Intravitreal Drug Research Articles

Intravitreal injectable hydrogel rods with long-acting bevacizumab delivery to the retina.

Retinal vascular diseases such as neovascular age-related macular degeneration (nAMD) are the leading cause of blindness worldwide. They can be treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents by inhibiting VEGF which is a major agent of abnormal blood vessel growth. However, because of drug's short half-life, clinical treatment often requires monthly repeated intravitreal injections, causing treatment burden and undertreatment. Among various kinds of drug carriers, in situ forming hydrogels have been studied as potential intravitreal drug carriers for the high drug loading, easy injection, controlled drug release, and protection of encapsulated drugs from the environment. However, gelation time, crosslinking degree, and drug release patterns following injection of a liquid that will be subsequently gelled in situ are susceptible to be hindered by dilution of the hydrogel precursor solution with body fluids (e.g., blood or vitreous). Here, we report an injectable pre-crosslinked hydrogel rod to overcome the limitations of in situ forming hydrogels and to extend intravitreal half-life of anti-VEGF for reducing intraocular injection frequency. Hydrogel rods can be simply prepared using in situ forming hydrogels, and injectable using a designed rod injector. The adjustable crosslinking degree of hydrogel rods easily controlled bevacizumab release profiles in a sustained manner. Compared with in situ forming hydrogels, hydrogel rods effectively reduced initial burst release, and showed sustained release with long-term drug efficacy in vitro. From the 4-month in vivo pharmacokinetic analysis, following the intravitreal injection of hydrogel rods, the half-life of bevacizumab in the vitreous and retina was significantly extended, and drug elimination to aqueous humor was effectively reduced. Finally, intraocular stability, degradation, and inflammatory response of hydrogel rods were evaluated. We expect that the hydrogel rod can be a potential drug delivery system for the treatment of nAMD and other conditions that need long-term and local sustained drug administration. STATEMENT OF SIGNIFICANCE: Herein, we report an injectable pre-crosslinked hydrogel rod based on an in situ forming hydrogel to achieve intravitreal long-acting anti-VEGF delivery to reduce injection frequency and improve the long-term visual outcomes of patients with retinal vascular diseases. Hydrogel rods were readily prepared using removable molds and injected using customized injectors. Compared to the in situ forming hydrogel, hydrogel rods showed significantly reduced initial burst release, controllable release profiles for several months, physical stability, and a long-acting anti-angiogenic effect. Animal studies demonstrated that the hydrogel rods dramatically prolonged the intraocular drug half-life while significantly reducing drug elimination for up to four months. Moreover, the biodegradability and safety of the hydrogel rods suggest their suitability as an advanced intravitreal DDS for treating retinal vascular diseases.

New ophthalmic drug delivery systems

For decades, topical ophthalmic drug administration through the use of eye drops has been the most widely used technique for the treatment of eye diseases. The development of galenic formulation has led to the use and commercialization of new formulations, such as suspensions, emulsions, and ophthalmic ointments that increase residence time in the site of action. Recently, new administration systems have been developed, such as devices and inserts that provide the sustained release of active substance. Some of these systems are already available on the market, whereas others are still undergoing clinical trials, such as promising systems based on nanostructures (nanocapsules, cyclodextrins, nanoemulsions, etc.). Similarly, various formulations and devices have been developed in the field of intravitreal administration, with different implants available on the European market for the treatment of age-related macular degeneration (AMD), diabetic macular edema, or infections that affect the posterior segment. This review includes current developments in ophthalmic topical and intravitreal drug administration routes as well as those under investigation.

Комбинированная операция на переднем и заднем отрезках глаза с дооперационным разрывом задней капсулы

