Intravitreal Drug Research Articles

Association between Industry Payments and Anti-vascular Endothelial Growth Factor Use in Medicare Beneficiaries

To test for associations between anti-vascular endothelial growth factor (VEGF) industry payments to ophthalmologists who provide intravitreal injections and specific anti-VEGF agent use. Cross-sectional Medicare database study. US fee-for-service Medicare beneficiaries and all ophthalmologists who submitted intravitreal injection claims for >10 Medicare beneficiaries between August 1, 2013, and December 31,2013. The Sunshine Act Open Payments database was searched for all industry financial relationships in ophthalmology. The Medicare Provider Utilization and Payment Database was searched for all intravitreal injection claims and anti-VEGF drug claims among fee-for-service Medicare beneficiaries. A novel algorithm was used to merge the 2 datasets to identify physician-specific associations between industry payments and specific anti-VEGF agent use. Odds ratios (ORs) and corresponding confidence intervals (CIs) were estimated by using logistic regression models. Ophthalmologists providing intravitreal injections (Current Procedural Terminology 67028); ophthalmologists with reported nonresearch payment from anti-VEGF industry; physician-specific anti-VEGF agent use (treatment specific J-codes J0178 and J2778). Of 3391 ophthalmologists who performed intravitreal injections, 1187 (35%) received nonresearch payments from anti-VEGF industry. Of these 1187 ophthalmologists, 422 (35%) received payments from Regeneron Pharmaceuticals, 363 (31%) received payments from Genentech, and 402 (34%) received payments from both industries. When compared with ophthalmologists who perform intravitreal injections and who do not receive anti-VEGF industry payments, ophthalmologists receiving Genentech payments (median, $90; interquartile range, $22-$149) were more likely to use ranibizumab (OR, 2.14; 95% CI, 2.12-2.16), those receiving Regeneron payments (median, $55; interquartile range, $22-$131) were more likely to use ranibizumab (OR, 1.55; 95% CI, 1.54-1.56) and aflibercept (OR, 1.23; 95% CI, 1.22-1.24), those with payments from both manufacturers were more likely to use ranibizumab (OR, 2.69; 95% CI, 2.67-2.71) and aflibercept (OR, 1.53; 95% CI, 1.52-1.54), and all were less likely to use bevacizumab (OR, 0.33-0.64; P < 0.001 for all comparisons). Industry payments to ophthalmologists who perform intravitreal injections were associated with higher odds of ranibizumab and aflibercept use, and lower odds of bevacizumab use. These findings reflect an association, not a cause-and-effect relationship.

Ocular drug delivery and pharmacokinetics: influence of drug properties and delivery systems

SummaryAlthough the eye is readily accessible for drug dosing, drug delivery to the eye remains a major challenge due to multiple static and dynamic barriers. After topical administration, much &lt;10% of the drug in the dosage form reaches intraocular tissues, primarily those in the anterior segment. No topical dosage form is currently approved for back of the eye drug therapy due to inadequate drug delivery. Topical dosing is currently viable only for small molecule drugs since macromolecules are not delivered adequately by this route of administration to be therapeutically effective. Intravitreal dosing through injections and surgical means, while allowing 100% dose delivery to the back of the eye, poses multiple challenges including rapid clearance of small molecules in solution, necessitating the use of slow release delivery systems. Macromolecules are cleared more slowly from the vitreous humor of the eye, allowing drug dosing once every month or two. Currently efforts are underway to reduce dosing frequencies for macromolecules as well. The purpose of this presentation is to describe mechanisms of topical and intravitreal drug delivery, with a key focus on drug and delivery system properties. Also, emerging routes of administration including suprachoroidal and transscleral routes will be discussed.

Estimation of Intra-vitreal Half-Lifes in the Rabbit Eye with Semi-mechanistic Equations.

