Albrecht v. Graefes Arch. klin. exp. Ophthal. 202, 81-86 ( 1977)
Graefes Archiv fLirklinischeundexperimentelle
Ophthalmologie ~ by Springer-Verlag 1977
The Intraocular Pressure Response of Glaucomatous Eyes to Topically Applied Bupranolol A Pilot Study G.K. Krieglstein, J. Sold-Darseff, and W. Leydhecker The Glaucoma Unit of the University Eye Hospital W~Jrzburg (Director: Prof. Dr. Dr. h. c. W. Leydhecker), J osef-Schneider-Str. 11, D-8700 Wfirzburg, Federal Republik of Germany
Summary. Bupranolol 0.5% oily solution applied topically lowered intraocular pressure of glaucomatous eyes significantly. The pressure decrease is related to pretreatment pressure levels. The maximum effect occurred within 4 hours and lasted for more than 24 hours. No objective or subjective irritation could be attributed to the ophthalmic preparation. There was no significant effect on outflow facility, on blood pressure or tear flow. However, bupranolol produces local anesthesia on the eye. The problem of tachyphylaxis is discussed in the treatment of glaucoma with bupranolol eye drops.
Zusammenfassung.Die 61ige L6sung von 0,5% Bupranolol bewirkt bei lokaler Applikation am Auge eine signifikante Augendrucksenkung um durchschnittlich 42 % des Ausgangsdruckes. Das Maximum der Drucksenkung war nach 4 Stunden zu beobachten, die Drucksenkung nach einmaliger Applikation dauerte mehr als 24 Stunden. Die verwendeten Bupranolol-Augentropfen f/ihrten zu keiner Reizung der vorderen Augenabschnitte. Es fand sich kein signifikanter Effekt auf die Abflugleichtigkeit, auf den Blutdruek oder den Tr~inenflug. Bupranolol bewirkt jedoch eine Lokalanaesthesie am Auge. Das Problem eines langsamen Wirkungsverlustes yon BupranololAugentropfen als Glaukom-Therapeutikum wird diskutiert.
I ntroduction Many of the beta-adrenergic blocking compounds widely used in the treatment of coronary diseases were found to lower intraocular pressure of healthy and glaucomatous human eyes after systemic or topical administration (Vale et al., 1972 i Sharaf et al., 1974; Elliot et al., 1975 ; Bonomi and Steindler, 1975 ; Katz et al., 1976). Although the mechanism of action of these drugs on the intraocular pressure is not yet clear, they have attracted
82
G.K. Krieglstein et al. Cl
CH3-C-"H-CH2-CH-CHrO CH3
o.
\
/ CH 3
Bupranolol Fig. 1. Chemical structure of bupranolol
the interest of ophthalmologists because of the lack of side effects on pupillary motility and accommodation. Bupranolol (Butylamino-3-(2-chlor-5-methylphenoxy)-2-propanol) is chemically related to propranolol (Fig. 1) with a stronger potency to block beta-adrenergic receptor sites (Waterloh et al., 1969). Since the drug has turned out to be safe for humans, having been given orally for some years now (Willems et al., 1971), we decided to test its ability to lower intraocular pressure of the glaucomatous eye after topical application.
Methods In a first series of 20 volunteer students, the objective and subjective tolerance of 0,5% bupranolol free base in a sterile oily solution was tested. Biomicroscopy before and 20 min after topical application of the drug preparation was used to determine objective drug tolerance b y the anterior segment of the eye. Each student was asked whether he felt discomfort after the topical application of the oily bupranolol solution. The i.o. pressure changes were not measured in normals, because anesthetics or manipulation of the eyes had to be avoided for testing the tolerance. The same bupranolol preparation was used in a random sample of open-angle glaucoma patients attending the glaucoma unit of the University Eye Hospital, Wfirzburg. Tests were carried out on 27 glaucomatous eyes of 16 patients. None of the patients had antiglaucomatous surgery before. No epinephrine or carboanhydrase inhibitor treatment was used in these patients, cholinergic drugs had been discontinued at least 48 h before the test. All intraocular pressure measurements were performed with a Goldmann applanation tonometer. In 13 of 27 glaucomatous eyes the IOP was followed up for 4 h, in 14 eyes a complete day tension curve over 24 h had been recorded after a single topical application of one drop bupranolol solution. In 4 eyes day tension curves were repeated over 4 days with one drop 0.5% bupranolol on each morning. Indentation tonography had been done in 9 glaucomatous eyes before and 120 minutes after the bupranolol administration (Elektronischer Schi6tz Tonograph; Chemie Griinenthal, Stolberg). Systolic and diastolic blood pressures were measured with a sphygmomanometer in four glaucoma patients after the topical application of bupranolol. Measurements were repeated every 30 minutes after treatment over 5 h. In three healthy volunteers the anesthetic properties of 0.5% bupranolol were compared to the local anesthesia produced b y one drop 0.5% proxymetacain (Kerakain R ; Chibret, Miinchen). In another three healthy volunteers the effect of 0.5% bupranolol on tear flow was tested using Schirmer's test on the treated and untreated eye.
