Abstract
OBJECTIVE
To determine the effect of topical ophthalmic administration of 0.005% latanoprost solution on aqueous humor flow rate (AHFR) and intraocular pressure (IOP) in ophthalmologically normal dogs.
ANIMALS
12 adult Beagles.
PROCEDURES
In a masked crossover design involving two 10-day experimental periods separated by a 7-day washout period, dogs were randomly assigned to first receive latanoprost or artificial tears (control) solution and then the opposite treatment in the later experimental period. Each experimental period was divided into a baseline phase (days 1 to 3), baseline fluorophotometry assessment (day 4), treatment phase (1 drop of latanoprost or artificial tears solution administered twice daily in each eye on days 5 to 9 and once on day 10), and posttreatment fluorophotometry assessment (day 10). Measured fluorescein concentrations were used to calculate baseline and posttreatment AHFRs. The IOP was measured 5 times/d in each eye during baseline and treatment (days 5 to 9) phases.
RESULTS
Mean baseline and posttreatment AHFR values did not differ significantly in either experimental period (latanoprost or control). In the latanoprost period, mean IOP was significantly lower during treatment than at baseline; there was no difference in corresponding IOP values during the control period. In the latanoprost period, mean IOP was significantly higher on the first day of treatment than on subsequent treatment days.
CONCLUSIONS AND CLINICAL RELEVANCE
In ophthalmologically normal dogs, topical ophthalmic administration of 0.005% latanoprost solution significantly decreased IOP but did not affect AHFR. Thus, the ocular hypotensive effect of latanoprost did not appear to have been caused by a reduction in aqueous humor production. (Am J Vet Res 2019;80:498–504)
Intraocular pressure is normally maintained by a delicate balance between aqueous humor production and drainage. Aqueous humor is produced by the nonpigmented epithelium of the ciliary body and exits the eye through either the conventional or unconventional outflow pathway.1 In the conventional outflow pathway, aqueous humor flows through the trabecular meshwork and empties into the episcleral venous system, with the amount of flow determined by the difference between IOP and episcleral venous pressure.1,2 In the unconventional (uveoscleral) outflow pathway, aqueous humor flows between the muscle fiber bundles in the ciliary body and exits through the sclera.2 In addition to maintaining IOP, aqueous humor also provides nutrients to the avascular structures of the eye (ie, the cornea and lens).
Glaucoma, a leading cause of blindness in dogs, develops when there is resistance to the outflow of aqueous humor from the eye.3 The term glaucoma refers to a collection of ocular diseases that result in damage to the retinal ganglion cells and optic nerve. High IOP is a common risk factor for these diseases in veterinary patients.3–5 Glaucoma is categorized as primary or secondary on the basis of the presumed or confirmed cause. In dogs, primary glaucoma results from a hereditary, anatomic malformation of the conventional aqueous humor outflow pathway (ie, goniodysgenesis).6,7 Secondary glaucoma occurs when the conventional aqueous humor outflow pathway is disrupted because of another ocular disease, such as anterior uveitis, lens luxation, intraocular neoplasia, or hyphema.8,9 The estimated combined prevalence of primary and secondary glaucomas in dogs is 1.7%.6,8
Treatment of glaucoma is directed at decreasing aqueous humor production, increasing aqueous humor outflow, or both.10 Prostaglandins and their analogs, such as latanoprost, travoprost, bimatoprost, and tafluprost, significantly decrease the IOP in many species, including dogs.4,11–19 In Beagles with and without glaucoma, IOP significantly decreases within 1 hour after topical ophthalmic administration of prostaglandins.20 The primary mechanism of action underlying the decrease in IOP in humans, monkeys, and rabbits is an increase in uveoscleral outflow.21–26 One potential mechanism for decreasing resistance to uveoscleral outflow is through remodeling of the uveoscleral outflow pathway.27,28 However, such changes take days to weeks to achieve, making this an unlikely explanation for the rapid onset of action seen with prostaglandins and their analogs. The rapidity with which these drugs decrease IOP may be the result of other mechanisms of action, such as a decrease in aqueous humor production or an increase in conventional outflow.