To develop an alternative method for estimating vitreal half-lifes in the rabbit eye based on simple equations for the physical processes of dissipation and the physiochemical properties of therapeutic substances applied by intravitreal drug administration. Equations were derived to describe diffusion in the vitreous humorand permeation through the back-of-the-eye tissue, and the volume of distribution. The model was validated using reported half-life values from 83 compounds collected from literature. The rate limiting step for dissipation from the vitreous depends mainly on the molecular weight. Dissipation of very low molecular weight (MW) substances (<350Da) is limited by diffusional transport to the back of the eye, for substances with a MW >350Da uptake into the back of the eye tissue becomes limiting, and large molecules >500Da predominantly take an alternative path being cleared through the front of the eye for which diffusion towards the posterior chamber turns out to be limiting. Taking the three rate determining processes into account, the derived model can estimate dissipation rates and respectively vitreal half-life values of small compounds and macromolecules from their molecular weight with very few exceptions. The equations derived in this analysis provide a simple method to predict vitreal half-lifes for a diverse group of molecules and can be easily implemented in early drug development.

How does macular grid laser photocoagulation compare with intravitreal drugs for the treatment of branch retinal vein occlusion?

How does macular grid laser photocoagulation compare with intravitreal drugs for the treatment of branch retinal vein occlusion?

Preliminary study for non-invasive magnetic resonance imaging and spectroscopy of the eye: A novel technique for monitoring pharmacokinetics of ocular drug delivery

Introduction Conventional pharmacokinetic methods for studying ocular drug delivery are invasive and cannot be conveniently applied to humans. The development of non-invasive techniques in monitoring pharmacokinetics of ocular drug delivery is of vital importance. Purpose The aim of this study was to develop a novel clinical technique that permits monitoring of in vivo intravitreal drug pharmacokinetics based on both Hydrogen Magnetic Resonance Spectroscopy (H-MRS) and/or quantitative Magnetic Resonance Imaging (qMRI) methodologies. Materials and methods Advanced qMRI and H-MRS were performed using a high resolution clinical MRI eye protocol based on T1w and T2w 3D-sequences as well as a standard single voxel. H-MRS protocol utilizing a clinical 1.5T whole-body scanner enforced with a specially designed small coil apparatus for signal detection. H-MRS single voxel dimensions were (1.5 × 1.5 × 1.5 cm 3 ). In vitro and ex vivo experiments were performed using pig eyes as reference standards and Flurbiprofen (a non-steroidal anti-inflammatory ocular drug) in concentrations 0.04 M–2 mM. All measurements performed at a fixed temperature of 37 °C utilizing an in-house developed temperature monitor/controller device. Results High resolution qMRI images and MRS spectra of the vitreous with and without the presence of ocular drugs at different concentrations were obtained. Characteristic H-MRS peaks on 1.5 and 7 ppm were observed on both Flurbiprofen concentrations. Differences on the relative NMR signal measurements were obtained using various Flurbiprofen concentrations. Characteristic water H-MRS peak on 4.7 ppm was observed in vitreous samples proved a valuable means for the assessment of pharmacokinetics on ocular drug delivery. Conclusion A clinical protocol of H-MRS and/or qMRI will become feasible with the development of a rapid, inexpensive, and automated technique that could be easily integrated on any conventional clinical MRI examination.

From the analysis of pharmacologic vitreolysis to the comprehension of ocriplasmin safety

ABSTRACTIntroduction: Pharmacologic vitreolysis is a strategy used to treat anomalous posterior vitreous detachment, by weakening vitreoretinal adhesion with an intravitreal drug. Pharmacologic vitreolysis facilitates surgery, and abnormalities of the vitreoretinal interface including vitreomacular traction (VMT) and early stage macular hole (MH) could be resolved. Ocriplasmin is a recombinant protease, active against fibronectin and laminin, which are important components of the vitreoretinal interface. Ocriplasmin has been approved for symptomatic treatment of VMT and MH with visible traction, and it functions by dissolving the proteins that link the vitreous to the macula, thereby creating a complete posterior vitreous detachment (PVD).Areas covered: This paper reviews the current knowledge and status of investigations regarding the use of ocriplasmin for pharmacologic vitreolysis and its safety.Expert opinion: Ocriplasmin is a non-specific enzyme; therefore, it dissolves vitreal proteins as well as possibly proteins associated with visual function in the retina, choroid, and lens. Ocular adverse events (OAEs) of ocriplasmin include transient visual loss, intraocular inflammation, vitreous floaters, lens opacification, zonular instability of the lens, and intraocular hemorrhage. The prevalence of the OAEs is very low; however, on rare occasions, they can result in widespread retinal dysfunction. Research into the acute and long-term safety of ocriplasmin is required.

