[Changes in intraocular pressure and biometric parameters of the anterior segment of the eye after intravitreal injections]. / Izmeneniya urovnya vnutriglaznogo davleniya i biometricheskikh pokazatelei perednego segmenta glaza posle intravitreal'nykh in"ektsii.

PURPOSE: This study compares the changes in the parameters of the anterior chamber of the eye using anterior segment optical coherence tomography (AS-OCT) in patients with a natural and artificial lens after treatment of neovascular age-related macular degeneration (nAMD) by multiple intravitreal injections (IVI) of anti-VEGF drugs. MATERIAL AND METHODS: The patients were divided into 2 groups: group 1 (control) included 30 patients (30 eyes) with a natural lens, group 2 - 30 patients (30 eyes) with an intraocular lens (IOL). AS-OCT was performed using the Revo NX tomograph (Optopol, Poland) to analyze anterior chamber depth (ACD) and the parameters of anterior chamber angle (ACA). Intraocular pressure (IOP) was measured with a contact tonometer ICare Pro. RESULTS: In patients with an IOL, the IOP level 1 minute after intravitreal injection (IVI) of an anti-VEGF drug was statistically lower than in the control group, on average by 17.8% during the first IVI and by 28.7% after 1 year of observation (p<0.001). ACD before treatment was statistically significantly higher in patients with IOL compared to patients of group 1 by an average of 39.3% (p<0.001). ACA from the nasal and temporal sides in the meridian 0°-180° before the start of treatment was statistically significantly wider in phakic patients than in the control group, by an average of 15.9±9.3° (p<0.001) and 16.9±8.2° (p<0.001), respectively. According to AS-OCT, there was no shift of the iris-lens diaphragm in patients with an IOL after multiple IVI of an anti-VEGF drug, in contrast to the control group. CONCLUSIONS: AS-OCT was used to determine for the first time the changes in the parameters of the anterior chamber of the eye in patients with a natural and artificial lens after multiple injections of an anti-VEGF drug in the treatment of nAMD.

Nanotechnology for Topical Drug Delivery to the Anterior Segment of the Eye.

Topical drug delivery is one of the most challenging aspects of eye therapy. Eye drops are the most prevalent drug form, especially for widely distributed anterior segment eye diseases (cataracts, glaucoma, dry eye syndrome, inflammatory diseases, etc.), because they are convenient and easy to apply by patients. However, conventional drug formulations are usually characterized by short retention time in the tear film, insufficient contact with epithelium, fast elimination, and difficulties in overcoming ocular tissue barriers. Not more than 5% of the total drug dose administered in eye drops reaches the interior ocular tissues. To overcome the ocular drug delivery barriers and improve drug bioavailability, various conventional and novel drug delivery systems have been developed. Among these, nanosize carriers are the most attractive. The review is focused on the different drug carriers, such as synthetic and natural polymers, as well as inorganic carriers, with special attention to nanoparticles and nanomicelles. Studies in vitro and in vivo have demonstrated that new formulations could help to improve the bioavailability of the drugs, provide sustained drug release, enhance and prolong their therapeutic action. Promising results were obtained with drug-loaded nanoparticles included in in situ gel.

Effect of astaxanthin on metabolic cataract in rats with type 1 diabetes mellitus.

OBJECTIVE: The purpose of this study was to investigate the effect of astaxanthin on metabolic cataract in rats with type 1 diabetes and its antioxidant capacity to lens. METHODS: Rats were randomly divided into four groups (n = 8): control group, diabetes mellitus (DM) group, low-dose astaxanthin (DM + AL) and low-dose astaxanthin (DM + AH) group. A rat model of type I diabetes mellitus was established by intraperitoneal injection of 60 mg/kg streptozotocin (STZ). After successful modeling, rats in the administration group were given different doses of astaxanthin (AST) for 12 weeks. The lens opacity of rats was observed by slit-lamp camera system. The double antibody sandwich method was used to detect the levels of advanced glycation end product (AGE), lipid peroxide/malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) in the lens. Hematoxylin-eosin (HE) staining was used to examine the morphologic changes in the lens. RESULTS: The severity of cataract in the lens was obviously increased after induced by STZ, whereas it was significantly decreased after treatment with AST (p < .05, respectively). In addition, in the AST groups, the levels of AGE and MDA in the lens tissue were notably decreased when compared with those in the DM group (p < .05, respectively). However, the levels of GSH, SOD, and CAT were increased in the AST group in comparison with those in the DM group (p < .05, respectively). CONCLUSIONS: Astaxanthin may play an antioxidant role in the lens. Additionally, it exerts a protective function in the lens by delaying the development and progression of metabolic cataract and inhibiting the oxidative stress of lens in diabetic rats.

Effects of selective serotonin reuptake inhibitors on intraocular pressure and anterior segment parameters in open angle eyes.

