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Background: Disease-modifying antirheumatic drugs (DMARDs) have been suggested in the treatment of inflammatory ophthalmological diseases. The aim of the present study was to investigate the effects of these DMARDs on bovine retinal function., Methods: Bovine retina preparations were perfused with a standard solution. After recording stable electroretinograms the nutrient solution was substituted by a DMARD medium with varying concentrations of different drugs (etanercept and infliximab) for 30 min. Afterwards b-wave recovery was observed., Results: Significant decreases in the b-wave amplitude (p < 0.05) were found for etanercept 0.5 mg/ml (p = 0.0022). Infliximab 2 mg/ml (p = 0.1276) did not result in any statistically significant b-wave reduction., Conclusion: The presented data suggest that infliximab might have the better safety profile than etanercept., (© 2015 S. Karger AG, Basel.)

Purpose: Abnormalities in electroretinograms (ERG), such as reduced amplitudes and delayed implicit times of a- and b-wave and oscillatory potentials (OPs), are one of the earliest features of diabetic retinopathy prior to obvious vascular changes in diabetic retinas. We have previously shown that serum levels of advanced glycation end products (AGEs) are correlated with a delayed latency of OPs in type 2 diabetic rats. However, the pathological role of AGEs in ERG abnormalities remains unclear. We examined here whether high-affinity DNA aptamer directed against AGEs (AGE-aptamer) prevents ERG abnormalities in experimental type 1 diabetic retinopathy., Methods: Streptozotocin-induced diabetic rats or control rats received continuous intraperitoneal infusion of either AGE-aptamer or control aptamer via an osmotic mini pump for 16 weeks. Anthropometric, metabolic, and hemodynamic variables were measured, and an ERG was performed., Results: Although AGE-aptamer did not affect body weight, fasting and random blood glucose, HbA1c, blood pressure, or lipid parameters, it completely prevented the increase in serum AGE levels as well as the reduction of a- and b-wave and OP amplitudes in diabetic rats., Conclusion: The present study demonstrated for the first time that AGE-aptamer prevents abnormalities in ERG in experimental diabetic retinopathy probably by blocking the harmful effects of AGEs., (© 2015 S. Karger AG, Basel.)

Background: Dye solutions such as indocyanine green (ICG) are used for the staining of intraocular structures. The aim of the presented study was to investigate the effects of ICG on bovine retinal function using different concentrations of ICG., Methods: Bovine retina preparations were perfused with a standard solution and the electroretinogram was recorded. The nutrient solution was substituted by an ICG solution at varying concentrations for 45 min. Afterwards the preparations were reperfused with standard solution for at least 85 min., Results: Significant reductions in b-wave amplitude were found for concentrations of 0.0025% (p = 0.0099) and 0.025% (p = 0.0378). For the concentration of 0.025%, the b-wave amplitude remained significantly decreased (p = 0.0082) after the observation period, but a full recovery of the b-wave was observed for the concentration of 0.0025% (p = 0.1917)., Conclusion: Intraocular application of sufficient ICG concentrations for internal limiting membrane staining seems not possible without interfering with retinal function., (© 2014 S. Karger AG, Basel.)

Purpose: To investigate the effects, and their reversibility, of multiple oral voriconazole doses on a variety of visual tests in healthy male volunteers., Methods: Single-center, double-blind, randomized, placebo-controlled, parallel-group study in 36 volunteers who received voriconazole (n=18, 400 mg every 12 h on day 1, then 300 mg every 12 h for 27.5 days) or matched placebo (n=18). Electroretinograms (ERGs) and ophthalmological examinations were performed at screening, throughout the study and at follow-up., Results: Fifteen (83.3%) volunteers treated with voriconazole experienced ≥1 treatment-related visual adverse events (AEs); these included enhanced visual perceptions, blurred vision, color vision changes and photophobia. No serious AEs were reported. Voriconazole reduced from baseline scotopic maximal a- and b-wave amplitude, shortened implicit time and decreased oscillatory potential amplitude compared with placebo. Under photopic conditions, the 30-Hz flicker response amplitude was significantly reduced and was accompanied by a slight but nonsignificant prolongation of peak time. These effects did not progress in degree over the treatment period, and mean changes from baseline in ERG parameters were similar to placebo by day 43 (14 days after end of treatment). In the first week, color vision discrimination was impaired in the tritan axis, although this resolved by end of treatment and was similar to placebo by day 43. Mean deviation in the static visual field indicated increased sensitivity following voriconazole treatment, correlating with decreased amplitude in conjunction with shortened implicit time., Conclusions: Effects of voriconazole on altered visual perception, ERG, color vision and static visual field thresholds are nonprogressive over a treatment period and reversible. It is hypothesized that voriconazole has a pharmacological effect on rod and cone pathways including a possible mechanism of disinhibition that reversibly puts the retina in a more light-adapted state and leads to increased relative contrast sensitivity., (© 2014 S. Karger AG, Basel.)

