Theoretical and Experimental Investigation of Autoxidation Propensity of Selected Drugs in Solution State.

The C-H bond dissociation energy (BDE) of drug molecules is often used to estimate their relative propensities to undergo autoxidation. BDE calculations based on electronic structures provide a convenient means to estimate the risk for a given compound to degrade via autoxidation. This study aimed to verify the utility of calculated C-H BDEs of a range of drug molecules in predicting their autoxidation propensities, in the solution state. For the autoxidation study, 2,2'-azobis (2-methylpropionitrile) was employed as the solution state stressor, and the experimental reaction rate constants were determined employing ultraperformance liquid chromatographic (UPLC) methods. Reaction rates in the solution state were compared to the calculated C-H BDE values of the respective compounds. The results indicated a poor correlation for compounds in the solution state, and their relative stabilities could not be explained with C-H BDE. On the other hand, a favorable relationship was observed between the relative extent of ionization and the autoxidation rates of the selected compounds. In the solution state, factors such as the type and extent of drug ionization, degree and type of solvation have been shown to contribute to differences in reactivity. By applying the computational method involving the effect of H-atom abstraction and potential ionization sites in the molecule, the calculated C-H BDE should relate better to the experimental autoxidation rates.

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs.

Mechanoactivation has attracted considerable attention in the pharmaceutical sciences due to its ability to generate amorphous materials and solid-state synthetic products without the use of solvent. Although some studies have reported drug degradation during milling, no studies have systematically investigated the use of mechanoactivation in predicting drug degradation in the solid state. Thus, this work explores the autoxidation of drugs in the solid state by comilling amorphous mifepristone (MFP):polyvinylpyrrolidone vinyl acetate (PVPVA) and amorphous olanzapine (OLA):PVPVA. MFP was amorphized by ball milling and OLA by quench cooling techniques. Subsequently, comilling the amorphous drugs in the presence of a 10-fold weight ratio of PVPVA (the excipient containing reactive free radicals) was performed at several milling frequencies to identify the kinetics of mechano-autoxidation over milling durations. Overall, milling led to the degradation of up to 5% drug in the solid state. The autoxidation mechanism was confirmed by performing a stress study in the solution at 50 °C for 5 h, by using a 10 mM azo-bis(isobutyronitrile) (AIBN) as a stressing agent. By deconvoluting the effect of milling frequency and the energy on the extent and kinetics of milling-induced autoxidation of amorphous drugs, it was possible to fit an extended Arrhenius model that allowed extrapolation of mechanoactivated degradation rates (Km) to zero milling frequencies. Further, the autoxidation rates of drugs stored at high temperatures were observed to follow an Arrhenius behavior. A good degree of agreement was observed between the model predictions obtained by mechanoactivation (Km) to the reaction rates observed under accelerated temperatures. Additionally, the impact of adding an antioxidant (e.g., butylated hydroxytoluene) to the mixture during comilling was also examined. This study can be helpful in evaluating the stability of amorphous solids stored in accelerated (non-hermetic) conditions, in screening solid-state autoxidation propensity of drugs, and for the rational selection of antioxidants.

Measuring glaucoma quality of life in an Asian population using item banking: psychometric evaluation and computerized adaptive testing simulations.

PURPOSE: To assess the psychometric properties of glaucoma-specific health-related quality of life (HRQoL) item banks (IBs), and explore their efficiency using computerized adaptive testing (CAT) simulations. METHODS: In this cross-sectional, clinical study, 300 Asian glaucoma patients answered 221 items within seven IBs: Ocular Comfort Symptoms (OS); Activity Limitation (AL); Lighting (LT); Mobility (MB); Glaucoma Management (GM); Psychosocial (PSY); and Work (WK). Rasch analysis was conducted to assess each IB's psychometric properties (e.g., item "fit" to the construct; unidimensionality) and a set of analytic performance criteria guiding decision making relating to retaining or dropping domains and items was employed. CAT simulations determined the mean number of items for 'high' and 'moderate' measurement precision (stopping rule: SEM 0.3 and 0.387, respectively). RESULTS: Participants' mean age was 67.2 ± 9.2 years (62% male; 87% Chinese). LT, MB, and GM displayed good psychometric properties overall. To optimize AL's psychometric properties, 16 items were deleted due to poor "fit", high missing data, item bias, low discrimination and/or a low clinical/patient importance rating. To resolve multidimensionality in PSY, we rehomed 16 items into a "Concern (CN)" domain. PSY and CN required further amendment, including collapsing of response categories, and removal of poorly functioning items (N = 7). Due to poor measurement precision, low applicability and high ceiling effect, low test information indices, and low item separation index the WK IB was not considered further. In CAT simulations on the final seven IBs (n = 182 items total), an average of 12.1 and 15.7 items per IB were required for moderate and high precision measurement, respectively. CONCLUSIONS: After reengineering our seven IBs, they displayed robust psychometric properties and good efficiency in CAT simulations. Once finalized, GlauCAT™-Asian may enable comprehensive assessment of the HRQoL impact of glaucoma and associated treatments.

