CLINICAL SCIENCES Increase in Outflow Facility With Unoprostone Treatment in Ocular Hypertensive Patients

Carol B. Toris, PhD; Guilin Zhan, MD; Carl B. Camras, MD

Objective: To determine the mechanism by which 0.15% Results: Compared with baseline, unoprostone signifi- unoprostone isopropyl reduces intraocular pressure (IOP) cantly (PϽ.001) reduced IOP by a mean±SEM of 5.6±0.4 by studying 33 patients with ocular hypertension or pri- mm Hg and 4.8±0.6 mm Hg on days 5 and 28, respec- mary open-angle . tively. The change from baseline with unoprostone was sig- nificantly (PϽ.001) greater than with placebo by 2.8±0.4 Methods: At baseline, IOP was determined by pneu- mm Hg on day 5 and by 3.2±0.5 mm Hg on day 28. Com- matonometry, aqueous flow and outflow facility by fluo- pared with baseline, unoprostone significantly (PՅ.001) rophotometry, episcleral venous pressure by venom- increased outflow facility by 0.05±0.01 and 0.08±0.02 anometry, and uveoscleral outflow by mathematical µL·min−1·mm Hg−1 on days 5 and 28, respectively. The base- calculation. Unoprostone was administered to one eye line-adjusted between-treatment differences were signifi- and placebo to the fellow eye of each patient twice daily cant (PՅ.04) on day 28 (0.06±0.02 µL·min−1·mm Hg−1). in a randomized masked fashion. In patients who dem- Other measures were not different from placebo. onstrated an IOP reduction of 3 mm Hg or more in either eye on day 5±1 (n=29), determinations were repeated Conclusion: In responsive patients, unoprostone de- on that day and on day 28±2. Treated eyes were com- creased IOP by increasing outflow facility. pared with control eyes, and treatment days were com- pared with baseline by paired t tests. Arch Ophthalmol. 2004;122:1782-1787

NTRAOCULAR PRESSURE (IOP) IS tating outflow of aqueous humor. An in- maintained by the production of crease in outflow facility6 and uveoscleral aqueous humor and its drainage outflow7 has been reported after topical ad- through the anterior chamber ministration of unoprostone in rabbits. No angle. Current glaucoma thera- effect on tonographic outflow facility was pies lower IOP by reducing aqueous hu- found in healthy humans8 or in patients I 9 mor production, increasing outflow with glaucoma, suggesting that a uveo- through the uveoscleral pathway, or in- scleral outflow effect accounted for the IOP creasing the facility of trabecular out- decrease. Recently, Thieme and cowork- flow. Some medications, such as bri- ers10 suggested that unoprostone lowers monidine tartrate,1 have been shown to IOP by affecting aqueous outflow through have multiple mechanisms of action. If tar- the trabecular meshwork via inhibition of get IOP is not reached after an appropri- endothelin-dependent mechanisms. ate period of monotherapy, combination This study was conducted to deter- treatments are used to achieve the de- mine the effects of unoprostone on aque- sired IOP-lowering effect, especially com- ous humor dynamics in patients with binations of drugs with differing modes of ocular hypertension (OHT) or primary action.2 An understanding of the IOP- open-angle glaucoma (POAG). lowering mechanism of action of each glaucoma medication would help predict METHODS additivity between drugs. Author Affiliation: Department Unoprostone isopropyl is a structural of Ophthalmology, University of This was a single-center, randomized, double- Nebraska Medical Center, analogue of (PG) F2␣ and has masked, placebo-controlled study in patients Omaha. been reported to be a docosanoid. It has with OHT or POAG. The number of patients Financial Disclosure: been shown to be a safe and efficacious to enroll was determined before the start of the Dr Camras was a consultant for IOP-lowering drug.3-5 Unoprostone ap- study by power estimates generated with the Pharmacia Corp. pears to lower IOP by increasing or facili- nQuery Advisor Version 2.0 (Statistical Solu-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 1. Schedule of Visits