Purpose: To compare the effect of a taurine-containing intraocular irrigation solution (PuriProtect TM) to a standard irrigation solution (BSS TM) we evaluated the retinal function using an electroretinogram (ERG) and analyzed the survival of retinal ganglion cells on isolated whole mount retinas., Materials and Methods: During ERG recordings, each irrigation solution was superfused for 45 min with the relevant irrigation solution. To investigate the effects on photoreceptor function, 1 m M asparate was added to obtain a-waves.The recovery of the a- and b-wave was monitored after superfusing the retinas with standard medium again. To evaluate the percentage of dead ganglion cells, retinas were stored for 24 h at 4°C in darkness and after staining the retinas with ethidium homodimer-1 the retinas were analyzed using fluorescence microscopy., Results: The application of standard medium supplemented with 2 m M taurine resulted in a significant increase of the b-wave amplitude compared to standard medium alone. The a-wave amplitudes showed no significant changes under taurine supplementation. Compared to standard medium BSS showed no significant decrease in b-wave amplitudes, but a significant decrease ina-wave amplitudes. In contrast to BSS there were no significant changes in the a- or b-wave amplitudes detectable after the application of PuriProtect. At the end of the washout period no significant changes in a- or b-wave amplitudes were recorded for any tested irrigation solution. Retinas stored for 24 h in PuriProtect or in standard medium with taurine had a statistically significant smaller amount of dead cells than retinas stored in standard medium without taurine supplementation., Conclusions: BSS does not seem to be an ideal irrigation solution, because it compromises the a-wave in the ERG. In contrast to BSS, PuriProtect showed no significant impact on the ERG and showed a better long-term effect on ganglion cell survival. Taurine supplementation,therefore, seems to be neuroprotective and its supplementation to an intraocular irrigation solution favorable for the retina.

Purpose: To describe the long-term outcome of canthaxanthin retinopathy., Methods: We identified 13 patients with small golden particles near the macular region among a group of 35 patients with known consumption of canthaxanthin somewhen between 1983 and 1988. One long-term follow-up examination was possible in 5 of 13 cases after 16-24 years. The examinations included determination of visual acuity, the Amsler grid, slit lamp examination, perimetry, electro-oculography, electroretinography, optical coherence tomography and fluorescein angiography., Results: Complete disappearance of the golden particles took approximately 20 years. The patients in our study were asymptomatic and no functional defect related to canthaxanthin could be detected., Conclusions: Ingestion of canthaxanthin causes no long-term adverse effects., (Copyright © 2011 S. Karger AG, Basel.)

Aim: To evaluate the in vitro effects of bevacizumab (Avastin®) on the electroretinogram (ERG) in rats using a model of isolated perfused retina ERG recording., Methods: Retinas were isolated from rat eyes and placed in a chamber continuously perfused with a nutrient solution. The ERG was recorded every 3 min. Once the ERG b-wave amplitude was at a steady state, bevacizumab was added at concentrations of 0.25 and 0.5 mg/ml to the perfusion medium for 3 h., Results: We observed no effect on ERG amplitudes or kinetics when bevacizumab was added to the perfusion medium. In addition, we found no significant differences in the survival curves of the b-wave and PIII wave during the application of bevacizumab between bevacizumab-exposed retinas and control retinas., Conclusions: We demonstrate that bevacizumab has no in vitro toxic effects on the ERG of isolated perfused rat retina. Our study supports the retinal safety of bevacizumab with respect to retinal function., (Copyright © 2011 S. Karger AG, Basel.)