Influence of Crystal Disorder on the Forced Oxidative Degradation of Vortioxetine HBr.

The present study investigates the impact of the solid-state disorder of vortioxetine hydrobromide (HBr) on oxidative degradation under accelerated conditions. A range of solid-state disorders was generated via cryogenic ball milling. The solid-state properties were evaluated by calorimetry, infrared-, and Raman spectroscopies. While salt disproportionation occurred upon milling, no chemical degradation occurred by milling. The amorphous fraction remained physically intact under ambient storage conditions. Subsequently, samples with representative disordered fractions were mixed with a solid oxidative stressor (PVP-H2O2 complex) and were compressed to compacts. The compacts were exposed to 40°C/75% RH for up to 6 h. The sample was periodically withdrawn and analyzed for the physical transformations and degradation. Two oxidative degradation products (DPs) were found to be formed, for which dissimilar relations to the degree of disorder and kinetics of formation were observed. The degradation rate of the major DP formation obtained by fitting the exponential model to the experimental data was found to increase up to a certain degree of disorder and decrease with a further increase in the disordered fraction. In contrast, the minor DP formation kinetics was found to increase monotonically with the increase in the disorder content. For the similar crystallinity level, the degradation trend (rate and extent) differed between the single-phase disorder generated by milling and physically mixed two-phase systems. Overall, the study demonstrates the importance of evaluating the physical and chemical (in)stabilities of the disordered solid state of a salt form of a drug substance, generated through mechano-activation.

Toward a new definition of glaucomatous optic neuropathy for clinical research.

PURPOSE OF REVIEW: A process is ongoing to produce a definition of glaucomatous optic neuropathy (GON) using quantitative, objective data from structural and functional tests. At present, a common practice is to define GON by subjective features said to be 'characteristic' as judged by those experienced in glaucoma care. RECENT FINDINGS: An objective definition would standardize the comparison of clinical research results across studies, without precluding simultaneous use of idiosyncratic definitions in the same reports. To achieve this goal, expert opinion was solicited to reach optimal agreement on one or more consensus, GON definitions. An interactive period of online discussion by 176 international experts led to 110 responses in an online survey that narrowed possible definitional structures into testable criteria. SUMMARY: Two approaches to validation of one or more sets of criteria for definite and possible GON are ongoing. The general principles include definition for each eye individually, inclusion of a borderline category, no intraocular pressure criterion, and both structural and functional defects in appropriate physical locations. Each validation approach uses clinician diagnosis as a standard against which objective criteria are compared, with the initial approach using a three-level categorical scale, and the second approach using 0--100 scaling.

Aqueous humor immune factors and cytomegalovirus (CMV) levels in CMV retinitis through treatment - The CRIGSS study.

