Ocular changes in beagle dogs following oral administration of CGS 24565, a potential hypolipidemic agent.

(11R)-N,15-dideoxo-1-deoxy-1,15-epoxy-11-hydroxy-4-0methy l-8-0-(2, 2-dimethyl-1-oxopropyl)-3-[4-¿(2,4, 6-trimethylphenyl)methyl¿-1-piperazinyl]rifamycin has been evaluated as a potential hypolipidemic agent. As part of a safety evaluation program, a 3-month oral toxicity study was performed in which CGS 24565 was administered to beagle dogs via gelatin capsules at 10, 50, or 300 mg/kg/day. Ophthalmoscopic examinations (using focal illumination and indirect opthalmoscopy) on day 83 (week 12) revealed bilateral adnexal and corneal changes affecting 5 dogs (3 males, 2 females, 300 mg/kg/day). Ophthalmoscopically, dogs from the 300 mg/kg dose level exhibited the adnexal changes characterized as ptosis, conjunctivitis, episcleritis, and relaxed membrane nictitans, while the corneal changes were characterized as posterior stromal edema (cloudy, diffuse opacity usually accompanied by deep neovascularization; the diffuse edema masked the complete evaluation of other ocular structures) and stromal infiltrates in the area of Decement's membrane (appeared to be multifocal, polymorphic changes/alterations in Decement's membrane, or endothelial swelling). No changes from normal were seen clinically in the eyes of other dogs on this experiment. In those dogs affected by the ocular changes caused by CGS 24565, a visual deficit in acuity was suspected. The corneal changes, as manifested, were suggestive of permanent, irreversible corneal damage. Subsequent ophthalmoscopic examinations performed at established intervals during weeks 15 through 26, revealed abatement of the adnexal changes, while the corneal changes, as described above, remained generally unchanged, confirming irreversibility of the corneal changes within the recovery period of 13 weeks. Light microscopy confirmed irreversible corneal neovascularization, vacuolar degeneration of the keratocytes at 300 mg/kg, and polymorphic infiltrates in the region of Decement's membrane. The results demonstrate that the cornea was the target tissue of toxicity for CGS 24565, and indicated that the findings represent a significant toxic effect. The correlation of histopathological findings support the hypothesis of the diagnosis of interstitial stromal degeneration/atrophy. The potential for a similar result to the cornea of humans does exist. Due to these changes and other toxic effects associated with this class of compound, further development was terminated.

The use of laboratory animals in toxicology: an ophthalmoscopic assessment.

In a recent text by Grant (3), approximately 2,800 substances are listed as having some type of untoward effect on ocular tissue. The kinds of substances that may cause toxic damage/effects range from carbolic acid (2) to oxygen (1). It is the purpose of this communication to briefly review ocular toxicology as investigated in laboratory animals.

Tapetal changes in beagle dogs following oral administration of CGS 14796C, a potential aromatase inhibitor.

CGS 14796C, cis-1-[(4-[(1-imidazolyl)methyl]-cyclohexyl)methyl)imidazole succinate, has been evaluated as a potential aromatase inhibitor. As part of the safety evaluation program, a 3-month oral toxicity study was performed in which beagle dogs were administered CGS 14796C by gavage at 5, 15, or 50 mg/kg/day. Ophthalmoscopically, changes in the tapetum lucidum affecting dogs from the 15 and 50 mg/kg dose levels were diffuse areas of pigmentation varying in appearance from a brownish peppered or mottled to a more uniform brown similar to that of the nontapetal area of the fundus. Tapetal reflectivity was absent or markedly reduced. Within the pigmented area, multiple islets (yellow, green, or orange) of tapetal cells were visible, suggestive of destruction of the tapetum. In no instance was retinal destruction, edema, vascular changes, or detachment observed. Ophthalmoscopic examinations performed during recovery revealed changes of slight increase in tapetal islets, suggestive of a slight progression and organization within the tapetum followed by an arrest of the toxic insult within the tapetal tissue. At light and electron microscopic examination of the ocular tissues, the lesions were tapetal cell degeneration/atrophy. These results demonstrated that the taptetum lucidum was a target tissue of toxicity for CGS 14796C, and indicated that the findings are without toxicological significance in atapetal species, including man, whose globes do not have this structure.

Tapetal changes in beagle dogs. I. Ocular changes after oral administration of a beta-adrenergic blocking agent--SCH 19927.

