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Britishgournal ofOphthalmology 1994; 78: 899-902 899 Additive effect oflatanoprost, a F2, analogue, and in patients with elevated Br J Ophthalmol: first published as 10.1136/bjo.78.12.899 on 1 December 1994. Downloaded from

Alexander H Rulo, Erik L Greve, Philip F Hoyng

Abstract Patients and methods A randomised observer masked clinical study Twenty patients were selected at the outpatient was conducted to assess the additive effect of clinic ofthe centre of the University of latanoprost (13,14-dihydro-17-phenyl-18,19, Amsterdam. The inclusion criteria were age over 20-trinorprostaglandin F2a-isopropylester) to 18 years, bilateral , or early timolol maleate in patients with elevated intra- primary open angle glaucoma (Aulhorn's classi- ocular pressure (IOP). Patients were randomly fication II) with two or more independent IOP assigned to two treatment groups. One group measurements of 22 mm Hg or higher. Female (n=10) received timolol, the other group (n=9) patients were admitted to the study if they were received latanoprost twice daily for 1 week. post-menopausal or used adequate contracep- After 1 week all patients received both timolol tives. and latanoprost. Eyes treated with timolol Exclusion criteria were: history of angle (mean diurnal IOP (SD) day 0, 24*2 (2.8) mm closure, severe ocular trauma, intraocular Hg) and latanoprost (mean diurnal IOP day 0, surgery or argon laser trabeculoplasty, use of 28*5 (5.6) mm Hg) showed an IOP reduction of contact lenses, history ofinfection and/or inflam- 5-9 (2.3) mm Hg (24%) and 8*9 (2.5) mm Hg mation during 3 months preceding the study, (31%), respectively after the first week. Adding or severe dry eye syndrome. Other exclusion latanoprost to the eyes treated with timolol as criteria were use ofsystemic or ocular medication well as timolol to the eyes receiving latano- known to affect IOP, cardiac, or pulmonary prost gave a further reduction of 2*6 (1.1) mm diseases, as well as diabetes mellitus requiring Hg (13%) and 2*6 (2.2) mm Hg (14%), respect- insulin therapy. ively. Only mild transient was The trial was designed as a randomised, observed in patients receiving latanoprost. observer masked study evaluating the additive The results indicate that latanoprost and effect of latanoprost and timolol in two parallel timolol can be combined successfully and that groups with two consecutive treatment periods complete or almost complete additivity is of 1 week each. Before the study patients under- reached even at pressu're levels below 20 went a washout period of 8 days or longer http://bjo.bmj.com/ mm Hg. for sympathicomimetics, 14 days or longer for (BrJ Ophthalmol 1994; 78: 899-902) cholinergic agents, and 21 days or longer for adrenergic antagonists. In the first week of the study, patients in group A administered one Investigations using animal models have shown drop (approx 35 gil) of latanoprost in both eyes that (PG) can effectively lower between 700 am and 900 am and one drop pressure in several In the second intraocular (IOP) species between 700 pm and 900 pm. on September 27, 2021 by guest. Protected copyright. including primates.'-5 week timolol was administered after latanoprost Although subsequent studies in normotensive with a 5 minute interval. and glaucomatous eyes showed that topical Patients in group B started with timolol, one application of PGF2a6 and prostaglandin F2a- drop in both eyes between 7 00 am and 9 00 am isopropylester (PGF2a-IE)'-9 can effectively and one drop between 700 pm and 900 pm. lower IOP in human subjects, dose dependent After the first week latanoprost was added 5 conjunctival hyperaemia and local irritation pre- minutes after timolol was administered. vented their use.6 Recently it has been reported Commercially available timolol (Timoptol that certain phenyl substituted prostaglandin 0-5%, MSD, Haarlem, the Netherlands) was analogues induce an effective IOP reduction used and latanoprost (0-006%: 60 ,ug/ml) was Glaucoma Center ofthe University ofAmsterdam with fewer side effects.10 In particular, PhXA34 provided by Kabi Pharmacia, Uppsala, Sweden. A H Rulo (13,14-dihydro- 15(R,S)- 17-phenyl- 18,19,20- All IOP measurements were performed using E L Greve trinor-PGF2a-isopropylester)" 12 and latano- a Goldmann applanation tonometer, with the Netherlands Ophthalmic prost'>'5 (its 15-R epimer) have been reported to scale masked for the investigator. The tonometer Research Institute, the decrease IOP at low concentrations with fewer scale was read by an assistant. Three consecutive Netherlands side effects. Two recent studies'617 showed a IOP measurements per eye were taken. Hyper- P F Hoyng marked additive effect of PGF2,-IE when aemia was graded 0 indicating absence of Correspondence to: Alexander H Rulo, MD, combined with timolol. We were, therefore, hyperaemia, 1 mild, 2 moderate, and 3 severe Glaucoma Center, interested in the combination therapy with hyperaemia. Half steps were used when appro- Department of Ophthalmology, Academic latanoprost and timolol. priate. Standard photographs were used to grade Medical Center, The purpose of this study was to evaluate the conjunctival hyperaemia. Medical and ocular Meibergdreef9, 1105 Az Amsterdam, the Netherlands. efficacy and side effect profile of latanoprost as history were obtained from all patients before Accepted for publication single therapy and in combination with the 13 entering the study. Subsequently all patients 2 August 1994 adrenergic antagonist timolol. underwent slit-lamp biomicroscopy, fundu- 900 Rulo, Greve, Hoyng