PURPOSE: This study aims to perform comprehensive longitudinal immune factor analysis of aqueous humor in relation to the aqueous CMV viral load and systemic CD4 counts during treatment of patients with co-infection of HIV and CMVR. METHODS: Aqueous humor samples were collected from 17 HIV-positive patients with CMVR scheduled to undergo weekly intravitreal ganciclovir therapy as part of the prospective CMV Retinitis Intravitreal Ganciclovir Singapore Study (CRIGSS) over the course of 1year. Full data across all the 4 time points was obtained and analyzed for CMV DNA viral load, 41 cytokine and chemokine factors using real-time PCR with the FlexMAP 3D (Luminex®) platform and assessed using the Milliplex Human Cytokine® kit. RESULTS: The following immune factors (Spearman correlation coefficient r value in parenthesis, p<0.05) showed strong correlation with CMV DNA load in the aqueous - MCP-1 (0.80, IFN-g (0.83), IP-10 (0.82), IL-8 (0.81), fractalkine (0.73), RANTES (0.68) - while the following showed moderate correlation - PDGF-AA (0.58), Flt-3L (0.59) and G-CSF (0.53). Only PDGF-AA revealed a statistically significant negative correlation with serum CD4 levels (r=-0.74). CONCLUSION: Immune factors that correlate with intraocular CMV DNA load are identified. They are indicative of a Th1 and monocyte-macrophage mediated response, and exhibit a decreasing trend longitudinally through the course of treatment. These factors may be an important new consideration in individualizing the treatment of patients with CMVR.

Anterior Segment Imaging Predicts Incident Gonioscopic Angle Closure.

PURPOSE: To investigate the incidence of gonioscopic angle closure after 4 years in subjects with gonioscopically open angles but varying degrees of angle closure detected on anterior segment optical coherence tomography (AS OCT; Visante; Carl Zeiss Meditec, Dublin, CA) at baseline. DESIGN: Prospective, observational study. PARTICIPANTS: Three hundred forty-two subjects, mostly Chinese, 50 years of age or older, were recruited, of whom 65 were controls with open angles on gonioscopy and AS OCT at baseline, and 277 were cases with baseline open angles on gonioscopy but closed angles (1-4 quadrants) on AS OCT scans. METHODS: All subjects underwent gonioscopy and AS OCT at baseline (horizontal and vertical single scans) and after 4 years. The examiner performing gonioscopy was masked to the baseline and AS OCT data. Angle closure in a quadrant was defined as nonvisibility of the posterior trabecular meshwork by gonioscopy and visible iridotrabecular contact beyond the scleral spur in AS OCT scans. MAIN OUTCOME MEASURES: Gonioscopic angle closure in 2 or 3 quadrants after 4 years. RESULTS: There were no statistically significant differences in age, ethnicity, or gender between cases and controls. None of the control subjects demonstrated gonioscopic angle closure after 4 years. Forty-eight of the 277 subjects (17.3%; 95% confidence interval [CI], 12.8-23; P < 0.0001) with at least 1 quadrant of angle closure on AS OCT at baseline demonstrated gonioscopic angle closure in 2 or more quadrants, whereas 28 subjects (10.1%; 95% CI, 6.7-14.6; P < 0.004) demonstrated gonioscopic angle closure in 3 or more quadrants after 4 years. Individuals with more quadrants of angle closure on baseline AS OCT scans had a greater likelihood of gonioscopic angle closure developing after 4 years (P < 0.0001, chi-square test for trend for both definitions of angle closure). CONCLUSIONS: Anterior segment OCT imaging at baseline predicts incident gonioscopic angle closure after 4 years among subjects who have gonioscopically open angles and iridotrabecular contact on AS OCT at baseline.

Efficiency, Precision, Validity, and Reliability of GlauCAT-Asian Computerized Adaptive Tests in Measuring Glaucoma-Related Quality of Life.

