BritishJournalofOphthalmology, 1991,75,519-523 519 Metipranolol-associated granulomatous anterior uveitis Br J Ophthalmol: first published as 10.1136/bjo.75.9.519 on 1 September 1991. Downloaded from

Tayo Akingbehin, Jose R Villada

Abstract hyperaemia, punctate keratopathy, corneal This paper presents for the first time anaesthesia, and dry eye syndrome.'0 It has been documented evidence, clinical details, and suggested that metipranolol is less tolerated than photographic illustrations, of metipranolol- the other n-blockers because of the stinging and associated granulomatous anterior uveitis burning sensation on instillation.7 ' in 26 eyes of 15 patients being treated for This paper documents for the first time case glaucoma. There were 56 episodes of granulo- histories of some patients receiving this drug for matous anterior uveitis, all associated with the treatment of glaucoma who developed large (mutton-fat) keratic precipitates, flare, granulomatous anterior uveitis. The clinical cells, and 'white eyes' (except in seven details are reviewed briefly, and photographic episodes). In 30 (53.6%) of these episodes evidence submitted. The clinical presentation there was loss of control of intraocular pres- and behaviour ofthe affected eyes are analysed. sure. Metipranolol 0-6% was implicated in 54 ofthe 56 episodes and metipranolol 0 3% in the remaining two. Fifty-one other cases of meti- Methods and materials pranolol-associated granulomatous anterior At the beginning of 1990 a cluster of cases of uveitis have so far been reported from other severe metipranolol-associated blepharocon- parts of the country to the Committee on junctivitis focused attention on this drug. The Safety of Medicines. As a result multidose reaction was more severe than usually seen and metipranolol in0-1%, 0.3%, and 0-6% strengths two patients (three eyes) had coincidental has been withdrawn from clinical use in the granulomatous anterior uveitis. The bottles of United Kingdom. The pathogenesis of this metipranolol were collected from all the patients adverse drug reaction is uncertain. who suffered from both forms of adverse reactions and their batch numbers identified. There was no consistency in the batch numbers The use of n-blockers as topical ophthalmic to suggest faulty preparation or contamination of preparations to reduce the intraocular pressure the drug. During this inquiry six more patients marked the start of a new era in the medical were identified in the clinics and ophthalmic management of glaucoma, because of their ward with granulomatous anterior uveitis while efficacy, prolonged therapeutic action, and few being treated with metipranolol for glaucoma. http://bjo.bmj.com/ serious systemic and ocular adverse effects. 2 As There were now eight patients, 15 eyes, with a result they became the first choice for the granulomatous anterior uveitis, all receiving medical treatment of glaucoma. However, in metipranolol andnoothercommondenominator. recent years the increasing number of systemic In view of these findings we decided to review and ocular adverse effects have led to their more the case notes of all the patients in the depart- cautious use despite the development of newer ment using metipranolol in any of its three drugs with supposedly fewer side effects.3 strengths. The patients were identified through on October 2, 2021 by guest. Protected copyright. In the United Kingdom there are five ,3- the Drug Register in the Pharmacy Department, blockers available as ophthalmic topical prepara- the records from January 1989 to March 1990 tions approved for clinical use, namely, beta- being examined. All the patients on metipranolol xolol, carteolol, levobunolol, metipranolol 0-6% were then invited for an ocular examina- (now withdrawn), and timolol. Metipranolol tion. (1,-(4 acetoxy-2,3,5-trimethylphenyloxy)-3-iso- propylacyno-propan-2-ol) was introduced in the UK in 1986 with the proprietary name of Results Glauline and available in three strengths: 0o 1%, Two hundred and forty-seven case notes 0 3%, and 0-6%. It is a non-selective f-blocker