Aims: Experimental retinal research has gained great importance due to the ophthalmic pharmacotherapy era. An increasing number of drugs are constantly released into the market for the treatment of retinal diseases. In this review, animal species, animal models and toxicity assays in retinal research are discussed., Methods: An extensive search of the literature was performed to review various aspects of the methods of investigation of drug toxicity. The different types of animal species, as well as single animal models available for the evaluation of safety and efficacy of retinal pharmacotherapy, were identified. In addition, a large variety of reported laboratory techniques were critically examined., Results: In vitro studies are the first-line experiments for the development of a new drug for retinal diseases, using retinal pigment epithelial cells and other cell lines. The next step involves in vivo animal studies where nonhuman primates are considered the gold standard. However, cost and legal issues make their use difficult. Mice and rats provide genetically controlled models for investigations. Pigs, dogs and cats represent good large-size animal models, while rabbits are one of the most used species for retinal toxicity evaluations. Various laboratory methods were identified, including light microscopy, electron microscopy, electroretinography and new emerging methods, such as optical coherence tomography and scanning laser ophthalmoscopy for experimental purposes., Conclusions: A great number of animal species and models are available that simulate retinal diseases and provide experimental data for further human use. Work with animal models should include properly designed toxicity assays to obtain reliable results for safety and efficacy., (Copyright 2010 S. Karger AG, Basel.)

Full-field electroretinography (ERG) using contact lenses with built-in LED was performed on albino rats, and used to evaluate the visual toxicity of sodium iodate (NaIO(3)). Experiment 1 was carried out to determine the optimal conditions in rats relating to stimulus intensity, background illumination, and light adaptation period. As a result, we found that a full-field ERG was recorded under the following conditions: stimulus intensity: -3.5 log cd s/m(2) in rod response; background intensity and light adaptation period: 10 cd/m(2) and 10 min in cone and flicker responses. Experiment 2 was carried out to confirm the usefulness of full-field ERG using rats with retinal toxicities induced by NaIO(3). Male rats were given NaIO(3) intravenously at a dose of 50 mg/kg. ERG was recorded before administration and after 3, 8, 24 h, and 7 days of administration, and histopathological analysis was conducted after 8 h of administration. The rod response disappeared completely at 3 h, based on a reduced maximal response and oscillatory potentials. On the other hand, cone and flicker responses were still present at 8 h. All responses disappeared on the 7th day. These findings indicate that the retinal toxicity induced by NaIO(3) was expressed first in rods, followed by cones. There were no microscopical changes after 8 h of administration, although the rod responses had completely disappeared by this time. These results suggest that full-field ERG in rats using an LED contact lens is useful for the separate evaluation of toxic effects on rods and cones.

Purpose: Optimal screening for ocular toxicity caused by chloroquine and hydroxychloroquine is still controversial. With the multifocal pattern electroretinogram (mfPERG), a new electrophysiological technique has recently become available to detect early changes of ganglion cells. In this study this new technique is applied to a series of 10 patients seen consecutively receiving long-term chloroquine medication., Methods: In 10 patients receiving chloroquine medication, clinical examination, Amsler visual field testing and computerized color vision testing were performed. If toxicity was suspected, automated perimetry was carried out. In addition, in all patients conventional pattern electroretinogram (PERG) and mfPERG testing were performed., Results: On clinical examination 8 patients showed no chloroquine-associated maculopathy, while 2 patients did. Of these 2, only 1 reported abnormalities when viewing the Amsler chart, while automated perimetry showed typical, ring-like paracentral scotomas in both affected patients and color vision was significantly abnormal. In the normal patients, 4 of 8 had a mild color vision disturbance, which correlated to age-related macular changes. The amplitudes of the PERG and the central (approximately 10 degrees ) responses of the mfPERG were markedly reduced in chloroquine maculopathy, while the latencies were unchanged. The peripheral rings of mfPERG (ranging to 48 degrees ) were not affected by chloroquine toxicity. Both PERG and mfPERG were less affected by age-related macular changes., Conclusions: The reduction of PERG and central mfPERG responses in chloroquine maculopathy may help with the early detection of toxicity., (Copyright 2004 S. Karger AG, Basel)

