Elsevier

Ophthalmology

Volume 106, Issue 10, 1 October 1999, Pages 1915-1923
Ophthalmology

Verteporfin photodynamic therapy retreatment of normal retina and choroid in the cynomolgus monkey1☆,

Presented in part at the Association for Research in Vision and Ophthalmology annual meeting, Fort Lauderdale, Florida, May 1997.
https://doi.org/10.1016/S0161-6420(99)90401-3Get rights and content

Abstract

Objective

This study evaluated the effect of repeated photodynamic therapy (PDT) applications on normal primate retina and choroid using an intravenous infusion of liposomal benzoporphyrin derivative (verteporfin).

Design

This was an experimental study in a primate model.

Animals/controls

Six cynomolgus monkeys were used as experimental subjects and one monkey was used as a control subject.

Intervention

Three consecutive PDT treatments at 2-week intervals were applied over the center of the fovea or the optic nerve of each eye. Verteporfin was delivered by intravenous infusion at a dose of 6 mg/m2, 12 mg/m2, or 18 mg/m2. Laser irradiation was then applied using a diode laser (689 nm) with light doses and spot sizes kept constant.

Main outcome measures

Findings were documented by fundus photography, fluorescein angiography, and light and electron microscopy.

Results

A cumulative dose response was seen angiographically and histologically with more severe damage to the retina and choroid noted at higher dye doses. Photodynamic therapy applied to the macula using the 6-mg/m2 verteporfin dose showed recovery of choriocapillaris, with mild retinal pigment epithelium and outer photoreceptor damage at 6 weeks. At this dose, the optic nerve showed few focal sites of axon atrophy and capillary loss. Treatments over the macula using the 12-mg/m2 and 18-mg/m2 doses led to chronic absence of choriocapillaris and photoreceptors at 6 weeks. One of two optic nerves became atrophic after PDT applications using dye doses of 12 mg/m2, and both optic nerves became atrophic in the 18-mg/m2 dye dose group.

Conclusion

Limited damage to the retina, choroid, and optic nerve was present in primates treated with multiple PDT sessions using 6 mg/m2 verteporfin with light doses and the timing of irradiation kept constant. However, PDT using higher dye doses of 12 mg/m2 and 18 mg/m2 led to significant chronic damage to the normal retina, choroid, and optic nerve.

Section snippets

Animals

Animals were used in accordance with the Association for Research in Vision and Ophthalmology resolution on the use of animals in research and in accordance with guidelines developed by the Animal Care Committee of the Massachusetts Eye and Ear Infirmary. Seven cynomolgus monkeys weighing 1.8 to 4.3 kg were anesthetized for all procedures as described previously.12, 13

Photography

Fundus photography and fluorescein angiography were performed with a Canon Fundus CF-60Z camera (Lake Success, Long Island, NY)

Fundus photography

Retinal whitening Figure 1, Figure 2 was observed after the initial PDT treatment in all cases. However, in the foveal treatment groups, severe whitening (characterized by whitening with mild obscuration of retinal vessels) was seen in several of the higher verteporfin dose study eyes (Table 2). Whitening at 24 hours after initial PDT was not apparent at 24 hours after the second or third application session. Crescents of whitening, however, were noted at the periphery of lesions when

Discussion

This study shows that recovery from serial treatments of normal retinal and choroidal areas in primate eyes appears to be related to the verteporfin dye dose when the light dose and the timing of irradiation are kept constant. Treatment parameters for this study were selected based on previous studies from this laboratory and from parameters under investigation in phase 1 and phase 2 clinical trials.11, 12, 13, 16, 17 The treatment parameters in the phase 1 and phase 2 study included a

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    • Cited by (0)

    ☆

    Supported in part by QLT Phototherapeutics, Inc., Vancouver, British Columbia, Canada; the Massachusetts Lions Eye Research Fund (J.W.M.); and Research to Prevent Blindness (J.W.M.).

    1

    The Massachusetts Eye and Ear Infirmary is an owner of a patent covering the use of verteporfin and photodynamic therapy. Should the Massachusetts Eye and Ear Infirmary receive royalties or other financial remuneration related to that patent, Drs. Miller and Gragoudas would receive a share of same in accordance with the Massachusetts Eye and Ear Infirmary’s institutional Patent Policy and Procedures, which includes royalty-sharing provisions. As faculty members of the Harvard Medical School, they also adhere to their general Faculty Policies on Integrity in Science, which govern research and conflict of interest issues.

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    Copyright © 1999 American Academy of Ophthalmology, Inc. Published by Elsevier Inc. All rights reserved.