scopy, Humphrey (Allergan, San Leandro, CA, In the group using latanoprost maximum IOP USA) 24/2 visual field examination, hyperaemia lowering effect was-seen on day 2 (Fig 1). On day grading, and IOP measurements. Blood pressure 7 an IOP reduction of 8-9 (2-5) mm Hg (p<0-01) Br J Ophthalmol: first published as 10.1136/bjo.78.12.899 on 1 December 1994. Downloaded from and pulse rate were also recorded. was observed in the latanoprost group compared On days 0, 2, 7, 9, and 14 the patients arrived with a reduction of 5 9 (2-3) mm Hg (p<0-01) in in the glaucoma centre between 8 00 am and 9 00 the timolol group (31% and 24% respectively). am. After recording any general or ocular symp- This difference in IOP reduction between the toms, hyperaemia was graded using the standard groups was not significant. The combined photographs for comparison. Thereafter three therapy revealed an additional IOP reduction consecutive IOP measurements of each eye were compared with either drug administered alone. taken. This procedure was repeated at noon and Latanoprost added to timolol further reduced 400 pm. Visual acuity, blood pressure, and IOP on day 14 compared with day 7 2-6 (2 2) mm pulse rate were recorded during the 800 am Hg (p<0-01) and timolol added to latanoprost visits. Both blood pressure and pulse rate were further reduced IOP 2-6 (I 1) mm Hg (p<0-01). measured three times consecutively. After day Conjunctival hyperaemia compared with base- 14 a post-study examination was performed. line was especially seen in the latanoprost treat- This examination was identical to the pre-study ment group on day 2 (Table 2). On day 7, less examination. Diurnal IOP values were obtained conjunctival hyperaemia was registered than on by calculating the mean of the 8 am, noon, and day 2. When latanoprost was added to timolol 4 pm IOP values for each patient. conjunctival hyperaemia increased slightly com- The IOP values, pulse rate, and blood pres- pared with day 7, being more pronounced on day sure were expressed as the arithmetical mean 9. No changes in hyperaemia were observed (SD). The primary objective of the study was to when timolol was added to latanoprost. The test whether latanoprost and timolol exert addi- difference in hyperaemia between the two tive effects on IOP. The null hypothesis accord- groups was, however, not statistically significant ingly was defined as the diurnal IOP reduction on days 2 and 7 (p>0 05, Wilcoxon rank sum on day 7 (monotherapy) being equal to the test). diurnal IOP reduction on day 14 (combined Latanoprost was well tolerated in the study. therapy) from the diurnal IOP on day 0. The Stinging sensations after both latanoprost and alternative hypothesis was that the combination timolol were noted in a few patients. The heart further reduced the IOP with at least 2 mm Hg rate was reduced with 5-8 (6 9) min-' (p<005) compared with treatment with only one drug. onday7and6-9(8 8)min-' (p<005)onday 14 The further reduction was presumed to repre- compared with day 0 in the timolol-latanoprost sent the additive effect of the second drug since group. There was no significant effect on the the effect on the first drug was assumed to be systolic or diastolic blood pressure in either stable after 7 days of treatment. The IOP reduc- group. tion was tested with analysis of covariance with baseline IOP as covariate. A comparison of the mean IOP reductions between the treatment Discussion

