Tsukamoto H, Larsson L. Aqueous Humor Flow in Normal Human Eyes Treated With Brimonidine andDorzolamide, Alone and in Combination. Arch Ophthalmol. 2004;122(2):190-193. doi:10.1001/archopht.122.2.190
To measure the effectiveness of topical 0.2% brimonidine tartrate asa suppressor of aqueous humor flow in the human eye compared with the effectivenessof 2% dorzolamide hydrochloride, and to measure the additivity of the effectsof the 2 drugs.
A randomized, double-masked, placebo-controlled study was performedin 20 healthy human subjects. The topical drugs were instilled twice dailythe day before and again in the morning on the day of the measurements. Therate 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.
Compared with placebo, brimonidine reduced the aqueous humor flow bya mean ± SD of 28.2% ± 18.0% (P<.001),dorzolamide by 19.3% ± 22.0% (P = .007), andthe combination of brimonidine and dorzolamide by 37.2% ± 20.6% (P<.001). The combination of both drugs statisticallysignificantly 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 ofdrugs reduced IOP better than dorzolamide (P<.001),but not more than brimonidine (P = .06).
The combination of brimonidine and dorzolamide caused a further reductionof aqueous humor flow compared with each drug applied alone. The IOP was furtherreduced by the combination compared with dorzolamide alone, but not comparedwith brimonidine alone.
The adrenergic α2-receptor agonist brimonidine tartrate1- 7 isa topically applied ocular hypotensive agent. Studies of brimonidine havedemonstrated that the ocular hypotensive effect primarily is caused by reductionof aqueous humor production,7- 15 butincreased uveoscleral outflow has also been reported in rabbits16 andin humans.11
Dorzolamide hydrochloride is a carbonic anhydrase inhibitor that isused for treatment of glaucoma. This topically applied drug lowers the intraocularpressure (IOP) by suppressing the aqueous humor production.17- 23 Comparedwith a systemically administered drug of the same class, it has fewer systemicadverse effects, but its ability to reduce the aqueous humor formation isweaker.17,20
Monotherapy is not always sufficient for an adequate control of theIOP in patients with glaucoma, and additional treatment may be prescribed.Because there are many ocular hypotensive drugs commercially available, differenttherapeutic regimens exist. Brimonidine added to treatment with β-adrenergicantagonists has been shown to lead to a significant additive lowering of theIOP and of the aqueous humor production.24 Brimonidineand dorzolamide are used in clinical practice not only as monotherapies butalso in different combination treatments.12- 15,25- 29 Thepurpose of the present study was to measure aqueous humor flow and IOP aftertopical administration of brimonidine, alone and in combination with dorzolamide,to determine whether the effects of the 2 drugs are additive on aqueous flowand IOP.
The study was carried out at the Department of Ophthalmology, UppsalaUniversity 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 medicaland ophthalmic history, visual acuity measurement, slitlamp examination, applanationtonometry, and ophthalmoscopy. Exclusion criteria were ocular disease, systemicdisease requiring long-term medical treatment, pregnancy or lactation, inabilityto comply with tonometry or fluorophotometry, an IOP difference between the2 eyes greater than 3 mm Hg, and known drug hypersensitivity. The researchprotocol followed the tenets of the Declaration of Helsinki and was approvedby the Ethical Committee of Uppsala University. An informed consent was obtainedfrom all participants. The study consisted of 2 parts. At least 4 weeks elapsedbetween the parts to ensure complete elimination of the drugs. In part 1,the effect of 0.2% brimonidine–treated eyes vs placebo-treated eyeswas studied. In part 2, topical application of 2% dorzolamide was added toboth eyes. Four treatment regimens were thus compared, with 20 eyes in eachtreatment group: (1) placebo-treated eyes, (2) brimonidine-treated eyes, (3)dorzolamide-treated eyes, and (4) brimonidine and dorzolamide–treatedeyes.
The study was randomized, double-masked, and placebo-controlled. Thebrimonidine, dorzolamide, and placebo eyedrops were given by random assignmentand were administered from identical-appearing dropper bottles labeled bysubject number, sequence, and right and left eyes. These sterile eyedropperbottles 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 andday 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 1drop of placebo in the other eye. The procedure was repeated at 5 PM. On day 2, when flow was measured, eyedrops were again instilledat 8 AM. As a precaution to prevent cross-contamination betweenthe eyes, subjects were given separate tissues for each eye and were askedto blot only one eye with each tissue. In part 2, brimonidine and placeboeyedrops were administered according to the same schedule as in part 1, butat every time point for eyedrop instillation, 1 drop of 2% dorzolamide wasalso administered to both eyes 5 minutes after the other eyedrops (ie, dorzolamidewas 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 day2 and instill 1 drop of 2% fluorescein into each eye 3 to 5 times, accordingto age, at 5-minute intervals, and then they returned to sleep. The subjectsreported to the test area at 8 AM and underwent measurementsof the fluorescence of the cornea and the anterior chamber with a fluorophotometer(Fluorotron Master; Coherent Radiation, Palo Alto, Calif). The procedure wasrepeated every other hour until 4 PM. Immediately after eachmeasurement of fluorescence, the IOP was measured with a Goldmann tonometer.Tonometry was started in the right eye, alternating between the eyes for atotal of 3 readings per eye. The IOP was then recorded as the mean of the3 measurements. Dilute milk rather than fluorescein was used as the disclosingagent to avoid the introduction of more fluorescein to the cornea and mismeasurementof aqueous humor flow.
