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MEDI2228 is an antibody drug conjugate (ADC) comprised of a fully human B-cell maturation antigen (BCMA) antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer. This phase 1 trial evaluated MEDI2228 in patients with relapsed/refractory (R/R) multiple myeloma (MM), who received prior treatment with approved agents from 3 classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies). Primary endpoint was safety and tolerability; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. A total of 107 patients were treated and the maximum tolerated dose (MTD) was 0.14 mg/kg Q3W. Two patients had dose-limiting toxicities (DLTs; thrombocytopenia; 0.20 mg/kg Q3W). The most frequent treatment-related adverse events were photophobia (43.9%), rash (29.0%), and thrombocytopenia (19.6%). In MTD cohort A (n = 41), the objective response rate (ORR) was 56.1%, with 1 stringent complete response, 9 very good partial responses, and 13 partial responses. ORR was 53.3% in triple refractory patients. In cohort B (n=25), ORR was 32%. Although MEDI2228 demonstrated efficacy in R/R MM, ocular toxicity precluded further development of this drug. KEY POINTS: MEDI2228 is an ADC comprised of a fully human anti-BCMA antibody conjugated to the cytotoxic PBD payload, tesirine. MEDI2228 monotherapy demonstrated efficacy across all dose levels; and responses were observed in patients with triple refractory MM. This study further validates BCMA as a target for ADC-based therapy in MM; ocular toxicity precluded further clinical development. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) are an emerging field of cancer treatments that are becoming more widespread in their use. However, there are potential ocular toxicities associated with these drugs that ophthalmologists need to be aware of to better maintain ocular health as patients undergo rigorous medical treatment for their conditions. While many ADCs have been approved by the Food and Drug Administration (FDA), many subsequent reports have been published regarding additional ocular side effects these drugs may cause. This review provides ophthalmologists with a practical guide on how to treat ocular toxicities associated with all FDA-approved ADCs to date. The potential pathophysiology of side effects is also discussed. [ABSTRACT FROM AUTHOR]

Objective: The widespread use of nanoparticles in recent years has increased the risk of ocular exposure. zinc oxide (ZnO) is widely used in the field of cosmetics because of its unique chemical properties. The application of graphene oxide (GO) as an emerging nanomaterial in the field of eye drops is also gradually emerging. Currently, research on ZnO and GO eye exposure mainly focuses on application or toxicity to optic nerve cells. There's less study on corneal wound healing effects. and the previous research hasn't compared ZnO and GO corneal toxicity. Methods: We systematically established a complete chain study of in vitro and in vivo experiments and mouse corneal injury model, and comprehensively evaluated the ocular safety and toxicity of ZnO and GO. Results: We found that 50 ug/mL GO and 0.5 ug/mL ZnO can reduce human corneal epithelial cells (HCEpiC) viability in a concentration-dependent manner. Short-term repeated exposure to ZnO can cause sterile inflammation of the cornea with concentration-dependence, while GO have not been significantly altered. 50 ug/mL ZnO could significantly delay the healing of corneal wounds, while GO did not change wound healing. Conclusion: The toxic effect of ZnO is higher than that of GO. Inflammatory signal transduction, oxidative stress and apopnano zitosis are involved in the ocular toxicity injury process of nanoparticles. Research can provide a judgement basis for people's eye health and eye protection risk control. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and tolerability of pooled human immune globulins, Flebogamma® 5% DIF and Flebogamma® 10% DIF, administered by topical ophthalmic instillation to New Zealand White (NZW) rabbits. Methods: Male NZW rabbits were used in this study. In the acute single dose tolerability study, rabbits (n = 12) received a single topical dose of Flebogamma® 5% DIF. In the two-week repeated-dose tolerability study, rabbits (n = 5 for each group) were administered either Flebogamma® 5% DIF or Flebogamma® 10% DIF by topical bilateral administration four times daily (q.i.d.) between 8 am and 6 pm for a period of two weeks. Full ophthalmic examinations were conducted to evaluate ocular tolerability at baseline, Day 7, and Day 14. Results: In the acute single dose study, mild hyperaemia was observed in 1 out of 4 eyes at each 4 h and 24 h post-instillation of Flebogamma® 5% DIF. In the repeated dose study, no ocular signs were detected after q.i.d. topical instillation of Flebogamma® 5% DIF, while Flebogamma® 10% DIF resulted in mild hyperaemia in 8 out of 10 eyes on Day 7, and 5 out of 10 eyes on Day 14. No positive corneal fluorescein staining was detected. Schirmer tear test results were unremarkable. No other ocular signs were observed. Administration of immune globulins had no effect on intraocular pressure. Conclusions: Flebogamma® 5% DIF and Flebogamma® 10% DIF were well-tolerated by NZW rabbits following single and repeat dose topical ophthalmic administration, supporting the future development of topical pooled human immune globulins for the treatment of ocular surface disease. [ABSTRACT FROM AUTHOR]

Objective: Miltefosine stands as the sole oral medication approved for the treatment of leishmaniasis. The appearance of severe ophthalmic toxicities induced by miltefosine in the context of leishmaniasis treatment is a matter of significant concern. The main objective of this study is to present a comprehensive summary of the ophthalmic adverse effects associated with miltefosine when used in the treatment of leishmaniasis. Methods: A systematic search was performed on PubMed, ScienceDirect, Embase, Scopus, and Google Scholar, covering articles from inception up to June 2023, without language restrictions, to identify relevant studies documenting ocular toxicity following miltefosine treatment for leishmaniasis. Results: A total of eight studies involving 31 leishmaniasis patients who developed ocular toxicities while undergoing miltefosine treatment were included in the analysis. These studies were conducted in various regions, with five originating from India, two from Bangladesh, and one from Nepal. Patients presented a spectrum of ophthalmic complications, including uveitis, keratitis, scleritis, and Mooren's ulcer. Commonly reported symptoms included pain, redness, excessive tearing, partial vision impairment, permanent blindness, light sensitivity, and the appearance of white spots on the eye. On average, patients received miltefosine treatment for a duration of 47 days before experiencing the onset of ocular problems. It is important to note that the risk of ocular toxicities increases with prolonged use of miltefosine. Conclusions: Therefore, to mitigate the potential for irreversible damage to the eyes, it is imperative that all individuals undergoing miltefosine therapy undergo regular eye examinations. [ABSTRACT FROM AUTHOR]

Systemic use of Ivermectin has been reported to incite blindness in humans and veterinary patients. This study was designed to investigate the systemic and intravitreal effect of Ivermectin on ocular and retinal health and its attenuation with topical Dexamethasone. Systemic injection of Ivermectin@ 1.6 mg/kg S/C was administered, thrice a week for three weeks to New Zealand White rabbits (N = 4) with and without topical drops of Verapamil (N = 4). Pre and post-treatment ocular examination was conducted. At the end of three weeks the eyes were collected for histopathology. 0.2 ml of Ivermectin solution (1.6 mg/ml) was injected intravitreally in one eye of the rabbit (N = 8), Half the rabbits received 0.1% dexamethasone drops thrice daily for 7 days, while the controls received PBS. Pre and post-treatment, detailed examination was conducted, which included the Schirmer Tear test, Fluorescein staining, Intraocular pressure, slit lamp biomicroscopy and fundus photography. The retina was harvested for histopathological and tunnel assay. Systemic therapy with Ivermectin, with and without Verapamil did not incite any adverse response in the eye. Intravitreal Ivermectin evoked severe uveitis 4/4, cataract 3/4, corneal erosion 3/4 eyes and severe inflammatory response. Eyes that received dexamethasone were rescued from the adverse changes as demonstrated clinically, by histopathology and prevention of apoptosis. Intravitreal Ivermectin incites severe inflammatory response. Topical dexamethasone counters the ocular toxicity incited by Ivermectin. [ABSTRACT FROM AUTHOR]

