Histopathological and Laboratory Assessment of Visual Dysfunction

Heywood, R.

doi:10.2307/3429474

Cited by 3 publications

(4 citation statements)

References 17 publications

(18 reference statements)

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“…With these compounds for examples, myelin bodies were located in all layers of the retina and were especially prominent in ganglion and bipolar cells (Rosenthal 1978). All amphophilic cationic compounds have the potential to affect the retina in rats and form myelin bodies, but the same mechanism evidently does not occur in man (Heywood 1982).…”

Section: Discussionmentioning

confidence: 98%

“…A~ though there are a variety of chemicals known to produce retinotoxicity in laboratory animals, several drugs have been described to cause retinopathy in humans as a side effect of drug treatment (Grant 1986). Ocular toxicity induced by high doses of chemicals in laboratory animals is thought to be of little predictive value for human risk assessment because of the limited correlation with huma~ experience (Heywood 1982). The test material, 2-phenyl-APB-144, is a member of the diaminodiphenoxyalkane class of related compounds which were studied in the 1950s as a possible treatment for schistosomiasis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pathogenesis and reversibility of retinopathy induced by 1,4-bis (4-aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in pigmented rats

Lee

Valentine

1991

Arch Toxicol

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Pigmented male rats were administered a suspension of 0, 25, or 100 mg/kg 2-phenyl-APB-144 in corn oil by gavage. The rats were killed at 4 and 12 h, and at 1, 2, 4, 7, 14, 28, 57, or 84 days after a single oral administration. The primary site of retinopathy appeared to be the retinal pigment epithelial (RPE) cells. The RPE cells showed necrosis within 12 h post-exposure (PE) at 25 mg/kg and within 4 h PE at 100 mg/kg. Subsequently, photoreceptor outer segments (POS) were disrupted with a hyperplastic RPE cell response within 2 days PE. Intact photoreceptor inner segments (PIS) and RPE cells apposing closely with distal POS were important determinants for reversibility of the damaged POS. The damaged RPE cells were regenerated prior to restoration of normal POS. At 25 mg/kg, both the RPE cells and POS were damaged, but PIS were intact. The damaged POS were regenerated from intact PIS with closely apposing RPE cells. By 14 days PE, the damaged POS had partially regenerated and attained approximately one third to one half of their normal length. By 57 and 84 days PE, the damaged retina had regained an essentially normal structure. In contrast, at 100 mg/kg, the POS and PIS were extensively disrupted, with marked RPE cell hyperplasia after 7 days PE resulting in the formation of multiple retinal arcades (foldings), and rosettes by 14 days PE. Subsequently, retinal arcades and rosettes gradually disappeared as the result of extensive loss of PIS and POS with progressive migration of photoreceptor nuclei toward the Bruch's membrane after 28 days PE. Focal regeneration of POS was observed by 57 days PE where intact PIS and a single layer of regenerated RPE cells were apposed closely with distal POS. The POS regeneration did not occur where the RPE cells were denuded or hyperplastic RPE cells were present. The hyperplastic RPE cells were devoid of slender apical processes, closely enclosing the distal POS. Approximately 20-30% of the retina had partially regained a normal structure by 84 days PE.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Pathogenesis and reversibility of retinopathy induced by 1,4-bis (4-aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in pigmented rats

Lee

Valentine

1991

Arch Toxicol

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“…72 Ocular findings in animals may be difficult to correlate with ocular findings in humans, since some drugs that cause retinal lesions in laboratory animals do not appear to cause retinal changes in humans. 73 One reason may be binding of the compound to melanin.…”

Section: Microscopic Findings In Ocular Toxicity Studiesmentioning

confidence: 98%

Ocular Toxicity Assessment From Systemically Administered Xenobiotics

et al. 2013

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The eye is a unique sensory structure, which must be evaluated for toxicity to determine the safety of drugs, industrial chemicals, and consumer products. Changes in the structure and/or function of ocular tissues following systemic administration of a potential new drug in preclinical animal models can result in significant delays in the development of a new therapeutic and in some cases lead to termination of the development. The ability to detect and characterize ocular toxicity in preclinical models and to predict risk in patients is critically dependent on the preclinical testing strategy, the availability and use of state-of-the-art ocular safety assessment tools, and the knowledge of drug mechanism of action and the current regulatory environment. This review describes the design and execution of toxicity studies with the incorporation of current methods for in vivo assessment of ocular toxicity, including methods for detecting early changes in the eye. In addition, anatomical differences among laboratory animals, preparation of globes for examination, and iatrogenic and spontaneous ocular findings are described that can affect interpretation of toxicological findings. Finally, the correlation between nonclinical outcomes and clinical evaluations is discussed in terms of expected therapeutic uses, indications, and regulatory consequences of ocular effects.

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“…essential to detect the ocular injury, and the validity of these studies assumes that extrapolation Offprint requests to: K. P. Lee from animal to man is possible. In numerous cases, however, retinopathies induced by some chemicals in laboratory animals have not been confirmed by human clinical experience (Grant 1974;Heywood 1982).…”

Section: Introductionmentioning

confidence: 97%

Retinotoxicity of 1,4,-bis(4-aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in albino and pigmented rats

Lee

Valentine

1990

Arch Toxicol

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Albino and pigmented strains of rats were administered 0, 5, 25, 100 or 500 mg/kg 2-phenyl-APB-144 by gavage and were killed 14 days later. Although no ocular lesions were found in rats dosed at 5 mg/kg, similar dose-related retinopathy was found at 25, 100, or 500 mg/kg in both albino and pigmented rats. The primary target site appeared to be retinal pigment epithelial (RPE) cells and photoreceptor outer segments (POS). At 25 mg/kg or greater, multifocal retinal detachment with disrupted POS occurred where the RPE cells showed necrotic changes and contact loss with POS due to fragmentation of apical processes in the RPE cells. Also, RPE cells showed hyperplasia, migration, and phagocytic activity toward disrupted POS. The photoreceptor nuclei (outer nuclear cells) were displaced into the areas occupied by disrupted POS. At 100 or 500 mg/kg, multifocal or diffuse disruption of POS and photoreceptor inner segments (PIS) was observed with markedly proliferating RPE cells. The photoreceptor nuclei were disorganized, less numerous, and necrotic. Some photoreceptor nuclei directly apposed the RPE cells or Bruch's membrane due to the absence of both POS and PIS. The cytoplasm of RPE cells was loaded with phagosomes, disrupted lamellar discs, myelin bodies, and lysosomal residual bodies. The morphological changes appeared to be related to lysosomal dysfunction of the RPE cells. The presence of melanin pigment in the RPE cells did not appear to be the primary factor in the development of the retinopathy.

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Histopathological and Laboratory Assessment of Visual Dysfunction

Cited by 3 publications

References 17 publications

Pathogenesis and reversibility of retinopathy induced by 1,4-bis (4-aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in pigmented rats

Pathogenesis and reversibility of retinopathy induced by 1,4-bis (4-aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in pigmented rats

Ocular Toxicity Assessment From Systemically Administered Xenobiotics

Retinotoxicity of 1,4,-bis(4-aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in albino and pigmented rats

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