Effect of different dose schedules of latanoprost on intraocular pressure and pupil size in the glaucomatous Beagle

Objective To evaluate the changes in intraocular pressure and pupil size in glaucomatous dogs after instillation of 0.005% latanoprost (Xalatan, Pharmacia and Upjohn, Kalamazoo, MI, USA) once in the morning, or once in the evening, or twice daily in five‐day multiple‐dose studies. Animals studied Eight Beagles with the moderate stage of inherited primary open‐angle glaucoma. Procedures Applanation tonometry (IOP) and pupil size (PS) measurements were obtained at 8 am, 10 am, 12 noon, 2 pm, and 4 pm in eight glaucoma dogs. Methylcellulose (0.5% as placebo) was instilled in the control eye, and 0.005% latanoprost was instilled in the opposite drug eye. Control and drug eyes were selected using a random table. For these three studies, 0.5% methylcellulose and 0.005% latanoprost were instilled the second through the fifth days with instillations in the morning (8.30 am), or evening (8 pm), or twice daily (8.30 am and 8 pm). Statistical comparisons between drug groups included control, placebo, and treated (0.005% latanoprost) eyes for three multiple‐dose studies. Results In the 8‐am latanoprost study, the mean ± SEM diurnal declines in IOP for the placebo and drug eyes for the first day were 6.5 ± 3.6 mmHg and 8.4 ± 4.0 mmHg, respectively. The mean ± SEM diurnal changes in IOP after 0.005% latanoprost at 8 am once daily for the next four days were 23.3 ± 5.0 mmHg, 25.4 ± 2.1 mmHg, 25.7 ± 1.7 mmHg, and 26.1 ± 1.7 mmHg, respectively, and were significantly different from the control eye. A significant miosis also occurred starting 2 h postdrug instillation, and the resultant mean ± SD pupil size was 1.0 ± 0.1 mm. In the first day of the second latanoprost study, the mean ± SEM diurnal changes in the placebo and drug eye IOPs were 11.6 ± 3.8 mmHg, and 12.0 ± 4.4 mmHg, respectively. For the following four days with latanoprost instilled at 8 pm, the mean ± SEM diurnal changes in IOP in the drug eyes were 24.9 ± 2.1 mmHg, 22.4 ± 1.8 mmHg, 21.6 ± 1.9 mmHg, and 26.6 ± 2.2 mmHg, respectively. Compared to the fellow placebo eyes, the diurnal changes in IOP were significantly different. Significant changes in pupil size were similar to the IOP changes, with miosis throughout the day and return to baseline pupil size the following morning before drug instillation. In the last study, the mean ± SEM diurnal changes in IOP for the placebo and drug eyes for the first day were 6.6 ± 2.1 mmHg and 9.4 ± 2.8 mmHg, respectively. For the four subsequent days with latanoprost instilled twice daily, the mean ± SEM diurnal IOP changes were 19.6 ± 1.5 mmHg, 19.1 ± 1.4 mmHg, 19.9 ± 1.7 mmHg, and 20.3 ± 0.7 mmHg, respectively, and were significantly different from the placebo eyes. The mean changes in PS were 3.1 ± 0.7 mm. Conclusion 0.005% latanoprost instilled once daily (am or pm) as well as twice daily produces significant decreases in IOP and PS in the glaucomatous Beagle. The evening instillation of 0.005% latanoprost produced less daily fluctuations in IOP than when the drug was instilled in the morning. 0.005% latanoprost instilled twice daily produced the greatest decline in IOP with the least daily fluctuations, but longer duration miosis.     

Expression and regulation of cyclooxygenase-2 in normal and neoplastic canine keratinocytes

