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Efficacy of combining timolol with other antiglaucoma medications
SURVEY
OF OPHTHALMOLOGY
VOLUME 28 - SUPPLEMENT * DECEMBER 1983
Efficacy of Combining Timolol With Other Antiglaucoma Medications MICHAEL
A. KASS, M.D.
Department
of Ophthalmology,
Clhshington
CTnirwsity School of Medicine,
St. Louis,
Missouri
Abstract. The ocular hypotensive effects of timolol and a carbonic anhydrase inhibitor (acetazolamide or methazolamide) are partially additive; that is, concurrent administration of these drugs produces a clinically useful reduction in intraocular pressure which is greater than the erect of either medication alone, but less than the arithmetic sum of the effects of the individual drugs. Similarly, concurrent administration of timolol and a miotic agent (pilocarpine, carbachol, or echothiophate iodide) produces a clinically useful response in most glaucoma patients. In contrast, the ocular hypotensive effects of timolol and epinephrine are poorly additive. Only a minority of patients maintain a substantial, longterm reduction in intraocular pressure when timolol is added to a regimen of epinephrine or vice versa. Ophthalmologists prescribing timolol or epinephrine for patients receiving the other drug are urged to use a therapeutic trial to one eye for several weeks to determine the efficacy of concurrent treatment. The addition of timolol to the medical regimen of patients uncontrolled on maximum tolerated antiglaucoma therapy (a miotic agent, epinephrine and a carbonic anhydrase inhibitor) reduces intraocular pressure substantially in one-third to one-half of the cases. (Surv Ophthalmol 28:274-279, 1983)
Key words. glaucoma pilocarpine
T
imolol
maleate
l
is now the most
commonly
ocular
hypotensive
United
States.
Yet, our knowledge
complete.
The
review the clinical concurrently with Pharmacologists calculating there
medication
purpose
tivity
in the
oftimolol
of this
though
pre-
paper
is is to
the additivity
of the two drugs.
is no universally
accepted
(IOP)
of the individual alone reduces
by 40%
and
drug
alone
than
less
the
than
involving
of
studies
drugs - e.g., ifdrug A intraocular pressure
B administered
is greater
this paper
Unfortu-
definition
full additivity is defined
miotic
l
the
effect
arithmetic
is restricted human
l
is not achieved.
as a clinically
Partial
useful
of either sum
response drug
of the
individual drugs. There is marked species variation to ocular hypotensive medications.
efficacy of administering timolol other antiglaucoma medications. assess concurrent treatment by
For the purposes of this pathe word, “additivity.” per, full additivity is defined as the arithmetic sum of the effects administered
l
l
l
scribed
far from
nately,
epmephrine carbonic anhydrase inhibitor ’ acetazolamide maximum tolerated medical therapy intraocular pressure timolol l
l
No
alone,
effects
but of the
in the response For that reason,
to observations
subjects.
addiwhich
data
and
studies
from
animal
are presented.
Timolol
and Acetazolamide
Timolol and acetazolamide both lower IOP by reducing aqueous humor formation.‘.‘i.2i Thus, it is administration is possible that concurrent
re-
duces IOP by 33%, with full additivity, the two drugs administered concurrently would reduce IOP by 73%. However, clinicians are concerned with the efficacy of combined therapy, not whether administration of the two drugs produces full additivity.
nonproductive. Several investigators have formed the impression that concurrent treatment with timolol and acetazolamide’.‘0,‘” or timolol and methazolamide”l is
Using the example given above, if concurrent administration of drugs A and B produces a 55% reduction in IOP, this would be clinically useful even
clinically useful. ed to a regimen 274
When oral acetazolamide of topical timolol, IOP
was addwas low-
COMBINING
TIMOLOL
WITH OTHER ANTIGLAUCOMA T:\BLE Studv Des&n:
Concurrent
.4dministration
275
MEDICATIONS
1 of‘ Timolol
Aceta:olamide”
Group A Baseline IOP measurement, 8 a.m., random allocation. Begin timolol 0.5%, 1 drop every I:! hours to a randomlk selected eye.
Group B Baseline IOP measurement. 8 a.m., random allocation. Begin acetazolamide. 500 mg orally every I:! hours.
\‘isit 2 (4 weeks)
Repeat IOP measuremrnt, 8 a.m. Begin acetazolamidc, 500 mg orally ever! 12 hours. Continue timolol.
Repeat IOP measurement. 8 a.m. Begin titnolol 0.5%. 1 drop every 12 hours to a randomly selected e\e. Continue acetazolamide.
\‘isit 3 (5 weeks)
Repeat IOP 8 a.m.
Repeat IOP 8 a.m.
Visit
1
measurement,
cred.‘.“.‘” Keates” found that timolol 0.25% twice daily reduced IOP substantially in patients recri\.ing oral acrtazolamide. Scharrer and Ober” rrportc-d that a single dose ofeither acetazolamide or timo101 lowered 10P in patients pretreated with the other medication. In single dose fluorophotometric studies conducted in normal volunteers, Dailey et al” noted that aqueous humor flow through the anterior chamber was decreased 27% by acetazolamidc 250 mg, 33% by 0.5% timolol, and 44% hy the combination of the two drugs. Berson and Epstein’ noted that timolol 0.5% twice daily fix three weeks lowered outflow pressure (outflow pressure defined as intraocular pressure minus episcleral venous pressure) 38.7% and oral acetazolamide 500 mg twice daily for one week lowered outflow pressure 46.6%. Cloncurrcnt administration of the two medications for one iveek decreased outflow pressure 61.3%. Kass and coworkers” conducted a five-week clinical trial of the concurrent administration of oral acctazolamidc and topical timolol. Thirty-eight ocular hypertensive patients were assigned randomly to one of two treatment groups. The plan of the study is summarized in Table 1. The time intervals for return visits were chosen to allow each dru,? to produce a reasonably stable ocular hypotensive vft‘ect. Topical timolol (group A, visit 2) produced a 36% decrease in outflow pressure from baseline (p < .OOOl, paired t test, Table 2). When administered to an rye pretreated with oral acetazolamide, timo101 (group B, visit 3) caused an additional 27.6% decrease in outflow pressure (p < .Ol , paired t test). Thus. concurrent therapy with acetazolamide does not substantially reduce the efrrctiveness of topical
measurement,
timolol treatment. Oral acctazolamide (group B, visit 2) produced a 48.6% reduction in outflow pressure from baseline (p < .OOOl, paired t test, Table 2). When administered to patients receiving topical timolol, acetazolamide (group A, visit 3) caused an additional 43.2% decrease in outflow pressure (p < .OOOl , paired t test). Thus, concurrent therapy with topical timolol does not substantially reduce the efFcti\peness of oral acetazolamidc treatment. C:oncurrent administration of timolol and acetazolamide produced mean reductions in outflow pressure from baseline of 64.1”/0 (group A, visit 3) and 62.3% (group B, \.isit 3).” This study supported the concept of administering oral acetazolamide and topical timolol concurrently to lower IOP.
