Ocular toxicity associated with anti-HER2 agents in breast cancer: A pharmacovigilance analysis using the FAERS database.

Anti-human epidermal growth factor receptor 2 (HER2) agents have exhibited pronounced tumor-inhibitory activity, yet the accompanying ocular toxicity has frequently been underestimated. We aim to conduct a comprehensive comparative analysis of ocular toxicity risk related to various anti-HER2 agents. We executed a retrospective pharmacovigilance investigation based on the FDA Adverse Event Reporting System (FAERS) database, covering the period from Q2 2018 to Q1 2023. The disproportionality analysis was performed to assess ocular toxicity risk. Multivariate logistic regression was implemented to mitigate potential biases. Moreover, the time to onset of ocular toxicity was also evaluated. A total of 3467 ocular adverse event (AE) reports concerning anti-HER2 agents were collected. At the preferred term (PT) level, there were 69 positive signals, among which excessive eye blinking, abnormal sensation in the eye, and asthenopia presented a significant risk. In comparison to tyrosine kinase inhibitors (TKIs), antibody drugs were associated with a broader range of ocular disorders at Standardized MedDRA Queries (SMQ)levels, including conjunctival disorders, corneal disorders, ocular infections, ocular motility disorders, optic nerve disorders, and retinal disorders. In terms of onset time, pertuzumab displayed an earlier onset at 21.5 days, while trastuzumab deruxtecan had the latest at 91.5 days. In summary, our study reveals varying degrees of ocular toxicity related to anti-HER2 agents, with a significantly higher risk observed in antibody drugs. Additionally, novel ocular toxicity signals, not documented in product labels, have been detected. In the future, further research will be necessary to validate our findings.

Investigating the therapeutic potential of Allium cepa extract in combating pesticide exposure induced ocular damage.

The ocular surface is subject to a range of potentially hazardous environmental factors and substances, owing to its anatomical location, sensitivity, and physiological makeup. Xenobiotic stress exerted by chronic pesticide exposure on the cornea is primarily responsible for ocular irritation, excessive tear production (hyper-lacrimation), corneal abrasions and decreased visual acuity. Traditional medicine hails the humble onion (Allium cepa) for its multi-faceted properties including but not limited to anti-microbial, antioxidant, anti-inflammatory and wound healing. However, there is a lacuna regarding its impact on the ocular surface. Thereby, the current study investigated whether topical application of crude extract of Allium cepa aided in mitigating pesticide-induced damage to the ocular surface. The deleterious effects of pesticide exposure and their mitigation through the topical application of herbal extract of Allium cepa were analysed initially through in vitro evaluation on cell lines and then on the ocular surface via various in-vivo and ex-vivo techniques. Pathophysiological alterations to the ocular surface that impacted vision were explored through detailed neurophysiological screening with special emphasis on visual acuity wherein it was observed that the murine group treated with topical application of Allium cepa extract had comparable visual capacity to the non-pesticide exposed group. Additionally, SOD2 was utilized as an oxidative stress marker along with the expression of cellular apoptotic markers such as Bcl-xL to analyse the impact of pesticide exposure and subsequent herbal intervention on oxidative stress-induced corneal damage. The impact on the corneal epithelial progenitor cell population (ABCG2 and TERT positive cells) was also flowcytometrically analysed. Therefore, from our observations, it can be postulated that the topical application of Allium cepa extract might serve as an effective strategy to alleviate pesticide exposure related ocular damage.

In silico prediction of ocular toxicity of compounds using explainable machine learning and deep learning approaches.