Bupranolol and Intraocular Pressure
83
Results
The 0.5% b u p r a n o l o l free base in a sterile oily solution was tolerated well, b o t h objectively and subjectively, b y all test persons. The topical application of 0.5% bupranolol to 27 open-angle glaucoma eyes gave a marked intraocular pressure r e d u c t i o n in all eyes tested. Figure 2 summarizes the day tension curves of 14 g l a u c o m a t o u s eyes after a single
30-
g
~. d
20-
10 I
2
4
,
,
6
8
II
, 24
time (hrs)
Fig. 2. Time course of mean intraocular pressure response to 0.5% bupranolol applied topically to 14 giancomatous eyes. Closed circles indicate arithmetic means, vertical bars the standard errors of means. Bupranolol treatment was given at time zero P0 mmHg
(
15
20
30
40
5O
i
)
10-
"r E
E a. 20-
30-
n=27 Fig. 3. Maximum intraocular pressure responses to 0.5% bupranolol in 27 glaucomatous eyes. Abscissa shows the base line pressure levels, ordinate the maximum effect in each individual eye after single topical application
84
G.K. Krieglstein et el.
a p p l i c a t i o n o f 0.5% b u p r a n o l o l . T h e m a x i m u m of t h e average pressure r e s p o n s e was 4 h a f t e r t r e a t m e n t , b u t t h e r e was a significant residual r e s p o n s e 2 4 h after t r e a t m e n t . T h e individual i n t r a o c u l a r pressure r e s p o n s e s t o t h e b u p r a n o l o l i n s t i l l a t i o n o f t h e 27 eyes studied are p r e s e n t e d in Figure 3. T h e effects varied f r o m
9 % t o 68% pressure r e d u c t i o n
o f t h e p r e t r e a t m e n t pressure levels (42% o n average, m a x i m u m effects 3-5 h a f t e r treatm e n t ) . In f o u r g l a u c o m a p a t i e n t s d a y t e n s i o n curves were r e p e a t e d over 4 days w i t h 1 d r o p 0.5% b u p r a n o l o l in t h e early m o r n i n g o f e a c h day. T h e s e f o u r p a t i e n t s s h o w e d a g r a d u a l decrease of t h e first d a y ' s m a x i m u m r e s p o n s e over t h e 4 - d a y o b s e r v a t i o n p e r i o d (Fig. 4). I n d e n t a t i o n t o n o g r a p h y b e f o r e a n d 120 m i n a f t e r b u p r a n o l o l a p p l i c a t i o n /
in 9
daya 4O-
a.
o 2o110
,
0
,
2
,
4
II
,)
,
9
,
2
4
2
4
time (hrs)
II
,
>
9 tk.e(hrs)
x~ ~ -
~ 0
2
4
9
0
tir~(hrs)
9
time(h~)
Fig. 4. Day tension curves of 4 consecutive days of 56-year-old open-angle glaucoma patient under bupranolol treatment. At time zero (about 8 a.m.) of each day 1 drop of 0.5% bupranolol was applied to both eyes. Closed circles indicate right eye, open circles left eye of patient Table 1. The effect of 1 drop 0.5% bupranolol on the facility of outflow of 9 glaucomatous eyes. The coefficient of outflow facility was calculated before and 120 min after topical treatment with bupranolol. Individual results and mean values with standard deviations are presented No. of eye
C (ul/min/mm Hg) Before treatment
120 min after treatment
1. 2. 3. 4. 5. 6. 7. 8. 9.