Timolol
and Epinephrine
Timolol, a beta adrenergic blocker, and cpinephrine, an alpha and beta adrencrgic agonist, have partially opposing pharmacologic properties. This naturally raises the question of whether their ocular hypotensive effects are additive. The puhlishrd reports on timolol and epinephrine have been contradictory. Nielsen,” Nielsen and Ericksen,“’ and Ohsthaum and coworkers”’ stated that concurrent treatment with timolol and epinrphrine was effecti\,r in lowering IOP. Boger and coworkers’ felt that concurrent treatment was no more rtfective than treatment with timolol alone. Keates” found that when timolol 0.25% twice daily was administered to patients already rrceiving 2% rpinephrine, a substantial decrease in IOP occurred. The magnitude of this decrease abated somewhat after right weeks of concurrent treat-
276
Surv Ophthalmol
28 (Suppl) December
KASS
1983 TABLE
ment. Goldberg and coworkers” found that a single drop of 2% epinephrine hydrochloride (HCl) produced only a small decrease in IOP when administered to patients who had been pretreated for one week with timolol 0.5% twice daily. Conversely, a single drop of timolol 0.5% produced a substantial decrease in IOP when administered to patients who had been pretreated for one week with 2% epinephrine twice daily. Keates and Stone” noted that when dipivefrin 0.1% twice daily was administered to patients already receiving timolol, a small decrease in IOP occurred. When timolol 0.25% twice daily was administered to patients already receiving dipivefrin, a modest decrease in IOP occurred. This effect diminished somewhat with time. In contrast, McGuinness and Frumar’” found concurrent treatment with timolol and dipivefrin to be clinically useful. In single dose fluorophotometric studies conducted in normal volunteers, Higgins and Brubaker”’ noted that timolol pretreatment blocked the epinephrine-induced increase in aqueous humor formation. Because of low baseline values, no conclusions concerning IOP reductions were reached. Schenker and coworkers” also utilized fluorophotometry to study the interaction of timolol and epinephrine. In shortterm studies (two weeks), the addition of timolol 0.5% to eyes already receiving 2% epinephrine HCl lowered IOP and decreased aqueous humor formation below baseline levels. The addition of 2% epinephrine to eyes already receiving 0.5% timolol lowered IOP modestly and slightly increased aqueous humor formation. Pretreatment with timolol did not block the epinephrine-induced increase in outflow facility. a controlled Thomas and Epstein>’ conducted
effect
Topical
Timolol
and Epinephrine
Timolol
and
Mean IOP (mm Baseline Dqv 91 8:00 9:00 1O:OO 1l:OO 1:OO 3:00 Mean
am am am am pm pm
Hg)
?
SD.
26.6
3.7
18.4 17.7 17.7 17.6 16.9 17.0
3.8 4.5 3.7 3.0 3.1 3.4
of Timolol and Acetazolamide
Mean
- 30.4 - 32.5 - 32.7 -33.1 - 35.8 - 35.2 - 33.9
IOP
GROUP A Baseline Visit 2 (week 4) on timolol alone Visit 3 (week 5) on timolol and acetazolamide
26.1 + 3.4
*From tFrom :From
baseline to visit visit to visit 3 baseline to visit
36.0?
2O.lk3.1
15.6?
GROUP B Baseline Visit 2 [week 1) on acetazolamide alone Visit 3 (week 5) on acetazolamide and timolol
23.0*
43.2 ? 29.9t 64.1 k21.4:
3.0
21X+-6.3 19.1 k6.3
48.6-+
15.2*
16.252.8
27.6? 62.3?
28.2t 21.2:
2 3
clinical trial assigning patients randomly to treatment with epinephryl borate 1% or timolol 0.5% twice daily. After two weeks, the other drug was added to the regimen. Initially, a further reduction in IOP was seen in both groups. However, after eight weeks of concurrent treatment, no substantial partial additive effect was noted. Cyrlin et al’ noted that treatment with timolol blocked the epinephrine-induced increase in outflow facility. They also noted that epinephrine administered three hours after timolol produced a
3
to One eye, and Epinephrine
to the Alloat
Eve”’ (n = 18)
Epinephrine
Mean IOP *
Pressure”
outflow Pressure + SD.
(mm Hg) ? SD.
Epinephrine Mean % Change of IOP from Baseline
on Intraocular
Mean % Decrease in
TABLE Groub A:
2
S.D.
13.8 19.3 15.4 13.6 13.0 14.0 13.4
(mm
W
?
S.D.
26.0
3.3
20.3 20.0 19.6 19.6 18.5 17.8
3.1 3.1 3.0 3.0 2.3 2.4
Mean % Change of IOP from Baseline
-21.1 - 22.0 - 23.8 - 24.0 - 28.3 - 30.8 - 25.8
r
S.D.
13.0 13.9 13.4 12.8 9.1 9.9 10.5
COMBINING
TIMOLOL
WITH OTHER ANTIGLAUCOMA TABLE
MEDICATIONS
277
4
Group B: Topical Timolol and Epinephrine to One
Mean IOP (mm W Baseline
Timolof
and Epinephrine
+- S.D.
Mean % Change of IOP from Baseline
25.4
4.7
18.6
2.7
- 24.8
17.8 18.0 18.0 16.8 16.7
3.6 3.3 2.1 2.0 1.9
-27.7 -27.6 - 27.0 - 30.9 -31.6 - 29.0
+ S.D.
Mean IOP (mm Hg)
t
S.D.
