CLINICAL SCIENCES Aqueous Humor Flow in Normal Human Eyes Treated With Brimonidine and Dorzolamide, Alone and in Combination Hidetoshi Tsukamoto, MD; Lill-Inger Larsson, MD, PhD Objectives: To measure the effectiveness of topical 0.2% 28.2%±18.0% (PϽ.001), dorzolamide by 19.3%±22.0% brimonidine tartrate as a suppressor of aqueous humor (P=.007), and the combination of brimonidine and dor- flow in the human eye compared with the effectiveness zolamide by 37.2%±20.6% (PϽ.001). The combination of 2% dorzolamide hydrochloride, and to measure the of both drugs statistically significantly suppressed aque- additivity of the effects of the 2 drugs. ous humor flow compared with dorzolamide alone (PϽ.001) and brimonidine alone (P=.04). The IOP was Design: A randomized, double-masked, placebo- reduced by a mean±SD of 11.6%±10.1% (PϽ.001) by controlled study was performed in 20 healthy human sub- brimonidine, 8.5%±14.1% (P=.02) by dorzolamide, and jects. The topical drugs were instilled twice daily the day 17.9%±16.5% (PϽ.001) by the combination. The com- before and again in the morning on the day of the mea- bination of drugs reduced IOP better than dorzolamide surements. The rate of aqueous humor flow was mea- (PϽ.001), but not more than brimonidine (P=.06). sured from 8 AM to 4 PM by clearance of topically ap- plied fluorescein using a fluorophotometer, after Conclusions: The combination of brimonidine and dor- administration of doses of each drug singly and both drugs zolamide caused a further reduction of aqueous humor flow together. Intraocular pressure (IOP) was measured with compared with each drug applied alone. The IOP was fur- applanation tonometry. ther reduced by the combination compared with dorzol- amide alone, but not compared with brimonidine alone. Results: Compared with placebo, brimonidine re- duced the aqueous humor flow by a mean±SD of Arch Ophthalmol. 2004;122:190-193 ␣ HE ADRENERGIC 2-RECEP- cause there are many ocular hypotensive tor agonist brimonidine tar- drugs commercially available, different trate1-7 is a topically ap- therapeutic regimens exist. Brimonidine plied ocular hypotensive added to treatment with ␤-adrenergic an- agent. Studies of brimon- tagonists has been shown to lead to a sig- idine have demonstrated that the ocular nificant additive lowering of the IOP and T 24 hypotensive effect primarily is caused by of the aqueous humor production. Bri- reduction of aqueous humor produc- monidine and dorzolamide are used in tion,7-15 but increased uveoscleral out- clinical practice not only as monothera- flow has also been reported in rabbits16 and pies but also in different combination treat- in humans.11 ments.12-15,25-29 The purpose of the pres- Dorzolamide hydrochloride is a car- ent study was to measure aqueous humor bonic anhydrase inhibitor that is used for flow and IOP after topical administration treatment of glaucoma. This topically ap- of brimonidine, alone and in combina- plied drug lowers the intraocular pres- tion with dorzolamide, to determine sure (IOP) by suppressing the aqueous hu- whether the effects of the 2 drugs are ad- mor production.17-23 Compared with a ditive on aqueous flow and IOP. systemically administered drug of the same class, it has fewer systemic adverse ef- METHODS fects, but its ability to reduce the aque- From the Department of 17,20 The study was carried out at the Department Ophthalmology, Uppsala ous humor formation is weaker. of Ophthalmology, Uppsala University Hospi- University Hospital, Uppsala, Monotherapy is not always suffi- tal. Twenty healthy volunteers were enrolled Sweden. The authors have no cient for an adequate control of the IOP into the study. There were 10 women and 10 relevant financial interest in in patients with glaucoma, and addi- men (mean age, 29.2 years; range, 24-49 years). this article. tional treatment may be prescribed. Be- All subjects underwent an eligibility examina- (REPRINTED) ARCH OPHTHALMOL / VOL 122, FEB 2004 WWW.ARCHOPHTHALMOL.COM 190 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Aqueous Humor Flow From 8 AM to 4 PM* % Difference (P Value) Aqueous Humor Flow, vs Dorzolamide vs Brimonidine Drug Applied No. of Eyes µL/min vs Placebo Hydrochloride Tartrate Placebo 20 3.04 ± 0.86 . Dorzolamide 20 2.45 ± 0.56 19.3 ± 22.0 (.007) . Brimonidine 20 2.18 ± 0.54 28.2 ± 18.0 (Ͻ.001) 11.0 ± 20.5 (Ͻ.09) . Brimonidine and dorzolamide 20 1.91 ± 0.50 37.2 ± 20.6 (Ͻ.001) 22.1 ± 18.7 (Ͻ.001) 12.5 ± 22.1 (.04) *Data are given as mean ± SD. tion consisting of a medical and ophthalmic history, visual acu- IOP was then recorded as the mean of the 3 measurements. Di- ity measurement, slitlamp examination, applanation tonom- lute milk rather than fluorescein was used as the disclosing agent etry, and ophthalmoscopy. Exclusion criteria were ocular