Purpose: To determine the efficiency, precision, and agreement of GlauCAT-Asian and its corresponding validity and reliability. Methods: In this cross-sectional study, 219 participants (mean ± standard deviation age, 66.59 ± 8.61 years; 34% female) across the spectrum of glaucoma severity and 50 glaucoma suspects were recruited from glaucoma clinics in Singapore. Participants answered seven computerized adaptive testing (CAT) evaluations (Ocular Comfort, Activity Limitation, Lighting, Mobility, Concerns, Psychosocial, Glaucoma Management) and underwent eye examinations. Efficiency (mean number of items required for each CAT and time taken for CAT versus full item banks [IBs]), agreement (concordance between CATs and full IB person measures, henceforth referred to as scores), and precision (standard error of measurement [SE]) were evaluated. Other validity and reliability metrics were also assessed. Results: The mean number of items administered ranged from 9 (Mobility/Glaucoma Management) to 12 (Ocular Comfort). Compared to answering the full IBs, CATs provided an average time saving of 38.3% (range, 10% to 70.6% for Lighting and Activity Limitation, respectively). Agreement between scores obtained by CAT versus full IB was high (intracorrelation coefficient ≥0.75), as was precision of score estimates (mean SE range: 0.35 for Psychosocial to 0.29 for Mobility). Scores from Activity Limitation, Mobility, Lighting, and Concerns decreased significantly as glaucoma severity increased (criterion validity; P-trend <0.05). All tests displayed good convergent/divergent validity and test-retest reliability. Conclusions: GlauCAT-Asian provides efficient, precise, accurate, valid, and reliable measurement of the patient-centered impact of glaucoma. Translational Relevance: GlauCAT-Asian may provide a valuable clinical tool for ophthalmologists to monitor impact of disease progression and the effectiveness of therapies.

Cytokine analysis of aqueous humor in HIV patients with cytomegalovirus retinitis.

PURPOSE: Cytomegalovirus retinitis (CMVR) is the most common opportunistic ocular infection in patients with AIDS. Comprehensive analysis of aqueous humor for immunologic factors has yet to be performed in patients with CMVR. This study aims to perform comprehensive immune factor analysis of aqueous humor in CMVR patients to determine the presence of any characteristic immunological profile in the aqueous humor. METHODS: Comparative prospective analysis of aqueous humor was performed across three groups: (1) AIDS patients with CMVR (CMVR group) (n=20), (2) HIV-positive patients without CMVR (HIV group) (n=6) and (3) patients undergoing cataract surgery with no underlying ocular infection or inflammation (control group) (n=11). At least 100µl of aqueous humor was drawn from all subjects and fractionated prior to analysis for 41 cytokines, chemokines and growth factors with the FlexMAP 3D (Luminex®) platform using the Milliplex Human Cytokine® kit. RESULTS: Three distinct immunologic signatures were observed in the aqueous humor of the three groups. Statistically significant differences (p<0.05) were observed across the three groups with the HIV group having lower levels and CMVR group having raised levels for the following factors: IP-10, fractalkine, PDGF-AA, G-CSF, Flt-3L and MCP-1. CONCLUSION: Aqueous humor though clinically quiescent in CMVR revealed a unique immunologic signature consistent with a combined Th-1 and monocyte-macrophage mediated response. Subsequent longitudinal analysis of aqueous cytokine levels of CMVR through the course of treatment would allow better understanding of the immunopathogenetic mechanisms of CMVR. This may also be used to better prognosticate the disease, predict complications and allow better assessment of treatment response and individualization of treatment in the future.

Role of Crystal Disorder and Mechanoactivation in Solid-State Stability of Pharmaceuticals.

Common energy-intensive processes applied in oral solid dosage development, such as milling, sieving, blending, compaction, etc. generate particles with surface and bulk crystal disorder. An intriguing aspect of the generated crystal disorder is its evolution and repercussion on the physical- and chemical stabilities of drugs. In this review, we firstly examine the existing literature on crystal disorder and its implications on solid-state stability of pharmaceuticals. Secondly, we discuss the key aspects related to the generation and evolution of crystal disorder, dynamics of the disordered/amorphous phase, analytical techniques to measure/quantify them, and approaches to model the disordering propensity from first principles. The main objective of this compilation is to provide special impetus to predict or model the chemical degradation(s) resulting from processing-induced manifestation in bulk solid manufacturing. Finally, a generic workflow is proposed that can be useful to investigate the relevance of crystal disorder on the degradation of pharmaceuticals during stability studies. The present review will cater to the requirements for developing physically- and chemically stable drugs, thereby enabling early and rational decision-making during candidate screening and in assessing degradation risks associated with formulations and processing.

Screening Autoxidation Propensities of Drugs in the Solid-State Using PVP and in the Solution State Using N-Methyl Pyrrolidone.