PURPOSE: To evaluate the short- and long-term effects of selective serotonin reuptake inhibitors (SSRIs) on intraocular pressure (IOP) and anterior segment parameters in open angle eyes. MATERIALS AND METHODS: This cross-sectional study included 325 eyes of 166 subjects. Subjects were divided into three groups: Group 1 included 116 eyes of 58 patients receiving SSRIs for 1 week-6 months, Group 2 included 102 eyes of 53 patients receiving SSRIs for longer than 6 months and Group 3 included 107 eyes of 55 healthy subjects not receiving any drugs. All of the patients receiving SSRIs were diagnosed as major depressive disorder. All groups were chosen to be similar in terms of age and gender. All patients underwent a detailed ophthalmologic examination including IOP measurement by Goldmann applanation tonometer and gonioscopy. Anterior segment parameters including pupil diameter (PD), central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber volume (ACV), and anterior chamber angle (ACA) were assessed by a Scheimpflug system. RESULTS: Pupil diameter was significantly larger in patients receiving SSRIs for <6 months and ≥6 months than the control subjects (3.53 ± 0.71 mm, 3.48 ± 0.60 mm versus 3.11 ± 0.72 mm, p < 0.05) but this effect was independent from the duration of SSRI treatment. IOP was significantly lower in patients receiving SSRIs for <6 months and ≥6 months than the control group (16.04 ± 2.17 mm Hg, 16.11 ± 2.13 mm Hg versus 17.34 ± 2.15 mmHg, p < 0.05), but there were no statistically significant differences between the patients receiving SSRIs for <6 months and ≥6 months. There were no statistically significant differences between the patient and the control group in values of CCT, ACD, ACV and ACA. The ACAs were measured between 25° and 55° with Scheimpflug system and also classified as grade 3-4 (Shaffer system) by gonioscopy. CONCLUSIONS: Selective serotonin reuptake inhibitors cause mydriasis which is persistent during the treatment. In depression patients with open angle eyes, short- and long-term use of SSRIs leads to decrease in IOP.

Effect of preservative-free tafluprost on intraocular pressure, pupil diameter, and anterior segment structures in normal canine eyes.

OBJECTIVE: This study was designed to evaluate the changes in intraocular pressure (IOP), pupil diameter (PD), and anterior segment parameters using ultrasound biomicroscopy (UBM) after instillation of preservative-free (PF) tafluprost in normal dogs. PROCEDURES: Six beagle dogs were used. PF tafluprost was instilled in one randomly selected eye, and PF artificial tear was instilled in the other eye (control). IOP and PD were measured every 15 min for the first hour, every 2 h for the next 17 h, and at 24 h and 36 h postinstillation (PI). Anterior segment parameters including geometric iridocorneal angle (ICA), width of the entry of the ciliary cleft (CCW), length of the ciliary cleft, area of the ciliary cleft, and depth of the anterior chamber were measured with UBM before and after PF tafluprost instillation. RESULTS: Compared with the control group, IOP was significantly lower from 4 h PI to 24 h PI and PD was significantly smaller from 30 min PI to 18 h PI (P < 0.05). Among UBM parameters, ICA and CCW significantly decreased and increased after PF tafluprost instillation, respectively (P < 0.05). Other parameters showed no significant changes. CONCLUSIONS: Instillation of PF tafluprost lowered IOP and induced miosis in normal canine eyes. Alterations in ICA and CCW occurred simultaneously, which probably affected the outflow of aqueous humor. PF tafluprost could be considered an alternative prostaglandin analog in the treatment of canine glaucoma.

Latanoprost-Eluting Contact Lenses in Glaucomatous Monkeys.

PURPOSE: To assess the ability of latanoprost-eluting contact lenses to lower the intraocular pressure (IOP) of glaucomatous eyes of cynomolgus monkeys. DESIGN: Preclinical efficacy study of 3 treatment arms in a crossover design. PARTICIPANTS: Female cynomolgus monkeys with glaucoma induced in 1 eye by repeated argon laser trabeculoplasty. METHODS: Latanoprost-eluting low-dose contact lenses (CLLO) and high-dose contact lenses (CLHI) were produced by encapsulating a thin latanoprost-polymer film within the periphery of a methafilcon hydrogel, which was lathed into a contact lens. We assessed the IOP-lowering effect of CLLO, CLHI, or daily latanoprost ophthalmic solution in the same monkeys. Each monkey consecutively received 1 week of continuous-wear CLLO, 3 weeks without treatment, 5 days of latanoprost drops, 3 weeks without treatment, and 1 week of continuous-wear CLHI. On 2 consecutive days before initiation of each study arm, the IOP was measured hourly over 7 consecutive hours to establish the baseline IOP. Two-tailed Student t tests and repeated-measures analysis of variance were used for statistical analysis. MAIN OUTCOME MEASURES: Intraocular pressure. RESULTS: Latanoprost ophthalmic solution resulted in IOP reduction of 5.4±1.0 mmHg on day 3 and peak IOP reduction of 6.6±1.3 mmHg on day 5. The CLLO reduced IOP by 6.3±1.0, 6.7±0.3, and 6.7±0.3 mmHg on days 3, 5, and 8, respectively. The CLHI lowered IOP by 10.5±1.4, 11.1±4.0, and 10.0±2.5 mmHg on days 3, 5, and 8, respectively. For the CLLO and CLHI, the IOP was statistically significantly reduced compared with the untreated baseline at most time points measured. The CLHI demonstrated greater IOP reduction than latanoprost ophthalmic solution on day 3 (P = 0.001) and day 5 (P = 0.015), and at several time points on day 8 (P < 0.05). CONCLUSIONS: Sustained delivery of latanoprost by contact lenses is at least as effective as delivery with daily latanoprost ophthalmic solution. More research is needed to determine the optimal continuous-release dose that would be well tolerated and maximally effective. Contact lens drug delivery may become an option for the treatment of glaucoma and a platform for ocular drug delivery.