Nowadays intravitreal drug administration occupies one of the leading places in the structure of the treatment of eye diseases. the technique for performing this manipulation is simple and universal. however, there may be complications during it. among them are transient ophthalmohypertension, uveitis, endophthalmitis, as well as damage to the lens and retina. a clinical case of surgical treatment of patient d., aged 81, with damage to the posterior lens capsule and fast cataract development was analyzed. Тhe operation was performed on the device EVa (dorc). retrobulbar anesthesia with ropivacaine (ropivacaine Kabi) FrESEnIUS KaBI norgE, aS (norway) 5.0 ml. paracentesis was performed at 2 and 10 o’clock, tunnel 2.2 mm, introduction of viscoelastic discoVisc (alcon). Сapsulorhexis 4 mm was performed using capsular tweezers. the swollen lens masses were washed with an irrigation-aspiration system. 25g ports were installed 3 mm from the limbus in the lower outer, upper outer, upper inner segments of the eyeball. Тotal vitrectomy was performed in the usual mode (vitreotome cuts 10 thousand per minute and irrigation 70 mm hg). the dislocated lens was also removed using a vitreotome with a frequency of 4,000 cuts per minute. Implantation of the intraocular lens rayone hydrofobic aspheric +22.0 diopters (rayner Intraocular lenses limited, United Kingdom) on the anterior capsulorhexis. Fixation of the Iol was not required because the diameter of the anterior rexis of 4 mm (which is smaller than the diameter of the Iol optics of 6 mm) made it possible to hold the lens. Interrupted 7/0 vicryl sutures were put on the sclera. Тhe approach to surgical treatment chosen by us, based on the patient’s history, examination, tactics of performing surgical intervention, showed its timeliness and effectiveness. Keywords: intravitreal injections, complications, damage of the lens capsule, lens luxation

Vitreous Floaters With New Intravitreal Drugs Administered by Retina Specialists

Vitreous Floaters With New Intravitreal Drugs Administered by Retina Specialists

Risk of renal damage associated with intravitreal anti-VEGF therapy for diabetic macular edema in routine clinical practice.

Vascular endothelial growth factor inhibitors (anti-VEGF) have been shown to be effective in the treatment of diabetic macular edema. However, there is little information about the systemic effects of intraocular administration of anti-VEGF drugs in patients with coexistent diabetic nephropathy because it can produce adverse renal effects. This retrospective cohort study analyzed the effect of intravitreal anti-VEGF drugs (bevacizumab, ranibizumab, or aflibercept) on eFGR and microalbuminuria (MicA) in patients with diabetic macular edema and nonproliferative retinopathy without chronic kidney disease (CKD). Sixty-six patients were included, 54.5% male and 45.5% female, with a mean age of 66.70 ± 11.6 years. The mean follow-up of patients with antiangiogenic treatment was 42.5 ± 28.07 months, and the mean number of injections was 10.91 ± 7.54. In 12.1% of the cases, there was a worsening of the glomerular filtration rate (eFGR) and a 19.7% worsening of the microalbuminuria (MicA). The number of injections was not related to the worsening of the eFGR (P = 0.74) or the MicA (P = 0.239). No relationship was found between the type of drug and the deterioration of the GFR (P = 0.689) or the MicA (P = 0.53). Based on the results, there is a small proportion of patients with increase in MicA and the decrease in eFGR after anti-VEGF therapy, and these was no associated with the number of injection or the drug type. Ophthalmologists should be aware of renal damage in order to do a close monitoring of renal function and proteinuria after intravitreal administration of anti-VEGF mainly in hypertensive patients.

Effect of repeated intravitreal anti-vascular endothelial growth factor drugs on corneal nerves.

To investigate the potential effect of repeated intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs on corneal nerves. A total of 64 patients were treated with intravitreal injection of anti-VEGF drugs. There were 19 cases of neovascular age-related macular degeneration (AMD), 20 cases of diabetic macular edema (DME) and 25 cases of retinal vein occlusion (RVO). Twenty-nine cases were treated with aflibercept (2 mg/0.05 mL) whereas 35 cases were managed with ranibizumab (0.5 mg/0.05 mL). A corneal confocal microscope was used to collect images of corneal subbasal nerve plexus, and Image J was used for image analysis. The changes in corneal nerve were compared between 1 month after each injection and before injection. There were no significant differences in the density and length of corneal nerve at specific time after the surgery in comparison with baseline in patients who were given 3 intravitreal injections. There was no significant correlation between the numbers of injections and the changes of the corneal nerves. After 3rd injection, the nerve length of the DME group was markedly lower than that of AMD and RVO groups, the difference was statistically significant (P < .05). The nerve density of the DME group was not significantly different from that of AMD and RVO groups, whereas the nerve length and nerve density of the AMD and RVO groups were not statistically significant between each other also. The corneal nerve length after the 2nd and 3rd injections of Aflibercept were lower than that before surgery, the difference was statistically significant. There were no significant differences in nerve density and nerve length at each time point after Ranibizumab injection. The length and density of the corneal nerve after multiple injections in contralateral eye displayed no significant changes compared with the baseline. Repeated intravitreal anti-VEGF drug can reduce the length of corneal nerves. For patients who need repeated intravitreal injections of anti-VEGF drugs, especially in DM, attention should be paid on the changes affecting the corneal nerves. It is also needed to strengthen the local anti-inflammatory therapy to avoid infection and to use artificial tears to protect the microenvironment of the ocular surface after the surgery.