To the authors’ knowledge, there is only 1 studya on the effect of latanoprost on AHFR in dogs; this study indicates that there is a 93% decrease in the AHFR of dogs that are topically administered a single dose of latanoprost. However, this finding is inconsistent with those from studies22–25,29,30 of other species and warrants further investigation. The purpose of the study reported here was to evaluate the effect of topical ophthalmic administration of 0.005% latanoprost solution on AHFR and IOP in ophthalmologically normal dogs by the use of fluorophotometry and rebound tonometry, respectively. We hypothesized that topical administration of latanoprost in ophthalmologically normal dogs would result in a significant decrease in IOP but have no effect on AHFR.
Materials and Methods
Dogs
Twelve sexually intact (8 males and 4 females) purpose-bred Beagles were used in the study. The mean age was 3.1 years (range, 3 to 3.6 years), and mean body weight was 11.4 kg (range, 9.3 to 13.5 kg). The dogs were housed in individual cages in a temperature-controlled environment on a 12-hour light and 12-hour dark cycle for the duration of the study. Approximately 1 week before the start of the study, all dogs underwent a brief physical examination and a complete ophthalmic examination by a board-certified veterinary ophthalmologist (AJR), including Schirmer tear testing,b rebound tonometry,c direct gonioscopy,d slit-lamp biomicroscopy,e and indirect ophthalmoscopy.f All dogs completed a 5-day training and acclimation period immediately prior to the start of the study, in which the IOP was measured in each eye thrice daily (8 am, 1 pm, and 5 pm). The study was approved by the Kansas State University Institutional Animal Care and Use Committee and adhered to the Association for Research in Vision and Ophthalmology's statement for the use of animals in ophthalmic and vision research.
Treatment
In a masked crossover design involving two 10-day experimental periods separated by a 7-day washout period, dogs were assigned by use of a random number sequence to first receive latanoprost or artificial tears (control) solution and then the opposite treatment in the later experimental period. Each experimental period was divided into a baseline (pretreatment) phase (days 1 to 3), baseline fluorophotometry assessment (day 4), treatment phase (days 5 to 10), and posttreatment fluorophotometry assessment (day 10).
One drop of topical ophthalmic 0.005% latanoprost solutiong or artificial tears solutionh was administered in each eye twice daily on days 5 to 9 (7 am and 7 pm) and at 7 am on day 10. The primary investigators did not administer the drops so they could remain masked to treatment assignments.
Ocular measurements
Tonometry—On days 1 to 3 and days 5 to 9, the IOP in each eye was measured by use of a rebound tonometerc 5 times/d (8 am, 10 am, 1 pm, 5 pm, and 9 pm) by a single investigator (KEF). All measurements were performed in triplicate. The overall mean IOP (both eyes) values during the baseline and treatment phases were calculated for the latanoprost and control experimental periods. In addition, the mean IOP values (both eyes) were calculated for each of the 5 time points by phase (baseline vs treatment) and by treatment day (days 5 to 9).
Fluorophotometry—One drop (50 μL) of 10% fluorescein sodiumi was instilled into each eye of each dog at 5-minute intervals over a 10-minute period (3 applications/eye). Five minutes after the last fluorescein drop was administered, the eyes of each dog were rinsed thoroughly with eyewash (99.05% purified water) solution to ensure that no fluorescein remained on the ocular surface. The forelimbs, chest, tail, and any other areas of the body that fluorescein may have dripped on were rinsed with tap water to ensure that no residual fluorescein could be inadvertently reintroduced into the eyes. Five hours after fluorescein administration, the dogs were sedated with a combination of ketamine hydrochloridej (5 mg/kg, IM) and dexmedetomidine hydrochloridek (0.008 mg/kg, IM) to allow for proper positioning in front of the fluorophotometer. A computerized scanning ocular fluorophotometer with an anterior chamber adapterl was used to measure the fluorescence of the cornea and midcentral anterior chamber at approximately 5, 6.5, and 8 hours after the last drop of fluorescein was administered.
