Drug Evaluation

Drugs 40 ( I): 75-90, 1990 0012-666 7/90/0007 -0075/$08.00/0 © Adis International Limited All rights reserved. DREND2094.

Ocular Betaxolol

A Review of its Pharmacological Properties, and Therapeutic Efficacy in Glaucoma and Ocular Hypertension Micaela M.-T. Buckley, Karen L. Goa and Stephen P. Clissold Adis Drug Information Services, Auckland, New Zealand

Various sections of the manuscript reviewed by: J.M. Atkins, Division of Cardiology, Department oflnternal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA; H. Bleckmann, Department of Ophthalmology, Akademisches Lehrkrankenhaus der Freien Universitat Berlin, West Germany; B. Brogliatti, Department of Ophthalmology, University of Turin, Turin, Italy; A.M.V. Brooks, Glaucoma Investigation and Research Unit, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; J.B. Clark, Glaucoma Investigation and Research Unit, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; K. Dickstein, Cardiology Department, Central Hospital in Rogaland, Stavangen, Norway; W.E. Gillies, Glaucoma Investigation and Research Unit, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; F.e. Hugues, Laboratorie de Therapeutique Appliquee, Service de Medecine Interne, Hopital Laennec, Paris, France; I .H. Leopold, Department of Ophthalmology, University of California, Irvine, California, USA; J. Pecori-Giraldi, Department of Ophthalmology, ~niversity of Rome, Rome, Italy; e.l. Phillips, Ophthalmology Unit, University Department of Surgery, University of Edinburgh, Edinburgh, Scotland; K. Segawa, Department of Ophthalmology, Shinshu University School of Medicine, Nagano-ken, Japan; P. Turner, Department of Clinical Pharmacolo~y, St Bartholomew's Hospital Medical College, University of London, London, England.

Contents

Summary ..................................................................................................................................... 76 I. Pharmacodynamic Properties .................................. .............................................................. 78 1.1 Effect on Intraocular Pressure ........................................................................................ 78 1.2 Other Ocular Effects .................................................... .. ........................ .......................... 78 1.3 Systemic Acti vity ............................. ............................ .. .................................................. 79 1.3. 1 Bronchopulmonary Effects ................. ............................................. ....................... 80 1.3.2 Cardiovascular Effects ........................................................................... ................. 81 1.3.3 CNS Effects ...............................................................•.............................................. 81 1.4 Mechanism of Action ...................................................................................................... 82 2. Pharmacokinetic Properties ................................................................................................... 83 2.1 Absorption and Distribution ........................................................................................... 83 2.2 Metabolism and Excretion .............................................................................................. 83 3. Therapeutic Trials .................................................................................................................. 84

Drugs 40 (I) 1990

76

3.1 Noncomparative Trials .................................................................................................... 84 3.2 Comparisons with Placebo .............................................................................................. 85 3.3 Comparisons with Timolol ............................................................................................. 86 3.4 Combination Use with Other Agents ............................................................................. 86 4. Adverse Effects ....................................................................................................................... 86 5. Dosage and Administration ................................................................................................... 88 6. Place of Betaxolol in Therapy ............................................................................................... 88

Summary Synopsis

Betaxolol is a lipophilic fJ-adrenoceptor antagonist relatively selective for fJl-adrenoceptors with only weak fJ2-blocking activity. Used topically in glaucoma and ocular hypertension. betaxolol 0.5% solution produces a reduction in intraocular pressure of between 13 and 30%. an e.ffect comparable with that of ocular timolo!' It may use.fully be combined with other types of anti-glaucoma agents. The most notable feature of its adverse e.ffect profile is transient local stinging or irritation. occurring in 25 to 40% ofpatients. Following ocular administration. betaxolol appears to be largely devoid ofadverse bronchopulmonary or cardiac e.ffects. in comparison with nonselective ocular fJ-adrenoceptor antagonists. which may be more likely to exert systemic effects. Betaxolol has negligible local anaesthetic activity. so that corneal desensitisation does not occur with its use. Thus. betaxolol is an alternative therapeutic option available to the physician for the management of chronic open-angle glaucoma and ocular h.vpertension. Its apparently lower propensity to affect the cardiopulmonary system represents a significant advantage over other ocular fJ-adrenoceptor antagonists.

Pharmacodynamic Properties

Betaxolol is a lipid-soluble (lipophilic) ~-adrenoceptor antagonist which is relatively cardioselective, with no intrinsic sympathomimetic activity and little or no membrane stabilising activity. In common with other ocular ~-adrenoceptor antagonists, the mechanism of the reduction in intraocular pressure observed with betaxolol is generally considered to be decreased production of aqueous humour by the ciliary body, with no apparent effect on aqueous outflow. The precise mechanism of this effect remains to be elucidated. Retinal and ciliary perfusion pressures in patients have been reported to be unaltered by betaxolol treatment. Betaxolol 0.5% was less toxic to regenerating corneal epithelium in rabbits than was timolol 0.5% or levobunolol 0.5%. Similarly, corneal healing rates were faster with betaxolol (and levobunolol) than with timolol. Although ocularly administered betaxolol may be absorbed from the nasopharyngeal and conjunctival mucosa into the systemic circulation, betaxolol appears to possess minimal systemic ~-blocking activity - approximately 5% that of timolol in I radioreceptor assay in rabbits. Ocular betaxolol also failed to antagonise the isoprenaline-induced increase in heart rate in monkeys, an index of systemic ~-blockade. Betaxolol appears to have less propensity for adverse effects on pulmonary function than nonselective ocular ~-adrenoceptor antagonists. In studies in patients with respiratory disease or timolol-induced bronchoconstriction, betaxolol has not had any effect on FEY" forced vital capacity, or relative forced expiratory volume. However, in an investigation in 85 patients followed for up to 2 years, symptomatic pulmonary obstruction was apparent in 5 patients after I to 554 days' betaxolol treatment. All patients had glaucoma and chronic obstructive pulmonary disease, asthma, or timolol-induced bronchoconstriction at baseline. In I study, no statistically significant difference was apparent between betaxolol and placebo in the histamine concentration necessary to produce a 15 to 20% reduction in FEY,. Despite its cardioselectivity, betaxolol has had minimal effects on resting or exercise

Ocular Betaxolol: A Review

77

heart rate, blood pressure or double product, after ocular administration, in several placebo-controlled studies. This is in contrast to timolol, which effects significant reductions . in these parameters. In I study in healthy volunteers, the incidence of CNS effects, including insomnia, depression, hypochondriasis and hysteria, tended to be less with betaxolol than with timolol. In 2 further studies, 16 of 18, and 5 of 7 patients experiencing CNS effects while receiving timolol improved after betaxolol treatment. Pharmacokinetic Properties

There are no published data detailing the pharmacokinetic properties of betaxolol following ocular administration in humans; such information is important to assess the extent of systemic availability. The bioavailability of oral betaxolol is 80 to 90% - it does not undergo extensive first pass metabolism. Excretion is mainly via O-dealkylation followed by aliphatic hydroxylation, yielding 2 major inactive metabolites. Betaxolol and its metabolites are excreted renally with an elimination half-life of between 14 and 22 hours, which is prolonged in neonates and the elderly. Total body clearance does not appear to be affected by liver disease but is reduced in patients with severe renal failure.