The Role of Laser Photocoagulation in Treating Diabetic Macular Edema in the Era of Intravitreal Drug Administration: A Descriptive Review.

Background and Objectives: This study aimed to elucidate the role of laser photocoagulation therapy in the treatment of diabetic macular edema (DME) as an alternative to, or in conjunction with, the first-line treatment, anti-vascular endothelial growth factor (VEGF). Materials and Methods: A comprehensive literature search to identify studies that evaluated the efficacy of laser photocoagulation therapy in the management of DME was performed. The relevant findings of the efficacy of focal/grid laser therapy from data in randomized, controlled trials were synthesized, and the potential of new laser technologies, such as navigated laser systems, pattern scan lasers, and subthreshold lasers, was explored. The usefulness of multimodal imaging-guided laser therapy was also evaluated, with a focus on the potential contribution to anti-VEGF therapy. Results: Focal laser photocoagulation targeting microaneurysms remains an effective therapeutic approach to chronic refractory edema, despite the widespread use of anti-VEGF therapy. To achieve the best possible treatment outcomes, precise identification of microaneurysms is essential. This requires the use of multimodal imaging-guided, highly accurate, minimally invasive coagulation techniques. Subthreshold laser therapy can also reduce the frequency of anti-VEGF injections and minimize treatment burden. Conclusions: Further studies are needed to determine the optimal timing and settings for laser photocoagulation therapy and the potential of new laser technologies in the management of DME. Nevertheless, laser photocoagulation therapy plays an important role in the management of DME, in conjunction with anti-VEGF therapy.

The Evolution of Triamcinolone Acetonide Therapeutic Use in Retinal Diseases: From Off-Label Intravitreal Injection to Advanced Nano-Drug Delivery Systems.

Ophthalmic drug delivery to the posterior segment of the eye has been challenging due to the complex ocular anatomy. Intravitreal injection of drugs was introduced to deliver therapeutic doses in the posterior segment. Different posterior segment diseases including age-related macular degeneration, diabetic macular edema, retinal vein occlusions, uveitis, and cystoid macular edema, among others, have been historically treated with intravitreal corticosteroids injections, and more recently with intravitreal corticosteroids drug implants. Triamcinolone acetonide (TA) is the most frequently used intraocular synthetic corticosteroid. Using nanoparticle-based TA delivery systems has been proposed as an alternative to intravitreal injections in the treatment of posterior segment diseases. From these novel delivery systems, topical liposomes have been the most promising strategy. This review is oriented to exhibit triamcinolone acetonide drug evolution and its results in treating posterior segment diseases using diverse delivery platforms.

Visual Outcomes of Anti-VEGF Treatment on Neovascular Age-Related Macular Degeneration: A Real-World Population-Based Cohort Study.

Neovascular age-related macular degeneration (nAMD) leads to visual impairment if not treated promptly. Intravitreal anti-VEGF drugs have revolutionized nAMD treatment in the past two decades. We evaluated the visual outcomes of anti-VEGF treatment in nAMD. A real-life population-based cohort study. The data included parameters for age, sex, age at diagnosis, laterality, chronicity, symptoms, visual outcomes, lens status, and history of intravitreal injections. A total of 1088 eyes (827 patients) with nAMD were included. Visual acuity was stable or improved in 984 eyes (90%) after an average of 36 ± 25 months of follow-up. Bevacizumab was the first-line drug in 1083 (99.5%) eyes. Vision improved ≥15 ETDRS letters in 377 (35%), >5 ETDRS letters in 309 (28%), and was stable (±5 ETDRS letters) in 298 (27%) eyes after anti-VEGF treatment. The loss of 5 ≤ 15 ETDRS letters in 44 (4%) eyes and ≥15 ETDRS letters in 60 (6%) eyes was noted. At the diagnosis of nAMD, 110 out of 827 patients (13%) fulfilled the criteria for visual impairment, whereas 179 patients (22%) were visually impaired after the follow-up. Improvement or stabilization in vision was noted in 90% of the anti-VEGF-treated eyes with nAMD. In addition, anti-VEGF agents are crucial in diminishing nAMD-related visual impairment.

