The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs.

Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1×, 3×, or 5× multiple of the dose of 2.6 mg/kg (50 µL/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1× group were transient and included a low prevalence (≤ 33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3× and 5× groups, which was associated with a dose-limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1× dose and describe the outcome of an overdose of up to 5× dose in the absence of opioid reversal.

Radiation effects of boron neutron capture therapy on brain, skin, and eye of rats.

PURPOSE: The present study was carried out to evaluate the radiation effects of boron neutron capture therapy (BNCT) on the brain, skin, and eyes of nude rats following systemic administration of boronophenylalanine (BPA) and neutron irradiation to the head. METHODS AND MATERIALS: A solution containing 120 mg of 10B-enriched-L-BPA complexed with fructose was administered IP to nude rats. Boron concentrations were approximately 8.4, 9.4, 10.0, and 11.0 micrograms/g in the brain, blood, skin, and eyes, respectively, at 6 h when the animals were irradiated at the Brookhaven Medical Research Reactor (BMRR). As determined in a study carried out in parallel with this one, the BNCT radiation doses were sufficient to cause tumor regression in nude rats carrying intracerebral implants of the human melanoma cell line MRA 27. RESULTS: Mild to moderate increases in loose fibrous tissue were observed in the choroid plexus at estimated physical doses to the brain and blood that ranged from 4.3-7.1 Gy and 4.6-7.7 Gy, respectively, and these appeared to be dose and time dependent. Other changes in the choroid plexus included occasional infiltrates of macrophages and polymorphonuclear leukocytes and vacuolation of epithelial cells. Dose-dependent moist desquamation of the skin was observed in all rats, but this had healed by 28 days following irradiation. Cataracts and keratitis developed in the eyes of most animals, and these were dose dependent. CONCLUSION: The minimal histopathological changes seen in the brain at doses that were sufficient to eradicate intracerebral melanoma indicates that BNCT has the potential to cure a tumor bearing host without producing the normal brain injury usually associated with conventional external beam radiation therapy. Studies in canines, which currently are in progress, should further define the dose-effect relationships of BNCT on critical neuroanatomic structures within the brain.

Cellular immunity in dogs with keratoconjunctivitis sicca before and after treatment with topical 2% cyclosporine.

Peripheral cellular immunity of ten dogs with keratoconjunctivitis sicca (KCS) that had not been treated with topical corticosteroids or cyclosporine was evaluated (by use of in vitro lymphocyte proliferation assays and CD4+/CD8+ lymphocyte subset analysis) before and after 1 and 3 months of treatment with topical ocular 2% cyclosporine (CsA). In vitro lymphocyte proliferation and CD4+/CD8+ lymphocyte subset analysis was done in eight normal dogs at the 0, 1 and 3 month time periods to use for comparison. There was no significant difference in lymphocyte proliferation or numbers of CD4+ or CD8+ lymphocytes in dogs with KCS and normal dogs prior to CsA treatment. However, by 1 month's time, lymphocyte proliferation had decreased in the CsA-treated Dogs with KCS, and by 3 months there was a significant difference (P < 0.0001) from the normal dogs. These results suggest that dogs with KCS may not have altered peripheral cellular immunity and that use of topical 2% cyclosporine for treatment of KCS causes a suppression of lymphocyte proliferation after 1 to 3 months of use.

A retrospective study of cavernous sinus syndrome in 4 dogs and 8 cats.

Cavernous sinus syndrome (CSS) is characterized by deficits in more than one of the cranial nerves (CN) that traverse the cavernous sinus at the base of the cranial vault: CN III (oculomotor), IV (trochlear), VI (abducens), and the first two branches of CN V (trigeminal). Records from 4 dogs and 8 cats with CSS diagnosed over a 14-year period were reviewed. The most common clinical signs were ophthalmoparesis or ophthalmoplegia, mydriasis with no direct or consensual pupillary light reflexes, ptosis, decreased corneal sensation, and decreased retractor oculi reflex. All cats had initial signs referable to a left CSS lesion (one had bilateral CSS), whereas in all dogs the lesions were localized to the right cavernous sinus. Median ages at diagnosis were 9 and 10 years of age for dogs and cats, respectively. Cerebel lomedullary cisternae cerebrospinal fluid analysis in 6 animals was useful as a sensitivebut nonspecific diagnostic test of an intracranial inflammatory or neoplastic lesion. Magnetic resonance imaging scans provided a more definitive diagnostic test in all dogs, revealing a contrast-enhancing mass on T1 weighted scans in the region of the cavernous sinus. A definitive pathological diagnosis was obtained in 2 dogs: a primary intracranial neoplasm and a metastatic intracranial neoplasm. A definitive diagnosis was obtained in 6 cats: metastatic neoplasm (n = 1), primary intracranial neoplasm (n = 1), primary intracranial infectious disease (n = 2), and associated systemic infectious disease (n = 2). The prognosis associated with CSS in dogs and cats was considered guarded to poor.