Therapeutic Trials

In comparisons with placebo, betaxolol has proven superior in reducing intraocular pressure. Mean reductions have ranged between 13 and 27% with betaxolol compared with about 2 to 13% with placebo. Trials comparing betaxolol with timolol reported reductions in intraocular pressure at the end of 6 months' treatment of between 26 and 36% with betaxolol, and between 29 and 37% with timolol. These 3 trials involved a total of 10 I patients. In a noncomparative trial a reduction of intraocular pressure was obtained within several hours of instillation of betaxolol 0.25%, was maximal at 2 weeks, at 30 to 35%, and was sustained for the duration of the study (I year). In a second noncomparative trial, patients previously administered pilocarpine showed a nonsignificant reduction in intraocular pressure of 8.4% following substitution with betaxolol; in newly diagnosed patients, mean diurnal intraocular pressure was significantly reduced with betaxolol by 17%. In 17 of 20 patients with open-angle glaucoma or ocular hypertension receiving betaxolol 0.5% alone (n = 15) or in combination with pilocarpine (n = 5), who had been treated with timolol, an additional mean reduction in intraocular pressure of 2.4mm Hg was apparent after 2 weeks, and was maintained for the 12 weeks of study. In specific investigations of combination use, betaxolol therapy resulted in small incremental reductions in intraocular pressure over those obtained with other monotherapies. After 2 weeks' treatment with dipivefrine 0.1% alone, intraocular pressure was reduced by 12%, and addition of betaxolol resulted in a total reduction of 15% at 4 weeks. Betaxolol 0.5% twice daily added to oral acetazolamide resulted in an incremental reduction in outflow pressure (intraocular pressure minus an episcleral venous pressure assumed to be IOmm Hg) of 17.6%. With acetazolamide alone the reduction was 42.5%. With betaxolol alone the reduction was 27.3% below baseline, decreased by an additional 35.1% with acetazolamide.

Adverse Effects

The most frequent adverse effect of topical betaxolol treatment is transient local irritation, which occurs in 25 to 40% of patients. A double-blind comparison indicated a higher incidence of ocular symptoms with betaxolol (89%), than with timolol (48%). Ocular symptoms reported include burning, stinging or irritation, pruritus, hyphaemia, vitreous separation and blurred vision. As a cardioselective agent, betaxolol is less likely to be associated with adverse respiratory effects than nonselective t/-adrenoceptor antagonists. While adverse respiratory effects have been observed in a small number of patients with underlying respiratory disease followed for up to 2 years on betaxolol, their relationship to treatment is uncertain. Of a total of 56 spontaneous reports of adverse drug experience attributed to betaxolol during its first year of marketing in the US, postmarketing surveillance identified II cases of asthma, 8 requiring hospitalisation. During a clinical trial in 101 patients treated with betaxolol for up to 2 years, cardiac

78

Drugs 40 (/) 1990

arrhythmia and shortness of breath occurred in I patient and bundle branch block in a second. There are case reports describing myocardial infarction, sinus arrest, and congestive heart failure in association with ocular betaxolol. Of the 56 spontaneous reports mentioned above, there were 4 instances of bradycardia, I with syncope, and I of cardiac arrhythmia. Other adverse effects reported in association with ocular betaxolol include depression, disorientation, vertigo and sleepwalking; and rhinitis, dysuria, alopecia, and prolonged prothrombin time. Dosage and Administration

The recommended dosage of ocular betaxolol in glaucoma or ocular hypertension is one drop of 0.5% solution in each eye twice daily.

1. Pharmacodynamic Properties Betaxolol is a lipid-soluble (lipophilic) phenoxypropanolamine {1-adrenoceptor antagonist (Manoury 1983; fig. I). The drug is relatively selective for cardiac ({1d receptors with only weak {12-blocking activity (Boudot et al. 1979; Palminteri & Kaik 1983; Riddell & Shanks 1985), no partial agonist (intrinsic sympathomimetic) activity (Boudot et al. 1979; Cavero & Lefevre-Borg 1983b) and little or no local anaesthetic (membrane stabilising) activity (Cavero & Lefevre-Borg 1983a). Table I compares the properties of betaxolol with those of other {1-adrenoceptor antagonists shown to reduce intraocular pressure (lOP). This review specifically addresses the role of ocular betaxolol in glaucoma and ocular hypertension. The use of orally administered betaxolol has been described in a previous review (Beresford &

Heel 1986), and for the most part will not be discussed further. 1.1 Effect on Intraocular Pressure Kitazawa et al. (1989) reported a double-blind crossover study in 12 patients with primary openangle glaucoma or ocular hypertension, which used betaxolol ophthalmic solution at 0.25, 0.5 and 1.0%; 12 hours after instillation, lOP was significantly decreased (p < 0.05) by 10%, 15% and 21 % at these respective concentrations. (The rather large incremental response to increasing doses of betaxolol apparent in this study requires further substantiation.) 1.2 Other Ocular Effects Betaxolol 0.5% instilled in rabbit eyes was less toxic to regenerating corneal epithelium than timolol 0.5% or levobunolol 0.5% (Liu et al. 1987; OCOCH3

CH3~CH3

y

H3 CH34 OCH29HCH2NHyH OH CH3 Metipranolol

r\ 0\.....JN

N,,8... N

J!--ll

yH3

CHCOOH OCH2CHCH2NHC-CH3·11 6H tH3 CHCOOH Timolol maleate

~

y

~

H3

OCH2CHCH2NHC-CH3 ·HCI bH

6H3

Levobunolol hydrochloride

Fig. 1. Structures of betaxolol hydrochloride and some other ocular ,6-adrenoceptor antagonists.

79

Ocular Betaxolol: A Review

Table I. Properties of some {3-adrenoceptor antagonists which have been shown to reduce intraocular pressure (after Bartsch et al. 1977; Dausch et al. 1983)

Drug

Atenolol Betaxolol Bupranolol Metipranolol Oxprenolol Pindolol Practolol Propranolol Timolol Levobunolol

Intrinsic sympathomimetic activity

Cardioselectivity

Membrane stabilising activity

+ + + + + +

+ +

Trope et al. 1988). Corneal healing rates at 48 to 96 hours were similar with betaxolol and levobunolol, and were faster with these 2 agents than with timolol in rabbit eyes burned with proparacaine (Trope et al. 1988). At day 16, all corneas treated with betaxolol healed without evidence of epithelial damage, whereas levobunolol-treated eyes showed some desquamation and loss of epithelial microvilli, and more extensive damage was evident in the timolol group. Liu et al. (1989) reported that betaxolol 0.5% produced less toxicity to rabbit corneal endothelium than timolol 0.5% or levobunolol 0.5%, in cornea with epithelial damage, and after penetrating keratoplasty. Elevated intraocular pressure may not be the only pathogenetic factor resulting in the optic nerve damage associated with glaucoma; aberrant blood supply to the optic disc may also be implicated. Pillunat and Stodtmeister (1988) investigated the effect of betaxolol and other ocular J3-adrenoceptor antagonists on ocular perfusion pressure in patients. As there is an inverse relationship between lOP and ocular perfusion pressure, reduction of intraocular pressure in patients with glaucoma could be therapeutically disadvantageous if the drug used affects the blood supply to the optic nerve. These authors found no alteration in retinal or ciliary perfusion pressure, despite significant decreases in lOP with betaxolol 0.5% (n = 10), timolol 0.5% (n = 10), pilocarpine 2.0% (n = 10), and oral acetazol-

