Additive Efficacy of Unoprostone Isopropyl 0.12% (Rescula) to Latanoprost 0.005% WILLIAM C. STEWART, MD, ELIZABETH D. SHARPE, MD, JEANETTE A. STEWART, RN, KERI T. HOLMES, BS, AND KRISTEN E. LATHAM, BS
● PURPOSE:
To evaluate the safety and efficacy of adding unoprostone isopropyl 0.12% vs placebo both given twice daily to latanoprost 0.005% given every evening. ● METHODS: We treated 41 patients with primary openangle glaucoma or ocular hypertension with latanoprost 0.005% for 1 month and then randomized each to either placebo or unoprostone isopropyl 0.12% for 8 weeks. Diurnal intraocular pressures were measured at 08:00, 10:00, 12:00, 18:00, and 20:00 hours, both at baseline (time of randomization) and after 8 weeks of treatment. ● RESULTS: Twenty patients were treated in the placebo group and 21 in the unoprostone isopropyl group. After 8 weeks of treatment in the placebo group, the trough intraocular pressure at 08:00 and the diurnal pressure were 20.4 ⴞ 3.2 and 19.1 ⴞ 2.2 mm Hg, respectively. In the unoprostone isopropyl group the pressures were 19.4 ⴞ 3.3 and 18.0 ⴞ 1.7 mm Hg (P ⴝ .22 and P ⴝ .042), respectively. However, eyes with a baseline pressure of 22 mm Hg or greater on latanoprost had an average 3.3 mm Hg greater reduction at trough (P < .01) and a 2.1 mm Hg greater decrease in diurnal pressure (P ⴝ .030) after adding unoprostone isopropyl (n ⴝ 14 eyes) compared with placebo (n ⴝ 16 eyes; P < .001). In addition, the range of the pressures throughout the diurnal curve was reduced from 2.7 mm Hg on latanoprost alone to 1.4 mm Hg after adding unoprostone isopropyl. Adverse events were similar between groups, and no patients were discontinued because of safety reasons. ● CONCLUSIONS: This study suggests that unoprostone isopropyl can safely improve the diurnal curve characteristics in patients who continue to have an elevated pressure on latanoprost 0.005% alone. (Am J OphthalAccepted for publication Sep 27, 2000. From the Pharmaceutical Research Corporation (Dr Stewart, Ms Stewart, Ms Holmes, and Ms Latham), Charleston, South Carolina; Carolina Eye Institute at the University of South Carolina School of Medicine (Dr Stewart), Columbia, South Carolina; Ophthalmology Consultants, P.A. (Dr Sharpe), Mt. Pleasant, South Carolina. This work was sponsored by unrestricted grants from Ciba Vision Corporation, Duluth, GA. Reprint requests to William C. Stewart, MD, Pharmaceutical Research Corporation, 1639 Tatum St, Charleston, SC 29412-2464. 0002-9394/01/$20.00 PII S0002-9394(01)00824-2
©
2001 BY
mol 2001;131:339 –344. © 2001 by Elsevier Science Inc. All rights reserved.)
L
ATANOPROST (XALATAN; PHARMACIA, BRIDGEWA-
ter, New Jersey) is a commercially available analog of a naturally occurring F2␣-prostaglandin. It is highly selective for the FP-receptor.1 Clinical and animal studies have suggested that latanoprost reduces intraocular pressure primarily by increasing the uveoscleral outflow.2–5 In contrast, unoprostone isopropyl (Rescula; Ueno Fine, Ltd, Japan), is a docosanoid that is related in structure to an F2␣-prostaglandin.6 Unoprostone isopropyl reduces the intraocular pressure by increasing outflow, but whether it acts through a conventional, uveoscleral, or a mixture of both mechanisms in humans has not yet been elucidated.7 In contrast to latanoprost unoprostone, isopropyl does not demonstrate activity at the human FP receptor.8 Consequently, despite a similar molecular structure, a different pharmacologic activity exists between these two drugs that could potentially indicate an additive ocular hypotensive action when used together. However, few data are currently available that evaluate the adjunctive use of unoprostone isopropyl to latanoprost. The purpose of this trial was to assess the additive safety and efficacy of unoprostone isopropyl 0.12% given twice daily compared with placebo added to latanoprost 0.005% given each evening.