groups was performed on days 7 and 14 using Previous studies using other prostaglandin http://bjo.bmj.com/ three way analysis of covariance with patients, analogues such as PGF2a,-IE were hampered by days, and treatment groups as factors and base- clinically unacceptable grades of conjunctival line IOP as covariate. Wilcoxon's rank sum test hyperaemia, local irritation, and pain sensation was used for analysis ofhyperaemia. Differences when optimal IOP lowering doses were adminis- with a p value <0 05 were considered significant. tered.6 Latanoprost, a new PGF2,1 analogue, The changes in blood pressure and pulse rate seems to have markedly fewer side effects as

were analysed statistically with the matched reported in previous studies.9 13-I5 on September 27, 2021 by guest. Protected copyright. paired t test, comparing the values during treat- The main mechanism of action to account for ment with those on baseline. the reduction in IOP following administration of The study was approved by the ethics review prostaglandin F2a and its analogues is thought to board of the Academic Medical Center, Amster- be an increase in uveoscleral outflow'8-20 and not dam and each patient gave written informed consent before entering the study. The study was performed in accordance with the principles Table I Demographic and clinical characteristics ofthe adopted by the 18th World Medical Assembly, treatment groups Helsinki, Finland, 1964 and later revisions. Latanoprost Timolol Age Mean (range) 612 (47-84) 64-1(40-82) Sex Results Male/female 5/5 3/7 Ten patients were allocated to latanoprost treat- Race to White 9 10 ment (group A) and 10 patients timolol Asian 1 0 treatment (group B). One patient in group A was colour was out Blue/green 8 9 excluded because it found that the Brown 2 0 patient had undergone only 2 days instead of Grey 0 1 2 Diagnosis weeks washout of and acetazola- Ocular hypertension 9 9 mide. There were no major differences between Glaucoma 1 1 groups to Duration (months) the with regard the demographic Median (range) 55 (2-350) 48 (2-140) characteristics such as mean age and male/female Previously treated 8 4 at Intraocular pressure ratio, but IOP day 0 differed markedly Mean (SD) (mm Hg) 28 5 (5 6) 24-2 (2-8) between the groups (Table 1). Additive effect oflatanoprost, a prostaglandin F2,, analogue, and timololinpatients with elevatedintraocularpressure 901

Figure I (A) Intraocular 40'r A seen mainly during the first week of treatment.'4 pressure reduction (mean As a single therapy latanoprost effectively (SD)) in group A, starting I Br J Ophthalmol: first published as 10.1136/bjo.78.12.899 on 1 December 1994. Downloaded from with latanoprost 60 Rglml E reduced IOP in this study. Maximum IOP twice daily. Adding timolol E 30 4 lowering effect was observed after 2 days of 0 5% twice daily to treatment, the decline in IOP being 42%; after latanoprost in the second to week gave a further IOP n4, 20)1- T 1 week an IOP reduction of 31% was present in reduction of2 5 mm Hg -_ patients with a mean initial IOP of 28-5 mm Hg. (13%). (B) Intraocular CU '111.-. 1 In the timolol group an IOP reduction of 24% pressure reduction (mean (SD)) in group B, , 10)- was observed during the first week of treatment. starting 0 with timolol 0-5% twice CU Latanoprost Timolol The difference in baseline IOP between the daily. Adding latanoprost C- treatment groups makes a comparison in efficacy 60 p.g/ml twice daily to l I timolol in the second week 0 2 7 9 14 of both drugs difficult. However, the results gave afurther IOP reduction Days indicate that latanoprost 60 ,tg/ml twice daily is of2-5 mm Hg (14%). at least as effective in reducing IOP as timolol

