Binding of Drugs to Eye Melanin Is Not Predictive of Ocular Toxicity

Leblanc, Bernard; Jezequel, S. G.; Davies, Teifion; Hanton, Gilles; Taradach, C.

doi:10.1006/rtph.1998.1243

Cited by 167 publications

(119 citation statements)

References 61 publications

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“…Possibly, the drug binds to melanin in ocular tissues such that only a small amount is available to reduce IOP. 36 Glaucoma medicines are not easily available to our patients in rural areas. 37,38 Most patients are poor and where these drugs are available they are fake and ineffective.…”

Section: Discussionmentioning

confidence: 99%

Pattern of presentation and outcome of surgical management of primary open angle glaucoma in Kano, Northern Nigeria

Abdu

2007

Ann Afr Med

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Background: Primary open angle glaucoma (POAG) is one of the leading causes of avoidable blindness. Unlike blindness from cataracts, glaucomatous optic nerve damage is irreversible, and prevention of glaucoma is one of the priorities of World Health Organization (WHO) Vision 2020 program. POAG is the commonest type of glaucoma and affects about 33.1 million people worldwide. This study is a five year review of 71 eyes of 63 patients who had trabeculectomy. The study evaluates the pattern of presentation and modality of surgical treatment in our environment. Methods: Records of all patients with primary open angle glaucoma operated over a five year period was retrieved. Information extracted included patients bio data, visual acuity, gonioscopic findings, intra ocular pressure as measured with applanation tonometer before and after surgery, and recorded in mmHg. Perimetry was done with 2 m tangent screen and recorded in a perimetry chart. All the patients had trabeculectomy with application of anti metabolite (5fluorouracil). Extra capsular cataract extraction with or, without posterior chamber intra ocular lens implantation was done on 13 patients. Biometry was not done on patients with cataract. Surgery was done on better eye first in all patients. Results: There were 71 eyes of 63 patients. The male to female ratio was 3:1. The age ranged between 18 to 75 years. 8 patients were below the age of 30 years. One third of the patients were between the ages of 50 to 59 years. At presentation 12 patients (19%) had normal vision (WHO vision category O), 26 patients (41%) were visually impaired, 12 patients (19%) were severely visually impaired and 13 patients (21%) were blind (from co existing cataracts). The cup disc(c: d) ratio assessed before surgery was 0.5 in 9 eyes (13%), 31 eyes (53%) had c: d ratio 0.6 to 0.8 and 18 eyes had c: d ratio of 0.9. All the patients had open anterior chamber angles (Schafer grade 3 and 4). Perimetric changes were; mild peripheral constriction in 5 eyes (8%), peripheral constriction with arcuate scotoma in 19 eyes (26%), constricted fields of 30°or less in 34 eyes (48%), and in 13 eyes there was inability to fixate on target. IOP before surgery was 21 to 30 mm Hg in 12 eyes (17%), and above 31 mm Hg in 69 eyes (83%). Post operative IOP of 10 to 15 mm Hg was obtained in 58 eyes (82%) and 11 eyes (15%) had IOP of 16 to 20 mm Hg. Only 2 eyes (3%) had IOP in the lower twenties. Conclusion:Primary open angle glaucoma is characterized by late presentation. Trabeculectomy with application of 5FU is the surgical treatment of choice in our environment and give good intra ocular pressure control. There is need to increase public awareness on glaucoma to limit this type of avoidable blindness. Key words: Glaucoma, late presentation, avoidable blindness,tTrabeculectomyResume Introduction: Angle d'ouverture du glaucome primaire (AOGP) est l'une des causes principales de la cécité évitable. Contrairement à la cécité de la cataracte dégât au glaucomateuses nerf optique est irréversible, et ...

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Section: Discussionmentioning

confidence: 99%

Pattern of presentation and outcome of surgical management of primary open angle glaucoma in Kano, Northern Nigeria

Abdu

2007

Ann Afr Med

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“…Drugs can bind to melanin with different affinities depending on their physicochemical properties. Chloroquine has a high affinity to melanin (Tsuchiya et al 1987;Leblanc et al 1998;Eves et al 1999), while binding of tamoxifen and toremifene to melanin has not been reported. The different affinities of the drugs to melanin may partly explain the differences detected between pig retinal pigment epithelium and D407 cells.…”

Section: Discussionmentioning

confidence: 99%

The Phagocytosis of Rod Outer Segments is Inhibited by Selected Drugs in Retinal Pigment Epithelial Cell Cultures