To investigate the potential of transscleral coulomb-controlled iontophoresis (CCI) for repetitive delivery of acetylsalicylic acid (ASA) into the eye, a total of 50 rabbits was included in this study. Fourteen animals received serial CCI treatment. Fourteen animals underwent CCI with either ASA or balanced salt solution (BSS) for at least 6 days at 24- and 48-hour intervals. Eighteen animals received a single CCI application, while 18 animals were injected with 15 mg ASA/kg body weight intravenously. HPLC analysis was performed to determine the levels of salicylic acid (SA) in ocular tissues. Apart from clinical follow-up, 2 rabbits in the ASA and BSS groups were examined by electroretinography, and 2 animals were examined histologically. Though high concentrations of SA were measured, no alterations were observed clinically, histologically and electrophysiologically. Repetitive CCI demonstrated its potential as a topical drug delivery system for ASA into the eye. This transscleral delivery of ASA resulted in significant and sustained intraocular concentrations of SA without side effects. Iontophoresis may be advantageous in clinical administration maintaining therapeutic levels of ASA while avoiding adverse effects associated with the systemic administration of nonsteroidal anti-inflammatory drugs., (Copyright 2003 S. Karger AG, Basel)

The purpose of this study was to investigate whether nipradilol, a beta-blocker having both vasodilating and alpha(1)-blocking activities, can protect retinal cells from the injury induced by ischemia and reperfusion. Rats were anesthetized and, after an intravitreal injection of nipradilol, the intraocular pressure was raised for 45 min to induce retinal ischemia and reperfusion. Before, and 3 and 7 days after the ischemia, electroretinograms were recorded. After the ischemia, the mean amplitude of the b-waves in rats receiving 5 microl of 1.0 x 10(-6) M nipradilol was significantly larger than of controls (injected with phosphate-buffered saline). Histologically, the reduction in the number of retinal ganglion cells (1.0 x 10(-6) M), and the thickness of the inner and outer plexiform layers and the inner nuclear layer (1.0 x 10(-6), 10(-7) and 10(-8) M) was suppressed by nipradilol. These results indicate that nipradilol protected the retina against retinal ischemia and reperfusion and should be considered for therapeutic use in cases of transient retinal ischemia., (Copyright 2002 S. Karger AG, Basel)

This study was performed to examine the retinal toxicity of trovafloxacin, a broad-spectrum fourth-generation fluoroquinolone, in rabbit eyes after intravitreal injection. The left eyes of 20 albino rabbits were divided into four groups, and each was injected intravitreally with 0.1 ml of trovafloxacin in a 50-microg, 100-microg, 250-microg or 500-microg concentration. The right eyes of these rabbits served as control and received normal saline solution. Retinal function was assessed from the electroretinogram (ERG), and retinal structure was also examined by ophthalmoscopy and histologic study (light microscopy). The intravitreal injections of 50 microg, 100 microg, and 250 microg trovafloxacin did not significantly change the ERG a-wave, b-wave or the oscillatory potential throughout the follow-up period of 4 weeks. While no ERG changes were observed at 4 weeks after injection, in the 3 eyes that received trovaloxacin 500 microg/0.1 ml, the a-wave amplitudes showed a diminution of 56-49% and those of b-waves one of 53-44% of the preinjection amplitudes at 4 weeks after injection, but oscillatory potentials remained unchanged in the other 2 rabbits intravitreally injected with 500 microg trovafloxacin. However, in none of the injected eyes and the control eyes in all groups were ophthalmoscopically visible fundus changes and histologic abnormality observed. The results suggest that intravitreally injected trovafloxacin at a dose of up to 500 microg is nontoxic to the rabbit retina. If future studies in other species confirm our findings, intravitreal trovafloxacin may be a good alternative in the treatment and prevention of clinical bacterial endophthalmitis., (Copyright 2001 S. Karger AG, Basel)