Ocular Surface Disease in Breast Cancer Patients Using Aromatase Inhibitors.

Aromatase inhibitors (AIs) are widely used as adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. The purpose of this study was to investigate the potential impact of AIs on the anterior segment of the eye and especially the ocular surface. Participants in our study were 41 hormone receptor-positive early stage breast cancer patients (80 eyes), treated with AIs, while 80 eyes of 40 age- and gender-matched healthy controls, not previously used AIs for any purpose, were also evaluated. All participants underwent a complete ophthalmological examination, including best corrected visual acuity (BCVA) assessment, slit-lamp biomicroscopy, and dilated fundus examination. Ocular surface disease-related symptoms and signs were also recorded. The most common symptom was found to be blurred vision, while other symptoms included foreign body sensation, tearing, redness, and photophobia. Slit-lamp examination revealed blepharitis and meibomian gland dysfunction in 75% and 42.5% of patients, respectively. Superficial punctate keratitis and conjunctival injection were also present. Our results demonstrated a high prevalence of ocular surface disease-related symptoms and signs in patients receiving AIs compared to healthy controls. This study may raise a flag regarding the use of AIs. However, further and larger prospective longitudinal studies are needed to examine the possible effect of AIs alone or in combination with chemotherapy in the eyes of breast cancer patients.

Anterior Segment Biometry Changes with Cycloplegia in Myopic Adults.

PURPOSE: To determine the effect of cycloplegia on corneal thickness, corneal curvature, anterior chamber depth (ACD), angle-to-angle (ATA) and white-to-white (WTW) distances, and axial length (AL). METHODS: Changes in corneal thickness, corneal curvature, ACD, ATA and WTW distances, and AL with and without cycloplegia were analyzed in 31 eyes of 31 young myopic adults, aged 26.4 ± 3.0 years. Pentacam was used to measure the corneal thickness, corneal volume, and corneal curvatures. Visante optical coherent tomography (OCT) measured corneal thickness, ATA distance, ACD, and pupil size. The AL and WTW distance were measured using IOLMaster. RESULTS: Cycloplegia induced significant flattening of corneal curvatures (p = 0.019, 0.001, and 0.003 for anterior sagittal, posterior tangential, and posterior sagittal curvatures, respectively). The difference in the posterior corneal curvature was greater in corneas with steeper posterior curvatures. Cycloplegia also induced significant deepening of ACD (0.08 ± 0.06, p < 0.001) and widening of both WTW (0.42 ± 0.43, p < 0.001) and ATA (0.08 ± 0.17, p = 0.015) distances. The cycloplegia-related increase in the ATA distance correlated negatively with AL (r = -0.361, p = 0.046), whereas the cycloplegia-related increase in WTW distance correlated weakly with the increase in ACD (r = 0.347, p = 0.056) but not with AL. The AL did not change with cycloplegia. Pentacam measured a slightly thicker cornea than OCT (p = 0.002). Both Pentacam and OCT detected a significant increase in corneal thickness of 4 µm, which could be attributed to reflex tearing, after cycloplegia. CONCLUSIONS: Cycloplegia resulted in deeper ACD, greater ATA distance, and flatter corneal curvatures. Surgeons should be aware of these cycloplegia-related alterations for more accurate phakic/functional intraocular lens selection and better refraction results.

Viscoelastic substance in prefilled syringe as an etiology of Toxic Anterior Segment Syndrome.

CONTEXT: Toxic Anterior Segment Syndrome (TASS) is an acute postoperative inflammatory reaction in which a noninfectious substance enters the anterior segment and induces toxic damage to the intraocular tissues. OBJECTIVE: To present etiologic investigation of two consecutive clusters of TASS. TASS outbreak and investigation: This paper presents two consecutive clusters of TASS in 15 of the 24 uneventful surgeries and the investigation carried out to find the etiology. After the occurrence of first cluster of TASS, sterilization-related etiology was explored; however, we did not find any lacunae in the sterilization and cleaning process in the operating theater (OT). Nevertheless, multiple changes in cleaning process were implemented. Still a second cluster of TASS was encountered in the following session of OT. Several other factors which include preservatives, hand gloves, intraocular lenses, medications/solutions, intraocular penetration of topically administered drugs, and viscoelastics were investigated as the possible etiology of the second consecutive cluster of TASS; however, most of them were ruled out. The newly introduced viscoelastic I-visc® 1.4% sodium hyaluronate (I medical, i-Medical Ophthalmic International GmbH, Heidelberg, Germany) was thought to be the most likely cause and was replaced with previously in use sodium hyaluronate 1.5% and lidocaine hydrochloride 1% (Visthesia, CZ, Germany) in the following session of OT. No further TASS incident was encountered after replacing the viscoelastic. CONCLUSION: Investigation revealed that 1.4% sodium hyaluronate in prefilled syringe (PFS) (I-visc® 1.4%) was the etiologic factor of two consecutive clusters of TASS. While TASS due to residual denatured ophthalamic viscosurgical devices (OVDs) is a common knowledge, current study brings out that even disposable viscoelastic material supplied in PFSs can be an etiology of TASS. It is important to recognize that contamination of OVDs with endotoxins can occur at the time of manufacturing. Therefore, in the absence of appropriate guidelines for ophthalmic preparations, endotoxin limit for medical preparations (i.e. <0.5 endotoxin units/ml) must be considered during OVD manufacture.

