Comparison of the Efficacy of Apraclonidine and Brimonidine As Aqueous Suppressants in Humans

CLINICAL SCIENCES Comparison of the Efficacy of Apraclonidine and Brimonidine as Aqueous Suppressants in Humans

Ramin Schadlu; Todd L. Maus, MD; Cherie B. Nau, BS; Richard F. Brubaker, MD

Objective: To measure and compare the effect of apra- flow between 39% and 44% and lowered intraocular clonidine hydrochloride and brimonidine tartrate on the pressure between 20% and 23%. Brimonidine sup- rate of aqueous humor flow in human subjects. pressed aqueous humor flow between 44% and 48% and lowered intraocular pressure between 19% and Subjects and Methods: Forty normal human subjects 22%. were given apraclonidine or brimonidine by topical instillation. Aqueous humor flow was measured by the rate of Conclusion: No statistically significant differences were disappearance of topically applied fluorescein. Intraocu- found between the effects of the 2 drugs on aqueous hu- lar pressure was measured by applanation tonometry. mor dynamics in normal subjects.

Results: Apraclonidine suppressed aqueous humor Arch Ophthalmol. 1998;116:1441-1444

NIMAL AND human stud- clonidine and brimonidine in normal hu- ies have shown that ␣2- man subjects. selective adrenergic agonists suppress aqueous humor formation and are RESULTS Aefficacious for lowering intraocular pressure. Two drugs in this class are available AQUEOUS HUMOR FLOW in topical formulations for the treatment of glaucoma: 0.5% apraclonidine hydro- In group 1, the flow of aqueous humor was chloride1-6 (Iopidine, Alcon Laborato- measured in the drug-treated eye and the ries, Fort Worth, Tex) and 0.2% bri- placebo-treated fellow eye at the same time. monidine tartrate7-12 (Alphagan, Allergan, In half of these subjects, apraclonidine Irvine, Calif). was studied first; in the other half, bri- Studies of apraclonidine have shown monidine was studied first. There was no that the ocular hypotensive effect is prin- statistically significant difference in the re- cipally caused by the suppression of aque- sults for each drug between the subjects ous humor flow.13-15 Studies of bri- who were treated with the drug first and monidine have also shown that its ocular subjects who were treated with the pla- hypotensive effect is primarily caused by cebo first (apraclonidine, P = .08; bri- aqueous suppression.16-19 However, there monidine, P = .36), so these groups of 10 is evidence from comparative studies in were combined into a single group of 20 animals that the 2 drugs are not identical for additional analysis. in their effects.17,19,20 Also, there is evi- The rate of aqueous humor flow in dence in humans that brimonidine has sig- the apraclonidine-treated eyes of the nificant outflow effects that contribute to 20 subjects was 1.39 ± 0.37 µL/min its ocular hypotensive efficacy.18 (mean ± SD), and in the fellow placebo- From the Department of It would be helpful to clinicians, who treated eyes, 1.94 ± 0.49 µL/min. Thus, Ophthalmology, Mayo Clinic must make therapeutic decisions on be- the rate of flow was 28% lower in the and Mayo Foundation, Rochester, Minn. Mr Schadlu is half of their glaucoma patients, to know treated eyes than in the placebo eyes currently a candidate for a the relative efficacy of these 2 drugs as (PϽ.001). The rate of aqueous humor medical degree at the aqueous suppressors. This study is a quan- flow in the brimonidine-treated eyes was Heinrich-Heine-Universitaet, tification and direct comparison of the 1.33 ± 0.47 µL/min, and in the fellow Dusseldorf, Germany. acute aqueous suppressing effects of apra- placebo-treated eyes, 1.93 ± 0.46 µL/min,

