EVALUATION O F T I M O L O L MALEATE COMBINATION THERAPY IN C H R O N I C OPEN-ANGLE GLAUCOMA E D W I N U. K E A T E S , Philadelphia,
Timolol maleate, a new (3-adrenergic blocking agent, has been shown to be effective for reduction of high intraocular pressure (IOP) in patients with openangle glaucoma. 1 " 8 These reports indicate that topical administration of timolol ma leate produces an ocular hypotensive ef fect that is not accompanied by signifi cant local irritation, changes in visual acuity or pupil diameter, or clinically important alterations in pulse or blood pressure. The drug lacks local anesthetic or intrinsic sympathomimetic activity 9 and has shown a duration of action last ing 24 hours. In a double-masked, controlled cross over study of paitents with open-angle glaucoma or ocular hypertension, 6 signif icantly more patients had controlled IOP with timolol maleate 0.1% to 0.5% than with epinephrine 0.5% to 2%. No signifi cant adverse effects occurred during ad ministration of timolol maleate, but in four patients therapy was discontinued because of adverse reactions during treat ment with epinephrine. In an open-label study, Nielsen 7 reported that timolol ma leate 0.25% to 0.5% given alone or with epinephrine or acetazolamide was effec tive for reduction of high IOP. Although its precise mechanism of action is as yet unknown, tonography studies 10 ' 11 have shown no significant change in mean outflow facility during administration of timolol maleate. Fluorophotometric determination of aqueous
From the Department of Ophthalmology, Jeffer son Medical College, Philadelphia, Pennsylvania. Reprint requests to Edwin U. Keates.M.D., Thom as Jefferson Health Sciences Center, 130 S. 9th St., Philadelphia, PA 19107.
M.D.
Pennsylvania
flow coefficients 12 supports the sugges tion that reduced aqueous production could account for the ocular hypotensive effect of timolol maleate. Ideally, the effect of any new antiglaucoma therapy should be additive to that of established regimens to extend the limits of maximal medical treatment. In an eval uation of long-term maintenance therapy, Boger and associates 3 reported that the IOP lowering effect of timolol maleate was additive to that of both miotics and carbonic anhydrase inhibitors in some patients. We report herein a study of the effects of an eight-week treatment with timolol maleate combined with either pilocarpine 2%, epinephrine 2%, carbachol 1.5%, or 500 mg per day of acetazolamide in four groups of patients under treatment for chronic open-angle glaucoma. S U B J E C T S AND M E T H O D S
All patients admitted to this observa tional study had chronic open-angle glau coma and had undergone at least two weeks of current treatment for high IOP with one of the following regimens: pilo carpine 2%, one drop four times a day (Group 1); epinephrine 2%, one drop twice a day (Group 2); carbachol 1.5%, one drop four times a day (Group 3); or 250 mg of acetazolamide taken orally twice a day (Group 4). The diagnosis of chronic open-angle glaucoma was based on high untreated IOP (greater than or equal to 22 mm Hg by Goldmann applanation tonometry) as well as characteristic optic nerve damage, visual field loss, or both. Patients with acute ocular infection or inflammation, or both, within three
AMERICAN JOURNAL O F OPHTHALMOLOGY 88:565-571, 1979
565
566
AMERICAN JOURNAL OF OPHTHALMOLOGY
months, imbedded corneal foreign body within one month, history of active herpetic keratitis or corneal ulcer within three months, any corneal abnormalities preventing reliable applanation tonometry, allergic bronchial asthma or chronic obstructive pulmonary disease, greater than first degree heart block or sinus bradycardia, or history of diabetic retinopathy or any progressive retinal disease were excluded from participation. Also excluded were pregnant or nursing wom en and women of childbearing potential not using reliable contraceptive methods, as well as patients who had worn contact lenses within one month preceding the study. Forty-five patients were admitted to the study after giving their written informed consent. Patients ranged in age from 25 to 81 years; their distribution according to sex and age is shown in Table 1. Chronic open-angle glaucoma, with onset ranging from one month to 28 years, was the primary diagnosis for all patients. Only two patients, one each in Groups 3 and 4, were newly treated glaucoma patients, who received initial therapy with carbachol and acetazolamide, respectively. Secondary diagnoses most frequently ob served were systemic hypertension (22 patients), cataracts (ten), unspecified carTABLE 1 A G E AND SEX DISTRIBUTIONS O F PATIENTS STUDIED