+

Relative potency as {3adrenoceptor antagonist (propranolol = 1) 4.0 1.0 0.4 1.8 10.3 2.5 0.2 1.0 4.7 14.6

amide 750mg (n = 10). However, carteolol 2.0% slightly decreased ocular perfusion pressure. J32-Adrenoceptors have been identified on human retinal arteries and veins (data on file, Alcon Laboratories Inc.); studies in the uveal vasculature of rabbits indicate that timolol produces a statistically significant vasoconstriction, while betaxolol has only a small nonsignificant effect, probably due to a greater effect of timolol at J32-receptors (Van Buskirk 1989). 1.3 Systemic Activity It is well recognised that ocularly administered drugs may traverse the nasolacrimal duct and be absorbed from the nasopharyngeal and conjunctival mucosa into the systemic circulation, to exhibit more general pharmacological activity. Thus, concentrations obtained with a topically applied 13adrenoceptor antagonist may be sufficient to cause systemic J3-blockade (Allen & Epstein 1986; Atkins et al. 1985). In general, the potential for ocular 13adrenoceptor antagonists to cause significant systemic effects, and the nature of those effects, represent a complex interaction between the drug's receptor binding properties, potency of action, and physicochemical properties determining its pharmacokinetic profile. Radioligand binding assays in animals have indicated the degree of systemic 13blocking activity with betaxolol 0.5% to be minor,

80

approximately 5% that of timolol (Bloom et al. 1986; Polansky & Alvarado 1985). Similarly, an in vivo study in monkeys showed marked inhibition of isoprenaline (isoproterenol)-induced tachycardia (~I-adrenoceptor-mediated) with timolol, metipranolol, levobunolol, bupranolol, carteolol, pindolol and befunolol, but not with betaxolol (DeSantis et al. 1987). Confirmation of these findings in animals has also been obtained from studies in humans. Radioligand binding studies, conducted in normal subjects 'of glaucoma age', demonstrated highly significant differences in plasma ~I- and ~2-adrenoceptor blocking activity between betaxolol 0.5% and timolol 0.5% (data on file, Alcon Laboratories Inc.). Timolol-treated subjects showed a mean plasma ~I-blocking activity of 17.8% of control. No significant plasma ~I­ blocking activity was detected in subjects treated with betaxolol. The mean plasma ~2-blocking activity was 33.7% of control in timolol-treated subjects vs 0.53% in those treated with betaxolol. 1.3.1 Bronchopulmonary Effects In relation to nonselective ~-adrenoceptor antagonists, ocularly administered betaxolol appears to have less propensity for adverse effects on pulmonary function resulting from blockade of ~2adrenoceptors (Cervantes & Hernandez y Hernandez 1986; Dunn et al. 1986; Ofner & Smith 1987; Schoene et al. 1984; Yukich et al. 1986) [fig. 2]. Pulmonary function was not affected in 2 trials of betaxolol 0.5% in a total of 20 patients with glaucoma and chronic obstructive airways disease (Brooks et al. 1987; Yan Buskirk et al. 1986), and in I trial of 6 months duration in 24 such patients (Pecori-Giraldi et al. 1988). In the latter trial, timolol reduced forced vital capacity (FYC), FEY I, and relative forced expiratory volume. Weinreb et al. (1988) investigated respiratory function following betaxolol treatment (0.5% solution administered twice daily for at least 2 weeks in 85 patients) and documented no significant effect on FEYI, FYC, and FEYI/FVC. Pulmonary function was sustained (mean FEY I/FVC ratio was 60.1 %) in a subgroup of 24 patients treated for I year but there was a nonsignificant decrease in

Drugs 40 (I) 1990

0.55

u

--

>

0.50

:>

w

u.

*

0.45

o----o~

______~~__ *

0.40 0

60

120

180

240

270

Time (min) Fig. 2. The ratio of forced expiratory volume in I second (FEV I) to vital capacity (Ve). as a function of time following administration ofbetaxolol 1% (e). timolol 0.5% (0). or placebo (0) eyedrops in 9 patients with reactive airway disease

(after Schoene et al. 1984); * = p < 0.05; /3-agonist (isoprenaline) [isoproterenol).

t = inhalation

of

FEY I/FYC (54.4%) in a group of 5 patients who received betaxolol for 2 years. All patients in this study had glaucoma and chronic obstructive pulmonary disease, asthma, or timolol-induced bronchoconstriction at baseline. Five patients, however, experienced symptomatic pulmonary obstruction after I to 554 days' treatment. Bleckmann and Dorow (1987) investigated the pulmonary effects ofbetaxolol in comparison with placebo, in to patients with glaucoma and reactive airway disease, by means of a histamine challenge test. There was no statistically significant difference between treatments in the histamine concentration necessary to produce a 15 to 20% reduction in FEY,. Brooks et al. (1989) observed no alteration in pulmonary function (and no symptoms of bronchospasm) in 5 patients treated with betaxolol eye drops who had previously reported symptoms suggestive of bronchospasm. Overall, betaxolol appears to have important advantages over nonselective ocular ~-adrenocep­ tor antagonists in the treatment of patients with coexistent respiratory disease, but further investigation is required. Moreover, since isolated occurrences of symptomatic pulmonary obstruction have been reported, great care is warranted if the drug is to be used in patients with compromised respi-

Ocular Betaxolol: A Review

81

ratory function, and further investigation is required in the clinical setting to estimate the extent of risk (also see section 4).

1.3.2 Cardiovascular Effects Betaxolol 0.5 or 1.0% appears to have no effect on heart rate or mean arterial pressure under conditions of exercise, in contrast with timolol 0.5%, bunolol 1.0%, befunolol 0.5%, metipranolol 0.6%, levobunolol 0.5% and pindolol 1.0% (Atkins et al. 1985; Cervantes & Hernandez y Hernandez }986; Dickstein 1989; Hernandez y Hernandez et al. 1983). Similarly, resting heart rate and blood pressure appear not to be affected by topical betaxolol therapy (Dunn et al. 1986; Pillunat & Stodtmeister 1988; Stewart et at. 1986). In elderly patients investigated by Le Jeunne et al. (1988), heart rate and systolic blood pressure were reduced by timolol 0.25 or 0.50%, metipran0101 0.30 or 0.60% and carteolol 1.0 or 2.0%, but not by betaxolol 0.5% (fig. 3). Dickstein (1989) found no marked effect of betaxolol on cardiopulmonary function during exercise in 12 volunteers. Exercise time at peak exercise was significantly reduced by 12 seconds, and workload at peak exercise by 6.8W, but there was no effect of betaxolol on V02 or oxygen pulse (V02/heart rate). Exercise heart rate was also unaffected. Studies in healthy volunteers have demonstrated that betaxolol, unlike timolol and carteolol, has no effect on isoprenaline-induced increases in heart rate and peripheral blood flow, indicating no effect on cardiovascular f3,- and f32-adrenoceptors, respectively (Hugues 1989; Le Jeunne et al. 1990). However, Le Jeunne et al. noted that while mean responses to betaxolol showed no inhibition of the effects of isoprenaline, some individual responses indicated rather pronounced antagonism by betax0101. Thus, in the clinical setting, these individuals may be somewhat more susceptible to systemic adverse effects. It should, moreover, be stressed that the apparent lack of consistent effect of betaxolol on cardiac parameters (in particular) is somewhat unexpected, given its relative f3,-selectivity. Though not proven with certainty, it appears that ocular betaxolol may undergo systemic absorption. A pos-

Time (min)

15

30

60

-5

-20

Fig. 3. Mean % change in heart rate and systolic pressure from baseline, against time following administration of betaxolol 0.5% (e), timolol 0.25 or 0.5% (0). metipranolol 0.3 or 0.6% (6), or carteolol 1.0 or 2.0% (0) in 60 elderly patients studied by Le Jeunne et al. (1988); • = p < 0.05, ** = p < 0.01 . *** = p < 0.001 vs baseline; significance values not stated for all means.

sible, entirely speculative, explanation for the absence of systemic cardiovascular effects may be that betaxolol's lipophilicity and greater degree of plasma protein binding (compared with timolol, for example) [section 2.1] result in less free drug being available for binding to cardiovascular f3-adrenoceptors.