0) 40' B 5 mg/ml twice daily. I In patients on PGF2,-IE an inconvenient E hyperaemia and local discomfort have been E 30 reported.67 In this study, a slight hyperaemia 5) was noted in half the patients on latanoprost. No Q significant ocular discomfort or evidence of pain 0. 201- L- I sensation were observed. Latanoprost was well 0 0 tolerated by all patients and the slight hyper-

4CL- ioH aemia did not cause them to withdraw from the Latanoprost Timolol study. Hence, latanoprost, unlike PGF2a-IE, is not hampered by clinically unacceptable ocular 0 2 7 9 side effects. In contrast with timolol, latanoprost Days had no significant effect on the heart rate which is a clear advantage. If long term studies can demonstrate a an increase in true trabecular outflow or an sustained IOP reducing effect with latanoprost, inhibition ofaqueous humour formation. The,re- it will be a valuable new drug in the therapeutic fore, when PGF2c, analogues are being combirned arsenal of glaucoma management. with agents like timolol which reduce IOP by an inhibition of production, an We thank Thomas Kaponen, MS and Johan Stiernschantz, MD, additive effect may be expected. for statistical and scientific advice. In a previous study by Villumsen and Alm" an 1 Wang RF, Camras CB, LeePY, Podos SM, Bito LZ. Effects of additive effect of approximately 30% was foumd prostaglandins F2 alpha, A2, and their esters in glauco- matous monkey eyes. Invest Ophthalmol Vis Sci 1990; 31: when PGF2a-IE was administered to patients on 2466-70. timolol treatment having a mean IOP of 25 nTI 2 Bito LZ, Camras CB, Gum GG, Resul B. The ocular hypoten- sive effects and side effects of prostaglandins on the eyes of http://bjo.bmj.com/ Hg. In another study by Lee et all' ocuilarilar experimental animals. ProgClinBiolRes 1989; 312: 349-68. hypertensive patients with very high initial IC)PS 3 Bito LZ, Miranda OC, Tendler MR, Resul B. as (>40 mm Hg) had a mean IOP of27 mm Hg affter A2-1-isopropyla new class of ocularester ishypotensivethe most potentagents.reported3. Prostaglandinhypotensive 1 week of timolol treatment. In their stu.idy agent on feline eyes. ExpEye Res 1990; 50: 419-28. 4 Hoyng PF, Groeneboer MC. The effects of prostacycin and its PGF20-IE also induced a similar additive efffect stable analog on intraocular pressure. Prog Clin Biol Reg when combined with timolol indicating more or 1989; 312: 369-78. less complete additivity ofPGF2a-IE to timolol 5 Groeneboer MC, Hoyng PF, Kuizenga A. Prostaglandin F2