Viscoelastic materials in veterinary ophthalmology.

Viscoelastic materials have applications in both human and veterinary ophthalmology and orthopedics and for humans in otorhinolaryngology, urinary incontinence, cosmetic surgery and cosmetics. In ophthalmology, viscoelasties are most commonly used in facilitating cataract and other anterior segment surgeries, but also have applications in posterior segment surgery and in the topical management of keratoconjunctivitis sicca. Viscoelastics are routinely used during anterior segment surgery in filling and maintaining the anterior chamber, repositioning the iris, and to coat and protect the corneal endothelium, and expand the capsular bag prior to intraocular lens implantation. Viscoelastics can also be essential in the management of intraoperative complications such as miosis, hemorrhage, posterior capsular tears, and vitreous presentation. The most common products available for ophthalmic use include various concentrations of sodium hyaluronate, chondroitin sulfate, and hydroxypropylmethylcellulose. The physical properties of each viscoelastic material are dependent on chain length, and intra-and interchain interactions. The rheologic properties of viscosity, pseudoplasticity, viscoelasticity, and surface tension dictate the usefulness of each material for a specific purpose.

Effect of single- and multiple-dose 0.5% timolol maleate on intraocular pressure and pupil size in female horses.

OBJECTIVE: To determine the effect of single and multiple-dose 0.5% timolol maleate on intraocular pressure (IOP) and pupil size between 8 AM and 8 PM. Animals Nine female horses with normotensive eyes. Procedure IOP, horizontal and vertical pupil size were measured on a single day, between 8 AM and 8 PM at hours 0, 0.5, 1, 2, 4, 6, 8, 10, and 12. A single dose of 0.5% timolol maleate was applied to both eyes immediately after the first measurement at 8 AM. IOP and pupil size were measured at 8 AM and 4 PM in a 5-day experiment of twice-daily application of 0.5% timolol maleate. RESULTS: A significant decrease in IOP from 24.9 +/- 4.2 mmHg prior to application of timolol maleate to 20.7 +/- 3.1 mmHg (4.2 mmHg = 17%) was observed 8 h after single-dose application. A significant decrease in horizontal pupil size (2.0 mm = 11%) was present 6 h after single-dose application. In the multiple-dose experiment, a significant decrease in IOP was present on days 4 and 5 as compared to IOP measured prior to application of timolol maleate. A significant decrease in horizontal and vertical pupil size was present throughout the 5-day study as compared to the values obtained prior to treatment. CONCLUSIONS: 0.5% timolol maleate significantly decreased IOP and pupil size in normo-tensive eyes of this group of female horses in both single and multiple twice daily applications.

Effects of topical administration of timolol maleate on intraocular pressure and pupil size in dogs.

Effects of topical administration of a single dose of timolol maleate on intraocular pressure (IOP) and pupil diameter were evaluated in normotensive eyes of 11 clinically normal dogs over 12 hours (7:00 AM to 7:00 PM). Mean (+/- SEM) normal IOP was 15.5 (+/- 1.1) mm of Hg and diurnal fluctuation was observed, with the highest IOP seen in the morning. Mean normal pupil diameter was 8.5 (+/- 0.3) mm. Topical treatment with 0.5% timolol resulted in reduction of IOP in the treated and nontreated eyes. Mean reduction of IOP in the treated eye was 2.5 mm of Hg, a reduction of 16.1%, with maximal reduction of 3.7 mm of Hg. Mean reduction of IOP in the nontreated eye was 1.4 mm of Hg, a reduction of 9.0%. The treated eye had reduced pupil diameter at 30 minutes after treatment, which persisted throughout the 12 hours of the study. Mean reduction of pupil diameter in the treated eye was 2.9 mm, a reduction of 34.1%. In addition, a contralateral effect on pupil diameter was seen in the nontreated eye, with mean reduction of 1.2 mm, a reduction of 14.1%. Topical administration of timolol maleate resulted in reduction of IOP and pupil diameter in treated and contralateral eyes, thus supporting the use of timolol for treatment of glaucoma in dogs. Miosis indicates possible beta-adrenergic inhibition or alpha-adrenergic activation of the sphincter muscle. beta-Adrenergic blockade would then result in miosis.