0.08 0.24 0.15 0.05 0.05 0.13 0.05 0.13 0.11
0.12 0.17 0.33 0.12 0.08 0.17 0.05 0.28 0.15
m -+ Sd
0.11 _+0.06
0.16 _+0.09
Bupranolol and Intraocular Pressure
85
eyes revealed little effect on the facility of outflow (Table 1). The average pretreatment facility improved from 0.11 + 0.06 to 0.16 + 0.09 ul/min/mm Hg, which is of no statistical relevance. Systolic and diastolic blood pressures were not affected within 5 h after bupranolol treatment. There is no doubt that bupranolol has local anesthetic porperties on the eye. Suppression of the corneal reflex after bupranolol lasted for about 15 min and was less intensive than after application of proxymetacain. The drug exhibited no effect on tear flow in the acute experiment when Schirmer's test was chosen methodically.
Comment
An oily solution of 0.5% bupranolol is well tolerated b y the eye when applied topically. There was no discomfort reported by the test persons, nor could any ocular irritation be detected by biomicroscopy. The membrane-stabilizing characteristic of this drug, made it useful in the treatment of cardiac dysrhythmia but in the same way it produces local anesthesia on the eye. This is an aspect of great importance to be considered before the drug is left in the hands of the patient for long-term glaucoma therapy. The ability of topically applied bupranolol to lower intraocular pressure in the glaucomatous eye was very impressive. IOP in all the 27 glaucomatous eyes tested in this pilot study responded welt, with a maximum effect up to 68% of the pretreatment pressure level. In one patient lOP came down from 47 to 15 mm Hg after a single application of 0.5% bupranolol. This was far more than could be achieved in this patient with any cholinergic drug. The maximum effect usually occurred after 3-4 h and lasted more than 24 h. In this respect the drug obviously behaves differently from its action in the heart, where the duration of action is on the average 9 h after a single intravenous dose (Willems et al., 1971). The attempt to reproduce the time course and magnitude of action on the basis of repeated treatment exhibited partial loss of action within 4 days. This points out that tachyphylaxis may be one of the major problems of this drug as an antiglaucomatous agent. The effect of bupranolol on intraocular pressure cannot be explained by a corresponding increase of facility of outflow. It seems probable that inflow is involved much more as has been suggested for the beta-blocking pindolol (Bonomi and Steindler, 1976). The absence of an effect on tear flow in the acute experiment is encouraging but no guarantee that bupranolol will not produce dry eye syndromes in long-term treatment as it was reported with practolol, another beta-blocking compound (Rahi et al., 1976). The topical application of 0.5% bupranolol on the eye did not change systemic blood pressure. Obviously the amount of drug absorbed into circulation is not enough to produce cardiodepression. In the light of these results, the IOP response of bupranolol offers an important alternative to cholinergic drugs. However, before further consideration for clinical routine the problems implicated in the anesthetic properties of the agent and the role of tachyphylaxis must be cleary elucidated. The authors are indebted to Dr. Winzer, chem.-pharm. Fabrik, Konstanz, for a generous supply of bupranolol in oily solution (OphthoreninR), and to Ms. E. Profitlich for able technical assistance.
86
G.K. Krieglsteinet al.
R eferences
Bonomi, I., Steindler, P.: Effect of pindolol on intraocular pressure. Brit. J. Ophthal. 59,301-303 (1975) Elliot, M.J., Cullen, P.M., Philipps, C.I.: Ocular hypotensive effect of atenolol (Tenormin, I.C.I.). Brit. J. Ophthal. 59,296-300 (1975) Katz, I.M., Hubbard, W.A., Getson, A.J., Gould, A.L.: Intraocular pressure decrease in normal volunteers following timolol ophthalmic solution. Invest. Ophthal. 15, 489-492 (1976) Rahi, A.H.S., Chapman, C.M., Gerner, A., Wright, P.: Pathology of practolol-induced ocular toxicity. Brit. J. Ophthal. 60, 312-323 (1976) Sharaf, E.D., Haroun, E.A., Ishaac, Z., E1 Shewy, T.M., Nassel, A.E.H. : The effect of some/3-adrenergic blockers on human intraocular pressure. Exp. Eye Res. 19,223225 (1974) Vale, J., Gibbs, A.C.C., Philipps, C.I.: Topical propranolol and ocular tension in the human. Brit. J. Ophthal. 56,770-775 (1972) Waterloh, E., Rittel, H.-F., Leide, E.: Untersuchungen fiber 1-(6'-Chlor-3'-methylphenoxy) 3-tert.-butylamino-propan-2-ol-hydrochlorid (KL 255). Arzneimittel-Forsch. 19, 153--156,330-333 (1969) Willems, D., Frisch, P., Klepzig, H. : Behandlung yon Angina pectoris und Herzrhytmusst6rungen mit einem Beta-Rezeptorenblocker. Zeitschr. Kreislaufforsch. 6 0 , 3 0 9 318 (1971) Received December 13, 1976
Graefes Archiv fLirklinischeundexperimentelle
Ophthalmologie ~ by Springer-Verlag 1977
The Intraocular Pressure Response of Glaucomatous Eyes to Topically Applied Bupranolol A Pilot Study G.K. Krieglstein, J. Sold-Darseff, and W. Leydhecker The Glaucoma Unit of the University Eye Hospital W~Jrzburg (Director: Prof. Dr. Dr. h. c. W. Leydhecker), J osef-Schneider-Str. 11, D-8700 Wfirzburg, Federal Republik of Germany
Summary. Bupranolol 0.5% oily solution applied topically lowered intraocular pressure of glaucomatous eyes significantly. The pressure decrease is related to pretreatment pressure levels. The maximum effect occurred within 4 hours and lasted for more than 24 hours. No objective or subjective irritation could be attributed to the ophthalmic preparation. There was no significant effect on outflow facility, on blood pressure or tear flow. However, bupranolol produces local anesthesia on the eye. The problem of tachyphylaxis is discussed in the treatment of glaucoma with bupranolol eye drops.