1.3.3 CNS Effects Cohn (1989) investigated the CNS effects of betaxolol and timolol for 5 weeks (dosages unstated) in 44 healthy volunteers. Although a larger scale study would be necessary to establish statistically significant differences between the 2 drugs, trends were apparent in favour of betaxolol, in terms of the incidence of insomnia, depression, hypochondriasis and hysteria.

82

Drugs 40 (1) 1990

Lynch et al. (1988) conducted 2 studies to determine the relative frequency of central effects with betaxolol and timolol. In the first study 18 patients experiencing adverse CNS effects including depression, emotional lability, sleep disturbance, decreased libido, and/or impotence durjng treatment with timolol 0.5% twice daily, were transferred to betaxolol treatment and re-evaluated after 3 months. 16 of the 18 patients experienced 'improvement' in their symptoms with betaxolol 0.5%. In a second study, 7 patients then received either betaxolol 0.5% or timolol 0.5% twice daily for I month. All patients had previously complained of depression, emotional lability, lethargy, decreased libido and/or impotence whilst receiving timolol. Five of the patients observed a subjective improvement in symptoms with betaxolol relative to timolol. However, the study design, while doubleblind, has clear deficiencies in selecting for patients who had previously tolerated timolol poorly. De Vries et al. (1989) described 40 patients experiencing CNS and other adverse effects with timolol, 32 (80%) of whom became free of adverse effects after betaxolol therapy was introduced. However, it was noted that the duration of follow-up with betaxolol was very short, while some adverse effects had only appeared after several years' successful treatment with timolol. 1.4 Mechanism of Action It is generally held that lOP is reduced by betaxolol and other ,6-adrenoceptor antagonists through decreased production (inflow) of aqueous humour by the ciliary body, with no apparent effect on aqueous outflow (Reiss & Brubaker 1983). However, the precise mechanism(s) by which ,6adrenoceptor antagonists elicit this effect remains to be fully elucidated. ,6-Adrenoceptors - primarily ,62 (75 to 90%) - have been identified in the ciliary processes, the active secretory site for the production of aqueous humour (see review of Lesar 1987). Polansky and Alvarado (1985) reported that, despite its relative ,6t-selectivity, after ocular instillation of betaxolol 0.5% in rabbits the concentration attained in the aqueous humour was sufficient

to block ,62-receptors. However, the precise relationship between ,62-blockade in the ciliary body and reduction of aqueous humour production remains unclear. Lesar (1987) points to the lack of evidence of sympathetic innervation of the ciliary body, and a similar absence of a relationship between inhibition of cyclic AMP synthesis and facility in lowering lOP. However, ,6-adrenoceptors have also been identified in the microvascular bed of the anterior segment, an area of dense (nor-) adrenergic innervation, from which the passive component of aqueous production, the ultrafiltrate, originates and into which it is partially resorbed. Gaul et al. (1989), comparing betaxolol with the nonselective agent levobunolol, did not observe a close correlation between the reduction of aqueous humour formation in humans and ,62-receptor affinity, measured in rat pulmonary membrane: levobunolol had a 500-fold greater in vitro receptor affinity, while its in vivo potency was greater than betaxolol's only by a factor of 3. (Possible differences between the ,62-receptors in rat pulmonary membrane and those in the human eye, or in ocular disposition of the 2 drugs, should not be discounted.) Wright et al. (1989) reported that the decrease in lOP produced by ,6-adrenoceptor antagonists is independent of relative ,61-selectivity or partial agonism at ,6-adrenoceptors, while Mekki et al. (1985) observed that ,62-blockade with the ,62selective agents LN-37-429 and LI 32-468 did not result in a reduction in lOP in human volunteers. Taken together, these data suggest that the effect of ,6-adrenoceptor antagonists on aqueous humour formation is not mediated entirely via ,62-receptors. Watanabe and Chiou (1983) have suggested that the reduction of aqueous humour formation produced by ,6-adrenoceptor antagonists is associated with a decrease in blood flow to the iris rootciliary body, which may in turn reflect dopamine levels in this tissue. There is some evidence that the microvascular system of the anterior segment also has a role in regulation of aqueous outflow (see Wax & Molinoff 1987), so that the characterisation of receptors in this area may be of further clinical relevance. Robinson and Kaufman (1990), in a study in cy-

Ocular Betaxolol: A Review

nomolgus monkeys, reported that pretreatment with timolol prevents the enhancement of aqueous outflow produced by epinephrine, while betaxolol has no effect. This observed difference is consistent with a !32-adrenoceptor-mediated mechanism for aqueous outflow; it also supports the findings of tonographic studies in humans (Allen & Epstein 1986; Schenker et al. 1981; Thomas & Epstein 1981) and radio ligand binding studies in human trabecular cells and trabecular meshwork, indicating that 132- (but not 131- or a-) adrenoceptors are present in the trabecular endothelium (Wax et al. 1989).

2. Pharmacokinetic Properties Following ocular instillation, !3-adrenoceptor antagonists are absorbed through the cornea into the aqueous humour (Lesar 1987). Subsequently they may be absorbed into conjunctival veins or through the puncta to the lacrimal sac and the nasal mucosa, where they may be rapidly absorbed into the systemic circulation. Thus, both ocular and systemic pharmacokinetics may be clinically relevant after ocular administration, and an overview of the pharmacokinetic properties of orally administered betaxolol is provided below. Very few data are available regarding the disposition of betaxolol following ocular instillation. 2.1 Absorption and Distribution After ocular instillation of betaxolol 0.5% in rabbits, the concentrations attained in the aqueous humour were sufficient to block !32-adrenoceptors, although no data regarding the concentration-time relationship were reported (Polansky & Alvarado 1985). Wright et al. (1988) observed that a significant contralateral decrease in lOP can occur after instillation of betaxolol to I eye in humans. Peak plasma concentrations of about 50 /-Lg/L are achieved within 2 to 4 hours of a single oral 20mg betaxolol dose in healthy volunteers (Balnave ef al. 1981; Giudicelli et al. 1980), and administration with food does not affect the rate or the extent of absorption (Thiercelin et al. 1984). Bioavailability of oral betaxolol is high, at about 80 to