Oxidative degradation of drugs is one of the major routes of drug substance and drug product instability. Among the diverse routes of oxidation, autoxidation is considered to be challenging to predict and control, potentially due to the multi-step mechanism involving free radicals. C-H bond dissociation energy (C-H BDE) is evidenced to be a calculated descriptor shown to predict drug autoxidation. While computational predictions for the autoxidation propensity of drugs are both swift and possible, no literature to date has highlighted the relationship between the computed C-H BDE and the experimentally-derived autoxidation propensities of solid drugs. The objective of this study is to investigate this missing relationship. The present work is an extension to the previously reported novel autoxidation approach that involves subjecting a physical mixture of pre-milled polyvinyl pyrrolidone (PVP) K-60 and a crystalline drug under high temperature and pressurized oxygen setup. The drug degradation was measured using chromatographic methods. An improved trend between the extent of solid autoxidation and C-H BDE could be observed after normalizing the effective surface area of drugs in the crystalline state, pointing to a positive relationship. Additional studies were conducted by dissolving the drug in N-methyl pyrrolidone (NMP) and exposing the solution under a pressurized oxygen setup at diverse elevated temperatures. Chromatographic results of these samples indicated a similarity in the formed degradation products to the solid-state experiments pointing to the utility of NMP, a PVP monomer surrogate, as a stressing agent for faster and relevant autoxidation screening of drugs in formulations.

Applying Material Science Principles to Chemical Stability: Modelling Solid State Autoxidation in Mifepristone Containing Different Degrees of Crystal Disorder.

Ball-milling and harsh manufacturing processes often generate crystal disorder which have practical implications on the physical and chemical stabilities of solid drugs during subsequent storage, transport, and handling. The impact of the physical state of solid drugs, containing different degrees/levels of crystal disorder, on their autoxidative stability under storage has not been widely investigated. This study investigates the impact of differing degrees of crystal disorder on the autoxidation of Mifepristone (MFP) to develop a predictive (semi-empirical) stability model. Crystalline MFP was subjected to different durations of ambient ball milling, and the resulting disorder/ amorphous content was quantified using a partial least square (PLS) regression model based on Raman spectroscopy data. Samples of MFP milled to generate varying levels of disorder were subjected to a range of (accelerated) stability conditions, and periodically sampled to examine their recrystallization and degradation extents. Crystallinity was monitored by Raman spectroscopy, and the degradation was evaluated by liquid chromatography. The analyses of milled samples demonstrated a competition between recrystallization and degradation via autoxidation of MFP, to different extents depending on stability conditions/exposure time. The degradation kinetics were analyzed by accounting for the preceding amorphous content, and fitted with a diffusion model. An extended Arrhenius equation was used to predict the degradation of stored samples under long-term (25°C/60% RH) and accelerated (40°C/75% RH, 50°C/75% RH) stability conditions. This study highlights the utility of such a predictive stability model for identifying the autoxidative instability in non-crystalline/partially crystalline MFP, owing to the degradation of the amorphous phases. This study is particularly useful for identifying drug-product instability by leveraging the concept of material sciences.

The dry eye disease activity log study.

Prolonged visually stressful activities aggravate dry eye disease (DED). The duration spent on such activities and their relationship with DED clinical features were investigated. Patients completed an activity log as they performed their usual activities over 1 typical rest day and 1 typical work day. The log included time spent in an air-conditioned environment, windy environment, driving, watching television, computer use, reading, watching a movie in the theatre, and wearing contact lens. Average daily activity hours were calculated and correlated with clinical features of DED. Thirty-five logs were returned. Positive correlation was found between watching television and episodic blurred vision (P < 0.01). Computer use was negatively correlated with episodic blur vision, burning sensation, and gritty sensation (P < 0.05). Negative correlation was found between time spent in windy environments, driving, reading, and certain DED symptoms (P < 0.05). Reading correlated positively with severity of corneal fluorescein staining and reduced Schirmer's values (P < 0.03). The use of air conditioning correlated negatively with episodic blur vision but positively with visual blurring that improves with lubricants (P = 0.02). This study is the first to evaluate the relationship between time spent on DED-aggravating activities and DED clinical features. Negative correlations between certain activities and DED symptoms suggest an unconscious modification of lifestyle to alleviate symptoms.

