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 glaucoma. 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 prostaglandin (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- (REPRINTED) ARCH OPHTHALMOL / VOL 122, DEC 2004 WWW.ARCHOPHTHALMOL.COM 1782 ©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% timolol maleate in each eye or acetazolamide, 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 latanoprost (n=7), timolol maleate (n=4), betaxolol 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), bimatoprost (n=1), latanoprost contained vehicle (placebo). Patients were instructed to instill plus dorzolamide (n=1), latanoprost plus brimonidine (n=1), 1 drop in the appropriate eye twice daily (8 AM and 8 PM) for 4 and timolol plus travoprost (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.