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Table 1. 
Aqueous Humor Flow From 8 AM to 4 PM*
Aqueous Humor Flow From 8 AM to 4 PM*
Table 2. 
Intraocular Pressure at 4 PM*
Intraocular Pressure at 4 PM*
Table 3. 
Previous Studies of Aqueous Humor Flow
Previous Studies of Aqueous Humor Flow
1.
Greenfield  DSLiebmann  JMRitch  R Brimonidine: a new α2-receptor agonist for glaucoma treatment. J Glaucoma. 1997;6250- 258
PubMedArticle
2.
Schuman  JSHorwitz  BChoplin  NT  et al. , Chronic Brimonidine Study Group, A 1-year study of brimonidine twice daily in glaucoma and ocular hypertension:a controlled, randomized, multicenter clinical trial. Arch Ophthalmol. 1997;115847- 852
PubMedArticle
3.
Derick  RJRobin  ALWalters  TR  et al.  Brimonidine tartrate: a one-month dose response study. Ophthalmology. 1997;104131- 136
PubMedArticle
4.
Serle  JBBrimonidine Study Group III, A comparison of the safety and efficacy of twice daily brimonidine0.2% versus betaxolol 0.25% in subjects with elevated intraocular pressure. Surv Ophthalmol. 1996;41suppl 1S39- S47
PubMedArticle
5.
Schuman  JS Clinical experience with brimonidine 0.2% and timolol 0.5% in glaucomaand ocular hypertension. Surv Ophthalmol. 1996;411S27- S37
PubMedArticle
6.
Walters  TR Development and use of brimonidine in treating acute and chronic elevationsof intraocular pressure: a review of safety, efficacy, dose response, anddosing studies. Surv Ophthalmol. 1996;41suppl 1S19- S26
PubMedArticle
7.
Burke  JSchwartz  M Preclinical evaluation of brimonidine. Surv Ophthalmol. 1996;41suppl 1S9- S18
PubMedArticle
8.
Schadlu  RMaus  TLNau  CBBrubaker  RF Comparison of the efficacy of apraclonidine and brimonidine as aqueoussuppressants in humans. Arch Ophthalmol. 1998;1161441- 1444
PubMedArticle
9.
Ogodigben  MChu  TCPotter  DE Alpha-2 adrenoreceptor mediated changes in aqueous dynamics: effectof pertussis toxin. Exp Eye Res. 1994;58729- 736
PubMedArticle
10.
Gabelt  BTRobinson  JCHubbard  WC  et al.  Apraclonidine and brimonidine effects on anterior ocular and cardiovascularphysiology in normal and sympathectomized monkeys. Exp Eye Res. 1994;59633- 644
PubMedArticle
11.
Toris  CBGleason  MLCamras  CBYablonski  ME Effects of brimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol. 1995;1131514- 1517
PubMedArticle
12.
Centofanti  MManni  GGregori  DCocco  FLorenzano  DBucci  MG Comparative acute effects of brimonidine 0.2% versus dorzolamide 2%combined with β-blockers in glaucoma. Graefes Arch Clin Exp Ophthalmol. 2000;238302- 305
PubMedArticle
13.
Lee  DAGornbein  JAbrams  CGlaucoma Trial Study Group, The effectiveness and safety of brimonidine as mono-, combination,or replacement therapy for patients with primary open-angle glaucoma or ocularhypertension: a post hoc analysis of an open-label community trial. J Ocul Pharmacol Ther. 2000;163- 18
PubMedArticle
14.
Stewart  WCSharpe  EDDay  DG  et al.  Comparison of the efficacy and safety of latanoprost 0.005% comparedto brimonidine 0.2% or dorzolamide 2% when added to a topical β-adrenergicblocker in patients with primary open-angle glaucoma or ocular hypertension. J Ocul Pharmacol Ther. 2000;16251- 259
PubMedArticle
15.
Strahlman  ERVogel  RTipping  RClineschmidt  CMDorzolamide Additivity Study Group, The use of dorzolamide and pilocarpine as adjunctive therapy to timololin patients with elevated intraocular pressure. Ophthalmology. 1996;1031283- 1293
PubMedArticle
16.