SCH 19927 [R,R)-(-)-2-Hydroxy-5-[1-hydroxy-2-[(1-methyl -3-phenylpropyl)amino]ethyl]benzamide hydrochloride) is a beta-adrenergic blocking agent which has vasodilating properties. In a subchronic oral toxicity study in beagle dogs, SCH 19927 was given by gavage at doses of 30, 60, and 90 mg/kg. Lesions were observed at weeks 13 and 19 in the tapetum lucidum, a light reflecting structure of the eye. The lesions consisted of focal to multifocal areas of discoloration of the tapetal portion of the ocular fundus, pigmentation in the tapetal area, and, in one dog, subretinal edema resulting in a focal retinal detachment. Light and electron microscopic examination of the ocular lesions demonstrated tapetal cell degeneration and necrosis with macrophages, lymphocytes, and occasional plasma cells in the tapetum and adjacent choroid. Local cellular infiltrates within the retina internal to the pigmented epithelium were observed in one dog (60 mg/kg) which was demonstrated to have focal retinal edema during the study. In a repeat study the lesion again occurred in tapetal beagle dogs but not in atapetal beagle dogs (90 mg/kg) or cynomolgous monkeys (360 mg/kg). The lesion had not occurred in a previous subchronic study in albino rats. These results demonstrated that the tapetum lucidum was a target organ of toxicity for SCH 19927 and indicated that the finding was without observable toxicological significance in animals, including man, whose eyes do not have this structure.

Multifocal retinal dysplasia in the Syrian hamster LAK:LVG (SYR).

Multifocal retinal dysplasia was diagnosed clinically in twenty-four of twelve hundred (2.0% incidence) LAK:LVG (SYR) Syrian Hamsters. The affected hamsters were part of twelve hundred animals to be used in oncogenic studies. Ther dysplastic retina were detected during ophthalmoscopic examinations of hamsters as young as 6 weeks and as old as 9 months. Ophthalmoscopically, the dysplastic foci varied from retinal streaks, sometimes called vermiform, to small, generally circular areas of cream-colored depigmentations. Blindness or othe apparent visual defects were not seen nor were the dysplasias associated with a generalized syndrome of disease. Histologic examination of the affected hamsters revealed focal dysplasias limited to the retina and were manifested as invaginations and rosette-like structures composed of elements of the photoreceptor layer, outer limiting membrane and outer nuclear layer. This paper describes the first incidence of a congenital retinal dysplasia found in an outbred strain of Syrian Hamster LAK:LVG (SYR), and correlates the ophthalmoscopic appearance and histopathology. In addition, a procedure for maintaining prolonged mydriasis for funduscopic photography is presented.

A rapid testing procedure to determine low levels of ocular irritation.

A new and rapid method for testing low levels of ocular irritation using a balanced incomplete block design, a new grading system, and statistical analysis of the results, has been developed. Two drops (0.1 ml) of 1 of 5 ophthalmic solutions were instilled into the conjunctival sac of the right or left eye of each of 10 New Zealand white [Deb:(NZW)] rabbits hourly for 9 hr on 4 consecutive da. Before the study and before the first instillation on each day, the eyes were examined with a direct ophthalmoscope, and the reactions were graded according to a modification of the system in the illustrated Guide for Grading Eye Irritation by Hazardous Substances. The new procedure showed that 1 of the 5 solutions elicited a significantly more severe (p less than or equal to 0.05) ocular response of redness, chemosis, and discharge than did any of the other 4 solutions. Previous testing of this solution in rabbits by standard laboratory procedures and the Draize method of grading ocular irritation failed to detect these reactions.

Cataracts in beagle dogs given diazoxide.

In two studies for toxicity, cataracts occurred in beagle dogs given diazoxide daily in high doses. Two of eighteen dogs given diazoxide intravenously at doses of 30.0 mg. per kilogram twice a day for fourteen days had reversible lenticular changes. These changes were not observed in dogs given 22.5 or 10.0 mg. per kilogram twice a day. By fifty-eight days after the last treatment, the cataracts had regressed or disappeared completely. In a study of diazoxide given orally for a maximum of seventy-eight weeks, cataracts developed in six of forty-two dogs given doses ranging from 50 to 200 mg. per kilogram daily, but none occurred in dogs receiving 15 or 30 mg. per kilogram daily. Hyperglycemia was observed at doses of 50 mg. per kilogram or higher. In five of the six dogs that had cataracts and hyperglycemia, vacuolation or absence of islet cells was seen on histologic examination of pancreatic tissue at necropsy. Ocular changes were attributed to the hyperglycemic effect of high doses of diazoxide given daily for prolonged periods. The daily doses given dogs in which cataracts developed were from ten to forty times that suggested in man (5 mg./kg.).