MATERIAL AND METHODS PATIENTS INCLUDED IN THIS STUDY MUST HAVE BEEN 18
years of age or older; been willing to comply with the investigator’s and protocol’s instructions; had a clinical diagnosis of primary open-angle, pigment dispersion, or exfoliation glaucoma, or ocular hypertension in at least one eye; had a baseline intraocular pressure 19 to 30 mm Hg inclusive in the study eye(s) while using latanoprost; and had a visual acuity of 20/200 or better. Patients were excluded from this study if they had any abnormality preventing reliable applanation tonometry in the study eye(s); any opacity or patient uncooperativeness
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that restricted adequate examination of the ocular fundus or anterior chamber in the study eye; any concurrent infectious/noninfectious conjunctivitis, keratitis, or uveitis in either eye; any history of allergic hypersensitivity or poor tolerance of any components of the preparations used in this trial, intraocular conventional surgery or laser surgery within 3 months of the study; according to the investigator’s best judgment risk of visual field or visual acuity worsening as a consequence of participation in the trial; progressive retinal or optic nerve disease apart from glaucoma; were women of childbearing potential not using reliable means of birth control; were pregnant or lactating women; had any clinically significant, serious, or severe medical or psychiatric condition; any anticipated change in systemic hypotensive therapy during the trial, including -adrenergic blockers, alpha agonists and blockers, angiotensin-converting enzyme inhibitors and calcium channel blockers; were individuals who wished to avoid any risk of darkened irides, eyelash changes, or ocular inflammation (including cystoid macula edema) during the trial; had history of ocular herpes simplex; had participated in any investigational drug or device trial within 30 days before screening for this trial; were unable to understand the trial procedures and were thus unable to given informed consent. After signing an informed consent document approved by an institutional review board, patients underwent a screening examination at least 28 days before the baseline day 0 visit. At this visit patients had their medical and ocular history taken and an ophthalmic examination performed, including gonioscopy, slit-lamp biomicroscopy, Early Treatment Diabetic Retinopathy Study visual acuity, Goldmann applanation tonometry, dilated funduscopy, and visual field testing performed with the Humphrey Visual Field Analyzer (Humphrey Instruments, San Leandro, California) using the program 24 –2. At this visit patients were discontinued from their current glaucoma medicine and placed on latanoprost 0.005% one drop to the study eye(s) at 20:00. At the baseline day 0 visit patients underwent, as well as at other active treatment visits, slit-lamp biomicroscopy, Early Treatment Diabetic Retinopathy Study visual acuity and trough Goldmann applanation tonometry. Patients also had a baseline ocular symptom survey as well as diurnal intraocular pressure measurements at hours ⫹2, ⫹4, ⫹10, and ⫹ 12 after the 08:00 trough. After these evaluations, patients were randomized to either placebo (Hypotears; Ciba Vision Ophthalmics, Atlanta, Georgia) or unoprostone isopropyl 0.12% one drop at 08:00 and 20:00 to the study eye(s). Medicine bottles were masked (by labeling and concealment in an opaque vial), and patients were instructed not to show the bottles to clinical evaluators. Patients returned to the clinic at day 14 (visit 3) for a safety intraocular pressure evaluation and anterior segment examination. Patients returned again on day 56 (visit 4) 340