Visit 1 Visit 2 Visit 3 Visit 4 (Day −31 to −1) Screening (Day 0) Baseline (Day 5 ± 1) (Day 28 ± 2)

Previous IOP therapy is discontinued. IOP is checked at 8 AM ±1h. IOP is checked at 8 AM ±1h. IOP is checked at 8 AM ±1h. Washout period begins. IOP should be 23-30 mm Hg IOP must be reduced by 3 mm Hg vs Masked study medication Inclusion/exclusion criteria in both eyes and Յ5mmHg baseline in at least 1 eye and IOP is instilled by investigator. are evaluated. difference between eyes. should be Յ30 mm Hg in both eyes; Aqueous humor dynamic Complete ophthalmic examination Baseline aqueous humor dynamic if not, patient exits study. parameters are collected. is given. parameters are collected. Masked study medication is instilled Complete ophthalmic Urine pregnancy test is performed After all measurements, 1 eye is by investigator. examination is given. (if applicable). randomly assigned to receive Aqueous humor dynamic parameters Urine pregnancy test unoprostone isopropyl, while the are collected. is repeated (if applicable). other receives placebo twice daily Patient continues to self-administer unoprostone and placebo twice daily.

Abbreviation: IOP, intraocular pressure.

tions, Boston, Mass). A sample size of 30 subjects was needed tween eyes on visit 2. Eligible patients then received 1 drop of to provide at least 75% power to detect a difference in aqueous 0.5% maleate in each eye or , 250 mg orally. flow of 15% between drug-treated and vehicle-treated eyes, as- These drugs reduce aqueous flow and IOP to enable calcula- suming a standard deviation of 0.75 µL/min and a 2-sided sig- tion of fluorophotometric outflow facility (Cfl), which pro- nificance level of .05. The study was approved by the Univer- vides an estimate of trabecular outflow facility.14 sity of Nebraska Medical Center Institutional Review Board, The following formula was used to calculate Cfl: Omaha, and all patients provided written informed consent be- [( ) ( )] fore initiation of any study-related assessments. Cflx= Fa−Fax / IOP−IOPx , Patients were scheduled for 4 visits, consisting of screen- where Fa indicates aqueous flow rate before treatment with ing, baseline, day 5±1 of treatment, and day 28±2 of treat- acetazolamide or timolol; Fax, aqueous flow rate at intervals ment. The protocol is summarized in Table 1. x=1, 2, and 3 after acetazolamide-timolol; IOP,the IOP just At visit 1 (screening), a medical history was collected from before acetazolamide-timolol administration; IOPx, average of each patient and a complete ophthalmic examination was per- IOP values taken at the beginning and end of intervals x=1, 2, formed. Main inclusion criteria at visit 1 included diagnosis of and 3; and Cfl , Cfl at intervals x=1, 2, and 3. The 3 calculated bilateral POAG or OHT for at least 1 year and corrected dis- x Cflx measurements were averaged to obtain the reported Cfl tance visual acuity of 20/200 or better (Early Treatment Dia- values. betic Retinopathy Study visual acuity chart). Main exclusion Uveoscleral outflow (Fu) was calculated by means of the criteria at visit 1 consisted of any visual field defect, known hy- following formula: persensitivity to study-related medication, previous glaucoma ( ) filtering procedure, cataract or laser surgery within the past year, Fu=Fa−Cfl IOP−Pev , ocular infection or inflammation within the past 3 months, or history of elevated IOP caused by processes other than POAG where Pev is episcleral venous pressure. or OHT. Before the baseline visit (visit 2), subjects