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Aqueous Humor Flow in Normal Human Eyes Treated With Brimonidine and Dorzolamide, Alone and in Combination
Hidetoshi Tsukamoto, MD;
Lill-Inger Larsson, MD, PhD
Arch Ophthalmol. 2004;122:190-193.
ABSTRACT
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Objectives To measure the effectiveness of topical 0.2% brimonidine tartrate as a suppressor of aqueous humor flow in the human eye compared with the effectiveness of 2% dorzolamide hydrochloride, and to measure the additivity of the effects of the 2 drugs.
Design A randomized, double-masked, placebo-controlled study was performed in 20 healthy human subjects. The topical drugs were instilled twice daily the day before and again in the morning on the day of the measurements. The rate of aqueous humor flow was measured from 8 AM to 4 PM by clearance of topically applied fluorescein using a fluorophotometer, after administration of doses of each drug singly and both drugs together. Intraocular pressure (IOP) was measured with applanation tonometry.
Results Compared with placebo, brimonidine reduced the aqueous humor flow by a mean ± SD of 28.2% ± 18.0% (P<.001), dorzolamide by 19.3% ± 22.0% (P = .007), and the combination of brimonidine and dorzolamide by 37.2% ± 20.6% (P<.001). The combination of both drugs statistically significantly suppressed aqueous humor flow compared with dorzolamide alone (P<.001) and brimonidine alone (P = .04). The IOP was reduced by a mean ± SD of 11.6% ± 10.1% (P<.001) by brimonidine, 8.5% ± 14.1% (P = .02) by dorzolamide, and 17.9% ± 16.5% (P<.001) by the combination. The combination of drugs reduced IOP better than dorzolamide (P<.001), but not more than brimonidine (P = .06).
Conclusions The combination of brimonidine and dorzolamide caused a further reduction of aqueous humor flow compared with each drug applied alone. The IOP was further reduced by the combination compared with dorzolamide alone, but not compared with brimonidine alone.
INTRODUCTION
The adrenergic  2-receptor agonist brimonidine tartrate1-7 is a topically applied ocular hypotensive agent. Studies of brimonidine have demonstrated that the ocular hypotensive effect primarily is caused by reduction of aqueous humor production,7-15 but increased uveoscleral outflow has also been reported in rabbits16 and in humans.11
Dorzolamide hydrochloride is a carbonic anhydrase inhibitor that is used for treatment of glaucoma. This topically applied drug lowers the intraocular pressure (IOP) by suppressing the aqueous humor production.17-23 Compared with a systemically administered drug of the same class, it has fewer systemic adverse effects, but its ability to reduce the aqueous humor formation is weaker.17, 20
Monotherapy is not always sufficient for an adequate control of the IOP in patients with glaucoma, and additional treatment may be prescribed. Because there are many ocular hypotensive drugs commercially available, different therapeutic regimens exist. Brimonidine added to treatment with  -adrenergic antagonists has been shown to lead to a significant additive lowering of the IOP and of the aqueous humor production.24 Brimonidine and dorzolamide are used in clinical practice not only as monotherapies but also in different combination treatments.12-15,25-29 The purpose of the present study was to measure aqueous humor flow and IOP after topical administration of brimonidine, alone and in combination with dorzolamide, to determine whether the effects of the 2 drugs are additive on aqueous flow and IOP.
METHODS
The study was carried out at the Department of Ophthalmology, Uppsala University Hospital. Twenty healthy volunteers were enrolled into the study. There were 10 women and 10 men (mean age, 29.2 years; range, 24-49 years). All subjects underwent an eligibility examination consisting of a medical and ophthalmic history, visual acuity measurement, slitlamp examination, applanation tonometry, and ophthalmoscopy. Exclusion criteria were ocular disease, systemic disease requiring long-term medical treatment, pregnancy or lactation, inability to comply with tonometry or fluorophotometry, an IOP difference between the 2 eyes greater than 3 mm Hg, and known drug hypersensitivity. The research protocol followed the tenets of the Declaration of Helsinki and was approved by the Ethical Committee of Uppsala University. An informed consent was obtained from all participants. The study consisted of 2 parts. At least 4 weeks elapsed between the parts to ensure complete elimination of the drugs. In part 1, the effect of 0.2% brimonidine–treated eyes vs placebo-treated eyes was studied. In part 2, topical application of 2% dorzolamide was added to both eyes. Four treatment regimens were thus compared, with 20 eyes in each treatment group: (1) placebo-treated eyes, (2) brimonidine-treated eyes, (3) dorzolamide-treated eyes, and (4) brimonidine and dorzolamide–treated eyes.