Effects of topical administration of timolol maleate on intraocular pressure and pupil size in cats.

Effects of topical administration of a single dose of timolol maleate, a nonselective beta-adrenergic blocking agent, on intraocular pressure (IOP) and pupil diameter were evaluated in the normotensive eyes of 10 clinically normal cats over 12 hours. Mean (+/- SEM) normal IOP was 17.1 (+/- 1.1) mm of Hg and diurnal fluctuation was observed, with the highest IOP seen in the evening. Mean (+/- SEM) normal pupil diameter was 10.1 (+/- 0.5) mm. Topical treatment with 0.5% timolol resulted in reduction of IOP in treated and nontreated eyes. This effect was time-dependent and was first observed at 6 hours after treatment. Mean reduction of IOP was 22.3% in the treated eye and 16.3% in the nontreated eye. The treated eye had reduced pupil diameter at 30 minutes after treatment, and miosis persisted throughout the 12 hours of the study. Mean reduction of pupil diameter was 38.7%. A contralateral effect on pupil diameter was not seen in the nontreated eye. Topical administration of timolol maleate results in a reduction of IOP in treated and contralateral eyes, which supports the use of timolol for treatment of glaucoma in cats. In addition, the treated eye becomes miotic. This effect may indicate beta-adrenergic inhibition or alpha-adrenergic activation of the iris sphincter muscle. beta-Adrenergic blockade would then result in miosis.

Effects of topical administration of 2.0% pilocarpine on intraocular pressure and pupil size in cats.

Effects of topical administration of a single dose of 2% pilocarpine on intraocular pressure (IOP) and pupil diameter were evaluated in normotensive eyes of 10 clinically normal cats over 12 hours. Mean (+/- SEM) normal IOP was 17.1 (+/- 1.1) mm of Hg and, diurnal fluctuation was observed, with the highest IOP seen in the evening. Mean (+/- SEM) normal pupil diameter was found to be 10.1 (+/- 0.5) mm. Topical treatment with pilocarpine resulted in reduction of IOP in treated and nontreated eyes. This effect was time-dependent and was first observed at 4 hours after treatment. Mean reduction of IOP was 15.2% in the treated eye and 9.3% in the nontreated eye. The treated eye had reduced pupil diameter at 30 minutes after treatment, and miosis persisted throughout the 12 hours of the study. Mean reduction in pupil diameter was 28.5% in the treated eye and 14.2% in the nontreated eye. Topically administered pilocarpine results in reduction of IOP and pupil diameter in treated and contralateral eyes, which supports the use of pilocarpine for treatment of glaucoma in cats.

Evaluation of intraocular pressure in eyes of clinically normal llamas and alpacas.

OBJECTIVE: To estimate intraocular pressure (IOP) in eyes of healthy camelids, using applanation tonometry. ANIMALS: The eyes of 34 camelids (16 llamas [Lama glamal and 18 alpacas [L. pacos]) that did not have major abnormalities of the ocular surface or intraocular abnormalities. PROCEDURE: Tonometry measurements were obtained from each eye 3 times during a 24-hour period. Each measurement was the mean of several corneal applanations obtained by use of an applanation tonometer. Data were analyzed, using an ANOVA for a repeated-measures design. RESULTS: Mean (+/- SEM) IOP of llamas and alpacas was 13.10+/-0.35 and 14.85+/-0.45 mm Hg, respectively. Range of IOP was 7 to 18 mm Hg for llamas and 11 to 21 mm Hg for alpacas. Mean IOP of llamas was significantly less than the mean IOP of alpacas. Significant differences in IOP were not detected between the right and left eye of animals. Significant differences in IOP were not attributed to sex, age, or time of measurement within llamas or alpacas. CONCLUSIONS AND CLINICAL RELEVANCE: Establishing the mean and range of IOP of clinically normal llamas and alpacas provides a frame of reference that is important for use in a complete ophthalmic examination of camelids, which can assist clinicians in the diagnosis of glaucoma and uveitis. Reasons for the difference in mean IOP between llamas and alpacas are unknown. Although the difference may be unimportant clinically, this finding reiterates the fact that caution must be used when extrapolating IOP among species.

Effect of auriculopalpebral nerve block and intravenous administration of xylazine on intraocular pressure and corneal thickness in horses.