who had Safety assessments were performed and eligible patients re- been taking medication to treat the elevated IOP discontinued ceived 2 bottles identical in appearance and labeled only by the these drugs before the baseline visit. The medications in- patient’s identification number and the words right eye or left cluded (n=7), timolol maleate (n=4), hy- eye. One bottle contained 0.15% unoprostone isopropyl (Res- drochloride (n=2), latanoprost plus timolol (n=2), dorzol- cula; Novartis Ophthalmics, East Hanover, NJ) and the other amide hydrochloride (n=1), (n=1), latanoprost contained vehicle (placebo). Patients were instructed to instill plus (n=1), latanoprost plus (n=1), 1 drop in the appropriate eye twice daily (8 AM and 8 PM) for 4 and timolol plus (n=1). The washout period was 3 to 6 days in a double-masked, randomized fashion. Patients were days for dorzolamide, 15 days for brimonidine, and 28 days for asked to record on a log sheet the time of each drug instilla- latanoprost, bimatoprost, travoprost, and timolol. tion and any omissions or errors in treatment. The night be- Between 9 PM and 4 AM the night before visit 2, patients in- fore visit 3, fluorescein was administered as before. stilled 1 drop of 2% fluorescein at 5-minute intervals until 6 to At visit 3 (day 5±1), only patients whose morning IOP was 10 drops were instilled in each eye. reduced by at least 3 mm Hg from baseline in at least one eye, At visit 2, central corneal thickness and anterior chamber and did not exceed 30 mm Hg, continued in the study. If the depth were measured by slitlamp pachymetry. From these mea- IOP criteria were not met, this visit served as an exit visit and surements, the anterior chamber volume was calculated for each further investigations were not performed. The morning dose eye.11 Four pairs of duplicate fluorophotometric scans of the of unoprostone or placebo was administered to the appropriate cornea and anterior chamber were collected at 45-minute in- eye by the investigator in the clinic, and all measurements were tervals between 8 AM and 11 AM, with the use of a scanning fluo- repeated as at visit 2. That evening, patients continued treat- rophotometer (OcuMetrics, Palo Alto, Calif). These values were ment with 0.15% unoprostone twice daily in one eye and pla- used to calculate baseline aqueous flow.12 An episcleral venoma- cebo twice daily in the fellow eye until visit 4. The night before nometer (Eyetech, Morton Grove, Ill) was used to measure epi- visit 4, fluorescein was administered to each eye by the patient scleral venous pressure.13 as before. At visit 4, the final dose of unoprostone or placebo was All IOP measurements were done with a pneumatonom- administered by the investigator immediately after the first IOP eter (Medtronic Xomed, Jacksonville, Fla). To be eligible for measurement. All measurements were repeated as at visit 2. the study, IOP had to be between 23 and 30 mm Hg in both The efficacy variables were the change from baseline in aque- eyes at 11 AM with no greater than a 5-mm Hg difference be- ous humor flow, fluorophotometric outflow facility, uveo-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 treat data set). All patients enrolled were diagnosed as 28 ∗P <.05 vs Day 0 Unoprostone having OHT except for one patient who was diagnosed †P <.05 vs Placebo Placebo as having POAG in the right eye and OHT in the left eye. 26 In patients who completed the study, unoprostone sig- nificantly reduced IOP at days 5 and 28 compared with