Serle  JBPodos  SMLee  P-YCamras  CBSeverin  CH Effect of α2-adrenergic agonists on uveoscleral outflow in rabbits. Invest Ophthalmol Vis Sci. 1991;32suppl867
17.
Maus  TLLarsson  LIMcLaren  JWBrubaker  RF Comparison of dorzolamide and acetazolamide as suppressors of aqueoushumor flow in humans. Arch Ophthalmol. 1997;11545- 49
PubMedArticle
18.
Wayman  LLarsson  LIMaus  TAlm  ABrubaker  RF Comparison of dorzolamide and timolol as suppressors of aqueous humorflow in humans. Arch Ophthalmol. 1997;1151368- 1371
PubMedArticle
19.
Wayman  LLarsson  LIMaus  TBrubaker  RF Additive effect of dorzolamide on aqueous humor flow in patients receivinglong-term treatment with timolol. Arch Ophthalmol. 1998;1161438- 1440
PubMedArticle
20.
Larsson  LIAlm  A Aqueous humor flow in human eyes treated with dorzolamide and differentdoses of acetazolamide. Arch Ophthalmol. 1998;11619- 24
PubMedArticle
21.
Vanlandingham  BDBrubaker  RF Combined effect of dorzolamide and latanoprost on the rate of aqueoushumor flow. Am J Ophthalmol. 1998;126191- 196
PubMedArticle
22.
Vanlandingham  BDMaus  TLBrubaker  RF The effect of dorzolamide on aqueous humor dynamics in normal humansubjects during sleep. Ophthalmology. 1998;1051537- 1540
PubMedArticle
23.
Ingram  CJBrubaker  RF Effect of brinzolamide and dorzolamide on aqueous humor flow in humaneyes. Am J Ophthalmol. 1999;128292- 296
PubMedArticle
24.
Larsson  LI Aqueous humor flow in normal human eyes treated with brimonidine andtimolol, alone and in combination. Arch Ophthalmol. 2001;119492- 495
PubMedArticle
25.
Boyle  JEGhosh  KGieser  DKAdamsons  IADorzolamide-Timolol Study Group, A randomized trial comparing the dorzolamide-timolol combination giventwice daily to monotherapy with timolol and dorzolamide. Ophthalmology. 1998;1051945- 1951
PubMedArticle
26.
Clineschmidt  CMWilliams  RDSnyder  EAdamsons  IADorzolamide-Timolol Combination Study Group, A randomized trial in patients inadequately controlled with timololalone comparing the dorzolamide-timolol combination to monotherapy with timololor dorzolamide. Ophthalmology. 1998;1051952- 1959
PubMedArticle
27.
Adamsons  IAPolis  AOstrov  CSBoyle  JEDorzolamide Safety Study Group, Two-year safety study of dorzolamide as monotherapy and with timololand pilocarpine. J Glaucoma. 1998;7395- 401
PubMed
28.
Le  HHChang  MRCheng  QLee  DAHartenbaum  D The effectiveness and safety of dorzolamide 2% in addition to multipletopical antiglaucoma medications. J Ocul Pharmacol Ther. 1999;15305- 312
PubMedArticle
29.
Emmerich  KH Comparison of latanoprost monotherapy to dorzolamide combined withtimolol in patients with glaucoma and ocular hypertension: a 3-month randomisedstudy. Graefes Arch Clin Exp Ophthalmol. 2000;23819- 23
PubMedArticle
30.
Brubaker  RF Measurement of aqueous flow by fluorophotometry. Ritch  RShields  MBKrupin  Teds.The Glaucomas 1 St Louis, Mo CV Mosby Co1989;337- 344
31.
Brubaker  RF Flow of aqueous humor in humans: the Friedenwald Lecture. Invest Ophthalmol Vis Sci. 1991;323145- 3166
PubMed
32.
Dixon  WJMassey  JF  Jr Introduction to Statistical Analysis.  New York, NY McGraw-Hill Book Co1969;516
33.
Maus  TLNau  CBrubaker  RF Comparison of the early effects of brimonidine and apraclonidine astopical ocular hypotensive agents. Arch Ophthalmol. 1999;117586- 591
PubMedArticle
34.
Brubaker  RFIngram  CJSchoff  EONau  CB Comparison of the efficacy of betaxolol-brinzolamide and timolol-dorzolamideas suppressors of aqueous humor flow in human subjects. Ophthalmology. 2000;107283- 287
PubMedArticle
Clinical Sciences
February 2004