AHFR calculation
The fluorescein concentration data were transformed by computation of the natural logarithm. Regression analysis was performed to derive the slope of fluorescein decay in the cornea and anterior chamber. The following equations were used to calculate the AHFR:
where A is the slope of the decreasing cornea and aqueous humor fluorescein concentrations, Vc is the corneal volume, Va is the anterior chamber volume, Cc is the corneal fluorescein concentration, Ca is the anterior chamber fluorescein concentration, 1.53 is a constant to correct for the underestimation of corneal fluorescence that is inherent to fluorophotometry measurements, and 1.2 is a constant to correct for an inherent difference in corneal and anterior chamber fluorescein concentrations as measured by the fluorophotometer.31 The values for Vc (100 μL) and Va (400 μL) were assigned on the basis of previous research31 involving Beagles with body weights and ages similar to the Beagles of the present study.
Statistical analysis
All statistical comparisons were performed by use of a commercial statistical package.m Within experimental periods, the paired t test was used to compare mean IOP (baseline vs treatment phase) and AHFR (baseline vs posttreatment phase) values. An independent t test was used to compare the mean IOPs and AHFR values between the control and latanoprost periods during baseline, treatment (IOP), and posttreatment (AHFR) phases. Repeated-measures ANOVA was used to compare mean IOP values between the baseline and treatment phases at each time point for both the control and latanoprost periods. For the latanoprost treatment phase, repeated-measures ANOVA was used to evaluate the change in mean IOP between days at each time point. Values of P ≤ 0.05 were considered significant.
Results
IOP
During the baseline phase, the mean ± SD IOPs were 16.5 ± 0.9 mm Hg and 16.1 ± 1.1 mm Hg in the latanoprost and control experimental periods, respectively (P = 0.57). During the treatment phase, these values were 12.3 ± 0.6 mm Hg and 16.5 ± 0.8 mm Hg, respectively (P < 0.001). In the latanoprost experimental period, the mean IOP was significantly (P < 0.001) lower during the treatment phase than during the baseline phase, representing a 4.2 mm Hg (25%) decrease. In the control experimental period, the mean IOP did not differ significantly (P = 0.23) between the baseline and treatment phases.
At each time point, the mean IOP in the latanoprost experimental period was significantly (P < 0.001) lower during the treatment phase than during the baseline phase (Figure 1). The mean IOP for the control experimental period was significantly higher at 1 pm (P = 0.04) and 9 pm (P = 0.002) during the treatment phase than at the same time points during the baseline phase (mean increase, 0.8 mm Hg). Within the latanoprost experimental period, the mean IOPs at each time point were significantly higher on the first day of the treatment phase (day 5) than on all subsequent treatment days (days 6 to 9), except the mean IOP at 5 pm, when there was no significant difference between days 5 and 7 (Figure 2).
Mean IOP in 12 ophthalmologically normal Beagles in a masked crossover study design involving two 10-day experimental periods separated by a 7-day washout period in which dogs were randomly assigned to first receive topical ophthalmic 0.005% latanoprost or artificial tears (control) solution and then the opposite treatment in the later experimental period. The IOP was measured in triplicate in both eyes at 5 time points each day during baseline (days 1 to 3) and treatment (days 5 to 9) phases to calculate mean values (both eyes) for each time point. At each time point, the mean IOP for the latanoprost experimental period was significantly lower during the treatment phase (vertically striped bars) than during the baseline phase (gray bars). At 1 pm and 9 pm, the mean IOP for the control experimental period was significantly higher during the treatment phase (dotted bars) than during the baseline phase (white bars). Error bars represent SD.
Citation: American Journal of Veterinary Research 80, 5; 10.2460/ajvr.80.5.498
Mean IOP in the dogs of Figure 1 at 5 time points during the latanoprost experimental period, by day of treatment phase (days 5 [black circles], 6 [black squares], 7 [triangles], 8 [white circles], and 9 [white squares]). Mean IOPs at each time point were significantly higher on the first day of treatment (day 5) than on all subsequent treatment days, except the mean IOP at 5 pm, when there was no significant difference between days 5 and 7. See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 80, 5; 10.2460/ajvr.80.5.498
AHFR
The mean ± SD AHFRs at baseline (day 4) were 3.6 ± 0.9 μL/min and 3.4 ± 1.5 μL/min in the latanoprost and control experimental periods, respectively (P = 0.71). The posttreatment (day 10) values were 3.9 ± 1.5 μL/min and 3.3 ± 1.3 μL/min, respectively (P = 0.28). The mean AHFR did not differ significantly between the baseline and posttreatment phases in either the latanoprost (P = 0.55) or control (P = 0.83) experimental periods.
