Variations In Aqueous Humor Flow In Response To Topical Beta-BlockerDavid M. Reed, PhD, Agnieszka Trzcinka, MD, Pauline A. Radenbaugh, MS, COA, Sayoko E. Moroi, MD, PhD

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI

PATIENT DEMOGRAPHICS

EVIDENCE LEVEL IORIGINAL

Coakes RL, Brubaker RF. The mechanism of timolol in lowering intraocular pressure. 1978. Arch Ophthalmol. 96: 2045-2048.

Mansberger SL, Hughes BA, Gordon MO, Spaner SD, Beiser JA, Cioffi GA, Kass MA, for the Ocular Hypertension Treatment Study Group. 2007. Comparison of initial intraocular pressure response with topical beta–adrenergic antagonists and prostaglandin analogues in African American and white individuals in the Ocular Hypertension Treatment Study. Arch Ophthalmol. 125: 454-459.

Radenbaugh PA, Goyal A, McLaren NC, Reed DM, Musch DC, Richards JE, Moroi SE. Concordance of aqueous humor flow in the morning and at night in normal humans. 2006. Invest Ophthalmol. Vis Sci. 47: 4860-4864.

McLaren JW. Measurement of aqueous humor flow. 2009. Experimental Eye Research. 88(4): 641-647 .

Johnson TV, Fan S, Camras CB, Toris CB. Aqueous humor dynamics in exfoliation syndrome. 2008. Arch Ophthalmol. 126: 914-920

Tu Y-K, Gilthorpe MS. 2007. Revisiting the relation between change and initial value: a review and evaluation. Statistics In Medicine 26 (2): 443-457.

Supported in part by the Summer Biomedical Research Program, University of Michigan (AT); NIH EY007003 Core Center for Vision Research, University of Michigan (DMR); Midwest Eye Banks and Transplantation Center (SEM); Career Development Award from Research to Prevent Blindness (SEM); the University of Michigan Office of the Vice President for Research (SEM); the Glaucoma Research Foundation (SEM); NIH Grant M01-RR00042 (GCRC). Commercial Disclosure: A. Trzcinka, None; P.A. Radenbaugh, None; D.M. Reed, None; S.E. Moroi, Pfizer Inc., Allergan Inc., (R).

Glaucoma is an intraocular pressure (IOP)-related optic neuropathy. Treatment is based on effective IOP lowering. Topical beta-blockers lower IOP by decreasing aqueous humor flow. It is well known that IOP varies in response to beta-blockers. Our hypothesis was to determine if aqueous humor flow phenotype was associated with timolol responsiveness.

1. As expected, aqueous humor flow decreased significantly after topical timolol administration, but there is variation in response to topical timolol in normal subjects.

2. Subjects with higher aqueous flow phenotypes demonstrated modest association with differences in flow between placebo–treated and timolol–treated eyes.

3. Given our results, we plan to conduct a pharmacogenetic association study to identify genotypes that contribute to the variable flow and IOP response to beta–blockers.

Flow (µL/min)Treatment mean ± 1 sdPlacebo 2.5 ± 0.7 Timolol 1.7 ± 0.5*

Suppression of aqueous humor �owby timolol treatment (%)

Minimum 0 Maximum 68 Mean 30

Di�erence in aqueous humor �owbetween placebo and timolol treated

eyes (µL/min) Minimum 0 Maximum 2.5 Mean 0.8

* Timolol signi�cantly decreased aqueous humor �ow (p–value < 0.0001).

REGRESSION PLOT COMPARING FLOW IN PLACEBO–TREATED EYES AND SUPPRESSION OF FLOW

AFTER TIMOLOL

REGRESSION PLOT COMPARING FLOW IN PLACEBO–TREATED EYES AND DIFFERENCE BETWEEN

PLACEBO–TREATED AND TIMOLOL–TREATED EYES

SUMMARY OF AQUEOUS HUMOR FLOW RATES

DENSITY PLOT OF FLOW SUPPRESSION AFTER TIMOLOL

Age (years)Average 32.5 ± 13.5Range 18 - 60

SexFemale 13Male 17

EthnicityCaucasian 18African-American 5Asian 4Hispanic 2Other 1Thirty subjects met study criteria and underwent �uorophotometry scanning. Percent Flow Suppression

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ABSTRACT

BACKGROUND

DESIGN & METHODS

RESULTS

RESULTS CONCLUSIONS

REFERENCES

ACKNOWLEDGMENTS

PURPOSEGlaucoma is an intraocular pressure (IOP)-related optic neuropathy. Topical beta-blockers lower IOP by decreasing aqueous humor flow. Because patients show variability in their IOP responses to this drug class, we designed a pilot study to explore the amount of variation in aqueous humor flow in response to topical timolol.