of patients treated with metipranolol in all with no intrinsic sympathomimetic or mem- strengths were reviewed. There were 109 case brane stabilising properties and only slight local notes ofpatients using metipranolol 0-6% and 76 anaesthetic activity.4 patients from this group attended special meti- The efficacy ofmetipranolol in lowering intra- pranolol clinics for examination. Eleven patients ocular pressure has been reported in several had active granulomatous anterior uveitis when Department of studies,5 and so have the adverse effects, which seen in either special or normal clinics, and four Ophthalmology, District (- in the case General Hospital, are similar to those ofother ophthalmic topical had had attacks, well documented Southport PR8 6NJ blockers. The ocular adverse effects attributed notes, but had quiet eyes when examined. In T Akingbehin to metipranolol have included: subjectively, total there were 15 patients (13-8% of the J R Villada burning or stinging on instillation, eye pain patients on metipranolol 0-6%) with presumed Correspondence to: sensa- Mr Tayo Akingbehin, FRCS. or uncomfortable dryness, foreign body metipranolol-associated granulomatous anterior Accepted for publication tion, itching, blurred vision; objectively, uveitis, 11 ofthese with bilateral attacks and four 19 February 1991 allergic blepharoconjunctivitis, conjunctival with unilateral, making a total of 26 eyes. All 520 Akingbehin, Villada

Table I Clinical details ofpatients with metipranolol-associated granulomatous anterior Table 2 Period on drug before thefirst episode of uveitis granulomatous anterior uveitis and distribution ofepisodes versus metipranolol dose Eyes Dose of No. of Other Br J Ophthalmol: first published as 10.1136/bjo.75.9.519 on 1 September 1991. Downloaded from Case Sex Age involved metipr. episodes eyedrops Ocular surgery Period on drug before Ist episode in months 1 F 87 RE 0-6% 2 Dipivefrine Cataract+1OL No. LE 0-6% 2 Dipivefrine Cataract+IOL Drug No. eyes episodes Range Mean 2 F 76 RE 0-6% 1 - - LE 0-6% 2 - - Metipranolol0 3% 1 2 31 3 F 70 RE 0-6% 1 - Cataract+IOL; trabeculectomy Metipranolol 0-6% 25 54 2-24 11-72 4 F 79 RE 0-6% 1 Dipivefrine Total 26 56 2-31 12-46 5 M 70 RE 0-6% 3 - - LE 0-6% 3 - - 6 M 86 RE 0-6% 4 Adrenaline LE 0-6% 4 Adrenaline 7 F 85 RE 0-6% 1 - - uveitis: pilocarpine 2% eyedrops (three eyes), LE 0-6% 1 - - dipivefrine 0-1% eyedrops (four eyes), adrena- 8 F 67 RE 0-6% 1 Levobunolol - LE 0-6% 1 Levobunolol - line 1% eyedrops (two eyes), levobunolol 0-5% 9 M 76 RE 0-6% 2 Timolol 0 - eyedrops (two eyes), and timolol eyedrops 0-5% LE 0-6% 2 Timolol 05% Cataract+IOL 10 F 84 RE 0-6% 1 Dipivefrine - (two eyes) (Table 1). LE 0-6% 1 Dipivefrine - Twenty-six eyes (13 right and 13 left) 11 M 75 RE 0-6% 3 - - LE 0-3% 2 - - developed uveitis with at least 56 separate 12 F 74 RE 0-6% 3 - - documented episodes (27 in the right eye and 29 LE 0-6% 3 - - 13 F 57 LE 0-6% 1 - Trabeculectomy in the left) over a period of 30 months, from 14 F 58 LE 0-6% 2 Dipivefrine Retinal detachment; cataract; October 1987 to March 1990. Fifty-four episodes trabeculectomy 15 F 82 RE 0-6% 4 Pilocarpine 2% - occurred in 25 eyes treated with metipranolol LE 0-6% 5 Pilocarpine 2% - 0-6% and two episodes in one eye treated with 26 56 metipranolol 0 3%. The interval between the beginning of the treatment and the first episode ofuveitis is shown in Table 2. Of the 26 eyes identified with uveitis 16 had these eyes except one developed granulomatous further episodes while they remained on the anterior uveitis while being treated with meti- metipranolol drops. The mean interval between pranolol 0-6% to both eyes; one patient received the first and second episodes in these 16 eyes was metipranolol 0 3% in one eye as shown in Table 4 75 months (range 3-9 months). Nine of the 16 1. The table also shows the age/sex distribution eyes had a third episode after a mean interval of ofthe patients. 