Assessment of Diverse Solid-State Accelerated Autoxidation Methods for Droperidol.

The present study aimed to investigate methods for accelerating autoxidation of crystalline drugs in the solid-state that can potentially predict real-time stability. Solid droperidol (DPD) was selected as the model drug. A common free-radical initiator, 2,2'-azobisisobutyronitrile (AIBN), was used to induce autoxidation in solutions. AIBN decomposes at elevated temperatures to yield carbon-centred cyano-isopropyl free radicals that can auto-oxidize neighboring drug molecules. Although the reaction of AIBN is relatively straightforward in solution, it is less so in solids. In this study, we used solid AIBN mixed with DPD powder in the presence and absence of pressurized oxygen headspace. Samples were prepared directly in the form of binary mixtures with DPD and additionally in the form of powder compact/pellet with DPD. The main challenge in carrying out the reaction was related to the preservation of AIBN at elevated temperatures due to the disintegration of the pellet containing the latter. A commercially available free-radical coated silica particle (i.e., 2,2,6,6-tetramethyl-1-piperinyloxy (TEMPO) or (SiliaCATTM TEMPO)) was tested as a potential stressor, but with limited success to induce autoxidation. The most valuable results were obtained when a physical mixture of pre-milled PVP K-60 containing free radicals and DPD was exposed to elevated oxygen-temperature conditions, which yielded significant degradation of DPD. The study highlights the practical challenges for conducting accelerated solid-state stress studies to assess the autoxidation susceptibility of drugs using traditional free-radical initiators and presents a proof of application of milled PVP with free-radical as a potential alternative.

The development of a glaucoma-specific health-related quality of life item bank supporting a novel computerized adaptive testing system in Asia.

BACKGROUND: A glaucoma-specific health-related quality of life (HRQoL) item bank (IB) and computerized adaptive testing (CAT) system relevant to Asian populations is not currently available. We aimed to develop content for an IB focusing on HRQoL domains important to Asian people with glaucoma; and to compare the content coverage of our new instrument with established glaucoma-specific instruments. METHODS: In this qualitative study of glaucoma patients recruited from the Singapore National Eye Centre (November 2018-November 2019), items/domains were generated from: (1) glaucoma-specific questionnaires; (2) published articles; (3) focus groups/semi-structured interviews with glaucoma patients (n = 27); and (4) feedback from glaucoma experts. Data were analyzed using the constant comparative method. Items were systematically refined to a concise set, and pre-tested using cognitive interviews with 27 additional glaucoma patients. RESULTS: Of the 54 patients (mean ± standard deviation [SD] age 66.9 ± 9.8; 53.7% male), 67 (62.0%), 30 (27.8%), and 11 (10.2%) eyes had primary open angle glaucoma, angle closure glaucoma, and no glaucoma respectively. Eighteen (33.3%), 11 (20.4%), 8 (14.8%), 12 (22.2%), and 5 (9.3%) patients had no, mild, moderate, severe, or advanced/end-stage glaucoma (better eye), respectively. Initially, 311 items within nine HRQoL domains were identified: Visual Symptoms, Ocular Comfort Symptoms, Activity Limitation, Driving, Lighting, Mobility, Psychosocial, Glaucoma management, and Work; however, Driving and Visual Symptoms were subsequently removed during the refinement process. During cognitive interviews, 12, 23 and 10 items were added, dropped and modified, respectively. CONCLUSION: Following a rigorous process, we developed a 221-item, 7-domain Asian glaucoma-specific IB. Once operationalised using CAT, this new instrument will enable precise, rapid, and comprehensive assessment of the HRQoL impact of glaucoma and associated treatment efficacy.

Defining glaucomatous optic neuropathy using objective criteria from structural and functional testing.