alpha isopropylester versus phenacyl ester in rabbit on September 27, 2021 by guest. Protected copyright. Although the combination of timolol and and beagle eyes. CurrEyeRes 1989; 8: 131-8. 6 Giuffre G. The effects of prostaglandin in the human eye. latanoprost induced an IOP lowering effectt°of GraefesArch Clin Exp Ophthalmol 1985;F2,,222: 139-41. not more than 13-14%, in contrast with previ4ous 7 Camras CB, Siebold EC, Lustgarten JS, Serle JB, Frisch SC, Podos SM, et al. Maintained reduction of intraocular observations, complete additivity may be pressure by prostaglandin F2 alpha-l-isopropyl ester applied present assuming that latanoprost is less effective in multiple doses in ocular hypertensive and glaucoma patients. Ophthalmology 1989; %: 1329-36. at lower IOP levels. 8 Villumsen J, Alm A. Ocular effects of two different prosta- In both groups there was an upward drifi in glandin F2 alpha esters. A doublemasked cross-over study on normotensive eyes. Acta Ophthalmol (Copenh) 1990; 68: IOP during latanoprost treatment. Such an 341-3. upward drift in IOP has previously bNeen 9 Villumsen J, Alm A. Prostaglandin F2 alpha-isopropylester eye drops: effects in normal human reported during latanoprost treatment.'4 Hc 1989; 73: 419-26. eyes. BrJI Ophthalmol ever, we do not believe that this phenomenon]has 10 Stiernschantz J, Resul B. Phenyl substituted prostaglandin analogs for glaucoma treatment. Drugs ofthe Future 1992; 17: affected the results significantly as the drifi isiS 691-704. 11 Alm A, Villumsen J. PhXA34, a new potent ocular hypoten- sive drug. A study on dose-response relationship and on aqueous humor dynamics in healthy volunteers. Arch Table 2 Hyperaemia score in the two treatment groups Ophthalmol 1991; 109: 1564-8. 12 Villumsen J, Alm A. PhXA34 - a prostaglandin F2,, analogue, A effect on intraocular pressure in patients with ocular hyper- Group Group B tension. BrJ7 Ophthalmol 1992; 76: 214-7. Hyperaemia 0 1 0 2-0 3-0 0 1.0 2-0 3 13 Nagasubramanian S, Sheth GP, Hitchings RA, Stjernschantz score 0-5 15 °-0 J. Intraocular pressure-reducing effect of PhXA41 in ocular 25 0.5 15 25 hypertension. Ophthalmology 1993; 100: 1305-11. Day 0 2 7 6 4 14 Alm A, Villumsen J. Tornquist P, Mandahl A, Airaksinen J, Day 2 1 4 2 1 1 6 4 Tuulonen A, et al. Intraocular pressure-reducing effect of Day7 4 2 3 8 2 PhXA41 in patients with increased eye pressure - a one- Day 9 1 6 2 3 2 3 2 month study. Ophthalmology 1993; 100: 1314-7. Day 14 2 6 1 4 5 1 15 Racz P, Ruzsonyi R, Nagy ZT, Bito LZ. Maintained intra- ocular pressure reduction with once-a-day application of a new prostaglandin F2,, ctvakoy (n1 XA4 I ). Arch Ophthalmol The data indicate the numbers of patients with a given hyperaemia score. 1993; 111:657-61. 902 Rulo, Greve, Hoyng

16 Villumsen J, Alm A. The effect of adding prostaglandin F2 pressure without decreasing aqueous humor flow. Am J alpha-isopropylester to timolol in patients with open angle Ophthalmol 1988; 105: 30-4. glaucoma. Arch Ophthalmol 1990; 108: 1102-5. 19 Kaufman PL, Crawford K. Aqueous humor dynamics: how

17 Lee PY, Shao H, Camras CB, Podos SM. Additivity of PGF2 alpha lowers intraocular pressure. Prog ClGn Biol Res Br J Ophthalmol: first published as 10.1136/bjo.78.12.899 on 1 December 1994. Downloaded from prostaglandin F2 alpha-l-isopropyl ester to timolol in 1989; 312: 387-416. glaucoma patients. Ophthalmology 1991; 98: 1079-82. 20 Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a 18 Kerstetter JR, Brubaker RF, Wilson SE, Kullerstrand LJ. new prostaglandin F2,, analog, on aqueous humor dynamics Prostaglandin F2 alpha-l-isopropylester lowers intraocular in human eyes. Ophthalmology 1993; 100: 1297-304.