Purpose: Favipiravir (FAV) used against COVID-19 is an antiviral drug that causes adverse reactions, such as hyperuricaemia, liver damage, and hematopoetic toxicity. The aim of the study was to investigate the systemic and ocular side-effects of FAV in rats, for the first time.Materials and methods: A total of 18 albino male Wistar rats were used in the study. The rats were divided into 3 groups as the healthy group (HG), the group given 50 mg/kg/day favipiravir (FAV50), and the group given 200 mg/kg/d favipiravir (FAV200). These doses were given to the experimental groups for one week. At the end of the experiment histopathological examinations were performed on the conjunctiva and sclera of the eye. In addition, malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), interleukin-1β (IL-1β), and tumor necrosis factor alpha (TNF-α) levels were measured in blood samples taken from rats. Results: Compared to HG, the MDA (1.37 ± 0.61 vs. 4.82 ± 1.40 µmol/mL), IL-1β (2.52 ± 1.14 vs. 6.67 ± 1.99 pg/mL), and TNF-α levels (3.28 ± 1.42 vs. 8.53 ± 3.06 pg/mL) of the FAV200 group were higher. The levels of tGSH (7.58 ± 1.98 vs. 2.50 ± 0.98 nmol/mL) and SOD (13.63 ± 3.43 vs. 3.81 ± 1.43 U/mL) the FAV200 group were lower than the HG (p < 0.05, for all). The degree of damage to the cornea and sclera of the FAV200 group was quite high according to HG (p < 0.001). Conclusions: FAV can cause damage to rat conjunctiva and sclera by increasing oxidant stress and inflammation at high dose. [ABSTRACT FROM AUTHOR]

Snakebite envenoming is a major public health issue in developing, often agricultural-based, tropical countries, which causes substantial mortality and morbidity. Most studies have been conducted on well-known toxic effects such as neurotoxicity, cytotoxicity, and hemotoxicity, however, there is scarce information on their indirect effects on the eye. In this review, we provide an overview of ocular pathologies caused by snakebite envenoming. In total, 65 cases, described in 42 case reports and series, were identified in the PubMed and Embase databases. Most reported ocular toxicities/disorders after snakebite envenoming were ophthalmoplegia (12 cases), intra- and peri-ocular hemorrhages (9 cases), and acute glaucoma (13 cases). We also discuss the possible mechanisms for these ocular pathologies. Interestingly, optic neuropathy might be an adverse effect of antivenom instead of directly being caused by envenoming. We prompt recognition of this largely overlooked topic within the field of snakebite, and further stress the need to combat this neglected tropical disease. [ABSTRACT FROM AUTHOR]

Mirvetuximab soravtansine (mirvetuximab) is an antibody drug conjugate (ADC) comprised of a humanized folate receptor alpha (FRα)-binding monoclonal antibody attached via a cleavable linker to the cytotoxic maytansinoid molecule, DM4. FRα is expressed in several epithelial cancers, including high grade serous ovarian cancer (HGSOC). Mirvetuximab received accelerated approval by the United States Food and Drug Administration (FDA) in November 2022 based on the results of the SORAYA trial, which tested mirvetuximab for the treatment of patients with recurrent platinum resistant HGSOC with high FRα expression and showed an overall response rate (ORR) of 32.4% and a median duration of response of 6.9 months. Mirvetuximab toxicities included low grade ocular and gastrointestinal toxicities. The National Comprehensive Cancer Network (NCCN) ovarian cancer 2023 guidelines adopted mirvetuximab as 2A, and mirvetuximab combined with bevacizumab as 2B, recommendations. This manuscript will review the preclinical and clinical development of mirvetuximab, the toxicities associated with mirvetuximab and mitigation strategies, and future applications of mirvetuximab. Mirvetuximab represents the first biomarker-directed therapy with an indication specifically for the treatment of PROC. The efficacy and favorable safety profile support further development of mirvetuximab and mirvetuximab combinations in platinum sensitive and newly diagnosed ovarian cancer. [ABSTRACT FROM AUTHOR]

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-1β (IL-1β), 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. [ABSTRACT FROM AUTHOR]

Mesothelin (MSLN) is an attractive therapeutic target for antibody drug conjugates (ADC) because of significant differences in expression pattern between diseased and normal tissues. RC88-ADC is a novel ADC, targeting MSLN, and inhibits tumor growth significantly in mice xenograft models. We performed an 11-week repeated dose toxicity study of RC88-ADC via intravenous injection in Cynomolgus Monkeys with an 8-Week recovery period according to International Conference on Harmonization (ICH) S9 and S6(R1). RC88-ADC was administered to groups of 5 male and 5 female monkeys at dose levels of 2.5, 5, and 10 mg/kg/2 weeks, meanwhile vehicle, naked antibody, small molecule groups were set up as the control. 4 animals died in 10 mg/kg group of RC88-ADC. The clinical symptoms mainly included ocular toxicity, weight loss and food intake decrease in the middle and high dose groups of RC88-ADC. RC88-ADC caused dose-related reversible myelosuppression, manifested as hematologic toxicity, which was consistent with the small molecule toxicity profile of its coupling. The highest non-severely toxic dose of RC88-ADC was 5 mg/kg in monkeys after repeated dosing. Nonetheless, the integrated analysis showed that RC88-ADC demonstrated an acceptable safety profile and provided an improved treatment window. These results pave the way for further investigation of RC88-ADC in humans. [ABSTRACT FROM AUTHOR]

Cyclosporine A (CsA) has been used as a topical treatment for various ocular surface diseases including dry eye disease (DED). Several CsA formulations are available as solutions or emulsions. This review describes the development and the preclinical testing of a cationic oil-in-water emulsion of CsA (CE-CsA) in terms of pharmacodynamics, pharmacokinetics, and ocular tolerance. Due to the cationic charge, CE electrostatically interacts with the negatively-charged ocular surface, improving its residence time. Compared to other CsA formulations, CE-CsA and CE itself were found to reduce the signs and symptoms of DED, by restoring tear film stability and properties, and inhibiting the expression and secretion of pro-inflammatory factors. No delay in wound healing nor ocular toxicity were observed using CE formulations. these findings indicate that the type of vehicle can significantly affect the performance of eye drops and play an ancillary role in DED treatment. CE appears as a promising strategy to deliver drugs to the ocular surface while maintaining its homeostasis. [ABSTRACT FROM AUTHOR]

To report a case of BRAF/MEK inhibitor-associated multifocal choroiditis that recurred after medication re-exposure and resolved after discontinuing BRAF/MEK inhibition and administering local steroid therapy. A 32-year-old woman with metastatic cutaneous melanoma on dabrafenib/trametinib presented with bilateral anterior uveitis and new bilateral multifocal chorioretinal scars. The anterior uveitis resolved after a course of topical steroids. She presented 18 months later with reactivation of bilateral multifocal choroiditis after starting encorafenib/binimetinib 1 month prior. The chorioretinal lesions appeared elevated with associated vitreous cell. Indocyanine angiography showed numerous foci of new choroiditis, more pronounced in the left eye. Encorafenib/binimetinib was discontinued and a subtenon triamcinolone injection was administered to the left eye. Her symptoms improved and the choroiditis resolved. BRAF/MEK inhibitors may be associated with ocular toxicity manifesting as multifocal choroiditis. The increasing use of these agents and risk of visual impairment warrants early detection and management. [ABSTRACT FROM AUTHOR]