The study was randomized, double-masked, and placebo-controlled. The brimonidine, dorzolamide, and placebo eyedrops were given by random assignment and were administered from identical-appearing dropper bottles labeled by subject number, sequence, and right and left eyes. These sterile eyedropper bottles contained 0.2% brimonidine tartrate (Alphagan; Allergan, Inc, Irvine, Calif), 2% dorzolamide hydrochloride (Trusopt; Merck Sharp and Dohme/Isotopes, St Louis, Mo), or placebo (Isopto-Plain; Alcon Laboratories, Fort Worth, Tex).
Each part of the study was performed on 2 sequential days, day 1 and day 2. On day 1, the subjects reported to the research area at 8 AM, and they were given 1 drop of 0.2% brimonidine in one eye and 1 drop of placebo in the other eye. The procedure was repeated at 5 PM. On day 2, when flow was measured, eyedrops were again instilled at 8 AM. As a precaution to prevent cross-contamination between the eyes, subjects were given separate tissues for each eye and were asked to blot only one eye with each tissue. In part 2, brimonidine and placebo eyedrops were administered according to the same schedule as in part 1, but at every time point for eyedrop instillation, 1 drop of 2% dorzolamide was also administered to both eyes 5 minutes after the other eyedrops (ie, dorzolamide was administered twice daily). The research personnel administered all eyedrops, except fluorescein, because of the risk of error with eyedrop self-administration.
The subjects were instructed to awaken at 2 AM on day 2 and instill 1 drop of 2% fluorescein into each eye 3 to 5 times, according to age, at 5-minute intervals, and then they returned to sleep. The subjects reported to the test area at 8 AM and underwent measurements of the fluorescence of the cornea and the anterior chamber with a fluorophotometer (Fluorotron Master; Coherent Radiation, Palo Alto, Calif). The procedure was repeated every other hour until 4 PM. Immediately after each measurement of fluorescence, the IOP was measured with a Goldmann tonometer. Tonometry was started in the right eye, alternating between the eyes for a total of 3 readings per eye. The IOP was then recorded as the mean of the 3 measurements. Dilute milk rather than fluorescein was used as the disclosing agent to avoid the introduction of more fluorescein to the cornea and mismeasurement of aqueous humor flow.
Aqueous humor flow was calculated from the clearance of fluorescein at each 2-hour interval by using the following equation: clearance =  M/(Cat), where M is the loss of mass of fluorescein in the combined cornea and anterior chamber during t interval, and Ca is the mean concentration in the anterior chamber during the interval, estimated from the initial and final fluorescence and assuming a single exponential decay. Aqueous humor flow was calculated from the rate of clearance of fluorescein after subtracting the presumed rate of diffusional clearance (0.25 µL/min).30
After completion of the study and tabulation of the data, the code was broken and the data stratified by drug. The statistical analysis was carried out using a 2-sided t test for paired samples. P<.05 was considered statistically significant. The coefficient of variation of measurements of aqueous humor flow under conditions similar to those in this experiment is approximately 23%.31 The mean ± SD aqueous humor flow in daytime is 2.75 ± 0.63 µL/min.30 A sample size of 20 in each group provided a power of 95% for detecting a true difference of 20% between the eyes.32
RESULTS
The effects of the different drugs on aqueous humor flow are presented in Table 1. Brimonidine reduced aqueous humor flow by a mean ± SD of 28.2% ± 18.0% (P<.001) and dorzolamide by 19.3% ± 22.0% (P = .007) compared with placebo, while there was no statistically significant difference between brimonidine and dorzolamide (P = .09). Brimonidine and dorzolamide applied in combination suppressed the flow by a mean ± SD of 37.2% ± 20.6% compared with placebo (P<.001). The aqueous humor flow was statistically significantly reduced by the combination of both drugs compared with dorzolamide alone (P<.001) and brimonidine alone (P = .04).