83

90% (Bianchetti et al. 1979; Warrington et al. 1980). Thus, unlike timolol and propranolol, it does not undergo extensive first-pass metabolism (Giudicelli et al. 1980). This is despite its being highly lipophilic, with an octanol : water partition coefficient reported as 3.5 (Davis & Turner 1979; Lynch et al. 1988) or 3.9 (Manoury 1983). [In any event, any ocularly administered drug which was absorbed through the conjunctival and nasopharyngeal mucosa would bypass the enterohepatic circulation.] The highest concentrations of betaxolol were found in the lungs, kidneys, heart, brain and liver following oral administration to rats (Ferrandes et al. 1983; Gillet et al. 1984). Betaxolol crosses the placenta and has been detected in breast milk in concentrations 3 times greater than in plasma (Boutroy et al. 1983). Estimates of the volume of distribution of betaxolol have ranged from 4.9 to 9.8 L/kg (Bianchetti et al. 1979; Ferrandes et al. 1983; Giudicelli et al. 1980; Shanks 1983). Betax0101 is not extensively bound to plasma proteins (50 to 55%) [Ferrandes et al. 1983; Ganansia et al. 1984; Shanks 1983]. 2.2 Metabolism and Excretion Betaxolol is extensively metabolised in humans (about 84%) via O-dealkylation followed by aliphatic hydroxylation, yielding 2 major reactive metabolites (Morselli et al. 1983). Hydroxylation of a carbon atom in the benzene ring gives rise to a minor metabolite (Hermann et al. 1982). The parent drug and metabolites are excreted renally. Around 16% of the dose is excreted as unchanged drug (Beresford & Heel 1986). The elimination halflife of betaxolol is between 14 and 22 hours in healthy adults (Ferrandes et al. 1983; Warrington et al. 1980), and is lengthened in neonates (Boutroy et al. 1983), and the elderly (to 27 hours) [Bianchetti et al. 1983]. Total body clearance is reduced only in the presence of severe renal failure but, despite extensive metabolism, apparently not in severe hepatic disease (Morselli et al. 1983).

84

Drugs 40 (1) 1990

3. Therapeutic Trials Glaucoma is characterised by an increased lOP, optic disc alterations and optic nerve atrophy, with resultant loss of visual field, and occurs in 0.5 to 1.5% of the population over 40 years of age. Ocular hypertension, a condition in which increased lOP is not associated with optic nerve damage or loss of visual field, occurs in 5 to 7% of the population (Lesar 1987). Although lOP does not always predict optic nerve damage, elevated intraocular pressure is held to be the usual cause of loss of visual field in glaucoma. Consequently, the ultimate aim of therapy in patients with glaucoma and ocular hypertension is to decrease elevated lOP to an acceptable, sustained level and thus lessen the risk of optic nerve damage. Ocular timolol was the first {3-adrenoceptor antagonist to be used as a successful alternative to standard therapies such as pilocarpine and remains a valuable drug, but its lack of receptor selectivity, and development of tolerance in some patients, has led to the introduction of newer agents such as betaxolol. Controlled investigations of ocular betaxolol in these indications have not been extensive. Studies in glaucoma and ocular hypertension have compared betaxolol with placebo for 6 weeks and with ocular timolol for 4 to 26 weeks. Additionally, in noncomparative trials, the efficacy ofbetaxolol has been evaluated over periods of up to 2 years. Criteria for patient inclusion in the various trials have generally consisted of a baseline lOP of 26mm Hg or greater in one or both eyes. The comparative studies generally excluded patients with asthma or chronic obstructive pulmonary disease, but the influence of ocular betaxolol on pulmonary function has been investigated in a number of studies in patients with reactive airways disease (see section 1.3.1). Although in ideally designed trials individual as well as mean response should be evaluated and the number of patients failing therapy or needing adjuvant therapy taken into account, few studies of betaxolol have reported these details. In general, 1 drop of betaxolol solution has been instilled into the affected eye, unless stated otherwise.

3.1 Noncomparative Trials A I-year noncomparative study, conducted in 12 patients with primary open angle glaucoma or ocular hypertension, determined that the attenuation of lOP was apparent within several hours of instillation of the first drops of betaxolol 0.25% (2 drops per eye), was maximal at 2 weeks with pressure falling by 30 to 35%, and that the effect was sustained below baseline for the duration of the study (Berrospi & Leibowitz 1982). Merte and Schnarr (1987) studied 14 patients with primary open-angle glaucoma, 6 of whom were receiving treatment with pilocarpine, and were administered betaxolol without a washout period. In these patients mean diurnal lOP was 16.4mm Hg, from a baseline of 17.9mm Hg (an 8.4% reduction which was not statistically significant). In the 8 newly diagnosed patients mean diurnal lOP was reduced with betaxolol from 22.3 to 18.5mm Hg (17%; p < 0.01). Brogliatti et al. (1987) investigated the results of treatment with betaxolol 0.5% alone (n = 15) or in combination with pilocarpine (n = 5), in 11 patients with open-angle glaucoma and 9

30 c;;

:r: E

EO)

;; r/) r/)

25

~

c.

a;

"3

g ~

E

20

o

i i i

2

3

4

iii

5

6

7

Time (weeks)

Fig. 4. Intraocular pressure as a function of treatment du; ation in 10 patients administered betaxolol 0.25% twice dail (e) or placebo (0 ) for 6 weeks (after Caldwell et al. 1984).

Ocular Betaxolol: A Review

85

Table II. Controlled clinical trials of ocular betaxolol (B) in patients with glaucoma or ocular hypertension Reference

No. of patients

Dosagea (%)

Duration of treatment (weeks)

Results mean baseline lOP (mmHg)

mean reduction in IOpb(mmHg)

[% change] Placebo (P) Caldwell et al. (1984)C Feghali & Kaufman (1985) Levy & Boone (1983) Radius (1983) Timolol (T) Allen et al. (1986) Berry et al. (1984) Clark et al. (1989)C Kitazawa et al. (1989) Levy et al. (1985) Stewart et al. (1986)

5 5 9 10 10 10 10 10

B P B P B P B P

38 20d 26 248 70 67 12 14 15 14

Combination with other agents Allen & Epstein (1986) 19 Smith et al. (1984)C 13

9

Weinreb et al. (1986)

35

0.25

6

0.25

6

0.25

6

0.125

6

B 0.25,0.5 T 0.25,0.5 B 0.5 T 0.5 B 0.5 T 0.25 B 0.5 T 0.5 B 0.5 T 0.5 B 0.5 T 0.5

26

B 0.5 + E 1.0 bid B 0.25 x 1 wk; B + A 500mg oral bid x 2 wks A 500mg oral bid x 1 wk; A + B 0.25 X 2 wks B 0.5 + D 0.1 bid

26 4 12 26 26

4 3

4

27.3 29.2 31.8 29.9 30.6 30.3 31.2 2ft.7

7.5 [27.0]' 3.7 [12.7] 4.2 [13.0]* 0.5 [1.7] 5.9 [19.3] 3.6 [11.9] 5.5 [17.5]' 1.6 [5.7]

27.2 26.6 29.8 29.8

(20.0) (? > 20.0) 8.6 [28.9] 9.9 [33.2] 2.9**· 3.2'" 4.6 5.6 11.1' [36.3]'" 10.6' [37.1]*' 7.6 [26.0] 8.4 [29.0]

? ? ? ? 30.6 28.6 29.0 27.6 24.5 25.5

3.8 [15] [27.3]9 [35.1]9 53.5

25.2

[42.5]' [18.1]' 49.6

24.2

3.7 [15]

1 drop (0.5%) or 2 drops (0.25 or 0.125%) instilled twice daily. At end of treatment. Patients had ocular hypertension only. 35 eyes were treated among 20 patients receiving B; 43 eyes among 26 patients receiving T. Some patients also received pilocarpine 1 or 2% or epinephrine 1%. e Crossover study. f Mean throughout treatment. g Measured as 'outflow pressure' reduction. Abbreviations: lOP = intraocular pressure; E = epinephrine (adrenaline); A = acetazolamide; D = dipivefrine; bid = twice daily; • = p < 0.05; •• = p < 0.02; ••• = P < 0.01. a b c d

with ocular hypertension. In 17 patients, timolol was replaced by betaxolol without a washout period. An additional mean reduction in lOP of 2.4mm Hg was apparent after 2 weeks, and was sustained for the 12 weeks of study.