The accurate identification of chemicals with ocular toxicity is of paramount importance in health hazard assessment. In contemporary chemical toxicology, there is a growing emphasis on refining, reducing, and replacing animal testing in safety evaluations. Therefore, the development of robust computational tools is crucial for regulatory applications. The performance of predictive models is heavily reliant on the quality and quantity of data. In this investigation, we amalgamated the most extensive dataset (4901 compounds) sourced from governmental GHS-compliant databases and literature to develop binary classification models of chemical ocular toxicity. We employed 12 molecular representations in conjunction with six machine learning algorithms and two deep learning algorithms to create a series of binary classification models. The findings indicated that the deep learning method GCN outperformed the machine learning models in cross-validation, achieving an impressive AUC of 0.915. However, the top-performing machine learning model (RF-Descriptor) demonstrated excellent performance with an AUC of 0.869 on the test set and was therefore selected as the best model. To enhance model interpretability, we conducted the SHAP method and attention weights analysis. The two approaches offered visual depictions of the relevance of key descriptors and substructures in predicting ocular toxicity of chemicals. Thus, we successfully struck a delicate balance between data quality and model interpretability, rendering our model valuable for predicting and comprehending potential ocular-toxic compounds in the early stages of drug discovery.

Relationship between tamoxifen and cataracts: a nationwide cohort study of women in South Korea.

PURPOSE: Although prospective randomized clinical trials have reported that the use of prophylactic tamoxifen in patients at a high risk of breast cancer is associated with an increased risk of cataracts development, such findings are inconsistent. This study aimed to clarify the relationship between adjuvant tamoxifen use and cataracts risk using a nationwide longitudinal population-based registry. METHODS: This retrospective cohort study was conducted using the Korean National Health Insurance claims database over a 15-year period (January 2007-December 2021). Data from all female patients diagnosed with ductal carcinoma in situ (DCIS) between 2009 and 2015 were extracted. We evaluated the incidence of cataracts diagnosis and surgery after adjuvant tamoxifen administration in patients with DCIS. RESULTS: A total of 43,434 patients who met the inclusion criteria were diagnosed with DCIS between 2009 and 2015. Data from 2849 patients receiving tamoxifen and 1615 patients not receiving tamoxifen were analyzed before matching. After matching for comorbidities, type of breast surgery, and age, both groups consisted of 1597 patients. Both before and after matching, adjuvant tamoxifen was not a significant factor for an increased risk of cataracts diagnosis alone or with surgery. CONCLUSION: Our study showed that adjuvant tamoxifen was not a risk factor for increased cataracts diagnosis and surgery in patients with DCIS. This finding provides a basis for physicians to reduce their ocular toxicity concerns regarding the risk of patients developing cataracts by tamoxifen treatment.

Ocular toxicity of investigational anti-cancer drugs in early phase clinical trials.

Ocular toxicities arising from anti-cancer drugs occur sporadically and are sometimes underestimated because they are not life-threatening. Reports focusing on ocular toxicities from cancer therapy are limited. We investigated the detailed progress of ocular toxicities of anti-cancer drugs including first-in-class ones. A retrospective review of medical records was conducted for patients who were involved in early phase clinical trials with scheduled ophthalmologic examinations according to their protocols between January 2014 and August 2021. Patients with ocular toxicity suspected to be related to the investigational drugs in the ophthalmic examination were investigated in detail. In total, 37 ocular toxicities related to investigational drugs occurred in 7.6% of patients (33/434). The median age of the 33 patients was 61 years (range, 33-76 years), and 20 were male. Causal drugs with a high incidence of ocular toxicities were HSP90 inhibitors and FGFR inhibitors. Retinopathy was most frequent, while conjunctivitis, dry eye, keratitis, keratopathy, and uveitis were also observed. Dim vision as a subjective finding was a unique adverse event. Most patients developed ocular toxicities even though their dose was below the drug's maximum tolerated dose. Except for one case, all ocular toxicities occurred bilaterally. About 60% (22/37) of ocular toxicity cases needed a temporary hold of the drug. All except for three cases fully recovered. This study reported the risks and timing of the onset of a variety of ocular toxicities of anti-cancer drugs, which were fundamentally controllable. (Trial registration number. Retrospectively registered).

Carbofuran pesticide toxicity to the eye.