Ex vivo investigation of ocular tissue distribution following intravitreal administration of connexin43 mimetic peptide using the microdialysis technique and LC-MS/MS.

This study aimed to develop and evaluate an ex vivo eye model for intravitreal drug sampling and tissue distribution of connexin43 mimetic peptide (Cx43MP) following intravitreal injection using the microdialysis technique and LC-MS/MS. An LC-MS/MS method was developed, validated, and applied for quantification of Cx43MP in ocular tissues. Microdialysis probes were calibrated for in vitro recovery studies. Bovine eyes were fixed in a customized eye holder and after intravitreal injection of Cx43MP, microdialysis probes were implanted in the vitreous body. Vitreous samples were collected at particular time intervals over 24h. Moreover, 24 and 48h after intravitreal injection ocular tissues were collected, processed, and analyzed for Cx43MP concentrations using LC-MS/MS. The LC-MS/MS method showed good linearity (r 2=0.9991). The mean percent recovery for lower (LQC), medium (MQC), and higher quality control (HQC) (0.244, 3.906, and 125μg/mL) was found to be 83.83, 84.92, and 94.52, respectively, with accuracy ranges between 96 and 99% and limits of detection (LOD) and quantification (LOQ) of 0.122 and 0.412μg/mL. The in vitro recovery of the probes was found to be over 80%. As per microdialysis sample analysis, the Cx43MP concentration was found to increase slowly in the vitreous body up to 16h and thereafter declined. After 48h, the Cx43MP concentration was higher in vitreous, cornea, and retina compared to lens, iris, and aqueous humor. This ex vivo model may therefore be a useful tool to investigate intravitreal kinetics and ocular disposition of therapeutic molecules after intravitreal injection.

Differential Response to Anti-VEGF Regimens in Age-Related Macular Degeneration Patients with Early Persistent Retinal Fluid

To compare the effect of intravitreal aflibercept or ranibizumab drug type and frequency on visual acuity outcomes in eyes with neovascular age-related macular degeneration (NVAMD) and early persistent retinal fluid after 3 initial monthly injections. A post hoc analysis of eyes enrolled in VIEW 1 and VIEW 2, 2 similarly designed, randomized, phase 3 trials. A total of 1815 eyes with NVAMD from VIEW 1 and VIEW2. Analyses included patients with known fluid status at baseline and weeks 4, 8, and 12 in 3 treatment groups: ranibizumab 0.5 mg every 4 weeks (Rq4) (n= 595), intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4) (n= 613), and IAI 2 mg every 8 weeks (2q8) after 3 monthly injections (n= 607). Mean best-corrected visual acuity (BCVA) change from baseline over weeks 16 to 52 and the proportion of eyes that gained ≥15 letters or lost ≥5 letters were evaluated in eyes with and without persistent fluid (cystic intraretinal or subretinal fluid at all 4 initial visits). Visual outcomes also were assessed in eyes with persistent fluid by fluid type (intraretinal and subretinal fluid). The proportions of eyes with persistent fluid were 29.4%, 18.8%, and 20.3% in the Rq4, 2q4, and 2q8 groups, respectively. In these eyes, mean BCVA gain from baseline to week 52 was greater with 2q4 compared with Rq4 (P < 0.01) and 2q8 (P < 0.05), whereas it was similar with Rq4 and 2q8 (P= 0.294). At week 52, similar proportions of eyes gained ≥15 letters (31.5%-35.2%), whereas fewer eyes lost ≥5 letters with 2q4 compared with Rq4 and 2q8 (6.5% vs. 16.6% and 16.2%). The pattern of visual outcomes was similar regardless of fluid type. In eyes without persistent fluid, BCVA changes were similar across treatment groups. In patients with early persistent fluid, 2q4 may provide additional clinical benefit over 2q8 or Rq4.

Hydrodynamic Radii of Ranibizumab, Aflibercept and Bevacizumab Measured by Time-Resolved Phosphorescence Anisotropy.