Mean % Change of IOP from Baseline
5 S.D.
26.6
4.5
15.6
21.0
3.5
- 20.2
11.4
19.1 16.3 15.3 18.4 16.9 15.4
19.5 19.3 19.4 18.3 18.3
3.2 2.9 2.6 2.9 2.0
- 25.3 - 26.2 -25.7 - 29.3 - 29.4 - 27.2
14.3 12.5 13.2 16.5 13.9 13.0
Da_y 91 8:00 am 9:00 am
10:00 am 11:OO am 1:00 pm 3:00 pm Mean
ocular hypotensive effect than epinephrine administered five minutes after timolol. However, this difference in response was seen only in the second phase ofa cross-over study. It is possible that an inadequate washout period before the second phase produced unreliable “baseline” IOP levels. Further studies of this observation are needed. Korey and coworkers’5 conducted a ninety-day clinical trial of the concurrent administration of timolol and epinephrine. Ocular hypertensive subjects were assigned alternately to one of two treatment groups. In group A, subjects administered one drop of epinephrine HCl 2% to both eyes every 12 hours. In addition, one eye was assigned randomly to receive one drop of timolol 0.5% every 12 hours (15 minutes after instillation of epinephrine). In group B, subjects administered one drop of timolol 0.5% to both eyes every 12 hours, and one eye was assigned randomly to receive one drop of epinephrine HCl2% every 12 hours ( 15 minutes after instillation of timolol). After 90 days of treatment, epinephrine caused a mean reduction of IOP from baseline of 25.8% as compared to a 33.9% reduction in fellow eyes treated with epinephrine and timolol (p < .009, analysis of variance, Table 3). On day 91, the mean IOP reduction from baseline in the eyes treated with combined therapy exceeded the mean reduction in fellow eyes receiving epinephrine alone by three or more mm Hg in eight of 18 subjects (44%). After 90 days of treatment, timolol caused a mean reduction of IOP from baseline of 27.2% as compared to a 29% reduction in fellow eyes treated with timolol and epinephrine (p > .47, analysis of variance, Table 4). On day 9 1, the mean IOP reduction from baseline in the eyes treated with combined therapy exceeded the mean reduction in fellow eyes receiving timolol alone by three or more greater
mm Hg in three of 14 subjects (21.4%).‘” From the controlled clinical trials, it appears that the ocular hypotensive effects of timolol and epinephrine are poorly additive. For the first few weeks, a substantial effect on IOP may be seen, especially when timolol is added to epinephrine therapy. However, only 20% to 45% of patients being treated with either drug are likely to have a substantial (2 3 mm Hg) longterm reduction in IOP when the other drug is added to their therapeutic regimen. Ophthalmologists are advised to add the second drug to one eye for several weeks as a therapeutic trial to determine the efftcacy of concurrent therapy. It is possible that administering epinephrine three or four hours after timolol may increase the efficacy of this combined treatment.
Timolol and Miotics Several investigators stated that concurrent treatment with timolol and a standard miotic agent (pilocarpine or carbachol) is clinically useful for reducing elevated IOP.‘.“.‘8.‘o.2” Ober and Scharrer’!’ noted that one drop of 2% pilocarpine, or 1.5% carbachol, produced a significant reduction of IOP in patients pretreated for a period of time with timo101 0.25% twice daily. Conversely, in patients who had received longterm treatment with 2% pilocarpine four times daily, one drop of 0.25% timolol produced a marked ocular hypotensive response. Keates’ studied glaucoma patients who had been receiving longterm therapy with either 2% pilocarpine or 1.5% carbachol four times daily. When timolol 0.25% twice daily was added, a substantial decrease in IOP was noted for the eight week period of the study. Zimmerman has noted that concurrent treatment with timolol and echothiophate iodide produces a
278
Surv Ophthalmol
28 (Suppl) December
clinically useful ocular hypotensive man TJ: Personal communication,
Timolol
1983
effect (ZimmerOctober 1981).
KASS TABLE Timolol Plus Maximum
and Maximum Tolerated Medical Therapy
and CanKerty and Horven14 and Zimmerman ale’” reported that adding timolol to maximum medical therapy led to better IOP control. Sonty and Schwartz” added timolol 0.1% to 0.5% twice daily to the medical regimen of 20 patients (3 1 eyes) on maximum tolerated medical therapy. Intraocular pressure was maintained at “desired levels” in 21 of31 eyes (670/ o ) over a 2.5 to 2 1 month follow-up period. The efficacy of adding timolol to maximum tolerated medical therapy was assessed in both shortterm and longterm studies. In the shortterm study, 18 patients were chosen because of IOPs 2 22 mm Hg while on maximum tolerated antiglaucoma therapy (a topical cholinergic agent, topical epinephrine, and a systemic carbonic anhydrase inhibitor).‘7 The patients received timololO.5% twice daily to one eye or placebo in a double-masked fashion for one week. After a one-week intertreatment period (during which the patients continued all previously administered antiglaucoma therapy), the treatment groups were reversed. The mean IOP + S.D. of the eyes on maximum tolerated antiglaucoma therapy was 28.7 2 5.5 mm Hg. When treated with placebo, the mean IOP was 26.4 + 7.8 mm Hg. After one week of timolol therapy, the mean IOP fell to 23.1 2 4.1 mm Hg. This was significantly different from the mean pretreatment IOP (P < .OOl, paired t test) and the placebotreated IOP (P < .025, paired t test). There was a wide range of responses upon adding timolol to maximum medical therapy. When the effect of timolol was corrected for the placebo effect, two patients had increases in IOP, eleven patients had decreases of one to four mm Hg, and live patients had decreases greater than 4 mm Hg. Six patients treated with timolol, as opposed to only three patients treated with placebo, reached IOPs d 21 mm Hg.27 The results of the shortterm study were suffrciently promising to stimulate a longterm study of the addition of timolol to maximum tolerated antiglaucoma therapy.’ Twenty-two patients (33 eyes) had topical timolol 0.1% to 0.5% twice daily added to maximum tolerated medical therapy (in most cases, a topical cholinergic agent, topical epinephrine, and a systemic carbonic anhydrase inhibitor). The concentration of timolol was increased if the IOP was greater than 22 mm Hg. A number of patients had borderline IOP control but no progression of glaucomatous damage and were continued in the proto-
Baseline 1 week 2 weeks l-3 months 4-6 months 7-9 months lo-12 months
5
Tolerated
Medical
Therapy’
Medically treated eyes IOP (mm Hg)
Eyes requiring surgery IOP (mm Hg)
? S.D. (n = 25)
? S.D. n=8
3O.Ok8.2 22.0 ?I 3.7 21.1 -c5.7 21.7k5.4 21.154.3 21.8k5.4 22.3 -t4.3
31.2T9.7 29.0 k9.6 30.1 +-6.9 31.2-t 11.2 -
co1 because the risk of continued medical therapy seemed less than the risk of surgery. Because the patients involved in this study had advanced glaucomatous damage and high IOPs, it was impossible to do a randomized masked study. It was necessary to vary medical regimens to improve IOP control. In some patients, the strength and/or number of medications were decreased as long as IOP remained controlled. Twenty-live of 33 eyes (76%) completed the oneyear follow-up. Only eight eyes (24%) required liltering surgery because of actual or anticipated progressive damage. The mean baseline IOP 2 S.D. for the 33 eyes was 30.3 -+ 8.4 mm Hg. There was no statistically significant difference between the mean IOPs for the eight eyes which required surgery and the 25 which were treated medically for the one-year follow-up (p > .30, student’s t test). However, the two groups responded very differently when timolol was added to the regimen (Table 5). The 25 eyes treated medically had significant and persistent decreases in IOP over the 12 months of the study (P < .0005, paired t test). The mean decrease in IOP + S.D. at the conclusion of the study was 7.7 2 6.9 mm Hg for the 25 eyes not requiring surgery. All 33 eyes had baseline IOPs greater than 22 mm Hg. Thirteen eyes (39%) achieved IOPs d 21 mm Hg at one year on timolol plus maximum tolerated medical therapy. After the addition of timolol, 17 of the 33 eyes (52%) completed the oneyear protocol with final mean IOP decreases greater than 5 mm Hg.’ Currently, the most common indication for laser trabeculoplasty or filtering surgery is the progression of glaucomatous damage while on maximum tolerated medical therapy. The addition of timolol to the medical regimen lowers IOP substantially in one-third to one-half of such eyes. Thus, it may be possible to postpone or avoid surgery in some pa-
COMBINING
TIMOLOL
WITH OTHER ANTIGLAUCOMA
tients previously uncontrolled ed medical therapy.