The purpose of this research was to explore the antifungal and anti-inflammatory effects of perillaldehyde (PAE) in Aspergillus fumigatus (A. fumigatus) keratitis and the underlying mechanism. The biofilm formation, adherence assay, and propidium iodide uptake test were used to determine the possible mechanism of PAE in terms of antifungal effects in vitro. The severity of corneal infection was evaluated by clinical scores. The immunofluorescence staining (IFS) was adopted to detect the number of macrophages in infected corneas. Draize test was performed to assess the ocular toxicity of PAE. Real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot reflected the expression of inflammatory cytokines and Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) in mice corneas and RAW264.7 cells. PAE was able to inhibit the formation of biofilm, reduce conidial adhesion, and damage the integrity of membranes to exert antifungal activity. In C57BL/6 mice models, PAE alleviated the severity of infected corneas, reduced the recruitment of macrophages and had low ocular toxicity. In addition, the mRNA and protein levels of TNF-α, CCL-2, and LOX-1 could be significantly decreased by the application of PAE after A. fumigatus infection in vivo and in vitro. Our study indicated that PAE protected against A. fumigatus keratitis by reducing fungal load, accumulation of macrophages, and inhibiting the expression of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background:Conventional delivery systems like solution and suspension are commonly used for the treatment of ocular diseases but have low corneal residence time and hence the duration of effect is limited. These drawbacks of conventional systems can be reduced by preparing bioadhesive chitosan (CH) coated noisome. Methods: Niosomes (NIM) of carteolol (CT) were developed by the thin-film hydration method and optimised by the Box-Behnken statistical design. Further, the optimised CT-NIM was coated with CH to enhance the ocular residence time. The optimised formulation was evaluated for vesicle size, entrapment efficiency, and in-vitro drug release and transcorneal permeation, histopathology, etc. Results: CT-NIM-opt showed the vesicle size and entrapment efficiency of 235 ± 3.54 nm, and 70.45 ± 0.87%, respectively. DSC spectra exhibited that CT was completely encapsulated into the CH-CT-NIM matrix. Drug release from CH-CT-NIM-opt was more sustained (68.28 ± 4.2%) than CT-NIM (75.69 ± 4.5% in 12 h) and CT solution (99.89 ± 2.8% in 4 h). The CH-CT-NIM-opt represented a strong bio-adhesion (89.76 ± 3.6%) than CT-NIM-opt (15.65 ± 3.4%). The permeation flux exhibited 1.13-fold higher permeation than CT-NIM and 3.23 fold than CT solution. The corneal hydration was found to be within the limit value. The histopathology study exhibited no structural damage to the cornea. HET-CAM results showed zero scores indicating no bleeding or haemorrhage. CH-CT-NIM-opt was found to be isotonic and exhibited good stability when stored at 4 °C for the stated duration of time. Conclusion: The above findings suggested that NIM can be a potential carrier for the delivery of CT with better ocular residence time. [ABSTRACT FROM AUTHOR]

This study aimed to determine if the corneal endothelium was affected by chemotherapy. Chemotherapy patients were recruited to undergo specular microscopy before treatment and again at 1- and 2-year follow-up visits. One eye per patient, per follow-up, was selected for comparison to baseline. Forty-six volunteers completed baseline and at least one follow-up assessment. From 51 eyes, there was no significant change in endothelial cell density for 41 eyes assessed at one year (MD = 0.73%, 95% CI −1.33 to 2.78%) and 18 eyes at two years (MD = 0.31%, 95% CI −3.53 to 4.15%). Although other studies have shown that chemotherapy can adversely affect the corneal epithelium, this study showed no measurable change in endothelial cell density. [ABSTRACT FROM AUTHOR]

Aim: Cisplatin is a widely used and highly effective anti-cancer agent and one of the limiting side effects of cisplatin is ocular toxicity. Achillea millefolium, also known as yarrow, is a plant that has been used for many years to treat various health problems including chemotherapy-related toxicities. Methods: The present investigation was designed to evaluate the biochemical, molecular and histopathological effects of Achillea Millefolium on cisplatin-induced oxidative and inflammatory ocular damage in rats. Twenty-four adult male rats were assigned randomly to four groups (n = 6) as (1) control, (2) cisplatin (7 mg/kg, intraperitoneally), (3) Cisplatin + Achillea millefolium (200 mg/kg, orally for 14 consecutive days), (4) Cisplatin + Achillea millefolium (400 mg/kg, orally for 14 consecutive days). Levels of total antioxidant capacity and total oxidant status, SOD, MDA, IL-1β, and IL-10 were measured in ocular tissue. The mRNA expressions of TNF-α, nuclear factor kappa B and Caspase-3 were evaluated. Also, ocular sections were evaluated histopathologically. Results: Achillea Millefolium upregulated ocular antioxidant enzymes and downregulated inflammation. The SOD activity and total antioxidant capacity increased whereas total oxidant status and MDA levels decreased significantly at high dose group. High dose Achillea millefolium treatment reduced the IL-1β concentrations, whereas IL-10 levels increased significantly in that group. Moreover, we observed that Achillea millefolium restored ocular histopathological structure and significantly suppressed apoptosis by reducing the expression of Caspase-3. Conclusion: Collectively, our results suggest that Achillea millefolium have protective effects against cisplatin-induced ocular toxicity and is a promising adjuvant therapy with the potential to prevent cisplatin related ocular toxicity. [ABSTRACT FROM AUTHOR]

Background: We investigated the ocular manifestations in patients with Kabuki syndrome(KS). Methods: A retrospective chart review was performed in 10 patients with KS were referred to the Department of Ophthalmology for evaluation of ocular manifestations. Data were collected from patient interviews, clinical examinations, and laboratory investigations. Ophthalmologic examinations included best-corrected visual acuity, intraocular pressure, anterior segment, adnexal examination, and dilated fundus examination. Results: Mutations in the KMT2D gene were identified in all of the 10 patients with KS. No deletion or point mutation was found in the KDM6A gene. In our patients, 20% had ptosis, 60% had strabismus, 90% had lid changes and 10% had amblyopia. Five patients did not undergo the visual acuity test due to intellectual disability. Conclusions: Ophthalmic abnormalities are frequently associated with KS. The importance of ophthalmological examination in all patients with KS for early detection of ocular anomalies to prevent visual impairment cannot be underemphasized. Abbreviations: KS: Kabuki syndrome [ABSTRACT FROM AUTHOR]

To investigate the efficacy of RSH-12, a novel selective matrix metalloproteinase 9 (MMP-9) inhibitor peptide in rabbit models of dry eye syndrome (DES). In vitro toxicity of RSH-12 on cultured human corneal fibroblasts was investigated with MTT. Ocular toxicity of RSH-12 was investigated by clinical examinations, histology, and TUNEL assay. Experimental model of dry eye was induced by 1.0% atropine sulfate administration followed after 15 min by treatment with PBS, RSH-12, and Restasis in individual groups, three times a day for 7 days. In addition to performing Schirmer's test for evaluating basic tear secretion and tear break-up time test for investigating tear stability, the occurrence of superficial punctate keratopathy was also investigated in the study groups. MTT assay demonstrated that RSH-12 was not toxic to human corneal fibroblasts in different concentrations. During the administration of atropine, TBUT values and tear volume were decreased in vehicle group while these indices improved significantly in groups treated with RSH-12 in a promising manner. RSH-12 increased the mean value of tear volume from 4.85 to 10.75 mm (P =.0001) and mean of TBUT values from 20.3 s to 34.5 s (P =.0001) compared with the vehicle. In contrast to the presence of severe superficial punctate keratopathy in the controls, no significant dotted staining was observed in the RSH-12 and Restasis groups. These outcomes propose that RSH-12 has a therapeutic effect in the rabbit model of dry eye and might be a potential treatment for severe DES. [ABSTRACT FROM AUTHOR]