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 SUBJECTS AND METHODS day when the drugs were given, apraclonidine and brimonidine were randomly assigned to the left or right eye. The code identifying the content of each container re- Two groups of 20 normal subjects were studied, totaling mained sealed until all subjects had completed the study 40 subjects. Group 1 (mean age, 28.7 years; 11 women and and all data had been recorded in their final form in a sta- 9 men) was studied to permit the simultaneous measure- tistical database. An exception was the study of the 16 sub- ment of aqueous flow when 1 eye was treated with 1 of the jects of subgroup 1. These subjects, all the members of group 2 ␣2-adrenergic agonists and the other eye was treated with 1 who were still available, were called back after the comple- a placebo. Group 2 (mean age, 27.0 years; 9 women and tion of their 2 experiments for a third experiment in which 11 men) was studied to permit comparison of the effect of placebo drops (Hypotears) were instilled into both eyes. the 2 drugs on flow when the measurements were made This third experiment was done because comparison of the simultaneously. This design has the greatest power to de- results of groups 1 and 2 suggested that each of the ␣2- tect differences between the drugs. adrenergic agonists had a significant crossover effect in the Each group underwent 2 days of tests so that each sub- fellow eye. ject would be treated with each drug. In addition, 16 mem- Three weeks or more was allowed between experi- bers of group 1 underwent a third day of testing in which ments to eliminate any lingering effects of the previous placebo was used in both eyes. experiment. Subjects were recruited from the students and employ- The day before the measurement of aqueous flow and ees of the Mayo Clinic, Rochester, Minn, and informed con- intraocular pressure, a technician (C.B.N.) administered the sent was obtained. Persons of either sex between the ages of coded labeled drugs to each subject at 8 AM, noon, and 4 21 and 60 years were eligible. Exclusion criteria included the PM. The day of the measurement, each subject received these following: pregnancy or lactation, use of systemic medica- eyedrops at 8:15 AM and 12:15 PM. After instillation of each tions, long-term use of eye medications, history of allergy to drop, the subjects were asked to close their eye for 2 min- ocular medications, history of a major systemic illness, his- utes. A separate blotting tissue was used for each eye to re- tory of notable eye disease, and concurrent or recent partici- duce the chance of transfer of the drug from one eye to the pation in any other study. In addition, subjects were ex- other, and subjects were asked not to touch either eye af- cluded on a preliminary examination for any of the following ter the instillation, closure, and blotting procedure had been reasons: intraocular pressures outside the inclusive range of completed. 10 to 20 mm Hg; intraocular pressures of the 2 eyes differ- At 2 AM the night before the measurement, each sub- ing by more than 3 mm Hg; obvious asymmetry of lids, globes, ject instilled 2% fluorescein sodium (IOLab) into each eye or pupils; pigment dispersion or pseudoexfoliation; myopia several times to produce a depot of fluorescein in the cor- or hyperopia of more than 5 diopters; narrow angles; and any nea for measurement of aqueous humor flow the follow- condition of lids, cornea, or anterior chambers that would ing morning. At 8 AM on the day of the experiment, each not permit accurate fluorometry and tonometry. subject underwent measurement of fluorescence in the cor- Commercial supplies of apraclonidine hydrochlo- nea and anterior chamber with a scanning ocular fluoro- ride, 0.5%, and brimonidine tartrate, 0.2%, and an artifi- photometer. This procedure was repeated every 2 hours cial tear preparation (Hypotears, IOLab, Claremont, Calif) through 4 PM. These data were used to calculate the rate of were obtained. These products were repackaged and rela- flow of aqueous humor through the anterior chamber. beled by a Mayo pharmacist. The new containers for all 3 Immediately after the 4 PM measurement, the intra- products were identical. The containers were filled accord- ocular pressure was measured with a Goldmann applana- ing to the randomization scheme and identified only by tion tonometer. The right eye was measured first; the left group number, subject number, experiment number, and eye, second; and these measurements were repeated for a right or left eye. In group 1, 1 eye was randomly assigned total of 3 measurements per eye. The intraocular pressure to receive placebo on both days of testing, and the fellow was recorded as the mean of the 3 measurements. eye was assigned to receive the drugs. In half of the sub- The data within each of the 2 groups were analyzed jects, apraclonidine was given on the first day, and bri- for statistical significance with a 2-sided Student t test for monidine, on the second day. In the other half of the sub- paired samples. A P value of .05 or less was considered sta- jects, brimonidine was given on the first day, and tistically significant. apraclonidine, on the second day. In addition, 16 mem- The coefficient of variation of measurements of aque- bers of group 1 underwent a third run; both eyes of each ous humor flow under the conditions of this experiment subject received placebo. is approximately 16%.21 For a paired test, a sample size of In group 2, half of the subjects received placebo in both 20 subjects has the power to detect a 16% difference in flow eyes on the first day, and half, on the second day. On the between drug and placebo (␣ = .05, ␤ = .95).