3-6 months (range 1-10 months). Four out of 26 Of the 15 patients with metipranolol- eyes had four episodes each; the intervals associated granulomatous anterior uveitis 11 between the third and fourth episodes ranged were females with an age range 57-87 years from one to 6 months, mean 2-5 months. Only (mean 74-4 years) and four males, age range 70- one of these eyes developed a fifth episode of 86 years (mean 76 7 years). The age range for all uveitis after a period of six months (Tables 3 and the patients was 57-87 years (mean 75 years). 4). The female to male ratio as 3:1, and the age The 56 episodes of granulomatous anterior http://bjo.bmj.com/ range and mean age of the 15 patients were all uveitis were managed in various ways, as sum- consistent with those of the glaucoma popula- marised in Table 5. tion. Of the 26 eyes affected the right and left Briefreports on some ofthe 15 patients follow. were equally involved (13 each), with a similar number of separate episodes of granulomatous anterior uveitis. CASE 2 There were no systemic or ocular disorders This was a 76-year-old Caucasian female with no on October 2, 2021 by guest. Protected copyright. common to these patients. Two of them had relevant past medical history or drug history. diabetes mellitus (one insulin-dependent and the Her bilateral open angle glaucoma was diagnosed other on oral hypoglycaemics). in July 1986 and she was started on timolol Six eyes of five patients had intraocular 0-25%. Owing to poor intraocular pressure surgery prior to treatment with metipranolol of any strength and the development of granulo- Table 3 Distribution ofepisodes ofgranulomatous anterior matous anterior uveitis. A total of nine intra- uveitis ocular operations had been performed on the No. ofepisodes % of Cumulative total of six eyes: cataract surgery (five eyes), trabecu- ofanterior uveitis No. ofeyes total eyes no. ofepisodes lectomy (two eyes), retinal detachment surgery 1 26 100 26 with silicone oil (one eye). One eye (case 14, LE) 2 16 61-5 42 had retinal detachment surgery, cataract extrac- 3 9 34-5 51 4 4 1.5-5 55 tion, and trabeculectomy at different times and 3-5 56 developed the first episode of granulomatous 5 1 anterior uveitis at least 15 months after the last Table 4 Time interval between episodes in eyes which operation. developed several attacks ofgranulomatous anterior uveitis Analysis of the drug history of the 15 patients with metipranolol-associated granulomatous Episodes of No. of Range in Mean in in months months anterior uveitis was unproductive. There was no anterior uveitis Interval months eyes common factor between the various systemic lst-2nd 3,3,3,3,3,9,9,4,4, 16 3-9 4.75 3,5,7,7,4,3,6 medications. Thirteen eyes ofeight patients were 2nd-3rd 1,1,1,1,4,10,10,2,3 9 1-10 3-60 on additional topical ophthalmic medications 3rd-4th 1,1,6,2 4 1-6 2-50 when they developed granulomatous anterior 4th-Sth 6 1 Metipranolol-associated granulomatous anterior uveitis 521

Table 5 Management ofepisodes ofgranulomatous anterior uveitis bilateral anterior uveitis with mutton-fat keratic precipitates, posterior synechiae (Fig 2),

Average time Br J Ophthalmol: first published as 10.1136/bjo.75.9.519 on 1 September 1991. Downloaded from No. Otherglaucoma ofresolution and uncontrolled IOPs. The possibility of Topical steroid used episodes Mydriatics treatments (weeks) metipranolol-associated uveitis was being Prednisolone 1% 24 Atropine 1% x2 Acetazolamide x 8 3-8 investigated, hence the metipranolol was discon- Cyclopent 1% x 2 tinued, and he was started on timolol 0-5% and Tropicamide 1%x2 Dexamethasone 01% 12 Cyclopent 1% x4 Acetazolamidex6 2-6 treated with eyedrops of prednisolone acetate, Fluoromethalone 01% 5 Cyclopent 1% x4 Acetazolamidex4 4-4 and atropine 1%. The condition resolved in two Betamethasone 0-1% 4 Cyclopent 1% x4 Acetazolamidex2 3 5 Prednisolone0 5% 1 - - 1-0 months. The visual acuity improved from hand No steroids 6 - - 6-0 movements in both eyes when was registered blind to 6/12 RE and 6/36 LE. The IOPs were In four ofthe episodes the time of resolution was not clear from the case notes and they are not included in this table. controlled with timolol 0 25%. x2=in two episodes, and likewise for x4.

