Validation of the use of zebrafish larvae in visual safety assessment

Richards, Frances M.; Alderton, Wendy K.; Kimber, G.M.; Liu, Z.; Strang, Isobel; Redfern, William S.; Valentin, Jean‐Pierre; Winter, Matthew J.; Hutchinson, Thomas H.

doi:10.1016/j.vascn.2008.04.002

Cited by 82 publications

(59 citation statements)

References 63 publications

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“…However, this process is partly hindered due to a lack of predictive, convenient methods as well as the high expense associated with testing drug candidates in mammals. 63,114 For many years, researchers have been using zebrafish assays for drug toxicity screening with a view to provide early drug safety assessments. 115,116 So far, zebrafish have been used to predict drug-related cardiotoxicity, ototoxicity, developmental toxicity, neurotoxicity, oculotoxicity, and many more.…”

Section: Drug-related Ophthalmological Toxicity Assessment In Zebrafishmentioning

confidence: 99%

“…In one of those, 27 drugs, 19 of which with known and 8 with no record of oculotoxicity in humans, were assessed in zebrafish using OMR. 63 Of the 19 compounds, 13 drug compounds, including chlorpromazine, quinine, digoxin, AZ compound 1, deferoxamine, flecainide, ganciclovir, ibuprofen, minoxidil, thioridazine, and vardenafil, were found to be oculotoxic in zebrafish. This finding is supported by another similar study that tested nine known drug compounds with oculotoxicity and found that 7 out of the 9 compounds had adverse effect on visual function of zebrafish as well.…”

Section: Drug-related Ophthalmological Toxicity Assessment In Zebrafishmentioning

confidence: 99%

“…62 Nevertheless, some drugs can inhibit motility, thus ending up with false impression on visual behaviour assays that is examined by the fish movement such as OMR, therefore further assessment in such condition is necessary. 63 Finally, defects in all processes and systems that are involved from the processing of visual information to the actual observed change of visual behaviour, such as motor function, have to be seen as possible sites that could influence results. As such, processing of the visual signal in the visual cortex (in higher vertebrates) or optic tectum (in case of zebrafish) only serves as a prerequisite for induced behaviour, therefore dysfunction not only in the visual cortex but also other brain areas involved in decision-making could potentially lead to unresponsiveness to the visual stimulation.…”

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confidence: 99%

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Zebrafish—on the move towards ophthalmological research

Chhetri

Jacobson

Gueven

2014

Eye

138

114

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Millions of people are affected by visual impairment and blindness globally, and the prevalence of vision loss is likely to increase as we are living longer. However, many ocular diseases remain poorly controlled due to lack of proper understanding of the pathogenesis and the corresponding lack of effective therapies. Consequently, there is a major need for animal models that closely mirror the human eye pathology and at the same time allow higher-throughput drug screening approaches. In this context, zebrafish as an animal model organism not only address these needs but can in many respects reflect the human situation better than the current rodent models. Over the past decade, zebrafish have become an established model to study a variety of human diseases and are more recently becoming a valuable tool for the study of human ophthalmological disorders. Many human ocular diseases such as cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration have already been modelled in zebrafish. In addition, zebrafish have become an attractive model for pre-clinical drug toxicity testing and are now increasingly used by scientists worldwide for the discovery of novel treatment approaches. This review presents the advantages and uses of zebrafish for ophthalmological research.