Aqueous Humor Flow in Normal Human Eyes Treated With Brimonidine andDorzolamide, Alone and in Combination

Author Affiliations

From the Department of Ophthalmology, Uppsala University Hospital,Uppsala, Sweden. The authors have no relevant financial interest in this article.

Arch Ophthalmol. 2004;122(2):190-193. doi:10.1001/archopht.122.2.190
Abstract

Objectives  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.

Design  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.

Results  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).

Conclusions  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 tartrate17 isa topically applied ocular hypotensive agent. Studies of brimonidine havedemonstrated that the ocular hypotensive effect primarily is caused by reductionof aqueous humor production,715 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.1723 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.1215,2529 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.

METHODS

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

RESULTS

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).

COMMENT

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.

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Article Information

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.

References
1.
Greenfield  DSLiebmann  JMRitch  R Brimonidine: a new α2-receptor agonist for glaucoma treatment. J Glaucoma. 1997;6250- 258
PubMedArticle
2.
Schuman  JSHorwitz  BChoplin  NT  et al. , Chronic Brimonidine Study Group, A 1-year study of brimonidine twice daily in glaucoma and ocular hypertension:a controlled, randomized, multicenter clinical trial. Arch Ophthalmol. 1997;115847- 852
PubMedArticle
3.
Derick  RJRobin  ALWalters  TR  et al.  Brimonidine tartrate: a one-month dose response study. Ophthalmology. 1997;104131- 136
PubMedArticle
4.
Serle  JBBrimonidine Study Group III, A comparison of the safety and efficacy of twice daily brimonidine0.2% versus betaxolol 0.25% in subjects with elevated intraocular pressure. Surv Ophthalmol. 1996;41suppl 1S39- S47
PubMedArticle
5.
Schuman  JS Clinical experience with brimonidine 0.2% and timolol 0.5% in glaucomaand ocular hypertension. Surv Ophthalmol. 1996;411S27- S37
PubMedArticle
6.
Walters  TR Development and use of brimonidine in treating acute and chronic elevationsof intraocular pressure: a review of safety, efficacy, dose response, anddosing studies. Surv Ophthalmol. 1996;41suppl 1S19- S26
PubMedArticle
7.
Burke  JSchwartz  M Preclinical evaluation of brimonidine. Surv Ophthalmol. 1996;41suppl 1S9- S18
PubMedArticle
8.
Schadlu  RMaus  TLNau  CBBrubaker  RF Comparison of the efficacy of apraclonidine and brimonidine as aqueoussuppressants in humans. Arch Ophthalmol. 1998;1161441- 1444
PubMedArticle
9.
Ogodigben  MChu  TCPotter  DE Alpha-2 adrenoreceptor mediated changes in aqueous dynamics: effectof pertussis toxin. Exp Eye Res. 1994;58729- 736
PubMedArticle
10.
Gabelt  BTRobinson  JCHubbard  WC  et al.  Apraclonidine and brimonidine effects on anterior ocular and cardiovascularphysiology in normal and sympathectomized monkeys. Exp Eye Res. 1994;59633- 644
PubMedArticle
11.
Toris  CBGleason  MLCamras  CBYablonski  ME Effects of brimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol. 1995;1131514- 1517
PubMedArticle
12.
Centofanti  MManni  GGregori  DCocco  FLorenzano  DBucci  MG Comparative acute effects of brimonidine 0.2% versus dorzolamide 2%combined with β-blockers in glaucoma. Graefes Arch Clin Exp Ophthalmol. 2000;238302- 305
PubMedArticle
13.
Lee  DAGornbein  JAbrams  CGlaucoma Trial Study Group, The effectiveness and safety of brimonidine as mono-, combination,or replacement therapy for patients with primary open-angle glaucoma or ocularhypertension: a post hoc analysis of an open-label community trial. J Ocul Pharmacol Ther. 2000;163- 18
PubMedArticle
14.
