Effect of Brimonidine on Corneal Thickness
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Effect of Brimonidine on Corneal Thickness
Matthias Grueb,1,2 Joerg Mielke,3 Jens Martin Rohrbach,1 and Torsten Schlote1,4
Purpose: Brimonidine, an alpha-2 adrenoceptor agonist, is an effective and safe medication that is widely used inglaucoma treatment. Although it is known that it is quickly taken up by the cornea following topical admin-istration and that the cornea has alpha-2 adrenoceptors, there are only few studies available on the impactbrimonidine has on the cornea.Methods: Twenty healthy test persons (12 female and 8 male subjects)mean age about 33 years (22 to 38years)were tested in a double-blind, prospective, randomized study. Intraocular pressure as well as epithelial,stromal, and endothelial thickness was measured before, at 25 days while, and at 5 days after administration ofbrimonidine 0.1% eye drops twice daily. To check the impact of this medication, placebo (proper solution ofpreservative) eye drops were administered to the other eye twice daily.Results: Administration of brimonidine 0.1% resulted in a reduction of intraocular pressure from an initial valueof 14 to 9 mmHg after 5 days (P = 0.001) as well as an increase in total corneal thickness from 556 mm from thetime of the baseline examination to 578 mm (P = 0.001), an increase of epithelial thickness from 58 to 66 mm(P < 0.001), and stromal thickness from 488 to 502 mm (P = 0.008) after 2 days each. Another 2 days later, totalcorneal thickness was 559 mm (P= 0.276), epithelial thickness 56 mm (P = 0.561), and stromal thickness 493 mm(P = 0.315), which means that the values had returned more or less toward the initial values measured. Incontrast, endothelial thickness did not vary following administration of brimonidine 0.1% (P = 0.965). Withtreatment with brimonidine 0.1%, mean intraocular pressure in thin corneas ( < 556 mm) was lower than in thethick corneas ( > 556 mm, P = 0.018).Conclusions: Topical administration of brimonidine 0.1% results in a reversible increase in corneal thickness. Thequestion whether this increase is of clinical significance and whether it is the result of epithelial and/or endo-thelial receptor stimulation cannot be finally answered at the present time.
Brimonidine is a selective alpha-2 adrenoceptor agonistthat is topically used in glaucoma treatment. Brimoni-dine reduces intraocular pressure by suppressing aqueousproduction, probably as a result of reduced blood circulationin the ciliary body.1 Following topical administration, bri-monidine is quickly taken up by the cornea and conjunctivaand quickly distributes within the whole eye.2 Although in-teraction between brimonidine and alpha-2 adrenoceptors ofthe posterior eye section has been the object of many researchprojects,3 there are just a few studies available on its recip-rocal action with corneal receptors. The intraocular pressurelowering effect of brimonidine seems to be associated withcentral corneal thickness.4,5
This is all the more amazing, because proof of the presenceof alpha-2 adrenoceptors in corneal epithelial and endothelialcells has been furnished. The stimulation of these adreno-ceptors by brimonidine resulted in a decrease in intracellularcAMP concentration and thus reduced proteinkinase A (PKA)activity.6,7 Blocking of corneal beta adrenoceptors, which alsocomes along with a reduction of intracellular cAMP concen-tration and a reduction of PKA activity, resulted in a mea-surable increase in central corneal thickness.68
The aim of the present study was to find out (1) whethertopical administration of brimonidine results in interactionwith corneal alpha-2 adrenoceptors in terms of an increasein corneal thickness and (2) whether there is any differencebetween the response of corneal epithelium, stroma, andendothelium to this interaction.
1Department of Ophthalmology, University of Tuebingen, Tuebingen, Germany.2Private Practice, Augenarztpraxis Breisach, Breisach am Rhein, Germany.3Private Practice, Pfullingen, Germany.4Day Clinic Ambimed, Basel, Switzerland.
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 27, Number 5, 2011 Mary Ann Liebert, Inc.DOI: 10.1089/jop.2010.0198
Twenty healthy test persons (12 female and 8 male sub-jects)mean age 33 years (2238 years)were tested in adouble-blind, prospective study. All test persons had a normalophthalmologic history. Persons with serious medical or neu-rologic conditions and/or regular use of local or systemicmedications were excluded from the study. All test personsgave consent to participate in this study and were informedabout the purpose of and procedure applied to the study andalso about the fact that they could stop participating at any timewithout stating any reason for stopping. The requirementspostulated in the Declaration of Helsinki were strictly observed(Clinical Trails Registration Reference No. NCT01250236).