Anti-VEGF and steroid combination therapy relative to anti-VEGF mono therapy for the treatment of refractory DME: A systematic review of efficacy and meta-analysis of safety.

The aim of the study was to determine the efficacy and safety of combined anti-VEGF and steroid therapy in treatment refractory DME patients. We conducted a systematic review and meta-analysis of peer-reviewed articles reporting on visual, anatomical and adverse outcomes to compare the efficacy and safety of combined intravitreal anti-VEGF/steroids versus anti-VEGF monotherapy for refractory DME. Seven studies (4 RCTs and 3 observational studies) reporting on 452 eyes were included. Our systematic review showed that combination therapy is significantly more effective for anatomical outcomes in the treatment of resistant DME compared to anti-VEGF monotherapy in six studies. Two studies found that addition of intravitreal steroids promoted faster visual improvement, but not significantly better final visual outcomes compared to anti-VEGF monotherapy. Combination therapy was associated with a higher incidence of IOP-related adverse events (RR = 0.10, 95% CI = [0.02, 0.42], p = 0.002) and cataract-related adverse events (RR = 0.10, 95% CI = [0.01, 0.71], p = 0.02). Our systematic review and meta-analysis of seven studies and 452 eyes revealed that combination therapy of anti-VEGF and steroid intravitreal drugs in the management of treatment refractory DME resulted in superior anatomical outcomes in all but one study. Combination therapy led to superior short-term visual outcomes in two studies, while others reported no difference between treatment groups. Meta-analysis revealed that combination therapy was associated with more adverse events. Future research should provide guidance on the standard definitions for treatment resistance and therapeutic alternatives for DME patients with sub-optimal response to anti-VEGF treatment.

Compliance with follow-up in patients with diabetic macular edema: Eye care center vs. diabetes care center.

The study was conducted to compare the compliance to intravitreal injection treatment and follow-up in patients with center-involving diabetic macular edema (CI-DME) and treatment outcomes between a tertiary eye care facility and a tertiary diabetes care center. A retrospective review was conducted on treatment naïve DME patients who had received intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections in 2019. Participants were people with type 2 diabetes who were under regular care at the eye care center or the diabetes care center in Chennai. The outcome measures were noted at months 1, 2, 3, 6, and 12. A review of 136 patients treated for CI-DME (72 from the eye care center and 64 from a diabetes care center) was carried out. The severity of diabetic retinopathy (DR) was similar in both centers. There was no statistically significant (P > 0.05) difference in the choice of initial intravitreal drug in the two centers. At 12-month follow-up, only 29.16% came for a follow-up in the eye center vs. 76.56% in a diabetes care center (P = 0.000). The multivariate logistic regression showed increasing age was associated with non-compliance in both the groups (eye care center: odds ratio [OR] 0.91; 95% confidence interval [CI] 0.82-1.21; P = 0.044) and diabetes care center (OR 1.15; 95% CI 1.02-1.29; P = 0.020). The follow-up rate between eye care and diabetic care center with DME showed a significant disparity. By providing comprehensive diabetes care for all complications under one roof, compliance with follow-up can be improved in people with DME.

In situ forming mesoporous polydopamine nanocomposite thermogel for combined chemo-photothermal therapy of intraocular cancer

Intraocular cancers such as retinoblastoma and uveal melanoma will induce severe vision loss or even death. Herein, a versatile nanocomposite thermogel based on hexanoyl glycol chitosan (HGC) and mesoporous polydopamine nanoparticles (MPDA NPs) was designed for potential use as an intraocular “drug depot” for the treatment of intraocular tumors. The integrated HGC-MPDA thermogel showed reversible sol-gel transition property as well as injectable and in-situ gelation abilities. The incorporated MPDA NPs endowed the thermogel with outstanding NIR laser-based photothermal conversion ability and enabled NIR light-controlled drug release. Moreover, in vitro study revealed that drug-loaded thermogel (HGC-MPDA@DOX) with the aid of 808 nm laser irradiation possessed superior anticancer effect than any single treatment via synergistic chemo-photothermal therapy. The present study demonstrated that HGC-MPDA could serve as a multifunctional platform for sustained and NIR light-responsive intravitreal drug delivery, avoiding repetitive injection, and the localized chemo-photothermal therapy provides a promising strategy against intraocular tumors.