DESIGNProspective, randomized clinical fluorophotometry study.

PARTICIPANTSStudy subjects, without glaucoma or ocular hypertension, were recruited using established inclusion and exclusion criteria in an approved IRBMED protocol.

METHODSSubjects were examined by visual acuity testing, biomicroscopy, gonioscopy, fundoscopy, IOP measurement, pachymetry, and A-scan. For fluorophotometry, 2% topical fluorescein was administered to each eye and allowed to reach steady state distribution. Subjects randomly received 1 drop of timolol 0.5% to their treated eye and 1 drop of artificial tears to their placebo eye. Fluorophotometry scans were performed hourly between 8 AM and noon. Data were analyzed using Oldham's correlation method.

MAIN OUTCOME MEASUREAqueous humor flow was calculated from hourly scans in the timolol-treated and placebo-treated eyes.

RESULTSThirty subjects were studied with an average age of 35 ± 14 years with 17 men and 13 women. Eight subjects were studied in an inpatient setting, while the remaining 22 were studied in an outpatient clinical setting. The aqueous flow for placebo-treated eyes was 2.5 ± 0.7 µL/min. The percent decrease in flow ranged from 0 to 68 percent. We observed an Oldham's unbiased correlation of 0.39 for the relationship of variance of aqueous flow response between placebo and timolol-treated eyes.

CONCLUSIONSAs expected, timolol decreased aqueous humor flow, but aqueous flow varied in treatment response according to individual baseline flows. We observed that individuals with higher aqueous flow showed greater response to timolol in comparison to individuals with lower aqueous flow. Future research will entail exploring a possible association between timolol response and beta-adrenergic receptor genotypes.

DESIGN

A prospective, randomized clinical study performed at the Kellogg Eye Center and the General Clinical Research Center of the University of Michigan, Ann Arbor.

METHODS

Subjects

Study subjects were recruited using established inclusion and exclusion criteria.

Clinical Assessment Methods

Subjects were examined by visual acuity testing, biomicroscopy, gonioscopy, fundoscopy, IOP measurement, pachymetry and A-scan.

Fluorophotometry Protocol

1. Topical fluorescein 2% was administered in each eye to allow steady state distribution.

2. The subjects were randomized to receive 1 drop of timolol 0.5% to the treated eye and 1 drop of artificial tears to the placebo eye.

3. Fluorophotometry scans were performed hourly between 8 AM and noon.

ANALYSIS

The quality of fluorophotometry data was evaluated and Fluorotron™ Master software was used to compute aqueous humor flow from the decay rates of fluorescein tracer. The flow rates were compared using the paired Student’s t-test. A p-value less than 0.05 indicated statistical significance. An ordinary least squares regression test was used to model the relationship between aqueous flow values in placebo-treated and timolol-treated eyes. Oldham's method was used to calculate an unbiased correlation adjusted for mathematical coupling.

DISCUSSION

In the table, timolol-treated eyes show a suppression of flow from between 0 and 68 percent, with a mean suppression of 30 percent. This equates to a difference in flow over placebo–treated eyes of up to 2.5 µL/min with a mean response of 0.8 µL/min.

In the density plot is shown the variance in percent flow suppression response to topical timolol.

In the top regression plot, timolol response is defined as percent flow suppression (((placebo – timolol)/placebo) × 100). There was poor association with placebo–treated flow phenotype (r2 = 0.08).

In the bottom plot, timolol response is defined as the difference in flows (placebo – timolol). A modest association exists with the placebo–treated flow phenotype (Oldham's correlation of 0.39).