Mannerström

Mäenpää

Toimela

et al. 2001

Pharmacology & Toxicology

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The effects of tamoxifen, toremifene and chloroquine on the phagocytosis of rod outer segments by retinal pigment epithelium were evaluated in human retinal pigment epithelial cell line D407 and pig retinal pigment epithelial cell culture. Retinal pigment epithelial cells were exposed to different concentrations of tamoxifen (1-20 mM), toremifene (1-20 mM) and chloroquine (1-1000 mM), and challenged with FITC-labeled rod outer segments for 24 hr. The phagocytized (bound and ingested) rod outer segments were measured fluorometrically, and the effect of the drugs on the phagocytosis was determined. The cytotoxicity of the drugs was evaluated by measuring their effects on mitochondrial enzyme activities (WST-1-test). The results showed that the test compounds inhibited the phagocytosis of rod outer segments in both D407 and pig retinal pigment epithelial cells. The phagocytic activity was more sensitive to tamoxifen (EC 50 7.2 mM for D407 cells and 3.6 mM for pig retinal pigment epithelial cells) and toremifene (EC 50 6.2 mM and 3.1 mM respectively) than to chloroquine (EC 50 77.2 mM for D407 cells). The inhibition of rod outer segment phagocytosis in both cell cultures started at lower dose levels of test compounds than the cytotoxicity indicated by the WST-1-test. The experiments were carried out both in serum-free medium and serum-containing medium. Serum seemed to be a critical factor in the medium and caused difficulties in the interpretation of the results.The phagocytosis of rod outer segments by the retinal pigment epithelium is one of the most important functions of these cells and essential for retinal homeostasis (Young 1969). The mechanisms of phagocytosis are complex and incompletely understood. The stages involve the recognition and binding of rod outer segments to retinal pigment epithelial cells, ingestion of rod outer segments, and digestion by lysosomal enzymes. The phagocytosis of rod outer segments is a highly specific receptor-mediated process (Hall & Abrams 1984;Mayerson & Hall 1986). However, cultured retinal pigment epithelial cells of one species are able to phagocytize rod outer segments isolated from another species (Reid et al. 1992). Disturbances in the phagocytosis can result in the accumulation of rod outer segment debris in the subretinal space, which can cause retinal degeneration and eventual blindness (Bok & Hall 1971; Edwards & Szamier 1977). Several agents, such as lysosomal enzyme inhibitors (Kennedy et al. 1994), protein glycosylation inhibitors (Hall et al. 1988;Boyle & McLaughlin 1990) and compounds that increase intracellular cAMP, reduce the rod outer segment phagocytosis by retinal pigment epithelial cells (Edwards & Bakshian 1980;Hall et al. 1993;Kuriyama et al. 1995).Chloroquine has been shown to be oculotoxic. It accumulates in the retina and causes degeneration in photoreceptors and retinal pigment epithelium in vivo (Rosenthal et al. 1978). In vitro chloroquine reduces the viability of retinal Author for correspondence: Hanna Tähti, Medical School, Universi...

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“…Several drugs are known to show significant affinity to melanin and the retinal pigmented epithelium is one of targets for systemically dosed drugs with melanin affinity (Mecklenburg and Schraermeyer, 2007). On the other hand, there are several drugs which bind to melanin without ocular effects (Leblanc et al, 1998). Therefore, it is important to accumulate background data of both albino and pigmented rodents for appropriate ocular risk assessments of drugs with or without melanin affinity (Imawaka et al, 1997;Shibuya et al, 1997).…”

Section: Ocular Pathological Findings and Risk Assessmentsmentioning

confidence: 99%

General considerations in ocular toxicity risk assessment from the toxicologists’ viewpoints

et al. 2015

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-Humans commonly obtain approximately 80% of external information from vision. Since loss of vision markedly decreases quality of life, risk assessments for visual toxicity of new drugs are extremely important. However, the ICH S4 guideline for nonclinical toxicity study of new drugs only indicates a brief instruction for ophthalmologic examinations, and submitted data for drug approval according only to this guideline are not always considered sufficient in light of ocular toxicity risk assessments. The eye is an assembly of many specialized sub-organs which have specific functions, and its integral maintenance of homeostasis plays an important role of visual function. When only a part of integrity of functions is lost, overall function of the eye might be commonly disturbed. Therefore, understanding of anatomy and physiology of these sub-organs may help know mechanisms of observed ocular changes. In ophthalmologic examinations in nonclinical toxicity studies, it is vital to understand the principles and features of each examination. Comparisons of findings between pre and post drug treatment as well as considerations of species differences, strain differences, age differences, and location/degree of abnormalities are essential. In addition, many kinds of spontaneous ocular findings are well known in experimental animals. To differentiate treatment-related changes from spontaneous findings, mastering basic skills for ophthalmologic examinations and taking advantage of collection of background data are necessary. For ocular toxicity risk assessments, while an evaluation of "sight-threatening" effects is most critical matter, "quality of vision" related findings also should be considered. To extrapolate animal data to human, clinical significances of ocular toxicity findings should be evaluated based on considerations for "species differences", "safety margins", "reversibility", and "risk-benefit balance". In addition, a detailed recording of features of lesions is also important for an appropriate judgment of clinical significance of ocular findings. For preparation of histopathological specimens, careful sampling of organs and suitable selection of fixatives are important. To accurately orient ocular lesions in the specimen for histopathological examinations, securing close communications prior to necropsy among ophthalmologists, gross necropsy pathologists and histopathology technicians should be effective and helpful. It is impossible to detect all ocular changes in histopathological examinations; that is, there is a limitation in histopathological examinations. Therefore, for ocular toxicity risk assessments, comprehensive evaluation with pathological findings as well as other results of various examinations in toxicity studies should be considered. In conclusion, for ocular toxicity risk assessments, integrated judgments from all examination data in nonclinical toxicity studies are required. To achieve appropriate risk assessments which can be extrapolated to human, close communications and sharing...

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Binding of Drugs to Eye Melanin Is Not Predictive of Ocular Toxicity

Cited by 167 publications

References 61 publications

Pattern of presentation and outcome of surgical management of primary open angle glaucoma in Kano, Northern Nigeria

Pattern of presentation and outcome of surgical management of primary open angle glaucoma in Kano, Northern Nigeria

The Phagocytosis of Rod Outer Segments is Inhibited by Selected Drugs in Retinal Pigment Epithelial Cell Cultures

General considerations in ocular toxicity risk assessment from the toxicologists’ viewpoints

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