[Ocular toxicity of intracamerally injected antibacterial and antifungal drugs (experimental and morphological study)].

OBJECTIVE: To study anterior eye segment toxicity of variously diluted brand name and generic antibiotic and antifungal drugs, including domestically produced generics (Moxifloxacin, asketin cefuroxime, amikacin, gentamicin, Diflucan, and amphotericin B), experimentally injected into the anterior chamber. MATERIAL AND METHODS: A total of 13 Chinchilla rabbits were included in the experiment. Group 1 (6 rabbits) received sterile intracameral injections of 0.2 ml antibiotics and antifungals in concentrations suitable for intravenous administration (Moxifloxacin 1.6 mg/ml, Diflucan 2 mg/ml, and the following generics: asketin cefuroxime 125 mg/ml, amikacin 50 mg/ml, gentamicin 40 mg/ml, amphotericin B 50 mg/m). BSS was injected into the fellow eye for control. Group 2 (7 rabbits) also received sterile intracameral injections of 0.2 ml antibiotics and antifungals, which were the same as for group 1 but highly diluted (Moxifloxacin 150 µg/ml and 500 µg/ml, Diflucan 10 µg/ml, asketin cefuroxime 1 mg/ml, gentamicin 200 µg/ml, amikacin 400 µg/ml, amphotericin B 10 µg/ml). RESULTS: There were no toxic effects in group 1 after BSS and Moxifloxacin 1.6 mg/ml injections into the anterior chamber. However, high concentrations of other antibiotic and antifungal drugs were associated with changes in the corneal endothelium of various severity (from cytoplasmic swelling of the endothelial cells to their complete desquamation), as well as fibrin exudation in the posterior chamber. In group 2 neither of injected drugs caused toxic, allergic, or inflammatory reactions according to histopathological examination. CONCLUSION: The experiment proved safety of the intracameral route of administration for highly diluted medications from the list and also demonstrated the absence of toxic reaction after intracameral injection of Moxifloxacin 1.6 mg/ml.

The effects of 3% diquafosol sodium application on the tear functions and ocular surface of the Cu,Zn-superoxide dismutase-1 (Sod1)-knockout mice.

PURPOSE: To investigate the role of a water and mucin secretagogue (3% diquafosol sodium eye drops) on the tear function and conjunctival ocular surface changes in Sod1(-/-) in comparison to the wild-type (WT) mice. METHODS: Fourteen eyes of 7 Sod1(-/-) male mice with C57BL/background and 14 eyes of 7 C57BL6 strain wild-type male mice were examined at 40 weeks in this study. All mice had application of 3% diquafosol ophthalmic solution six times a day for 2 weeks. Tear film stability and corneal epithelial damage was evaluated by fluorescein and Rose Bengal stainings. Anterior segment photography was performed before and after eye drop instillations. Aqueous tear quantity was measured with phenol red-impregnated cotton threads without anesthesia. Animals were sacrificed at 42 weeks after diquafosol treatment and the whole globe specimens were subjected to periodic acid Schiff staining. Goblet cell density was quantified by J Image software. Quantitative real-time PCR for conjunctival muc 5AC messenger RNA expression was also performed. RESULTS: Sod1(-/-) mice had significantly higher fluorescein staining scores compared to the WT mice before eye drop instillation. The mean tear film breakup time, Rose Bengal staining scores, and muc5 messenger RNA expression improved significantly with diquafosol treatment in both the WT and the knockout mice. The mean fluorescein staining score and aqueous tear quantity significantly improved in the Sod1(-/-) mice with treatment. A notable and consistent increase in goblet cells and decrease in inflammatory cell infiltrates could be confirmed in all specimens after 2 weeks of diquafosol eye drop application. CONCLUSIONS: Three percent diquafosol ophthalmic solution appears to be effective in the treatment of ocular surface disease in this age-related dry eye disease mouse model.

Effects of topically applied tocotrienol on cataractogenesis and lens redox status in galactosemic rats.