Polytherapy and Multimorbidity Pattern of Users of Anti-VEGF Drugs and Dexamethasone for the Treatment of Age-Related Macular Degeneration and other Vascular Retinopathies in Clinical Practice.

Introduction: Our aim was to describe the polytherapy and multimorbidity pattern of users of anti-VEGF and dexamethasone drugs for the treatment of these conditions, and to investigate their polytherapy and multimorbidity profiles, together with adherence and the burden of care. Methods: Descriptive, population-based, pharmacoepidemiology study on the users of anti-VEGF drugs, and secondarily intravitreal dexamethasone, for the treatment of age-related macular degeneration and other vascular retinopathies in clinical practice, using administrative databases of Lazio region, Italy. We used a cohort of 50,000 residents in Lazio in 2019 with same age as comparison. Polytherapy was assessed using databases of prescribed drugs intended for outpatient use. Multimorbidity was investigated with additional sources, such as hospital discharge records, outpatient care records, and disease-specific exemptions from co-payment. Each patient was followed for 1 to 3 years from the first intravitreal injection received. Results: 16,266 residents in Lazio who received the first IVI from 1 January 2011 to 31 December 2019, with at least 1 year of observation before index date, were included. The proportion of patients with at least one comorbidity was 54.0%. Patients used an average 8.6 (SD 5.3) concomitant drugs other than anti-VEGF used for injections. A large percentage of patients (39.0%) used 10 or more concomitant drugs, including antibacterials (62.9%), drugs for peptic ulcers (56.8%), anti-thrombotics (52.3%), NSAIDs (44.0%), and anti-dyslipidaemics (42.3%). The same proportions were found across patients of all ages, probably due to high prevalence of diabetes (34.3%), especially in younger age groups. When stratified by diabetes, a comparison of multimorbidity and polytherapy with a sample of 50,000 residents of the same age found that patients receiving IVIs used more drugs and had more comorbidities, particularly in non-diabetics. Lapses of care, whether short (absence of any type of contact for at least 60 days in the first year of follow-up and 90 in the second year) or long (90 days in the first and 180 days in the second year) were common: 66% and 51.7%, respectively. Conclusions: Patients receiving intravitreal drugs for retinal conditions have high multimorbidity and polytherapy rates. Their burden of care is aggravated by the large number of contacts with the eye care system for examinations and injections. Pursuing Minimally Disruptive Medicine to optimise patient care is a difficult goal for health systems, and more research on clinical pathways and their implementation is warranted.

Peptide Nanofiber System for Sustained Delivery of Anti-VEGF Proteins to the Eye Vitreous.

Ranibizumab is a recombinant VEGF-A antibody used to treat the wet form of age-related macular degeneration. It is intravitreally administered to ocular compartments, and the treatment requires frequent injections, which may cause complications and patient discomfort. To reduce the number of injections, alternative treatment strategies based on relatively non-invasive ranibizumab delivery are desired for more effective and sustained release in the eye vitreous than the current clinical practice. Here, we present self-assembled hydrogels composed of peptide amphiphile molecules for the sustained release of ranibizumab, enabling local high-dose treatment. Peptide amphiphile molecules self-assemble into biodegradable supramolecular filaments in the presence of electrolytes without the need for a curing agent and enable ease of use due to their injectable nature-a feature provided by shear thinning properties. In this study, the release profile of ranibizumab was evaluated by using different peptide-based hydrogels at varying concentrations for improved treatment of the wet form of age-related macular degeneration. We observed that the slow release of ranibizumab from the hydrogel system follows extended- and sustainable release patterns without any dose dumping. Moreover, the released drug was biologically functional and effective in blocking the angiogenesis of human endothelial cells in a dose-dependent manner. In addition, an in vivo study shows that the drug released from the hydrogel nanofiber system can stay in the rabbit eye's posterior chamber for longer than a control group that received only a drug injection. The tunable physiochemical characteristics, injectable nature, and biodegradable and biocompatible features of the peptide-based hydrogel nanofiber show that this delivery system has promising potential for intravitreal anti-VEGF drug delivery in clinics to treat the wet form age-related macular degeneration.