No. of Patients Age Range Group 1 Group 2 Group 3 Group 4 M F M (yrs) 21-30 31-40 41-50 51-60 61-70 71-80 81-90 Total
0 0 0 1 1 2 0 4
0 0 0 0 3 4 0 7
1 0 2 0 1 3 0 7
SEPTEMBER, 1979
diovascular disease (six), and diabetes (four). Within two days of the start of timolol maleate therapy, patients had a complete baseline evaluation, including applana tion tonometry, measurement of visual acuity, pupil size, visual fields, and vital signs, Schirmer test for tear production, and tonography for facility of outflow. Ocular examination included ophthalmoscopy, slit-lamp examination, and ex amination of cornea, conjunctiva, and eyelids. These values, then, represented the effects of the current antiglaucoma regimens, and they are used throughout this report as baseline. On study day 1, patients continued their established antiglaucoma regimens and began eight weeks of concomitant therapy with timolol maleate ophthalmic solution 0.25%, one drop in each eye twice daily. No other concurrent antiglau coma therapy was allowed during the study. Measurements of IOP, visual acu ity, pupil size, and vital signs were re peated after two, four, and eight weeks of combination therapy. Schirmer test, to nography, and evalution of visual fields were performed after eight weeks. At each follow-up visit, any objective signs of ocular irritation were obtained by ophthalmoscopy and examination of cornea, conjunctiva, and eyelids; subjective symp toms of local irritation (for example, headache, blurred vision, burning) were specifically elicited by questioning. At each visit IOP measurements were per formed twice for each eye at least one hour apart, and the readings were aver aged. A mean IOP value was obtained for each patient by averaging results for both eyes. At follow-up visits, IOP readings were made at approximately the same time of day to reduce the effect of diurnal variation. McNemar's test was used to compare the percentage of patients with controlled
VOL. 88, NO. 3, PART II
TIMOLOL MALEATE COMBINATION THERAPY
IOP (
Timolol maleate, a new (3-adrenergic blocking agent, has been shown to be effective for reduction of high intraocular pressure (IOP) in patients with openangle glaucoma. 1 " 8 These reports indicate that topical administration of timolol ma leate produces an ocular hypotensive ef fect that is not accompanied by signifi cant local irritation, changes in visual acuity or pupil diameter, or clinically important alterations in pulse or blood pressure. The drug lacks local anesthetic or intrinsic sympathomimetic activity 9 and has shown a duration of action last ing 24 hours. In a double-masked, controlled cross over study of paitents with open-angle glaucoma or ocular hypertension, 6 signif icantly more patients had controlled IOP with timolol maleate 0.1% to 0.5% than with epinephrine 0.5% to 2%. No signifi cant adverse effects occurred during ad ministration of timolol maleate, but in four patients therapy was discontinued because of adverse reactions during treat ment with epinephrine. In an open-label study, Nielsen 7 reported that timolol ma leate 0.25% to 0.5% given alone or with epinephrine or acetazolamide was effec tive for reduction of high IOP. Although its precise mechanism of action is as yet unknown, tonography studies 10 ' 11 have shown no significant change in mean outflow facility during administration of timolol maleate. Fluorophotometric determination of aqueous
From the Department of Ophthalmology, Jeffer son Medical College, Philadelphia, Pennsylvania. Reprint requests to Edwin U. Keates.M.D., Thom as Jefferson Health Sciences Center, 130 S. 9th St., Philadelphia, PA 19107.
M.D.