on maximum
tolerat-
Summary The ocular hypotensive effects of timolol and a carbonic anhydrase inhibitor (acetazolamide or methazolamide) are partially additive. Similarly, concurrent administration of timolol and a miotic agent (pilocarpine, carbachol, or echothiophate iodide) produces a clinically useful reduction of IOP in most patients. In contrast, the ocular hypotensive effects of timolol and epinephrine are poorly additive. Ophthalmologists prescribing timolol or epinephrine for patients receiving the other drug are urged to use a therapeutic trial to one eye for several weeks. The addition of timolol to the medical regimen of patients uncontrolled on maximum tolerated medical therapy reduces IOP substantially in onethird to one-half of the cases.
References
Il.
12.
13.
14. 15.
16. 17.
18.
19.
20.
I. Ashburn
2. 3.
4.
5.
6.
FS, Gillespie JE, Kass MA, Becker B: Tim&l plus maximum tolerated medical therapy: a one-year follow-up study. Surv Ophthalmol 23:38%394, 1979 Becker B: Decrease in intraocular pressure by a carbonic anhydrase inhibitor, Diamox. Am J Ophthalmol37: 13-15, 1954 Berson FG, Epstein DL: Separate and combined eFfects of timolol maleate and acetazolamide in open-angle glaucoma. Am J O.bhthalmol 92:788-791, 1981 Boger WP III, Puliafito CA, Steinert RF, Langston DP: Longterm experience with timolol ophthalmic solution in patients with open-angle glaucoma. Ophthalmology &5:25%267, 1978 Calissendorff B, Maren N, Wettrell K, Ostberg A: Timolol versus pilocarpine separately or combined with acctazolamide - Effects on intraocular pressure. Acln Ophthalmol58;62~63 I. 1980 Coakes RL, Brubaker RF: The mechanism of timolol in lowering intraocular pressure in the normal eye. Arch Ophthalmol
96:2045-2048,
21.
22.
23.
24.
25.
26.
1978
MEDICATIONS
279
1980 Kass MA, Korey M, Gordon M, Becker B: Timolol and acetazolamide: A study ofconcurrent administration. Arch Ophthalmol lOOt941-944, 1982 Keates EU: Evaluation of timolol maleate combination therapy in chronic open-angle glaucoma. Am J Ophthalmol 88:565-571, 1979 Keates EU, Stone RA: Safety and efFectiveness of concomitant administration of dipivefrin and timolol maleate. .4m J Ophthalmol91:243-248, 1981 Kerty E, Horven I: Glaucoma treatment with timolol. Acta Ophthalmol56:705-713, 1978 Korey MS, Hodapp E, Kass MA, et al: Timolol and epinephrine. Long-term evaluation of concurrent administration. Arch Ophthalmol 100:742-745, 1982 McCuinnes R, Frumar KD: Timolol and dipivalyl epinephrine combination therapy. Aust J Ophthalmol IO: I7’&182, 1982 Nielsen NV: Hypotensive effect used alone and in combination for treatment of increased intraocular pressure. Acta Ophthalmol 56:504-509, 1978 Nielsen NV. Ericksen JS: Timolol in maintenance treatment of ocular hypertension and glaucoma. Acta Ophthalmol 57: lO7CL 1077, 1979 Ober M, Scharrer A: Timolol and Parasympathicomimetica bei de Behandlung des erhohten intraocularen Druckes. Albrecht van CraeJ& Arch Klin f&p Ophthatmol 211:5%66, 1979 Ostbaum SA, Galin MA, Katz I>i: Timolol: Effect on intraocular pressure in chronic open-angle glaucoma. Ann Ophthalmol IOtl347-1351, 1978 Scharrcr A, Ober M: Timolol und Acetazolomid bei der Behandlung des erhohten intraocularen Druckes. Albrrcht uon Graefes Arch Klin E.xp Ophthalmol 212: 129-134, 1979 Schenker HI, Yablonski ME, Podos SM, Lender I,: Fluorophotometric study of epinephrine and timolol in human sutjrcts. Arch Ophthalmol 99:1212-1216, 1981 Sonty S, Schwartz B: The additive effect of timolol on open angle glaucoma in patients on maximum tolerated medical therapy. Sure Ophthalmol 23:381-388, 1979 Thomas ,JV, Epstein DL: Timolol and epinephrine in primary open-angle glaucoma. Transient additive effect. Arch Ophthalmol 99:91-95, 1981 Yahlonski ME. Zimmerman TJ. \Valtman SR, Becker B: A lluorophotometric study of the effect of topical timolol on aqueous humor dynamics. Ex.6 Eve Res 27:135-142, 1978 Zimmerman TJ, Canale P:-Timolol ~ furthw observations. Ophthalmoloev R6:166-169. 1979 Zimmerman TJ. Gillespie,JE, Kass MA, Yablonski ME, Becker B: Timolol plus maximum tolerated anti-glaucoma therapy. Arch Opthalmol 97:278-279, 1979 L_
7. Cyrlin MN, Thomas JV, Epstein DL: Additive effect of epinephrine to timolol therapy in primary open-angle glaucoma. Arch Ophthalmol 100:414-418, 1982 8. Dailey RA, Brubaker RF, Bourne WM: The effects of timolol maleate and acetazolamide on the rate of aqueous formation in normal human eyes. .4m J Ophthalmol 93:232-237. 1982 9. Goldberg I, Ashburn FS, Palmberg PF, et al: Timolol and epinephrine. A clinical study ofocular interactions. Arch Ophthalmol 98:4&l-486. 1980 IO. Higgins RG, Brubaker RF: Acute eflect ofepinephrine on aqueous humor formation in the timolol-treated normal eye as measured by lluorophotometry. best Ophthalmol 1% Sci 19:42&423,
27.
This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc.. New York, New York. Reprint requests should be addressed to Michael A. Kass, ,M.D., Department of Ophthalmology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis. Missouri 631 IO.