PurposeTo measure the hydrodynamic radii of intravitreal anti-VEGF drugs ranibizumab, aflibercept and bevacizumab with μs time-resolved phosphorescence anisotropy.MethodsRuthenium-based dye Ru(bpy)2(mcbpy − O − Su − ester)(PF6)2, whose lifetime of several hundred nanoseconds is comparable to the rotational correlation time of these drugs in buffer, was used as a label. The hydrodynamic radii were calculated from the rotational correlation times of the Ru(bpy)2(mcbpy − O − Su − ester)(PF6)2-labelled drugs obtained with time-resolved phosphorescence anisotropy measurements in buffer/glycerol solutions of varying viscosity.ResultsThe measured radii of 2.76±0.04 nm for ranibizumab, 3.70±0.03 nm for aflibercept and 4.58±0.01 nm for bevacizumab agree with calculations based on molecular weight and other experimental measurements.ConclusionsTime-resolved phosphorescence anisotropy is a relatively simple and straightforward method that allows experimental measurement of the hydrodynamic radius of individual proteins, and is superior to theoretical calculations which cannot give the required accuracy for a particular protein.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-016-1940-2) contains supplementary material, which is available to authorized users.

Diabetic macular oedema: pathophysiology, management challenges and treatment resistance.

Diabetic macular oedema (DMO) is the leading cause of vision loss in patients living with diabetes. DMO results from hyperglycaemia-induced activation of pathways that lead to oxidative stress and release of cytokines, impairing the inner and outer blood-retinal barriers. Improved understanding of the pathophysiological mechanisms leading to DMO have led to the development of effective therapies, including vitreoretinal surgery, laser photocoagulation, intravitreal anti-vascular endothelial growth factor drugs and corticosteroids. Advances in imaging, including fluorescein angiography and optical coherence tomography, have also enhanced diagnosis and management of the condition. Despite these advances, there remain patients who do not respond completely to therapy, reflecting the complex pathophysiology of DMO. These patients may be considered treatment-resistant. In this review, we summarise the pathophysiology of DMO, as well as the available treatments and their mechanism of action. Additionally, we focus on treatment-resistant disease and review the literature on potential options for managing this complication of diabetes.

Episcleral drug film for better-targeted ocular drug delivery and controlled release using multilayered poly-ε-caprolactone (PCL)

Triamcinolone acetonide (TA) and poly-ε-caprolactone (PCL) were engineered into a micro drug film for episcleral application to better manage chronic vitreoretinal diseases such as proliferative vitreoretinopathy (PVR). Compared to an intravitreal drug injection, this drug film is much safer without breaking into ocular barriers. Compared to a traditional subtenon injection, this drug film demonstrated superior therapeutic duration, better drug bioavailability in the choroid and retina, and better-targeted drug delivery ability. The rabbit eye study demonstrated that using the PCL-TA film led to 5.6 and 3.4 times higher drug AUC in the choroid and the retina respectively than in eyes following a subtenon drug injection. The mean drug residence time in the rabbit choroid was also doubled by using the episcleral TA film (86days versus 43days). Remaining TA in the drug film was consistently higher than that in the subtenon space, indicating controlled release of TA by the PCL-TA film. The pharmacokinetics of triamcinolone in the choroid and retina were optimized from typical first-order kinetics to a more sustained release by use of this film. This episcleral film system worked better on rabbit eyes than on guinea pig eyes, indicating that scleral thickness and eye size may be crucial aspects to consider when choosing an animal model or when designing a transscleral delivery device for human use. This engineered drug film may be very useful in preventing and managing PVR associated with open globe trauma or surgical repair for retinal detachment. Statement of SignificanceThis study demonstrated a novel micro episcleral drug film that is made from the engineering of triamcinolone acetonide (TA) into poly-ε-caprolactone (PCL). The film can be conveniently placed at the injury or disease site during primary surgery and provide controlled release of TA for four months that covers the high-risk time window for developing proliferative vitreoretinopathy (PVR). This engineered drug film may be very useful in preventing and managing PVR associated with open globe trauma or intraocular surgery.

Management of Cytomegalovirus Retinitis in HIV and Non-HIV Patients.