24 baseline and with placebo (Figure 1). Mean baseline IOP values were 25.5±0.6 mm Hg and 25.7±0.7 mm Hg in the unoprostone-treated eyes and placebo-treated eyes, 22 respectively. Average reduction from baseline in eyes Mean IOP, mm Hg Mean IOP, treated with unoprostone was 5.6±0.4 mm Hg (PϽ.001) 20 and 4.8±0.6 mm Hg (PϽ.001) on days 5 and 28, respec- tively, whereas the average reduction in the placebo- treated eyes was 2.5±0.04 mm Hg (PϽ.001) and 1.7±0.1 18 0 4 8 12 16 20 24 28 mm Hg (P=.008; Figure 1), respectively. The baseline- Days of Treatment adjusted between-treatment differences were statisti- cally significant on day 5 (2.8±0.4 mm Hg; PϽ.001) and Figure 1. Mean intraocular pressure (IOP) in 29 patients with ocular on day 28 (3.2±0.5 mm Hg; PϽ.001). hypertension or glaucoma treated with 0.15% unoprostone isopropyl in one eye and placebo in the contralateral eye, twice daily for 28 days. Bars Compared with baseline values, both unoprostone and represent standard error of the mean. placebo significantly decreased aqueous humor flow on day 5 of treatment but not on day 28 (Table 2). The baseline-adjusted between-treatment differences were not scleral outflow, episcleral venous pressure, and IOP. These vari- statistically significant at either day 5 (0.14±0.11 µL/ ables were assessed at visits 2, 3, and 4. Baseline values for min; P=.21) or day 28 (0.18±0.14 µL/min; P=.22). statistical purposes were the assessments taken on day 0 (visit The average changes in outflow facility from baseline 2). In addition, treated eyes were compared with contralateral values in eyes treated with unoprostone were statistically control eyes at each visit. The primary time point for evaluat- significant (PՅ.001) on days 5 and 28, whereas the aver- ing the effects of treatment on aqueous humor dynamics was age changes in the placebo-treated eyes were not signifi- day 28 (visit 4). Both an intent-to-treat and per-protocol set of patients were cant (Table 2, Figure 2). The baseline-adjusted between- analyzed for efficacy. For the between-treatment comparison treatment differences were statistically significant on day −1 −1 of each efficacy variable, the null hypothesis to be tested was 28 (0.06±0.03 µL·min ·mm Hg ; P=.04) but not day 5. that there was no difference between the 2 treatment groups. Unoprostone and placebo did not significantly alter The alternative hypothesis was that there was a difference be- episcleral venous pressure (Table 2). Both unoprostone tween the groups. and placebo reduced uveoscleral outflow on day 28 com- Within each treatment group, tests were made to deter- pared with baseline (PՅ.04; Table 2). However, the base- mine whether the mean change from baseline differed signifi- line-adjusted between-treatment differences were not sta- cantly from zero. The change-from-baseline values were used tistically significant at day 5 or 28. to determine whether the 2 treatment groups were different. There were no serious adverse events and no clinical These analyses were performed by means of a paired t test. As there was one primary time point (day 28) compared with base- concerns detected during the comprehensive ophthal- line, there were no adjustments made for multiple compari- mic examinations. The incidence of burning, stinging, sons. All statistical tests in this trial were 2 sided, and all tests or conjunctival hyperemia on drug instillation was more with a corresponding PՅ.05 were considered statistically sig- frequent with unoprostone than with placebo treat- nificant. All values are reported as mean±SEM. ment. Most reported adverse events were mild and ocu- Changes from baseline in brachial artery blood pressure, lar. No patients were discontinued from the trial be- radial pulse, and visual acuity were tested within each treat- cause of adverse events. ment group by a paired t test. Changes from baseline in the slitlamp examination, ocular symptoms, and ophthalmoscopy were evaluated. COMMENT

RESULTS In the patients who completed the current study, uno- prostone reduced IOP in a clinically significant manner Thirty-three patients were enrolled in the double- similar to previous studies.3,4 This reduction in IOP ap- masked treatment period of this study. Twenty-nine pa- peared to be primarily the result of increased outflow fa- tients completed the study. Four patients were discon- cility. Compared with baseline, unoprostone increased tinued on day 5 (visit 3) because of insufficient IOP outflow facility by 67% at 5 days and 100% at 28 days. reduction in either eye. The increase in outflow facility was confirmed by the be- The average age of the patients was 57.7±2.0 years tween-treatment comparisons. (range, 32-84 years). Thirteen (39%) of the patients were Data presented herein support the view of Yama- male and 25 (76%) were white. Fifteen patients (45%) moto et al,15 who had hypothesized that the IOP- had dark-colored (black or brown) irides and 18 pa- lowering effect of unoprostone may be due to factors other tients (55%) had light-colored (hazel, green, blue, or gray) than increasing the rate of uveoscleral outflow. An effect irides. Mean IOP was 15.6±0.4 mm Hg at screening, rang- of unoprostone on the trabecular meshwork is one pos- ing from 11 to 22 mm Hg before washout (intent-to- sibility. An increase in outflow facility was found in rab-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 2. Aqueous Humor Dynamics Before and After Topical Application of Unoprostone or Placebo*

