Lens and eye toxicity research最新文献

Post surgical cataracts induced by corticosteroids as immunosuppressive agents were investigated in recipients undergoing triple therapy with ciclosporin and the results were compared with those who had therapy without ciclosporin administration. The subjects of the triple therapy group were 54 cases with a mean age of 31.7 years. The mean observation period was 25 months. The incidence of posterior subcapsular cataract was 77.8%. 7.9% of them developed progressed cataract. Early cataractous changes were noticed within one post-operative year in half of the cases. 3 out of 22 cases that were followed up over three years showed progressed cataractous changes. The total doses of methylprednisolone during the period of the first post-transplant year in recipients with Grades I or II and over Grade III were 7.7 +/- 1.9g and 9.8 +/- 3.6g, respectively. They were significantly higher than those in the conventional therapy group. However, a 2 to 3 g reduction in the total dose of steroids during the first year had no influence on cataract occurrence.

The preliminary conclusions of a survey of possible non-animal alternatives to the Draize rabbit eye irritancy test, recently conducted for the Commission of the European Communities, are presented. The various types of alternatives to animal tests are reviewed in terms of their current state of development and validation, and also their potential in relation to the type of exposure, level of testing, type of testing, type of effect, location of effect, and type of test material. Various problems concerning the availability and quality of in vivo eye irritation data, and the use of this data in in vitro/in vivo comparisons, are highlighted. Finally, the use of step-wise and integrated animal/non-animal and non-animal/non-animal test systems and strategies are discussed.

Epithelial wound closure following superficial corneal abrasions precipitates a complex series of cellular changes in the stroma. Transmission electron microscopy and light microscopy have demonstrated that keratocytes in the anterior stroma show prominent cytoplasmic process and granularity within an hour after this injury. Cell degeneration follows rapidly, with almost complete depletion of these keratocytes by 6-12 hours. Regeneration then occurs by 24-48 hours. These findings were confirmed in-vivo by tandem-scanning confocal light microscopy in rabbits. The optical sectioning capability of this instrument allowed us to demonstrate the three-dimensional array of fibroblast process, their subsequent condensation, and loss by sequential examinations on the same animals. Cell shrinkage and other fixation artifacts common in corneal histological sections were avoided by this technique. Using this method, we investigated the corneal cytotoxicity of an antimitotic agent, mitomycin-C and a muscarinic antagonist, atropine sulphate. Mitomycin-C, an antimetabolite used in pterygium treatment, led to irreversible keratocyte depletion even after four days of observation. However, cellular reaction to the wound were attenuated by atropine sulphate suggesting that it may be useful as a novel inhibitor of fibroblast proliferation.

This paper reviews advances in the validation of alternative methods for eye irritation testing since the 1987 publication, A Critical Evaluation of Alternatives to Acute Ocular Irritation Testing (1). We have highlighted details of methods that appear promising and identified the minimum needs and endpoints necessary to develop a battery or batteries of in vitro tests to evaluate eye irritancy. We have recommended a series of workshops to provide identified batteries for specific classes of chemicals or for specific uses of eye irritancy testing. We have also identified the need for consensus meetings and peer-reviewed publication to ensure that the most predictive batteries become parts of validation studies. Finally, we note that academic scientists, industry, government and the animal protection community must work together in order to replace in vivo eye irritancy testing with appropriately validated in vitro methods.

Electroretinography was used to investigate the preventive action of Ginkgo biloba extract (EGb 761) in experimental chloroquine-induced retinopathy in rats. EGb 761 contains flavones and anthocyanosides known for their oxygenated radical scavenging properties. Chronic administration of chloroquine (20 days) caused an overall lengthening of the duration of the ERG b-wave, together with delayed peaking. These anomalies became more marked with increased duration of treatment. In rats treated simultaneously with chloroquine and EGb 761 no such modification of the electroretinogram (ERG) was observed. These results suggest that retinal toxicity may be related to a localized inflammation releasing oxygenated free radicals and/or PAF. EGb 761 may thus afford a useful preventive treatment for chloroquine-induced retinopathy, and generally for xenobiotic retinotoxicities.

Light Therapy is a new treatment for patients with Seasonal Affective Disorder (SAD), a depressive state occurring during the winter as a result of decreased sunlight. The treatment involves placing the patient in front of a light box (2-10,000 lux) for approximately 30 min to 1 hour per day during the winter months. Although there have been no reports of damage to the eye from this treatment with light alone there is increased risk in light damage to the lens and retina if these depressed patients are being treated with antidepressant/neuroleptic drugs concurrently with their light therapy. As we have been previously reported certain drugs, having absorptions longer than 295 nm can act as photosensitizers resulting in enhanced light damage to the eye. Using a screening method developed by Roberts, we examined the potential phototoxicity of a variety of antidepressant and neuroleptic drugs.