As CMVR continues to affect HIV-positive and non-HIV immunosuppressed patients, ophthalmologists must continue to tailor diagnostics and therapeutics to individual cases. In HIV-related disease, ocular fluid sampling and intravitreal drug delivery are considerations, but systemic antiviral therapy is paramount in the initial management from both ophthalmic and systemic morbidity standpoints. Non-HIV-related disease should be approached with a multidisciplinary team, including an ophthalmologist/vitreoretinal/uveitis specialist for consideration of intravitreal antiviral therapy with qualitative and quantitative aqueous PCR monitoring, and consideration of PCR genome sequencing for CMV strains that may become resistant to antiviral therapies from long-term antiviral prophylactic exposure. Hematologists or oncologists may help with patients who remain bone marrow-suppressed following transplantation or systemic chemotherapy. Because of related toxicities of the anti-CMV medications and immunosuppressive medications (eg, bone marrow suppression and cytopenias), infectious disease consultation can help in the treatment and monitoring of side effects.

"Magic Bullet": Eccentric Macular Hole as a Complication from Dexamethasone Implant Insertion.

Introduction. Intravitreal drug injections and implants are generally safe but do carry some risk, from both the procedure itself and adverse effects of the medications. We report a case of an eccentric macular hole after dexamethasone implant (Ozurdex®) administration. Ex vitro force testing was performed to evaluate dexamethasone implant injection force. Methods. Five dexamethasone implant (Ozurdex) applicators were placed 16 mm from a force plate and the force of the injected dexamethasone pellet was recorded in Newtons. Four dexamethasone implant applicators were placed 16 mm from a force plate in a basic saline solution and the force of the pellet was recorded. Results. Average maximum force in air was 0.77 N and 0.024 N in a basic saline solution (BSS). Conclusion. We present a case report of an eccentric macular hole after dexamethasone implant administration. We hypothesize a mechanical injury to the retina during insertion caused the macular hole. Force testing done in air demonstrated sufficient force from the pellet injection to cause retinal damage though injections done in BSS showed reduced forces.

A novel multifunctional, intravitreal injection assistant: evaluation and comparison with conventional technique

Aim The aim of this work is to evaluate the use of a newly developed multifunctional intravitreal injection (IVI) assistant (IIA) to assist the delivery of intravitreal drugs that are the mainstay of current retinal medical therapy, and to compare the assistant with the conventional IVI technique used by most surgeons as regards ease of use, safety, simplicity of the technique, stabilization of the eye during injection, and complications regarding the use of this device. Design This is an interventional study. Patients and methods A total of 90 eyes of 90 patients attending and referred to the retina clinics of Research Institute of Ophthalmology complaining of diminution of visual acuity and/or metamorphopsia, with varying vitreoretinal and macular pathologies and in need of IVIs of either antivascular endothelial growth factor and/or triamcinolone acetonide as a means to treat their eye problem were recruited into the study. The patients were randomly divided into two groups of 45 patients in each group, irrespective of their age, sex, diagnosis of the retinal condition, or the material required for injection. Group A patients had their IVI with the conventional freehand technique, whereas in group B patients IVI was proceeded using the novel multifunctional IVI assistant. Evaluation of the technique used for both groups and all allied problems and comments as regards patient satisfaction, surgeon’s impression, ease of insertion and use of the device, stabilization of the eye, and complications during and postinjection were recorded and analyzed. Treatment and re-treatment protocols were the same for both groups. All the patients were followed up after the injection the first day, first week, weekly for 1 month, and then monthly thereafter. Re-injections for each patient were planned as ‘re-treat as needed’ protocol. Results In all, 68.9% of the patients had diabetic macular edema, 13.3% had neovascular age-related macular degeneration (wet type AMD), 10% had macular edema following retinal vein occlusion, and 7.8% had leaking choroidal neovascularization associated with high myopia. In group A, 62.2% were male and 37.8% were female. The mean age of these patients was 48±4 years. In group B, 53.3% were male and 46.7% were female, and the mean age was 54±6 years. Complications met with during IVI procedure were categorized into two separate entities: procedure-related complications and complications specific to the agent used. The injection procedure was successful for both groups of patients. There was no difficulty met with in group B patients using the IIA, and there was no need to use caliper, fixation forceps, or cotton wool bud. Injections were performed posterior to the limbus at 3.5 mm for aphakic and pseudophakic and at 4 mm for phakic patients. Pressure applied by the assistant was gentle enough and patients had no annoying pain, and even most of them did not notice the needle used for injection. There were no complications related to the injection technique. Subconjunctival hemorrhage was noted in six patients in group A and in two patients in group B. In all, 11.1% of patients from group A and 15.5% of patients from group B complained of postinjection vitreal floaters. One diabetic patient in group A had corneal abrasion. No traumatic lens injury, retinal hemorrhage, tear, or detachment were recorded in any of the patients in both groups. Not a single case of postinjection toxic inflammatory reaction or endophthalmitis was observed. Drug reflux from the injection site was noticed in 8.9% in group A, and no reflux was noted in group B patients. None of the patients had postinjection increase of increased intraocular pressure. Conclusion The newly developed IVI assistant facilitated IVI and provided safe, accurate, consistent, and rapid injections into the intravitreal compartment of the eye. It guided the needle at a fixed angle to penetrate the eye either at a distance of 3.5 or 4 mm from the limbus, allowed a stepped injection, ability to simultaneously inject two types of medication, as well as provided a guided controlled paracentesis. It is a multifunctional device, believed to be a worthy addition to the ophthalmological surgical armamentarium.