PURPOSE: Oxidative and nitrosative stress underlies cataractogenesis, and therefore, various antioxidants have been investigated for anticataract properties. Several vitamin E analogs have also been studied for anticataract effects due to their antioxidant properties; however, the anticataract properties of tocotrienols have not been investigated. In this study, we investigated the effects of topically applied tocotrienol on the onset and progression of cataract and lenticular oxidative and nitrosative stress in galactosemic rats. METHODS: In the first part of this study, we investigated the effects of topically applied microemulsion formulation of tocotrienol (TTE) using six concentrations ranging from 0.01% to 0.2%. Eight groups of Sprague-Dawley rats (n = 9) received distilled water, vehicle, or one of the six TTE concentrations as pretreatment topically twice daily for 3 weeks while on a normal diet. After pretreatment, animals in groups 2-8 received a 25% galactose diet whereas group 1 continued on the normal diet for 4 weeks. During this 4-week period, topical treatment continued as for pretreatment. Weekly slit-lamp examination was conducted to assess cataract progression. At the end of the experimental period, the animals were euthanized, and the proteins and oxidative stress parameters were estimated in the lenses. In the second part of the study, we compared the anticataract efficacy of the TTE with the liposomal formulation of tocotrienol (TTL) using five groups of Sprague-Dawley rats (n = 15) that received distilled water, TTE, TTL, or corresponding vehicle. The mode of administration and dosing schedule were the same as in study 1. Weekly ophthalmic examination and lens protein and oxidative stress estimates were performed as in study 1. Lens nitrosative stress was also estimated. RESULTS: During the 4-week treatment period, the groups treated with 0.03% and 0.02% tocotrienol showed slower progression of cataract compared to the vehicle-treated group (p<0.05), whereas the group treated with 0.2% tocotrienol showed faster progression of cataract compared to the vehicle-treated group (p<0.05). The lenticular protein content, malondialdehyde, superoxide dismutase, and catalase levels were normalized in the groups that received 0.03% and 0.02% tocotrienol. The lenticular reduced glutathione also showed a trend toward normalization in these groups. In contrast, the group treated with 0.2% tocotrienol showed increased lenticular oxidative stress. When the microemulsion and liposomal formulations were compared, the effects on cataract progression, lens oxidative and nitrosative stress, and lens protein content did not show significant differences. CONCLUSIONS: Topically applied tocotrienol within the concentration range of less than 0.05% and more than 0.01% tends to delay the onset and progression of cataract in galactose-fed rats by reducing lenticular oxidative and nitrosative stress. However, topical tocotrienol at a concentration of 0.2% and higher aggravates cataractogenesis in galactose-fed rats by increasing lens oxidative stress. The anticataract efficacy of 0.03% microemulsion of tocotrienol did not differ from its liposomal formulations at the same concentration.

sCD44 overexpression increases intraocular pressure and aqueous outflow resistance.

PURPOSE: CD44 plays major roles in multiple physiologic processes. The ectodomain concentration of the CD44 receptor, soluble CD44 (sCD44), is significantly increased in the aqueous humor of primary open-angle glaucoma (POAG). The purpose of this study was to determine if adenoviral constructs of CD44 and isolated 32-kDa sCD44 change intraocular pressure (IOP) in vivo and aqueous outflow resistance in vitro. METHODS: Adenoviral constructs of human standard CD44 (Ad-CD44S), soluble CD44 (Ad-sCD44), and empty viral cDNA were injected into the vitreous of BALB/cJ mice, followed by serial IOP measurements. Overexpression of CD44S and sCD44 was verified in vitro by enzyme-linked immunosorbent assay (ELISA) and western blot analysis. Anterior segments of porcine eyes were perfused with the isolated sCD44. sCD44-treated human trabecular meshwork (TM) cells and microdissected porcine TM were examined by confocal microscopy and Optiprep density gradient with western blot analysis to determine changes in lipid raft components. RESULTS: Intravitreous injection of adenoviral constructs with either Ad-CD44S or Ad-sCD44 vectors caused prolonged ocular hypertension in mice. Eight days after vector injection, Ad-CD44S significantly elevated IOP to 28.3±1.2 mmHg (mean±SEM, n=8; p<0.001); Ad-sCD44 increased IOP to 18.5±2.6 mmHg (n=8; p<0.01), whereas the IOP of uninjected eyes was 12.7±0.2 mmHg (n=16). The IOP elevation lasted more than 50 days. Topical administration of a γ-secretase inhibitor normalized Ad-sCD44-induced elevated IOP. sCD44 levels were significantly elevated in the aqueous humor of Ad-CD44S and Ad-sCD44 eyes versus contralateral uninjected eyes (p<0.01). Anterior segment perfusion of isolated 32-kDa sCD44 significantly decreased aqueous outflow rates. Co-administration of isolated sCD44 and CD44 neutralizing antibody or of γ-secretase inhibitor significantly enhanced flow rates. sCD44-treated human TM cells displayed cross-linked actin network formation. Optiprep density gradient and western blot analysis of human TM cells treated with sCD44 showed decreased annexin 2 expression and increased phosphorylated annexin 2 and caveolin 1 expression. CONCLUSIONS: Our data suggest that sCD44 increases outflow resistance in vivo and in vitro. Viral overexpression of both CD44S and sCD44 is sufficient to cause ocular hypertension. Infusion of sCD44 in porcine anterior segment eyes significantly decreased flow rates. Notably, sCD44 enhanced cross-linked actin network formation. The elevated sCD44 levels seen in POAG aqueous humor may play an important causative role in POAG pathogenesis.