Pennsylvania
flow coefficients 12 supports the sugges tion that reduced aqueous production could account for the ocular hypotensive effect of timolol maleate. Ideally, the effect of any new antiglaucoma therapy should be additive to that of established regimens to extend the limits of maximal medical treatment. In an eval uation of long-term maintenance therapy, Boger and associates 3 reported that the IOP lowering effect of timolol maleate was additive to that of both miotics and carbonic anhydrase inhibitors in some patients. We report herein a study of the effects of an eight-week treatment with timolol maleate combined with either pilocarpine 2%, epinephrine 2%, carbachol 1.5%, or 500 mg per day of acetazolamide in four groups of patients under treatment for chronic open-angle glaucoma. S U B J E C T S AND M E T H O D S
All patients admitted to this observa tional study had chronic open-angle glau coma and had undergone at least two weeks of current treatment for high IOP with one of the following regimens: pilo carpine 2%, one drop four times a day (Group 1); epinephrine 2%, one drop twice a day (Group 2); carbachol 1.5%, one drop four times a day (Group 3); or 250 mg of acetazolamide taken orally twice a day (Group 4). The diagnosis of chronic open-angle glaucoma was based on high untreated IOP (greater than or equal to 22 mm Hg by Goldmann applanation tonometry) as well as characteristic optic nerve damage, visual field loss, or both. Patients with acute ocular infection or inflammation, or both, within three
AMERICAN JOURNAL O F OPHTHALMOLOGY 88:565-571, 1979
565
566
AMERICAN JOURNAL OF OPHTHALMOLOGY
months, imbedded corneal foreign body within one month, history of active herpetic keratitis or corneal ulcer within three months, any corneal abnormalities preventing reliable applanation tonometry, allergic bronchial asthma or chronic obstructive pulmonary disease, greater than first degree heart block or sinus bradycardia, or history of diabetic retinopathy or any progressive retinal disease were excluded from participation. Also excluded were pregnant or nursing wom en and women of childbearing potential not using reliable contraceptive methods, as well as patients who had worn contact lenses within one month preceding the study. Forty-five patients were admitted to the study after giving their written informed consent. Patients ranged in age from 25 to 81 years; their distribution according to sex and age is shown in Table 1. Chronic open-angle glaucoma, with onset ranging from one month to 28 years, was the primary diagnosis for all patients. Only two patients, one each in Groups 3 and 4, were newly treated glaucoma patients, who received initial therapy with carbachol and acetazolamide, respectively. Secondary diagnoses most frequently ob served were systemic hypertension (22 patients), cataracts (ten), unspecified carTABLE 1 A G E AND SEX DISTRIBUTIONS O F PATIENTS STUDIED
No. of Patients Age Range Group 1 Group 2 Group 3 Group 4 M F M (yrs) 21-30 31-40 41-50 51-60 61-70 71-80 81-90 Total
0 0 0 1 1 2 0 4
0 0 0 0 3 4 0 7
1 0 2 0 1 3 0 7
SEPTEMBER, 1979
diovascular disease (six), and diabetes (four). Within two days of the start of timolol maleate therapy, patients had a complete baseline evaluation, including applana tion tonometry, measurement of visual acuity, pupil size, visual fields, and vital signs, Schirmer test for tear production, and tonography for facility of outflow. Ocular examination included ophthalmoscopy, slit-lamp examination, and ex amination of cornea, conjunctiva, and eyelids. These values, then, represented the effects of the current antiglaucoma regimens, and they are used throughout this report as baseline. On study day 1, patients continued their established antiglaucoma regimens and began eight weeks of concomitant therapy with timolol maleate ophthalmic solution 0.25%, one drop in each eye twice daily. No other concurrent antiglau coma therapy was allowed during the study. Measurements of IOP, visual acu ity, pupil size, and vital signs were re peated after two, four, and eight weeks of combination therapy. Schirmer test, to nography, and evalution of visual fields were performed after eight weeks. At each follow-up visit, any objective signs of ocular irritation were obtained by ophthalmoscopy and examination of cornea, conjunctiva, and eyelids; subjective symp toms of local irritation (for example, headache, blurred vision, burning) were specifically elicited by questioning. At each visit IOP measurements were per formed twice for each eye at least one hour apart, and the readings were aver aged. A mean IOP value was obtained for each patient by averaging results for both eyes. At follow-up visits, IOP readings were made at approximately the same time of day to reduce the effect of diurnal variation. McNemar's test was used to compare the percentage of patients with controlled
VOL. 88, NO. 3, PART II
TIMOLOL MALEATE COMBINATION THERAPY
IOP (