The effect of an intravitreal injection of ornithine on the retina of rats was studied electroretinographically. Rats were injected intravitreally with 5 microl of 0.02, 0.25 and 0.5 M ornithine. Electroretinograms (ERGs) were recorded before, and 1, 3 and 9 days after the injection. High doses of ornithine (0.5 M) reduced while low doses (0.02 M) enhanced the ERG amplitudes. The implicit time of the a-wave was delayed at all concentrations after ornithine injection, which suggests that implicit times may be a more sensitive parameter of the ornithine effect. There were significant changes in the stimulus intensity necessary to obtain the one half of the maximum amplitude of the b-wave that may have been caused by damage of the photoreceptors and retinal pigment epithelium cells by ornithine. We conclude that the effect of ornithine on retinal function is dose dependent and can either enhance or depress the ERG amplitudes., (Copyright 2001 S. Karger AG, Basel.)

The retinal toxicity of botulinum toxin A (BTA) was electroretinographically studied in rats. Sixteen rats were injected intravitreally with 10 ng of BTA. A response-amplitude series was recorded before and 1, 6, 13 and 21 days after the injection of BTA. BTA did not alter the amplitude and the peak latency of the a-wave. The amplitude of the b-wave was not changed except for 2 rats, in which the b-wave was diminished. The peak latency of the b-wave was significantly prolonged after injection of 10 ng BTA (p < 0.05). Except for these latter 2 rats, the results indicated that the dosage used therapeutically appears to have no deleterious effect on retinal integrity or function at least in the short term, but multiple injections or higher doses of BTA could alter retinal function.

The onset of reperfusion and the recovery of the ERG b-wave following retinal ischemia was examined among three groups of rats: group 1 (n = 12) and group 2 (n = 6) received pretreatment with NG-nitro-L-arginine (20 mg/kg, i.p., 2 h before ischemia) followed by intravenous injection of saline (group 1) or of 200 mg/kg L-arginine (group 2) 5 min before the end of ischemia; group 3 (n = 7) received saline pretreatment followed by intravenous injection of saline as a control. Group 1 showed delayed onset of reperfusion compared to the other two groups and a reduction in the rate of the b-wave recovery compared to the control on the 1st day after reperfusion (group 1 vs. group 3; p = 0.0357). The L-arginine posttreatment significantly increased the b-wave recovery (group 2 vs. group 1; p = 0.0005 on day 1 and p < 0.0006 on day 3). The rate of the b-wave recovery in group 1 was inversely proportional to the time to establish complete reperfusion. Inhibition of nitric oxide synthase during the initial phase of reperfusion may worsen the recovery of the b-wave following retinal ischemia, at least in part, by inhibiting establishment of reperfusion.

Platelet-activating factor (PAF) has been shown to alter the trans-retinal potential recorded from light-stimulated isolated retina. In the present study, we investigated the effect of cholera and pertussis toxins on PAF-induced impairment of the electroretinogram (ERG). Administered alone, 2 x 10(-7) M PAF induced a very marked and rapid drop in the b-wave amplitude. When 75 micrograms/l of cholera toxin was coadministered with PAF in the perfusion solution, no b-wave drop was observed, suggesting that the effect of PAF on retinal function was mediated by GTP-binding protein (G protein). Similarly, a low dose of pertussis toxin (5 micrograms/l) was sufficient to antagonize the action of PAF on the ERG. Our results suggest that the irreversible and deleterious effect of PAF on ERG is mediated by a G protein mechanism, located in the neural retina.