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for the active treatment diurnal curve and ocular symptom survey performed as on day 0. The following morning (day 57) patients were exited from the study after performing a visual field examination and having dilated funduscopy performed. All data analyses were one sided, and a 0.05 alpha level was used. Primary and secondary efficacy variables were analyzed by an unpaired t test for intergroup analysis.9 A one-way analysis was used, because a greater lowering effect from placebo compared with unoprostone isopropyl was not anticipated. A standard deviation of 3.5 mm Hg (approximately a 20% reduction) was assumed. This study (if 20 patients completed in each group) provided an 80% power that a difference of 3.0 mm Hg could be excluded from the placebo and the unoprostone isopropyl groups. Patient history and examination characteristics for intergroup analysis were evaluated with a Mann Whitney U, chi-squared test on Fisher’s exact test as appropriate, except mean deviation, visual acuity, and age, which were analyzed with an unpaired t test.9,10 An average eye analysis was used for those patients with two eyes included in the trial. Adverse events were evaluated with a chisquared or Fisher’s exact test as appropriate.10
RESULTS THE PATIENT CHARACTERISTICS OF THE SUBJECTS IN-
cluded in the trial are shown in Table 1. There was no statistical difference in the age, gender, race, diagnosis, medical history, visual acuity, or mean deviation between groups, except there was a greater number of patients with systemic hypertension in the placebo group. The diurnal curve of the intraocular pressure after 8 weeks of treatment for both placebo and unoprostone isopropyl added to latanoprost is shown in Figure 1. The mean trough intraocular pressure at 08:00 for the placebo group was 20.4 ⫾ 3.2 mm Hg and for the unoprostone isopropyl group was 19.4 ⫾ 3.3 mm Hg (P ⫽ .225). The diurnal curve of the intraocular pressure for the placebo group was 19.1 ⫾ 2.2 mm Hg and for the unoprostone isopropyl group was 18.0 ⫾ 1.7 mm Hg (P ⫽ .042). At the other time points there was no statistically additional reduction in intraocular pressure in using placebo over latanoprost alone (P ⬎ .05). However, there was a statistical reduction at time points 2 hours and 4 hours after dosing (P ⫽ .041 and 0.045, respectively) from placebo for unoprostone isopropyl added to latanoprost. A marginal difference existed at 10 hours after dosing (P ⫽ .079, respectively) but not at 12 hours after dosing (P ⫽ .15). In contrast, a statistical reduction from baseline in the unoprostone isopropyl group existed at the 08:00 trough, and at 2 and 4 hours after dosing (P ⬍ .001) and a marginal significance at 10 hours (P ⫽ .078), but not at 12 hours after dosing (P ⫽ .20). Within the group of subjects treated with unoprostone OF
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TABLE 1. Patient Characteristics
Placebo
Unoprostone Isopropyl
P Value
Age (years) 61.9 ⫾ 9.8 60.4 ⫾ 12.8 .58 Gender Male 7 6 .50 Female 13 15 Ethnicity Caucasian 9 11 .54 African American 11 10 Systemic diseases Hypertension 12 5 .01 Adult onset diabetes 6 4 .48 Hypercholesterolemia 4 2 .40 Osteoarthritis 3 5 .45 Headaches 1 6 .09 Diagnosis Ocular hypertension 12 13 .88 Open-angle glaucoma 8 7 Exfoliation 0 1 Visual field, mean ⫺3.69 ⫾ 4.74 ⫺4.59 ⫾ 4.77 .45 deviation (dB) Visual acuity, Early 0.04 ⫾ 0.09 0.02 ⫾ 0.09 ⬎.90 Treatment Diabetic Retinopathy Study units