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Table 1. Aqueous Humor Flow From 8 AM to 4 PM*
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The IOP (Table 2) was statistically significantly reduced by a mean ± SD of 11.6% ± 10.1% by brimonidine alone (P<.001) and 8.5% ± 14.1% by dorzolamide alone (P = .02) compared with placebo, but there was no difference between the effects of the 2 drugs in reducing IOP (P = .35). The combination of both drugs statistically significantly reduced IOP compared with dorzolamide (P<.001), but not compared with brimonidine (P = .06).
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Table 2. Intraocular Pressure at 4 PM*
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COMMENT
The results of this study confirm previous results that 0.2% brimonidine tartrate and 2% dorzolamide hydrochloride suppress the aqueous humor formation. There was no statistically significant difference in the flow reduction when brimonidine or dorzolamide was given separately. When they were applied in combination, a further reduction of flow was seen.
Table 3 lists the aqueous humor flow rates in this study along with those in other studies involving brimonidine and dorzolamide. The studies used the fluorophotometric technique for determining flow, and there is good consistency between the studies in the effects of the different drugs.
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Table 3. Previous Studies of Aqueous Humor Flow
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The effect on aqueous humor flow of short-term administration of apraclonidine hydrochloride and brimonidine in healthy volunteers was measured by Schadlu and coworkers.8 The reduction of aqueous humor flow by each drug could explain the reduction of IOP. In addition, a consensual effect on aqueous humor flow in the fellow eye was noted: 16% for apraclonidine and 17% for brimonidine. The total effect of brimonidine on reducing the aqueous humor flow was 44% to 48% in their study. Considering the consensual effect, the reduction of 28% by brimonidine alone that was found in the present study corresponds well with their findings. The consensual effect of brimonidine could also have affected the second part of the present study, when the combination of brimonidine and dorzolamide was administered to one eye and dorzolamide was instilled in the other eye. The flow measured in the dorzolamide-treated eye could thus reflect a crossover effect of brimonidine.
In the present study, the IOP was further reduced by the combination of brimonidine and dorzolamide compared with dorzolamide alone, but not with brimonidine. This finding was inconsistent with the results from the flow measurements. Only healthy volunteers were included in the study, and the mean ± SD baseline IOP of 11.5 ± 2.5 mm Hg was low. A deviation of 1 to 2 mm Hg from the true IOP is inherent in the technique, and the discrepancy between the results from the IOP measurements and the flow measurements could be explained by this.
Traditionally, the medical treatment of glaucoma has consisted of empirical trials of single drugs or combinations of drugs in individual patients, a process that is efficient when few effective choices are available. With the increasing number of effective ocular hypotensive drugs for glaucoma treatment, the number of potential trial sequences or combinations rapidly increases. Clinicians need a management strategy based on pharmacological mechanisms and relative efficacy. Previous investigations suggest that the efficacy of combining different aqueous flow suppressants would be less than the combined effect of each given as monotherapy,27 and the present study supports this. Studies of the effects of combinations of drugs are thus important as a basis for predicting the most efficient strategy in the medical management of glaucoma.
In conclusion, the effect of short-term administration of dorzolamide was partly additive to the effect of brimonidine. The combination of brimonidine and dorzolamide caused a further reduction of aqueous humor flow compared with each drug applied alone. The IOP was further reduced by the combination compared with dorzolamide alone, but not compared with brimonidine alone.
AUTHOR INFORMATION
Corresponding author and reprints: Lill-Inger Larsson, MD, PhD, Department of Ophthalmology, Uppsala University Hospital, S-751 85 Uppsala, Sweden (e-mail: Lill-Inger.Larsson{at}ogon.uu.se).
Submitted for publication June 21, 2002; final revision received August 17, 2003; accepted September 10, 2003.
This study was supported in part by grants from the Glaucoma Research Foundation, Uppsala University, and from Kronprinsessans Arbetsnämnd för de Synskadade, Stockholm, Sweden.
From the Department of Ophthalmology, Uppsala University Hospital, Uppsala, Sweden. The authors have no relevant financial interest in this article.
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