(IOP) control her medications were varied until CASE 9 January 1988, when timolol was stopped and she This was a 76-year-old Caucasian male with no was started on metipranolol 0-6% twice daily to relevant medical history. He was diagnosed as both eyes as the only antiglaucoma treatment. suffering from bilateral cataracts and open angle Two years later (January 1990) she developed glaucoma in December 1987, and was started on bilateral anterior uveitis with keratic precipitates treatment with metipranolol 0 3% twice daily to and loss ofIOP control. This episode was treated both eyes. He underwent left cataract extraction with topical steroids (fluorometholone eye- with IOL in January 1988, and the IOPs drops), mydriatics, and acetazolamide, and remained stable without treatment for six recovered completely in three weeks with return months. The pressures then rose in both eyes of the IOP to normal. She was recalled to the and led to gradually increasing treatment, even- Special Metipranolol Review Clinic in April 1990 tually to metipranolol 0-6% and timolol 0-5% and found to have bilateral blepharoconjunctivi- twice daily to both eyes in March 1989. The first tis, left anterior uveitis with keratic precipitates, episode of bilateral anterior uveitis with keratic and loss ofIOP control in both eyes. The left eye precipitates was in November 1989; it was was photographed (Fig 1). This second episode treated with topical steroids (prednisolone was not treated with topical steroids, the meti- acetate), and recovered in three weeks. The pranolol 0-6% was stopped, and she was started second episode with fresh keratic precipitates on carteolol 2% twice daily to both eyes. Two and loss of IOP control occurred in March 1990 weeks later both eyes were white and quiet, the (both eyes photographed, Figs 3 and 4) and led to keratic precipitates old, and IOPs within normal the metipranolol drops being changed to timolol limits. 0 5% twice daily to both eyes. This episode was not treated with steroids. He had a slower recovery but with complete resolution in eight CASE 6 weeks. This was an 86-year-old Caucasian man who http://bjo.bmj.com/ suffered from gastrointestinal haemorrhage and secondary anaemia treated with ferrous sulphate CASE 10 tablets. Glaucoma was diagnosed in about 1983. This was an 84-year-old diabetic woman on oral The first record of treatment with metipranolol hypoglycaemic treatment and also being treated 0-6% was in September 1987; in addition he for systemic hypertension and arthritis. She had received adrenaline 1% twice daily to both eyes. bilateral open angle glaucoma which needed He developed bilateral anterior uveitis with increasing treatment, and her first contact with on October 2, 2021 by guest. Protected copyright. keratic precipitates and posterior synechiae in metipranolol 0-6% was in April 1989. She was April 1989. He was treated as a case of bilateral listed for filtration surgery in December 1989, Fuchs's cyclitis at another hospital and regis- and at that time her treatment was metipranolol tered fully blind. Later he was transferred to a 0-6% twice daily and dipivefrine 0-1% twice rest home in Southport and an ophthalmic daily to both eyes. When admitted for surgery, in opinion was requested. At this time he had February 1990, she was found to have bilateral anterior uveitis with mutton-fat keratic precipi-

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Figure 2 Case 6. Posterior synechiae after repeated episodes Figure I Case 2. Left eye: keratic precipitates. ofanterior uveitis. 522 Akingbehin, Villada Br J Ophthalmol: first published as 10.1136/bjo.75.9.519 on 1 September 1991. Downloaded from