isopropyl there were 25 eyes that did have at least a 2 mm Hg further reduction in intraocular pressure at trough and 17 that did not. The relationship of responders and nonresponders was not based on age, race, gender, or medical history. However, there did appear to be a response based on baseline intraocular pressure on latanoprost. The diurnal pressures in patients treated with
unoprostone isopropyl are listed in Table 2, ranked according to the intraocular pressure. Of the 14 eyes the baseline pressures of which were 22 mm Hg or greater, 13 had a reduction of 2 mm Hg or greater at trough. The average trough pressure in these eyes on unoprostone isopropyl was 18.3 ⫾ 2.8 mm Hg (P ⬍ .001) and 22.7 ⫾ 3.7 mm Hg in placebo treated eyes (n ⫽ 16) (P ⬍ .001). The diurnal curve in these patients after unoprostone isopropyl was 18.4 ⫾ 2.3 mm Hg (P ⬍ .001) and 20.5 ⫾ 2.7 in the placebo-treated eyes (P ⫽ .030). The mean intraocular pressure response in eyes that had a baseline pressure on latanoprost of 22 mm Hg or greater are shown in Figure 2. In contrast, eyes (n ⫽ 28) with a baseline pressure of 21 mm Hg or less had a 0.7 mm Hg mean reduction in trough pressure and a 0.3 mm Hg mean reduction in diurnal pressure after adding unoprostone isopropyl (P ⫽ .013 and P ⫽ .474, respectively). Two patients were discontinued from this study based on poor intraocular pressure control. One patient was on unoprostone isopropyl (Table 2) and one on placebo. No patients were discontinued because of adverse events. Adverse events are listed in Table 3. There were no significant differences in adverse events between groups, except increased stinging was noted upon instillation with unoprostone isopropyl (P ⫽ .012). Specifically, we did not note cases of uveitis, cystoid macular edema, or conjunctival hyperemia over latanoprost alone.
DISCUSSION UNOPROSTONE ISOPROPYL 0.12% GAINED REGULATORY AP-
proval for the treatment of elevated intraocular pressure several years ago in Japan, where this medicine was
FIGURE 1. Eight weeks after the onset of treatment, the diurnal curve of the intraocular pressures in all subjects of both placebo (diamonds) and unoprostone isopropyl (squares) added to latanoprost.
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approximately 22%.11–13 Concentrations lower than 0.12% provided less ocular hypotensive response.11,12,14 In studies in which unoprostone isopropyl 0.12% was compared with timolol maleate 0.5% given twice daily, the ocular hypotensive action of both medicines was statistically similar.12,14 The use of unoprostone isopropyl 0.12% in patients on maximum medical therapy for glaucoma has been evaluated over 24 weeks by Azuma, who showed a reduction in intraocular pressure from 28.8 to 19.0 mm Hg (32%) in patients over 6 months.15 Outside of Japan, Stewart and associates showed that unoprostone isopropyl 0.12% given twice daily reduced intraocular pressure from baseline 23%, similar to timolol maleate, between 08:00 and 20:00.16 In Japanese regulatory trials ocular side effects noted with unoprostone isopropyl 0.12% have been mild and similar in incidence to timolol maleate.12 Individual cases of conjunctival follicles, burning, and hyperemia have been noted. Systemic side effects noted in clinical studies have been few. Single mild episodes of nausea and vomiting, headache, and nasal congestion have been noted. Unoprostone isopropyl, in a concentration of 0.15%, is currently under commercial development in Europe and the United States (Ciba Vision