OF OPHTHALMOLOGY
VOLUME 28 - SUPPLEMENT * DECEMBER 1983
Efficacy of Combining Timolol With Other Antiglaucoma Medications MICHAEL
A. KASS, M.D.
Department
of Ophthalmology,
Clhshington
CTnirwsity School of Medicine,
St. Louis,
Missouri
Abstract. The ocular hypotensive effects of timolol and a carbonic anhydrase inhibitor (acetazolamide or methazolamide) are partially additive; that is, concurrent administration of these drugs produces a clinically useful reduction in intraocular pressure which is greater than the erect of either medication alone, but less than the arithmetic sum of the effects of the individual drugs. Similarly, concurrent administration of timolol and a miotic agent (pilocarpine, carbachol, or echothiophate iodide) produces a clinically useful response in most glaucoma patients. In contrast, the ocular hypotensive effects of timolol and epinephrine are poorly additive. Only a minority of patients maintain a substantial, longterm reduction in intraocular pressure when timolol is added to a regimen of epinephrine or vice versa. Ophthalmologists prescribing timolol or epinephrine for patients receiving the other drug are urged to use a therapeutic trial to one eye for several weeks to determine the efficacy of concurrent treatment. The addition of timolol to the medical regimen of patients uncontrolled on maximum tolerated antiglaucoma therapy (a miotic agent, epinephrine and a carbonic anhydrase inhibitor) reduces intraocular pressure substantially in one-third to one-half of the cases. (Surv Ophthalmol 28:274-279, 1983)
Key words. glaucoma pilocarpine
T
imolol
maleate
l
is now the most
commonly
ocular
hypotensive
United
States.
Yet, our knowledge
complete.
The
review the clinical concurrently with Pharmacologists calculating there
medication
purpose
tivity
in the
oftimolol
of this
though
pre-
paper
is is to
the additivity
of the two drugs.
is no universally
accepted
(IOP)
of the individual alone reduces
by 40%
and
drug
alone
than
less
the
than
involving
of
studies
drugs - e.g., ifdrug A intraocular pressure
B administered
is greater
this paper
Unfortu-
definition
full additivity is defined
miotic
l
the
effect
arithmetic
is restricted human
l
is not achieved.
as a clinically
Partial
useful
of either sum
response drug
of the
individual drugs. There is marked species variation to ocular hypotensive medications.
efficacy of administering timolol other antiglaucoma medications. assess concurrent treatment by
For the purposes of this pathe word, “additivity.” per, full additivity is defined as the arithmetic sum of the effects administered
l
l
l
scribed
far from
nately,
epmephrine carbonic anhydrase inhibitor ’ acetazolamide maximum tolerated medical therapy intraocular pressure timolol l
l
No
alone,
effects
but of the
in the response For that reason,
to observations
subjects.
addiwhich
data
and
studies
from
animal
are presented.
Timolol
and Acetazolamide
Timolol and acetazolamide both lower IOP by reducing aqueous humor formation.‘.‘i.2i Thus, it is administration is possible that concurrent
re-
duces IOP by 33%, with full additivity, the two drugs administered concurrently would reduce IOP by 73%. However, clinicians are concerned with the efficacy of combined therapy, not whether administration of the two drugs produces full additivity.
nonproductive. Several investigators have formed the impression that concurrent treatment with timolol and acetazolamide’.‘0,‘” or timolol and methazolamide”l is
Using the example given above, if concurrent administration of drugs A and B produces a 55% reduction in IOP, this would be clinically useful even
clinically useful. ed to a regimen 274
When oral acetazolamide of topical timolol, IOP
was addwas low-
COMBINING
TIMOLOL
WITH OTHER ANTIGLAUCOMA T:\BLE Studv Des&n:
Concurrent
.4dministration
275
MEDICATIONS
1 of‘ Timolol
Aceta:olamide”
Group A Baseline IOP measurement, 8 a.m., random allocation. Begin timolol 0.5%, 1 drop every I:! hours to a randomlk selected eye.
Group B Baseline IOP measurement. 8 a.m., random allocation. Begin acetazolamide. 500 mg orally every I:! hours.
\‘isit 2 (4 weeks)
Repeat IOP measuremrnt, 8 a.m. Begin acetazolamidc, 500 mg orally ever! 12 hours. Continue timolol.
Repeat IOP measurement. 8 a.m. Begin titnolol 0.5%. 1 drop every 12 hours to a randomly selected e\e. Continue acetazolamide.
\‘isit 3 (5 weeks)
Repeat IOP 8 a.m.
Repeat IOP 8 a.m.
Visit
1
measurement,
cred.‘.“.‘” Keates” found that timolol 0.25% twice daily reduced IOP substantially in patients recri\.ing oral acrtazolamide. Scharrer and Ober” rrportc-d that a single dose ofeither acetazolamide or timo101 lowered 10P in patients pretreated with the other medication. In single dose fluorophotometric studies conducted in normal volunteers, Dailey et al” noted that aqueous humor flow through the anterior chamber was decreased 27% by acetazolamidc 250 mg, 33% by 0.5% timolol, and 44% hy the combination of the two drugs. Berson and Epstein’ noted that timolol 0.5% twice daily fix three weeks lowered outflow pressure (outflow pressure defined as intraocular pressure minus episcleral venous pressure) 38.7% and oral acetazolamide 500 mg twice daily for one week lowered outflow pressure 46.6%. Cloncurrcnt administration of the two medications for one iveek decreased outflow pressure 61.3%. Kass and coworkers” conducted a five-week clinical trial of the concurrent administration of oral acctazolamidc and topical timolol. Thirty-eight ocular hypertensive patients were assigned randomly to one of two treatment groups. The plan of the study is summarized in Table 1. The time intervals for return visits were chosen to allow each dru,? to produce a reasonably stable ocular hypotensive vft‘ect. Topical timolol (group A, visit 2) produced a 36% decrease in outflow pressure from baseline (p < .OOOl, paired t test, Table 2). When administered to an rye pretreated with oral acetazolamide, timo101 (group B, visit 3) caused an additional 27.6% decrease in outflow pressure (p < .Ol , paired t test). Thus. concurrent therapy with acetazolamide does not substantially reduce the efrrctiveness of topical
measurement,
timolol treatment. Oral acctazolamide (group B, visit 2) produced a 48.6% reduction in outflow pressure from baseline (p < .OOOl, paired t test, Table 2). When administered to patients receiving topical timolol, acetazolamide (group A, visit 3) caused an additional 43.2% decrease in outflow pressure (p < .OOOl , paired t test). Thus, concurrent therapy with topical timolol does not substantially reduce the efFcti\peness of oral acetazolamidc treatment. C:oncurrent administration of timolol and acetazolamide produced mean reductions in outflow pressure from baseline of 64.1”/0 (group A, visit 3) and 62.3% (group B, \.isit 3).” This study supported the concept of administering oral acetazolamide and topical timolol concurrently to lower IOP.