Aqueous humor flow was calculated from the clearance of fluoresceinat each 2-hour interval by using the following equation: clearance = ΔM/(CaΔt), where ΔM is the loss of mass of fluorescein in thecombined cornea and anterior chamber during Δt 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 exponentialdecay. Aqueous humor flow was calculated from the rate of clearance of fluoresceinafter subtracting the presumed rate of diffusional clearance (0.25 µL/min).30
After completion of the study and tabulation of the data, the code wasbroken and the data stratified by drug. The statistical analysis was carriedout using a 2-sided t test for paired samples. P<.05 was considered statistically significant. Thecoefficient of variation of measurements of aqueous humor flow under conditionssimilar to those in this experiment is approximately 23%.31 Themean ± SD aqueous humor flow in daytime is 2.75 ± 0.63 µL/min.30 A sample size of 20 in each group provided a powerof 95% for detecting a true difference of 20% between the eyes.32
The effects of the different drugs on aqueous humor flow are presentedin Table 1. Brimonidine reducedaqueous 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 significantdifference between brimonidine and dorzolamide (P =.09). Brimonidine and dorzolamide applied in combination suppressed the flowby a mean ± SD of 37.2% ± 20.6% compared with placebo (P<.001). The aqueous humor flow was statistically significantlyreduced by the combination of both drugs compared with dorzolamide alone (P<.001) and brimonidine alone (P =.04).
The IOP (Table 2) was statisticallysignificantly reduced by a mean ± SD of 11.6% ± 10.1% by brimonidinealone (P<.001) and 8.5% ± 14.1% by dorzolamidealone (P = .02) compared with placebo, but therewas no difference between the effects of the 2 drugs in reducing IOP (P = .35). The combination of both drugs statistically significantlyreduced IOP compared with dorzolamide (P<.001),but not compared with brimonidine (P = .06).
The results of this study confirm previous results that 0.2% brimonidinetartrate and 2% dorzolamide hydrochloride suppress the aqueous humor formation.There was no statistically significant difference in the flow reduction whenbrimonidine or dorzolamide was given separately. When they were applied incombination, a further reduction of flow was seen.
Table 3 lists the aqueoushumor flow rates in this study along with those in other studies involvingbrimonidine and dorzolamide. The studies used the fluorophotometric techniquefor determining flow, and there is good consistency between the studies inthe effects of the different drugs.
The effect on aqueous humor flow of short-term administration of apraclonidinehydrochloride and brimonidine in healthy volunteers was measured by Schadluand coworkers.8 The reduction of aqueous humorflow by each drug could explain the reduction of IOP. In addition, a consensualeffect on aqueous humor flow in the fellow eye was noted: 16% for apraclonidineand 17% for brimonidine. The total effect of brimonidine on reducing the aqueoushumor 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 studycorresponds well with their findings. The consensual effect of brimonidinecould also have affected the second part of the present study, when the combinationof brimonidine and dorzolamide was administered to one eye and dorzolamidewas instilled in the other eye. The flow measured in the dorzolamide-treatedeye could thus reflect a crossover effect of brimonidine.
In the present study, the IOP was further reduced by the combinationof brimonidine and dorzolamide compared with dorzolamide alone, but not withbrimonidine. This finding was inconsistent with the results from the flowmeasurements. Only healthy volunteers were included in the study, and themean ± SD baseline IOP of 11.5 ± 2.5 mm Hg was low. A deviationof 1 to 2 mm Hg from the true IOP is inherent in the technique, and the discrepancybetween the results from the IOP measurements and the flow measurements couldbe explained by this.
Traditionally, the medical treatment of glaucoma has consisted of empiricaltrials of single drugs or combinations of drugs in individual patients, aprocess that is efficient when few effective choices are available. With theincreasing 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 mechanismsand relative efficacy. Previous investigations suggest that the efficacy ofcombining different aqueous flow suppressants would be less than the combinedeffect of each given as monotherapy,27 andthe present study supports this. Studies of the effects of combinations ofdrugs are thus important as a basis for predicting the most efficient strategyin the medical management of glaucoma.
In conclusion, the effect of short-term administration of dorzolamidewas partly additive to the effect of brimonidine. The combination of brimonidineand dorzolamide caused a further reduction of aqueous humor flow comparedwith each drug applied alone. The IOP was further reduced by the combinationcompared with dorzolamide alone, but not compared with brimonidine alone.
Corresponding author and reprints: Lill-Inger Larsson, MD, PhD, Departmentof Ophthalmology, Uppsala University Hospital, S-751 85 Uppsala, Sweden (e-mail: Lill-Inger.Larsson@ogon.uu.se).
Submitted for publication June 21, 2002; final revision received August17, 2003; accepted September 10, 2003.
This study was supported in part by grants from the Glaucoma ResearchFoundation, Uppsala University, and from Kronprinsessans Arbetsnämndför de Synskadade, Stockholm, Sweden.