Squamous cell carcinoma (SCC) is one of the most common cancers in dogs, yet relatively little is known about the molecular events involved in its development. Increasing evidence implicates cyclooxygenase‐2 (COX‐2) in the pathogenesis of various cancers in humans and animals. COX‐2 overexpression has recently been demonstrated in canine SCCs. The objective of our study was to characterize the expression and regulation of COX‐2 in normal and neoplastic canine keratinocytes (CKs) to provide an in vitro system to investigate the implication of COX‐2 in SCC oncogenesis in dogs. Cell lines derived from normal CKs and neoplastic CKs (SCCs) were cultured in the absence or presence of agonists, and immunoblots, immunocytochemistry, radioimmunoassays and a cell proliferation assay were used to characterize COX‐2 expression and action. Results showed that neoplastic keratinocytes had a higher basal COX‐2 expression than normal keratinocytes. In both cell lines, stimulation with the tumour promoter phorbol 12‐myristate 13‐acetate induced a time‐dependent increase in COX‐2 protein, with COX‐2 induction being stronger in cancerous SCC than in normal CK cells. Moreover, SCC cells produced significantly more PGE₂ than CK cells, under both baseline and stimulated conditions (P < 0.05). NS‐398, a selective COX‐2 inhibitor, inhibited prostaglandin (PG)E₂ synthesis and decreased proliferation of CK and SCC cells (P < 0.05). Collectively, our results indicate that the canine neoplastic keratinocyte SCC cell line expresses more COX‐2 and produces more PGE₂ than the normal keratinocyte CK cell line, thus providing an in vitro system to study the molecular basis of elevated COX‐2 expression in SCCs in dogs.     

Effect of single and multiple doses of 0.2% brimonidine tartrate in the glaucomatous Beagle

The objective of this study was to evaluate the changes in intraocular pressure (IOP) in glaucomatous dogs after instillations of 0.2% brimonidine once, twice and three times daily in single day studies, and after twice and three times daily for 4 days in multiple dose studies. We studied eight Beagles with inherited primary open angle glaucoma. Applanation tonometry (IOP), pupil size (PS) and heart rate (HR) measurements were obtained at 8 am, 10 am, 1 pm, 3 pm and 5 pm. The studies were divided into: eight glaucoma dogs and five of the eight dogs that demonstrated greater response to 0.2% brimonidine. Single-dose drug studies are divided into placebo (0.5% methylcellulose), 0.2% brimonidine administered once daily (8 am); twice daily (8 am and noon); and three times daily (8 am, noon and 5 pm). The 5-day multiple-dose studies included: day 1, no drug; and 4 days, 0.2% brimonidine instillations either twice daily (8 am and 2 pm) or three times daily (8 am, 2 pm and 9 pm). Statistical comparisons between drug groups included control (nondrug) and treated (placebo/0.2% brimonidine) eyes for both single- and multiple-dose studies. The mean +/- SEM diurnal decrease in IOP in the eight glaucomatous Beagles for the control and placebo eyes were 3.4 +/- 4.7 and 5.4 +/- 2.8 mmHg, respectively. The mean +/- SEM diurnal decrease in IOP after 0.2% brimonidine once, twice and three times daily was 6.4 +/- 3.5, 8.0 +/- 6.1 and 9.8 +/- 8.1 mmHg, respectively; this trend was not significant statistically. Significant miosis occurred starting 2 h postinstillations, and the resultant mean +/- SD pupil size was 2.7 +/- 0.3 mm. A significant decrease in heart rate also occurred (12%). In the five most responsive dogs the changes in PS and HR during these studies were similar to the larger group, but significant decreases in IOP occurred at most measurement times. In the multiple-dose study with 0.2% brimonidine twice daily the mean +/- SEM decrease in IOP for day 1 to day 4 was 5.0 +/- 1.3, 5.7 +/- 1.3, 1.4 +/- 3.3 and 4.9 +/- 1.3 mmHg, respectively. When 0.2% brimonidine was instilled three times daily the mean +/- SEM diurnal IOP decrease was from day 1 to day 4 and was 0.75 +/- 1.3, 2.4 +/- 1.5, 1.2 +/- 2.7 and 1.4 +/- 1.8 mmHg, respectively. The mean change in pupil diameter was 1.3 +/- 0.5 mm. Decrease in HR averaged 22%. In the same single-dose studies with the five most responsive dogs, PS and HR were similar, but the decreases in IOP were significant at more measurement intervals. We conclude that 0.2% brimonidine produces a decrease in IOP in dogs, a statistically significant miosis, and a reduced heart rate (12-22%). However, because of the limited drug-induced ocular hypotension, brimonidine should be combined with other drugs when used for the glaucomas in the dog.     