To investigate the combined toxic effect of ultraviolet (UV) radiation and benzalkonium chloride (BAK), a common preservative in ophthalmic eye drops, on human corneal epithelial cells (HCEC). Cultured HCEC were exposed to different combined and separate UV (280–400 nm) and BAK solutions at relevant human exposure levels. Human exposure to UV can occur before, during, or after eye drop installation, therefore, three different orders of ocular exposures were investigated: UV and BAK at the same time, UV first followed by BAK, and BAK first followed by UV. Control treatments included testing HCEC exposed to BAK alone and also HCEC exposed to UV alone. In addition, phosphate-buffered saline (PBS) was used as a negative control. After exposure, cell metabolic activity of the cultures was measured with PrestoBlue, and cell viability was determined using confocal microscopy with viability dyes. BAK alone reduced the metabolic activity and cell viability of HCEC in a dose- and time-dependent manner. UV alone at a low dose (0.17 J/cm2) had little toxicity on HCEC and was not significantly different from PBS control. However, UV plus BAK showed combined effects that were either greater than (synergistic) or equal to (additive) the sum of their individual effects. The synergistic effects occurred between low dose UV radiation (0.17 J/cm2) and low concentrations of BAK (0.001%, 0.002%, 0.003%, and 0.004%). This investigation determined that at relevant human exposure levels, the combination of UV radiation (280–400 nm) and BAK can cause synergistic and additive toxic effects on human corneal epithelial cells. This finding highlights the importance of considering the combined ocular toxicity of BAK and solar radiation in the risk assessment of BAK-preserved ophthalmic solutions. [ABSTRACT FROM AUTHOR]

OptiSafe is an in chemico test method that identifies potential eye irritants based on macromolecular damage following test chemical exposure. The OptiSafe protocol includes a prescreen assessment that identifies test chemicals that are outside the applicability domain of the test method and thus determines the optimal procedure. We assessed the usefulness and limitations of the OptiSafe test method for identifying chemicals not requiring classification for ocular irritation (i.e. bottom-up testing strategy). Seventeen chemicals were selected by the lead laboratory and tested as an independent study. Ninety-five unique coded chemicals were selected by a validation management team to assess the intra- and interlaboratory reproducibility and accuracy of OptiSafe in a multilaboratory, three-phased validation study. Three laboratories (lead laboratory and two naïve laboratories) evaluated 35 chemicals, with the remaining 60 chemicals evaluated by the lead laboratory only. Test method performance was assessed by comparing classifications based on OptiSafe results to classifications based on available retrospective in vivo data, using both the EPA and GHS eye irritation hazard classification systems. No prospective in vivo testing was conducted. Phase I testing of five chemicals showed that the method could be transferred to naïve laboratories; within-lab reproducibility ranged from 93% to 100% for both classification systems. Thirty coded chemicals were evaluated in Phase II of the validation study to demonstrate both intra- and interlaboratory reproducibility. Intralaboratory reproducibility for both EPA and GHS classification systems for Phase II of the validation study ranged from 93% to 99%, while interlaboratory reproducibility was 91% for both systems. Test method accuracy for the EPA and GHS classification systems based on results from individual laboratories ranged from 82% to 88% and from 78% to 88%, respectively, among the three laboratories; false negative rates ranged from 0% to 7% (EPA) and 0% to 15% (GHS). When results across all three laboratories were combined based on the majority classification, test method accuracy and false negative rates were 89% and 0%, respectively, for both classification systems, while false positive rates were 25% and 23% for the EPA and GHS classification systems, respectively. Validation study Phase III evaluation of an additional 60 chemicals by the lead laboratory provided a comprehensive assessment of test method accuracy and defined the applicability domain of the method. Based on chemicals tested in Phases II and III by the lead laboratory, test method accuracy was 83% and 79% for the EPA and GHS classification systems, respectively; false negative rates were 4% (EPA) and 0% (GHS); and false positive rates were 40% (EPA) and 42% (GHS). Potential causes of false positives in certain chemical (e.g. ethers and alcohols) or hazard classes are being further investigated. The OptiSafe test method is useful for identifying nonsurfactant substances not requiring classification for ocular irritancy. OptiSafe represents a new tool for the in vitro assessment of ocular toxicity in a tiered-testing strategy where chemicals can be initially tested and identified as not requiring hazard classification. [ABSTRACT FROM AUTHOR]

At first blush, methanol poisoning may be seen as an arcane problem generally associated with rapid ocular neuropathy. The emerging clinical reality is that methanol poisoning around the globe has claimed increasingly large numbers of deaths largely due to the press of poverty and the delay in suspecting and diagnosing methanol toxicity. With the onset of the COVID-19 pandemic, false beliefs about methanol's preventive potential vs viral infection of have arisen. In March of this year, more than 300 Iranians died and 1000 became ill after consuming methanol in the hope that it would protect them against the novel coronavirus. We review the context and magnitude of methanol toxicity, pathophysiology, principal medical issues, and human variability in metabolism. While toxicologists and clinicians may need to be especially attentive to this problem, it is becoming clear that the social and economic underpinnings of the methanol poisoning crisis must be actively and urgently explored and managed as vigorously as its toxicologic and pathophysiologic components. [ABSTRACT FROM AUTHOR]

Stickler syndrome is a collagenopathy caused by mutations in the genes COL2A1 (STL1) or COL11A1 (STL2). Affected patients manifest ocular, auditory, articular, and craniofacial manifestations in varying degrees. Ocular symptoms include myopia, retinal detachment, cataract, and glaucoma. The aim of this systematic review was to evaluate the prevalence of ocular manifestations and the outcome of prophylactic treatment on reducing the risk of retinal detachment. A systematic literature search was performed in the PubMed database. Information on the cross-study prevalence of myopia, retinal detachment, cataract, glaucoma, visual impairment, severity and age of onset of myopia and retinal detachments. Studies that reported on the outcome of prophylactic treatment against a control group were explored. 37 articles with 2324 individual patients were included. Myopia was found in 83% of patients, mostly of a moderate to severe degree. Retinal detachments occurred in 45% of patients. Generally, the first detachment occurred in the second decade of life in STL1 patients and later in STL2. Cataracts were more common in STL2 patients, 59% versus 36% in STL1. Glaucoma (10%) and visual impairment (blind: 6%; vision loss in one eye: 10%) were rare. Three studies reported on the effect of prophylactic treatment being protective. Ocular manifestations are common in Stickler patients, but the comparison between studies was difficult because of inconsistencies in diagnostic and inclusion criteria by different studies. Sight-threatening complications such as retinal detachments are common but although prophylactic therapy is reported to be effective in retrospective studies, evidence from randomized trials is missing. [ABSTRACT FROM AUTHOR]

Background: Hydroxychloroquine retinal toxicity can occur in up to 7.5% of patients receiving treatment; however, possible genetic risk factors are poorly understood. The main objective of the study was to explore candidate genetic risk factors for retinal toxicity. Materials and Methods: Case–control study of patients with confirmed hydroxychloroquine retinal toxicity identified through ophthalmology departments of tertiary care hospitals and private ophthalmic practice in Australia. Participants were 26 Caucasian patients with hydroxychloroquine retinal toxicity who were matched with control subjects for age, gender, treatment duration and indication for hydroxychloroquine treatment. Participants underwent clinical examination, optical coherence tomographic scanning, automated field testing and whole exome sequencing of DNA extracted from saliva or blood. Outcome measures were grade of hydroxychloroquine toxicity and mutations in a panel of 40 candidate genes. Results: No susceptibility or protective factors were identified in either the cohort as a whole or any subset of patients. Conclusions and relevance: Further larger studies, with whole-exome analysis and consideration of additional modifying genes are needed. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of bilateral retinal inflammation under long-term therapy with dabrafenib/trametinib for metastatic cutaneous melanoma.Methods: Retrospective chart review.Results: A 59-year-old patient with metastatic cutaneous melanoma diagnosed in 2004 under treatment with dabrafenib/trametinib since 2014 presented to our department with intraretinal hemorrhage and extrafoveal macula edema on the right eye and optic disc swelling on the left eye. The patient did not report visual complaints. After cessation of dabrafenib/trametinib and subconjunctival and intravitreal corticosteroid injections, optic disc swelling on the left eye recovered after 6 months. The macula edema on the right eye was treated with one intravitreal anti-VEGF (vascular endothelial growth factor) injection after encroaching upon the fovea 10 months after initial presentation. The final visual acuity was 20/20 on both eyes.Conclusion: Even after years of treatment with low dose dabrafenib/trametinib, ocular toxicity can develop. Such cases can respond well to intravitreal corticosteroids. [ABSTRACT FROM AUTHOR]