Zusammenfassung.Die 61ige L6sung von 0,5% Bupranolol bewirkt bei lokaler Applikation am Auge eine signifikante Augendrucksenkung um durchschnittlich 42 % des Ausgangsdruckes. Das Maximum der Drucksenkung war nach 4 Stunden zu beobachten, die Drucksenkung nach einmaliger Applikation dauerte mehr als 24 Stunden. Die verwendeten Bupranolol-Augentropfen f/ihrten zu keiner Reizung der vorderen Augenabschnitte. Es fand sich kein signifikanter Effekt auf die Abflugleichtigkeit, auf den Blutdruek oder den Tr~inenflug. Bupranolol bewirkt jedoch eine Lokalanaesthesie am Auge. Das Problem eines langsamen Wirkungsverlustes yon BupranololAugentropfen als Glaukom-Therapeutikum wird diskutiert.
I ntroduction Many of the beta-adrenergic blocking compounds widely used in the treatment of coronary diseases were found to lower intraocular pressure of healthy and glaucomatous human eyes after systemic or topical administration (Vale et al., 1972 i Sharaf et al., 1974; Elliot et al., 1975 ; Bonomi and Steindler, 1975 ; Katz et al., 1976). Although the mechanism of action of these drugs on the intraocular pressure is not yet clear, they have attracted
82
G.K. Krieglstein et al. Cl
CH3-C-"H-CH2-CH-CHrO CH3
o.
\
/ CH 3
Bupranolol Fig. 1. Chemical structure of bupranolol
the interest of ophthalmologists because of the lack of side effects on pupillary motility and accommodation. Bupranolol (Butylamino-3-(2-chlor-5-methylphenoxy)-2-propanol) is chemically related to propranolol (Fig. 1) with a stronger potency to block beta-adrenergic receptor sites (Waterloh et al., 1969). Since the drug has turned out to be safe for humans, having been given orally for some years now (Willems et al., 1971), we decided to test its ability to lower intraocular pressure of the glaucomatous eye after topical application.
Methods In a first series of 20 volunteer students, the objective and subjective tolerance of 0,5% bupranolol free base in a sterile oily solution was tested. Biomicroscopy before and 20 min after topical application of the drug preparation was used to determine objective drug tolerance b y the anterior segment of the eye. Each student was asked whether he felt discomfort after the topical application of the oily bupranolol solution. The i.o. pressure changes were not measured in normals, because anesthetics or manipulation of the eyes had to be avoided for testing the tolerance. The same bupranolol preparation was used in a random sample of open-angle glaucoma patients attending the glaucoma unit of the University Eye Hospital, Wfirzburg. Tests were carried out on 27 glaucomatous eyes of 16 patients. None of the patients had antiglaucomatous surgery before. No epinephrine or carboanhydrase inhibitor treatment was used in these patients, cholinergic drugs had been discontinued at least 48 h before the test. All intraocular pressure measurements were performed with a Goldmann applanation tonometer. In 13 of 27 glaucomatous eyes the IOP was followed up for 4 h, in 14 eyes a complete day tension curve over 24 h had been recorded after a single topical application of one drop bupranolol solution. In 4 eyes day tension curves were repeated over 4 days with one drop 0.5% bupranolol on each morning. Indentation tonography had been done in 9 glaucomatous eyes before and 120 minutes after the bupranolol administration (Elektronischer Schi6tz Tonograph; Chemie Griinenthal, Stolberg). Systolic and diastolic blood pressures were measured with a sphygmomanometer in four glaucoma patients after the topical application of bupranolol. Measurements were repeated every 30 minutes after treatment over 5 h. In three healthy volunteers the anesthetic properties of 0.5% bupranolol were compared to the local anesthesia produced b y one drop 0.5% proxymetacain (Kerakain R ; Chibret, Miinchen). In another three healthy volunteers the effect of 0.5% bupranolol on tear flow was tested using Schirmer's test on the treated and untreated eye.