Expression of cyclooxygenase-2 in canine epithelial nasal tumors

Cyclooxygenase-2 (COX-2) is an enzyme upregulated in some human and animal tumors. Enzymatic products are associated with tumorigenic activities. Given the poor response of canine nasal tumors to radiation, we considered the possibility that some of this resistance may be associated with COX-2 expression. To test this, 21 formalin-fixed, paraffin-embedded, and archived biopsy samples from canine epithelial nasal tumors were analyzed for COX-2 expression using immunohistochemistry. The biopsies were collected from dogs prior to radiation therapy. COX-2 expression was present in 17 of 21 (81%) tumors. The expression was observed in several different tumor types, including nasal carcinomas, adenocarcinomas, and squamous cell carcinomas. Samples from five control dogs without nasal neoplasia were also analyzed for COX-2 staining. These specimens were characterized by varying degrees of lymphoplasmacytic rhinitis with scattered regions of COX-2 positive respiratory epithelial and stromal cells. Whether the intensity and distribution of COX-2 expression in nasal tumors can be used as a prognostic marker requires further investigation. A combination therapy of irradiation and a selective COX-2 inhibitor appears worthy of clinical investigation in the treatment of canine epithelial nasal tumors.     

Effect of different dose schedules of travoprost on intraocular pressure and pupil size in the glaucomatous Beagle

Objective To evaluate changes in intraocular pressure and pupil size in glaucomatous dogs after instillation of 0.004% travoprost once in the morning, or once in the evening, or twice daily in 5‐day multiple dose studies. Materials and methods Applanation tonometry (IOP) and pupil size (PS) measurements were obtained at 8 a.m., 10 a.m., 12 noon, 2 p.m. and 4 p.m. in eight glaucoma dogs. Methylcellulose (0.5% as placebo) was instilled in the control eye, and 0.004% travoprost was instilled in the opposite drug eye. Methylcellulose (0.5%) and 0.004% travoprost were instilled on the 2nd through to the 5th day with instillations in the morning (8.30 a.m.), or evening (8 p.m.), or twice daily (8.30 a.m. and 8 p.m.). Results The mean ± SEM diurnal changes from baseline IOP in the control and placebo eyes in all three studies ranged from 1.2 ± 0.3 mmHg to 3.2 ± 0.9 mmHg. The mean ± SEM diurnal changes from the baseline IOP after 0.004% travoprost at 8 a.m. once daily for the next 4 days were 19.0 ± 2.7 mmHg, 24.7 ± 2.7 mmHg, 24.9 ± 3.1 mmHg, and 24.7 ± 3.1 mmHg, respectively, and were significantly different from the control eye. After travoprost was instilled at 8 p.m., the mean ± SEM baseline changes from the baseline IOP in the drug eyes were 23.5 ± 2.2 mmHg, 24.2 ± 2.2 mmHg, 24.5 ± 2.3 mmHg, and 24.2 ± 2.3 mmHg, respectively. When 0.004% travoprost was instilled twice daily, the mean ± SEM baseline IOP changes were 27.7 ± 2.1 mmHg, 28.1 ± 2.1 mmHg, 28.4 ± 2.2 mmHg, and 28.5 ± 2.2 mmHg, respectively, and were significantly different from the control eyes. Miosis of varying duration was frequent during the three studies. Conclusion Travoprost instilled once daily (a.m. or p.m.) as well as twice daily produces significant decreases in IOP and PS in the glaucomatous Beagle.     

Metastatic intraocular chondrosarcoma in a dog

Chondrosarcoma accounts for about 10% of all canine bone tumors and is the second most common primary bone tumor in dogs. In veterinary medicine, chondrosarcomas are classified as skeletal and extraskeletal. Extraskeletal chondrosarcomas are mesenchymal neoplasms of soft tissues and visceral organs that produce neoplastic chondrocytes in a fibrillary matrix. There is no involvement of bone or periosteal tissues in extraskeletal chondrosarcomas. The aim of this report is to describe the first case of a metastatic intraocular extraskeletal chondrosarcoma in a dog.     

