula-off RRD presenting between January 1, 2016, and May 31, 2021. Thirty-six patients (27.9%) had ILM peeling and 93 (72.0%) did not. The primary outcome was the rate of recurrent RRD. Secondary outcomes included preoperative and postoperative best-corrected visual acuity (BCVA), epiretinal membrane (ERM) formation, and macular thickness. Results: No significant difference was found in the risk for recurrent RRD between patients who had ILM peeling and those who did not (2.8% [1/36] and 5.4% [5/93], respectively) (P = 1.00). The final postoperative BCVA was better in eyes that did not have ILM peeling (P< .001). No ERM occurred in the group with ILM peeling, whereas ERM occurred in 27 patients (29.0%) who did not have ILM peeling. The temporal macular retina was thinner in eyes in which ILM peeling was performed. Conclusions: The risk for recurrent RRD was not statistically lower in eyes having ILM peeling of the macula in uncomplicated, primary macula-off RRD. Despite a reduction in postoperative ERM formation, eyes having macular ILM peeling had worse postoperative VA.

Gene therapy for cross-correction of somatic organs and the CNS in mucopolysaccharidosis II in rodents and non-human primates.

Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by deficient activity of iduronate-2-sulfatase (I2S), leading to pathological accumulation of glycosaminoglycans (GAGs) in tissues. We used iduronate-2-sulfatase knockout (Ids KO) mice to investigate if liver-directed recombinant adeno-associated virus vectors (rAAV8-LSP-hIDSco) encoding human I2S (hI2S) could cross-correct I2S deficiency in Ids KO mouse tissues, and we then assessed the translation of mouse data to non-human primates (NHPs). Treated mice showed sustained hepatic hI2S production, accompanied by normalized GAG levels in somatic tissues (including critical tissues such as heart and lung), indicating systemic cross-correction from liver-secreted hI2S. Brain GAG levels in Ids KO mice were lowered but not normalized; higher doses were required to see improvements in brain histology and neurobehavioral testing. rAAV8-LSP-hIDSco administration in NHPs resulted in sustained hepatic hI2S production and therapeutic hI2S levels in cross-corrected somatic tissues but no hI2S exposure in the central nervous system, perhaps owing to lower levels of liver transduction in NHPs than in mice. Overall, we demonstrate the ability of rAAV8-LSP-hIDSco to cross-correct I2S deficiency in mouse somatic tissues and highlight the importance of showing translatability of gene therapy data from rodents to NHPs, which is critical for supporting translation to clinical development.

TOPICAL DORZOLAMIDE-TIMOLOL WITH INTRAVITREOUS ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR FOR RETINAL VEIN OCCLUSION: A PILOT STUDY.

PURPOSE: To evaluate topical dorzolamide hydrochloride-timolol maleate as an adjunct therapy to intravitreous anti-vascular endothelial growth factor injections in eyes with retinal vein occlusion resistant to treatment. METHODS: Retinal vein occlusion patients with a history of persistent macular edema, despite fixed-interval intravitreous anti-vascular endothelial growth factor injections, were enrolled between April 4, 2016, and June 4, 2017. On enrollment, patients were instructed to administer one drop of topical dorzolamide-timolol twice daily for the duration of the study. They were maintained on the same anti-vascular endothelial growth factor drug and same interval between injections as preenrollment for the subsequent two visits. Primary outcome measures were change in central foveal thickness, central subfield thickness, and thickest macular cut at the final study visit. RESULTS: Eight patients (8 eyes) were eligible for enrollment and completed the study. There was a significant decrease in central foveal thickness (P = 0.02), central subfield thickness (P = 0.03), and thickest macular cut (P = 0.01) between the enrollment visit and the final visit. There was a decrease in mean (±SD) logarithm of the minimal angle of resolution from 0.52 (±0.35) (20/66, Snellen equivalent) at the enrollment visit to 0.41 (±0.35) (20/51, Snellen equivalent) at the final visit (P = 0.08). CONCLUSION: Topical dorzolamide-timolol may have a beneficial anatomical and functional effect in eyes with macular edema secondary to retinal vein occlusion resistant to treatment.