Day 5 Day 28 Baseline, Mean ± SEM Mean ± SEM P Value† Mean ± SEM P Value† Outflow facility, µL·min−1·mm Hg−1 (n = 28) (n = 28) (n = 27) Unoprostone eye 0.09 ± 0.01 0.15 ± 0.02 .001 0.18 ± 0.02 Ͻ.001 Placebo eye 0.11 ± 0.02 0.13 ± 0.02 .55 0.14 ± 0.02 .24 P value‡ .17 .11 .04 Uveoscleral outflow, µL/min (n = 28) (n = 27) (n = 27) Unoprostone eye 1.24 ± 0.09 1.02 ± 0.12 .14 1.00 ± 0.11 .02 Placebo eye 1.14 ± 0.11 0.99 ± 0.11 .57 0.86 ± 0.10 .04 P value‡ .22 .56 .80 Episcleral venous pressure, mm Hg (n = 29) (n = 29) (n = 29) Unoprostone eye 10.6 ± 0.2 10.7 ± 0.3 .85 10.7 ± 0.2 .76 Placebo eye 10.4 ± 0.2 10.6 ± 0.2 .43 10.4 ± 0.2 .93 P value‡ .32 .62 .78 Aqueous humor flow, µL/min (n = 28) (n = 29) (n = 29) Unoprostone eye 2.37 ± 0.14 2.08 ± 0.11 .007 2.40 ± 0.11 .84 Placebo eye 2.50 ± 0.15 2.07 ± 0.11 .001 2.34 ± 0.12 .39 P value‡ .20 .21 .22

*Placebo or 0.15% unoprostone isopropyl was applied twice daily for 28 days in patients with ocular hypertension or glaucoma. Numbers of patients varied from 27 to 29 because some values were excluded for the following reasons: failure of the fluorophotometer preventing determination of aqueous flow; insufficient reduction in intraocular pressure or aqueous flow from timolol maleate resulting in inability to calculate outflow facility and uveoscleral outflow; and value of uveoscleral outflow calculated to be more than 2 SDs away from the mean (outlier). †Compared with baseline by means of a paired t test. ‡Compared with contralateral placebo-treated eye by means of a paired t test.

bits treated with 1 drop of unoprostone.6,7 In vitro find- 0.25 ings10 suggested that the IOP-lowering effect of Unoprostone ∗P <.05 vs Day 0 unoprostone was likely due to its effect on calcium- –1 Placebo †P <.05 vs Placebo gated potassium channels, intracellular calcium, and some mm Hg

⋅

degree of smooth-muscle relaxation in the trabecular –1 0.20 min meshwork. Taken together with data from the current ⋅

L

study, these findings suggest that one possible mecha- µ nism of the IOP-lowering effect of unoprostone is modu- lation of the trabecular meshwork function. 0.15 Contrary to experiments in rabbits6,7 and the current clinical study, previous investigations of 0.12% unopros- 8 0.10