Schwalbe line's cell in the normal and glaucomatous dog

Objective The canine iridocorneal angle contains an operculum, which is similar to that in nonhuman primates and consists of a peripheral extension of the inner cornea that overlies the anterior‐most portion of the corneoscleral trabecular meshwork. This region contains cells, the Schwalbe line’s (SL) cells, that have been found to have secretory and epithelial characteristics. This region of the iridocorneal angle represents the nonfiltering portion and becomes altered early during spontaneous glaucoma in the Beagle. The present study describes the SL cell for the first time in the dog and changes associated with canine primary open angle glaucoma. Procedures The iridocorneal angles from 18 Beagles with inherited glaucoma (3 months–8 years old) and 17 normal, age‐matched Beagles were placed in 10% buffered formalin for light microscopic evaluation, or 2.5% glutaraldehyde for ultrastructural evaluation. Using at least three fields from each region of the iridocorneal angle (opercular, corneoscleral, and uveal) at ×1000 magnification, trabecular cell nuclei were counted. Results The operculum in the canine iridocorneal angle consisted of the peripheral extension of the corneal endothelium and underlying anterior‐most corneoscleral meshwork, having no direct contact with the angular aqueous plexus. The SL cells associated with operculum‐retained epithelial morphology (polyhedral in shape with rER, Golgi apparatus, and secretory vesicles) in both normal, pre‐and early glaucomatous dogs. In animals with moderate and advanced stages the SL cells often became less epithelial and secretory in appearance. The number of SL cells in normal dogs declined by approximately one‐third by the end of their first year with gradual loss thereafter. In the glaucoma group the decline was more substantial and continuous through the first three years. Conclusions The SL cell is morphologically a distinct cell type within the canine iridocorneal angle that is specifically associated with the nonfiltering portion of the corneoscleral trabecular meshwork. Changes in the SL cells of the glaucomatous dog occurred with regard to age and progression of the disease.     

Uveitis and pupillary block glaucoma in an aphakic dog

Unilateral uveitis with pupillary occlusion and secondary glaucoma was treated with neodymium:YAG laser iridotomy and iridencleisis in an aphakic 2-year-old male Miniature Schnuauzer. The dog presented 4 months after bilateral phacoemulsification with a complaint of blepharospasm of the left eye. Examination revealed anterior uveitis with pupillary occlusion and iris bombé. A slit-lamp mounted Q-switched Nd:YAG laser was used to create a central iridotomy to deepen the anterior chamber and an iridencleisis was performed to recreate a pupil. The eye remained visual and normotensive over a 6-month follow-up period.     

Ahmed valve implantation to control intractable glaucoma after phacoemulsification and intraocular lens implantation in a dog

An 11-year-old spayed female Miniature Poodle presented with bilateral senile cataracts. Treatment was cataract removal by phacoemulsification and intraocular lens implantation. Five hours after surgery the operated right eye was partially closed and painful. The right pupil was fully dilated, there was generalized corneal edema, and intraocular pressure (IOP) was increased. After 12 h of medication IOP was controlled. Ten weeks after surgery the owners reported cloudiness of right eye, and the dog was again evaluated. The IOP was again increased and an Ahmed valve was implanted. This case describes describe the progression of this case and benefits of controlling postcataract surgery glaucoma by the implantation of an Ahmed valve.     

Collie eye anomaly in a mixed-breed dog

A 5-year-old, mixed-breed dog was presented for tetraparesis. Neurologic alterations included a decreased menace response in both eyes. Therefore, an ophthalmic examination was requested. The dog was visual, but menace response, dazzle and pupillary light reflexes were reduced bilaterally. Indirect ophthalmoscopy revealed bilateral optic nerve coloboma and severe choroidal hypoplasia. These lesions closely resembled the ophthalmoscopic features of Collie eye anomaly (CEA). In spite of treatment, the dog's condition worsened and the animal was therefore euthanized. Histology of the globes confirmed severe choroidal hypoplasia and optic disc coloboma in both eyes. The dog was diagnosed to have a lymphoma involving the spinal cord. The two entities were considered not related. As only moderate sight impairment was caused by the posterior segment anomalies, it is by chance that these lesions resembling CEA were found in this mixed-breed dog.     