Pesticide exposure to eyes is a major source of ocular morbidities in adults and children all over the world. Carbofuran (CF), N-methyl carbamate, pesticide is most widely used as an insecticide, nematicide, and acaricide in agriculture, forestry, and gardening. Contact or ingestion of carbofuran causes high morbidity and mortality in humans and pets. Pesticides are absorbed in the eye faster than other organs of the body and damage ocular tissues very quickly. Carbofuran exposure to eye causes blurred vision, pain, loss of coordination, anti-cholinesterase activities, weakness, sweating, nausea and vomiting, abdominal pain, endocrine, reproductive, and cytotoxic effects in humans depending on amount and duration of exposure. Pesticide exposure to eye injures cornea, conjunctiva, lens, retina, and optic nerve and leads to abnormal ocular movement and vision impairment. Additionally, anticholinesterase pesticides like carbofuran are known to cause salivation, lacrimation, urination, and defecation (SLUD). Carbofuran and its two major metabolites (3-hydroxycarbofuran and 3-ketocarbofuran) are reversible inhibitors of acetylcholinesterase (AChE) which regulates acetylcholine (ACh), a neurohumoral chemical that plays an important role in corneal wound healing. The corneal epithelium contains high levels of ACh whose accumulation by AChE inhibition after CF exposure overstimulates muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs). Hyper stimulation of mAChRs in the eye causes miosis (excessive constriction of the pupil), dacryorrhea (excessive flow of tears), or chromodacryorrhea (red tears). Recent studies reported alteration of autophagy mechanism in human cornea in vitro and ex vivo post carbofuran exposure. This review describes carbofuran toxicity to the eye with special emphasis on corneal morbidities and blindness.

Ocular toxicity following carboplatin chemotherapy for neuroendocrine tumour of the bladder.

INTRODUCTION: Carboplatin is a commonly used platinum analogue chemotherapeutic agent that is similar to cisplatin but is known to be better tolerated. This case report outlines a case of ocular toxicity following carboplatin chemotherapy used for the management of a neuroendocrine tumour of the bladder. CASE REPORT: A 70-year-old man with a history of neuroendocrine bladder cancer underwent chemotherapy with carboplatin and etoposide. He presented 4 weeks following his fourth chemotherapy cycle with a 1-week history of right eye blurriness. The patient had suffered a similar episode 2 weeks following his third chemotherapy cycle in his left eye. Carboplatin-induced ocular toxicity was suspected and his vision remained stable following cessation of carboplatin chemotherapy. DISCUSSION: Current literature on carboplatin-induced ocular toxicity remains scanty, however, previous cases have reported symptoms beginning 5 days to 2 weeks following carboplatin use. Visual disturbance in the form of altered colour vision, blind spot, blurred vision and metamorphopsia have been reported by previous literature. This case report emphasised a case of bilateral sequential blurring of vision following carboplatin chemotherapy. CONCLUSION: It remains critical for ophthalmologists and oncologists to look out for ocular side effects of chemotherapy due to its devastating effects.

Bromelain protects against cisplatin-induced ocular toxicity through mitigating oxidative stress and inflammation.

The aim of this study was to investigate the molecular, biochemical, and histopathological effects of bromelain, which has antioxidant and anti-inflammatory properties, against cisplatin-induced ocular toxicity. The groups were designed as (1) Control, (2) Cisplatin (7 mg/kg, intraperitoneally), (3) Cisplatin + Bromelain (50 mg/kg, orally for 14 consecutive days), (4) Cisplatin + Bromelain (100 mg/kg, orally for 14 consecutive days). The activity of total antioxidant capacity (TAC) and total oxidant status (TOS) and levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-1ß (IL-1ß), IL-10, nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) and 8-OHdG were measured in ocular tissue. The mRNA expression of NF-κB and Caspase-3 was also evaluated. Also, ocular sections were evaluated histopathologically. Bromelain demonstrated a dose-dependent protective effect in cisplatin-induced toxicity by regulating oxidative stress, inflammation, and tissue damage. Our results suggested that bromelain may be a potential adjuvant that can protect the eye from cisplatin-induced toxicity.

