Pharmacokinetics of an antisense oligonucleotide injected intravitreally in monkeys.

The kinetics of an intravitreally administered phosphorothioate oligonucleotide, ISIS 2922, were studied in cynomolgus monkeys. Vitreal and retinal concentrations were measured after administration of 11, 57, or 115 microg/eye. ISIS 2922 concentrations in vitreous and retina were compared, after single, weekly, or biweekly doses, for potential accumulation. ISIS 2922 levels were quantified using solid-phase extraction followed by capillary gel electrophoresis. Concentrations of ISIS 2922 in the vitreous were proportional to the dose and were nearly linear with respect to the dose. The ISIS 2922 concentrations 3 days after dosing ranged from 80 nM to approximately 1.5 microM. By 14 days after intravitreal injection, the concentrations were below the limit of quantitation (<10 nM) for all dose groups. There was no accumulation in the vitreous after multiple weekly or biweekly doses. The concentrations of ISIS 2922 in the retina 2 days after a single intravitreal injection ranged from 50 nM to 1.1 microM. The uptake and disposition of ISIS 2922 in the retina appeared to have been saturated between the 57- and 115-microg doses; the average concentrations were 0.71 +/- 0.24 microM (N = 4) and 0.88 +/- 0.27 microM (N = 3) for the two doses, respectively. Electrophoretic profiles of extracts revealed multiple chain-shortened oligonucleotides in the vitreous and retina, suggesting extensive metabolism in both compartments. Analyses from the multiple-dose study suggested that accumulation was dependent on the total administered dose, with accumulation occurring after biweekly dosing in the 115-microg dose group and only after weekly dosing in the 57-microg dose group.

Allergic- and immunologic-mediated diseases of the eye and adnexae.

Significant allergic- and immunologic-mediated diseases of the eye are reviewed. Included are diseases of the lacrimal gland namely keratoconjunctivitis sicca, immune-mediated diseases of the conjunctiva, atopic blepharoconjunctivitis, and marginal blepharitis, uveitis including lens-induced uveitis, episcleritis, orbital cellulitis, and optic neuritis. Significant diagnostic features, an approach to diagnostic workup, and treatment are presented.

Serologic correlation of suspected Leptospira interrogans serovar pomona-induced uveitis in a group of horses.

After the observation of 2 horses with uveitis on a horse farm in the Minnesota River valley, 100 horses from this geographic area were given ophthalmologic examinations and were evaluated serologically for leptospirosis. A statistically significant (P less than 0.001) association was observed between the finding of antibodies against Leptospira interrogans serovar pomona and uveitis.

Glutathione metabolism in lenses of dogs and rabbits: activities of five enzymes.

Several biochemical parameters were examined in clear dog and rabbit lenses as functions of age, and in posterior subcapsular cataracts in the Alaskan malamute. Tabulated data include soluble protein, reduced sulfhydryl content of soluble protein, reduced glutathione, water, and activity of five enzymes of glutathione metabolism. The enzymes include the glutathione biosynthesis system consisting of gamma-glutamylcysteine synthetase and glutathione synthetase, as well as glutathione peroxidase, glutathione reductase and glutathione-S-transferase. Each enzyme, acting last in a sequential reaction of either two or three reactions, was in excess activity over the preceding enzyme(s) in every case but one. In the exception, the ratio of glutathione reductase to glutathione peroxidase activity was about 1:600 and 1:155 in the dog and rabbit lens, respectively.

Neuroepithelial tumor of the optic nerve in a horse.

A nine-year-old horse was presented with severe exophthalmos of the right eye and a large mass in the vitreal cavity. The affected globe was enucleated and two months following surgery the horse was euthanized because of spread of the tumor into the calvarium producing compression of the brain stem and neurologic signs. Examination of tumor tissue by light and electron microscopic examination showed a mixed neoplasm of primitive neuroepithelium.

Ocular manifestations of low level phenothiazine administration to cattle.

Feeding white face Hereford cattle a high protein dietary supplement containing 1.25% phenothiazine resulted in severe corneal edema when the cattle were exposed to sunlight. The corneal edema was located in the inferior two-thirds of the cornea. In one animal a severe secondary ulcerative keratitis developed. The corneal edema resolved in about 60-90 days after the phenothiazine containing concentrate was removed and the cattle not exposed to bright sunlight.

Clinical aspects of mycotic keratitis in the horse.

Several manifestations of equine corenal ulcers caused by mycotic agents are discussed. Antifungal therapy is reviewed. Mycotic keratitis should be suspected when routine corneal ulcer therapy is nonproductive.

Serological response of the bovine fetus to bovine viral diarrhea virus.

Susceptible pregnant heifers were inoculated with bovine viral diarrhea virus at 150 days of gestation and earlier. Fetuses were surgically collected at selected times after inoculation. Serum immunoglobulins were quantitated, and the presence of specific antibodies was determined. In fetuses from heifers inoculated at 150 days, immunoglobulin M (IgM) appeared approximately 2 weeks after inoculation and was followed in 7 days by IgG1. Later IgG2 was detected in the sera of three fetuses. Serum-neutralizing and complement-fixing antibodies were first detected in a fetus taken at 206 days of gestation. Fetuses taken at later times also had specific serum antibodies. Possible explanations for the appearance of serum immunoglobulin substantially before specific bovine viral diarrhea antibodies include the viral alteration of host tissues rendering them antigenic viral activation of polyclonal B cells, and viral modulation of virus-specific lymphocytes causing specific interference with the appearance of antiviral antibodies. In one of the fetuses having IgG2, the serum also contained IgA. Placental leakage of material immunoglobulins was thought to be responsible for the presence of IgA and IgG2 in this fetus. Small quantities of IgM were found in the serum of two fetuses taken from heifers inoculated between 65 and 95 days of gestation, but specific antibodies were found in none.