3.2 Comparisons with Placebo Betaxolol is superior to placebo in reducing lOP. Mean reductions have been of the magnitude of 13 to 27% with betaxolol, compared with about 2 to

86

Drugs 40 (I) 1990

13% with placebo (fig. 4; table II). Interestingly, lOP values remained below baseline during the week following discontinuation ofbetaxolol (Caldwell et al. 1984; Radius 1983), although Radius (1983) detected no difference between betaxolol and placebo at this time. 3.3 Comparisons with Timolol In a trial of 4 weeks duration comparing beta x0101 0.5% with ti,molol 0.25%, reductions in lOP of 2.9 and 3.2mm Hg, respectively, were observed (Clark et al. 1989). In 3 trials of 6 months duration involving a total of 101 patients, the reductions in lOP with betaxolol 0.5% were 26% (Stewart et al. 1986), 29% (Berry et al. 1984) and 36% (Levy et al. 1985), while for timolol 0.5% the reductions observed were 29, 33 and 37%, respectively (table II). Allen et al. (1986) conducted a double-blind trial over 6 months in 38 patients, comparing betaxolol with timolol at concentrations of 0.25 and 0.5%. They observed a greater decrease in lOP with timolol than with betaxolol at both concentrations, and a significantly greater need for adjunctive therapy with betaxolol, but commented that approximately half the patients had been treated with timolol before study enrolment. (A separate randomisation procedure was employed according to whether patients had received prior treatment with timolol). In a double-blind trial, 353 patients with elevated lOP controlled (to < 22mm Hg) with timolol 0.5%, received either timolol 0.5% (n = 173) or betaxolol 0.5% (n = 180) twice daily for 3 months (Vogel et al. 1989). Pilocarpine could be added if lOP was not adequately controlled. While at all time points lOP was increased from baseline by both drugs, as assessed by mean eye analysis, the increase in lOP was significantly greater at I, 2 and 3 months in betaxolol vs timolol recipients. However, by worse eye analysis, mean lOP was reduced at all time points by timolol, significantly so at I and 4 weeks. The findings from this study should, however, be interpreted with some caution, given that patients were selected for positive response to timolol at the outset.

Thus, although the conventional clinical view appears to hold that betaxolol is somewhat less effective than timolol jn reducing lOP, further controlled trials are required to confirm their relative efficacies. Allen et al. (1986) noted that betaxolol is administered as the racemate, while only the 1isomer is active, whereas timolol is administered as a pure solution of the active I-isomer, so that comparison of equal concentrations of both drugs may not be appropriate. 3.4 Combination Use with Other Agents Weinreb et al. (1986) investigated the effect of adding betaxolol 0.5% twice daily to dipivefrine (dipivefrin; dipivalyl epinephrine) 0.1% twice daily. After 2 weeks' dipivefrine therapy alone, mean lOP was reduced by 12% from baseline, and addition of betaxolol resulted in a total reduction of 15% at 4 weeks. In a study to determine the combined effect of topical betaxolol (0.5%, I drop twice daily) and orally administered acetazolamide (500mg twice daily), Smith et al. (1984) observed a mean reduction in outflow pressure (lOP minus an episcleral venous pressure of IOmm Hg) of 27.3% from baseline with betaxolol alone, which decreased to a ,total reduction of 53.5% from baseline with acetazolamide added. With acetazolamide alone the reduction was 42.5%, the subsequent addition of betaxolol further reducing outflow pressure to a total reduction of 49.6% from baseline.

4. Adverse Effects The most notable adverse effect associated with instillation of betaxolol is transient local irritation, occurring in 25 to 40% of patients (Goldberg 1989). Between September 1985 and September 1986, an estimated 1.1 million retail prescriptions were dispensed for ocular betaxolol in the US; of the 56 spontaneous reports of adverse drug experience attributed to reports of betaxolol, Nelson and Kuritsky (1987) described 25 reports of eye burning, stinging or irritation, 3 reports of conjunctivitis, 2 of ocular pruritus, and I each of hyphaemia, vitreous separation and blurred vision. In I clinical study, 40% of patients experienced ocular 'discom-

Ocular Betaxolol: A Review

fort' with betaxolol vs 27% with timolol; none of the adverse effects reported was considered clinically significant (Stewart et al. 1986). Ryan et al. (1987), who conducted a double-blind comparison of betaxolol 0.5% and timolol 0.5% for 7 days in 30 healthy volunteers, reported a higher incidence of ocular symptoms, according to patients' reports, with betaxolol than with timolol (89 vs 48%, p < 0.01). Symptoms were not detailed, but were described as 'more severe' with betaxolol. There was no difference between drugs with respect to ocular signs. 89% of patients preferred timolol vs II % preferring betaxolol (p < 0.01). In 353 patients previously well controlled with timolol, burning/stinging and tearing occurred significantly more frequently in patients subsequently treated with betaxolol than in those who again received timolol (after washout) [Vogel et al. 1989]. 14% of patients receiving timolol and 26% receiving betaxolol experienced adverse effects, with 5 and 10 patients, respectively, withdrawing from the trial. (Possible selection bias in favour of timolol cannot be discounted in this trial conducted in timolol responders; some patients earlier experiencing adverse effects with timolol may have withdrawn from or complied poorly with treatment.) On theoretical grounds, betaxolol, as a cardioselective agent, is less likely to be associated with adverse respiratory effects than is timolol or other nonselective agents. There are few data regarding this question from clinical trials, since in most cases patients with respiratory disease have been excluded from study entry. Adverse respiratory effects have been described in 5 of 101 patients with chronic obstructive pulmonary disease, asthma, or timolol-induced bronchoconstriction, followed for up to 2 years on betaxolol (Weinreb et al. 1988). However, their relationship to treatment is uncertain. Harris et al. (1986) reported the occurrence of ' respiratory difficulty strongly suggestive of obstructive airway disease' after treatment with betaxolol in 5 patients, 3 of whom were known to be asthmatics, while the remaining 2 had no history of respiratory disease. Roholt (1987) described a case of reduction in pulmonary capacity associated