Transcriptome Profiling of Etridiazole-Exposed Zebrafish (Danio rerio) Embryos Reveals Pathways Associated with Cardiac and Ocular Toxicities.

Etridiazole (EDZ) is a thiadiazole-containing fungicide commonly used to control Pythium and Phytophthora spp. Although previous studies have shown that EDZ is teratogenic, the exact molecular mechanisms underlying its toxicity remain unknown. In this study, a zebrafish (Danio rerio; ZF) model was used to explore the molecular pathways associated with EDZ toxicity. The whole transcriptome of ZF embryos exposed to 96 h of EDZ was analyzed, along with developmental abnormalities. EDZ-induced malformations were primarily related to the eyes, heart, and growth of the ZF. Compared to untreated ZF, etridiazole-treated ZF had 2882 differentially expressed genes (DEGs), consisting of 1651 downregulated genes and 1231 upregulated genes. Gene ontology enrichment analysis showed that DEGs were involved in biological processes, such as sensory perception, visual perception, sensory organ development, and visual system development, and showed transmembrane transporter and peptidase regulator activities. Metabolism, phototransduction, aminoacyl-tRNA biosynthesis, MAPK signaling pathway, calcium signaling pathway, and vascular smooth muscle contraction were among the most enriched KEGG pathways. The qPCR analyses of the eight random genes were in good agreement with the transcriptome data. These results suggest several putative mechanisms underlying EDZ-induced developmental deformities in ZF.

Nano-emulsomes for back of the eye delivery of Ganciclovir: formulation optimization, characterization & in vitro/in vivo evaluation.

In this work, novel carriers- nanoemulsomes (NE) of ganciclovir (GCV) and a fluorescent marker sodium fluorescein (SF) were developed and evaluated for posterior ocular delivery via topical route. GCV loaded emulsomes (GCV NE) were optimized by a factorial design and various characterization parameters were performed on the optimized batch. The optimized batch had particle size of 131.04 ± 1.87 nm, % entrapment efficiency of 36.42 ± 3.09% and its TEM image showed discrete spherical structures below 200 nm. Ocular irritation potential of excipients and formulation were evaluated by cell line based in vitro tests on SIRC cell line, results confirmed the safety of excipients for ocular use. Precorneal retention and pharmacokinetic studies of GCV NE were performed in rabbit eyes which showed significant retention of GCV NE in the cul-de-sac. The ocular distribution study of SF-loaded nanoemulsomes (SF NE) were performed in mice eyes by confocal microscopy, images showed fluorescence in the various internal layers of retina, suggesting efficacy of emulsomes in delivering agents to the back of eye via topical administration.

Rare ocular toxicity induced by pertuzumab/QL1209 in healthy chinese subjects: case reports and whole-exome sequencing analysis.

Pertuzumab is a recombinant anti-HER2 humanized monoclonal antibody widely used for the adjuvant treatment of HER2-positive breast cancer. Its safety is well established with the most common adverse effects being diarrhea and rash. To our knowledge, severe pertuzumab-induced ocular adverse events have never been reported. Herein, we describe several cases of pertuzumab/QL1209 (pertuzumab biosimilar)-induced blurred vision in healthy Chinese male subjects after a single injection of 420 mg pertuzumab/QL1209. Persistent optic nerve damage and vision loss occurred in the most severe case even after ophthalmic treatment. We conducted whole-exome sequencing (WES) of DNA samples from 5 cases and 13 controls to analyze the potential genetic factors and identified some associated variants (rs80303690 in RBM24, rs117375173 in CASR, rs1805097 in IRS2, and rs1227049 in CDH23). Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) terms gene enrichment analyses were carried out for differentially expressed genes clustered in the PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways, which were exactly activated by HER2 phosphorylation. In summary, this is the first report describing the occurrence of ocular toxicity induced by pertuzumab in the Chinese population and exploring the possible genetic mechanisms. These findings could provide evidence for clinicians to raise concerns about the risk of ocular toxicity with the clinical use of pertuzumab.