Cytomegalovirus retinitis is the most frequent ocular opportunistic infection in AIDS patients. In selected cases intravitreal injections of foscarnet may be the sole therapeutic possibility. The retinal toxicity of the drug, however, has not yet been thoroughly investigated. Our present study in the rabbit eye concerns the retinal toxicity of 2, 4, and 6 intravitreal injections of 3.6 mg of foscarnet, using ophthalmoscopy, histology and electrophysiology to evaluate retinal damage. The results show that foscarnet may be employed intravitreally without substantial damage to the retina, but only in short courses of injections when no other therapeutic possibility may be utilized.

We examined the effects of the antioxidant enzymes, 10,000 U/kg of superoxide dismutase (SOD) and 50,000 U/kg of catalase (CAT) on cat electroretinograms during the reperfusion after retinal ischemia. The intravenous administrations of SOD and CAT promoted the recovery of the c-wave after 30 min of ischemia but not the b-wave. At 5 min after onset of reperfusion, SOD- and CAT-treated eyes showed 90 and 110% recovery of the c-wave amplitude respectively, against 50% recovery in the untreated eyes. These results suggested that the oxygen-derived free radicals affected the retinal pigment epithelium at the early period of reperfusion.

Chloroquine retinopathy is a severe toxic retinal impairment which may result in loss of vision by alterations of the retinal pigment epithelium and photoreceptors. Currently, there is no specific treatment for this retinopathy. Platelet-activating factor (PAF) is known to modulate retinal function and is one of the major immunomediators of the retina. In order to test the possible involvement of PAF in chloroquine-induced retinopathy and the effectiveness of PAF antagonists in the prevention of this condition, we investigated the effects of BN 50730, a specific PAF antagonist, on the electroretinogram (ERG) of the isolated rat retina exposed to chloroquine. When retinas from normal rats were perfused with chloroquine (10(-6) M), a marked and rapid decrease in b-wave amplitude was observed. In contrast, chloroquine had no effect on the b-wave of the retina isolated from animals pretreated with the PAF antagonist BN 50730 (30 mg/kg/day, i.p., for 5 days). The results obtained indicate that (i) chloroquine is a toxic drug for retinal function, (ii) PAF plays a key role in the mediation of chloroquine retinopathy and (iii) PAF antagonists may constitute valuable agents for the treatment of this retinal impairment.

We studied the intraocular concentration of flomoxef sodium in nonvitrectomized and vitrectomized eyes of albino rabbits after intravenous administration of 100 mg/kg flomoxef sodium. The concentration of flomoxef sodium in the vitreous body was undetectable (< 0.1 micrograms/ml) in nonvitrectomized eyes. Retinal toxicity of flomoxef sodium was investigated with ophthalmoscopy, electroretinography (ERG) and light microscopy after intravitreal injection of 200, 500, 1,000 and 2,000 micrograms flomoxef sodium in albino and pigmented rabbits. No ERG changes were induced with 200 micrograms. Other higher doses caused transient ERG changes. After the 200-micrograms injection, the intravitreal concentration decreased exponentially, the half-life being 4.4 h. The antibacterial activity, broad coverage and low intravitreal toxicity of flomoxef sodium suggest that this compound may be used to treat bacterial endophthalmitis.

Twelve patients with juvenile (insulin-dependent, type I) diabetes were treated either with prostacyclins or placebo in a double-masked randomized study. The electroretinogram (ERG) was recorded before, 1 day and 8 months after treatment. An analysis of variance and covariance was carried out to evaluate possible treatment or time effects on the a and b waves and the oscillatory potentials of the ERG. Mean values of potentials displayed a decrease of amplitude and an increase of latency over the follow-up period in all patients. No statistically significant difference between treated and placebo groups could be proven.

The neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) was used to destroy the indoleamine-accumulating amacrine cells located in the cat's retina. With 100 micrograms of 5,7-DHT, the alterations in the electroretinogram (ERG) were present in all of the treated eyes and the morphological changes were confined to some of the processes in the inner plexiform layer. The ERGs recorded from treated eyes consisted of negative waves at low intensities and depressed b wave amplitude at higher intensities. The duration of the b wave was not altered but the oscillatory potentials were strongly depressed. The changes were probably permanent. The differences in the ERG changes in cats and rabbits were suggested to arise from the differences in signal processing in the inner retina of rabbits and cats.