tone in ocular normotensive volunteers and patients with Mean Outflow Facility, POAG9 did not find an effect on outflow facility when measured by tonography. These apparent discrepancies 0528 may be due to differences in study design, method of mea- Days of Treatment surement, and concentration of drug. The current study enrolled only patients who responded to treatment with Figure 2. Fluorophotometric outflow facility in 29 patients with ocular hypertension or glaucoma treated unilaterally with 0.15% unoprostone at least a 3-mm Hg decrease in IOP. Unoprostone ap- isopropyl in one eye and placebo in the contralateral eye, twice daily for 28 pears to work well in some individuals and not well in days. Bars represent Standard error of the mean. others16 (unpublished pilot data, C.B.T., G.L.Z., and C.B.C., December 1998). Enrolling only responders in- creased the power of the study to find differences in the human eyes primarily affects uveoscleral outflow,18-22 aqueous humor dynamic parameters under investiga- though it and other PGF2␣ analogues, including bima- tion and to identify the mechanism by which the IOP was toprost, have been found to increase outflow facility as decreased. The fluorophotometric method to assess out- well.18,23-25 The outflow facility increase with bimato- flow facility was used, which detects differences not al- prost was insufficient to account for the entire IOP de- ways found by tonography.17 The 0.15% unoprostone in crease, suggesting that uveoscleral outflow also was in- the current study was expected to provide a greater effect creased,24 similar to the effects of latanoprost.21,23 on IOP than the 0.12% used in some earlier studies. All Travoprost increases uveoscleral outflow in monkeys of these differences in study design made it possible to without affecting other parameters of aqueous humor detect an increase in outflow facility with unoprostone dynamics,26 but its effects in humans have not been treatment. reported. The PGF2␣ analogues increase outflow predomi- A reduction of aqueous flow in unoprostone-treated nantly, or at least partially, through the uveoscleral path- eyes occurred after 5 days of treatment, but a similar de- way.18,19 Latanoprost in normotensive and hypertensive crease was also noted in placebo-treated eyes compared