Exploration of the Plausible Mechanism of Ethambutol Induced Ocular Toxicity by Using Proteomics Informed Physiologically Based Pharmacokinetic (PBPK) Modeling.

PURPOSE: Ethambutol (EMB) is a first-line anti-tubercular drug that is known to cause optic neuropathy. The exact mechanism of its eye toxicity is unknown; however, proposition is metal chelating effect of both EMB and its metabolite 2,2'-(ethylenediamino)-dibutyric acid (EDBA). The latter is formed by sequential metabolism of EMB by alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). The purpose of this study was to predict the levels of drug and EDBA in the eye using physiologically based pharmacokinetic (PBPK) modeling. METHODS: The PBPK model of EMB was developed using GastroPlus. The intrinsic hepatic clearance of ALDH, calculated by the model, was scaled down using proteomics data to estimate the rate of formation of EDBA in the eye. Additionally, the comparative permeability of EMB and EDBA was assessed by employing in silico and in vitro approaches. The rate of formation of EDBA in the eye and permeability data were then incorporated in a compartmental model to predict the ocular levels of EMB and EDBA. RESULTS: The simulation results of compartmental model highlighted that there was an on-site formation of EDBA upon metabolism of EMB. Furthermore, in silico and in vitro studies revealed that EDBA possessed much lower permeability than EMB. These observations meant that once EDBA was formed in the eye, it was not permeated out and hence achieved higher ocular concentration. CONCLUSION: The on-site formation of EDBA in the eye, its higher local concentration due to lower ocular clearance and its pre-known characteristic to chelate metal species better explains the ocular toxicity shown by EMB.

Safety of intravitreal metoprolol in eyes with central serous chorioretinopathy.

PURPOSE: To investigate ocular safety of intravitreal metoprolol in eyes with central serous chorioretinopathy. METHODS: Five eyes of five patients diagnosed with chronic central serous chorioretinopathy (cCSC) previously treated unsuccessfully with oral spironolactone, micropulse laser and intravitreal anti-vascular endothelial growth factor agents were enrolled and received off-label intravitreal metoprolol (50 µg/0.05 ml). Baseline and follow-up examinations included measurement of best-corrected visual acuity (BCVA), intraocular pressure, anterior chamber cellular/flare scores, vitritis classification, fluorescein and indocyanine green angiography, spectral domain optical coherence tomography and electroretinography (ERG), recorded by means of DTL electrodes and following the standard suggested by the International Society for Clinical Electrophysiology of Vision (ISCEV). The total follow-up period was 4 weeks. RESULTS: There were no significant differences between baseline and follow-up ERG parameters: scotopic or photopic, a- and b-wave amplitude and implicit time, nor oscillatory potentials amplitude, or whatsoever. No intraocular inflammation sign was observed. In addition, BCVA showed small improvement in 4 or kept baseline values in 1 patient. The subretinal and/or intraretinal fluid volume reduced in all patients at 1 month after treatment. CONCLUSION: Patients with refractory cCSC treated with intravitreal 50 µg/0.05 ml metoprolol showed no signs of acute ocular toxicity, along with intraretinal fluid reduction and slight BCVA improvement 1 month after injection. This data suggest that intravitreal metoprolol may be a safe alternative for cCSC.

Looking into the Eyes-In Vitro Models for Ocular Research.