Introduction: Since the approval of immune checkpoint inhibitors (ICIs), there has been continuing and significant progress in urothelial cancer (UC) treatment. However, only about one fifth of UC patients respond to ICI. Recently, erdafitinib was developed for treating locally advanced or metastatic UC (mUC) with FGFR3 or FGFR2 alterations, accounting for 15–20% of patients. Erdafitinib is the first targeted therapy ever approved for mUC. Areas covered: This review summarizes the preclinical and clinical data on erdafitinib for UC. PubMed search and relevant articles presented at international conferences were used for the literature search. Expert opinion: The FDA approval of erdafitinib provided a new treatment option for FGFR-altered UC progressing on platinum-based chemotherapy. It is not clear whether FGFR inhibitor is a preferred second-line treatment choice to ICI. Compared to ICI, erdafitinib has a better response rate in patients with visceral metastases. However, a shorter duration of response and toxicity profile of erdafitinib, particularly ocular toxicity, is an important consideration. Regular eye exams are recommended by the FDA. Tumor profiling during upfront therapy may help identify those who benefit at the time of progression. In summary, a high unmet need remains for new drugs in chemotherapy- and ICI-refractory UC. [ABSTRACT FROM AUTHOR]

Background: Congenital disorders of glycosylation (CDG) are a group of hereditary multisystem disorders characterized by hypoglycosylation of glycoproteins. CDG type I results in a defect in the assembly of lipid-linkedoligosaccharides or their transfer onto nascent glycoproteins. Ocular abnormalities are common in CDG, but there is no report of detailed ophthalmologic evaluation in patients with CDG type Ig in the literature. Materials and Methods: Retrospective chart review of a case of CDG type Ig with novel variant in the associated gene: ALG12. Results: In addition to typical systemic findings of CDG, our case was found to have exotropia, bilateralcataracts, and retinitis pigmentosa with extinguished electroretinography in photopic and scotopic conditions. Conclusions: We hope to extend the understanding of ALG12-related CDG type Ig with these ophthalmologic observations. [ABSTRACT FROM AUTHOR]

Objective: To determine possible associations between long-term HCQ use and corneal changes in patients who used HCQ for at least 3 years. Materials and methods: The study included 62 healthy controls and 62 consecutive patients who used HCQ for the treatment of rheumatologic disease and were referred to the ophthalmology department between August 2018 and November 2018 for HCQ retinal toxicity screening. Central corneal thickness (CCT), corneal endothelial cell density (ECD), the coefficient of variation (CV) of cell size, and the percentage of hexagonal cells (HEX%) were measured to evaluate changes in the cornea. Results: The mean age of the patient group and control group was 50.10 ± 10.91 and 50.53 ± 10.67 years, respectively. The mean ECD was 2742 ± 347 (cells/mm2) in the patient group and 2875 ± 188 cells/mm2 in the control group. There was a significant difference between groups (p = 0.01). The mean CCT was 567.05 ± 32.35 µm in the patient group and 540.15 ± 38.50 µm in the control group. CCT was significantly higher in the patient group compared with control group (p < 0.001). There was no significant difference between groups in terms of mean CV and HEX values (p > 0.05). Conclusions: Patients using long-term HCQ demonstrated lower ECD and higher CCT than the control group. However, the CV of cell sizes and the HEX % values were not significantly different from the controls. [ABSTRACT FROM AUTHOR]

Purpose: To determine the ocular and systemic toxicity of a novel, topically applied ophthalmic gel preparation of povidone-iodine (PVP-I) and dimethylsulfoxide (DMSO) in Dutch-Belted rabbits. Materials and Methods: Rabbits were administered doses of the test material or control by ocular instillation four times/eye/day, 7 d/week, for a minimum of 14 consecutive days. Dosing consisted of instillation of 50 µl of the appropriate test material solution or control material (saline) into each eye of the rabbit. On the last dose of the day, 250 µl of the appropriate test material solution or control material was applied to the eyelids of each eye. Results: Treatment-related clinical signs observed during the study were limited to mild non-inflammatory changes to the eyelids and eyelashes. There was no associated pathology upon histological examination of ocular or systemic tissues. Body weights and body weight gains were unaffected by treatment. Evaluation of clinical pathology profiles (haematology, coagulation, and clinical chemistry) did not reveal any test article-related toxicity and there were no macroscopic or microscopic findings at the terminal sacrifice. Conclusions: The compositions studied in the present investigation were developed to enable repeat-dosed application to the ocular surface and periocular skin surfaces without ocular, skin or systemic toxicity. The PVP-I/DMSO compositions tested did not cause any toxicity to the ocular surface or the periocular skin. Systemic toxicity from the preparations under study was not observed in any histological or gross pathological examination. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the epidemiology of ocular exposures reported to poison control centers in the United States. Methods: A retrospective analysis of ocular exposures from 2000 to 2016 was conducted using National Poison Data System data. Results: United States poison control centers received 1,436,683 reports of ocular exposures during 2000-2016, averaging 7,043 exposures per month. The annual frequency of ocular exposures declined significantly by 37.2% from 2006 to 2016. The ocular exposure rate per 10,000 US residents was highest among children < 6 years of age (10.7), particularly among 2-year-olds (20.5), and was lowest among adults ≥ 20 years of age (1.9). The majority of the exposures resulted in minor effects (51.4%). Among exposed individuals, 23.0% were treated and released and 0.3% were admitted to a healthcare facility. Household cleaning products (22.2%), cosmetics/personal care products (15.7%), and pesticides (7.4%) were the most common substance categories associated with exposures, but exposures to building and construction products (18.1%), industrial cleaners (14.9%), and chemicals (14.1%) resulted in a higher percentage of moderate or major effects. In addition, exposures to alkaline substances had a higher percentage of moderate or major effects. Conclusion: Although the annual frequency of ocular exposures declined during the last decade, the number of exposures remains high, particularly among young children. The commonly associated substance categories identified in this study represent important preventable sources of morbidity. [ABSTRACT FROM AUTHOR]

Introduction: Ocular dysfunctions and toxicities induced by antiepileptic drugs (AEDs) are rarely reviewed and not frequently received attention by treating physicians compared to other adverse effects (e.g. endocrinologic, cognitive and metabolic). However, some are frequent and progressive even in therapeutic concentrations or result in permanent blindness. Although some adverse effects are non-specific, others are related to the specific pharmacodynamics of the drug. Areas covered: This review was written after detailed search in PubMed, EMBASE, ISI web, SciELO, Scopus, and Cochrane Central Register databases (from 1970 to 2019). It summarized the reported ophthalmologic adverse effects of the currently available AEDs; their risks and possible pathogenic mechanisms. They include ocular motility dysfunctions, retinopathy, maculopathy, glaucoma, myopia, optic neuropathy, and impaired retinal vascular autoregulation. In general, ophthalmo-neuro- or retino-toxic adverse effects of AEDs are classified as type A (dose-dependent), type B (host-dependent or idiosyncratic) or type C which is due to the cumulative effect from long-term use. Expert opinion: Ocular adverse effects of AEDs are rarely reviewed although some are frequent or may result in permanent blindness. Increasing knowledge of their incidence and improving understanding of their risks and pathogenic mechanisms are crucial for monitoring, prevention, and management of patients' at risk. [ABSTRACT FROM AUTHOR]