Stewart  WCSharpe  EDDay  DG  et al.  Comparison of the efficacy and safety of latanoprost 0.005% comparedto brimonidine 0.2% or dorzolamide 2% when added to a topical β-adrenergicblocker in patients with primary open-angle glaucoma or ocular hypertension. J Ocul Pharmacol Ther. 2000;16251- 259
PubMedArticle
15.
Strahlman  ERVogel  RTipping  RClineschmidt  CMDorzolamide Additivity Study Group, The use of dorzolamide and pilocarpine as adjunctive therapy to timololin patients with elevated intraocular pressure. Ophthalmology. 1996;1031283- 1293
PubMedArticle
16.
Serle  JBPodos  SMLee  P-YCamras  CBSeverin  CH Effect of α2-adrenergic agonists on uveoscleral outflow in rabbits. Invest Ophthalmol Vis Sci. 1991;32suppl867
17.
Maus  TLLarsson  LIMcLaren  JWBrubaker  RF Comparison of dorzolamide and acetazolamide as suppressors of aqueoushumor flow in humans. Arch Ophthalmol. 1997;11545- 49
PubMedArticle
18.
Wayman  LLarsson  LIMaus  TAlm  ABrubaker  RF Comparison of dorzolamide and timolol as suppressors of aqueous humorflow in humans. Arch Ophthalmol. 1997;1151368- 1371
PubMedArticle
19.
Wayman  LLarsson  LIMaus  TBrubaker  RF Additive effect of dorzolamide on aqueous humor flow in patients receivinglong-term treatment with timolol. Arch Ophthalmol. 1998;1161438- 1440
PubMedArticle
20.
Larsson  LIAlm  A Aqueous humor flow in human eyes treated with dorzolamide and differentdoses of acetazolamide. Arch Ophthalmol. 1998;11619- 24
PubMedArticle
21.
Vanlandingham  BDBrubaker  RF Combined effect of dorzolamide and latanoprost on the rate of aqueoushumor flow. Am J Ophthalmol. 1998;126191- 196
PubMedArticle
22.
Vanlandingham  BDMaus  TLBrubaker  RF The effect of dorzolamide on aqueous humor dynamics in normal humansubjects during sleep. Ophthalmology. 1998;1051537- 1540
PubMedArticle
23.
Ingram  CJBrubaker  RF Effect of brinzolamide and dorzolamide on aqueous humor flow in humaneyes. Am J Ophthalmol. 1999;128292- 296
PubMedArticle
24.
Larsson  LI Aqueous humor flow in normal human eyes treated with brimonidine andtimolol, alone and in combination. Arch Ophthalmol. 2001;119492- 495
PubMedArticle
25.
Boyle  JEGhosh  KGieser  DKAdamsons  IADorzolamide-Timolol Study Group, A randomized trial comparing the dorzolamide-timolol combination giventwice daily to monotherapy with timolol and dorzolamide. Ophthalmology. 1998;1051945- 1951
PubMedArticle
26.
Clineschmidt  CMWilliams  RDSnyder  EAdamsons  IADorzolamide-Timolol Combination Study Group, A randomized trial in patients inadequately controlled with timololalone comparing the dorzolamide-timolol combination to monotherapy with timololor dorzolamide. Ophthalmology. 1998;1051952- 1959
PubMedArticle
27.
Adamsons  IAPolis  AOstrov  CSBoyle  JEDorzolamide Safety Study Group, Two-year safety study of dorzolamide as monotherapy and with timololand pilocarpine. J Glaucoma. 1998;7395- 401
PubMed
28.
Le  HHChang  MRCheng  QLee  DAHartenbaum  D The effectiveness and safety of dorzolamide 2% in addition to multipletopical antiglaucoma medications. J Ocul Pharmacol Ther. 1999;15305- 312
PubMedArticle
29.
Emmerich  KH Comparison of latanoprost monotherapy to dorzolamide combined withtimolol in patients with glaucoma and ocular hypertension: a 3-month randomisedstudy. Graefes Arch Clin Exp Ophthalmol. 2000;23819- 23
PubMedArticle
30.
Brubaker  RF Measurement of aqueous flow by fluorophotometry. Ritch  RShields  MBKrupin  Teds.The Glaucomas 1 St Louis, Mo CV Mosby Co1989;337- 344
31.
Brubaker  RF Flow of aqueous humor in humans: the Friedenwald Lecture. Invest Ophthalmol Vis Sci. 1991;323145- 3166
PubMed
32.
Dixon  WJMassey  JF  Jr Introduction to Statistical Analysis.  New York, NY McGraw-Hill Book Co1969;516
33.
Maus  TLNau  CBrubaker  RF Comparison of the early effects of brimonidine and apraclonidine astopical ocular hypotensive agents. Arch Ophthalmol. 1999;117586- 591
PubMedArticle
34.
Brubaker  RFIngram  CJSchoff  EONau  CB Comparison of the efficacy of betaxolol-brinzolamide and timolol-dorzolamideas suppressors of aqueous humor flow in human subjects. Ophthalmology. 2000;107283- 287
PubMedArticle
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