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Section: Drug-related Ophthalmological Toxicity Assessment In Zebrafishmentioning

confidence: 99%

Section: Drug-related Ophthalmological Toxicity Assessment In Zebrafishmentioning

confidence: 99%

mentioning

confidence: 99%

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Zebrafish—on the move towards ophthalmological research

Chhetri

Jacobson

Gueven

2014

Eye

138

114

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“…Indeed, of drugs entering clinical development, druginduced organ toxicity is the leading factor associated with failure to reach the market (Kola & Landis, 2004). The toxic effects of drugs on vision are significant, with ~6.8% of drugs removed from clinical trials because of visual toxicity (Richards, et al, 2008). Notably, adverse effects associated with drug-induced ocular toxicity are difficult to manage once they occur, and even though cardiovascular and gastrointestinal toxicity are of higher incidence, ocular toxicity has the highest negative influence on drug development Verdugo-Gazdik, Simic, Opsahl, & Tengowski, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Behavioural tests have long been used to assess vision and to screen for visual deficits (Brockerhoff, et al, 1995). An optomotor response assay (OMR) examines the position of zebrafish placed in elongated chambers to moving black and white stripes presented underneath the transparent chambers (Neuhauss, et al, 1999;Richards, et al, 2008). The optokinetic response (OKR) assay is commonly used assay to examine larval eye movements to a rotating black-and-white striped drum (Brockerhoff, 2006;Fleisch & Neuhauss, 2006).…”

Section: Introductionmentioning

confidence: 99%

Early safety assessment of human oculotoxic drugs using the zebrafish visualmotor response

Deeti

O’Farrell

Kennedy

2014

Journal of Pharmacological and Toxicological Methods

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Publication informationJournal of Pharmacological and Toxicological Methods, 69 (1): 1-8 Publisher ElsevierItem record/more information http://hdl.handle.net/10197/7931 Publisher's statementThis is the author's version of a work that was accepted for publication in Journal of Pharmacological and Toxicological Methods. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Pharmacological and Toxicological Methods (VOL 69, ISSUE 1, ((2014) Abstract Introduction: Many prescribed drugs can adversely affect the eye by causing damage to the function of visual pathways or toxicity to the retina. Zebrafish have the potential to efficiently predict drugs with adverse ocular effects at pre-clinical stages of development. In this study, we explore the potential of using a semi-automated visual behaviour assay to predict druginduced ocular toxicity in wild-type zebrafish larvae. Methods: 3 dpf larvae were treated with six known oculotoxic drugs and five control drugs in embryo medium containing 0.1% DMSO. After 48 hours, larvae were assessed using the visualmotor response (VMR), an assay which quantifies locomotor responses to light changes; the optokinetic response (OKR), a behavioural assay that quantifies saccadic eye responses to rotating stimuli; and the touch response, a locomotor response to tactile stimuli. Results: 9 of 10 negative control drugs had no effect on zebrafish visual behaviour. 5 of the 6 known oculotoxic drugs (digoxin, gentamicin, ibuprofen, minoxidil and quinine) showed adverse effects on zebrafish visual behaviour assessed by OKR or the more automated VMR. No gross morphological changes were observed in treated larvae. The general locomotor activity of treated larvae, tested using the touch response assay, showed no differences with respect to controls. Overall the VMR assay had a sensitivity of 83%, a specificity of 100% and a positive predictive value of 100%. Discussion: This study confirms the suitability of the VMR assay as an efficient and predictive pre-clinical approach to evaluate adverse ocular effects of drugs on visual function in vivo.

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Predicting Human Adverse Drug Reactions from Nonclinical Safety Studies

Valentin

Keisu

Hammond

2010

Pharmaceutical Sciences Encyclopedia

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An adverse drug reaction (ADR) is an adverse event where a causal relationship between the adverse event (AE) and the medicinal product is at least a reasonable possibility. Lack of safety remains the major cause of attrition during clinical development, accounting for approximately 35–40 percent of all drug discontinuation. This article focuses on the nature, frequency, and consequences of ADRs in two different clinical situations.

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Validation of the use of zebrafish larvae in visual safety assessment

Cited by 82 publications

References 63 publications

Zebrafish—on the move towards ophthalmological research

Zebrafish—on the move towards ophthalmological research

Early safety assessment of human oculotoxic drugs using the zebrafish visualmotor response

Predicting Human Adverse Drug Reactions from Nonclinical Safety Studies

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