Evaluation of intraocular reactivity to organic contaminants of ophthalmic devices in a rabbit model.

OBJECTIVE: To evaluate the intraocular reactivity to organic contaminants of ophthalmic devices in the rabbit. DESIGN: Experimental animal study. PARTICIPANTS: Fifty New Zealand white rabbits. METHODS: The rabbits were allocated to 10 groups of 5 each to receive 2 different doses of human albumin and nonhuman nucleic acids and their respective vehicle controls, a denatured cohesive ophthalmic viscosurgical device (OVD) and a denatured dispersive OVD and their respective nondenatured controls. All 10 eyes in each treatment group received bilateral intracameral injection of the test materials. All the eyes in the study were examined by slit-lamp biomicroscopy at baseline and 6, 9, 24, 48, and 72 hours. Pachymetry was also performed on eyes exposed to albumin, protein vehicle control, and the OVDs at these time points. MAIN OUTCOME MEASURES: Corneal thickness, grade of corneal clouding, anterior chamber (AC), cells, flare and fibrin, iridal hyperemia, cell and fibrin on lens surface, and onset time. RESULTS: There were no inflammatory signs in any eyes exposed to human albumin. Anterior chamber cells (1+ to 3+) and flare and fibrin (1+ to 2+), along with cells and fibrin on the lens surface, were seen in the eyes exposed to the nucleic acid samples, and they resolved in 24 hours. Mild (mostly 1+) conjunctival congestion, cells, flare, and fibrin were seen in a few eyes exposed to the 2 denatured OVDs and their controls, with the response durations being shorter in the denatured OVD eyes (24 hours) than in the nondenatured OVD eyes (48 hours). Anterior chamber inflammation was generally observed in fewer denatured OVD eyes than in nondenatured OVD eyes, particularly the dispersive OVD eyes. CONCLUSIONS: Intracameral injection of human albumin protein did not cause ocular inflammation. Nucleic acid intracamerally injected into rabbit eyes caused acute inflammation that quickly resolved. Cohesive and dispersive OVD denatured by drying and steam sterilization alone did not cause ocular inflammation.

Scleritis therapy.

OBJECTIVE: To delineate factors associated with a successful response to treatment in patients with various manifestations of scleritis. DESIGN: Retrospective case series. PARTICIPANTS: A total of 392 patients with noninfectious anterior scleritis. METHODS: We reviewed the electronic health records of 392 patients with noninfectious anterior scleritis seen at 2 tertiary referral centers and studied the factors associated with successful treatment. MAIN OUTCOME MEASURES: Patient characteristics (age, sex); ocular disease characteristics (laterality, type of scleritis, degree of scleral inflammation, ocular complications, delay in presentation, and follow-up period), systemic disease association (associated disease, potentially lethal associated disease); and anti-inflammatory and immunosuppressive medications were studied in patients with scleritis. Successful treatment response to nonsteroidal anti-inflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs (SAIDs), immunosuppressive therapy drugs (immunomodulatory therapy [IMT]), or biologic response modifiers (BRMs) was assessed. RESULTS: Treatment of 392 patients with noninfectious anterior scleritis included NSAIDs in 144 (36.7%), SAIDs in 29 (7.4%), IMT in 149 (38.0%), BRMs in 56 (14.3%), and none (N = 14). Successful response to treatment with NSAIDs was associated with idiopathic diffuse or nodular scleritis with a low degree of scleral inflammation (≤ 2+) (odds ratio [OR] = 2.89, P < 0.001) and with idiopathic diffuse or nodular scleritis without ocular complications (OR = 3.13, P < 0.001). Successful treatment with SAIDs was associated with idiopathic diffuse or nodular scleritis with a high degree of scleral inflammation (>2+) (OR = 4.70, P = 0.001). Successful treatment with IMT was associated with diffuse or nodular scleritis with associated systemic disease (OR = 1.57, P = 0.047), mainly potentially lethal (OR = 17.41, P=0.007), and necrotizing scleritis (OR = 4.73, P = 0.026). Successful treatment with BRMs was associated with diffuse or nodular scleritis with associated systemic disease (OR = 3.15, P < 0.001). This study did not require institutional review board approval because the information does not contain any subject identifiers. CONCLUSIONS: Patients with idiopathic diffuse or nodular scleritis with a low degree of scleral inflammation or without ocular complications may respond to NSAIDs. Patients with idiopathic diffuse or nodular scleritis with a high degree of scleral inflammation may respond to SAIDs. Patients with diffuse or nodular scleritis with associated systemic disease may respond to IMT or BRMs. Patients with necrotizing scleritis may respond to IMT, mainly alkylating agents. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Evaluation of intraocular reactivity to metallic and ethylene oxide contaminants of medical devices in a rabbit model.