Treatment of Diabetic Macular Oedema – Clinical Trial Findings and Real-world Outcomes Data

In recent years, several intravitreal drug applications have become available for the treatment of diabetic macular oedema (DME). This review aims to summarise and compare available results. Based on a PubMed search, appropriate studies or reviews were evaluated. Clinical trial data suggest that the intravitreal administration of both vascular endothelial growth factor (VEGF) inhibitors and corticosteroids is effective and that overall outcomes are comparable between treatments. Sustained delivery of corticosteroids presents a less treatment-intensive alternative, potentially reducing side effects and enhancing compliance. Compared with clinical development data, recent findings from clinical practice suggest a lesser, more flexible injection frequency in VEGF inhibitors is associated with less pronounced efficacy results. In contrast, corticosteroids treatment frequency seems to correspond with pivotal trial results, reporting equal (or slightly higher or lower) treatment schedules, resulting in similar or higher efficacy values. Safety issues differ between drug classes. Corticosteroid side effects are essentially of local nature and mainly consist of intraocular pressure increases and progression of cataract, limiting their use to pseudophakic patients or those for whom alternative treatments are not effective or are inappropriate. Anti-VEGF treatment is also associated with ocular side effects, but also with reports on systemic side effects, such myocardial infarctions or vascular thromboembolic events. More long-term clinical practice data need to be generated to inform about effectiveness and safety of available therapies in specific patient populations.

Prediction of Ocular Drug Distribution from Systemic Blood Circulation.

Systemically circulating drugs may distribute to ocular tissues across the blood-ocular barriers. Ocular distribution is utilized in the treatment of ocular diseases with systemic medications, but ocular delivery of systemic drugs and xenobiotics may also lead to adverse ocular effects. Ocular distribution after systemic drug administration has not been predicted or modeled. In this study, distribution clearance between vitreous and plasma was obtained from a previous QSPR model for clearance of intravitreal drugs. These values were used in a pharmacokinetic simulation model to describe entry of unbound drug from plasma to vitreous. The simulation models predicted ocular distribution of 10 systemic drugs in rabbit eyes within 1.96 mean fold error and the distribution of cefepime from plasma to vitreous in humans. This is the first attempt to predict ocular distribution of systemic drugs. Reliable predictions were obtained using systemic concentrations of unbound drug, computational value of ocular distribution clearance, and a simple pharmacokinetic model. This approach can be used in drug discovery to estimate ocular drug exposure at an early stage.

