Ocular toxicity assessment from systemically administered xenobiotics: considerations in drug development.

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.

A current practice for predicting ocular toxicity of systemically delivered drugs.

The ability to predict ocular side effects of systemically delivered drugs is an important issue for pharmaceutical companies. Although animal models involving standard clinical ophthalmic examinations and postmortem microscopic examinations of eyes are still used to identify ocular issues, these methods are being supplemented with additional in silico, in vitro, and in vivo techniques to identify potential safety issues and assess risk. The addition of these tests to a development plan for a potential new drug provides the opportunity to save time and money by detecting ocular issues earlier in the program. This review summarizes a current practice for minimizing the potential for systemically administered, new medicines to cause adverse effects in the eye.

The pathophysiologic role of cyclo-oxygenases in the eye.

Cyclooxygenase isoenzymes (COX-1 and -2) catalyze the conversion of arachidonic acid to prostaglandins (PGs) and play a significant role in the health and disease of the eye. Experimental animal models of ocular diseases have been used to assess the effects of the selective COX inhibitors (COXIBs), and nonselective, nonsteroidal anti-inflammatory drugs (ns-NSAIDs) are currently employed in the management of various ophthalmic conditions. This paper provides a review of the comparative expression of COX-1 and COX-2 in the eye under normal and pathologic conditions, including the pathophysiologic role of PGs, and the effects of ns-NSAIDs and selective COX-2 inhibitors in the treatment of ophthalmic conditions.

Ocular melanosis in the Cairn Terrier: histopathological description of the condition, and immunohistological and ultrastructural characterization of the characteristic pigment-laden cells.

OBJECTIVE: To describe the microscopic features and lineage of proliferating/infiltrating pigmented cells in ocular melanosis of Cairn Terriers. Animals studied Forty-nine globes removed from 45 Cairn Terriers with ocular melanosis and three globes from control dogs were available for microscopic examination. PROCEDURES: All globes were examined histologically, eight affected and three control globes were also examined by immunohistochemistry, and three affected and three control globes by transmission electron microscopy. RESULTS: Large round pigment-laden cells infiltrated the anterior uvea, obscured the drainage angle and were present within the sclera and episclera of affected globes. Similar pigmented cells were present in lower numbers in the posterior segment of the globe, the optic nerve meninges and periphery of the optic nerve. Changes due to chronic glaucoma were present in many globes and some had evidence of uveitis. Many of the pigmented cells were immunoreactive to HMB45 and some were MITF and vimentin positive. One globe, which was inflamed when removed, had many pigmented cells that were CD18 immunoreactive. The other eyes had lower numbers of CD18 positive cells. The pigmented cells were not immunoreactive to smooth muscle actin, S-100, MART/Melan A, chromogranin A/B, PGP 9.5, synaptophysin, MNF116, AE1/AE3, and CD45. Ultrastructurally many of the pigmented cells had features typical of melanocytes while a smaller number appeared to be melanophages. CONCLUSIONS: Ocular melanosis in Cairn Terriers is characterized by an infiltration of pigment-laden cells predominantly, but not exclusively, within the anterior uvea and anterior sclera. Most of these cells appear to be melanocytes although a variable proportion are pigment-laden melanophages.

Acquired structural kyphoscoliosis in a captive adult female rhesus macaque (Macaca mulatta).

A female, wild-caught, rhesus macaque (Macaca mulatta), in captivity for 23 years and estimated to be older than 26 years, had an 8-year history of progressive spinal curvature. Scoliosis was initially noted 1 year after a therapeutic bilateral ovariectomy to treat endometriosis. Eight years after the initial diagnosis, the curvature had progressed to a structural (nonflexible), lumbar scoliosis with a curvature to the left and a structural thoracolumbar kyphosis. The spinal curvature was characterized radiographically by a severe, major lumbar curve to the left with vertebral rotation and severe thoracolumbar kyphosis. The Cobb method of measurement identified a major left lumbar curve of 80 degrees. When the animal's condition deteriorated, the animal was euthanized, and a necropsy with postmortem radiographic and microscopic examination was performed. Radiographically and grossly, multiple intervertebral disc spaces were narrowed along the entire spine with ventral bridging intervertebral spondylosis of the lumbar spine. Radiographically, vertebral bodies appeared to be less radiodense and multiple features of degenerative disc disease were present. No clinical evidence of concurrent neuromuscular or mesenchymal disease was noted, and development of lesions after bilateral ovariectomy suggested the kyphoscoliosis was secondary to osteopenia that developed as the result of a surgically induced estrogen deficiency.

An activin receptor-like kinase 5 inhibitor reduces collagen deposition in a rat dermal incision wound healing model.

BACKGROUND: Excessive dermal scarring is characterized by an overabundant deposition of extracellular matrix caused by fibrosis. The purpose of this study was to modify a rodent model of cutaneous healing for use in the development of compounds to minimize scarring, and to test the model with a small molecule inhibitor of transforming growth factor-ß type I receptor, activin receptor-like kinase 5, because this class of inhibitors has been demonstrated to be effective in minimizing fibrosis in other organs. METHODS: The rodent model of cutaneous healing consists of uniform full-thickness incisional dermal wounds in rats. Wounds were allowed to heal by secondary intention, generally over a 14-day period. The usefulness of the model was tested by the application of an activin receptor-like kinase 5 inhibitor, CP-639180. Activin receptor-like kinase 5 inhibition antagonizes the transforming growth factor-ß pathway, and was used to determine whether there was an effect on collagen deposition in wounds. The compound was applied once per day for 7 days starting at postwounding day 0 or 7 (early or late treatment regimens). Wounds were analyzed histologically for collagen deposition and biochemically for quantification of collagen changes. RESULTS: Early and late treatment regimens with the activin receptor-like kinase 5 inhibitor significantly reduced collagen deposition without impairing wound healing. CONCLUSIONS: Application of a small molecular inhibitor of activin receptor-like kinase 5 appears to significantly reduce collagen deposition in rat dermal wounds as reported here for the first time. Activin receptor-like kinase 5 inhibition may offer a novel approach to reducing proliferative scars in humans because collagen accumulation is a core event in scarring.

Histologic examination of the eye of acid-sensing ion channel 1a knockout mice.

Various subtypes of the acid sensing ion channel have been detected in the retina of rodents and other mammalian species, but the functional importance of this finding is not clearly understood. The purpose of the study was to determine if retinal degeneration was present in ASIC1a-/- mice. The eyes of ASIC1a-/- mice, heterozygote ASIC1a+/- mice, and wild type ASIC1a+/+ mice that were 5 or 22-27 weeks old were processed by routine histotech-nological methods and examined for histologic changes in the retina and other portions of the eye. Additional sections of eyes from ASIC1a-/- and ASIC1a+/+ mice were labeled with peanut agglutinin (PNA) to evaluate cone pho-toreceptors. The retinas of ASIC1a-/-, ASIC1a+/-, and ASIC1a+/+ mice at 5 or 22-27 weeks of age were unremarkable and no morphologic changes in cone photo receptors were detected. Additional findings detected in the eye of ASIC1a+/+ mice included swelling of lens fibers or cataract that were also detected in some of the ASIC1a-/- or ASIC1a+/- mice. Lenticular findings were not considered to be associated with an absence of ASIC1a.