Effect of Brimonidine on Corneal Thickness

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<ul><li><p>Effect of Brimonidine on Corneal Thickness</p><p>Matthias Grueb,1,2 Joerg Mielke,3 Jens Martin Rohrbach,1 and Torsten Schlote1,4</p><p>Abstract</p><p>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 &lt; 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 ( &lt; 556 mm) was lower than in thethick corneas ( &gt; 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.</p><p>Introduction</p><p>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</p><p>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</p><p>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.</p><p>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.</p><p>JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 27, Number 5, 2011 Mary Ann Liebert, Inc.DOI: 10.1089/jop.2010.0198</p><p>503503503</p></li><li><p>Methods</p><p>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).</p><p>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.</p><p>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.</p><p>Results</p><p>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&lt; 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</p><p>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).</p><p>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&lt; 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&lt; 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).</p><p>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&lt; 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).</p><p>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).</p><p>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 day (P = 0.005), 12 3 mmHgafter 2 days (P= 0.002), 11 3 mmHg after 3 days (P = 0.001),11 3 mmHg after 4 days (P = 0.001), and 9 1 mmHg after5 days (P = 0.001). Mean pressure reduction was 36%(P&lt; 0.001) in the active drug group compared with the pla-cebo group. After administration of brimonidine 0.1% wasstopped on day 26, intraocular pressure returned to almostthe same level as the initial value measured (day 30,13 1 mmHg, P = 0.661). In contrast, there was no variance inintraocular pressure on administration of placebo eye dropstwice daily (P = 0.962; Fig. 5).</p><p>The mean baseline intraocular pressure was not differentwhen comparing subjects with thick or thin corneas or whencomparing the eyes to be treated with brimonidine 0.1% eyedrops versus placebo eye drops within the 2 groups (Table 1).With treatment with brimonidine 0.1% eye drops, mean in-traocular pressure in the thin cornea group (9 2 mmHg) waslower than in the thick cornea group (10 2 mmHg, P = 0.018;Table 1). Mean intraocular pressure of contralateral placebo-treated control eyes was not significantly different betweensubjects with thin (13 2 mmHg) or thick (14 2 mmHg) cor-neas (P = 0.241; Table 1).</p><p>504 GRUEB ET AL.</p></li><li><p>No structural changes of the entire cornea or its individuallayers were detected, neither on regular administration ofbrimonidine 0.1% eye drops nor of placebo eye drops.</p><p>Discussion</p><p>Since the introduction of brimonidine in 1996, it hasclearly found its way as a selective alpha-2 adrenoceptoragonist in glaucoma treatment and treatment of ocular hy-pertension and is considered to be a safe and well-toleratedmedication.1012 In addition to the ciliary bodythe genuinesite where brimonidine shows its impact1it is especially theretina, which has edged ever closer to the spotlight of bri-monidine research under the aspect of neuroprotection.3</p><p>Although it is known that, following topical administration,brimonidine is quickly taken up by the cornea2 and thatactive alpha-2 adrenoceptors have been found to be present</p><p>in the corneal epithelium and endothelium,6,7,13 there areonly few data available regarding the impact of brimonidineon the cornea. Although it has been reported that almost allother glaucoma medications do have an effect on cornealthickness,1420 the effect of brimonidine on corneal thicknesshas so far not been the focus of scientific studies.</p><p>Johnson et al.4 suggested that central corneal thicknessmay affect the efficacy of some ocular hypotensive medica-tions. The present study also could demonstrate that eyeswith thinner corneas had a lower intraocular pressure whileon treatment with brimonidine 0.1% than eyes with thickercorneas, even though intraocular pressure was statisticallysimilar before treatment (Table 1). The authors of the OHTS5</p><p>analyzed the effect of central corneal thickness on the re-duction of intraocular pressure by ocular hypotensive med-ication. They found that the efficacy of ocular hypotensivedrug treatment significantly correlated inversely with central</p><p>FIG. 1. Central corneal thickness before (day - 1), while (days 025), and after (days 2630) application of brimonidine 0.1%(verum) eye drops in 1 eye (n = 20) and placebo eye drops in the partner eye (n = 20).</p><p>FIG. 2. Epithelial thickness before (day - 1), while (days 025), and after (days 2630) application of brimonidine 0.1%(verum) eye drops in 1 eye (n = 20) and placebo eye drops in the partner eye (n = 20).</p><p>BRIMONIDINE AND CT 505</p></li><li><p>corneal thickness and identified 3 mechanisms to account forthese findings: (1) limited drug penetration through thickercorneas, (2) trends in differences in baseline intraocularpressure, and (3) the effect of central corneal thickness onintraocular pressure measurement. Unlike some previousstudies,5,2123 our study did not demonstrate a statisticallysignificant positive correlation between baseline intraocularpressure and central corneal thickness and the effect of cor-neal thickness on Goldmann applanation tonometry may besmall in the present study, as total corneal thickness has onlya narrow range (543560 mm). Thus, our findings indicatethat differential pharmacokinetics may explain the negativecorrelation between the efficacy of brimonidine and centralcorneal thickness.</p><p>Corneal transparency is dependent on regulation of thehydration of the corneal stroma. Water is driven into thecornea across the epithelial and endothelial cell layers by</p><p>the stromal swelling pressure. This fluid leak into the corneais counterbalanced by the corneal fluid pump, which ispredominantly attributed to the ion and fluid transportcapacity of the endothelial cell layer. Primary and secondaryactive transport mechanisms are responsible for generating anet ion flux from the stromal to anterior chamber site of theendothelium.24 Both the epithelium and endothelium pre-vent corneal swelling by functioning as diffusion barriers tothe fluid and by acting as sites of active ion transport.25</p><p>Although this pump-leak hypothesis was postulated severaldecades ago, the mechanisms underlying regulation of thebalance between the pump and leak functions remain largelyunknown.26 Two important signaling pathways have beendemonstr...</p></li></ul>


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