Discussion
Twice-daily topical ophthalmic administration of 0.005% latanoprost solution for 5.5 days did not significantly affect the AHFR in the ophthalmologically normal dogs of the present study. This finding contrasts with those of a previous studya in which a 93% decrease in AHFR was noted in dogs after a single dose of latanoprost was topically administered. That study used an interventional fluorophotometry protocol described by Yablonski et al32 in which latanoprost is administered between fluorophotometry measurements. The results of the present study cannot be directly compared with those from the previous reporta because of differences between the 2 studies in the fluorophotometry protocol that was used.
Fluorophotometry is widely accepted as a method for accurate and noninvasive measurement of AHFR.31–35 With this technique, the cornea is saturated with fluorescein, which diffuses into the anterior chamber until it reaches a steady state. During this steady state, fluorescein concentrations in the cornea and anterior chamber change at an equal rate, with decreases in measured concentrations as fluorescein exits the anterior chamber and is diluted by new aqueous humor production.31 We used a 3-drop fluorescein protocol in which the corneal and anterior chamber fluorescein concentrations reached a steady state by 4 hours following the last drop and remained in this state for an additional 6 hours, which permitted use of a previously described and validated method for calculation of AHFR.31–33,36 The fluorophotometry protocol that was used for our study has been well established for use in dogs.31,34,36–38
Studies of cats,11,29,30 rabbits,22 nonhuman primates,24,29,30 and humans23,25,29 have shown that topical ophthalmic administration of prostaglandins does not decrease aqueous humor production, which is consistent with the findings of the present study. If the decrease in IOP observed in the study dogs following latanoprost administration could not be explained by a decrease in AHFR, then other possible explanations should be considered. Studies21,23–25,30,39 evaluating the effect of prostaglandins on conventional aqueous humor outflow in cats, nonhuman primates, and humans have yielded somewhat mixed results, although most demonstrated either no effect or a decrease in conventional outflow. In the 2 studies25,30 that showed an increase in conventional outflow, the authors concluded that the increase was not sufficient to explain the extent of the IOP decrease. In dogs, latanoprost has been shown to increase episcleral venous pressure by 55%, which would lead to a decrease in conventional outflow.40 On the other hand, the reported accumulation of intracameral tracers, such as iodine-labeled albumin, in the ciliary body and sclera of cynomolgus monkeys21,24 and rabbits22 treated with prostaglandins indicates an increase in uveoscleral aqueous humor outflow. Toris et al23 used fluorophotometry and tonography to demonstrate an increase in uveoscleral outflow in humans receiving topical ophthalmic latanoprost treatment twice daily for 1 week. Collectively, these findings support the supposition that prostaglandins act primarily by increasing uveoscleral outflow rather than conventional outflow.
One potential mechanism for the effect of prostaglandins on uveoscleral aqueous humor outflow appears to be through remodeling of the uveoscleral outflow pathway. In cell cultures of human ciliary body muscle, concentrations of promatrix metalloproteinases 1 and 3 increase after exposure to PGF2α.41 After treatment with PGF2α twice daily for 5 days, immunoreactivity to matrix metalloproteinases 1, 2, and 3 in the sclera of cynomolgus monkeys reportedly increase,27 whereas immunoreactivity to collagen types I, III, and IV decreases in the ciliary body and to types I and III decreases in the sclera.42 Also in cynomolgus monkeys, ciliary body intermuscular spaces reportedly widen and incomplete endothelial linings develop following latanoprost treatment once daily for 1 year.43
Because remodeling of the uveoscleral outflow pathway takes days to months, this mechanism does not explain the rapid IOP-lowering effect of prostaglandins observed in the present and other studies. Ciliary muscle fibers from rhesus monkeys that are precontracted with carbachol are relaxed by PGF2α, but not beyond the resting state of the muscles.44 The ability of prostaglandins to decrease ciliary body muscle tone may indicate a rapid mechanism for increased uveoscleral outflow and is deserving of further study.