87

with ocular betaxolol in a patient with minimal reactive airways disease. In the postmarketing surveillance of Nelson and Kuritsky (1987) described above, 8 cases requiring hospitalisation for asthma (n = 6), asthma with cardiac arrhythmia (I), and respiratory distress (I) were documented. In 4 cases underlying respiratory disease was present. There were 3 further cases of asthma not requiring hospitalisation associated with betaxolol - all patients had a history of asthma - and I of apnoea. Herschman and Kaufman (1989) described the occurrence of bronchospasm in a patient receiving ocular betaxolol and oral labetalol. Thus, despite its 11 I-selectivity, the possibility of adverse respiratory effects with betaxolol should not be discounted. Weinreb et al. (1988), in a trial involving 101 patients treated for up to i years, reported cardiac arrhythmia and shortness of breath in I patient, and bundle branch block in a second, hyperthyroid patient. Myocardial infarction occurred in a third patient, but whether this event was related to betaxolol therapy is uncertain. A recent case report described myocardial infarction in an elderly patient with well-controlled systemic hypertension, occurring within minutes of administration of a single drop of betaxolol to I eye (Chamberlain 1989). Sinus arrest (Zabel & MacDonald 1987) and congestive heart failure [Ball 1987; Herschman & Kaufman 1989 (in a patient receiving concurrent labetalol)] have also been reported in association with ocular betaxolol. Nelson and Kuritsky (1987) described 3 spontaneous reports of bradycardia, and I each of bradycardia with syncope and asthma with cardiac arrhythmia, the latter 2 patients requiring hospitalisation. It is not clear from their paper whether underlying cardiovascular disease was already present in these cases. Nelson and Kuritsky (1987) also described I report each of depression, disorientation, vertigo and sleepwalking. Orlando (1986) reported a case of clinical depression temporally associated with betaxolol treatment and resolving on cessation of betaxolol.

88

Drugs 40 (I) 1990

Other adverse effects reported in association

tercurrent cardiovascular and pulmonary disease.

with ocular betaxolol include rhinitis (n = I), dysuria (I), and prolonged prothrombin time (I) [Nelson

& Kuritsky 1987], and alopecia (Fraunfelder et

al. 1990).

5. Dosage and Administration The recommended dosage of ocular betaxolol in patients with glaucoma or ocular hypertension is 1 drop of 0.5% solution in each affected eye twice daily.

6. Place of Betaxolol in Therapy In topical use, betaxolol appears to be of comparable efficacy to timolol in reducing intraocular pressure. There are insufficient data to determine the extent to which ocularly administered betaxo-

101 is absorbed from the nasopharyngeal and conjunctival mucosa into the systemic circulation. However, it tends to produce fewer /31- and /32adrenoceptor-mediated systemic effects than does timolol: in particular, betaxolol appears less likely to cause the adverse bronchopulmonary effects at times associated with timolol therapy. This is consistent with its relative !31-selectivity. Further, the lack of local anaesthetic activity of betaxolol means that corneal desensitisation is not associated with its use. However, its adverse effect profile remains to be fully delineated with wider clinical experience. The apparent absence of cardiac effects would not be predicted from its pharmacological profile, and requires further clarification. Its relative disadvantages are the local effects observed, such as irritation, burning and stinging. In summary, betaxolol appears to provide a valuable option for topical treatment of primary openangle glaucoma and ocular hypertension, especially in patients with bronchopulmonary disease such as asthma. Its apparently lesser propensity to cause adverse

cardiovascular and

respiratory

effects

compared with other /3-adrenoceptor antagonists used for these conditions offers an important potential advantage, particularly since the majority of patients are elderly, with a high incidence of in-

References Allen RC Epstein DL. Additive effect of betaxolol and epinephrine in primary open angle glaucoma. Archives of Ophthalmology 104: 1178-1184. 1986 Allen RC Hertzmark E. Walker AM. Epstein DL. A doublemasked comparison of betaxolol vs timolol in the treatment of open-angle glaucoma. American Journal of Ophthalmology 101: 535-541. 1986 Atkins JM. Pugh Jr BR. Timewell RM. Cardiovascular effects of topical beta-blockers during exercise. American Journal of Ophthalmology 99: 173-175. 1985 Ball S. Congestive heart failure from betaxolol: ocular. Archives of Ophthalmology 105 (3): 320. 1987 Balnave K. Neill JD. Russell JD. et al. Observations on the efficacy and pharmacokinetics ofbetaxolol (SL75212). a cardioselective i3-adrenoceptor blocking drug. British Journal of Clinical Pharmacology II: 171.1981 Bartsch W. Dietmann K. Leinert H. Sponer G. Cardiac action of carazolol and methypranol in comparison with other i3-receptor blockers. Arzneimittel-Forschung 27: 1022-1026. 1977 Beresford R. Heel RC. Betaxolol: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in hypertension. Drugs 31: 6-28. 1986 Berrospi AR. Leibowitz HM. Betaxolol: a new i3-adrenergic blocking agent for treatment of glaucoma. Archives of Ophthalmology 100: 943-946. 1982 Berry Jr DP. Van Buskirk EM. Shields MB. Betaxolol and timolol: a comparison of efficacy and side effects. Archives of Ophthalmology 102: 42-45. 1984 Bianchetti G. Gomeni R. Kilborn J. Morselli P. et al. Blood concentrations and pharmacodynamic effect of SL 75212. a new beta-adrenoceptor antagonist. after oral and intravenous administration. British Journal of Clinical Pharmacology 8: 403P-404P. 1979 Bianchetti G. Padovani P. Thiercelin J. Thenot J. Morselli P. Pharmacokinetic studies of betaxolol - evaluation of the effects of age. hypertension. presence of food. and concomitant administration of hydrochlorothiazide on the disposition of the drug. In Morselli et al. (Eds) LERS Monograph Series. Vol. I. pp. 123-131. Raven Press. New York. 1983 Bleckmann H. Dorow P. Betaxolol vs placebo in ten patients with glaucoma and reactive airway disease. New Trends in Ophthalmology 2: 114-123. 1987 Bloom E. Richmond C Alvarado J. Polansky J. Betaxolol vs timolol: plasma radio-receptor assays to evaluate systemic complications of beta blocker therapy for glaucoma. Investigative Ophthalmology and Visual Science 26 (Suppl): 125-129. 1986 Boudot J. Cavero I. Fenard S. Lefevre-Borg F. et al. Preliminary studies on SL 75212. a new potent cardioselective beta-ad renoceptor antagonist. British Journal of Pharmacology 66: 445P. 1979 Boutroy M. Vert p. Bianchetti G. Morselli P. Betaxolol: pharmacokinetics and pharmacodynamic effects of a new cardioselective beta-blocker in pregnant women. Abstract no. 565. II World Conference on Clinical Pharmacology and Therapeutics. Washington DC, July 31-August 5. 1983 Brogliatti B. Rolle T. Franzone M. Effects of topical betaxolol on ocular hypertensive or glaucomatous eyes. New Trends in Ophthalmology 2: 87-94. 1987 Brooks AMV. Burdon JGW. Gillies WE. The significance of reactions to betaxolol reported by patients. Australian and New Zealand Journal of Ophthalmology 17: 353-355. 1989 Brooks AMV. Gillies WE. West RH. Betaxolol eye drops as a safe medication to lower intraocular pressure. Australian and New Zealand Journal of Ophthalmology 15: 125-129. 1987 Caldwell DR. Salisbury CR. Guzek JP. Effects of topical betaxolol