Baseline examination of the test persons was carried out at08:00 h and included taking their individual medical historiesas well as a vision test plus slit-lamp micro-ophthalmoscopy,funduscopy, spectral optical coherence tomography (SOCT)of the anterior eye section, and at last, intraocular pressuretesting. Then these were followed by randomized adminis-tration of brimonidine 0.1% eye drops (Alphagan P; Aller-gan, Irvine, CA; brimonidine tartrate 0.1%, PURITE 0.005%as a preservative, sodium carboxymethylcellulose, sodiumborate, boric acid, sodium chloride, potassium chloride, cal-cium chloride, magnesium chloride, purified water, andhydrochloric acid and/or sodium hydroxide), a commercialmedication used in glaucoma treatment, to 1 eye (n= 20) andadministration of placebo eye drops (Cellufresh; Allergan,Irvine, CA; PURITE 0.005% as a preservative and sodiumcarboxymethylcellulose) to the other eye (n = 20). SOCT andintraocular pressure testing were repeated 10 min later. Thetest persons were requested to continue to take both eyedrops for 25 days twice daily (08:00 and 20:00 h). Follow-upSOCTs and intraocular pressure testing were carried out inthe morning hours of all subsequent 30 days. All tests andchecks as well as the analyses of the SOCT scans were per-formed by only 1 examiner.
To determine corneal thickness and thickness of its in-dividual layers, central axial scans of SOCT (Copernicus;EyeTec, Lubeck, Germany), which measure corneal thicknesswith an accuracy of 5mm, were used.9 Foveal fixation wasused for centering the scan and automatic corneal mappingwas used to prove centering. Two manual measurementswere taken at 1-min intervals. Intraocular pressure wasmeasured with a Goldmann applanation tonometer. Again,2 measurements were taken at 1-min intervals. The meanvalue of the 2 SOCT and tonometry measurements was usedfor statistical evaluation. Jump (SAS, Cary, NC) was used tocalculate and visualize the values measured for cornealthickness and intraocular pressures. Statements regardingtheir significance were made using the ANOVA test.
Regular administration of brimonidine 0.1% eye dropstwice daily resulted in a consecutive increase of central cor-neal thickness from 556 6mm (range: 543560 mm) duringthe period from the baseline examination to 578 13mm atthe follow-up examination at 2 days later (P = 0.001). Com-pared with the placebo group, this corresponds to an in-crease in central corneal thickness in the active drug groupby 4% (P< 0.001). However, in the course of the subsequent2 days, central corneal thickness returned to 559 9mm,which is almost the same value measured at the time the
baseline examination was carried out (P = 0.276). On theother hand, corneal thickness on administration of placeboeye drops did not vary from the time the baseline examina-tion with a measured value of 553 17mm was carried out tothe last examination at 30 days later with a measured valueof 555 26 mm (P = 0.944; Fig. 1).
Assessment of the corneal epithelium alone also revealed anincrease in thickness from 58 6mm at the time of the baselineexamination to 66 5mm on the second day (P< 0.001) on reg-ular administration of brimonidine 0.1% eye drops twice daily.In the course of the subsequent 2 days, epithelial thickness againreturned to almost the same level as the initial value measured(56 6mm; P= 0.561). Mean increase in epithelial thickness was14% (P< 0.001) in the active drug group compared with theplacebo group. In contrast, epithelial thickness did not varyduring the period from the time of the baseline examinationwith a measured value of 56 4mm to the last examination at30 days later with a measured value of 54 3mm (P= 0.118) onadministration of placebo eye drops (Fig. 2).
Corneal stroma also showed an increase in thickness from488 10mm at the time of the baseline examination to502 10mm at 2 days later (P= 0.008) on regular administra-tion of brimonidine 0.1% eye drops twice daily. Another2 days later there was only a marginal variance with a mea-sured value of 493 11mm (P= 0.315) compared with thebaseline examination. The increase in stromal thickness on thesecond day was 3% in the active drug group compared withthe placebo group (P< 0.001). The latter showed no varianceon administration of placebo eye drops during the periodfrom the baseline examination with a measured value of488 15mm to the last examination at 30 days later with ameasured value of 492 24mm (P= 0.725; Fig. 3).
Corneal endothelium showed no increase in thickness,neither on regular administration of brimonidine 0.1% eyedrops twice daily (P = 0.479) nor on administration of placeboeye drops (P = 0.684). In addition, there was no differencebetween the active drug group and the placebo group(P= 0.965; Fig. 4).
Regular administration of brimonidine 0.1% eye dropstwice daily resulted in a reduction of intraocular pressurefrom an initial value of 14 3 to 13 2 mmHg (day 0,P = 0.026), 12 3 mmHg after 1