In the present study, the IOP decreased by a mean of 4.2 mm Hg, or 25%, in dogs that were treated twice daily for 5.5 days with 0.005% latanoprost solution, which is consistent with findings from previous studies. For example, in clinically normal dogs, the IOP decreased by 24.5% following once-daily topical ophthalmic administration of 0.005% latanoprost solution,16 with similar decreases in IOP (21.6% and 31%) when latanoprost was administered twice daily.12,45 Tofflemire et al45 reported that administration of latanoprost thrice daily for 5 days was associated with a greater ocular hypotensive effect (33% decrease in IOP) than twice-daily administration (31% decrease); however, they concluded that this did not represent a clinically relevant difference. In clinically normal dogs, single doses of latanoprost reportedly decrease the IOP by 19.2%40 to 35%,46 with greater decreases achieved in glaucomatous dogs.20,47
During the latanoprost experimental period in the present study, the mean IOP was significantly higher on the first day of the treatment phase than on all subsequent treatment days. This finding was consistent with those of previous studies12,16,45,47 of dogs. During the control experimental period, the mean IOP was significantly higher at 1 pm and 9 pm during the treatment phase than at the corresponding times during the baseline phase, although the mean increase (0.8 mm Hg) was not clinically relevant.
The primary investigators in the present study were theoretically masked to the treatment assignments by having others administer the treatments; however, miosis was observed in many dogs during ocular measurements and thus treatment assignment could have been inferred despite masking. Miosis is an expected side effect of latanoprost administration in dogs that results from activation of F-prostanoid receptors in the iris.47 The pupil diameter in dogs decreases significantly following administration of latanoprost either once (morning or evening) or twice daily.12,16,45–47
The mechanism for the rapid ocular hypotensive effects of latanoprost and other prostaglandin analogs remains unknown. High-resolution ultrasonographic images of the anterior segment of the eye in dogs with primary angle closure glaucoma show that the miotic effect of latanoprost causes a break of the reverse pupillary block, whereas in dogs with primary open-angle glaucoma, the collapsed ciliary cleft reopens following treatment with latanoprost.n These findings suggest that latanoprost may increase conventional aqueous humor outflow, in addition to the previously established effects on uveoscleral outflow. A study46 to evaluate the effect of latanoprost on the anterior segment of the eye in clinically normal dogs by use of spectral domain optical coherence tomography revealed shallowing of the anterior chamber with narrowing of the anterior chamber angle and angle opening distance and no change in the angle recess area. Because these morphological changes would be expected to decrease conventional outflow, the investigators concluded that latanoprost acts through another mechanism. The increase in episcleral venous pressure in dogs treated with latanoprost would be expected to decrease conventional outflow, which is a pressure-dependent pathway.40 The difference in the resting anterior segment morphology between clinically normal and glaucomatous dogsn and the heightened IOP-reducing effect of prostaglandin analogs in glaucomatous dogs suggest that the hypotensive effect of these drugs in glaucomatous dogs may be partly the result of an increase in conventional outflow following miosis.20,46
Park et al48 used ultrasonographic biomicroscopy to evaluate the anterior segment in clinically normal dogs following administration of latanoprost; a decrease in the iridocorneal angle and ciliary cleft entry width and an increase in the midciliary cleft were observed. These morphological changes were also associated with thinning of the ciliary body at 2 hours after latanoprost administration. The investigators concluded that the initial decrease in ciliary body thickness was associated with relaxation of the ciliary body musculature, which would widen the intermuscular spaces, thereby increasing uveoscleral outflow.48
In the present study, twice-daily administration of 0.005% latanoprost resulted in a significant decrease in IOP with no effect on AHFR in ophthalmologically normal dogs. On the basis of these findings, we concluded that a decrease in aqueous humor production does not contribute to the ocular hypotensive effect of latanoprost in dogs. Additional studies to simultaneously evaluate multiple aspects of the effect of latanoprost on aqueous humor dynamics, including AHFR and conventional aqueous humor outflow, are needed to better understand the mechanisms that underlie the ocular hypotensive effect of prostaglandin analogs (eg, latanoprost) in dogs.