Bupranolol and Intraocular Pressure
83
Results
The 0.5% b u p r a n o l o l free base in a sterile oily solution was tolerated well, b o t h objectively and subjectively, b y all test persons. The topical application of 0.5% bupranolol to 27 open-angle glaucoma eyes gave a marked intraocular pressure r e d u c t i o n in all eyes tested. Figure 2 summarizes the day tension curves of 14 g l a u c o m a t o u s eyes after a single
30-
g
~. d
20-
10 I
2
4
,
,
6
8
II
, 24
time (hrs)
Fig. 2. Time course of mean intraocular pressure response to 0.5% bupranolol applied topically to 14 giancomatous eyes. Closed circles indicate arithmetic means, vertical bars the standard errors of means. Bupranolol treatment was given at time zero P0 mmHg
(
15
20
30
40
5O
i
)
10-
"r E
E a. 20-
30-
n=27 Fig. 3. Maximum intraocular pressure responses to 0.5% bupranolol in 27 glaucomatous eyes. Abscissa shows the base line pressure levels, ordinate the maximum effect in each individual eye after single topical application
84
G.K. Krieglstein et el.
a p p l i c a t i o n o f 0.5% b u p r a n o l o l . T h e m a x i m u m of t h e average pressure r e s p o n s e was 4 h a f t e r t r e a t m e n t , b u t t h e r e was a significant residual r e s p o n s e 2 4 h after t r e a t m e n t . T h e individual i n t r a o c u l a r pressure r e s p o n s e s t o t h e b u p r a n o l o l i n s t i l l a t i o n o f t h e 27 eyes studied are p r e s e n t e d in Figure 3. T h e effects varied f r o m
9 % t o 68% pressure r e d u c t i o n
o f t h e p r e t r e a t m e n t pressure levels (42% o n average, m a x i m u m effects 3-5 h a f t e r treatm e n t ) . In f o u r g l a u c o m a p a t i e n t s d a y t e n s i o n curves were r e p e a t e d over 4 days w i t h 1 d r o p 0.5% b u p r a n o l o l in t h e early m o r n i n g o f e a c h day. T h e s e f o u r p a t i e n t s s h o w e d a g r a d u a l decrease of t h e first d a y ' s m a x i m u m r e s p o n s e over t h e 4 - d a y o b s e r v a t i o n p e r i o d (Fig. 4). I n d e n t a t i o n t o n o g r a p h y b e f o r e a n d 120 m i n a f t e r b u p r a n o l o l a p p l i c a t i o n /
in 9
daya 4O-
a.
o 2o110
,
0
,
2
,
4
II
,)
,
9
,
2
4
2
4
time (hrs)
II
,
>
9 tk.e(hrs)
x~ ~ -
~ 0
2
4
9
0
tir~(hrs)
9
time(h~)
Fig. 4. Day tension curves of 4 consecutive days of 56-year-old open-angle glaucoma patient under bupranolol treatment. At time zero (about 8 a.m.) of each day 1 drop of 0.5% bupranolol was applied to both eyes. Closed circles indicate right eye, open circles left eye of patient Table 1. The effect of 1 drop 0.5% bupranolol on the facility of outflow of 9 glaucomatous eyes. The coefficient of outflow facility was calculated before and 120 min after topical treatment with bupranolol. Individual results and mean values with standard deviations are presented No. of eye
C (ul/min/mm Hg) Before treatment
120 min after treatment
1. 2. 3. 4. 5. 6. 7. 8. 9.
0.08 0.24 0.15 0.05 0.05 0.13 0.05 0.13 0.11
0.12 0.17 0.33 0.12 0.08 0.17 0.05 0.28 0.15
m -+ Sd
0.11 _+0.06
0.16 _+0.09
Bupranolol and Intraocular Pressure
85
eyes revealed little effect on the facility of outflow (Table 1). The average pretreatment facility improved from 0.11 + 0.06 to 0.16 + 0.09 ul/min/mm Hg, which is of no statistical relevance. Systolic and diastolic blood pressures were not affected within 5 h after bupranolol treatment. There is no doubt that bupranolol has local anesthetic porperties on the eye. Suppression of the corneal reflex after bupranolol lasted for about 15 min and was less intensive than after application of proxymetacain. The drug exhibited no effect on tear flow in the acute experiment when Schirmer's test was chosen methodically.