History ofophthalmology

John Martin Wheeler, 1879-1938

John Martin Wheeler was a well known published many of the landmark papers of the ophthalmologist in the 1930s, whose career time. Most of his patients were soldiers encompassed episodes of both spectacular wounded by gunshot or explosives in France good fortune and misfortune. His father, a in 1918. Operating under ether, Wheeler country lawyer who had fought in the obviously did his utmost to repair facial American civil war, could only afford to send fractures, skin defects, and the hasty exentera- his son to the small, inexpensive Burlington tions of the battlefield, constantly aware of the University of Vermont. Having graduated in importance (in view ofthe extreme youth ofhis arts and medicine, Wheeler was very lucky to patients) of good cosmetic results. obtain his ophthalmological internship in New Returning to civil practice, Wheeler's stroke York in 1909. During training, he was remark- of good fortune occurred. The King of Siam, able for his diligence and his manual dexterity. arriving in New York with his retinue, chose Constantly having good ideas for papers and Wheeler to operate on his eye. Although many reports, he was so hesitant and cautious that of his colleagues must have felt extreme envy, most of these ideas were eventually taken up the quiet and retiring Wheeler found the media and published by colleagues - which he never interest quite distressing, miserably trying to minded! evade the press when arriving at the hospital. His forte was meticulous surgical technique, The King was delighted with the result and in in which he was inspired by his boss, 1931 awarded a protesting Wheeler the

D W Hunter. One of Hunter's most daring Commander ofthe Order ofthe Cross of Siam. http://bjo.bmj.com/ procedures was the opening of secondary He could literally have made a fortune in cataract by running a Graefe knife along the private practice from then on . . . However, membrane in a single, rapid act of forearm having his log cabin in Vermont as a holiday supination. Wheeler describes the result as home, and sufficient equipment for golf, he felt 'sure and beautiful'. He combined his admira- no need for a fortune, and coolly cut back his tion with pragmatism, in noting that most of private practice to concentrate on postgraduate

the surgeons who came to watch Hunter were teaching. This must have amazed his envious on September 27, 2021 by guest. Protected copyright. too terrified of slashing the to use the colleagues, and probably arouses incredulous technique themselves. Wheeler then developed feelings still. a less risky method, which he published in Tragedy then struck, in the form of a the British Journal of Ophthalmology, with choroid sarcoma which necessitated the meticulous pencil drawings of exactly how the removal of John Wheeler's left eye. It seemed operator's thumb and forefinger should rest on that a great operative talent would be lost, yet the knife. The reader was exhorted to keep the he adapted to this and continued to show the hand and wrist joints perfectly immobile, same degree ofmanual dexterity. (His patients' creating the incision by a 'a rapid, free' move- reactions on learning that their surgeon had ment of the whole arm. If correctly done, 'the only one eye are not recorded.) Because of knife handle should rotate as if impaled on a his fame and the value of his pioneering pin', and full drawings of the hypothetical pin's work, Wheeler's death three years later was position were included. noted widely by ophthalmologists and plastic Wheeler frequently stated that the surgeon surgeons. Both specialties continued to should have nothing less than a keen and fault- profit from his operative techniques for long less knife with which to ply his trade, and that afterwards. this should be ground to perfect sharpness. FIONA ROMAN One can imagine his wrath when anything less was found on his instrument table. Wheeler JM. War injuries of the eyelids: plastic operations. During the first world war, Wheeler entered Arch Ophthahnol 1920; 49: 35-42. the medical corps and the care of blinded and Wheeler JM. Restoration of the obliterated eye socket. Am J3 Ophthalnol 1921; 4: 481-8. disfigured veterans turned his interest perma- Wheeler JM [Obituary]. Arch Ophthalnol 1938; 6: 885-8. nently towards plastic surgery, on which he Wheeler JM [Obituary]. BrJ Ophthalhnol 1938; 22: 76-8.