Intraocular pressure (IOP) was measured, using applanation tonometry, in both eyes of 20 horses after topical application of 0.5% proparacaine to the cornea. Ultrasonic pachymetry was used to measure central, mid-peripheral, and peripheral corneal thickness (CT) in all 4 quadrants of both eyes of 25 horses. All measurements were repeated after auriculopalpebral nerve block, sedation by IV administration of xylazine, or combination of nerve block and sedation. Mean IOP after topical anesthesia of the cornea was 20.6 +/- 4.7 mm of Hg for the left eye and 20.35 +/- 3.7 mm of Hg for the right eye. Mean central CT was 793.2 +/- 42.3 microns. The peripheral part of the cornea was significantly (P < 0.05) thicker, on average, than the central part of the cornea. Auriculopalpebral nerve block had no significant effect on IOP or CT. Intravenous administration of xylazine resulted in a significant (P < 0.05) decrease in IOP, but had no effect on CT.

Normal variation in, and effect of 2% pilocarpine on, intraocular pressure and pupil size in female horses.

OBJECTIVE: To determine normal variation in, and effect of 2% pilocarpine hydrochloride on, intraocular pressure (IOP) and pupil size in female horses during a specified period. ANIMALS: 10 female horses with normotensive eyes. PROCEDURE: IOP and horizontal and vertical pupil size were measured on a single day between 8 AM and 8 PM at hours 0, 0.5, 1, 2, 4, 6, 8, 10, and 12. Measurements were repeated after single- dose application of 2% pilocarpine to both eyes. IOP and pupil size were measured at 8 AM and noon in a 5-day experiment of twice-daily application of 2% pilocarpine. RESULTS: Variation in IOP and pupil size was not significant between 8 AM and 8 PM. Change in IOP or pupil size after a single dose of 2% pilocarpine also was not significant. In the multiple-dose experiment, the IOP at noon on the fifth day was significantly higher than the IOP in the morning on the first and second days. The IOP in the morning on the fifth day was significantly higher than the IOP in the morning and at noon on the first and second days. The IOP at noon on the fourth day was significantly higher than the morning IOP on the first and second days and at noon on the first day. The decrease in vertical pupil size was significant. CONCLUSIONS: Between 8 AM and 8 PM, variation in IOP and pupil size in normotensive eyes of horses is not significant. Two percent pilocarpine does not significantly change IOP between 8 AM and 8 PM in clinically normal horses after a single dose or multiple twice-daily applications. After multiple twice-daily applications, a trend toward an increase in IOP was seen, and the decrease in vertical pupil size was significant.

Effect of topical administration of 2% dorzlamide hydrochloride or 2% dorzlamide hydrochloride-0.5% timolol maleate on intraocular pressure in clinically normal horses.

OBJECTIVE: To evaluate the effect of topical administration of 2% dorzolamide hydrochloride or 2% dorzolamide hydrochloride-0.5% timolol maleate on intraocular pressure (IOP) in clinically normal horses. ANIMALS: 18 healthy adult horses without ocular abnormalities. PROCEDURE: The IOP was measured at 5 time points (7 AM, 9 AM, 11 AM, 3 PM, 7 PM) over 11 days. On days 1 and 2, baseline values were established. On days 3 through 5, horses received 2% dorzolamide HCI (group D, n = 9) or 2% dorzolamide HCl-0.5% timolol maleate (group DT, 9) in 1 randomly assigned eye every 24 hours immediately following each daily 7 AM IOP measurement. On days 6 through 9, each drug was given every 12 hours (7 AM and 7 PM) in the treated eye. Measurements on days 10 and 11 assessed return to baseline. Mixed linear regression models compared mean IOP difference for each drug at each time period. RESULTS: Mean IOP decreased significantly in all eyes during the 2 dose/d period, compared with the baseline, 1 dose/d, and follow-up periods. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of either drug every 24 hours for short-term treatment does not reduce IOP significantly. Administering either drug every 12 hours induced a significant reduction of IOP; however, controlling for all variables, the reduction was less than 2 mm Hg.

Use of an intravitreal sustained-release cyclosporine delivery device for treatment of equine recurrent uveitis.