Animal research undoubtedly provides scientists with virtually unlimited data but inflicts pain and suffering on animals. Currently, legislators and scientists alike are promoting alternative in vitro approaches allowing for an accurate evaluation of processes occurring in the body without animal sacrifice. Historically, one of the most infamous animal tests is the Draize test, mainly performed on rabbits. Even though this test was considered the gold standard for around 50 years, the Draize test fails to mimic human response mainly due to human and rabbit eye physiological differences. Therefore, many alternative assays were developed to evaluate ocular toxicity and drug effectiveness accurately. Here we review recent achievements in tissue engineering of in vitro 2D, 2.5D, 3D, organoid and organ-on-chip ocular models, as well as in vivo and ex vivo models in terms of their advantages and limitations.

Late-onset Ocular Toxicity Presenting as Uveitis Caused by Crizotinib.

A 64-year-old female suffering from lung cancer was treated with crizotinib. Two years later, whitish massive optic disc oedema was observed in the right eye. The fluorescein angiography results were suggestive of uveitis but also revealed leakage from the optic disc, retinal veins, and capillaries in the posterior retina and the periphery. These findings remained for over a year without deterioration of vision and disappeared immediately after crizotinib was replaced with alectinib. Late-onset ocular toxicity by crizotinib was strongly suspected, given the clinical course. This is the first report precisely documenting crizotinib-induced morphological changes in the optic disc and retina.

Development of an experimental model for ocular toxicity screening in Zebrafish.

BACKGROUND: To investigate the efficacy of a novel experimental model for exploring visual function using a contrast-optomotor response (C-OMR) assay made by applying the contrast sensitivity test to the OMR assay in zebrafish. METHODS: Zebrafish larvae were treated with 0 (control), 5, 10, or 15 µM gentamicin and digoxin for 24 h at four days post-fertilization (dpf). Zebrafish larvae were assessed using the C-OMR assay with graded contrast gray-white stripes at 5 dpf, and the results were expressed as the percentage of larvae that finished swimming for 30 s (n = 20 per each group). The same C-OMR assay was repeated four times using different larvae. RESULTS: The percentage of larvae that finished swimming within 30 s was significantly reduced in larvae treated with 5, 10, and 15 µM gentamicin and 10 and 15 µM digoxin as compared to the Control groups. The C-OMR assay could distinguish that the decrease in visual function was different depending on the concentration of gentamicin and digoxin (5, 10, and 15 µM), whereas the OMR test with one contrast gray-white stripe could not. CONCLUSIONS: The method of analyzing zebrafish OMR using graded contrast gray-white stripes is more sensitive than the OMR assay alone and may be more useful for assessing the drug toxicity and eye-related diseases to improve the understanding of drug-induced ocular side effects in the clinic.

Zebrafish as an Animal Model for Ocular Toxicity Testing: A Review of Ocular Anatomy and Functional Assays.

Xenobiotics make their way into organisms from diverse sources including diet, medication, and pollution. Our understanding of ocular toxicities from xenobiotics in humans, livestock, and wildlife is growing thanks to laboratory animal models. Anatomy and physiology are conserved among vertebrate eyes, and studies with common mammalian preclinical species (rodent, dog) can predict human ocular toxicity. However, since the eye is susceptible to toxicities that may not involve a histological correlate, and these species rely heavily on smell and hearing to navigate their world, discovering visual deficits can be challenging with traditional animal models. Alternative models capable of identifying functional impacts on vision and requiring minimal amounts of chemical are valuable assets to toxicology. Human and zebrafish eyes are anatomically and functionally similar, and it has been reported that several common human ocular toxicants cause comparable toxicity in zebrafish. Vision develops rapidly in zebrafish; the tiny larvae rely on visual cues as early as 4 days, and behavioral responses to those cues can be monitored in high-throughput fashion. This article describes the comparative anatomy of the zebrafish eye, the notable differences from the mammalian eye, and presents practical applications of this underutilized model for assessment of ocular toxicity.

Neuroanatomy and Sampling of Central Projections for the Visual System in Mammals Used in Toxicity Testing.