OBJECTIVE: To evaluate the intraocular reactivity to metallic and ethylene oxide (EO) contaminants of ophthalmic devices in rabbits. DESIGN: Two experimental animal studies. PARTICIPANTS: Thirty-five New Zealand white rabbits. METHODS: A metallic exposure study and an EO exposure study were performed. In the first study, both eyes of 25 rabbits were equally allocated to intracameral injections of alumina 0.2 µg, alumina 20 µg, copper sulfate 0.4 µg, copper sulfate 20 µg, or an aqueous control. In the second study, 10 rabbits were allocated (5 per group) to receive intracamerally an ophthalmic viscosurgical device (OVD) exposed to EO or not exposed to EO (control). All eyes were examined by slit lamp at baseline and 3, 6, 9, 24, 48, and 72 hours after exposure, with dilated indirect ophthalmoscopy being performed at 24 and 72 hours. Tonometry was performed only in the first study. MAIN OUTCOME MEASURES: Grade of corneal clouding, anterior chamber (AC) flare, AC cells, AC fibrin, iridal hyperemia, cell and fibrin on the lens surface, vitreous haze and cells, lens opacities, intraocular pressure, and onset time. RESULTS: For metallic compounds at the study's low doses, mean inflammatory grades were 0.2 or less above the control for all responses at all time points. For the high-dose alumina, mean inflammatory grades peaked at 6 to 9 hours at 0.5 to 0.7 above the control responses for conjunctival congestion, iris hyperemia, AC cells, flare, and fibrin and declined over the remaining time points. For the high-dose copper sulfate, mean inflammatory grades peaked between 3 and 24 hours at 1.2 to 1.8 above the control responses for conjunctival congestion, iris hyperemia, AC cells, flare, fibrin, and corneal clouding, then subsequently declined. The intraocular pressure changes appeared significant for only high-dose copper sulfate, with mean declines of 4.3 to 7.5 mmHg at 6 to 72 hours. No clinically meaningful differences in ocular inflammation were observed between the OVD exposed to EO and the OVD not exposed to EO. CONCLUSIONS: Alumina and copper sulfate did not cause clinically meaningful ocular inflammation at the low study levels (levels expected with ophthalmic devices). Ethylene oxide exposure of an OVD was not associated with inflammation.

An investigation of enzymatic detergents as a potential cause of toxic anterior segment syndrome.

OBJECTIVE: To investigate whether enzymatic detergents used in cleaning ophthalmic surgical instruments can cause toxic anterior segment syndrome (TASS)-like responses in a rabbit model. DESIGN: Randomized, investigator-masked, controlled experimental animal study. PARTICIPANTS: Thirty-five New Zealand white rabbits. METHODS: The rabbit eyes were randomized into 7 treatment groups to receive intracameral injection of 1 of 3 different doses of Medline Dual Detergent or Enzol Detergent, or sterile limulus amoebocyte lysate reagent water as a control. The eyes were evaluated for anterior segment inflammation at baseline and at 1, 3, 6, 24, 48, and 72 hours after treatment by slit-lamp biomicroscopy. MAIN OUTCOME MEASURES: Anterior chamber (AC) inflammation, including cells, flare, fibrin, and iris injection; time course of inflammation; and residual detergent levels in luminated instruments. RESULTS: Moderate to marked injection of the iris vessels was seen as early as 1 hour after treatment with the enzymatic detergents in 41 of 60 eyes, with the response being more severe in the Enzol Detergent-exposed eyes. Severe iris hemorrhages were accompanied by blood in the AC in 13 eyes, which usually persisted through 72 hours, with an associated increase in AC cell and flare. Corneal haze was present in 52 of 56 eyes 1 hour after treatment, but was mild and resolved within 24 hours in all but the Enzol 4.5%-exposed eyes. Median AC cell and flare peaked at 6 hours and resolved by 48 hours. CONCLUSIONS: Enzymatic detergents caused a severe but unusual response from the iris when injected intracamerally into rabbit eyes. This response has not been reported in humans with TASS. The time course of inflammation was faster (peak at 6 hours) and resolved more quickly (within 48 hours) than TASS. Simulated cleaning and extraction studies indicate that the level of residual detergent to which a patient could be exposed is significantly less than the lowest dose used in this study. Because that low dose caused no significant observations other than injection of the iris vessels, these results do not support residual enzymatic detergents on surgical instruments as a cause for TASS.

The Food and Drug Administration's Proactive toxic anterior segment syndrome Program.

Toxic anterior segment syndrome (TASS) is a rare inflammatory condition usually observed within the first 48 hours after uncomplicated anterior segment surgery. Over the decades since its initial description, a number of TASS outbreaks have been reported. For a few of these outbreaks, the inciting factors were identified, but for the majority, the precipitating factors were often postulated but not confirmed. In light of the limitations identified in these outbreak investigations, the Food and Drug Administration's (FDA's) Center for Devices and Radiological Health staff has embarked on a number of activities aimed at mitigating medical device-related TASS outbreaks. Under the FDA-designed Proactive TASS Program (PTP), FDA scientists have conducted animal studies to better explore the inflammatory potential of suspected ophthalmic device contaminants implicated in prior cases of TASS. For contaminants displaying a TASS-like reaction in these animal models, the FDA scientists have developed analytic test methods to measure the level of those contaminants in or on ophthalmic devices. Moreover, FDA researchers have developed methods to better capture the clinical information necessary to assist investigations of potential future outbreaks. Last, the FDA has partnered with the Centers for Disease Control and Prevention to facilitate a potential TASS investigation, including expediting the analysis of potentially contaminated medical devices. The PTP is an example of the FDA proactively developing test methods and disease surveillance methods geared toward protecting the public's health.