Purpose: To correlate the anatomical extent of ocular surface toxicity due to colours using anterior segment optical coherence tomography (ASOCT) with the clinical findings. Methods: Patients presenting to our emergency department with ocular colour toxicity during the Holi festival celebrations from March 2 2018 to March 5 2018 were assessed for any adnexal, conjunctival, corneal, and anterior chamber findings, as well as findings on anterior segment optical coherence tomography. Results: A total of 21 patients were observed. The average age was 23 years with 16 patients being male (76.19%). Bilateral ocular involvement was more common (13 patients, 61.90%). Clinically, the corneal changes included localized punctate epitheliopathy (type I) in 12 patients (57.14%) and diffuse punctate epitheliopathy admixed with a variable sized epithelial defect (type II) in the other 9 patients (42.85%). The visual acuity among the former group varied from 6/6 to 6/9, whereas for the latter, it ranged from 6/12 to 6/24. On ASOCT in both the types, the superficial stromal involvement was noted up to 60 microns. Interestingly in two patients with type II corneal involvement, anterior segment involvement was noted in the form of staining of the lens capsule and dense anterior chamber inflammation. Conclusions: Ocular toxicity due to colours used during Holi mainly involves the surface epithelium and the superficial stroma. This was observed clinically and also confirmed on ASOCT. The colour can rarely diffuse into the anterior chamber causing an inflammatory reaction and staining of the lens capsule. However, if managed appropriately, vision-threatening complications can be averted. [ABSTRACT FROM AUTHOR]

Purpose: As ophthalmic elective surgeries resume amidst the COVID-19 pandemic, protocols for testing patients for SARS-CoV-2 is important due to the transmissibility of the virus. Here, we describe the protocol our institution has implemented for screening asymptomatic patients before proceeding to elective ophthalmic surgery. Methods: A retrospective chart review analyzed the number of elective surgeries, results of SARS-CoV-2 testing, and the effect of a positive result on surgery scheduling. Results: We display the screening protocol our institution used to test for SARS-CoV-2. Through its implementation, we found 2 asymptomatic patients who were positive for SARS-CoV-2 resulting in cancellation of their surgeries. Conclusion: Because of the possibility of positive COVID-19 status in asymptomatic patients and the risk this poses to patients and staff, we recommend testing all asymptomatic patients for SARS-CoV-2 prior to elective surgeries. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) therapy is evolving, and several new drugs are now available, extending patients' life and exposure to different compounds and toxicities. We conducted a cross-sectional observational study enrolling 93 consecutive patients on active treatment for MM, aiming to assess their ocular complications. All the patients underwent a comprehensive ophthalmic evaluation. In our cohort, prevalence of low visual acuity was in line with similar age healthy population reported in registry studies. Interestingly, we recorded a higher prevalence of lens opacities (46%) and dry eye syndrome (53%). Nevertheless, we did not find any significant association between ocular disorders and anti-myeloma treatments, even steroid therapy. This observation suggests that other factors besides treatments, such as M-protein deposition in eye structures, may have a role in developing ocular toxicities. Since MM patients are elderly patients at higher risk of age-related eye disorders, we recommend periodic ophthalmic assessment in daily practice. [ABSTRACT FROM AUTHOR]

Purpose: To determine the clinical features, treatment, and visual outcome in ocular toxocariasis.Methods: A total of 16 cases diagnosed as ocular toxocariasis clinically and/or serologically were analyzed retrospectively.Results: The mean age of the patients was 22.6 years. Cases were categorized into three clinical types with peripheral granuloma (43.7%) as the most common presentation. Of the patients, 10 (62.5%) had positive serum ELISA for T. canis; five (31.2%) received combination treatment with anthelmintic and corticosteroid, and eight (50%) patients had vitreous surgery. The visual outcome in eyes which underwent surgery was better, however the difference in medically and surgically treated groups was insignificant (p = 0.11). There was also no difference in visual outcome among the three clinical groups (p = 0.20).Conclusions: Ocular toxocariasis has a varied presentation spectrum. Serum ELISA for T. canis aids in diagnosis. The difference in visual outcome among clinical and treatment groups was insignificant. However, in general, ocular toxocariasis resulted in a poor visual outcome. [ABSTRACT FROM AUTHOR]

The aim of this study is to develop and evaluate niosomal dispersions loaded with the hydrophilic drug; lomefloxacin Hcl (LXN) for the management of ocular bacterial conjunctivitis. LXN-loaded niosomes were prepared by the thin film hydration method following a full factorial formulation design. Two independent variables were evaluated: the type of surfactant (X1) and the surfactant:cholesterol ratio (X2). The dependent variables comprised entrapment efficiency (EE%: Y1), particle size (PS: Y2) and zeta potential (ZP: Y3). The optimum formulation, N-LXN14 (Tw60: CH, 1:1), was spherical in shape and exhibited EE% of 68.41 ± 0.07, PS of 176.0 ± 0.98 and ZP of -40.70 ± 2.20 with a sustained release profile over 8 hours following the Higuchi model. N-LXN14 proved good physicochemical stability under refrigeration up to 3 months. Ocular irritancy test showed no signs of ocular toxicity, confirming the safety and suitability for ocular application. Microbiological evaluation of the antibacterial effect of N-LXN14 was conducted using the susceptibility test and through the induction of topical conjunctivitis byStaphylococcus aureus(S. aureus) followed by topical therapy. Susceptibility test manifested significantly higher percent inhibition ofS. aureusand higher AUC0–12 hof N-LXN14 (604.59 ± 0.05) compared to the commercial product (126.25 ± 0.049). Both clinical observation and colony count of the infected eyes after eight days of treatment demonstrated significant improvement in therapeutic response. The infected eyes were completely healed with eradication ofS. aureus. In conclusion, the results showed that LXN niosomal dispersions may serve as a promising superior ocular delivery system in the treatment of bacterial conjunctivitis. [ABSTRACT FROM PUBLISHER]

Purpose: To assess clinical findings of eye examination in children having attention deficit hyperactivity disorder (ADHD) administered with methylphenidate hydrochloride. Methods: Fifty-seven consecutive patients diagnosed of ADHD and administered with oral methylphenidate hydrochloride treatment for at least one year were involved in this study (Group 1). Sixty healthy subjects (Group 2) having demographic features similar to group 1 were involved as a control group. All patients underwent detailed ophthalmological examination. Results: One hundred and seventeen consecutive subjects with a mean age of 11.2 ± 2.4 years (7–18 years) were enrolled. Fifty-seven consecutive patient (32 males, 25 females) under oral methylphenidate hydrochloride treatment (Group 1) and 60 healthy control subjects (30 males, 30 females) (Group 2)) were recruited for this prospective study. The mean methylphenidate hydrochloride dosage was 0.9 ± 0.1 mg/kg/day and the mean duration of methylphenidate hydrochloride usage was for 2.73 ± 0.73 years (1–7 years). High intraocular pressure was not observed in any of the patients in our study. We detected lens opacities in five eyes of five patients in group 1 (p = 0.019). The patient with the highest degree of cataract formation had been using MPH for 84 months and this patient’s cataract score was P4. Conclusion: Long-term use of methylphenidate may cause lens opacities. In particular, patients who have been using methylphenidate for more than two years should go for regular eye examination. [ABSTRACT FROM PUBLISHER]

Purpose: Behçet disease (BD) is predominantly found between East Asia and the Mediterranean basin along the historic Silk Road. HLA-B51 is known to be strongly associated with BD. We investigated the association between HLA-B51 and the ocular manifestations of BD among various ethnic groups.Methods: A literature survey was conducted, and 18 articles written in English were reviewed.Results: A strong correlation was found between HLA-B51 and ocular lesions in the entire cohort discussed in the reviewed articles (OR = 1.76, p = 0.000057). HLA-B51 was shown to have a strong association with ocular manifestations of BD patients in East-Eurasian (OR = 2.40, p = 0.0030) and Middle-Eurasian (OR = 1.87, p = 0.0045), but not in West-Eurasian (OR = 1.28, p = 0.35) areas. This correlation seemed to become stronger towards the east.Conclusions: A meta-analysis showed that the correlation became stronger towards the east along the Silk Road. The study results may facilitate understanding of the etiology and characteristics of BD. [ABSTRACT FROM AUTHOR]