Acknowledgments
Funded by the Kansas State University Mark Derrick Canine Research Fund.
The funding source did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the results for this project.
The authors declare that there were no conflicts of interest.
Presented in abstract form at the American College of Veterinary Ophthalmologists Annual Conference 2017, Baltimore, October 2017.
The authors thank Drs. Emily Sharpe and Akaterina Davros for technical assistance.
ABBREVIATIONS
| AHFR | Aqueous humor flow rate |
| IOP | Intraocular pressure |
| PGF2α | Prostaglandin F2α |
Footnotes
Ward DA. Effects of latanoprost on aqueous humor flow rate in normal dogs (abstr), in Proceedings. 36th Annu Meet Am Coll Vet Ophthalmol 2005;437.
Schirmer tear test, Schering-Plough Animal Health, Union, NJ.
TonoVet Tonometer, Jorgensen Laboratories Inc, Loveland, Colo.
Koeppe Gonio Lens, Ocular Instruments Inc, Bellevue, Wash.
SL-17, Kowa Co Ltd, Tokyo, Japan.
Vantage Plus binocular indirect ophthalmoscope, Keeler Instruments Inc, Broomall, Pa.
Akorn, Lake Forest, Ill.
Geiss, Destin, & Dunn Inc, Peachtree City, Ga.
AK-Fluor (fluorescein sodium 10% solution), Akorn, Lake Forest, Ill.
VetOne, Boise, Idaho.
Dexdomitor, Zoetis Inc, Kalamazoo, Mich.
FM-2 Fluorotron Master, OcuMetrics Inc, Mountain View, Calif.
WINKS SDA, version 7.0.9, TexaSoft, Cedar Hill, Tex.
Miller PE, Bentley E, Diehl K, et al. High resolution ultrasound imaging of the anterior segment of dogs with primary glaucoma prior to and following the topical application of 0.005% latanoprost (abstr), in Proceedings. 34th Annu Meet Am Coll Vet Ophthalmol 2003;360.
References
1. Gum GG, MacKay EO. Physiology of the eye. In: Gelatt KN, Gilger BC, Kern TJ, eds. Veterinary ophthalmology. Vol 1. 5th ed. Ames, Iowa: Wiley-Blackwell, 2013;171–207.
2. Gabelt BT, Kaufman PL. Production and flow of aqueous humor. In: Levin LA, Nilsson SFE, Ver Hoeve J, et al, eds. Adler's physiology of the eye. 11th ed. Edinburgh: Elsevier Inc, 2011;274–307.
3. Ofri R, Narfström K. Light at the end of the tunnel? Advances in the understanding and treatment of glaucoma and inherited retinal degeneration. Vet J 2007;174:10–22.
4. Willis AM, Diehl KA, Robbin TE. Advances in topical glaucoma therapy. Vet Ophthalmol 2002;5:9–17.
5. McLellan GJ, Miller PE. Feline glaucoma—a comprehensive review. Vet Ophthalmol 2011;14(suppl 1):15–29.
6. Gelatt KN, MacKay EO. Prevalence of the breed-related glaucomas in pure-bred dogs in North America. Vet Ophthalmol 2004;7:97–111.
7. Strom AR, Hässig M, Iburg TM, et al. Epidemiology of canine glaucoma presented to University of Zurich from 1995 to 2009. Part 1: congenital and primary glaucoma (4 and 123 cases). Vet Ophthalmol 2011;14:121–126.
8. Gelatt KN, MacKay EO. Secondary glaucomas in the dog in North America. Vet Ophthalmol 2004;7:245–259.
9. Strom AR, Hässig M, Iburg TM, et al. Epidemiology of canine glaucoma presented to University of Zurich from 1995 to 2009. Part 2: secondary glaucoma (217 cases). Vet Ophthalmol 2011;14:127–132.
10. Plummer CE, Regnier A, Gelatt KN. The canine glaucomas. In: Gelatt KN, Gilger BC, Kern TJ, eds. Veterinary ophthalmology. 5th ed. Ames, Iowa: Wiley-Blackwell, 2013;1050–1129.