Rabbit intraocular reactivity to endotoxin measured by slit-lamp biomicroscopy and laser flare photometry.

OBJECTIVE: To evaluate the ocular reactivity of the rabbit to an intracameral injection of a dispersive ophthalmic viscosurgical device (OVD) containing various levels of bacterial endotoxin using slit-lamp biomicroscopy and laser flare photometry. DESIGN: Experimental, randomized, masked animal study. PARTICIPANTS: Thirty Dutch-Belted rabbits. METHODS: The rabbits were randomized into 6 groups to receive 0.05 ml of a hydroxypropyl methylcellulose-based dispersive OVD to which had been added one of 5 different doses of bacterial endotoxin ranging from 0.02 to 1.4 endotoxin units (EUs) or a vehicle control to both eyes. The eyes were evaluated for anterior segment inflammation at baseline and 3, 6, 9, 24, 48, and 72 hours after injection using slit-lamp biomicroscopy and laser flare photometry. MAIN OUTCOME MEASURES: Corneal clarity and anterior chamber (AC) inflammation. RESULTS: All the corneas remained clear throughout the study. Anterior chamber cells were seen at 6, 9, and 24 hours in 60% to 100% of the eyes intracamerally injected with endotoxin-containing OVD, and the response declined rapidly after 24 hours. A dose-response effect was seen between the concentration of endotoxin and the AC cell response. The aqueous flare response in eyes injected with the 2 highest doses of endotoxin was significantly greater (P<0.05) than that of controls. The amounts of fibrin observed in the AC were random, with no apparent dose-response effect seen. The flare values as obtained by laser flare photometry were consistent with the slit-lamp biomicroscopy flare findings up to grade 3+. However, the increase in laser flare value seemed to level off in eyes with more than 3+ flare. Neither measure of flare correlated with endotoxin level. CONCLUSIONS: Among the parameters evaluated in this study, the AC cell response, evaluated by slit-lamp biomicroscopy and graded using a standard grading system, was found to be the most reliable indicator of the amount of endotoxin in the dispersive OVD. The use of laser flare photometry alone does not seem to be useful in detecting an ocular response to endotoxin contamination in OVDs.

Rabbit ocular reactivity to bacterial endotoxin contained in aqueous solution and ophthalmic viscosurgical devices.

OBJECTIVE: To describe the ocular reactivity of the rabbit to bacterial endotoxin contained in an aqueous medium and in a cohesive and a dispersive ophthalmic viscosurgical device (OVD). DESIGN: Experimental, randomized animal study. PARTICIPANTS: Seventy-five New Zealand white rabbits. METHODS: This study was performed using 75 rabbits to evaluate the ocular reactivity to bacterial endotoxin contained in Dulbecco's phosphate-buffered saline (DPBS), a cohesive OVD, and a dispersive OVD. For each test material, 25 rabbits were randomized into 5 groups and were exposed to the test material containing 0.75 endotoxin units (EU), 0.25 EU, 0.08 EU, and 0.02 EU of endotoxin or the vehicle control. The rabbits in each group received bilateral intracameral injection of 0.05 ml of the same test material. All eyes were examined by slit-lamp biomicroscopy at baseline, 3, 6, 9, 24, 48, and 72 hours after injection. At 24 and 72 hours, slit-lamp biomicroscopy (and additionally indirect ophthalmoscopy) was performed through dilated pupils. MAIN OUTCOME MEASURES: Corneal clouding, anterior chamber (AC) flare, cells and fibrin, vitreous haze and cells, cells and fibrin on lens surface, lens opacities, and onset time. RESULTS: The inflammation seen after exposure to the 3 endotoxin-spiked materials followed the same general time course. Anterior chamber cells, flare, iris hyperemia, and conjunctival congestion were seen as early as 3 hours. They started to diminish after 6 hours (DPBS eyes) and 9 hours (OVDs) and were not detectable at 48 and 72 hours, respectively. The AC inflammation was more severe in the OVD eyes than in the DPBS eyes. Anterior chamber fibrin was seen in the OVD eyes only, which persisted through 72 hours in many eyes. A trend toward a dose-response relationship was seen for AC cells and flare and the presence of cells and fibrin on the lens surface in all 3 treatment groups in the first 24 hours. CONCLUSIONS: Inflammation was seen after intracameral injection of as little as 0.02 and 0.08 EU in OVD and DPBS eyes, respectively. Observed responses to intracamerally injected endotoxin in OVDs were more severe and of longer duration than those in aqueous medium.