Corporation, Bu¨lach, Switzerland). The purpose of this trial was to evaluate the efficacy and safety of adding unoprostone isopropyl 0.12% versus placebo to latanoprost 0.005% given every evening. This study found that there was not a significant reduction in the mean diurnal curve of the intraocular pressure compared with placebo when adding unoprostone isopropyl to latanoprost. However, within the active treatment group there was a variance in response that appeared to be based primarily on the baseline intraocular pressure when treated with latanoprost alone. Those eyes that on latanoprost alone had a trough pressure of 22 mm Hg or greater demonstrated an additional mean reduction of 4.4 mm Hg at trough with unoprostone isopropyl compared with placebo. Also, the addition of unoprostone isopropyl was associated with a greater flattening of the diurnal curve compared with patients treated with latanoprost only. However, the additive ocular hypotenstive effect was mostly observed in the morning with little increased advantage observed in the afternoon. It remains unclear if unoprostone isopropyl does not have a 12-hour effect when added to latanoprost or if an additional reduction would have been observed if the afternoon baseline pressure had been higher. Those patients who had a pressure of 21 mm Hg or less on latanoprost had only a variable response when placed on unoprostone isopropyl with approximately 40% demonstrating a 2 mm Hg or greater response at trough. The difference in response based on pretreatment intraocular pressure was a surprise to the authors but is consistent with the lack of intraocular pressure response in healthy subjects in Japan in one regulatory trial.17 The
TABLE 2. Diurnal Intraocular Pressures (mm Hg) of Patients Treated With Unoprostone Isopropyl Baseline Identification
121 RE 121 LE 135 RE 135 LE 117 RE 117 LE 114 RE 114 LE 105 RE 105 LE *134 RE *134 LE 120 RE 120 LE 131 RE 131 LE 115 RE 115 LE † 101 RE † 101 LE 119 RE 119 LE 108 RE 108 RE 113 RE 113 LE 111 RE 111 RE 123 RE 123 LE 128 RE 128 LE 139 RE 139 LE 140 RE 140 LE 129 RE 129 LE 125 RE 125 LE 107 RE 107 LE
Treated
Trough
Trough
Hour ⫹2
Hour ⫹4
Hour ⫹10
Hour ⫹12
26 26 23 24 22 24 22 23 23 22 23 21 21 23 23 20 20 23 21 21 21 20 20 20 20 20 19 20 19 20 19 20 17 19 19 19 19 19 19 19 19 19
18 22 15 17 18 16 18 18 19 19 19 18 24 22 17 17 18 18 31 27 24 24 15 16 20 18 24 24 21 21 17 18 17 17 16 19 21 20 17 15 20 20
15 26 16 16 18 16 16 15 18 17
16 26 18 18 18 17 16 16 21 20
16 26 18 20 18 18 18 18 16 16
18 26 18 18 18 19 16 16 17 16
22 20 17 18 18 19
22 21 20 19 18 20
24 23 18 18 18 19
24 24 17 17 18 20
20 20 15 18 18 16 13 10 19 19 16 15 15 16 15 16 17 16 20 18 19 20
18 18 16 18 16 16 16 16 20 18 16 16 15 15 22 22 16 16 16 16 17 18
18 19 15 16 16 16 16 17 18 17 18 17 16 15 19 17 22 20 17 17 15 15
18 18 14 14 16 15 20 20 17 17 16 16 15 14 18 15 22 22 18 17 15 15
*Diurnal curve is not available for this patient because of inconsistent medicating. † Diurnal curve is not available for this patient because of early exit. RE ⫽ right eye; LE ⫽ left eye.
developed. In regulatory studies performed in Japan in patients with ocular hypertension and primary open-angle glaucoma, unoprostone isopropyl 0.12% given twice daily as monotherapy reduced intraocular pressure from baseline 342
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FIGURE 2. The intraocular pressure response in those patients with a pressure on latanoprost alone of 22 mm Hg or greater (diamonds) and after adjunctive treatment with unoprostone isopropyl and versus placebo (squares).