disease, to avoid the introduction of more fluorescein to the cornea and systemic disease requiring long-term medical treatment, preg- mismeasurement of aqueous humor flow. nancy or lactation, inability to comply with tonometry or fluo- Aqueous humor flow was calculated from the clearance rophotometry, an IOP difference between the 2 eyes greater than of fluorescein at each 2-hour interval by using the following ⌬ ⌬ ⌬ 3 mm Hg, and known drug hypersensitivity. The research pro- equation: clearance= M/(Ca t), where M is the loss of mass tocol followed the tenets of the Declaration of Helsinki and was of fluorescein in the combined cornea and anterior chamber ⌬ approved by the Ethical Committee of Uppsala University. An during t interval, and Ca is the mean concentration in the an- informed consent was obtained from all participants. The study terior chamber during the interval, estimated from the initial consisted of 2 parts. At least 4 weeks elapsed between the parts and final fluorescence and assuming a single exponential de- to ensure complete elimination of the drugs. In part 1, the effect cay. Aqueous humor flow was calculated from the rate of clear- of 0.2% brimonidine–treated eyes vs placebo-treated eyes was ance of fluorescein after subtracting the presumed rate of dif- studied. In part 2, topical application of 2% dorzolamide was fusional clearance (0.25 µL/min).30 added to both eyes. Four treatment regimens were thus com- After completion of the study and tabulation of the data, the pared, with 20 eyes in each treatment group: (1) placebo- code was broken and the data stratified by drug. The statistical treated eyes, (2) brimonidine-treated eyes, (3) dorzolamide- analysis was carried out using a 2-sided t test for paired samples. treated eyes, and (4) brimonidine and dorzolamide–treated eyes. PϽ.05 was considered statistically significant. The coefficient of The study was randomized, double-masked, and placebo- variation of measurements of aqueous humor flow under condi- controlled. The brimonidine, dorzolamide, and placebo eye- tions similar to those in this experiment is approximately 23%.31 drops were given by random assignment and were adminis- The mean±SD aqueous humor flow in daytime is 2.75±0.63 µL/ tered from identical-appearing dropper bottles labeled by subject min.30 A sample size of 20 in each group provided a power of 95% number, sequence, and right and left eyes. These sterile eye- for detecting a true difference of 20% between the eyes.32 dropper bottles contained 0.2% brimonidine tartrate (Alpha- gan; Allergan, Inc, Irvine, Calif), 2% dorzolamide hydrochlo- RESULTS ride (Trusopt; Merck Sharp and Dohme/Isotopes, St Louis, Mo), or placebo (Isopto-Plain; Alcon Laboratories, Fort Worth, Tex). The effects of the different drugs on aqueous humor flow Each part of the study was performed on 2 sequential days, are presented in Table 1. Brimonidine reduced aque- day 1 and day 2. On day 1, the subjects reported to the re- Ͻ search area at 8 AM, and they were given 1 drop of 0.2% bri- ous humor flow by a mean±SD of 28.2%±18.0% (P .001) monidine in one eye and 1 drop of placebo in the other eye. and dorzolamide by 19.3%±22.0% (P=.007) compared The procedure was repeated at 5 PM. On day 2, when flow was with placebo, while there was no statistically significant measured, eyedrops were again instilled at 8 AM. As a precau- difference between brimonidine and dorzolamide (P=.09). tion to prevent cross-contamination between the eyes, sub- Brimonidine and dorzolamide applied in combination sup- jects were given separate tissues for each eye and were asked pressed the flow by a mean±SD of 37.2%±20.6% com- to blot only one eye with each tissue. In part 2, brimonidine pared with placebo (PϽ.001). The aqueous humor flow and placebo eyedrops were administered according to the same was statistically significantly reduced by the combina- schedule as in part 1, but at every time point for eyedrop in- tion of both drugs compared with dorzolamide alone stillation, 1 drop of 2% dorzolamide was also administered to Ͻ both eyes 5 minutes after the other eyedrops (ie, dorzolamide (P .001) and brimonidine alone (P=.04). was administered twice daily). The research personnel admin- The IOP (Table 2) was statistically significantly re- istered all eyedrops, except fluorescein, because of the risk of duced by a mean±SD of 11.6%±10.1% by brimonidine error with eyedrop self-administration. alone (PϽ.001) and 8.5%±14.1% by dorzolamide alone The subjects were instructed to awaken at 2 AM on day 2 (P=.02) compared with placebo, but there was no dif- and instill 1 drop of 2% fluorescein into each eye 3 to 5 times, ference between the effects of the 2 drugs in reducing IOP according to age, at 5-minute intervals, and then they returned (P=.35).