BACKGROUND/AIMS: To identify objective criteria from optical coherence tomography (OCT) and perimetry that denote a useful, specific definition of glaucomatous optic neuropathy (GON) in eyes with open-angle glaucoma for comparisons among glaucoma research studies. METHODS: A cross-sectional study of adult patients with glaucoma from nine centres on five continents evaluated de-identified physician diagnosis, OCT and perimetry results for 2580 eyes (1531 patients) in an online database. Each eye was graded by their glaucoma specialist as either definite, probable or not GON. Objective measures from OCT and perimetry, derived from an online consensus panel comprising 176 glaucoma specialists globally, were compared against the three diagnostic levels. RESULTS: Diagnoses were 54% 'definite', 22% 'probable' and 24% 'not GON'. Using only OCT data or only field data had inadequate specificity (<90%). The best definitional choice for data from either the most recent or the preceding OCT/field pair had 77% sensitivity at 98% specificity and consisted of abnormal OCT superior or inferior nerve fibre layer quadrant with matching, opposite, abnormal Glaucoma Hemifield Test. CONCLUSIONS: Objective criteria to define GON are practical and may be useful for comparisons among clinical studies to supplement subjective clinical assessment.

Long-Term Outcomes from an Intraoperative Bleb Needling Procedure Augmented with Continuous Infusion.

PURPOSE: To investigate long-term outcomes of a modified bleb needling technique performed in the operating room in controlling intraocular pressure (IOP) and to report risk factors for procedure failure. DESIGN: Retrospective, observational cohort study. PARTICIPANTS: One hundred six eyes of 98 consecutive patients undergoing intraoperative bleb needling with a continuous infusion of balanced salt solution at the Wilmer Eye Institute, Johns Hopkins Hospital, in the setting of a failed trabeculectomy or express shunt, between May 2011 and December 2015. METHODS: Postoperative data were collected between May 2011 and August 2019. Success was defined as achieving a previously determined target IOP regardless of (qualified success) or without (complete success) glaucoma medications. Patients who underwent additional glaucoma surgery were censored in the survival analysis. MAIN OUTCOME MEASURES: Primary outcome measures included IOP, attainment of target IOP, and number of glaucoma medications used at different time points pre- and post-operatively. RESULTS: Needling was performed in 106 eyes at an average of 4.3 years from the time of trabeculectomy (standard deviation [SD], 6.5 years) and an average baseline IOP of 20.7 mmHg (SD, 7.2 mmHg). Further glaucoma surgery was required for 33 eyes. We observed a 70% qualified success rate with a mean IOP lowering of 25% (95% confidence interval [CI], 13.8%-36.4%) at 1 year after surgery and a 52% qualified success rate and 44.3% reduction in IOP (95% CI, 34.9%-53.6%) at 5 years after surgery. Nearly half and a third of the eyes did not require medications after 1 and 5 years, respectively. The average medication reduction was 0.8 at year 1 (95% CI, 0.5-1.1) and 0.4 at year 5 (95% CI, -0.2 to 1.0). Postoperative complications were uncommon. Poorer outcomes were not associated with the age of the bleb but were more likely in Black patients. CONCLUSIONS: Reductions in IOP were maintained in most patients over the long term using a modified bleb needling technique, despite an average time from trabeculectomy of over 4 years. No significant adverse events were observed. Bleb needling may defer or avoid more invasive procedures such as tube-shunts or repeat trabeculectomy.

Outcomes of a Modified Trabeculectomy Closure Technique.

PRECIS: A modified closure for trabeculectomy in which the conjunctiva is incised posterior to the limbus and reapproximated using 2 nylon sutures, provided similar surgical outcomes to the standard trabeculectomy closure technique. PURPOSE: To examine the surgical outcomes of a modified trabeculectomy closure technique in which the conjunctiva is incised posterior to the limbus and reapproximated using 2 sutures, burying the posterior conjunctiva under an anterior lip of conjunctiva. MATERIALS AND METHODS: This retrospective review included 73 eyes that underwent trabeculectomies between 2015 and 2017 at Johns Hopkins Hospital by a single surgeon. We analyzed traditional closures used from January 2015 to May 2016, and modified closures used from July 2016 to March 2017. The main outcome measures were a reduction in intraocular pressure at 3, 6, and 12 months, reduction in the number of medications at 12 months, and total number of postoperative complications. RESULTS: There was no difference in reduction of intraocular pressure at 3 months (9.9±8.2 vs. 10.5±8.7 mm Hg), 6 months (10.8±9.6 vs. 10.6±8.3 mm Hg), or 12 months (12.2±8.9 vs. 10.0±9.3 mm Hg) in the standard (n=44) and modified groups (n=29), respectively. There was a similar reduction in the use of glaucoma medications in the standard group (1.2±1.5 vs. 1.0±1.1) compared with the modified group and no difference in the number of postoperative complications (25.0% vs. 17.2%, respectively) (P>0.05 for all). CONCLUSIONS: The modified closure provided similar results to the standard closure for trabeculectomy. Further studies are needed to determine whether the 2 techniques differ in surgical outcomes over a longer follow-up or other surgical parameters (eg, ease, surgical time, learning curve).