TABLE 3. Adverse Events
Adverse Event
Ocular Hyperemia Punctuate epithelial erosion Stinging upon instillation Foreign body sensation Eyelid scurf Burning sensation Visual field restriction at night Stye Ocular tenderness Lid swelling Systemic Increased blood pressure Leg injury Kidney stone Upper respiratory infection Sinus
Placebo, n ⫽ 20
Unoprostone Isopropyl, n ⫽ 21
8 1 0 1 2 0 0
7 5 7 1 0 1 1
P P P P P P P
1 1 1
0 0 0
P ⫽ .49 P ⫽ .49 P ⫽ .49
1 1 1 1 1
0 0 0 0 0
P P P P P
P Value
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
⫽ ⫽ ⫽ ⫽ ⫽
.50 .19 .07 .49 .23 .49 .49
.49 .49 .49 .49 .49
reason for this finding is not clear. However, the poor effect of unoprostone isopropyl within the normal range may help indicate its mechanism is based in part on the conventional (pressure-dependent) outflow tract as opposed to uveoscleral outflow.18 However, whether unoprostone isopropyl acts primarily through conventional or uveoscleral outflow has not been explained. Any role of VOL. 131, NO. 3
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latanoprost limiting the effect of unoprostone isopropyl in the normal pressure range also remains unknown. This study suggests that latanoprost and unoprostone isopropyl may work by two different pharmacologic mechanisms, despite similar molecular structure. This was evidenced by the additional ocular hypotensive response in patients with higher baseline pressures. These data are additive to pharmacologic studies that indicate that latanoprost, but not unoprostone isopropyl, is a strong FP-agonist. However, the molecular biologic process by which unoprostone isopropyl reduces the intraocular pressure has not been explained. This information is important clinically in that it shows that when unoprostone isopropyl becomes available commercially in the United States and Europe, it can be used safely, at least short term, in combination with latanoprost in selected patients to further reduce intraocular pressure. This is important because of the current widespread use of latanoprost in treating elevated intraocular pressure. Although a significant trough and diurnal reduction in pressure with unoprostone isopropyl was observed in this study, the number of patients was too small to determine exactly the additive diurnal characteristics of unoprostone isopropyl in patients with elevated pressures on latanoprost alone. Additionally, this study did not describe the mechanism of action for unoprostone isopropyl on a molecular basis. Hopefully, future research will further elucidate the additive effects of unoprostone isopropyl and latanoprost as well as help clarify its mode of action. This study suggests that unoprostone isopropyl can safely improve the diurnal curve characteristics in patients who
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9. Book SA. Essentials of statistics. New York: McGraw Hill Book Company, 1978:117–122, 205–215. 10. Moses L, Emerson J, Hosseini H. Statistics in practice: analyzing data from ordered categories. N Engl J Med 1984; 311:442– 448. 11. Takase M, Namba H, Kato M, Yano N, Adachi N, MomikiItsu T. Early phase II study of UF-021 ophthalmic solution in primary open-angle glaucoma or ocular hypertension patients. J Eye 1992;9:1917–1925. 12. Azuma I, Masuda K, Kitazawa Y, Takase M, Yamamura H. Phase II double masked dose-determination study of UF-201 ophthalmic solution in primary open-angle glaucoma and ocular hypertension. Folia Ophthalmol Jpn 1992;43:1425– 1431. 13. Azuma I, Masuda K, Kitazawa Y, Takase M, Yamamura H. Double masked comparative study of UF-201 and timolol ophthalmic solutions in primary open-angle glaucoma and ocular hypertension. Jpn J Ophthalmol 1993;37:514 –525. 14. Takase M, Murao M, Koyano S, Oita M. Ocular effects of topical instillation of UF-201 ophthalmic solution in healthy volunteers. Acta Soc Ophthalmol Jpn 1992;96: 1261–1267. 15. Azuma I. Clinical evaluation of UF-021 ophthalmic solution in glaucoma patients refractory to maximum tolerable therapy. J Jpn Ophthalmol Soc 1993;97:232–238. 16. Stewart WC, Stewart JA, Kapik BM. The effect of unoprostone isopropylate 0.12% versus timolol maleate 0.5% on the diurnal IOP. J Glaucoma 1998;7:402– 407. 17. Takase M, Murao M, Koyano S, Okita M. Ocular effects of topical instillation of UF-021 ophthalmic solution in healthy volunteers. Acta Soc Ophthalmol Jpn 1996:1261–1267. 18. Kaufman PL. Pressure-dependent outflow. In: Ritch R, Shield MB, Krupin T, editors. The glaucomas. St. Louis: Mosby-Year Book, 1996:307–335.
continue to have a mildly elevated pressure on latanoprost 0.005% alone.
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