Cytotoxicity assessment of porous silicon microparticles for ocular drug delivery

Porous silicon (PSi) is a promising material for the delivery and sustained release of therapeutic molecules in various tissues. Due to the constant rinsing of cornea by tear solution as well as the short half-life of intravitreal drugs, the eye is an attractive target for controlled drug delivery systems, such as PSi microparticles. Inherent barriers ensure that PSi particles are retained in the eye, releasing drugs at the desired speed until they slowly break down into harmless silicic acid. Here, we have examined the in vitro cytotoxicity of positively and negatively charged thermally oxidized (TOPSi) and thermally carbonized (TCPSi) porous silicon microparticles on human corneal epithelial (HCE) and retinal pigment epithelial (ARPE-19) cells. In addition to ocular assessment under an inverted microscope, cellular viability was evaluated using the CellTiter Blue™, CellTiter Fluor™, and lactate dehydrogenase (LDH) assays. CellTiter Fluor proved to be a suitable assay but due to non-specific and interfering responses, neither CellTiter Blue nor LDH assays should be used when evaluating PSi particles. Our results suggest that the toxicity of PSi particles is concentration-dependent, but at least at concentrations less than 200μg/ml, both positively and negatively charged PSi particles are well tolerated by human corneal and retinal epithelial cells and therefore applicable for delivering drug molecules into ocular tissues.

Controversies in Pharmacological Treatment of Inflammatory Component of Macular Edema.

Macular edema (ME) is a common, final pathway for many different ocular and systemic diseases. The most common diseases include: diabetic retinopathy (DR), retinal vascular disorders (such as central and branch retinal vein occlusion), and uveitis. The complex and multifactorial pathophysiological mechanisms leading to ME, are still poorly understood. Inflammation plays a crucial role in the genesis of ME, as demontrsated by significant increase of different cytokines and chemokines, (besides vascular endothelial growth factors-VEGF) in ocular fluids. Currently, intravitreal steroids and anti-VEGF drugs are the most used treatments in ME of retinal vascular origin. This review will address the most important (with highest level of scientific evidence and longest followup) results on the use of intravitreal steroids and anti-VEGF drugs, starting from molecular basis to the most updated randomized clinical trials.

Intravitreal treatment in patients with exudative age-related macular degeneration and visual acuity ≤ 0.05.

BackgroundTo investigate intravitreal treatment efficiencies in patients suffering from exudative ARMD with a BCVA ≤ 0.05.MethodsRetrospective analysis: Analysis parameters were lesion type, BCVA at baseline and at follow-up, the intravitreal drug used, and its application frequency. Patients were divided into: 1) following injections of bevacizumab, triamcinolone, their combination, or ranibizumab regardless of their lesion subtype, 2) or by lesion subtype. Statistical tests were performed using Wilcoxon signed-rank tests, Kruskal-Wallis tests and multivariable logistic regressions.ResultsSeventy four eyes of 74 patients were analyzed. Follow-up was at 12.0 to 15.7 weeks. Median difference of BCVA (logMAR) between baseline and follow-up was 0.000 (−0.030, 0.175) in classic (p = 0.105), 0.000 (−1.15, 0.20) in occult (p = 0.005), −0.200 (−1.20, 0.60) in cases with subretinal fluid (p = 0.207), 0.000 (-0.60, 0.30) in pigment epithelial detachment (p = 0.813), and 0.050 (−0.40, 0.70) in Junius Kuhnt maculopathy (p = 0.344). BCVA increased ≥ 0.2 logMAR in 4 (24 %) classic, 9 (47 %) occult, 6 (33 %) pigment epithelial detachment, 6 (55 %) subretinal fluid, in 29 (39 %) eyes regardless of the lesion type, and reached a BCVA ≥ 0.05 in 7 (9 %) of those with a baseline BCVA <0.05.ConclusionsResults indicate that in patients with ARMD and a BCVA lower 0.05, intravitreal treatment may improve visual acuity, most probably in cases with occult lesions.

Sustained-release steroids for the treatment of diabetic macular edema.

Glucocorticoids have been used for decades in the treatment of ocular disorders via topical, periocular, and more recently intravitreal routes. However, their exact mechanisms of action on ocular tissues remain imperfectly understood. Fortunately, two recently approved intravitreal sustained-release drug delivery systems have opened new perspectives for these very potent drugs. To date, among other retinal conditions, their label includes diabetic macular edema, for which a long-lasting therapeutic effect has been demonstrated both morphologically and functionally in several randomized clinical trials. The rate of ocular complications of intravitreal sustained-release steroids, mainly cataract formation and intraocular pressure elevation, is higher than with anti-vascular endothelial growth factor agents. Yet, a better understanding of the mechanisms underlying these adverse effects and the search for the minimal efficient dose should help optimize their therapeutic window.