Figure 3 Case 9. Right eye: keratic precipitates. Figure 4 Case 9. Left eye: keratic precipitates. tates and very elevated IOPs (62 mm Hg in the case report of metipranolol-associated conjunc- right eye and 66 mm Hg in the left). There were tivitis with epithelial keratinisation, similar to no positive radiological or biochemical findings the conjunctival reaction seen after oral use of and she was treated with topical steroids practolol.'2 We have documented a case of (prednisolone acetate). The metipranolol was bilateral marginal keratitis associated with meti- changed to timolol 0-5% twice daily, and pranolol 0 3%. acetazolamide. She continued with the This paper presents the first documented dipivefrine 0-1% The uveitis recovered in three reports of ophthalmic topical 3-blocker- weeks with normal intraocular pressures on the associated intraocular inflammation. In 1980 above treatment until bilateral trabeculectomy. Van Buskirk"3 reviewed 547 reports of adverse reactions to timolol maleate received by the American National Registry for Drug induced CASE 1 1 ocular side effects and found six cases of uveitis This was a 75-year-old Caucasian man suffering associated with the use oftimolol in an 1 1-month from angina and pernicious anaemia. He was period. No details were available. Three years diagnosed as having open angle glaucoma first in later Zimmermann et al'4 updated the review of the right eye and two years later in the left. In the American National Registry ofDrug induced February 1989 his treatment was increased to ocular side effects of timolol, and the number of metipranolol 0-6% to the right eye and meti- associated cases of uveitis had increased to 14, pranolol 0 3% to the left eye. He developed right but no details were given. To put this in perspec- anterior uveitis with keratic precipitates and tive, they also found 98 cases ofocular irritation, loss of pressure control seven months later 64 cases of blepharoconjunctivitis, 38 cases of

(September 1989). This eye was treated with keratitis, and 29 cases of 'corneal lesions' due to http://bjo.bmj.com/ dexamethasone-hypromellose eyedrops, with timolol from 1472 case reports. No cause-and- full recovery from the uveitis and return to effect relationship was implied or demonstrated normal of the IOP. Three months later (Decem- for any ofthese reported reactions. ber 1989) he developed bilateral anterior uveitis This paper presents evidence for meti- with keratic precipitates; both eyes were treated pranolol-induced granulomatous anterior uveitis with prednisone eyedrops, with full recovery. in 15 patients, with 26 eyes affected. We are also

He had a third episode of bilateral blepharocon- aware of 51 patients, at the time of submitting on October 2, 2021 by guest. Protected copyright. junctivitis, bilateral anterior uveitis with keratic this paper, from other parts of the country with precipitates, loss of pressure control, and right suspected metipranolol-induced anterior uveitis ectropion secondary to the skin changes. The (Committee on Safety of Medicines, personal metipranolol drops were stopped, he was started communication). In this study 25 affected eyes on timolol 0-25% twice daily to both eyes, and were receiving metipranolol 0-6%, and one eye both eyes were treated with prednisolone eye- metipranolol 0 3%. By comparing the number of drops. The ectropion and the ocular inflamma- cases reported with sales figures for metipranolol tion resolved in six weeks. 