Many drugs are known to induce ocular toxicity (corneal opacity or keratopathy in particular) on continued administration, e.g. chlorpromazine, chloroquine, chlorphenteramine, iprindole, tamoxifen, tilorone, quinacrine, amiodarone and meperidine. This drug induced ocular disorder appears quite similar to the lipidosis encountered in a variety of genetic metabolic disorders of lipid metabolism. While the biochemical abnormalities in the genetic lipidoses have been studied in much detail and have been largely identified, ultrastructural and histocytologic data represent the sole source of information from which current conclusions have been drawn regarding the nature and etiology of the drug induced disorder. Several hypotheses exist regarding the possible mechanisms of drug induced keratopathy. It has been suggested that these drugs, by virtue of their chemical characteristics (lipophyllic cationic bases) preferentially concentrate in the lysosomal structures and may subsequently precipitate or complex with intralysosomal phospholipids, thereby producing areas of easily observed opacity in either the cornea or lens. Direct access of the drug to the avascular cornea and lens would presumably be necessary in order for this hypothesis to be valid. An alternative hypothesis is that the ocular abnormalities are secondary manifestations of a primary, iatrogenic (drug induced) disorder of phospholipid metabolism, which might explain the phenotypical similarity between chlorpromazine and amiodarone induced keratopathy and that seen in Fabry's disease. An indirect, peripheral effect of these drugs on factors controlling phospholipid metabolism could induce such a biochemical abnormality.
The specific aim of this proposal is to develop an animal model for drug induced ocular toxicity, which duplicates the histopathological and biochemical lesions seen in man. The successful development of such an animal model will provide the necessary preliminary data for a more exhaustive study on the detailed elucidation of the underlying etiology and pathophysiology of this drug induced keratopathy. This information can then be used in the evaluation of strategies designed to minimize or eliminate these undesirable side effects in patients who are refractory to alternative drug therapy.