Timolol
and Epinephrine
Timolol, a beta adrenergic blocker, and cpinephrine, an alpha and beta adrencrgic agonist, have partially opposing pharmacologic properties. This naturally raises the question of whether their ocular hypotensive effects are additive. The puhlishrd reports on timolol and epinephrine have been contradictory. Nielsen,” Nielsen and Ericksen,“’ and Ohsthaum and coworkers”’ stated that concurrent treatment with timolol and epinrphrine was effecti\,r in lowering IOP. Boger and coworkers’ felt that concurrent treatment was no more rtfective than treatment with timolol alone. Keates” found that when timolol 0.25% twice daily was administered to patients already rrceiving 2% rpinephrine, a substantial decrease in IOP occurred. The magnitude of this decrease abated somewhat after right weeks of concurrent treat-
276
Surv Ophthalmol
28 (Suppl) December
KASS
1983 TABLE
ment. Goldberg and coworkers” found that a single drop of 2% epinephrine hydrochloride (HCl) produced only a small decrease in IOP when administered to patients who had been pretreated for one week with timolol 0.5% twice daily. Conversely, a single drop of timolol 0.5% produced a substantial decrease in IOP when administered to patients who had been pretreated for one week with 2% epinephrine twice daily. Keates and Stone” noted that when dipivefrin 0.1% twice daily was administered to patients already receiving timolol, a small decrease in IOP occurred. When timolol 0.25% twice daily was administered to patients already receiving dipivefrin, a modest decrease in IOP occurred. This effect diminished somewhat with time. In contrast, McGuinness and Frumar’” found concurrent treatment with timolol and dipivefrin to be clinically useful. In single dose fluorophotometric studies conducted in normal volunteers, Higgins and Brubaker”’ noted that timolol pretreatment blocked the epinephrine-induced increase in aqueous humor formation. Because of low baseline values, no conclusions concerning IOP reductions were reached. Schenker and coworkers” also utilized fluorophotometry to study the interaction of timolol and epinephrine. In shortterm studies (two weeks), the addition of timolol 0.5% to eyes already receiving 2% epinephrine HCl lowered IOP and decreased aqueous humor formation below baseline levels. The addition of 2% epinephrine to eyes already receiving 0.5% timolol lowered IOP modestly and slightly increased aqueous humor formation. Pretreatment with timolol did not block the epinephrine-induced increase in outflow facility. a controlled Thomas and Epstein>’ conducted
effect
Topical
Timolol
and Epinephrine
Timolol
and
Mean IOP (mm Baseline Dqv 91 8:00 9:00 1O:OO 1l:OO 1:OO 3:00 Mean
am am am am pm pm
Hg)
?
SD.
26.6
3.7
18.4 17.7 17.7 17.6 16.9 17.0
3.8 4.5 3.7 3.0 3.1 3.4
of Timolol and Acetazolamide
Mean
- 30.4 - 32.5 - 32.7 -33.1 - 35.8 - 35.2 - 33.9
IOP
GROUP A Baseline Visit 2 (week 4) on timolol alone Visit 3 (week 5) on timolol and acetazolamide
26.1 + 3.4
*From tFrom :From
baseline to visit visit to visit 3 baseline to visit
36.0?
2O.lk3.1
15.6?
GROUP B Baseline Visit 2 [week 1) on acetazolamide alone Visit 3 (week 5) on acetazolamide and timolol
23.0*
43.2 ? 29.9t 64.1 k21.4:
3.0
21X+-6.3 19.1 k6.3
48.6-+
15.2*
16.252.8
27.6? 62.3?
28.2t 21.2:
2 3
clinical trial assigning patients randomly to treatment with epinephryl borate 1% or timolol 0.5% twice daily. After two weeks, the other drug was added to the regimen. Initially, a further reduction in IOP was seen in both groups. However, after eight weeks of concurrent treatment, no substantial partial additive effect was noted. Cyrlin et al’ noted that treatment with timolol blocked the epinephrine-induced increase in outflow facility. They also noted that epinephrine administered three hours after timolol produced a
3
to One eye, and Epinephrine
to the Alloat
Eve”’ (n = 18)
Epinephrine
Mean IOP *
Pressure”
outflow Pressure + SD.
(mm Hg) ? SD.
Epinephrine Mean % Change of IOP from Baseline
on Intraocular
Mean % Decrease in
TABLE Groub A:
2
S.D.
13.8 19.3 15.4 13.6 13.0 14.0 13.4
(mm
W
?
S.D.
26.0
3.3
20.3 20.0 19.6 19.6 18.5 17.8
3.1 3.1 3.0 3.0 2.3 2.4
Mean % Change of IOP from Baseline
-21.1 - 22.0 - 23.8 - 24.0 - 28.3 - 30.8 - 25.8
r
S.D.
13.0 13.9 13.4 12.8 9.1 9.9 10.5
COMBINING
TIMOLOL
WITH OTHER ANTIGLAUCOMA TABLE
MEDICATIONS
277
4
Group B: Topical Timolol and Epinephrine to One
Mean IOP (mm W Baseline
Timolof
and Epinephrine
+- S.D.
Mean % Change of IOP from Baseline
25.4
4.7
18.6
2.7
- 24.8
17.8 18.0 18.0 16.8 16.7
3.6 3.3 2.1 2.0 1.9
-27.7 -27.6 - 27.0 - 30.9 -31.6 - 29.0
+ S.D.
Mean IOP (mm Hg)
t
S.D.