We report a 52-year-old man with methanol intoxication who showed optic nerve damage as assessed by magnetic resonance imaging (MRI). He was admitted to the hospital with blurred vision after the consumption of alcohol (600–700 ml of cologne). He was treated with intravenous ethanol, NaHCO3and hemodialysis. On admission, a brain and orbital MRI was performed. Bilateral mild contrast enhancement was detected on the contrast-enhanced images in the retrobulbar segment of the optic nerves (RBONs). Also, diffusion-weighted images showed restricted diffusion in the RBONs. Diagnosis was considered as methanol-induced optic neuropathy based on the MRI findings of the optic nerves. [ABSTRACT FROM AUTHOR]

Primary intraocular lymphoma (PIOL) is a rare malignancy with poor outcomes. Concerns regarding toxicity lead some clinicians to exclude orbital radiation therapy (RT). We aimed to quantify the ocular toxicity of RT in 11 PIOL patients treated with chemoimmunotherapy and bilateral orbital RT (median 36 Gy). A multidisciplinary team, including an ocular oncologist, followed patients for a median of 42 months after RT. Common adverse events included dermatitis (100%), conjunctivitis (82%), xerophthalmia (64%), and keratopathy (45%). All phakic eyes developed cataracts (100%); correction resulted in good vision recovery. New, visually significant retinopathy was observed in only one eye (<5%) and affected a patient with preexisting diabetes. This report suggests that severe, vision-threatening complications following orbital RT are uncommon. In the absence of comorbidities, orbital RT should not be withheld due to fear of vision-threatening toxicity. The risk of toxicity may be augmented by comorbidities, so an individualized approach is recommended. [ABSTRACT FROM PUBLISHER]

Context: Tuberculosis in developed countries is on the rise, and the main treatment ethambutol is known to induce ocular toxicity. However, to date, there are unknown tests or protocols for detecting subclinical ethambutol-induced ocular toxicity, which is important as early detection is related to symptom reversibility. We defined the ethambutol induced ocular toxicity as stastically siginificant change of visual function which was induced by ethambutol. Objective: We aimed to identify a visual function test for the early detection of subclinical ethambutol-induced ocular toxicity. Furthermore, we also investigated the continuity or reversibility of early subclinical changes that were observed during the visual function tests after stopping ethambutol treatment. Materials and methods: The age range of 31 patients was from 13 to 72 years. The range of dosage was 15–19 mg/kg/day. The average period of dosage was 5 months. We performed a visual acuity test, visual field test, color vision test, contrast sensitivity test, fundus examination, retinal nerve fiver layer optical coherence tomography test (RNFL OCT) per month and pattern visual evoked potential test (pattern VEP) every 2 months before and during ethambutol treatment in 62 eyes of 31 patients. Among these patients, selected 21 patients were rexamined by these tests at the 3, 6 and 12 months after stopping ethambutol treatment. We compared the test results from the last follow-up during ethambutol treatment and after ethambutol stoppage with those obtained before ethambutol treatment (baseline). Results: RNFL OCT showed that average RNFL thickness increased 5 months after ethambutol treatment (p = 0.032), and pattern VEP showed that P100 latency was delayed in 2 and 4 months after ethambutol treatment (p = 0.001;p < 0.001, respectively). These early changes observed on RNFL OCT and pattern VEP progressed 6 months after ethambutol stoppage in 21 patients. Twelve months after ethambutol stoppage, these early changes returned to baseline levels. During the study, no changes in visual acuity, color vision, fundus, contrast sensitivity or visual field were observed. Conclusions: Pattern VEP and RNFL OCT are suitable tests for the early detection of subclinical ethambutol-induced ocular toxicity. These tests should be performed until 12 months after ethambutol stoppage. [ABSTRACT FROM AUTHOR]

Context: Ethambutol-induced retinal oxidative damage in patients with tuberculosis is still not being adequately treated. The protective effect of thiamine pyrophosphate against oxidative damage in some tissues has been reported, but no information on the protective effects of thiamine pyrophosphate against ethambutol-induced oxidative retinal damage has been found in the medical literature. Objective: The objective is to investigate whether thiamine pyrophosphate has a protective effect against oxidative retinal damage in rats induced by ethambutol. Materials and methods: Experimental animals divided into four groups (n = 10): the healthy group (HG), the ethambutol control group (EMB), thiamine + ethambutol group (Thi–EMB) and thiamine pyrophosphate + ethambutol group (TPP–EMB). The rats in the TPP–EMB and Thi–EMB groups were administered thiamine pyrophosphate and thiamine, respectively, at doses of 20 mg/kg intraperitoneally. Distilled water was administered intraperitoneally to the HG and the EMB groups as a solvent in the same volumes. One hour after drug injection, 30 mg/kg ethambutol was administered via an oral gavage to the TPP–EMB, Thi–EMB and EMB groups. This procedure was repeated once a day for 90 days. At the end of this period, all rats were euthanized under high-dose thiopental sodium anesthesia, and biochemical and histopathological investigations of the retinal tissue were performed. Results: Malondialdehyde (MDA) and DNA damage product 8-hydroxyguanine levels were significantly lower in the retinal tissue of TPP–EMB and HG groups compared to those of the Thi–EMB and EMB groups, and total glutathione (tGSH) was also found to be higher. In addition, severe retinal tissue vascularization, edema and loss of ganglion cells were observed in the Thi–EMB and EMB groups, whereas histopathological findings for the TPP–EMB group were observed to be close to normal. Discussion and conclusion: These findings suggest that thiamine pyrophosphate protects retinal tissues from ethambutol-induced oxidative damage, and thiamine does not. This positive effect of thiamine pyrophosphate may be useful in the prevention of ocular toxicity that occurs during ethambutol use. [ABSTRACT FROM AUTHOR]

We report a case of a 54-year-old woman presented at the emergency service with complaints of transitory visual obscurations for four days, and headache, nausea and occasional vomiting in the last two months. She had been diagnosed of colorectal cancer one year ago and she was on treatment with oxaliplatin on a FOLFOX schedule. On ophthalmic examination, the vision was of 20/20 in both eyes and bilateral disc swelling was noted. The neurologic examination was normal. Magnetic resonance revealed no changes. A diagnostic lumbar puncture demonstrated an elevated opening pressure of 290 mm H2O with normal compounds. Due to the suspicion of ocular toxicity, oxaliplatin treatment was stopped. Treatment with oral acetazolamide was started and maintained for one month. In three weeks ocular and systemic symptoms totally disappeared and disc swelling gradually improved in the following months. Ocular toxicity has been reported as an infrequent adverse effect of oxaliplatin, but intracranial idiopathic pressure has not yet been described. Findings in this case suggest that oxaliplatin could be the cause for these symptoms. As the use of oxaliplatin is increasing as first-line treatment in colorectal cancer, we have to be alert to its potential toxicity. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in the elimination of infections, the removal of debris and in tissue repair after infection and trauma.In vitromodels that assess ocular biomaterials for toxicity typically focus on the effects of these materials on epithelial or fibroblast cells. This investigation evaluated known ocular toxins deposited on model materials for their effects on the viability and activation of macrophages. THP-1-derived macrophages were cultured onto silicone films (used as a base biomaterial) deposited with chemical toxins (benzalkonium chloride (BAK), zinc diethyldithiocarbamate (ZDEC) and lipopolysaccharide (LPS)). Utilizing three fluorescent dyes calcein, ethidium homodimer-1 (EthD-1) and annexin V, the viability of macrophages attached to the biomaterial was determined using confocal microscopy. Propidium iodide (PI) staining and alamarBlue® (resazurin) reduction were used to assess cell death and metabolic activity. CD14, CD16, CD33, CD45, and CD54 expression of adherent macrophages, were also evaluated to detect LPS activation of macrophages using flow cytometry. The sensitivity of this test battery was demonstrated as significant toxicity from treated surfaces with ZDEC (0.001–0.01%), and BAK (0.001%–0.1%) was detected. Also, macrophage activation could be detected by measuring CD54 expression after exposure to adsorbed LPS. Thesein vitromethods will be helpful in determining the toxicity potential of new ocular biomaterials. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the ocular toxicity and pharmacokinetics of intrastromal injection of amphotericin B (AmB) in a rabbit model. Methods: Forty albino rabbits were randomly divided into five groups (eight per group). The rabbits were anesthetized before they received the medication. Intrastromal injection of 0.1 ml balanced salt solution containing 0, 5, 10, 20 or 30 μg of AmB was performed on eyes of each group five times (once per four days), respectively. The presence of possible corneal clouding, epithelial erosion and corneal neovascularization was monitored with a slit-lamp biomicroscope. Corneal ultrasonic pachymetry was used to detect the corneal thickness of intrastromal-injected eyes. Thirty days after the last injection, the corneal transparency as well as the number and ultrastucture of corneal endothelial cells were examined. The concentrations of the AmB in the cornea and aqueous humor were evaluated at 30 min, 6 h and at 1, 3 and 7 days after the intrastromal injection of 10 µg AmB. Results: Intrastromal injection of AmB at concentrations of 5 and 10 μg per 0.1 ml did not induce obvious toxicity to the cornea when compared with the controls. However, when the concentration of AmB increased to 20 μg per 0.1 ml or more, corneal edema, corneal epithelial erosion and severe neovascularization appeared. A single intrastromal injection of 10 μg AmB achieved an effective drug level in corneas which was maintained for up to 7 days. Conclusions: Intrastromal injection of AmB at a concentration of less than10 μg per 0.1 ml is safe to the rabbit corneas. Intrastromal injection of AmB may be an adjunctive treatment for deep recalcitrant fungal keratitis. [ABSTRACT FROM AUTHOR]