Effect of Coherin™ on intraocular pressure,pupil size and heart rate in the glaucomatous Beagle: a pilot study

Objective To evaluate effects of Coherin? on intraocular pressure (IOP), pupil size (PS), and heart rate (HR) in glaucomatous Beagles in single‐dose studies in a pilot study. Materials and methods Intraocular pressure, PS, and HR were measured in eight glaucomatous Beagles. One randomly chosen eye received single 50 μL doses of differing concentrations of Coherin? (treated eye) or vehicle (placebo‐treated eye), and the fellow eye served as the untreated control. After the first measurements, a single dose of either Coherin? or sterile water vehicle was instilled in the drug and placebo eyes, respectively. Results The mean ± SEM diurnal changes in IOP after 0.005%, 0.01%, 0.2%, 0.284%, 1%, 2%, and 4% topical Coherin? once daily were 7.6 ± 3.2 mmHg, 15.5 ± 5.3 mmHg, 11.2 ± 4.4 mmHg, 11.8 ± 4.4 mmHg, 19.1 ± 3.8 mmHg, 5.0 ± 1.8 mmHg, and 8.8 ± 2.8 mmHg, respectively. The declines in IOP were significantly different (P < 0.05) from the untreated control eyes with the 0.2% and 0.284% Coherin?‐treated eyes and suggestive for 1% Coherin? concentrations. No signs of irritation, significant PS, and HR changes were detected in the Coherin?‐treated eyes. Conclusion Of seven different concentrations, 2% and 0.248% Coherin? produced significant declines in IOP in the glaucomatous beagle in single‐dose studies when compared to both untreated control and placebo‐treated eyes. One percent Coherin? solution produced significant IOP decreases compared with the placebo‐treated eye but not the untreated control eyes. No local ocular irritation, PS and HR changes were observed in Coherin?‐treated eyes. This pilot study suggests that topical Coherin? has potential as an ocular hypotensive agent.     

Immunohistochemical analysis of cyclooxygenase-2 induction during wound healing in dog skin

Cyclooxygenase (COX)-2 is an inducible isoform of COX and is expressed under abnormal health conditions. This study elucidated the cutaneous induction of COX-2 during the wound healing processes in dog skin. Dog skin was sutured after punch biopsy and investigated histologically and immunohistochemically on days 0 (normal), 1, 3, 5, 7, 10, and 14 after injury. Histological changes, including infiltration of inflammatory cells and proliferation of fibroblast-like cells, were observed as predicted, and there was a close and significant correlation between these 2 events. COX-2-positive cells were detected in the epidermis between days 1 and 7, and bimodal peaks were observed in the case of the percentage of COX-2-positive cells. In inflammatory cells, COX-positive signals were detected on day 3 only. Here, we clarified the localization and pattern of the induced COX-2 expression during wound healing in dog skin.     

Comparison of the effects of topical administration of a fixed combination of dorzolamide-timolol to monotherapy with timolol or dorzolamide on IOP, pupil size, and heart rate in glaucomatous dogs

OBJECTIVE: To determine whether the combination multiple-dose dorzolamide-timolol administered topically has any greater effects on the reduction of intraocular pressure, pupil size, and heart rate in dogs with glaucoma than do either timolol or dorzolamide alone. PROCEDURE: Applanation tonometry, pupil size, and heart rate measurements were made at 7 a.m., 1 p.m., and 7 p.m. daily of 12 laboratory Beagles with inherited primary open-angle glaucoma during each active phase of this study. Timolol 0.5% was administered first twice daily for 4 consecutive days. Dorzolamide 2.0% was administered next three times daily for 4 consecutive days. The fixed combination of the two (timolol 0.5% and dorzolamide 2.0%) was administered twice daily for 4 consecutive days during the final week of the study. Between administration of each drug, a withdrawal period of at least 10 days was instituted. Statistical comparisons between the effects of the three drugs were performed. RESULTS: Intraocular pressure (IOP) was decreased with the administration of all three drugs: timolol alone, dorzolamide alone, and the combination of the two decreased IOP after 1 day of treatment 2.83 +/- 0.70 mmHg, 6.47 +/- 0.32 mmHg, and 6.56 +/- 0.37 mmHg, respectively. After 4 days of treatment, the IOP decreased even further: timolol alone, dorzolamide alone, and the combination of the two decreased IOP 3.75 +/- 0.88 mmHg, 7.50 +/- 0.29 mmHg, and 8.42 +/- 0.58 mmHg, respectively. Heart rate was significantly decreased with timolol (-11.9 +/- 2.0 bpm) and the combination preparation (-8.6 + 2.4 bpm), but not with dorzolamide (-3.7 +/- 1.8 bpm) alone. Pupil size was significantly decreased with timolol (-1.42 + 0.40 mm) and the combination preparation (-1.3 + 0.33 mm), but not with dorzolamide (0.97 +/- 0.36 mm) alone. CONCLUSIONS: The combination dorzolamide-timolol appears to be more effective at reducing intraocular pressure in glaucomatous dogs than is either timolol or dorzolamide alone.     