Mean % Change of IOP from Baseline
5 S.D.
26.6
4.5
15.6
21.0
3.5
- 20.2
11.4
19.1 16.3 15.3 18.4 16.9 15.4
19.5 19.3 19.4 18.3 18.3
3.2 2.9 2.6 2.9 2.0
- 25.3 - 26.2 -25.7 - 29.3 - 29.4 - 27.2
14.3 12.5 13.2 16.5 13.9 13.0
Da_y 91 8:00 am 9:00 am
10:00 am 11:OO am 1:00 pm 3:00 pm Mean
ocular hypotensive effect than epinephrine administered five minutes after timolol. However, this difference in response was seen only in the second phase ofa cross-over study. It is possible that an inadequate washout period before the second phase produced unreliable “baseline” IOP levels. Further studies of this observation are needed. Korey and coworkers’5 conducted a ninety-day clinical trial of the concurrent administration of timolol and epinephrine. Ocular hypertensive subjects were assigned alternately to one of two treatment groups. In group A, subjects administered one drop of epinephrine HCl 2% to both eyes every 12 hours. In addition, one eye was assigned randomly to receive one drop of timolol 0.5% every 12 hours (15 minutes after instillation of epinephrine). In group B, subjects administered one drop of timolol 0.5% to both eyes every 12 hours, and one eye was assigned randomly to receive one drop of epinephrine HCl2% every 12 hours ( 15 minutes after instillation of timolol). After 90 days of treatment, epinephrine caused a mean reduction of IOP from baseline of 25.8% as compared to a 33.9% reduction in fellow eyes treated with epinephrine and timolol (p < .009, analysis of variance, Table 3). On day 91, the mean IOP reduction from baseline in the eyes treated with combined therapy exceeded the mean reduction in fellow eyes receiving epinephrine alone by three or more mm Hg in eight of 18 subjects (44%). After 90 days of treatment, timolol caused a mean reduction of IOP from baseline of 27.2% as compared to a 29% reduction in fellow eyes treated with timolol and epinephrine (p > .47, analysis of variance, Table 4). On day 9 1, the mean IOP reduction from baseline in the eyes treated with combined therapy exceeded the mean reduction in fellow eyes receiving timolol alone by three or more greater
mm Hg in three of 14 subjects (21.4%).‘” From the controlled clinical trials, it appears that the ocular hypotensive effects of timolol and epinephrine are poorly additive. For the first few weeks, a substantial effect on IOP may be seen, especially when timolol is added to epinephrine therapy. However, only 20% to 45% of patients being treated with either drug are likely to have a substantial (2 3 mm Hg) longterm reduction in IOP when the other drug is added to their therapeutic regimen. Ophthalmologists are advised to add the second drug to one eye for several weeks as a therapeutic trial to determine the efftcacy of concurrent therapy. It is possible that administering epinephrine three or four hours after timolol may increase the efficacy of this combined treatment.
Timolol and Miotics Several investigators stated that concurrent treatment with timolol and a standard miotic agent (pilocarpine or carbachol) is clinically useful for reducing elevated IOP.‘.“.‘8.‘o.2” Ober and Scharrer’!’ noted that one drop of 2% pilocarpine, or 1.5% carbachol, produced a significant reduction of IOP in patients pretreated for a period of time with timo101 0.25% twice daily. Conversely, in patients who had received longterm treatment with 2% pilocarpine four times daily, one drop of 0.25% timolol produced a marked ocular hypotensive response. Keates’ studied glaucoma patients who had been receiving longterm therapy with either 2% pilocarpine or 1.5% carbachol four times daily. When timolol 0.25% twice daily was added, a substantial decrease in IOP was noted for the eight week period of the study. Zimmerman has noted that concurrent treatment with timolol and echothiophate iodide produces a
278
Surv Ophthalmol
28 (Suppl) December
clinically useful ocular hypotensive man TJ: Personal communication,
Timolol
1983
effect (ZimmerOctober 1981).
KASS TABLE Timolol Plus Maximum
and Maximum Tolerated Medical Therapy
and CanKerty and Horven14 and Zimmerman ale’” reported that adding timolol to maximum medical therapy led to better IOP control. Sonty and Schwartz” added timolol 0.1% to 0.5% twice daily to the medical regimen of 20 patients (3 1 eyes) on maximum tolerated medical therapy. Intraocular pressure was maintained at “desired levels” in 21 of31 eyes (670/ o ) over a 2.5 to 2 1 month follow-up period. The efficacy of adding timolol to maximum tolerated medical therapy was assessed in both shortterm and longterm studies. In the shortterm study, 18 patients were chosen because of IOPs 2 22 mm Hg while on maximum tolerated antiglaucoma therapy (a topical cholinergic agent, topical epinephrine, and a systemic carbonic anhydrase inhibitor).‘7 The patients received timololO.5% twice daily to one eye or placebo in a double-masked fashion for one week. After a one-week intertreatment period (during which the patients continued all previously administered antiglaucoma therapy), the treatment groups were reversed. The mean IOP + S.D. of the eyes on maximum tolerated antiglaucoma therapy was 28.7 2 5.5 mm Hg. When treated with placebo, the mean IOP was 26.4 + 7.8 mm Hg. After one week of timolol therapy, the mean IOP fell to 23.1 2 4.1 mm Hg. This was significantly different from the mean pretreatment IOP (P < .OOl, paired t test) and the placebotreated IOP (P < .025, paired t test). There was a wide range of responses upon adding timolol to maximum medical therapy. When the effect of timolol was corrected for the placebo effect, two patients had increases in IOP, eleven patients had decreases of one to four mm Hg, and live patients had decreases greater than 4 mm Hg. Six patients treated with timolol, as opposed to only three patients treated with placebo, reached IOPs d 21 mm Hg.27 The results of the shortterm study were suffrciently promising to stimulate a longterm study of the addition of timolol to maximum tolerated antiglaucoma therapy.’ Twenty-two patients (33 eyes) had topical timolol 0.1% to 0.5% twice daily added to maximum tolerated medical therapy (in most cases, a topical cholinergic agent, topical epinephrine, and a systemic carbonic anhydrase inhibitor). The concentration of timolol was increased if the IOP was greater than 22 mm Hg. A number of patients had borderline IOP control but no progression of glaucomatous damage and were continued in the proto-
Baseline 1 week 2 weeks l-3 months 4-6 months 7-9 months lo-12 months
5
Tolerated
Medical
Therapy’
Medically treated eyes IOP (mm Hg)
Eyes requiring surgery IOP (mm Hg)
? S.D. (n = 25)
? S.D. n=8
3O.Ok8.2 22.0 ?I 3.7 21.1 -c5.7 21.7k5.4 21.154.3 21.8k5.4 22.3 -t4.3
31.2T9.7 29.0 k9.6 30.1 +-6.9 31.2-t 11.2 -
co1 because the risk of continued medical therapy seemed less than the risk of surgery. Because the patients involved in this study had advanced glaucomatous damage and high IOPs, it was impossible to do a randomized masked study. It was necessary to vary medical regimens to improve IOP control. In some patients, the strength and/or number of medications were decreased as long as IOP remained controlled. Twenty-live of 33 eyes (76%) completed the oneyear follow-up. Only eight eyes (24%) required liltering surgery because of actual or anticipated progressive damage. The mean baseline IOP 2 S.D. for the 33 eyes was 30.3 -+ 8.4 mm Hg. There was no statistically significant difference between the mean IOPs for the eight eyes which required surgery and the 25 which were treated medically for the one-year follow-up (p > .30, student’s t test). However, the two groups responded very differently when timolol was added to the regimen (Table 5). The 25 eyes treated medically had significant and persistent decreases in IOP over the 12 months of the study (P < .0005, paired t test). The mean decrease in IOP + S.D. at the conclusion of the study was 7.7 2 6.9 mm Hg for the 25 eyes not requiring surgery. All 33 eyes had baseline IOPs greater than 22 mm Hg. Thirteen eyes (39%) achieved IOPs d 21 mm Hg at one year on timolol plus maximum tolerated medical therapy. After the addition of timolol, 17 of the 33 eyes (52%) completed the oneyear protocol with final mean IOP decreases greater than 5 mm Hg.’ Currently, the most common indication for laser trabeculoplasty or filtering surgery is the progression of glaucomatous damage while on maximum tolerated medical therapy. The addition of timolol to the medical regimen lowers IOP substantially in one-third to one-half of such eyes. Thus, it may be possible to postpone or avoid surgery in some pa-
COMBINING
TIMOLOL
WITH OTHER ANTIGLAUCOMA
tients previously uncontrolled ed medical therapy.