Background: Behçet's disease (BD) is a multisystemic vasculitis with unknown etiology. Vitamin K epoxide reductase complex subunit 1 ( VKORC1) is the key enyzme in the formation of active vitamin K that is a cofactor of various coagulation factors. Polymorphisms of the VKORC1 may affect the levels of active forms of vitamin K-dependent coagulation proteins and the tendency to thrombosis. The current study aimed to evaluate the role of VKORC1 gene polymorphisims in ocular and non-ocular Behçet's disease. Methods: VKORC1 C1173T (rs 9934438) and G-1639A (rs 9923231) gene polymorphisms were evaluated by real-time polymerase chain reaction-based DNA analysis. The frequency of alleles and distribution of genotypes were assessed by the chi-squared test. Genotype distribution and Hardy-Weinberg equilibrium were tested with the χ2 test for quality of fit. Results: The distribution of GG, GA and AA and CC, CT, TT genotypes and the frequency of G,A and C,T alleles were not found to be different between patients and controls ( p = 0.5651; p = 0.335 respectively), as well as patients with or without eye involvement ( p = 0.9267; p = 0.384 respectively). Conclusion: VKORC1 polymorphisms seem not to be related with the thrombotic state of systemic and ocular Behçet's disease. [ABSTRACT FROM AUTHOR]

Purpose: Cisplatin and Paclitaxel are two chemotherapeutic agents known to produce neurotoxicity when used for cumulative dose regimens. In this study we aim to assess their toxicity in the optic nerve, and to evaluate the retinal nerve fibre layer (RNFL) thickness and visual field changes in lung cancer patients treated with Cisplatin and Paclitaxel. Methods: Fifteen patients who were treated intravenously with 75 mg/m2 cisplatin and 175 mg/m2 paclitaxel every 3 weeks, up to a maximum of six courses, were enrolled in this prospective clinical trial. All patients underwent complete ophthalmological assessments before their treatments began, as well as three months after the completion of their treatments. The RNFL thickness measurements were performed using optical coherence tomography (OCT). Functional testing included the use of frequency-doubling technology (FDT) perimetry and the Humphrey visual field analyser (HFA). The main outcome measurements included the average RNFL thicknesses and visual field indices (mean deviation [MD] and pattern standard deviation [PSD]). Results: The median age of the 15 patients (nine male and six female) was 63.49 years old (range: 53-77). The average RNFL thickness measurement during the baseline examination was 103.73 μm (range: 97-111). Three months after the cessation of treatment the RNFL thickness declined to 97.4 μm (range: 91-102). Statistical analysis showed a significant thinning between the two measurements ( p = 0.032). The MD and PSD values recorded by the HFA demonstrated no statistically significant changes 3 months after the cessation of treatment ( p > 0.207 and p > 0.186, respectively). There were statistically significant decreases in both the MD (0.48 to −1.13 dB) and PSD (2.13 to 0.65 dB) indices measured by the FDT perimetry ( p = 0.041 and p = 0.025, respectively). Conclusions: In our study, the systemic administration of Cisplatin and Paclitaxel affected the peripapillary RNFL thicknesses and visual field indices as revealed by FDT perimetry. OCT and FDT perimetry may be adjunctive tools for the screening of ocular toxicity in patients treated with these agents. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the in vivo release and ocular toxicity of a tacrolimus-loaded PLGA intravitreal implant. Methods: Tacrolimus-loaded PLGA implants were inserted into the vitreous cavity of rabbits' eye. At different time points, the vitreous was retrieved and the concentration of tacrolimus released from the implants was determined. Clinical examination was performed to evaluate the implant tolerance. Results: PLGA implants provided controlled and prolonged release of tacrolimus. Approximately 99.97% of the drug was released from the devices at 6 weeks. Ophthalmic examination revealed no evidence of toxic effects of implants. Conclusions: Tolerance and feasibility of the tacrolimus-loaded PLGA implants, as sustained intraocular drug delivery systems, were demonstrated. [ABSTRACT FROM AUTHOR]

Purpose: This study intended to examine the effect of caffeic acid phenethyl ester (CAPE) on isoniazid (INH) and/or ethambutol (ETM)-induced retina and optic nerve toxicity in a rat model. Methods: This study included eight groups, each containing 10 rats. The groups were Control, INH, ETM, CAPE, INH+CAPE, ETM+CAPE, INH+ETM and INH+ETM+CAPE. Rats were given orally 50 mg/kg/d of INH and 50 mg/kg/d of ETM in tap water for 30 d. 10 μmol/kg of CAPE were intraperitoneally injected for 30 d. The first dose of CAPE was given 24 h before the INH and ETM treatment and continued until sacrifice. Control group was given only tap water for 30 d. Rats were anaesthetized and sacrificed on the 30th day of experiment. Superoxide dismutase (SOD) activities, malondialdehyde (MDA), total anti-oxidant status (TAS), total oxidant status (TOS) were measured on the dissected and excised retina and optic nerve samples. Fellow eyes were used for histopathologic evaluation and the retinal ganglion cell (RGC) count. In addition, CAPE, INH and ETM interaction with SOD isoforms were calculated in silico. Results: The SOD activity and TAS levels were found significantly higher in CAPE-treated groups compared to INH and/or ETM-treated groups ( p < 0.0001). But the MDA, and TOS levels were significantly lower in CAPE-treated groups ( p < 0.0001). The mean RGC count is significantly decreased in INH, ETM and INH+ETM groups compared with INH+CAPE, ETM+CAPE and INH+ETM+CAPE groups, respectively ( p values 0.001, 0.042, and 0.001 respectively). Besides, in silico calculations showed that binding affinity of CAPE to SOD isotypes was higher than that of INH and ETM. Conclusion: This study demonstrates that CAPE treatment may decrease the oxidative stress in the retina and optic nerve of INH- and ETM-treated rats and may prevent RGC loss. As an underlying mechanism, CAPE and SOD interaction seems crucial for alleviation of ocular oxidative stress and RGCs toxicity. [ABSTRACT FROM AUTHOR]