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 with baseline. The effect on aqueous flow disappeared surements to ensure that the treatment was correct while after 28 days of dosing. This suggests a possible short- data were being collected. It is unlikely that sufficient term, contralateral effect of unoprostone on aqueous flow, numbers of patients administered the drops errone- a finding that requires confirmation. At no point during ously to account for the contralateral effects. the study was the aqueous flow difference between treated In clinical practice, IOP-lowering drugs often are com- and contralateral control eyes statistically significant. bined to achieve target IOPs. Drugs that increase facility Therefore, a unoprostone-induced effect on aqueous flow of outflow might be used in combination therapy with cannot account for the IOP reduction in the treated com- IOP-lowering drugs that inhibit inflow. Unoprostone and pared with contralateral control eyes. timolol (an aqueous flow suppressant) have been found 4,16,32 Unlike most other PGF2␣ analogues, unoprostone to be additive in several clinical trials. On the other did not increase uveoscleral outflow in the present hand, combination therapy of unoprostone with drugs study. Instead, a reduction in uveoscleral outflow was that increase aqueous humor outflow may or may not be observed compared with baseline measurements. Be- effective. There is no apparent additivity of unopros- cause a reduction in uveoscleral outflow also was ob- tone with latanoprost.9,33-35 served in the contralateral placebo-treated eyes, with no In conclusion, unoprostone significantly reduced IOP difference between treated and the contralateral control in patients with ocular hypertension by increasing the eyes, the effect was not considered to be clinically im- facility of outflow through the trabecular meshwork. Uno- portant. The reduction of uveoscleral outflow is more prostone was safe and well tolerated, and may be a suit- likely the indirect effect of increased outflow facility able adjunct drug to aqueous flow suppressants. than a direct effect on uveoscleral outflow. The balance in resistance factors between the trabecular meshwork Submitted for Publication: July 14, 2003; final revision and uveoscleral pathway may have shifted in favor of received April 1, 2004; accepted June 1, 2004. the trabecular meshwork, causing a redirection of some Correspondence: Carol B. Toris, PhD, Department of fluid from the uveoscleral pathway into the trabecular Ophthalmology, 985840 Nebraska Medical Center, meshwork. In other words, the fluid took the path of Omaha, NE 68198-5840 ([email protected]). least resistance. Funding/Support: This study was supported in part by The finding that unoprostone did not affect uveo- Novartis Ophthalmics and by an unrestricted grant from scleral outflow is contrary to published studies in hu- Research to Prevent Blindness Inc, New York, NY. Dr mans8 and rabbits.7 It should be noted, however, that the Camras was a Research to Prevent Blindness Senior Sci- earlier clinical study concluded an effect on uveoscleral entific Investigator. outflow only when an effect on aqueous flow and out- Acknowledgment: Generous assistance in analyzing the flow facility was not detected. Our pilot study (unpub- data and reviewing the manuscript was provided by Reza lished data), which included some nonresponders and M. Haque, MD, PhD, Naveed Shams, MD, PhD, Chris- patients with relatively low baseline IOPs, also failed to tine Kubilus, RN, Kim Truett, MS, Jennifer Johnson, Barry find a significant effect on aqueous flow and outflow fa- Kapik, MS, Natalia Yannoulis, PhD, Lindsay Cook, MA, cility, and when calculated mathematically, uveoscleral and Ken Green, PhD, of Novartis Ophthalmics. outflow remained unchanged as well. It is possible that the power of the earlier studies was insufficient to de- tect changes in outflow facility. The increase in uveo- REFERENCES scleral outflow with unoprostone treatment in rabbits not found in humans might be explained by species differ- 1. Toris CB, Camras CB, Yablonski ME. Acute versus chronic effects of bri- monidine on aqueous humor dynamics in ocular hypertensive patients. Am J ences in the structures of the anterior chamber angle and Ophthalmol. 1999;128:8-14. the unique sensitivity of the rabbit blood-aqueous bar- 2. Hoyng PFJ, van Beek LM. Pharmacological therapy for glaucoma: a review. Drugs. rier,27,28 especially to topical PGs.29 Breakdown of the 2000;59:411-434. blood-aqueous barrier alone can increase uveoscleral out- 3. Nordmann J-P, Mertz B, Yannoulis NC, et al. A double-masked randomized com- flow.30 Rabbit eyes do not respond well to topical latano- parison of the efficacy and safety of unoprostone with timolol and betaxolol in pa- 31 tients with primary open-angle glaucoma including pseudoexfoliation glaucoma prost, yet this drug has become the gold standard for or ocular hypertension: 6 month data. Am J Ophthalmol. 2002;133:1-10. IOP reduction in humans. The rabbit is a poor model 4. Hommer A, Kapik B, Shams N; Unoprostone Adjunctive Therapy Study Group. for the study of PGs and aqueous humor dynamics in Unoprostone as adjunctive therapy to timolol: a double masked randomised study humans. versus brimonidine and dorzolamide. Br J Ophthalmol. 2003;87:592-598. 5. de Arruda Mello PA, Yannoulis NC, Haque RM. Safety of unoprostone isopropyl It is always a concern in studies of this nature that pa- as mono- or adjunctive therapy in patients with primary open-angle glaucoma tients may have instilled some of their drops in the in- or ocular hypertension. Drug Saf. 2002;25:583-597. correct eye at some time during the treatment period. 6. Taniguchi T, Haque MSR, Sugiyama T, Hori N, Kitazawa Y. Ocular hypotensive These errors might account for apparent contralateral ef- mechanism of topical isopropyl unoprostone, a novel prostaglandin metabolite- fects. Each patient was informed repeatedly of the need related drug, in rabbits. J Ocul Pharmacol Ther. 1996;12:489-498. 7. Sakurai M, Araie M, Oshika T, Mori M, Shoji N, Masuda K. Effects of topical ap- for accurate adherence to their regimen and the need to plication of UF-021, a novel prostaglandin-related compound, on aqueous hu- report any errors in drug administration. All patients filled mor dynamics in rabbit. Jpn J Ophthalmol. 1993;37:252-258. out a daily log reporting the exact times of each drop ap- 8. Sakurai M, Araie M, Oshika T, et al. Effects of topical application of UF-021, a novel plication and any problems. Patients rarely reported omis- prostaglandin derivative, on aqueous humor dynamics in normal human eyes. Jpn J Ophthalmol. 1991;35:156-165. sions, delays in administration of drops, or administra- 9. Saito M, Takano R, Shirato S. Effects of latanoprost and unoprostone when used tion of the wrong drop to an eye. The drops were alone or in combination for open-angle glaucoma. Am J Ophthalmol. 2001; administered by the investigator on each day of mea- 132:485-489.

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