Comment
An oily solution of 0.5% bupranolol is well tolerated b y the eye when applied topically. There was no discomfort reported by the test persons, nor could any ocular irritation be detected by biomicroscopy. The membrane-stabilizing characteristic of this drug, made it useful in the treatment of cardiac dysrhythmia but in the same way it produces local anesthesia on the eye. This is an aspect of great importance to be considered before the drug is left in the hands of the patient for long-term glaucoma therapy. The ability of topically applied bupranolol to lower intraocular pressure in the glaucomatous eye was very impressive. IOP in all the 27 glaucomatous eyes tested in this pilot study responded welt, with a maximum effect up to 68% of the pretreatment pressure level. In one patient lOP came down from 47 to 15 mm Hg after a single application of 0.5% bupranolol. This was far more than could be achieved in this patient with any cholinergic drug. The maximum effect usually occurred after 3-4 h and lasted more than 24 h. In this respect the drug obviously behaves differently from its action in the heart, where the duration of action is on the average 9 h after a single intravenous dose (Willems et al., 1971). The attempt to reproduce the time course and magnitude of action on the basis of repeated treatment exhibited partial loss of action within 4 days. This points out that tachyphylaxis may be one of the major problems of this drug as an antiglaucomatous agent. The effect of bupranolol on intraocular pressure cannot be explained by a corresponding increase of facility of outflow. It seems probable that inflow is involved much more as has been suggested for the beta-blocking pindolol (Bonomi and Steindler, 1976). The absence of an effect on tear flow in the acute experiment is encouraging but no guarantee that bupranolol will not produce dry eye syndromes in long-term treatment as it was reported with practolol, another beta-blocking compound (Rahi et al., 1976). The topical application of 0.5% bupranolol on the eye did not change systemic blood pressure. Obviously the amount of drug absorbed into circulation is not enough to produce cardiodepression. In the light of these results, the IOP response of bupranolol offers an important alternative to cholinergic drugs. However, before further consideration for clinical routine the problems implicated in the anesthetic properties of the agent and the role of tachyphylaxis must be cleary elucidated. The authors are indebted to Dr. Winzer, chem.-pharm. Fabrik, Konstanz, for a generous supply of bupranolol in oily solution (OphthoreninR), and to Ms. E. Profitlich for able technical assistance.
86
G.K. Krieglsteinet al.
R eferences
Bonomi, I., Steindler, P.: Effect of pindolol on intraocular pressure. Brit. J. Ophthal. 59,301-303 (1975) Elliot, M.J., Cullen, P.M., Philipps, C.I.: Ocular hypotensive effect of atenolol (Tenormin, I.C.I.). Brit. J. Ophthal. 59,296-300 (1975) Katz, I.M., Hubbard, W.A., Getson, A.J., Gould, A.L.: Intraocular pressure decrease in normal volunteers following timolol ophthalmic solution. Invest. Ophthal. 15, 489-492 (1976) Rahi, A.H.S., Chapman, C.M., Gerner, A., Wright, P.: Pathology of practolol-induced ocular toxicity. Brit. J. Ophthal. 60, 312-323 (1976) Sharaf, E.D., Haroun, E.A., Ishaac, Z., E1 Shewy, T.M., Nassel, A.E.H. : The effect of some/3-adrenergic blockers on human intraocular pressure. Exp. Eye Res. 19,223225 (1974) Vale, J., Gibbs, A.C.C., Philipps, C.I.: Topical propranolol and ocular tension in the human. Brit. J. Ophthal. 56,770-775 (1972) Waterloh, E., Rittel, H.-F., Leide, E.: Untersuchungen fiber 1-(6'-Chlor-3'-methylphenoxy) 3-tert.-butylamino-propan-2-ol-hydrochlorid (KL 255). Arzneimittel-Forsch. 19, 153--156,330-333 (1969) Willems, D., Frisch, P., Klepzig, H. : Behandlung yon Angina pectoris und Herzrhytmusst6rungen mit einem Beta-Rezeptorenblocker. Zeitschr. Kreislaufforsch. 6 0 , 3 0 9 318 (1971) Received December 13, 1976