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Ocular Betaxolol: A Review

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distribution of betaxolol and metoprolol in various tissues in the ral. In Aiache and Hirtz (Eds) Proceedings of 2nd European Congress of Biopharmaceutics and Pharmacokinetics, pp. 529-535, Vol. II, Experimental Pharmacokinetics, 24-27 April, Salamanca, Spain, 1984 Giudicelli J, Chauvin M, Thuillez C Richer C Bianchetti G, et a!. Beta-adrenoceptor blocking effects and pharmacokinetics of betaxolol (SL 75212) in man. British Journal of Clinical Pharmacology 10: 41-49, 1980 Goldberg I. Betaxolol. Australian and New Zealand Journal of Ophthalmology 17: 9-13, 1989 Harris LS, Greenstein SH, Bloom AF. Respiratory difficulties with betaxolol. American Journal of Ophthalmology 102: 274-275, 1986 Hermann P, Thenot J, Warrington S, Ganansia J, Morselli P. Metabolism of betaxolol in man. Abstract no. 272. 8th European Workshop on Drug Metabolism, Sart Tilman, Belgium, September 5-9, 1982 Hernandez y Hernandez H, Cervantes R, Frati A. Cardiovascular effects of topical glaucoma therapies in normal subjects. Journal of Toxicology - Cutaneous and Ocular Toxicology 2: 99106, 1983 Herschman Z, Kaufman B, Complications arising from the use of ophthalmologic medications in an intensive care unit patienl. New York State Journal of Medicine 89: 537-538, 1989 Hugues Fe Clinical studies of systemic effects of topical beta blockers. International Ophthalmology Clinics 29 (Suppl.): S19S20, 1989 Kitazawa Y, Azuma I, Araie M. Clinical evaluation of betaxolol hydrochloride in the treatment of primary open angle glaucoma and ocular hypertension: multicentre double-masked study in comparison with timolol. Rinsho Hyokal7: 243-274, 1989 Le Jeunne C, Bringer L, Mondjee-Tahura Munera Y, Hugues Fe. Effets cardio-vasculaires des collyres au timolol, au carteolol, au metipranolol, au betaxolol chez Ie sujet age. Therapie 43: 89-92, 1988 Le Jeunne C, Munera Y, Hugues Fe. Systemic effects of 3 betablocker eyedrops: comparison in healthy volunteers of /'II and 1i2 adrenoceptor inhibition. Clinical Pharmacology and Therapeutics, in press, 1990 Lesar TS. Comparison of ophthalmic /'I-blOCking agents. Clinical Pharmacy 6: 451-463, 1987 Levy NS, Boone LR. Effects of 0.25% betaxolol vs placebo. Glaucoma 5: 230, 1983 Levy NS, Boone L, Ellis E. A controlled comparison ofbetaxolol and timolol with long-term evaluation of safety and efficacy. Glaucoma 7: 54-62, 1985 Liu GS, Trope GE, Basu PK. A comparison of topical betoptic and timoptic on corneal re-epithelialization in rabbits. Journal of Toxicology - Cutaneous and Ocular Toxicology 6 (4): 335. 343, 1987 Liu GS, Trope GE, Basu PK. Ultrastructural effects of topical Betoptic, Betagan, and Timoptic on the rabbit corneal endothelium. Journal of Ocular Pharmacology 5: 329-342, 1989 Lynch M~ Whitson JT, Brown RH, Nguyen H, Drake MM. Topical fj-blocker therapy and central nervous system side effects, a preliminary study comparing betaxolol and timolol. Archives of Ophthalmology 106: 908-911, 1988 Manoury P. Betaxolol: chemistry and biological profile in relation to its physicochemical properties. In Morselli et al. (Eds) LERS Monograph Series, Vol. I, pp. 13-19, Raven Press,. New York, 1983 Mekki QA, Davies IB, Sinclair AJ, Turner P. Effect of i32-selective adrenoceptor blockers on intraocular pressure in man. Abstracl. British Journal of Clinical Pharmacology 21: 596P-597P, 1985 Merte HI, Schnarr KD. Ophthalmic betaxolol: a twelve-week study

Z:

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in glaucoma patients. New Trends in Ophthalmology 2: 98108. 1987 Morselli PL. Thiercelin JF. Padovani P. Bianchetti G. Fries D. et al. Comparative pharmacokinetics of several beta-blockers in renal and hepatic insufficiency. In Morselli et al. (Eds) LERS Monograph Series. Vol. I. pp. 233-241. Raven Press, New York. 1983 Nelson WL. Kuritsky IN. Early postmarketing surveillance of betaxolol hydrochloride, September I 985-September 1986. American Journal of Ophthalmology 103: 592. 1987 Ofner S. Smith TJ . Betaxolol in chronic obstructive pulmonary disease. Journal of Ocular Pharmacology 3: 171-176. 1987 Orlando RG. Clinical depression associated with betaxolol. Correspondence. American Journal of Ophthalmology 102: 275. 1986 Palminteri R. Kaik G. Time course of the bronchial response to salbutamol after placebo. betaxolol and propranolol. European Journal of Clinical Pharmacology 24: 741-745. 1983 Pecori-Giraldi J. Collini S, Planner-Terzaghi A. Arrico L. Grechi G. Timolol. Betaxolol und Befunolol in der Glaukombehandlung. U ntersuchung tiber die bronchopulmonalen Effekte. Fortschritte der Ophthalmologie 85: 235-238. 1988 Pillunat L. Stodtmeister R. Effect of different antiglaucomatous drugs on ocular perfusion pressures. Journal of Ocular Pharmacology 4: 231-242. 1988 Polansky JR. Alvarado JA. Isolation and evaluation of target cells in glaucoma research: hormone recepttlrs and drug responses. Current Eye Research 4: 267-279, 1985 Radius RL. Use of betaxolol in the reduction of elevated intraocular pressure. Archives of Ophthalmology 101 : 898-900.1983 Reiss GR. Brubaker RF. The mechanism ofbetaxolol. a new ocular hypotensive agent. Ophthalmology 90: 1369-1372. 1983 Riddell JG. Shanks RG. Comparative effects of betaxolol. propranolol and atenolol on isoprenaline-induced responses in man. British Journal of Clinical Pharmacology 19: 138P. 1985 Robinson JC, Kaufman PL. Effects and interactions of epinephrine. norepinephrine. timolol and betaxolol on outflow facility in the cynomolgus monkey. American Journal of Ophthalmology 109: 189-194. 1990 Rohol! Pc' Betaxolol and restrictive airway disease. Archives of Ophthalmology 105: 1172. 1987 Ryan M. Jain AK. Ryan JR, McMahon FG. Richards J. Relative ocular tolerance of ophthalmic solutions oftimolol and betax0101 in normal volunteers. Clinical Pharmacology and Therapeutics 41 : 193. 1987 Scheuker HI. Tablouski ME, Podos SM. Linder L. Fluorophotometric study of epinephrine and timolol in human subjects. Archives of Ophthalmology 99: 1212, 1981 Schoene RB. Abuan T. Ward RL. Beasley CH. Effects of topical betaxolol, timolol and placebo on pulmonary function in asthmatic bronchitis. American Journal of Ophthalmology 97: 8692. 1984 Shanks RG. Clinical pharmacology ofbeta-adrenoceptor blocking drugs. In Morselli et al. (Eds) LERS Monograph Series. Vol. I. pp. 73-88. Raven Press. New York. 1983 Smith JP. Weeks RH , Newland EF. Ward RL. Betaxolol and acetazolam ide. combined ocular hypotensive effect. Archives of Ophthalmology 102: 1794-1795. 1984 Stewart RH . Kimbrough RL. Ward RL. Betaxolol vs timolol. a

Drugs 40 (I) 1990

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