11. McDonald JE, Kiland JA, Kaufman PL, et al. Effect of topical latanoprost 0.005% on intraocular pressure and pupil diameter in normal and glaucomatous cats. Vet Ophthalmol 2016;19 (suppl 1):13–23.
12. Smith LN, Miller PE, Felchle LM. Effects of topical administration of latanoprost, timolol, or a combination of latanoprost and timolol on intraocular pressure, pupil size, and heart rate in clinically normal dogs. Am J Vet Res 2010;71:1055–1061.
13. Bean GW, Camras CB. Commercially available prostaglandin analogs for the reduction of intraocular pressure: similarities and differences. Surv Ophthalmol 2008;53(suppl 1):S69–S84.
14. Alexander CL, Miller SJ, Abel SR. Prostaglandin analog treatment of glaucoma and ocular hypertension. Ann Pharmacother 2002;36:504–511.
15. Willis AM, Diehl KA, Hoshaw-Woodard S, et al. Effects of topical administration of 0.005% latanoprost solution on eyes of clinically normal horses. Am J Vet Res 2001;62:1945–1951.
16. Studer ME, Martin CL, Stiles J. Effects of 0.005% latanoprost solution on intraocular pressure in healthy dogs and cats. Am J Vet Res 2000;61:1220–1224.
17. Perry CM, McGavin JK, Culy CR, et al. Latanoprost: an update of its use in glaucoma and ocular hypertension. Drugs Aging 2003;20:597–630.
18. Kwak J, Kang S, Lee ER, et al. Effect of preservative-free tafluprost on intraocular pressure, pupil diameter, and anterior segment structures in normal canine eyes. Vet Ophthalmol 2017;20:34–39.
19. Bito LZ, Camras CB, Gum G, et al. The ocular hypotensive effects and side effects of prostaglandins on the eyes of experimental animals. Prog Clin Biol Res 1989;312:349–368.
20. Gum GG, Kingsbury S, Whitley R, et al. Effect of topical prostaglandin PGA2, PGA2 isopropyl ester, and PGF2 alpha isopropyl ester on intraocular pressure in normotensive and glaucomatous canine eyes. J Ocul Pharmacol 1991;7:107–116.
21. Gabelt BT, Kaufman PL. Prostaglandin F2-alpha increases uveoscleral outflow in the cynomolgus monkey. Exp Eye Res 1989;49:389–402.
22. Poyer JF, Gabelt B, Kaufman PL. The effect of topical PGF2-alpha on uveoscleral outflow and outflow facility in the rabbit eye. Exp Eye Res 1992;54:277–283.
23. Toris CB, Camras C, Yablonski M. Effects of PhXA41, a new prostaglandin F2-alpha analog, on aqueous humor dynamics in human eyes. Ophthalmology 1993;100:1297–1304.
24. Nilsson SFE, Samuelsson M, Bill A, et al. Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2 alpha-1-isopropylester in the cynomolgus monkey. Exp Eye Res 1989;48:707–716.
25. Ziai N, Dolan JW, Kacere RD, et al. The effects on aqueous dynamics of PhXA41, a new prostaglandin F2 alpha analogue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol 1993;111:1351–1358.
26. Crawford K, Kaufman PL. Pilocarpine antagonizes prostaglandin F2 alpha-induced ocular hypotension in monkeys. Evidence for enhancement of uveoscleral outflow by prostaglandin F2 alpha. Arch Ophthalmol 1987;105:1112–1116.
27. Weinreb RN. Enhancement of scleral macromolecular permeability with prostaglandins. Trans Am Ophthalmol Soc 2001;99:319–343.
28. Alm A, Nilsson SFE. Uveoscleral outflow—a review. Exp Eye Res 2009;88:760–768.
29. Toris CB, Camras CB, Yablonski ME, et al. Effects of exogenous prostaglandins on aqueous humor dynamics and blood-aqueous barrier function. Surv Ophthalmol 1997;41(suppl 2):S69–S75.