on maximum
tolerat-
Summary The ocular hypotensive effects of timolol and a carbonic anhydrase inhibitor (acetazolamide or methazolamide) are partially additive. Similarly, concurrent administration of timolol and a miotic agent (pilocarpine, carbachol, or echothiophate iodide) produces a clinically useful reduction of IOP in most patients. In contrast, the ocular hypotensive effects of timolol and epinephrine are poorly additive. Ophthalmologists prescribing timolol or epinephrine for patients receiving the other drug are urged to use a therapeutic trial to one eye for several weeks. The addition of timolol to the medical regimen of patients uncontrolled on maximum tolerated medical therapy reduces IOP substantially in onethird to one-half of the cases.
References
Il.
12.
13.
14. 15.
16. 17.
18.
19.
20.
I. Ashburn
2. 3.
4.
5.
6.
FS, Gillespie JE, Kass MA, Becker B: Tim&l plus maximum tolerated medical therapy: a one-year follow-up study. Surv Ophthalmol 23:38%394, 1979 Becker B: Decrease in intraocular pressure by a carbonic anhydrase inhibitor, Diamox. Am J Ophthalmol37: 13-15, 1954 Berson FG, Epstein DL: Separate and combined eFfects of timolol maleate and acetazolamide in open-angle glaucoma. Am J O.bhthalmol 92:788-791, 1981 Boger WP III, Puliafito CA, Steinert RF, Langston DP: Longterm experience with timolol ophthalmic solution in patients with open-angle glaucoma. Ophthalmology &5:25%267, 1978 Calissendorff B, Maren N, Wettrell K, Ostberg A: Timolol versus pilocarpine separately or combined with acctazolamide - Effects on intraocular pressure. Acln Ophthalmol58;62~63 I. 1980 Coakes RL, Brubaker RF: The mechanism of timolol in lowering intraocular pressure in the normal eye. Arch Ophthalmol
96:2045-2048,
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26.
1978
MEDICATIONS
279
1980 Kass MA, Korey M, Gordon M, Becker B: Timolol and acetazolamide: A study ofconcurrent administration. Arch Ophthalmol lOOt941-944, 1982 Keates EU: Evaluation of timolol maleate combination therapy in chronic open-angle glaucoma. Am J Ophthalmol 88:565-571, 1979 Keates EU, Stone RA: Safety and efFectiveness of concomitant administration of dipivefrin and timolol maleate. .4m J Ophthalmol91:243-248, 1981 Kerty E, Horven I: Glaucoma treatment with timolol. Acta Ophthalmol56:705-713, 1978 Korey MS, Hodapp E, Kass MA, et al: Timolol and epinephrine. Long-term evaluation of concurrent administration. Arch Ophthalmol 100:742-745, 1982 McCuinnes R, Frumar KD: Timolol and dipivalyl epinephrine combination therapy. Aust J Ophthalmol IO: I7’&182, 1982 Nielsen NV: Hypotensive effect used alone and in combination for treatment of increased intraocular pressure. Acta Ophthalmol 56:504-509, 1978 Nielsen NV. Ericksen JS: Timolol in maintenance treatment of ocular hypertension and glaucoma. Acta Ophthalmol 57: lO7CL 1077, 1979 Ober M, Scharrer A: Timolol and Parasympathicomimetica bei de Behandlung des erhohten intraocularen Druckes. Albrecht van CraeJ& Arch Klin f&p Ophthatmol 211:5%66, 1979 Ostbaum SA, Galin MA, Katz I>i: Timolol: Effect on intraocular pressure in chronic open-angle glaucoma. Ann Ophthalmol IOtl347-1351, 1978 Scharrcr A, Ober M: Timolol und Acetazolomid bei der Behandlung des erhohten intraocularen Druckes. Albrrcht uon Graefes Arch Klin E.xp Ophthalmol 212: 129-134, 1979 Schenker HI, Yablonski ME, Podos SM, Lender I,: Fluorophotometric study of epinephrine and timolol in human sutjrcts. Arch Ophthalmol 99:1212-1216, 1981 Sonty S, Schwartz B: The additive effect of timolol on open angle glaucoma in patients on maximum tolerated medical therapy. Sure Ophthalmol 23:381-388, 1979 Thomas ,JV, Epstein DL: Timolol and epinephrine in primary open-angle glaucoma. Transient additive effect. Arch Ophthalmol 99:91-95, 1981 Yahlonski ME. Zimmerman TJ. \Valtman SR, Becker B: A lluorophotometric study of the effect of topical timolol on aqueous humor dynamics. Ex.6 Eve Res 27:135-142, 1978 Zimmerman TJ, Canale P:-Timolol ~ furthw observations. Ophthalmoloev R6:166-169. 1979 Zimmerman TJ. Gillespie,JE, Kass MA, Yablonski ME, Becker B: Timolol plus maximum tolerated anti-glaucoma therapy. Arch Opthalmol 97:278-279, 1979 L_
7. Cyrlin MN, Thomas JV, Epstein DL: Additive effect of epinephrine to timolol therapy in primary open-angle glaucoma. Arch Ophthalmol 100:414-418, 1982 8. Dailey RA, Brubaker RF, Bourne WM: The effects of timolol maleate and acetazolamide on the rate of aqueous formation in normal human eyes. .4m J Ophthalmol 93:232-237. 1982 9. Goldberg I, Ashburn FS, Palmberg PF, et al: Timolol and epinephrine. A clinical study ofocular interactions. Arch Ophthalmol 98:4&l-486. 1980 IO. Higgins RG, Brubaker RF: Acute eflect ofepinephrine on aqueous humor formation in the timolol-treated normal eye as measured by lluorophotometry. best Ophthalmol 1% Sci 19:42&423,
27.
This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc.. New York, New York. Reprint requests should be addressed to Michael A. Kass, ,M.D., Department of Ophthalmology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis. Missouri 631 IO.