Migration of dexamethasone implant (OZURDEX®) into the anterior chamber in a pseudophakic eye with an intact capsular bag

Ozurdex® (Allergan, Inc., Irvine, CA, USA) is an intravitreal sustained-release drug delivery system containing dexamethasone, mainly used for the treatment of macular edema in diabetes, retinal vein occlusions or treatment of non-infectious posterior uveitis, as approved by the US FDA. It can be implanted into the vitreous cavity via the pars plana route. Migration of this implant into the anterior chamber may occur in cases of aphakia, pseudophakia with defective lens capsule, zonular dehiscence, iatrogenic, or as in pseudoexfoliation syndrome. We report a case of a pseudophakic patient with intact posterior capsule and no significant history suggesting a zonular weakness, who presented with diminution of vision due to anterior migration of the dexamethasone implant and its effects on the cornea. Measurements of specular microscopy provide useful information which may aid in management pre- and post-removal of migrated implant.

Clinical analysis of peripheral exudative hemorrhagic chorioretinopathy

Objective: To evaluate the clinical features and outcomes of eyes with peripheral exudative hemorrhagic chorioretinopathy (PEHCR). Methods: It was a retrospective case series study. A total of 12 patients (12 eyes) diagnosed with PEHCR at Peking University People's Hospital from October 2016 to December 2019 were included. The clinical data of visual acuity, slit-lamp microscopy, indirect ophthalmoscopy, fundus photography, B-ultrasound, optical coherence tomography, fluorescein fundus angiography and indocyanine green angiography, surgical procedures, therapeutic effects and follow-up were analyzed. Results: Among all 12 patients included, 7 were male and 5 were female. The age was (58.0±8.8) years. All patients had unilateral disease. The right eye was involved in 6 cases and the left eye in 6 cases. All cases presented with vitreous hemorrhage, 9 of which presented with intraocular space-occupying lesions. In the patients with intraocular space-occupying lesions, the maximum basal diameter was (8.3±1.6) mm and the height was (3.5±1.2) mm measured by B-ultrasound. A-scan ultrasonography was characterized by intermediate high reflectivity or intermediate low reflectivity. Fundus fluorescence angiography revealed nonspecific alterations corresponding to the visible fundoscopic changes such as window defects, blockage, staining, but no neovascular membrane. No polyps were found on indocyanine green angiography. All patients received vitrectomy. The intraocular lesions were found to be subretinal bleeding and exudative masses intraoperatively. Two patients had combined cataract surgery; three patients received gas or silicone oil tamponade, and three patients received adjunct intravitreal anti-vascular endothelial growth factor drugs during the follow-up. The follow-up period was (30.0±12.6) months. At the last visit, the visual acuity was improved in 11 patients and remained stable in 1 patient. Conclusions: PEHCR is a peripheral hemorrhagic retinal degenerative disorder that simulates choroidal melanoma and lacks characteristic angiography changes. The overall therapeutic effect and prognosis are good.

In Vivo CaV3 Channel Inhibition Promotes Maturation of Glucose-Dependent Ca2+ Signaling in Human iPSC-Islets

CaV3 channels are ontogenetically downregulated with the maturation of certain electrically excitable cells, including pancreatic β cells. Abnormally exaggerated CaV3 channels drive the dedifferentiation of mature β cells. This led us to question whether excessive CaV3 channels, retained mistakenly in engineered human-induced pluripotent stem cell-derived islet (hiPSC-islet) cells, act as an obstacle to hiPSC-islet maturation. We addressed this question by using the anterior chamber of the eye (ACE) of immunodeficient mice as a site for recapitulation of in vivo hiPSC-islet maturation in combination with intravitreal drug infusion, intravital microimaging, measurements of cytoplasmic-free Ca2+ concentration ([Ca2+]i) and patch clamp analysis. We observed that the ACE is well suited for recapitulation, observation and intervention of hiPSC-islet maturation. Intriguingly, intraocular hiPSC-islet grafts, retrieved intact following intravitreal infusion of the CaV3 channel blocker NNC55-0396, exhibited decreased basal [Ca2+]i levels and increased glucose-stimulated [Ca2+]i responses. Insulin-expressing cells of these islet grafts indeed expressed the NNC55-0396 target CaV3 channels. Intraocular hiPSC-islets underwent satisfactory engraftment, vascularization and light scattering without being influenced by the intravitreally infused NNC55-0396. These data demonstrate that inhibiting CaV3 channels facilitates the maturation of glucose-activated Ca2+ signaling in hiPSC-islets, supporting the notion that excessive CaV3 channels as a developmental error impede the maturation of engineered hiPSC-islet insulin-expressing cells.