Infiltrative corneal lesions resembling fibrous histiocytoma: clinical and pathologic findings in six dogs and one cat.

Infiltrating corneal lesions developed in 6 dogs and 1 cat. In each case, the site of origin appeared to be the corneal limbus. The lesions were characterized by continuous growth, a benign appearance, and a tendency to recur following excision keratoplasty. Each lesion was of a proliferative, inflammatory nature, histologically resembling fibrous histiocytoma. Of the 6 dogs in the series, 4 were Collies.

Fetal and adult bovine interferon production during bovine viral diarrhea virus infection.

Levels of interferon in adult bovine serum and in fetal bovine serum and tissues were examined during the course of transplacental bovine viral diarrhea virus infection. The cows produced circulating interferon between 2 and 9 days after viral inoculation, with mean peak levels in the serum on day 4. Interferon could be routinely detected in fetal tissues (e.g., thymus, spleen, and kidney) between days 4 and 21 after viral inoculation of the cows at 149 to 150 days of gestation (mid-second trimester) and in fetal serum from day 13 through day 21. Interferon was also detectable in the serum and tissues of fetuses from dams infected at day 95 of gestation (the beginning of the second trimester). In general, no differences were found between the ability of the adult and fetus to produce interferon. Fetal lamb kidney cells were more sensitive to the antiviral effects of bovine interferon than were fetal bovine kidney cells. The antiviral substance from the fetal and adult animals was characterized as interferon by standard criteria.

Hereditary corneal dystrophy in the Manx cat: a preliminary report.

A progressive, apparently inherited corneal dystrophy is described in an inbred line of Manx cats. Initial changes in the cornea are seen at four months of age and characterized by anterior stromal edema. Progressive worsening of the condition produces severe bullous keratopathy with eventual breakdown of both epithelium and stroma. Light microscopic and ultrastructural studies in the advanced disease state revealed marked edema of the corneal stroma, disintegration of collagen material, and the formation of epithelial bullae. Ultrastructural evidence shows a normal endothelium to be present. The pathogenesis of this corneal dystrophy is not clear and further studies are underway.

Viral-antibody complexes in canine adenovirus type 1 (CAV-1)ocular lesions: leukocyte chemotaxis and enzyme release.

Canine adenovirus-type 1 (CAV-1)-antibody complexes caused severe anterior uveitis with corneal edema ("blue eye") when injected into the anterior chamber of normal dogs. The response of the anterior uvea to such immune complexes (IC) was similar to the spontaneously occurring disease. In the presence of complement (C'), IC caused release of neutrophile chemotactic factors. Following phagocytosis of IC-C' leukocytes released lysosomal enzymes, as indicated by the presence of acid phosphatase in the surrounding medium. Membrane bound viral aggregates, presumably IC, were common in neutrophiles and in macrophages that had infiltrated the anterior chamber of opaque eyes that occurred after intravenous (IV) inoculation with attenuated CAV-1. These data were incorporated into a postulated scheme for the pathogenesis of CAV-1 uveitis with corneal edema.

Corneal endothelium in viral induced anterior uveitis. Ultrastructural changes following canine adenovirus type 1 infection.

Dogs inoculated intravenously with attenuated canine adenovirus type 1 developed anterior segment inflammation and corneal edema. During the stage of mild anterior uveitis, virus was isolated from the aquious fluid, and by electron microscopy, viral replication was found to occur in corneal endothelial cells. Later, at the stage of severe anterior uveitis with corneal edema, virus was not isolated from the aqueous fluid and cells containing intranuclear (replicating) virus were not found. At this stage, many inflammatory cells had infiltrated the anterior chamber and contained numerous membrane-bound viral aggregates (viral-antibody complexes). Phagocytized viral-antibody complexes were present in the areas of most prominent endothelial cell destruction. Peripheral to the principal lesion sites, inflammatory cells had dissected the endothelium from Descemet membrane. After recovery from the disease, an intact endothelial cell layer was present.

Teratogenesis in cats associated with griseofulvin therapy.

Multiple congenital malformations occurred in kittens of three cats treated orally at weekly intervals with 500-1000 mg of the antifungal drug griseofulin. Malformations of the brain included exencephaly, malformed prosencephalon, caudal displacement, and hydrocephalus. Skeletal malformations included cranium bifidium, spina bifida (C1 through C4, and sacral), abnormal atlantooccipital articulation, cleft palate, absence of maxillae, and lack of tail vertebrae. Cyclopia and anophthalmia with absence of optic nerves and rudimentary optic tracts were also observed. Atresia ani, atresia coli, lack of atrioventricular valves in the heart, and absence of external nares and soft palate were other abnormalities present.

Pathogenetic studies of infection of the bovine fetus with bovine viral diarrhea virus. II. Ocular lesions.

Twenty-three susceptible pregnant heifers were inoculated with bovine viral diarrhea virus at 150 +/- 1 days of gestation. Seven additional heifers were inoculated between 65 and 115 days of gestation. Acute ocular lesions were seen in fetuses taken 17-21 days after inoculation of the dams at 150 days. By the fourth week, the acute lesions were beginning to resolve, and in newborn animals focal to total retinal atrophy was seen. The acute lesions were characterized by a mild to moderate retinitis that resulted in various degrees of destruction of the different layers, mononuclear cuffing of inner retinal vessels, proliferation of pigment epithelium, and choroiditis. Residually there was an absence of cellular elements in the atrophied areas of the retina, frequently a loss of layering and various numbers of pigment-containing cells. Moderately severe acute inflammation was seen in the retina of the fetus taken at 22 days after inoculation of its dam at 95 days. Ocular lesions did not occur in the other fetuses taken from heifers inoculated at earlier stages of gestation.