0-6% and metipranolol 0-3% in the UK we believe the incidence of metipranolol-associated anterior uveitis is about 3-8 per thousand for Discussion metipranolol 0-6%, 1-13 per thousand for Almost all the ocular adverse effects of the metipranolol 0 3%, and 0 5 per thousand for ophthalmic topical ,-blockers reported to date metipranolol 0 1% (Smith and Nephew Pharma- have affected adnexal or external ocular struc- ceuticals Ltd. personal communication). These tures and are thought to be related to their figures appear to be increasing with greater property of membrane stabilisation or to reflect awareness ofthis adverse drug reaction. the different vehicles, the pH, and concentra- Granulomatous anterior uveitis is character- tions of the drugs.'0 Metipranolol is known to ised by a tendency to form iris nodules (Koeppe produce external ocular inflammatory reactions or Busacca type) and mutton-fat keratic precipi- which include periorbital dermatitis, urticaria, tates. Non-granulomatous anterior uveitis has blepharitis, blepharoconjunctivitis, keratitis and little or no tendency to form either nodules or 'eye pain' (Committee on Safety of Medicines, mutton-fat keratic precipitates.'5 All 26 eyes personal communication). There has also been a affected had keratic precipitates on the first and Metipranolol-associated granulomatous anterioruveitis 523

subsequent attacks of anterior uveitis. The anterior uveitis. As a result of reporting these attacks of granulomatous anterior uveitis cases to the Committee on Safety of Medicines recorded in the case notes before the establish- and to Smith and Nephew Pharmaceuticals Ltd a Br J Ophthalmol: first published as 10.1136/bjo.75.9.519 on 1 September 1991. Downloaded from ment of the Special Metipranolol Clinics letter was written by Smith and Nephew to all recorded mutton-fat keratic precipitates in about ophthalmologists in the UK on 2 April 1990 to 50% of the episodes and diagramatically showed advise them on the possible association of meti- large keratic precipitates in the other 50%. All pranolol 0-6% with granulomatous anterior the cases of active uveitis found by chance at the uveitis. A subsequent communication to all beginning of this investigation and during the ophthalmologists, general practitioners, and recall examinations had mutton-fat keratic pre- pharmacists on 3 August 1990 from Smith and cipitates. The keratic precipitates seen by the Nephew announced the withdrawal of meti- investigators were white initially, with no pranolol 0-6% from the UK market as from 1 particular pattern to their distribution on the October. The 0 I% and 0 3% strengths of meti- corneal endothelium. No episode of anterior pranolol continued to be available for prescrip- uveitis was associated with Koeppe or Busacca tion for another six months. After further reports type nodules. of metripranolol-associated granulomatous All 56 episodes of anterior uveitis in the 26 anterior uveitis (the latest figures being: 48 eyes were therefore characterised by keratic patients on metipranolol 0 6%, 17 on 0 3%, and precipitates, flare, and cells in the anterior 1 on 0 I% - Committee on Safety on Medicines, chamber. Most of the eyes were described as personal communication) Smith and Nephew 'white' when the diagnosis of anterior uveitis wrote again, on 4 January 1991, to all ophthal- was made, but seven episodes had coexisting mologists announcing the withdrawal from the significant blepharoconjunctivitis. Three eyes market of the remaining two strengths of meti- developed posterior synechiae. In 30 out of the pranolol 0-1% and 0 3%. This drug is still 56 attacks of granulomatous anterior uveitis available for prescription in the single disposable (53 8%) the IOP was raised, and additional form. The pathogenesis of these adverse therapy was required to control the pressure in reactions remains uncertain but is being most of them. Acetazolamide was used on every investigated. occasion (Table 5). The IOP of eyes with meti- Our thanks to Sister Anne E Lewis for help in carrying out this pranolol associated side effects is the subject of a study, and to Miss Sharon A A McGowan and Mrs Elizabeth separate investigation. Warrington