31% lower in the brimonidine-treated eyes than in the apraclonidine was given in the opposite eye was placebo eyes (PϽ.001). 1.92 ± 0.46 µL/min. The rate of aqueous flow in the When the aqueous-suppressing effect of apracloni- placebo-treated eyes when placebo was given in the dine was compared with the effect of brimonidine, there opposite eye was 2.30 ± 0.46 µL/min, a 16% difference. was no statistically significant difference (P = .63). This difference was statistically significant (P = .004), At a later time, 16 members of group 1 were indicating that apraclonidine has a consensual effect restudied when placebo was instilled into both eyes on aqueous humor flow. and neither active drug was used in either eye. The A similar consensual effect was observed for bri- rate of aqueous flow in the placebo-treated eyes when monidine. The rate of aqueous flow in the placebo-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 treated eyes when brimonidine was given in the oppo- clonidine has a consensual effect on intraocular pres- site eye was 1.90 ± 0.47 µL/min. When placebo was given sure that is consistent with its consensual effect on aque- in the opposite eye, the flow was 2.30 ± 0.46 µL/min, a ous humor flow. difference of 17%. This difference was statistically sig- A similar consensual effect was observed for nificant (P = .007). brimonidine. The intraocular pressure in the placebo- In group 2, in 1 session, apraclonidine was in- treated eyes when brimonidine was given in the oppo- stilled into 1 eye and brimonidine was instilled into the site eye was 11.9 ± 2.1 mm Hg. When placebo was given other. In the other session, placebo was instilled into both in the opposite eye, the intraocular pressure was 12.9 ± 1.7 eyes. In half of the subjects (n = 10), the placebos were mm Hg, a difference of 8%. However, this difference was studied first; in the other half, the drugs were studied first. not statistically significant (P = .12). There were no statistically significant differences be- In group 2, the intraocular pressure in the apra- tween the results in one sequence or the other (apraclonidine-treated eyes when the fellow eyes had been clonidine, P = .22; brimonidine, P = .83), so the data were treated with brimonidine was 10.2 ± 2.4 mm Hg. The in- combined into a single group of 20 subjects for addi- traocular pressure in the same eyes when placebo had tional statistical analysis. been instilled in both eyes was 12.8 ± 2.5 mm Hg, a dif- The rate of aqueous flow in the apraclonidine- ference of 20% (PϽ.001). treated eyes when the fellow eyes had been treated with The intraocular pressure in the brimonidine- brimonidine was 1.39 ± 0.34 µL/min. The rate of aque- treated eyes when the fellow eyes had been treated with ous flow in the same eyes when placebo had been in- apraclonidine was 9.6 ± 2.0 mm Hg. The intraocular pres- stilled in both eyes was 2.26 ± 0.49 µL/min, a difference sure in the same eyes when placebos had been instilled of 39% (PϽ.001). in both eyes was 12.4 ± 2.3 mm Hg, a difference of 22% The rate of aqueous flow in the brimonidine- (PϽ.001). treated eyes when the fellow eyes had been treated with When apraclonidine’s effect on pressure was com- apraclonidine was 1.24 ± 0.28 µL/min. The rate of aque- pared with brimonidine’s effect on pressure, there was ous flow in the same eyes when placebo had been in- no statistically significant difference (P = .37). stilled in both eyes was 2.20 ± 0.38 µL/min, a difference of 44% (PϽ.001). COMMENT When apraclonidine’s effect on flow was compared with brimonidine’s effect on flow, there was a trend for The results of this study indicate that apraclonidine and brimonidine’s effect to be greater (39% vs 44%; P = .05). brimonidine both suppress aqueous humor formation, an effect that is sufficient to account for their ability to INTRAOCULAR PRESSURE lower intraocular pressure. Toris and coworkers18 studied patients with ocular hypertension whose baseline in- In groups 1 and 2, the intraocular pressure was mea- traocular pressures were 21 mm Hg and who were treated sured in each eye at 4 PM, after the completion of the last for 8 days with brimonidine. In that study, brimonidine measurement of fluorescence. All the subsequent data in suppressed aqueous humor flow by 20% and increased this section refer to these afternoon measurements, taken uveoscleral outflow by more than 4 times. In this study, 4 hours after the last instillation of drug. aqueous suppression was 44% to 48%. The effect on in- In group 1, the intraocular pressure in the apra- traocular pressure could be attributed entirely to the drug’s clonidine-treated eyes of the 20 subjects was 10.2 ± 1.8 effect on flow, but this notion cannot be proved from our mm Hg (mean ± SD) and in the fellow placebo-treated eyes data since outflow resistance or uveoscleral flow was not was 11.4 ± 1.8 mm Hg. Thus, the intraocular pressure was measured. However, we presume that if the short-term 11% lower in the treated eyes than in the control eyes administration (1 day) of 1 drug had had a significant (P = .005). The intraocular pressure in the brimonidine- effect on outflow and the other drug had not, we would treated eyes was 10.6 ± 2.0 mm Hg and in the fellow pla- have seen a difference between the 2 drugs in their rela- cebo-treated eyes was 11.8 ± 2.0 mm Hg, 11% lower in tive effects on pressure and flow. We do not know whether the brimonidine-treated eyes than in the placebo eyes the differences in results of the 2 studies are caused by (P = .005). differences in the condition of the subjects, the length When the intraocular pressure–lowering effect of of treatment with brimonidine, or the techniques of apraclonidine was compared with the effect of bri- measurement. monidine, there was no statistically significant differ- Apraclonidine and brimonidine, like timolol, have ence (P = .60). a consensual effect on aqueous humor flow in the fel- At a later time, when the 16 members of group 1 low eye. The reason for this effect is not known, but were restudied by instillation of placebo into both eyes could result from systemic absorption of the drugs.5,8 In and neither active drug was used in either eye, the in- this experiment, we made every effort to prevent direct traocular pressures were also measured at 4 PM. The in- transfer of the drug into the placebo-treated eye by hav- traocular pressure in the placebo-treated eyes when apra- ing the technician, rather than the subject, instill the clonidine was given in the opposite eye was 11.3 ± 1.9 drops and by using different tissues for blotting after mm Hg. The intraocular pressure in the same placebo- instillation. However, there remains the chance that the treated eyes when placebo was given in the opposite eye subject may not have followed directions and may have was 12.9 ± 1.7 mm Hg, a 12% difference. This difference manually transferred some drug from one eye to the was statistically significant (P = .02), indicating that apra- other.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 The results of group 1 and group 2, taking into ac- REFERENCES count the consensual effects of each drug, are very com-