The alkaloid vincristine is widely used for its anti-leukemic and anti-tumor activity. However, the drug also displays considerable toxicity, particularly for the retina. Indeed, vincristine has been shown to induce alteration of photoreceptor outer segments in animals and impairment of scotopic vision in man. This type of retinopathy is an inflammatory disease in which PAF may be implicated and for which specific PAF antagonist may have a therapeutic role. Thus, we measured the effects of a new hetrapezine derived PAF antagonist, BN 50730, on a vincristine-induced retinopathy in the rat. Retinal impairments were established by recording several parameters of the electroretinogram (ERG) obtained from isolated retina. Our results indicate that, first, the increase in PIII duration induced by vincristine is significantly reduced by BN 50730 administration and, second, the decrease in the value of the PIII/b wave ratio caused by vincristine is partially inhibited by treatment with BN 50730. These experiments suggest that PAF is implicated in vincristine retinopathy and demonstrate the therapeutic effect of a specific antagonist of the mediator.

Eye irritation testing is a salient public issue and continues to escalate on the public agenda. Issues relevant to this milieu include legislative proposals to ban animal use for cosmetic testing, adequacy of the current standard (viz., the Draize Eye Irritancy Test), availability of non-animal methodologies, validation paradigm for new testing models, international harmonization of testing standards and methods, and the regulatory role in product testing and enforcement. The Food and Drug Administration (FDA) feels that enactment of legislation proposed to ban animal use from testing products for safety would pose serious problems from a public health perspective. FDA encourages the development of alternative test methods and is aware that many such tests are in various stages of evolution. At this time, however, none of these tests has been accepted by the scientific community as total replacement to the Draize test. FDA's basic positions on the use of non-animal alternatives are as follows: 1) The use of animal tests by industry to establish the safety of regulated products is necessary to minimize the risks from such products to humans, 2) The Draize eye irritancy test is currently the most valuable and reliable method for evaluating the hazard or safety of a substance introduced into or around the human eye, and 3) No non-animal tests are presently available to completely replace the Draize. FDA is actively involved with U.S. and international groups to harmonize protocols for product development, evaluate the current status of non-whole animal methodologies, and standardize testing requirements. The Agency has recently participated in several scientific symposia evaluating the status of non-whole animal methods in toxicity testing. Moreover, FDA representatives are currently scheduled to participate in international meetings and workshops planned for the immediate future addressing several issues in product safety determination.

A Triazin-derivative from a group of industrial chemicals was found to cause cataracts in albino rats during a subchronic toxicity study. To get more insight into this effect, a study was designed with 20 albino (Wistar) and 40 pigmented (black-hooded FB 30) rats using different dosages of the test compound. In a 3 months study period, all rats were photographed with a Scheimpflug camera TOPCON SL-45 3 times, at a baseline examination, prior to any treatment, in the middle and at the end of the study period, prior to sacrifice. The black-and-white film (Kodak T-Max 400R) was standardly developed and evaluated with a Joyce-Loebl microdensitometer in 3 regions of the lens, the capsule, the cortex and the nucleus. The density data from the second and third examination clearly demonstrate that cataract development in the albino rats takes place in the cortical region, whereas in the pigmented rats it takes place in the cortical and partly in the nuclear region. In addition, one albino and two pigmented animals of the groups investigated developed bilateral mature cataracts. Differences in cataract morphology between albino and pigmented rats are presented by Eiben and Wegener (1). The results underline the importance of toxicity testings in pigmented rats, they evidence that the data derived solely from albino animals can be misleading.

Lens permeability has been shown to be compromised during galactose-induced cataract development in rats. Recent studies have demonstrated permeability and diffusion pathways as well as endocytotic activity in normal lenses of different species using tracers of different molecular weights. We investigated the permeability and diffusion of tracers in normal rat lenses and in lenses during cataract development using three different molecular weight tracers, lanthanum nitrate (LN, MW 430), ruthenium red (RR, MW 858.5) and horseradish peroxidase (HRP, MW 40.000) for this study. Sprague Dawley rats weighing 50gms were fed Purina Rat Chow with or without galactose. Our results, based on transmission electron microscopy, show that all tracers penetrated through the capsule and the basal portion of the intercellular spaces. While the diffusion of RR was restricted to the epithelial cell layer, LN and HRP were observed in intercellular spaces in cortical fiber cells. In the HRP "washout" studies, HRP could be readily removed from the intercellular spaces in the basal region in the epithelial cell layer. This and other observations suggest the presence of a barrier (tight-junction) in the apical region. Our studies also suggest an influx of tracers in the lens, specifically LN and HRP, through the equatorial region. The permeability of the tracers increased and endocytotic vesicles with tracers were often found associated with the lateral and basal membranes of epithelial cells in the galactose-fed rats at the precataractous and mature cataractous stages. This study provides further support for the presence of a tight-junction between epithelial cells and indicates the movement of tracers through the equatorial region. Moreover, it confirms previous observations that indicated alterations in lens permeability during galactose cataractogenesis.