Visual system toxicity may manifest anywhere in the visual system, from the eye proper to the visual brain. Therefore, effective screening for visual system toxicity must evaluate not only ocular structures (ie, eye and optic nerve) but also multiple key brain regions involved in vision (eg, optic tract, subcortical relay nuclei, and primary and secondary visual cortices). Despite a generally comparable pattern across species, the neuroanatomic organization and function of the visual brain in rodents and rabbits exhibit appreciable differences relative to nonrodents. Currently recognized sampling practices for general toxicity studies in animals, which are based on easily discerned external neuroanatomic landmarks and guided by extant stereotaxic brain atlases, typically will permit histopathologic evaluation of many brain centers involved in visual sensation (eg, optic chiasm, optic tract, dorsal lateral geniculate nucleus, primary and secondary visual cortices) and often some subcortical brain nuclei involved in light-modulated nonvisual activities needed for visual attention and orientation (eg, rostral colliculus in quadrupeds, termed the superior colliculus in bipeds; several cranial nerve nuclei). Pathologic findings induced by toxicants in the visual brain centers are similar to those that are produced in other brain regions.

Retinal and Lens Degeneration in New Zealand White Rabbits Administered Intravitreal TSG-6 Link Domain-Rabbit FAb Fusion Proteins.

Fusion of biologic therapeutics to hyaluronic acid binding proteins, such as the link domain (LD) of Tumor necrosis factor (TNF)-Stimulated Gene-6 (TSG-6), is expected to increase vitreous residence time following intravitreal injection and provide for long-acting delivery. The toxicity of a single intravitreal dose of free TSG-6-LD and fusion proteins of TSG-6-LD and a nonbinding rabbit antibody fragment (RabFab) were assessed in New Zealand White rabbits. Animals administered free TSG-6-LD exhibited extensive lens opacities and variable retinal vascular attenuation, correlated with microscopic findings of lens and retinal degeneration. Similar but less severe findings were present in animals dosed with the RabFab-TSG-6-LD fusion proteins. In-life ocular inflammation was noted in all animals from 7-days postdose and was associated with high anti-RabFab antibody titers in animals administered fusion proteins. Inflammation and retinal degeneration were multifocally associated with evidence of retinal detachment, and hypertrophy and migration of vimentin, glial fibrillary acidic protein, and glutamine synthetase positive Müller cells to the outer nuclear layer. Further assessment of alternative hyaluronic acid binding protein fusions should consider the potential for retinal degeneration and enhanced immune responses early in development.

Intravitreal metoprolol for circumscribed choroidal hemangiomas: a phase I clinical trial.

BACKGROUND: Choroidal hemangioma is a visual threatening condition for which treatments is neither uniform nor widely available. New management options are necessary. The purpose of this study is to assess the safety and early outcome of intravitreal metoprolol tartrate in five patients with CCH. METHODS: Five eyes of five patients diagnosed with subfoveal or peripapillary CCH and unsuccessfully treated with intravitreal anti-VEGF agents were enrolled and received off-label intravitreal injections of metoprolol (50µg/0.05 ml). Baseline and follow-up evaluations included best-corrected visual acuity, intraocular pressure measurement, assessment of anterior chamber cellular score/flare and vitritis, retinography, fundus autofluorescence, and ERG. Patients were followed for a period of 30 days. Statistical analysis involved comparison of pre- and post-treatment findings using a paired t-test. RESULTS: There was no significant difference in all ERG parameters regarding a- and b-wave amplitude and implicit time, and oscillatory potentials' maximal amplitude. There were no significant changes in visual acuity. None of the patients developed clinical signs of intraocular inflammation. The subretinal and/or intraretinal fluid improved in 3 out of 5 patients 4 weeks after the metoprolol injection. CONCLUSIONS: Patients with CCH treated with a single injection of 50µg/0.05ml intravitreal metoprolol injections showed no signs of acute ocular toxicity. This pilot study did not assess long-term retinal toxicity, different concentrations, drug resistance, and complications from repeated-intravitreal injections.