OBJECTIVE: To evaluate the use of an intravitreal sustained-release cyclosporine (CsA) delivery device for treatment of horses with naturally occurring recurrent uveitis. ANIMALS: 16 horses with recurrent uveitis. PROCEDURES: Horses with frequent recurrent episodes of uveitis or with disease that was progressing despite appropriate medication were selected for this study. Additional inclusion criteria included adequate retinal function as determined by use of electroretinography, lack of severe cataract formation, and no vision-threatening ocular complications (eg, retinal detachment, severe retinal degeneration, and posterior synechia). Sustained-release CsA delivery devices (4 microg of CsA/d) were implanted into the vitreous through a sclerotomy at the pars plana. Reexaminations were performed 1, 3, 6, and 12 months after implantation, then continued annually. Ophthalmic changes, number of recurrent episodes of uveitis, and vision were recorded. RESULTS: The rate of recurrent episodes after device implantation (0.36 episodes/y) was less than prior to surgery (75 episodes/y). In addition, only 3 horses developed episodes of recurrent uveitis after surgery. Vision was detected in 14 of 16 affected eyes at a mean follow-up time of 13.8 months (range, 6 to 24 months). CONCLUSIONS AND CLINICAL RELEVANCE: This intravitreal sustained-release CsA delivery device may be a safe and important tool for long-term treatment of horses with chronic recurrent uveitis.

Repair of superior palpebral defect in a horse by use of silicone subdermal implant.

A silicone subdermal implant was used in the surgical repair of a superior palpebral defect in a horse. The right superior palpebra was missing from the lateral canthus superiorly to the 1 o'clock position, and a corneal ulcer, anterior uveitis, and right micropalpebral fissure also were observed. Lateral canthotomy and canthoplasty were performed to enlarge the palpebral fissure, and a silicone implant was inserted in the superior palpebra to replace the missing tarsal plate. These procedures resulted in a successful reconstruction, with improvement of palpebral function.

Treatment of epibulbar melanocytoma in a dog, using full-thickness eyewall resection and synthetic graft.

A limbal, epibulbar melanocytoma was treated by use of a full-thickness eyewall resection. The resulting defect was repaired by use of a synthetic graft of polytetrafluoroethylene. The graft remained in place for 7 weeks and was well tolerated, but failed to be incorporated by the surrounding tissues. New, healthy tissue did grow beneath the graft and allowed the graft to be surgically removed at 7 weeks.

Methemoglobinemia associated with dermal application of benzocaine cream in a cat.

Benzocaine, an ester-type local anesthetic, was believed responsible for apparent methemoglobinemia in a cat. The cat was admitted with acute respiratory distress, vomiting, and collapse, which began 15 to 20 minutes after topical application of the drug. Treatment consisted of supportive therapy and intravenous administration of methylene blue. The respiratory rate improved within 5 to 10 minutes of methylene blue administration and continued over a period of 2 hours. Benzocaine-induced methemoglobinemia has been reported in man, dogs, and cats. This report supports the findings of others regarding the potential toxicity of topical ester-type local anesthetics.

Combined treatment of ocular squamous cell carcinoma in a horse, using radiofrequency hyperthermia and interstitial 198Au implants.

Unilateral ocular squamous cell carcinoma in a horse was treated effectively with a combination of repeated radiofrequency hyperthermia and interstitial radiotherapy. These 2 modalities of treatment are synergistic. Interstitial irradiation was achieved, using 198Au implants to deliver a total dose of approximately 5,000 rads/implant over an area of 1 cm2. Radio frequency hyperthermia was repeated 3 times, and radiotherapy was used twice. Treatment resulted in complete regression of the tumor, and ocular complications have not been seen.

Repair of anomalous nasolacrimal duct in a bull by use of conjunctivorhinostomy.

A proximal nasolacrimal duct anomaly, believed to be congenital, in a bull was repaired by use of conjunctivorhinostomy. Initial attempts at correction, using prolonged nasolacrimal duct catheterization, were unsuccessful. Trephination from the medial canthus to the ventral nasal meatus, combined with long-term catheterization of this new passage, was successful in resolving clinical signs of disease.

Mineralized corneal sequestrum in a cat.

An 8-month-old 3-kg (6.6-lb) sexually intact male cat was evaluated for chronic refractory keratitis and a corneal plaque that developed after treatment with a corticosteroid-containing ophthalmic preparation. Pertinent ophthalmic findings included blepharospasm, conjunctivitis, corneal vascularization, and a tan raised corneal plaque with a dense and gritty composition. Lamellar keratectomy was performed to excise the plaque. The cornea healed with mild scarring. Histologic examination revealed extensive coagulation necrosis and mineralization of the corneal stroma with increased inflammatory cells, blood vessels, and fibrosis, which is compatible with a diagnosis of mineralized corneal sequestrum. The history suggested chronic feline herpesvirus-1 (FHV-1)-induced keratoconjunctivitis as the underlying cause. Topical corticosteroid administration may have potentiated the preexisting corneal necrosis and initiated mineralization. To our knowledge, mineralization of a corneal sequestrum in a cat has not been reported in a clinical case but has been reported in cats experimentally infected with FHV-1.