Ocular lubricant use in medically and surgically treated glaucoma: a retrospective longitudinal analysis.

BACKGROUND: Chronic use of intraocular pressure-lowering medications is associated with ocular surface disease (OSD). In this study, we assess the incidence of topical lubricant use as a surrogate marker for underlying OSD, in medically and surgically treated glaucoma patients. METHODS: Retrospective chart review was performed for newly diagnosed glaucoma patients who were started on topical medications in 2007 and followed up over a 5-year period. Primary outcome measure was the incidence of topical lubricant use in these patients and a subset of these patients who required glaucoma or cataract surgery during follow-up. RESULTS: Charts of 505 newly diagnosed glaucoma patients with no prior history of ocular lubricant use were analyzed. Mean age was 63.9 years (SD 11.1), 42.8% were women. One hundred one (20.0%) patients underwent phacoemulsification surgery, 80 underwent mitomycin C (MMC) augmented phacotrabeculectomy, 16 underwent MMC-augmented trabeculectomy and 3 underwent tube surgery during the course of follow-up as their only type of surgery. Five-year incidence of lubricant use was 59% in all glaucoma subjects; 54.1% of patients were on medical treatment and 74.0% of patients who underwent phacotrabeculectomy or trabeculectomy were started on lubricants, respectively (P=0.0011); 60.4% of glaucoma subjects who underwent phacoemulsification surgery were started on lubricants. Incidence of lubricant use increased from 17.7% preoperatively to 74.0% postoperatively in subjects who required trabeculectomy or phacotrabeculectomy. Incidence of lubricant use was similar in patients on one or multiple glaucoma medications, with the mean onset of lubricant use being 10 months after starting glaucoma medication in both groups. Females were more likely to use artificial tears compared with males (P=0.002). CONCLUSION: Both medical and surgical management of glaucoma have an adverse effect on the ocular surface. Chronic use of glaucoma medications was associated with a high incidence of ocular lubricant use. MMC-augmented trabeculectomy was associated with an even higher incidence of ocular lubricant use.

Conventional Versus Accelerated Collagen Cross-Linking for Keratoconus: A Comparison of Visual, Refractive, Topographic and Biomechanical Outcomes.

OBJECTIVE: The aim was to compare the visual, refractive, topographic and biomechanical outcomes in patients with progressive keratoconus treated with either conventional or accelerated crosslinking at one year follow up. METHODS: It is a prospective, non-randomised interventional study of 76 patients who underwent conventional (CXL; 3mW/cm2 for 30 minutes) or accelerated cross linking (KXL; 30mW/cm2 for 4 minutes) for progressive keratoconus. Baseline and postoperative visual acuity, manifest refraction, corneal topography, pachymetry, endothelial cell density and biomechanical parameters of corneal hysteresis and corneal resistance factor were evaluated and compared. RESULTS: The 2 groups were comparable in terms of uncorrected and best corrected visual acuity and spherical equivalent. Both groups showed no significant increase in K1, K2 and Kmean from baseline at 12 months. There was also no difference between the CXL and KXL group for postoperative corneal topography as well as central and minimal pachymetry up to 12 months. There was a significant increase in both corneal hysteresis (0.62mm Hg, P=0.04) and corneal resistance factor (0.91mm Hg, P=0.003) in the KXL group at 12 months but not in the CXL group. There was no significant endothelial cell loss throughout follow up in both the groups. CONCLUSION: We have established comparability of the 2 protocols in stabilizing the progression of keratoconus. Our findings also suggested an added biomechanical advantage of accelerated crosslinking at 1 year follow up.