Secondary glaucomas in the dog in North America

OBJECTIVE: To determine the prevalence of secondary glaucomas in dogs associated with cataract formation, lens luxation or displacement, cataract surgery, uveitis, hyphema and intraocular neoplasia. METHODS: Information was obtained from the Veterinary Medical Data Base (VMDB) from all veterinary medical teaching hospitals in North America from March 1964 to March 2003. Secondary glaucomas were diagnosed at the same examination or after the primary diagnosis was made, and included those associated with cataract formation, lens luxation, cataract surgery, uveitis of unknown cause, hyphema of unknown cause, and intraocular neoplasia. The data were evaluated by decade, breed, gender and age of presentation. RESULTS: A total of 1 592 831 dogs were presented, and 9695 canine secondary glaucomas. Secondary glaucoma associated with cataract formation represented 81% of all the canine secondary glaucomas. Breeds (n = 7890 dogs) predisposed to secondary glaucoma and cataracts had an overall prevalence of 0.5%, but nearly 20% of all the cataractous dogs developed secondary glaucoma in at least one eye. For the years 1994-2003, these breeds included the American Cocker Spaniel; Boston Terrier; Toy, Miniature and Standard Poodle; English Springer Spaniel; Bichon Frise; and Labrador Retriever. The other forms of secondary glaucoma occurred less frequently, and included those glaucomas with lens luxation or displacement (779 dogs; 12.0%), postcataract surgery (528 dogs; 5.1%), with uveitis from unknown cause (399 dogs; 7.1%), with hyphema from unknown cause (117 dogs; 7.3%), and with intraocular neoplasia (19 dogs; 3.5%). The risk of the secondary glaucomas from 1984 to 2002 was highest after the intracapsular lens extraction (ICLE), less in the extracapsular technique (ECLE), and lowest for the phacoemulsification/phacofragmentation method. CONCLUSION: Prevalence of the canine secondary glaucomas ranges from 0.25% (1964-1973), 0.46% (1974-1983), 0.79% (1984-1993), to 0.80% (1994-2003) and are as frequent as the primary or breed-related glaucomas during these same time periods.     

Parotid duct transposition in dogs: a retrospective review of 92 eyes from 1999 to 2009

Objective The aim of this study was to perform a retrospective review of parotid duct transposition (PDT) in the dog to determine the rate and nature of complications, the success and failure rates and to evaluate owner satisfaction. Methods Medical records of 56 dogs (92 eyes) that underwent PDT and subsequent follow‐up by a veterinary ophthalmologist were reviewed. Forty owners (40 dogs/66 eyes) were contacted by telephone and 37 owners (37 dogs/60 eyes) also completed a visual analog scale questionnaire. Statistical evaluation included Wilcoxon Signed Rank tests, one‐way analysis of variance and Kaplan–Meier survival analysis with Wilcoxon and Log‐rank tests. Results The mean follow‐up was 38.7 months (range 1–109 months). The surgical success rate was 92% (85/92 eyes). Total failures (8%, 7/92 eyes) were because of severe saliva intolerance (n = 5 eyes) and PDT failure (n = 2 eyes). The complication rate was 50% (46/92 eyes) of which 61% (28/46 eyes) were managed medically and 39% (18/46 eyes) required further surgery. Ninety percent (36/40) of owners indicated that they would proceed with surgery again. Statistically significant improvements in owner perception of ocular comfort, number of daily topical treatments, ocular wetness, and postoperative vision were identified. Conclusions This study shows that PDT is a successful procedure based on clinical findings and in terms of owner perception. It has also demonstrated that PDT improves ocular comfort and vision in medically refractive cases of keratoconjunctivitis sicca, and that a low level of on‐going management is required in 33% of cases.