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are preferably conducted in subjects who have elevated 15. Serle JB, Steidl S, Wang R-F, Mittag TW, Podos SM. Selective ␣2-adrenergic ago- intraocular pressure. Also, the data on flow pertain to nists B-HT 920 and UK14304-18: effects on aqueous humor dynamics in mon- the short-term effects of these drugs; effects may be keys. Arch Ophthalmol. 1991;109:1158-1162. 16. Ogidigben M, Chu TC, Potter DE. Alpha-2 adrenoceptor mediated changes in aque- greater than the sustained effects during long-term ous dynamics: effect of pertussis toxin. Exp Eye Res. 1994;58:729-736. usage. 17. Gabelt BT, Robinson JC, Hubbard WC, et al. Apraclonidine and brimonidine effects on anterior ocular and cardiovascular physiology in normal and sympa- Accepted for publication July 10, 1998. thectomized monkeys. Exp Eye Res. 1994;59:633-644. 18. Toris CB, Gleason ML, Camras CB, Yablonski ME. Effects of brimonidine on aque- This study was supported in part by research grant EY ous humor dynamics in human eyes. Arch Ophthalmol. 1995;113:1514-1517. 00634 from the National Eye Institute, National Institutes 19. Burke J, Schwartz M. Preclinical evaluation of brimonidine. Surv Ophthalmol. of Health, Bethesda, Md; Research to Prevent Blindness Inc, 1996;41(suppl 1):S9-S18. New York, NY; Corella and Bertram F. Bonner Foundation 20. Burke J, Kharlamb A, Shan T, et al. Adrenergic and imidazoline receptor- Inc, Princeton, NJ; and Mayo Foundation, Rochester, Minn. mediated responses to UK-14,304-18 (brimonidine) in rabbits and monkeys: a species difference. Ann N Y Acad Sci. 1995;763:78-95. Reprints: Richard F. Brubaker, MD, Mayo Clinic, 21. Brubaker RF. Clinical measurements of aqueous dynamics: implications for ad- 200 First St SW, Rochester, MN 55905 (e-mail: dressing glaucoma. In: Civan M, ed. Current Topics in Membranes. Vol 45. San [email protected]). Diego, Calif: Academic Press; 1998:233-284.

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