Characteristics of corneal phospholipidosis induced by topical ocular application of chloroquine and amiodarone in rabbits

Abstract

Several cationic-amphiphilic drugs such as chloroquine and amiodarone are known to induce phospholipidosis in the cornea by systemic administration. However, the characteristics of ophthalmological and pathological changes when phospholipidosis-inducing drugs are topically applied have not been well studied. This study was conducted to investigate the characteristics of corneal changes caused by topical application of chloroquine and amiodarone to Japanese white rabbits. The changes were evaluated by ophthalmological, histopathological, and ultrastructural examinations. An in vivo confocal microscopy was also applied to the chloroquine-treated corneas. In both chloroquine- and amiodarone-treated corneas, diffuse cloudiness was observed by slit-lamp biomicroscopy, and its transparency increased with duration of dosing. Confocal microscopy showed punctate dots in the corneal epithelium. Histopathologically, cytoplasmic vacuolation was found in the corneal epithelium and keratocytes in both chloroquine- and amiodarone-treated eyes. Furthermore, foamy cytoplasm of the corneal endothelium was observed in the chloroquine-treated eyes. Ultrastructural examination showed multi-lamellar inclusion bodies or membrane-like debris in the lysosome-like vacuoles in the cytoplasm of corneal cells, which is a characteristic of the lesions of phospholipidosis. These changes disappeared after a withdrawal period. Continuous dosing of chloroquine resulted in corneal erosion and focal corneal opacity as shown by gross observation and slit-lamp biomicroscopy. Confocal microscopy could detect the corneal changes prior to the appearance of these ophthalmological changes. The present study showed that phospholipidosis caused by ocular administration of chloroquine and amiodarone first induces reversible diffuse corneal cloudiness. Confocal microscopy is a useful method for monitoring induction of corneal phospholipidosis.

Pathological Features of Corneal Phospholipidosis in Juvenile White Rabbits Induced by Ocular Instillation of Chloroquine or Amiodarone

“…Ultrastructural examination of the cornea in juvenile rabbits revealed cytoplasmic vacuoles composed of multilamellar inclusion bodies in lysosome-like vesicles, which is a characteristic of PLD (Halliwell 1997; Nonoyama and Fukuda 2008). This result indicates that topical ocular application of chloroquine or amiodarone induces PLD in juvenile rabbits, as previously noted in adult rabbits (Yamagiwa et al 2017). Continuous dosing of chloroquine or amiodarone induces diffuse corneal cloudiness and inflammatory changes in adult rabbits (Yamagiwa et al 2017).…”

“…This result indicates that topical ocular application of chloroquine or amiodarone induces PLD in juvenile rabbits, as previously noted in adult rabbits (Yamagiwa et al 2017). Continuous dosing of chloroquine or amiodarone induces diffuse corneal cloudiness and inflammatory changes in adult rabbits (Yamagiwa et al 2017). In this study, the incidence of diffuse corneal cloudiness was similar between juvenile and adult rabbits when chloroquine or amiodarone was applied to their eyes.…”

“…Several marketed ophthalmic pharmaceuticals also contain CADs as active ingredients, such as antimicrobial aminoglycosides (Raizman et al 2017). No studies have assessed the effects of ocular medication on corneal PLD in humans; however, drug-induced corneal PLD also develops after topical ocular application of chloroquine and amiodarone in rats and rabbits (Drenckhahn, Jacobi, and Lüllmann-Rauch 1983; Bockhardt, Drenckhahn, and Lüllmann-Rauch 1978; Yamagiwa et al 2017). These results suggest that the topical application of CADs containing ophthalmic pharmaceuticals has the potential to induce PLD.…”

Repeatability of Corneal Densitometry Measurements Using a Scheimpflug Camera in Healthy Normal Corneas

“… 4 It is also used to investigate the corneal effects of systemic diseases and drugs. 5 6 Different methods such as slit-lamp biomicroscopy, confocal microscopy, and Scheimpflug imaging are used to evaluate corneal transparency. 7 8 9 The Pentacam uses Scheimpflug principles to evaluate the transparency of the cornea and crystalline lens using the densitometry factor.…”