for secretarial assistance. All but six episodes of anterior uveitis were 1 Phillips CI, Howitt G, Rowlands DJ. Propranolol as an ocular treated with topical steroids (Table 5). The hypotensive agent. BrJ Ophthalmol 1967; 51: 222-6. average resolution period of the anterior uveitis 2 Zimmermann TJ, Kaufman HR. Timolol: a beta-adrenergic blocking agent for the treatment of glaucoma. Arch when treated ranged from 2-6 to 4-4 weeks, but Ophthalmol 1977; 95: 601-4. in the six eyes which received no topical steroids 3 Krieglstein GK. Current beta-blocker therapy. Diagnosis and management of early glaucoma. Practical concepts and future and were treated only by discontinuation of the trends. Rome: 1984: 133-6. metipranolol drops the average time for recovery 4 Battershill PE, Sorkin EM. Ocular metipranolol: a preliminary was review of its pharmacodynamic and pharmacokinetic longer at six weeks. This difference was properties, and therapeutic efficacy in glaucoma and ocular statistically significant (p<0-0125). A mydriatic hypertension. Drugs 1988; 36: 601-15. http://bjo.bmj.com/ was 5 Mills KB, Wright G. A blind randomised cross-over trial used in combination with topical steroids in comparing metipranolol 0 3% with timolol 0 25% in open treating 18 episodes of granulomatous anterior angle glaucoma: a pilot study. BrJ Ophthalmol 1986; 70: 39- The 42. uveitis. eyes recovered fully without 6 Blackman H, Pham Duy T, Grajewski 0. Therapeutic any sequelae except for the three eyes which efficiency of metipranolol eye drops 0-3% versus timolol eye drops 0-25%. A double blind cross over-study. In: Merte developed posterior synechiae. The IOP in HJ, ed. Metipranolol. Vienna: Springer, 1983: 106-20. the eyes which required additional glaucoma 7 Krieglstein GK, Novack GD, Voepel E, et al. Levobunolol returned to and metipranolol: comparative ocular hypotensive efficacy, on October 2, 2021 by guest. Protected copyright. therapy preuveitic levels on recovery safety, and comfort. BrJ Ophthalmol 1987; 71: 250-3. and did not need the continuation of the addi- 8 Denffer H. Efficacy and tolerance ofmetipranolol: results of a multi-center long-term study. In: Merte HJ, ed. Meti- tional therapy. When metipranolol was discon- pranolol. Vienna: Springer, 1983: 121-5. tinued, the IOP was controlled easily with an 9 Muller 0, Knobel HR. Wirksamkeit und Vertraglichkeit von Metipranolol - Resultate einer multizentrischen alternative therapy. Langzeitstudie in der Schweiz. Klin Monatsbl Augenheilkd All the 26 eyes have now been followed up for a 1986; 188: 62-3. 10 Akingbehin T, Sunderraj P. Ophthalmic topical beta- minimum period of 10 months following the blockers: review of ocular and systemic adverse effects. discontinuation of metipranolol. None of the J ToxicolCutan Ocul Toxicol 1990; 9: 131-47. 11 Kruse W. Metipranolol - ein neuer beta rezeptoren blocker. eyes has shown any evidence of further intra- Klin Monatsbl Augenheilkd 1983; 182: 582-4. ocular inflammation with the substituted 12 Derous D, de Keizer RJW, de Wolff-Rouendaal D, Soudiin W. Conjunctival keratinisation, an abnormal reaction to an antiglaucoma therapy, which includes other ocular beta-blocker. Acta Ophthalmol(Kbh) 1989; 67: 333-8. commonly used ophthalmic topical 13-blockers. 13 Van Buskirk EM. Adverse reactions from timolol administra- In tion. Ophthalmology 1980; 87: 447-50. conclusion, this paper presents clinical and 14 Zimmermann TJ, Baudmann JD, Hetherington J. Side effects photographic evidence for the first time of a of timolol. Surv Ophthalmol 1983; 28: 243-9. hitherto adverse 15 Smith RE, Nozik RA. Uveitis. A clinical approach to diagnosis unreported association between and management. 2nd ed. Baltimore: Williams and Wilkins, metipranolol therapy and granulomatous 1989:3.