30. Lee PY, Podos SM, Severin C. Effect of prostaglandin F2 alpha on aqueous humor dynamics of rabbit, cat, and monkey. Invest Ophthalmol Vis Sci 1984;25:1087–1093.
31. Ward DA, Cawrse MA, Hendrix DVH. Fluorophotometric determination of aqueous humor flow rate in clinically normal dogs. Am J Vet Res 2001;62:853–858.
32. Yablonski ME, Zimmerman TJ, Waltman SR, et al. A fluorophotometric study of the effect of topical timolol on aqueous humor dynamics. Exp Eye Res 1978;27:135–142.
33. Jones RF, Maurice DM. New methods of measuring the rate of aqueous flow in man with fluorescein. Exp Eye Res 1966;5:208–220.
34. Rankin AJ, Crumley WR, Allbaugh RA. Effects of ocular administration of ophthalmic 2% dorzolamide hydrochloride solution on aqueous humor flow rate and intraocular pressure in clinically normal cats. Am J Vet Res 2012;73:1074–1078.
35. Crumley WR, Rankin AJ, Allbaugh RA. Evaluation of the aqueous humor flow rate in the eyes of clinically normal cats by use of fluorophotometry. Am J Vet Res 2012;73:704–708.
36. Cawrse MA, Ward DA, Hendrix DVH. Effects of topical application of a 2% solution of dorzolamide on intraocular pressure and aqueous humor flow rate in clinically normal dogs. Am J Vet Res 2001;62:859–863.
37. Skorobohach BJ, Ward DA, Hendrix DV. Effects of oral administration of methazolamide on intraocular pressure and aqueous humor flow rate in clinically normal dogs. Am J Vet Res 2003;64:183–187.
38. Fischer KM, Ward DA, Hendrix DVH. Effects of a topically applied 2% delta-9-tetrahydrocannabinol ophthalmic solution on intraocular pressure and aqueous humor flow rate in clinically normal dogs. Am J Vet Res 2013;74:275–280.
39. Camras CB, Podos SM, Rosenthal JS, et al. Multiple dosing of prostaglandin F2 alpha or epinephrine on cynomolgus monkey eyes. I. Aqueous humor dynamics. Invest Ophthalmol Vis Sci 1987;28:463–469.
40. Tsai S, Miller PE, Struble C, et al. Topical application of 0.005% latanoprost increases episcleral venous pressure in normal dogs. Vet Ophthalmol 2012;15(suppl 1):71–78.
41. Lindsey JD, Kashiwagi K, Boyle D, et al. Prostaglandins increase proMMP-1 and proMMP-3 secretion by human ciliary smooth muscle cells. Curr Eye Res 1996;15:869–875.
42. Sagara T, Gaton DD, Lindsey JD, et al. Topical prostaglandin F2-alpha treatment reduces collagen types I, III, and IV in the monkey uveoscleral outflow pathway. Arch Ophthalmol 1999;117:794–801.
43. Richter M, Krauss AHP, Woodward DF, et al. Morphological changes in the anterior eye segment after long-term treatment with different receptor selective prostaglandin agonists and a prostamide. Invest Ophthalmol Vis Sci 2003;44:4419–4426.
44. Poyer JF, Millar C, Kaufman PL. Prostaglandin F2 alpha effects on isolated rhesus monkey ciliary muscle. Invest Ophthalmol Vis Sci 1995;36:2461–2465.
45. Tofflemire KL, Whitley EM, Allbaugh RA, et al. Comparison of two- and three-times-daily topical ophthalmic application of 0.005% latanoprost solution in clinically normal dogs. Am J Vet Res 2015;76:625–631.
46. Tsai S, Almazan A, Lee SS, et al. The effect of topical latanoprost on anterior segment anatomic relationships in normal dogs. Vet Ophthalmol 2013;16:370–376.
47. Gelatt KN, MacKay EO. Effect of different dose schedules of latanoprost on intraocular pressure and pupil size in the glaucomatous Beagle. Vet Ophthalmol 2001;4:283–288.
48. Park S, Kang S, Lee E, et al. Ultrasound biomicroscopic study of the effects of topical latanoprost on the anterior segment and ciliary body thickness in dogs. Vet Ophthalmol 2016;19:498–503.