Do intravitreal anti-vascular endothelial growth factor agents lead to renal adverse events? A pharmacovigilance real-world study.

Intravitreal vascular endothelial growth factor (VEGF) blockade is essential in many macular edema diseases treatment. However, intravitreal VEGF treatment has been reported to lead to deteriorated proteinuria and renal function. This study aimed to explore the relationship between renal adverse events (AEs) and the intravitreal use of VEGF inhibitors. In the FDA's Adverse Event Reporting System (FAERS) database, we searched for renal AEs of patients receiving various anti-VEGF drugs. We performed statistics on renal AEs in patients treated with Aflibercept, Bevacizumab, Ranibizumab, and Brolucizumab (from January 2004 to September 2022) using disproportionate and Bayesian analysis. We also investigated the time to onset, fatality, and hospitalization rates of renal AEs. We identified 80 reports. Renal AEs were most frequently associated with Ranibizumab (46.25%) and Aflibercept (42.50%). However, the association between intravitreal anti-VEGFs and renal AEs was insignificant since the reporting odds ratio of Aflibercept, Bevacizumab, Ranibizumab, and Brolucizumab were 0.23 (0.16, 0.32), 0.24 (0.11, 0.49), 0.37 (0.27, 0.51) and 0.15 (0.04, 0.61), respectively. The median time to renal AEs onsets was 37.5 (interquartile range 11.0-107.3) days. The hospitalization and fatality rates in patients who developed renal AEs were 40.24 and 9.76%, respectively. There are no clear signals for the risk of renal AEs following various intravitreal anti-VEGF drugs based on FARES data.

Life Quality in Patients with Impaired Visual Acuity Undergoing Intravitreal Medication Applications

This cross-sectional study aims to examine the quality of life and difficulties in the daily functioning of patients with impaired visual acuity treated with intravitreal drugs. The survey included 180 adult respondents (78 male and 102 female). The standardized, validated questionnaire VFQ 25 version 2000 was used to measure the quality of life. Results show that, in general, regarding visual functioning, men are significantly more satisfied than women, they rate less intensity of pain, and their distance vision is better. Men report fewer restrictions than women, better color, peripheral vision, and overall visual functioning. The best vision results are in individuals under the age of 60 who also report significantly better social functioning, mental health, fewer restrictions, and less dependence on others. The only significant association between the number of drug applications and the scale of visual functioning is driving motor vehicles-the more applications of the drug they received, the less likely they are to drive a car. The quality of life in patients with chronic ophthalmic diseases treated with intravitreal drugs is reduced, particularly in elderly and female patients who have poorer visual acuity, poorer health in general, and limited social roles.

International consortium for innovation and quality: An industry perspective on the nonclinical and early clinical development of intravitreal drugs.

The eye, which is under constant exposure to environmental pathogens, has evolved various anatomic and immunological barriers critical to the protection of tissues lacking regenerative capacity, and the maintenance of a clear optic pathway essential to vision. By bypassing the ocular barriers, intravitreal (IVT) injection has become the mainstay for the delivery of drugs to treat conditions that affect the back of the eye. Both small molecules and biotherapeutics have been successfully administered intravitreally, and several drugs have been approved for the treatment of (wet) age-related macular degeneration and diabetic macular edema. However, IVT injection is an invasive procedure, which requires sufficient technical expertise from the healthcare professional administering the drug. Potential side effects include bleeding, retinal tear, cataracts, infection, uveitis, loss of vision, and increased ocular pressure. Pharmaceutical companies often differ in their drug development plan, including drug administration techniques, collection of ocular tissues and fluids, ophthalmology monitoring, and overall conduct of nonclinical and clinical studies. The present effort, under the aegis of the Innovation & Quality Ophthalmic Working Group, aims at understanding these differences, identifying pros and cons of the various approaches, determining the gaps in knowledge, and suggesting feasible good practices for nonclinical and early clinical IVT drug development.